Belimumab Pregnancy Registry Interim Report V12 ... - GSKpregnancyregistry.gsk.com/documents/...Annual_Interim_Report_201… · review the data and update this report and to discuss

CONFIDENTIAL 2010N108011_00 GlaxoSmithKline group of companies WWEpi Project # BEL114256

1

TITLE PAGE

Division: Worldwide Development Information Type: Worldwide Epidemiology Interim Study Report Control: Non-Interventional.

Title: The Belimumab Pregnancy Registry

Phase: Late Phase

Compound Number:

Not Applicable

Effective Date: 14 Aug 2014

Description: A Post-Authorization Safety Study Conducted by GlaxoSmithKline

The purpose of the Belimumab Pregnancy Registry (BPR) is to evaluate pregnancy and infant outcomes for pregnancies in women with systemic lupus erythematosus (SLE) exposed to commercially supplied belimumab within the four months prior to and/or during pregnancy.

Subject: Pregnancy Registry

Author(s): TBD

This study was performed in compliance with Good Clinical Practices, Good Pharmacoepidemiology, and GlaxoSmithKline Standard Operating Procedures for all processes involved, including the archiving of essential documents.

Copyright 2014 the GlaxoSmithKline group of companies. All rights reserved. Unauthorized copying or use of this information is prohibited.


4

TABLE OF CONTENTS

PAGE

1 FOREWARD .............................................................................................................. 6

2 LIST OF ABBREVIATIONS ..................................................................................... 13

3 MILESTONES .......................................................................................................... 14

4 OTHER RESPONSIBLE PARTIES .......................................................................... 14

5 RATIONALE AND BACKGROUND ......................................................................... 14

6 RESEARCH QUESTION AND OBJECTIVES ......................................................... 15

7 PROTOCOL AMENDMENTS AND UPDATES ........................................................ 15

8 RESEARCH METHODS .......................................................................................... 16 8.1 Study design ................................................................................................ 16 8.2 Participants/eligibility criteria ........................................................................ 17 8.3 Variables ...................................................................................................... 17

8.3.1 Birth defects .................................................................................. 18 8.3.2 Serious and/or clinically significant infections in infants ................ 19

8.4 Data sources and measurement .................................................................. 19 8.5 Statistical methods ....................................................................................... 24

8.5.1 Additional analysis cohorts ........................................................... 24 8.5.1.1 Subgroup analyses ...................................................... 25

8.5.2 Missing values .............................................................................. 25 8.5.3 Ethical approval and subject consent ........................................... 26 8.5.4 Subject confidentiality ................................................................... 26 8.5.5 Scientific Advisory Committee ...................................................... 26

9 RESULTS ................................................................................................................ 26 9.1 New data ...................................................................................................... 26 9.2 All registry data (prospective and retrospective data) .................................. 27

9.2.1 Excluded birth defects and other reported conditions ................... 27 9.2.2 Cases lost to follow-up .................................................................. 28 9.2.3 Invalid cases ................................................................................. 28 9.2.4 Pregnancy participant demographics and baseline

characteristics ............................................................................... 28 9.3 Prospective data .......................................................................................... 28

9.3.1 Belimumab exposure .................................................................... 28 9.3.2 Other medication exposures ......................................................... 29 9.3.3 SLE disease severity .................................................................... 30

9.4 Prospective pregnancy outcome results ...................................................... 30 9.4.1 Spontaneous miscarriages ........................................................... 30 9.4.2 Live birth outcomes ....................................................................... 31 9.4.3 Preterm births ............................................................................... 31 9.4.4 Birth defects .................................................................................. 32 9.4.5 Infant outcomes ............................................................................ 32

9.5 Adverse events ............................................................................................ 33


5

9.6 Retrospective reports of pregnancy ............................................................. 34

10 DATA FROM OTHER SOURCES ............................................................................ 34 10.1 Other non-registry reports of belimumab-exposed pregnancies .................. 34 10.2 Literature review ........................................................................................... 36

11 AWARENESS ACTIVITIES...................................................................................... 37

12 POTENTIAL BIAS .................................................................................................... 37

13 COMMITTEE CONSENSUS .................................................................................... 38

14 REFERENCES ........................................................................................................ 39

APPENDICES ................................................................................................................. 42


6

1 FOREWARD

This interim report describes the experience of the Belimumab Pregnancy Registry (BPR) and covers the period 16 Jul 2012 through 08 Mar 2014. The BPR is a non-interventional, prospective drug exposure observational study (prospective cohort study) enrolling women who have been exposed to commercially supplied belimumab within the four months prior to and/or during pregnancy. The BPR is a global, observational study with the primary objective of evaluating birth defects and secondary objectives that include reporting on pregnancy outcomes and infant outcomes through the age of one year.

The ultimate utility of BPR data will be to satisfy post-authorization safety commitments to regulatory agencies. A secondary aim is to provide clinicians with relevant human data on the potential risks and benefits of belimumab exposure within the four months prior to and/or during pregnancy so they can more effectively counsel women who have been prescribed commercially supplied belimumab and are pregnant or are planning to become pregnant.

A Scientific Advisory Committee (SAC) of external clinical researchers has been established to provide expert review of the data, increase awareness and enrollment in the BPR, and disseminate information about the BPR. The SAC meets on a periodic basis to review the data and update this report and to discuss the general conduct of the BPR. The names of the SAC members are indicated in a footnote in Table 1. The BPR Steering Committee (SC) provides oversight of the conduct of the BPR. The SC is composed of the SAC along with representatives from the sponsor company, GlaxoSmithKline (GSK), and the company managing the BPR, PPD.

Table 1. BPR Steering Committee

Name Title Michelle Petri, MD, MPH1, Chair

Professor, Department of Medicine, Director, Lupus Center, Division of Rheumatology, Johns Hopkins University, Baltimore, MD

James Fettiplace, MBBS, BSc MRCS

GSK Director of Clinical Development, Belimumab (Medical Monitor)

Helain Landy, MD1 Professor and Chair, Department of Obstetrics and Gynecology, Georgetown University Hospital, Department of Obstetrics & Gynecology, Washington, DC

Carl Laskin, MD1 Professor, Department of Medicine (Rheumatology) and Obstetrics & Gynecology, University of Toronto, Toronto, ON

Richard Miller, PhD1 Professor, Department of Obstetrics and Gynecology, University of Rochester School of Medicine and Dentistry

M. Anthony Moody, MD1

Assistant Professor of Pediatrics and Assistant Professor of Immunology, Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC

Hugh Tilson, MD, DrPH1

Adjunct Professor, Public Health Leadership, University of North Carolina, Gillings School of Global Public Health, Chapel Hill, NC

Deanna Hill, PhD, MPH GSK Belimumab Pregnancy Registry Clinical Investigation Lead, Director, Worldwide Epidemiology

Marcy Powell, MD GSK Director, Safety Evaluation and Risk Management, Global Clinical


7

Safety and Pharmacovigilance Greg Giguere, MS GSK Principal Statistician Mary Beth Welch, PharmD

GSK Manager, Safety Evaluation and Risk Management, Global Clinical Safety and Pharmacovigilance

Ann Mallard, MPH PPD Epidemiologist Deborah Covington, DrPH

PPD Global Head, Observational Studies & Pregnancy Registries

Laura McKain, MD PPD Principal Investigator Paige Churchill, BA PPD Director, Global Late Stage Research Kim Freeman, BA PPD Global Project Manager 1Member of the Scientific Advisory Committee (SAC)

EXECUTIVE SUMMARY

Introduction

The purpose of the Belimumab Pregnancy Registry (BPR) is to evaluate pregnancy and infant outcomes for pregnancies in women with systemic lupus erythematosus (SLE) exposed to commercially supplied belimumab within the four months prior to and/or during pregnancy. The primary endpoint is birth defect, and secondary endpoints include spontaneous miscarriage, live birth, including preterm birth, birth of infants classified as small for gestational age (SGA), stillbirth, elective termination, and serious and/or clinically significant infections in infants through one year of age.

The BPR is a global, prospective cohort study with voluntary participant registration following informed consent by the pregnant woman for her participation and assent for participation of her infant and enrollment following confirmation from her health care providers (HCPs). Confirmation of commercially supplied belimumab exposure is obtained from the belimumab prescriber, and confirmation of the pregnancy may be obtained from the belimumab prescriber or the obstetrical provider. Data are collected at enrollment, at the end of the second trimester of pregnancy (approximately 26 weeks’ gestational age), and at pregnancy outcome (delivery or early termination). For live births, infant data are collected at pregnancy outcome, four months, and 12 months of age. Data regarding participants’ SLE disease severity are sought from the belimumab prescriber. Data regarding the pregnancy and pregnancy outcome are sought from the obstetric HCP, and data on live-born infants are sought from the pediatric HCP. (For more details, see Section 8, Research Methods.)

Data summary

All Registry Data

Cumulatively from 16 Jul 2012 through 08 Mar 2014, 10 participants were enrolled into the BPR (prospective = 9; retrospective = 1), and all 10 participants were exposed to belimumab within four months prior to conception. Nine prospective evaluable reports of pregnancy were enrolled into the BPR from North America. An evaluable registry report is a case with data submitted or confirmed by a HCP that meets the minimum criteria for a registry report; for prospective reports, the pregnancy outcome is not known at the time


8

of enrollment. One participant from Europe was enrolled retrospectively into the BPR, meaning the pregnancy outcome was known at the time of enrollment.

Pregnancy outcomes observed through the end of the reporting period included live birth (n=6), spontaneous miscarriage (i.e. spontaneous abortion; n=1), elective termination (n=1), and pregnancy ongoing (n=2). Among the nine prospective cases, pregnancy outcomes have been reported for seven participants; one participant has completed infant follow-up and is now considered a closed case, five participants who had live births are in follow-up, and one case with a spontaneous miscarriage has been closed.

The mean gestational age for the six live infant births in the BPR was 366/7 weeks. Three (50.0%) of the six infants were considered preterm (born at <370/7 weeks’ gestational age), but no preterm births were considered to be attributable to belimumab. Through 08 Mar 2014, there was one reported congenital anomaly or birth defect in an infant born at 366/7 weeks’ gestational age via caesarean section, considered by the HCP to have a “reasonable possibility” of attribution to belimumab: a very mild Ebstein anomaly of the tricuspid valve. The Birth Defect Evaluator (BDE) also noted that this defect is a very mild functional cardiac defect and was unable to rule out a temporal association between the belimumab exposure and the development of the observed defect.

Through 08 Mar 2014, the infants of five BPR participants had data reported at the four-month follow-up visit: two full-term infants and three preterm infants. The pediatric HCPs confirmed that, at four months of age, the full-term infants had no birth defects noted and that they met appropriate developmental milestones for gross and fine motor skills, language, cognitive, and social/emotional areas. One (20.0%) preterm infant born at 360/7 weeks’ gestational age did not meet the appropriate developmental milestones for gross motor skills at the four-month follow-up visit. This preterm infant also completed the infant 12-month follow-up visit and did not meet the appropriate developmental milestones for gross motor skills, social/emotional, and language areas. However, the infant met the milestones for cognitive and fine motor skills at the final follow-up visit.

New data

From 01 Jun 2013 through 08 Mar 2014 (i.e., enrollment period since last reporting period, 16 Jul 2012 – 31 May 2013), three participants from North America were enrolled prospectively and one participant from Europe was enrolled retrospectively in the BPR. During this time period, there were five pregnancy outcomes reported from prospective North American participants. Four were live birth outcomes (one in a newly enrolled participant and three in participants enrolled in the previous period). One of those births was considered a preterm birth. The fifth pregnancy outcome was a spontaneous miscarriage.

The spontaneous miscarriage was reported as the outcome of a pregnancy for a 31-year-old participant who received belimumab for approximately seven months, with the last dose taken 05/7 weeks’ gestational age, for a cumulative total of eight doses. At 123/7 weeks’ gestational age, the participant was diagnosed with “fetal demise” by ultrasound and underwent dilation and evacuation, which corresponds to the protocol definition of spontaneous miscarriage. She was reported as having hypothyroidism preconception


9

through pregnancy outcome by both the belimumab prescriber and the obstetrical HCPs. Preconception medication exposures included prednisone, methotrexate, folate, and anti-malarial drugs. At outcome, she had been prescribed anti-malarial drugs. Other medication exposures noted by the prescriber HCP included Celexa, Wellbutrin, Synthroid, Zofran, and prenatal vitamins. The belimumab prescriber HCP did not indicate whether this event had a reasonable possibility of attribution to belimumab.

For two new participants from North America, pregnancy outcomes are pending through the data cut-off date of 08 Mar 2014. For the European retrospectively enrolled participant, an outcome of elective termination was reported by the belimumab prescriber HCP.

A female infant born preterm at 366/7 weeks’ gestational age via caesarean section during this period was reported by the pediatric HCP as having a birth defect, mild to moderate tricuspid valve regurgitation. The 38-year-old, white, non-Hispanic participant received belimumab preconception through the third trimester of pregnancy for a cumulative total of 16 doses. For preconception, she also received prednisone, aspirin, heparin, and anti-malarial drugs. Prednisone, aspirin, and anti-malarial drugs were continued throughout the pregnancy. The nulliparous participant was diagnosed with SLE at the age of 27 years; duration of SLE was 11 years. The Systemic Lupus International Collaborating Clinics (SLICC)/American College of Rheumatology (ACR) Damage Index (SDI) was not done, and the physician global assessment (PGA) disease activity score was reported as mild (PGA=1) at all time points: preconception and at enrollment, end of second trimester, and at outcome. On 09 Aug 2013, one day after birth, an echocardiogram of the infant revealed tricuspid valve regurgitation with possible mild Ebstein anomaly, patent ductus arteriosus, and patent foramen ovale. At approximately 11 weeks’ postnatal age on 25 Oct 2013, a repeat echocardiogram revealed minimal displacement of septal leaflet of tricuspid valve, indicating a diagnosis of very mild Ebstein anomaly of the tricuspid valve as reported by the pediatric HCP, corresponding to the protocol definition of a birth defect. The pediatric HCP also reported a reasonable possibility that the observed birth defect was attributable to exposure to belimumab. The pediatric HCP reported relevant medical conditions and other possible risk factors potentially contributing to the event as SLE, lupus nephritis, presence of SSA antibodies, and antiphospholipid syndrome. It was also noted that the participant had elevated liver enzyme levels preconception through the first trimester of pregnancy, as well as proteinuria and hypothyroidism preconception through pregnancy outcome. The BPR BDE was unable to rule out a temporal association between the belimumab exposure and the development of the observed defect. The BDE noted genetic factors as an alternative etiology and indicated that maternal age, prednisone exposure during pregnancy, and having an autoimmune disease are not known to be associated with this defect. The BDE also noted that this defect is a very mild functional cardiac defect and recommended follow-up in two years. Specifics for recommended follow-up were not provided.

The European retrospective participant enrolled during this period on 25 Nov 2013, approximately seven months after an elective termination of pregnancy. The participant received a cumulative total of four doses of belimumab, the last within four months prior to conception. The participant’s duration of SLE was 11 years, and the belimumab prescriber reported that the participant had all ACR criteria for classification of SLE


10

except the neurologic disorder criterion. The participant was reported as having a history of positive anti-double-stranded (anti-ds) DNA and low complement component 3 (C3) and complement component 4 (C4), but all were reported as normal at the most recent assessment. It was reported that the participant had a severe lupus flare and hypertension preconception at the start of pregnancy. The PGA score was reported as mild (PGA=1) preconception and at enrollment. The SDI was not done. Termination of her pregnancy at 53/7 weeks’ gestational age was recommended following an episode of severe pancreatic pseudocysts requiring surgery, which corresponds to the protocol definition of elective termination. The participant was exposed to belimumab within four months prior to conception, and the belimumab prescriber indicated it was a “reasonable possibility” that the severe pancreatic pseudocysts event in the mother was attributable to belimumab. Other medication exposures included hydroxychloroquine, prednisolone, and omeprazole. The timing of exposure for these medications was not specified.

One prospective participant with a preterm live birth outcome, an infant born at 360/7 weeks’ gestational age, completed the 12-month infant follow-up and is considered a closed case. A total of seven participants continue to be active in the follow-up period, five with live births and two whose pregnancy outcomes are pending.

Supplemental Data

Thirty-four cases possibly related to administration of belimumab during pregnancy or lactation cases were received by Global Clinical Safety and Pharmacovigilance, GSK Research and Development during the period of this report of 09 Sep 2013 to 08 Mar 2014 and entered in the GSK Safety Database (OCEANS). The search is based on Medical Dictionary for Regulatory Activities (MedDRA) Standardised MedDRA Queries Pregnancy and Neonatal Topics. In addition, all cases involving a pregnant woman are included. Cases involving females over 60 years of age and adult males (where the case was not reported as a partner pregnancy) have been excluded.

Of the 34 new cases of pregnancy reported during the period of this report, 14 were from clinical trials (11 blinded; three belimumab):

nine pregnancies ongoing

three elective terminations with NO apparent congenital anomaly

two spontaneous abortions with NO apparent congenital anomaly

Of the remaining 20 cases (eight postmarketing surveillance; 12 spontaneous):

13 pregnancies ongoing

three live infant births with NO apparent congenital anomaly

two elective terminations with NO apparent congenital anomaly


Of the five elective terminations with no apparent congenital anomalies that were received during the reporting period, three of the five cases had no rationale provided for the termination, one case occurred in a woman with concurrent cysts, and the final


11

elective termination occurred in conjunction with surgery for severe pancreatitis with pseudocysts. None of the women who underwent elective termination had reported complications.

The four reports of spontaneous abortion received during the reporting period occurred without complications at the following time points: three weeks (n=1), approximately eight weeks (n=2), and at an unspecified time within the first trimester (n=1).

Three subjects delivered live infants with no congenital anomaly during the reporting period.

During the time period covered in this report, there were 10 pregnancy cases received prior to the data lock point of this report that have received follow-up during the current period. Four cases lacked significant follow-up information and there were no changes in the reported outcomes; there were two reports of live birth with NO congenital anomaly; and the last four cases were from the BPR (discussed below).

Pregnancy outcomes from both clinical and spontaneous report sources for the current reporting period and cumulative totals are summarized in Table 2. Table 2. Pregnancy Outcomes (Excluding Partner Pregnancies) in OCEANS

Outcome1, 2 In Period (n) Cumulative (n)3 Live infant, no apparent congenital anomaly 3 43 Live infant with congenital anomaly 0 5 Elective termination, no apparent congenital anomaly 5 27 Elective termination with congenital anomaly 0 0 Spontaneous abortion, no apparent congenital anomaly 4 30 Spontaneous abortion with congenital anomaly 0 0 Stillbirth, no apparent congenital anomaly 0 2 Stillbirth with congenital anomaly 0 0 Ectopic pregnancy 0 0 Molar pregnancy 0 0 Pregnancy ongoing, lost to follow-up or unknown 22 40 Total 34 147

1Changes in the numbers of the cumulative outcomes since the previous safety update reflect not only the addition of new cases but also follow-up obtained on previously received cases.

2Pregnancy outcome categories stating "no apparent congenital anomaly” include outcomes where it is unknown whether a congenital anomaly occurred.

3Six pregnancy outcomes were reported in placebo subjects: spontaneous abortion no apparent congenital anomaly (n=3), elective termination no apparent congenital anomaly (n=2), and stillbirth no apparent congenital anomaly (n=1).

No new partner pregnancies were reported in the reporting period. Cumulative counts of outcomes from partner pregnancies include two “Live infant, NO apparent congenital anomaly”, one “Spontaneous abortion, NO apparent congenital anomaly”, and one pregnancy that was “lost to follow-up”.


12

Scientific Advisory Committee Consensus

On 08 Jul 2014, the SAC independently reviewed all data reported to the BPR as well as supplemental data and concluded that there is insufficient information at this time to reach a conclusion about the risk for birth defects and the secondary endpoints of interest for pregnancies exposed to commercially supplied belimumab.

The BPR is ongoing. Eligible pregnant women and their HCPs are encouraged to participate in the BPR by calling 1-877-681-6296 (within North America) and +44 (0) 208 990 9000 (outside of North America).


13

2 LIST OF ABBREVIATIONS

ACR American College of Rheumatology AE Adverse Event Anti-ds Anti-double-stranded BDE Birth Defect Evaluator BPR Belimumab Pregnancy Registry C3 Component 3 C4 Component 4 CDC Centers for Disease Control and Prevention CIOMS Council for International Organizations of Medical Sciences EC Ethics Committee EUROCAT European Surveillance of Congenital Anomalies GSK GlaxoSmithKline HCP Health Care Provider IRB Institutional Review Board MACDP Metropolitan Atlanta Congenital Defects Program MedDRA Medical Dictionary for Regulatory Activities NSAIDs Non-Steroidal Anti-inflammatory Drugs PGA Physician Global Assessment SAE Serious Adverse Event SAC Scientific Advisory Committee SC Steering Committee SDI Systemic Lupus International Collaborating Clinics/American

College of Rheumatology Damage Index SGA Small for Gestational Age SLE Systemic Lupus Erythematosus SLICC Systemic Lupus International Collaborating Clinics

Trademark Information

Trademarks of the GlaxoSmithKline group of companies

Trademarks not owned by the GlaxoSmithKline group of companies

BENLYSTA belimumab


14

3 MILESTONES

Milestone Start/Cut-off

date End/Effective

date Comments Data collection 16 Jul 2012 Interim report 1 (31 May

2013 – cut-off date)

Jul-2013

03 Jan 2014

Interim report 2 (08 Mar 2014 – cut-off

date) Mar 2014

Jul 2014 Awaiting Final Approval

4 OTHER RESPONSIBLE PARTIES

The Belimumab Pregnancy Registry (BPR) is managed by PPD under the sponsorship of GlaxoSmithKline (GSK). This interim report covers data from 16 Jul 2012 through 08 Mar 2014, and contains a summary of voluntary reports of prenatal/pregnancy exposures to commercially supplied belimumab. Supplemental data are reported by GSK and collected through routine pharmacovigilance practices.

Data from retrospective or non-systemic lupus erythematosus (SLE) reports will also be collected and the outcomes reviewed and evaluated. However, no non-SLE cases have been reported through 08 Mar 2014.

5 RATIONALE AND BACKGROUND

Data from the BPR will satisfy post-authorization safety commitments to regulatory agencies for belimumab. The purpose of the global BPR is to add to the current clinical experience with commercially supplied belimumab and to complement reproductive data from animal toxicology studies. The BPR will also assist clinicians in weighing the potential risks against the benefits of treatment with belimumab for individuals with SLE.

SLE is an autoimmune disease that can affect a wide range of organ systems, mainly the skin and musculoskeletal system, but also the kidney, heart, lungs, and central nervous system. In the United States, the estimated average of the reported prevalence of SLE is approximately 10 cases per 10,000 persons, representing about 300,000 persons diagnosed with SLE in the United States; the female-to-male ratio in the childbearing years has been reported to be as high as 12:1 [Danchenko, 2006]. In the European Union, an estimated overall average of the reported prevalences is 4-5 cases per 10, 000 persons [Alamanos, 2003; Benucci, 2005; Eilertsen, 2006; Gourley, 1997; Govoni, 2006; Gudmundsson, 1990; Hopkinson, 1993; Johnson, 1995; López, 2003; Nightingale, 2007; Nossent, 2001; Piette, 2004; Samanta, 1992; Ståhl-Hallengren, 2000; Voss, 1998]. As many as four million people may be affected worldwide. Women with SLE are at a higher risk to have poor obstetric outcomes than women without SLE, including a greater


15

likelihood of fetal loss (approximately three-fold increase) and a greater incidence of preterm deliveries (~40% vs. 10%) [Clark, 2003; Clowse, 2005].

Belimumab is a recombinant, human, IgG1λ monoclonal antibody that binds soluble BLyS with high affinity and inhibits its biological activity [Baker, 2003]. Following in vitro and animal model studies [Belimumab Investigator’s Brochure, 2014], belimumab was identified as a potential therapeutic agent for autoimmune diseases in which BLyS may play a role in disease pathogenesis. No data are available from human subjects who received substantial exposure to belimumab during pregnancy. In preclinical studies, treatment with belimumab was not associated with direct or indirect harmful effects with respect to maternal toxicity, developmental toxicity, or teratogenicity.

6 RESEARCH QUESTION AND OBJECTIVES

The primary endpoint is birth defect, and secondary endpoints include spontaneous miscarriage, live birth, preterm birth, small for gestational age [SGA]), stillbirth, elective termination, and serious and/or clinically significant infections in infants through one year of age.

7 PROTOCOL AMENDMENTS AND UPDATES

Number Date Section of study protocol amended 1 24 Feb 2012

HGS Sponsor Signatory information Abbreviations Protocol Summary Methodology (Section 4) Summary Table of Evaluations, including

addition of breastfeeding status Reporting of Adverse Events (Section 7.4) References Appendices Correct minor typographical errors

2 11 Apr 2013 Change registry name to use generic in title

vs. brand name Update Sponsor Signatory Page Delete HGS Sponsor Signatory Page Delete HGS Sponsor Contact

Information Delete HGS Protocol Number Delete HGS Study Number Update Investigator Protocol

Agreement Page Remove HGS throughout body of protocol Update Trademark Information Update Protocol Summary


16

Number Date Section of study protocol amended Revise definition for retrospective reports of

pregnancy; add definitions for traditional prospective and pure prospective reports of pregnancy per the EMA in the following sections:

Protocol Summary Update Section 4.1 Update Section 4.2 Update Section 4.6 Update Section 4.8 Update Section 5 Update Section 6 Update Glossary Update Section 4.5 Update Section 7.2 Update Section 7.4 Update Section 7.7 Update Section 7.9 Update References Update Appendices Correct minor typographical errors

8 RESEARCH METHODS

8.1 Study design

The BPR is a global, prospective cohort study with voluntary participant registration following informed consent by the pregnant woman for her participation and assent for participation of her infant and enrollment following confirmation from her health care providers (HCPs). Confirmation of commercially supplied belimumab exposure is obtained from the belimumab prescriber, and confirmation of the pregnancy may be obtained from the belimumab prescriber or the obstetrical provider. Traditional prospective reports of pregnancy include all women who enroll in the BPR before the end of pregnancy (live birth, fetal loss), regardless of known normal or abnormal prenatal test results. Pure prospective reports of pregnancy are a subset of traditional prospective reports and include those where (a) the enrollee does not know, at the time of enrollment, whether the fetus had a malformation, and (b) no prenatal testing was completed prior to enrollment. Prenatal testing includes any diagnostic or screening evaluations that may provide insight into the outcome of the pregnancy. Examples include ultrasound, amniocentesis, chorionic villus sampling, nuchal translucency testing, and maternal serum screening for aneuploidy or neural tube defects.

Retrospective reports of pregnancy are those in which the pregnancy ended (live birth, fetal loss) before enrollment or at the time of first contact with the BPR. All retrospective cases reported to the BPR have data collected and entered into the database (as


17

appropriate for the underlying disease) using the same procedures as prospective cases (traditional or pure); however, retrospective cases are summarized separately. If a pregnancy is reported to the BPR from a woman who is not diagnosed with SLE, the BPR collects that data, but summarizes it separately from the SLE pregnancies.

8.2 Participants/eligibility criteria

Women with SLE who have been exposed to commercially supplied belimumab within the four months prior to and/or during pregnancy are eligible to participate in the BPR.

Minimum criteria for enrollment include the following:

Sufficient evidence to confirm that exposure to commercially supplied belimumab occurred within the four months prior to and/or during pregnancy

Sufficient information to classify the pregnancy as prospective or retrospective (i.e., whether the outcome of pregnancy was known at the time of first contact with the BPR)

Full initial reporter (i.e., pregnant woman or HCP) contact information to allow for follow-up (name, address, telephone number/email address), and contact information for applicable HCPs if initial reporter is the pregnant woman

Consent provided by the pregnant woman for her participation and assent for participation of her infant

Reported cases that do not meet the minimum criteria for BPR enrollment are ineligible for inclusion in the BPR and are not entered into the database. In such cases, the report is forwarded to GSK and handled using routine pharmacovigilance measures.

The primary study population for which analyses are presented includes pure prospective evaluable cases in participants having SLE considered exposed to belimumab (i.e., received one complete or partial dose of commercially supplied belimumab) within the four months (i.e., a period of approximately five belimumab terminal half-lives) prior to and/or during pregnancy that are not lost to follow-up (i.e., cases with appropriate outcome information that meet the minimum criteria for evaluation as previously specified).

8.3 Variables

The following pregnancy outcomes are collected by the BPR:

Spontaneous miscarriage: fetal death or expulsion of products of conception prior to 200/7 weeks’ gestational age

Live birth: the birth of a living fetus at 200/7 weeks’ gestational age or greater or, if gestational age is unknown, a fetus weighing 500 g or more (≥500 g)

Stillbirth: a fetal death occurring at 200/7 weeks’ gestational age or greater, or, if gestational age is unknown, a fetus weighing 500 g or more (≥500 g)


18

Elective termination: voluntary interruption of pregnancy, including pregnancy termination that occurs electively, to preserve maternal health, or due to fetal abnormalities

Preterm birth: an infant born at less than 370/7 weeks’ gestational age

Neonatal death: an infant who after live birth expired within the first 28 days of life

Ectopic pregnancy: implantation of a conception outside of the uterus

Molar pregnancy: a conception that results in a gestational trophoblastic tumor

SGA: an infant whose birth weight, length, or head circumference is less than the 10th percentile for the gestational age. It is based on data derived from an appropriate reference population. The BPR utilizes the sex-specific international growth reference currently recommended by the World Health Organization [de Onis, 1996; Williams, 1982]. The parameters used to calculate SGA are collected for all infants. Therefore, SGA calculations can be performed based on the needed parameters for various region or country-specific criteria where warranted.

8.3.1 Birth defects

The BPR defines and codes birth defects with criteria specified by Centers for Disease Control and Prevention (CDC)’s Metropolitan Atlanta Congenital Defects Program (MACDP) [CDC, 2007]. Newborn and infant conditions that are not necessarily considered birth defects appear in the Exclusion List for the MACDP. These conditions may be included under certain circumstances by CDC criteria and are to be considered “conditional defects” in the BPR.

The BPR defines a birth defect as any major structural or chromosomal defect or combination of two or more of the conditional defects in live-born infants, stillbirths, or fetal losses of any gestational age (including outcomes prior to 200/7 weeks’ gestational age or weighing <500 g). This definition is consistent with, but not restricted to, the CDC MACDP definition. Clusters of conditional defects (as defined by CDC MACDP) and data from aborted fetuses of less than 200/7 weeks’ gestational age, when available, will be included to increase sensitivity of monitoring. The MACDP includes conditional defects only if in the presence of a major structural defect. In contrast, the BPR considers reports of two or more conditional defects as a birth defect case, to increase potential signal generation and to capture instances where a combination of conditional defects might constitute a major birth defect or syndrome.

The BPR conforms to the CDC MACDP guidelines in disqualifying birth defects if those findings are present in infants born at less than 360/7 weeks’ gestational age and are attributable to the preterm delivery itself, such as patent ductus arteriosus, patent foramen ovale, or inguinal hernias. The CDC MACDP classification includes chromosomal defects. Though these defects are not likely to contribute to a risk for a drug exposure, the BPR includes these birth defects to maintain consistency with the CDC MACDP. Live-born infants with only transient or infectious conditions or with biochemical abnormalities (e.g., jaundice) are classified as being without reported birth defects unless there is a possibility that the condition reflects an unrecognized birth defect. Detected and


19

reported transient or infectious conditions or biochemical abnormalities in infants without reported birth defects and defects that are excluded by the CDC guidelines are reviewed and noted in the BPR reports as they occur.

Because the BPR is conducted in North America and Europe, the BPR refers to the European Surveillance of Congenital Anomalies (EUROCAT) in addition to the United States-based CDC MACDP in subgroup analyses and/or with specific SLE comparator cohorts, if data are available or applicable. The prevalence of birth defects reported to the BPR is calculated as the percentage of birth defects from the total number of live births. Fetal losses with reported birth defects occurring at or after 200/7 weeks’ gestational age are included in the numerator of the estimate of risk for birth defects to increase sensitivity and to allow comparison of the BPR prevalence rates with the CDC MACDP [CDC, 2007] and EUROCAT [EUROCAT, 2012].

Because the BPR is being conducted to identify potential signals that may indicate an increased risk of major birth defects in offspring of women with SLE following exposure to commercially supplied belimumab, it is necessary to monitor the cumulative data to identify/generate the pattern of potential signals and to determine the necessary course of action if a signal is suspected. The BPR employs the strategy of “threshold” based on the method recommended by the Council for International Organizations of Medical Sciences (CIOMS) [CIOMS, 1999]. The threshold for action is determined by the extent of certainty about the cases and tempered by the specifics of each case. The BPR cannot formally detect an increased risk of a specific rare outcome following exposure to commercially supplied belimumab within the four months prior to and/or during pregnancy.

To aid in hypothesis generation, the Birth Defect Evaluator (BDE) reviews all birth defects in an aggregate manner and on an ongoing basis to identify any possible reporting patterns. Any potential patterns that are identified are discussed with the GSK medical monitor.

8.3.2 Serious and/or clinically significant infections in infants

All infections that meet the serious adverse event (SAE) criteria as per the protocol are reported for infants through 12 months of age. Certain non-serious events are additionally reported as clinically significant and include:

Infants from birth through six months of age: infections requiring treatment

Infants from birth through three months of age: fevers of unknown origin or of known infectious etiology

8.4 Data sources and measurement

HCPs serve as primary data reporters to the registry. The BPR is strictly observational; the schedule of office visits and all treatment regimens are determined by the belimumab prescriber and other HCPs. The BPR collects data that are routinely documented in the participant’s medical record in the course of usual care, with the possible exception of the physician global assessment (PGA) of SLE disease activity and The Systemic Lupus International Collaborating Clinics (SLICC)/American College of Rheumatology (ACR)


20

Damage Index (SDI). The PGA is a simple, concise, global index of disease activity that is completed at enrollment (including a preconception assessment for the six months prior to pregnancy), the end of second trimester, and at pregnancy outcome for BPR participants with SLE. SLE disease activity is often assessed in usual clinical care, and collection of this information is integral to evaluating disease severity during the preconception period through the end of pregnancy.

Data regarding participants’ SLE clinical history and disease severity are sought from the belimumab prescriber. Data regarding the pregnancy and pregnancy outcome are sought from the obstetric HCP, and data on live-born infants are sought from the pediatric HCP. Appropriate members of the woman’s and infant’s health care team are contacted to complete missing data as needed. Participant-reported data are verified from the HCP overseeing that component of the participant’s care. All data are collected from the participant or the relevant HCP on case report forms. Targeted follow-up may be requested to gather additional information, if required, to assist data interpretation on events and outcomes of interest.

Study procedures and enrollment criteria are consistent among all participants regardless of country of residence. Table 3 presents the scheduled evaluations from the study protocol.


21

Table 3. Table of Evaluations

Information Requested

Data Sourcea

Registration/ Enrollment

Interim Prenatal Follow-up (end of 2nd trimester)

Pregnancy Outcome

Infant Follow- up (4 & 12 months)

Targeted Follow-up

Maternal Information

Maternal contact information, alternate contact information, HCP contact information

Participant and/or HCP

b

b

b

Maternal characteristics (age, ethnicity, etc)

Obstetric HCP

Maternal prenatal information (LMP, EDD, CEDD, prenatal imaging and aneuploidy screening/testing results & timing)

Obstetric HCP

b

b

Maternal disease severity (to include pre-conception assessment)c

Belimumab prescriber

b

b

Obstetrical history Obstetric HCP b d

Family history of birth defects Obstetric HCP d

Belimumab exposure information

Belimumab prescriber

b b g b

Concurrent conditions, Belimumab


22


Data Sourcea



Pregnancy Outcome


Targeted Follow-up

concomitant medications, pregnancy complications, alcohol, tobacco and recreational drug use during pregnancy

prescriber & obstetric HCP

b

b

Pregnancy Outcome Information

Pregnancy status Obstetric HCP b

Outcome information (live birth, fetal loss, weight)

Obstetric HCP

e

e

Birth defect noted & description

Obstetric HCP e e

Contributing factors Obstetric HCP e e d

Infant Follow-up Information

Birth defect noted & description

Pediatric HCP f d

Contributing factors Pediatric HCP f d

Developmental milestones Pediatric HCP f f f

History of serious and/or clinically significant infections, fevers of unknown origin, treatment, & outcomes

Obstetric & pediatric HCP

f

f

d


23


Data Sourcea



Pregnancy Outcome


Targeted Follow-up

Lactation status Obstetric HCP

Breastfeeding status

Obstetric & pediatric HCP

f

Abbreviations: CEDD: corrected estimated date of delivery; EDD: estimated date of delivery; HCP=health care provider; LMP=last menstrual period; SLE=systemic lupus erythematosus.

a. Under ideal circumstances, the registry collected data from the data source noted. In the case of extenuating circumstances that precluded data collection from the identified source, the registry could seek the data from a secondary source. Every effort was made to verify patient-reported data.

b. Obtained updated information since the previous contact. c. Included maternal disease severity pre-conception and at registration/enrollment. If a registry participant did not have SLE, SLE-specific assessments were not required. d. Collected information not previously obtained, to facilitate characterization of the fetal loss, birth defects, or serious and/or clinically significant infections or fevers of unknown

origin in the infant(s). e. Obtained if outcome occurred. f. Collected only for live birth outcomes. g. Collected for registry participants who received belimumab during lactation.


24

8.5 Statistical methods

All data, where applicable, are summarized using descriptive statistics. Categorical variables are summarized by number and percentage in each category. Missing data are displayed as a separate category where appropriate. The denominator for all percentages reflects the number of participants within the cohort, unless otherwise stated.

8.5.1 Additional analysis cohorts

Data are summarized separately for participants included in the traditional prospective cohort, which includes all evaluable cases enrolled in the BPR before the end of pregnancy, regardless of known normal or abnormal prenatal test results.

The following cohorts will be evaluated after 20 cases per cohort have been enrolled:

Retrospective cases: Evaluable cases for which the enrollees make first contact with the BPR after the end of pregnancy (i.e., live birth, stillbirth, or fetal loss). The cases must have SLE.

Non-SLE cases: Retrospectively and prospectively enrolled (pure or traditional) evaluable cases where the participant has not been diagnosed with SLE upon entry into the BPR.

Invalid participant-reported cases: Cases for which the pregnancy outcome is reported by the participant but is not confirmed by both the obstetric and the belimumab prescriber HCPs. These cases are not enrolled into the registry.

Cases that are lost to follow-up are defined as all prospective reports (pure or traditional) for which the pregnancy outcome (live birth, stillbirth, fetal loss) is never obtained, unavailable, and/or where the indication of a birth defect is designated as unknown. When no pregnancy outcome data are available, then the participant is assumed lost to follow-up for both the pregnancy outcome endpoints and the infant outcome endpoints. Participants with data available at pregnancy outcome and missing data at four-month follow-up and/or 12-month follow-up are not considered lost to follow-up.


25

8.5.1.1 Subgroup analyses

Table 4 shows a list of the subgroup variables that will be utilized for summarizing primary and secondary outcomes as well as other summaries, if possible, once a reasonable sample size of data has been collected.

Table 4. Subgroup Variables

Definition Outcomes Lost to Follow-up Participants with no data on

pregnancy outcome or birth Maternal information, Maternal obstetric history, Maternal SLE disease history, Maternal belimumab and other medication exposures

Level of Exposure Defined level categories using cumulative belimumab exposure and body weight

Primary and Secondary Endpoints

Gestational Age at Enrollment

<80/7 weeks’ gestational age 80/7 - 116/7 weeks’ gestational age 120/7 - 136/7 weeks’ gestational age 140/7 - 200/7 weeks’ gestational age

Secondary Endpoints: Spontaneous miscarriage and elective termination

Maternal Age <35 years and ≥35 years based on age at time of registration


Region North America or Europe Primary and Secondary Endpoints Breastfeeding Based on CRF completion at

pregnancy outcome, and infant follow-up at months 4 and 12

Secondary Endpoint: Serious and/or clinically significant infections

Disease Severity 1 PGA ≥2 at any time during pregnancy Primary and Secondary Endpoints Disease Severity 2 SDI >1 at registration/enrollment Primary and Secondary Endpoints Immunosuppressants/ Contraindicated Medications

Contraindicated medications including immunosuppressives, antiplatelets, anticoagulants, antihypertensives, analgesics, and anti-inflammatories. Reviewed by medical monitor for accuracy.


Pregnancy Drug Category D or X

Any medication that is in categories D or X for pregnancy safety. Reviewed by medical monitor for accuracy.


Note: CRF=case report form; PGA=physician global assessment; SDI= Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index; SLE=systemic lupus erythematosus

8.5.2 Missing values

There may be occurrences of partial missing dates for exposures or medical conditions of interest. No date imputation has been conducted for calculating summary estimate


26

outcomes. It is of interest in this study to evaluate the frequency of birth defects based on timing of belimumab exposure. As a conservative estimate of the number of birth defects in this study, a missing date will be imputed to correspond to the first trimester of exposure when belimumab exposure is assessed in future reports.

8.5.3 Ethical approval and subject consent

The study was reviewed and granted approval by an institutional review board (IRB)/ethics committee (EC) that included a waiver of documentation of signed informed consent for participation based on the BPR’s process for collecting data and protecting participant privacy. The IRB approval also included a Health Insurance Portability and Accountability Act authorization waiver. IRB/EC approval or notification has been obtained or performed, respectively, in countries where this is required.

In order to collect data from the participant’s HCPs and her newborn’s pediatric HCP, BPR participants in all countries must complete medical release forms for each clinician who will report data to the BPR.

8.5.4 Subject confidentiality

In the BPR, participant confidentiality is strictly upheld. Each participant’s identity is known only to the third-party vendor (Research Coordination Center), the BPR site, enrolling individual (i.e., participant or HCP), and relevant HCPs (i.e., belimumab prescriber, obstetrician, pediatrician). The BPR assigns participant and infant identification numbers, which are used to identify BPR participants and their infant offspring. The dataset used in each analysis of data from the BPR contained coded BPR participant identifiers only for both the pregnant mothers and infants.

Regulatory authorities or GSK-approved auditors may inspect the BPR data files, which may include personal identifier information of BPR participants.

8.5.5 Scientific Advisory Committee

A Scientific Advisory Committee (SAC) of external clinical researchers has been established to provide expert review of the data, promote awareness and enrollment in the BPR, and disseminate information about the BPR. The SAC meets on a periodic basis to review the data, update this report, and discuss the general conduct of the BPR. The names of the members of the SAC are indicated with a footnote in Table 1. The BPR Steering Committee (SC) provides oversight of the conduct of the BPR. The SC is composed of the SAC along with representatives from the Sponsor Company, GSK, and the company managing the BPR, PPD.

9 RESULTS

9.1 New data

From 01 Jun 2013 through 08 Mar 2014 (i.e., enrollment period since last reporting period, 16 Jul 2012 – 31 May 2013), three participants from North America were enrolled prospectively and one participant from Europe was enrolled retrospectively in the BPR.


27

During this time period, there were five pregnancy outcomes reported from prospective North American participants. Four were live birth outcomes (one in a newly enrolled participant and three in participants enrolled in the previous period). One of those births was considered a preterm birth (born less than 370/7 weeks), and the infant, born at 366/7 weeks’ gestational age via caesarean section, had a reported congenital anomaly or birth defect. Two live births were considered early term births (born between 370/7 weeks and 386/7 weeks) and one was considered a full-term birth (born between 390/7 weeks and 406/7

weeks) [ACOG, 2013]. The fifth pregnancy outcome was a spontaneous miscarriage.

9.2 All registry data (prospective and retrospective data)

From 16 Jul 2012 through 08 Mar 2014, nine evaluable participants from North America had been enrolled into the BPR. An evaluable registry report is a case with data submitted or confirmed by a HCP that meets the minimum criteria for a registry report; for prospective reports, the pregnancy outcome is not known at the time of enrollment. One participant from Europe was enrolled retrospectively into the BPR.

Of the 10 participants (nine prospective and one retrospective) enrolled into the BPR, four (40.0%) participants are considered to be pure prospective cases, as the participants enrolled into the BPR prior to having any prenatal testing performed. Five (50.0%) cases are considered traditional prospective cases, as the women enrolled prior to knowing the outcome of the pregnancy but after having early routine screening through prenatal testing. One (10.0%) participant is considered a retrospective report of pregnancy, as the pregnancy ended (live birth, fetal loss) prior to enrollment or at the time of first contact with the BPR. All enrolled participants received a belimumab infusion during the four months prior to pregnancy (preconception); seven (77.8%) received at least one dose during the first trimester, two (22.2%) during the second trimester, and one (11.1%) during the third trimester. Exposure is defined as date of last infusion plus an additional four months, due to the drug’s half-life. All participants prospectively enrolled have SLE and continued to be exposed to belimumab during pregnancy: through the first trimester for seven (77.8%) participants, through the second trimester for two participants (22.2%), and through the third trimester for two (22.2%) participants.

Table 6 (Appendix 1) describes the current study enrollment status and analysis cohort distribution for prospective and retrospective reports of pregnancy. Two prospectively enrolled participants have pending outcomes, and no participants are considered lost to follow-up. Five (83.3%) of the six participants who had live births have completed their infant four-month follow-up visits. One (16.7%) participant who had a live birth has also completed the infant 12-month follow-up visit. Data collection for one participant who experienced a spontaneous miscarriage and for the one retrospective participant has been completed. These three cases are considered closed.

9.2.1 Excluded birth defects and other reported conditions

During an examination following a repeat caesarean section occurring at 391/7 weeks’ gestational age for one participant, an obstetrical provider’s assistant completed case report forms reporting there was a note in the participant’s chart written by the obstetrical provider stating that the participant’s infant had a diagnosis of Dandy Walker variant.


28

However, it was later confirmed by the obstetrical provider that this defect was not noted at pregnancy outcome, with further confirmation from the pediatrician six days after birth. The suspected Dandy Walker variant diagnosis was later confirmed to be a normal variant of mega cistern magna by the pediatrician. Therefore, Dandy Walker variant is not included as a defect or a solicited SAE in this report.

9.2.2 Cases lost to follow-up

No cases have been identified as lost to follow-up.

9.2.3 Invalid cases

Two cases have been considered invalid as they lacked confirmation from both the obstetric and belimumab prescriber HCPs to meet minimum criteria for enrollment. These cases are not included in the BPR analysis cohort. They have been included in the GSK Safety Database (OCEANS) and will be followed by routine pharmacovigilance by the Sponsor. See Table 21 (Appendix 1) for a description of the invalid cases.

9.2.4 Pregnancy participant demographics and baseline characteristics

Table 7 (Appendix 1) describes the demographics and baseline characteristics of the participants in the prospective and retrospective cohorts. Seven (77.8%) of the nine prospectively enrolled participants were in the 18- to 34-year age group, and two (22.2%) were in the 35- to 44-year age group. Eight (88.9%) prospectively enrolled participants were White or Caucasian, two of whom were of Hispanic ethnicity. One prospectively enrolled participant was Black or African American. One (100.0%) retrospectively enrolled participant was 21 years of age and White or Caucasian and of Hispanic ethnicity.

Eight (88.9%) of the nine prospectively enrolled participants entered the BPR during the first trimester of pregnancy, and one was enrolled in the second trimester of pregnancy. These nine prospective participants had a mean of 106/7 weeks’ gestational age at enrollment.

9.3 Prospective data

From 16 Jul 2012 through 08 Mar 2014, nine evaluable prospective participants from North America had been enrolled into the BPR. An evaluable prospective registry report is a case with data submitted or confirmed by an HCP that meets the minimum criteria for a registry report and for which the pregnancy outcome is not known.

9.3.1 Belimumab exposure

Table 8 (Appendix 1) describes the belimumab exposure overall and by timing of exposure for all prospectively enrolled participants and all participants with pregnancy outcomes. Overall exposure is presented by the number of doses recorded with non-missing treatment dates. The number of days exposed is calculated by adding four


29

months (120 days) to the non-missing exposure treatment date due to the half-life of the drug.

The nine prospectively enrolled participants were all exposed to belimumab within four months preconception. Date of treatment was missing for one participant. Therefore, the overall summaries for some time points in Table 8 exclude this participant. Overall, prospectively enrolled participants had a cumulative mean number of 5.8 doses over a mean of 252.6 days. Those participants with pregnancy outcomes had a mean number of 5.0 doses over a mean of 263.1 days.

Participants’ mean number of days of exposure were higher during the preconception time period than during pregnancy. Of those participants with pregnancy outcomes (n=7), five were exposed during the first trimester with a mean of 2.2 doses and a mean of 154 days exposed, two participants were exposed during the second trimester with a mean of 3.0 doses and a mean of 177.0 days exposed, and two participants were exposed during the third trimester with a mean of 2.5 doses and a mean of 162.0 days exposed. Only one participant with a pregnancy outcome was reported by the pediatrician to be exposed after outcome, while breastfeeding, with four doses and exposure for 207 days. Overall, information on belimumab exposure post-pregnancy outcome and during breastfeeding was incomplete as of the 08 Mar 2014 data lock date.

9.3.2 Other medication exposures

Table 9 (Appendix 1) summarizes exposure to other medications either within six months preconception or during pregnancy for all participants enrolled prospectively. Participants may be represented in one or several time points (preconception and during pregnancy). Participants may also have been exposed to one or several medications; therefore, percentages may not add to 100%. Overall, nine prospectively enrolled participants, including seven participants with pregnancy outcomes, had exposure to other medications preconception and during pregnancy. Drug names and classes are listed in Table 22 (Appendix 1). Three (42.9%) of the seven participants with pregnancy outcomes and five (55.6%) of the nine participants overall were exposed to corticosteroids both preconception and during pregnancy with mean doses <7.5 mg/day. Overall, two (22.2%) of the nine participants, both with severe lupus flares, were exposed to azathioprine preconception, and no participants were exposed during pregnancy.

Six (66.7%) of the nine participants were exposed to anti-malarial drugs both preconception and during pregnancy, and five (55.6%) participants were exposed to other immunosuppressants preconception (including azathioprine, methotrexate, and mycophenolate). Overall, less than half (44.4%) of the nine participants reported folate use preconception or during pregnancy.

Four (57.1%) of the seven participants with pregnancy outcomes were exposed to anti-malarial drugs preconception, four (57.1%) of the seven participants with pregnancy outcomes were exposed to other immunosuppressants preconception, and four (57.1%) of the seven participants with pregnancy outcomes reported folate use preconception or during pregnancy.


30

9.3.3 SLE disease severity

The PGA of SLE disease activity is a simple, concise, global index of disease activity that is completed at enrollment (including a preconception assessment), the end of the second trimester, and at pregnancy outcome for BPR participants with SLE.

The SDI records irreversible organ system damage occurring in participants with SLE regardless of etiology. Damage may be attributed to active SLE disease, concomitant medication, or intercurrent illness. The SDI is completed at enrollment but can be completed at any time during follow-up if the data are incomplete.

Table 10 (Appendix 1) summarizes the nine prospectively enrolled participants’ disease severity by each time point of data collection in the study. All participants presented were exposed to belimumab within four months prior to conception. During the preconception period, five (55.6%) participants had a PGA score of mild disease activity (PGA=1) and one (11.1%) had a PGA score of severe disease activity (PGA=3) preconception. Three (33.3%) participants had PGA assessments that were either missing or not done.

Upon enrollment, three (33.3%) participants had a PGA score of mild disease activity (PGA=1). One (11.1%) participant was reported for each of the other disease activity scores (none [PGA=0], moderate [PGA=2], severe [PGA=3]). Three (33.3%) participants had PGA assessments that were either missing or not done.

Of the eight participants who completed the second trimester follow-up assessment, three (37.5%) had a PGA score of mild disease activity (PGA=1). Five (62.5%) participants had PGA assessments that were either missing or not done for this time period.

Of the seven participants who had pregnancy outcomes, one (14.3%) had a PGA score of no disease activity (PGA=0) and two (28.6%) had a PGA score of mild disease activity (PGA=1). Four (57.1%) participants had PGA assessments that were either missing or not done at both the second trimester follow-up and pregnancy outcome.

The SDI was completed for four (44.4%) of the nine participants and was missing or not done for all other participants. A score of SDI=0 was reported for all participants for whom the SDI was completed.

9.4 Prospective pregnancy outcome results

From 16 Jul 2012 through 08 Mar 2014, seven prospective pregnancy outcomes were reported. A summary of the pregnancy outcomes is presented in Table 11 (Appendix 1).

Six (85.7%) live births and one (14.3%) spontaneous miscarriage occurred. All live births were delivered via caesarean section, and three (50.0%) live births were preterm births.

9.4.1 Spontaneous miscarriages

The spontaneous miscarriage occurring this period was reported as the outcome of a pregnancy for a 31-year-old participant who received belimumab for approximately seven months, with the last dose taken at 05/7 weeks’ gestational age, for a cumulative


31

total of eight doses. At 123/7 weeks’ gestational age, the participant was diagnosed with “fetal demise” by ultrasound and underwent dilation and evacuation, which corresponds to a protocol definition of spontaneous miscarriage. She was reported as having hypothyroidism preconception through pregnancy outcome by both the belimumab prescriber and the obstetrical HCPs. Preconception medication exposures included prednisone, methotrexate, folate, and anti-malarial drugs. At outcome, she had been prescribed anti-malarial drugs. Other medication exposures noted by the prescriber HCP included Celexa, Wellbutrin, Synthroid, Zofran, and prenatal vitamins. The belimumab prescriber HCP did not offer an opinion regarding the reasonable possibility of attribution of this event to belimumab.

9.4.2 Live birth outcomes

Seven prospective pregnancy outcomes were reported through 08 Mar 2014, resulting in six live births. Details regarding the six live births are presented in Table 12 (Appendix 1). Four (66.7%) infants were female, and the mean gestational age for the six live births was 366/7 weeks’ gestational age. Three (50.0%) of the six infants were considered preterm (born at <370/7 weeks’ gestational age), but no preterm births were considered to be attributed to belimumab. One (16.7%) preterm infant had a confirmed birth defect, Ebstein anomaly. Two (33.3%) infants had low birth weight (birth weight less than 2500 g), both preterm births, but no infants were considered SGA based on Williams 1982 reference data (protocol definition) [Williams, 1982]. During this reporting period, no serious and/or clinically significant infections, fevers of unknown origin, or fevers of known infectious etiology were reported for live births during infant follow-up.

9.4.3 Preterm births

Three (50.0%) of the six live births were considered preterm (born at less than 370/7

weeks’ gestational age). The characteristics of the participants with preterm births are presented in Table 13 (Appendix 1). The mean gestational age at birth for the preterm births was 352/7 weeks. The earliest belimumab exposure occurred preconception for this subset and the latest belimumab exposure occurred during the third trimester. Three (100.0%) of the participants that had preterm births were exposed to corticosteroids during pregnancy and three (100.0%) were also exposed to anti-malarial drugs during pregnancy.

PGA disease activity score was reported as mild (PGA=1) for all three (100.0%) participants at preconception, one each as none (PGA=0), mild (PGA=1), and moderate (PGA=2) at enrollment, two as mild (PGA=1) and one missing at end of second trimester, and one each as none (PGA=0), mild (PGA=1), and missing at outcome.

Pediatric HCPs confirmed that at four months of age (Table 13), there was one birth defect noted (Ebstein anomaly) among the preterm infants, and all met appropriate developmental milestones for fine motor skills, language, cognitive, and social/emotional areas. One (33.3%) preterm infant born at 360/7 weeks’ gestational age did not meet the appropriate developmental milestones for gross motor skills at the four-month follow-up


32

visit. This infant also completed the 12-month follow-up visit and did not meet the appropriate developmental milestones for gross motor skills, social/emotional, and language areas. However, the infant met the milestones for cognitive and fine motor skills at this visit.

During this reporting period, no serious and/or clinically significant infections, fevers of unknown origin, or fevers of known infectious etiology were reported for the preterm births during infant follow-up at four months and at 12 months for the infant who completed the 12-month visit.

9.4.4 Birth defects

As previously noted, one infant born preterm during this period was reported as having a birth defect. The 38-year-old, white, non-Hispanic participant received belimumab during preconception through the second trimester of pregnancy for a cumulative total of 16 doses. During preconception, she also received prednisone, aspirin, heparin, and anti-malarial drugs. Prednisone, aspirin, and anti-malarial drugs were continued throughout the pregnancy. The nulliparous participant was diagnosed with SLE at the age of 27 years; duration of SLE was 11 years. The SDI was not done, and the PGA disease activity score was reported as mild (PGA=1) at all time points: preconception and at enrollment, end of second trimester, and at outcome. A female infant was born at 366/7 weeks’ gestational age via caesarean section. On 09 Aug 2013, one day after birth, an echocardiogram of the infant revealed tricuspid valve regurgitation with possible mild Ebstein anomaly, patent ductus arteriosus, and patent foramen ovale. At approximately 11 weeks’ postnatal age on 25 Oct 2013, a repeat echocardiogram revealed minimal displacement of septal leaflet of tricuspid valve, indicating a diagnosis of very mild Ebstein anomaly of the tricuspid valve. The belimumab prescriber HCP reported relevant medical conditions and other possible risk factors potentially contributing to the event as SLE, lupus nephritis, presence of SSA antibodies, and antiphospholipid syndrome. It was also noted that the participant had elevated liver enzyme levels preconception through the first trimester of pregnancy, as well as proteinuria and hypothyroidism preconception through pregnancy outcome. The BDE was unable to rule out a temporal association between the belimumab exposure and the development of the observed defect. The BDE noted genetic factors as an alternative etiology and indicated that maternal age, prednisone exposure during pregnancy, and having an autoimmune disease are not known to be associated with this defect. The pediatric HCP reported a “reasonable possibility” that the observed defect was attributable to exposure to belimumab. The BDE also noted that this defect is a very mild functional cardiac defect and recommended follow-up in two years. Specifics for recommended follow-up were not provided.

9.4.5 Infant outcomes

Five (83.3%) of the six participants who had live births have completed their infant four-month follow-up visits (two full-term infants and three preterm infants) (Table 15). One participant was due for the four-month follow-up visit in Mar 2014; however, data collected for this assessment had not been received at the time of this report.

The two pediatric HCPs for the full-term infants confirmed that, at four months of age, the infants had no birth defects noted and that they met appropriate developmental


33

milestones for gross motor skills, fine motor skills, language, cognitive, and social/emotional areas.

The pediatric HCPs also noted that all preterm infants met the appropriate developmental milestones for fine motor skills, language, cognitive, and social/emotional areas at four months. One (33.3%) preterm infant born at 360/7 weeks’ gestational age did not meet the appropriate developmental milestones for gross motor skills at the four-month follow-up visit. This infant also completed the infant 12-month follow-up visit and did not meet the appropriate developmental milestones for gross motor skills, social/emotional, and language areas. However, the infant met the milestones for cognitive and fine motor skills at this visit.

Pediatric HCPs confirmed that, at four months of age (Table 14), there was one birth defect noted (Ebstein anomaly) among the preterm infants. It was also noted during this time period that this infant met all developmental milestones. The infant has yet to complete the 12-month follow-up assessment. During this reporting period, no serious and/or clinically significant infections, fevers of unknown origin, or fevers of known infectious etiology were reported for infant follow-up at both four months and 12 months.

9.5 Adverse events

A solicited adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product, which does not necessarily have a causal relationship with the treatment. An SAE is any AE that results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; or is a congenital anomaly/birth defect.

The following outcomes for the BPR objectives represent a number of potential serious/adverse drug experiences or events, which include but may not be limited to:

Reports of congenital anomalies in the fetus or infant

Reports of adverse pregnancy outcomes, including spontaneous miscarriages and stillbirths

Reports of solicited serious and/or other clinically significant infections in the infant

Reports of solicited SAEs in the mother or infant

Table 15 (Appendix 1) summarizes that from 16 Jul 2012 through 08 Mar 2014, among all registry participants (n=9), there was one report (11.1%) of a participant who experienced at least one solicited non-serious AE, and eight (88.9%) participants were reported as having experienced at least one solicited SAE. Among participants with pregnancy outcomes (n=7), one (14.3%) participant experienced a non-serious AE and all seven (100.0%) participants experienced solicited SAEs. The non-serious solicited AE report included vomiting, nausea, and insomnia for one participant with a pregnancy outcome.


34

There were a total of five solicited maternal SAEs and nine solicited infant SAEs reported for all participants enrolled prospectively.

The solicited maternal SAEs reported included heavy vaginal bleeding, placental abruption, lupus flare, pre-eclampsia, and postpartum hypertension. The solicited infant SAEs report included preterm birth (two reports), bilateral club foot as indicated during prenatal testing, nonreassuring fetal status, very mild Ebstein anomaly of tricuspid valve, fetal hydrops, supraventricular tachycardia, nonreassuring fetal heart rate, and intrauterine “fetal demise.”

No new important safety information regarding use in pregnancy has been identified from the registry or other cases received in the reporting period. The occurrence of SAB reported for patients exposed to belimumab during preconception/pregnancy in OCEANS was similar to background estimates in SLE patients (20%; Vinet 2011) or patients treated with biologic therapies (22%; Chakravarty 2011), although data remain limited.

9.6 Retrospective reports of pregnancy

From 16 Jul 2012 through 08 Mar 2014, one participant from Europe was enrolled retrospectively into the BPR.

The European retrospective participant enrolled during this period on 25 Nov 2013, approximately seven months after an elective termination of pregnancy. The participant received a cumulative total of four doses of belimumab, the last within four months prior to conception. The participant’s duration of SLE was 11 years, and the HCP belimumab prescriber reported that the participant had all ACR SLE criteria for classification of SLE except the neurologic disorder criterion. The participant was reported as having a history of positive anti-double-stranded (anti-ds) DNA and low complement component 3 (C3) complement component 4 (C4), but all were reported as normal at the most recent assessment. It was reported that the participant had a severe lupus flare and hypertension preconception and hypertension at the start of pregnancy. The PGA score was reported as mild (PGA=1) at preconception and at enrollment. The SDI was not done. Termination of her pregnancy at 53/7 weeks’ gestational age was recommended following an episode of severe pancreatic pseudocysts requiring surgery, which corresponds to a protocol definition of elective termination. The participant was exposed to belimumab within four months prior to conception, and the HCP belimumab prescriber indicated it was a “reasonable possibility” that the severe pancreatic pseudocysts event in the mother was attributable to belimumab. Other medication exposures noted by the HCP included hydroxychloroquine, prednisolone, and omeprazole. The timing of exposure for these medications was not specified.

10 DATA FROM OTHER SOURCES

10.1 Other non-registry reports of belimumab-exposed pregnancies

Thirty-four cases possibly related to administration of belimumab during pregnancy or lactation were received at Global Clinical Safety and Pharmacovigilance, GSK Research


35

and Development during the period of this report of 09 Sep 2013 to 08 Mar 2014. The search is based on Medical Dictionary for Regulatory Activities (MedDRA) Standardised MedDRA Queries Pregnancy and Neonatal Topics. In addition, all cases involving a pregnant woman are included. Cases involving females over 60 years of age and adult males (where the case was not reported as a partner pregnancy) have been excluded.

Of the 34 new cases of pregnancy reported during the period of this report, 14 were from clinical trials (11 blinded; three belimumab):

nine pregnancies ongoing

three elective terminations with NO apparent congenital anomaly


Of the remaining 20 cases (eight post-marketing surveillance; 12 spontaneous):

13 pregnancies ongoing

three live infant births with NO apparent congenital anomaly

two elective terminations with NO apparent congenital anomaly


Of the five elective terminations with no apparent congenital anomalies that were received during the reporting period, three of the five cases had no rationale provided for the termination, one case occurred in a woman with concurrent cysts, and the final elective termination occurred in conjunction with surgery for severe pancreatitis with pseudocysts. None of the women who underwent elective termination had reported complications.

The four reports of spontaneous abortion received during the reporting period occurred without complications at the following time points: three weeks (n=1), approximately eight weeks (n=2), and at an unspecified time within the first trimester (n=1).

Three subjects delivered live infants with no congenital anomaly during the reporting period.

During the time period covered in this report, there were 10 pregnancy cases received prior to the data lock point of this report that have received follow-up during the current period. Four cases lacked significant follow-up information and there were no changes in the reported outcomes; there were two reports of live birth with no congenital anomaly; and the last four cases were from the BPR (discussed below).

Pregnancy outcomes from both clinical and spontaneous report sources for the current reporting period and cumulative totals are summarized in Table 5.

Table 5. Pregnancy Outcomes (Excluding Partner Pregnancies) in OCEANS

Outcome1, 2 In Period (n) Cumulative (n)3 Live infant, no apparent congenital anomaly 3 43


36

Outcome1, 2 In Period (n) Cumulative (n)3 Live infant with congenital anomaly 0 5 Elective termination, no apparent congenital anomaly 5 27 Elective termination with congenital anomaly 0 0 Spontaneous abortion, no apparent congenital anomaly

4 30

Spontaneous abortion with congenital anomaly 0 0 Stillbirth, no apparent congenital anomaly 0 2 Stillbirth with congenital anomaly 0 0 Ectopic pregnancy 0 0 Molar pregnancy 0 0 Pregnancy ongoing, lost to follow-up or unknown 22 40 Total 34 147 1Changes in the numbers of the cumulative outcomes since the previous safety update reflect not only the addition of

new cases but also follow-up obtained on previously received cases. 2Pregnancy outcome categories stating “no apparent congenital anomaly” include outcomes where it is unknown

whether a congenital anomaly occurred. 3Six pregnancy outcomes were reported in placebo subjects: spontaneous abortion no apparent congenital anomaly

(n=3), elective termination no apparent congenital anomaly (n=2), and stillbirth no apparent congenital anomaly (n=1).

10.2 Literature review

MEDLINE and EMBASE were searched by BPR for literature reports of pregnancies exposed to belimumab. The following keywords and subject headings were used in the search:

Keywords where $ represents truncation:

gestation$

pregnan$

prenatal$

fetus

fetal

foetal

teratogen$

Subject Heading Terms:

Subject headings as entered in database:

parameters concerning the fetus, newborn and pregnancy/

pregnancy disorder/

prenatal exposure/

prenatal development/


37

prenatal exposure delayed effects/

exp pregnancy complications/

maternal exposure/

In a recent publication, it is noted that human pregnancy data are limited to unintended pregnancies that occurred during GSK’s placebo-controlled phase 2 and 3 studies. Patients received belimumab and standard therapy for SLE (corticosteroids, immunosuppressives, anti-malarial drugs, non-steroidal anti-inflammatory drugs [NSAIDs], or a combination thereof). The belimumab treatment was stopped immediately after learning of the pregnancy exposure, and the patient was removed from the trial. At this time, 83 pregnancies that occurred during these trials have known outcomes: 24% elective terminations, 27.7% spontaneous abortions, and 42% live births. Of the three congenital anomalies (rate of 3.6%) that developed in these pregnancies, one was a chromosomal translocation also found in the mother, and thus was unrelated to belimumab [Peart, 2014].

11 AWARENESS ACTIVITIES

Because participants are enrolled in this study on a voluntary basis, it is important that HCPs be aware that the BPR is ongoing. In order to increase awareness among the HCPs, the activities listed in Appendix 2 have been conducted through 08 Mar 2014, are ongoing, or are planned as future activities.

12 POTENTIAL BIAS

Since participation in the BPR is voluntary, BPR participants may not be representative of the overall SLE pregnant population. The most appropriate external comparator data and published literature available may be used to assist the interpretation of pregnancy outcome data from the BPR when applicable. Care is taken during data interpretation since external data may differ from BPR data with regard to factors other than belimumab exposure.

While the primary analysis population in the BPR is limited to pure prospective reports, some belimumab-exposed pregnancies are reported to the BPR after the pregnancy ends or following notification of an abnormal prenatal test result. In general, reports made to the BPR after the pregnancy has ended and/or notification of an abnormal prenatal test result are biased toward reporting of the severe and unusual cases and are not reflective of the general experience with the medication. Moreover, information about the total number of exposed persons is not known. Therefore, rates of outcomes cannot be calculated from these data. However, a series of reported birth defects can be evaluated to detect patterns of specific birth defects and can assist with identification of potential early signals of therapy risks.

As reporting of pregnancies is totally voluntary, it is possible that even in pure prospective reported cases, potential bias could exist. For example, high-risk pregnancies or low-risk pregnancies may be more likely to be reported. Those pregnancies that have reached the estimated date of delivery but for which pregnancy outcome information was unobtainable after multiple attempts are considered lost to follow-up. It is possible that


38

outcomes among pregnancies lost to follow-up could differ from those with documented outcomes. Because of differences in follow-up procedures across countries and individual reporting patterns, it is currently not possible to assess with any certainty what impact on potential bias the losses to follow-up may have on the analysis. However, efforts to compare some of the characteristics of each cohort may be undertaken in an attempt to address this potential source of bias.

Fetal losses for which no birth defects have been reported may introduce misclassification bias. The percentage of these pregnancies consisting of potentially normal outcomes or birth defects is unknown.

13 COMMITTEE CONSENSUS

On 08 Jul 2014, the SAC independently reviewed all data reported to the BPR as well as supplemental data and concluded that there is insufficient information at this time to reach a conclusion about the risk for birth defects and the secondary endpoints of interest for pregnancies exposed to commercially supplied belimumab.


39

14 REFERENCES

Alamanos Y, Voulgari PV, Siozos C, et al. Epidemiology of systemic lupus erythematosus in northwest Greece 1982-2001. J Rheumatol. 2003;30(4):731-5.

American College of Obstetricians and Gynecologists (AGOC). ACOG Committee Opinion No 579: Definition of term pregnancy. Obstet Gynecol. 2013;122(5):1139-40.

Andrade R, Sanchez ML, Alarcon GS, et al. Adverse pregnancy outcomes in women with systemic lupus erythematosus from a multiethnic US cohort: LUMINA (LV1). Clin Exp Rheumatol. 2008;26:268-74.

Baker KP, Edwards BM, Main SH, et al. Generation and characterization of LymphoStat B, a human monoclonal antibody that antagonizes the bioactivities of B lymphocyte stimulator. Arthritis Rheum. 2003;48(11):3253-65.

Balluz L, Philen R, Ortega L, et al. Investigation of systemic lupus erythematosus in Nogales, Arizona. Am J Epidemiol. 2001;154(11):1029-36.

Human Genome Sciences Inc. and GlaxoSmithKline. Belimumab (BENLYSTA™) Investigator’s brochure, version 12. King of Prussia, PA; 2014.

Benucci M, Del Rosso A, Li Gobbi F, et al. Systemic lupus erythematosus (SLE) in Italy: an Italian prevalence study based on a two-step strategy in an area of Florence (Scandicci-Le Signe). Med Sci Monit. 2005;11(9):CR420-5.

Centers for Disease Control and Prevention (CDC), Division of Birth Defects and Developmental Disabilities. Birth defects and genetic diseases branch 6-digit codes for reportable congenital anomalies. Available from: http://www.cdc.gov/ncbddd/bd/documents/MACDPcode%200807.pdf. Updated August 2007. Accessed August 27, 2010.

Chakravarty EF, Murray ER, et al. Pregnancy outcomes after maternal exposure to rituximab. bloodjournal.hematologylibrary.org. 2011;1499-1506.

Clark CA, Spitzer KA, Nadler JN, et al. Pre-term deliveries in women with systemic lupus erythematosus. J Rheumatol. 2003; 30:2127-32.

Clowse ME, Magder LS, Witter F et al. The impact of increased lupus activity on obstetric outcomes. Arthritis Rheum. 2005;52(2):514-21.

Cortes-Hernandez J, Ordi-Ros J, Paredes F, et al. Clinical predictors of fetal and maternal outcome in systemic lupus erythematosus: a prospective study of 103 pregnancies. Rheumatology. 2002; 41(6):643-50.

Council for International Organizations of Medical Sciences (CIOMS) Working Groups III (revised) and V (new). Guidelines for preparing core clinical-safety information on drugs. 2nd ed. Geneva, Switzerland: World Health Organization, 1999.


40

Danchenko N, Satia JA, Anthony MS. Epidemiology of systemic lupus erythematosus: a comparison of worldwide disease burden. Lupus. 2006;15(5):308-18.

de Onis M, Habicht JP. Anthropometric reference data for international use: recommendations from a World Health Organization Expert Committee. Am J Clin Nutr 1996; 64(4):650-8.

Eilertsen GO, Becker-Merok A, Nossent HC. Increasing prevalence of systemic lupus erythematosus in northern Norway due to stable incidence and mortality. 70th Annual Scientific Meeting of the American College of Rheumatology/41st Annual Scientific Meeting of the Association of Rheumatology Health Professionals; November 10 -15, 2006; Washington, DC. Arthritis Rheum; 2006; 54(9 Suppl S):100.

European Surveillance of Congenital Anomalies (EUROCAT). Prevalence tables. Cases and prevalence (per 10,000 births) for all full member registries form 2008 to 2012. http://www.eurocat-network.eu/accessprevalencedata/prevalencetables. Accessed June 13, 2014

Gourley IS, Patterson CC, Bell AL. The prevalence of systemic lupus erythematosus in Northern Ireland. Lupus. 1997;6(4):399-403.

Govoni M, Castellino G, Bosi S, et al. Incidence and prevalence of systemic lupus erythematosus in a district of north Italy. Lupus. 2006;15(2):110-3.

Gudmundsson S, Steinsson K. Systemic lupus erythematosus in Iceland 1975 through 1984. A nationwide epidemiological study in an unselected population. J Rheumatol.1990;17(9):1162-7.

Helmick CG, Felson DT, Lawrence RC, et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part I. Arthritis Rheum. 2008;58(1):15-25.

Hopkinson ND, Doherty M, Powell RJ. The prevalence and incidence of systemic lupus erythematosus in Nottingham, UK, 1989-1990. Br J Rheumatol. 1993;32(2):110-5.

Johnson AE, Gordon C, Palmer RG, et al. The prevalence and incidence of systemic lupus erythematosus in Birmingham, England. Relationship to ethnicity and country of birth. Arthritis Rheum. 1995;38(4):551-8.

Julkunen H, Jouhikainen T, Kaaja R, et al. Fetal outcome in lupus pregnancy: a retrospective case-control study of 242 pregnancies in 112 patients. Lupus. 1993;2(2):125-31.

López P, Mozo L, Gutiérrez C, et al. Epidemiology of systemic lupus erythematosus in a northern Spanish population: gender and age influence on immunological features. Lupus. 2003;12(11):860-5.

Naleway AL, Davis ME, Greenlee RT, et al. Epidemiology of systemic lupus erythematosus in rural Wisconsin. Lupus. 2005;14(10):862-6.


41

Nightingale AL, Farmer RD, de Vries CS. Systemic lupus erythematosus prevalence in the UK: methodological issues when using the General Practice Research Database to estimate frequency of chronic relapsing-remitting disease. Pharmacoepidemiol Drug Saf. 2007;16(2):144-51.

Nossent HC. Systemic lupus erythematosus in the Arctic region of Norway. J Rheumatol. 2001;28(3):539-46.

Peart E, Clowse ME. Systemic lupus erythematosus and pregnancy outcomes: an update and review of the literature. Curr Opin Rheumatol. 2014;26(2):118-23.

Piette J-C, Papo T, Amoura Z, et al. Lupus érythémateux systémique. In: Godeau P, Herson S, Piette J-C, eds. Traité de Médecine. 4ème ed. Paris: Médecine Sciences Flammarion; 2004:142-7.

Rahman P, Gladman DD, Urowitz MB. Clinical predictors of fetal outcome in systemic lupus erythematosus. J Rheumatol. 1998; 25(8):1526-30.

Samanta A, Roy S, Feehally J, et al. The prevalence of diagnosed systemic lupus erythematosus in whites and Indian Asian immigrants in Leicester city, UK. Br J Rheumatol. 1992;31(10):679-82.

Smyth A, Oliveira GH, Lahr BD, et al. A systematic review and meta-analysis of pregnancy outcomes in patients with systemic lupus erythematosus and lupus nephritis. Clin J Am Soc Nephrol. 2010;5(11):2060-8.

Somers EC, Lewis EE, Francis S, et al. Michigan Lupus Epidemiology & Surveillance (MILES) program: preliminary prevalence estimates for SLE in southeastern Michigan, 2002-2005. Presented at: American College of Rheumatology 70th Annual Scientific Meeting; November 7-11, 2007; Boston, MA.

Ståhl-Hallengren C, Jönsen A, Nived O, Sturfelt G. Incidence studies of systemic lupus erythematosus in Southern Sweden: increasing age, decreasing frequency of renal manifestations and good prognosis. J Rheumatol. 2000;27(3):685-91.

Uramoto KM, Michet CJ Jr, Thumboo J, et al. Trends in the incidence and mortality of systemic lupus erythematosus, 1950-1992. Arthritis Rheum. 1999;42(1):46-50.

Vinet E, Clarke AE, et al. Decreased Live Births in Women With Systemic Lupus Erythematosus. American College of Rheumatology. 2011;1068-1072.

Voss A, Green A, Junker P. Systemic lupus erythematosus in Denmark: clinical and epidemiological characterization of a county-based cohort. Scand J Rheumatol. 1998;27(2):98-105.

Ward MM. Prevalence of physician-diagnosed systemic lupus erythematosus in the United States: results from the third National Health and Nutrition Examination Survey. J Womens Health (Larchmt). 2004;13(6):713-8.


42

Williams RL, Creasy RK, Cunningham, GC, et al. Fetal growth and perinatal viability in California. Obstet Gynecol 1982;59(5):624-32.

Yasmeen S, Wilkins EE, Field NT, et al. Pregnancy outcomes in women with systemic lupus erythematosus. J Matern Fetal Med. 2001;10(2): 91-6.

APPENDICES

Appendix 1. Additional Tables

Table 6. Participant Enrollment: All Enrolled Participants (N=10)

Participant Enrollment Prospective (SLE)

Cohort (N=9)

Retrospective Cohort1 (N=1)

Total number of pregnancies enrolled n=9 n=1 Pregnancies pending pregnancy outcomes 2(22.2%) 0 Participants with live births pending infant follow-up 5(55.6%) 0 Lost to follow-up/participant withdrew consent prior to pregnancy outcome

0

0

Lost to follow-up/participant withdrew consent post- pregnancy outcome data (at time of birth)

0

0

Completed registry participation2 2 1 Spontaneous miscarriage/stillbirth3 1(50.0%) 0 Elective termination3 0 1(100.0%) Completed live birth follow-up data3 1(50.0%) 0 Infant follow-up status Live birth n=6 n=0 4-month follow-up data complete4 5(83.3%) 0 12-month follow-up data complete4 1(16.7%) 0 Note: No participants have re-enrolled with a sequential pregnancy. Denominator is the total number of participants in

each column (N). SLE=systemic lupus erythematosus. 1Retrospective cases are pregnant participants reporting to the Belimumab Pregnancy Registry after exposure to

belimumab with known pregnancy outcomes at the time of enrollment (i.e., abnormal prenatal test result, adverse pregnancy outcome, or infant with congenital anomaly), and are not included in the primary analysis.

2Completed registry participation is defined as (1) spontaneous miscarriage or a stillbirth, (2) elective termination, (3) pregnancy loss, or (3) live birth with follow-up completed through month 12.

3Denominator is the number of participants completing the registry. 4Denominator is the number of live births.


43

Table 7. Demographics and Baseline Characteristics of Pregnancy Participants:

All Enrolled Participants (N=10)

Prospective (SLE) Cohort (N=9)

Retrospective Cohort (N=1)

Age at enrollment (years) n=9 n=1 Mean (SD) 29.4 (5.6) 21 Median 30 21 Min – max 20 – 37 21 - 21 Q1, Q3 27.0, 33.0 21.0, 21.0 Age group at enrollment (years) <18 0 0 18 – 34 7(77.8%) 1(100.0%) 35 – 44 2(22.2%) 0 >44 0 0 Duration of SLE (years) n=9 n=1 Mean (SD) 12.3(6.3) 11.0 Median 12 11 Min – max 3 – 26 11 – 11 Q1, Q3 9.0, 14.0 11.0, 11.0 Race American Indian or Alaska Native 0 0 Asian 0 0 Black or African American 1(11.1%) 0 Native Hawaiian or Other Pacific Islander 0 0 White or Caucasian 8(88.9%) 1(100.0%) Other 0 0 Multi-racial1 0 0 Ethnicity Hispanic or Latino 2(22.2%) 1(100.0%) Not Hispanic or Latino 7(77.8%) 0 Region North America 9(100.0%) 0 Europe 0 1(100.0%) Height (in) n=9 n=1 Mean (SD) 63.6 (2.6) 61.0 Median 65 61 Min – max 60 – 67 61 – 61


44


Retrospective Cohort (N=1)

Q1, Q3 61.0, 65.0 61.0, 61.0 Pre-pregnancy weight (kg) n=8 n=1 Mean (SD) 67.0 (11.0) 60.0 Median 65.1 60.0 Min – max 53.6 – 86.3 60 – 60 Q1, Q3 59.0, 73.8 60.0, 60.0 Missing n=1 n=0 Pre-pregnancy body mass index (kg/m2)2 n=8 n=1 Mean (SD) 25.8 (3.2) 25.0 Median 25.9 25.0 Min – max 21.6 – 30.7 25 – 25 Q1, Q3 23.1, 27.9 25.0, 25.0 Missing n=1 n=0 Trimester of enrollment3 First 8(88.9%) N/A Second 1(11.1%) Third 0 Gestational age at enrollment (weeks) n=9 N/A Mean (SD) 106/7 (42/7) Median 100/7 Min – max 50/7 – 210/7 Q1, Q3 90/7, 120/7 Note: Denominator is the total number of participants in each column (N). “n” is the number of non-missing responses. max=maximum; min=minimum; N/A=not applicable; Q=quartile; SD=standard deviation; SLE= systemic lupus erythematosus. 1 If the woman has more than one race assigned, then race is summarized under multi-racial. 2 Body mass index is calculated based on pre-pregnancy weight. 3 First trimester begins day after date of conception, second trimester begins at week 14 after the date of conception or last menstrual period (14 - 27 weeks and 6 days), and the third trimester begins at week 28.


45

Table 8. Belimumab Treatment Exposure: All Prospectively Enrolled Participants

(N=9)


All Participants

(n=9)

Participants with Pregnancy Outcomes

(n=7) Commercially supplied belimumab dosage 10 mg/kg 9(100.0%) 7(100.0%) Earliest belimumab exposure1 Prior (>4 months prior to conception) 2(22.2%) 2(28.6%) Preconception (within 4 months prior to conception) 7(77.8%) 5(71.4%) 1st trimester 0 0 2nd trimester 0 0 3rd trimester 0 0 Last belimumab exposure by treatment date2 Preconception (within 4 months prior to conception) 2(22.2%) 2(28.6%) 1st trimester 5(55.6%) 3(42.9%) 2nd trimester 0 0 3rd trimester 1(11.1%) 1(14.3%) Post pregnancy 1(11.1%) 1(14.3%) Last belimumab exposure (treatment date + 4 months)3 Preconception (within 4 months prior to conception) 0 0 1st trimester 1(11.1%) 1(14.3%) 2nd trimester 6(66.7%) 4(57.1%) 3rd trimester 0 0 Post pregnancy 2(22.2%) 2(28.6%) Prior (>4 months prior to conception) cumulative number of doses4

N 1 1 Mean (SD) 1.0(0) 1.0(0) Median 1.0 1.0 Min – max 1.0 – 1.0 1.0 – 1.0 Q1, Q3 1.0, 1.0 1.0, 1.0 Prior (>4 months prior to conception) total estimated exposure (days) (n=1)4

N 1 1 Mean (SD) 120.0(0) 120.0(0) Median 120.0 120.0


46


All Participants

(n=9)


(n=7) Min – max 120.0 – 120.0 120.0 – 120.0 Q1, Q3 120.0, 120.0 120.0, 120.0 Overall (preconception through 3rd trimester) cumulative number of doses4

N 9 7 Mean (SD) 5.8(4.4) 5.0(5.1) Median 4.0 4.0 Min – max 1.0 – 14.0 1.0 – 14.0 Q1, Q3 3.0, 6.0 2.0, 12.0 Overall (preconception through 3rd trimester) total estimated exposure (days)4

N 9 7 Mean (SD) 252.6(125.8) 263.1(141.3) Median 204.0 204.0 Min – max 120.0 – 484.0 120.0 – 484.0 Q1, Q3 175.0, 274.0 153.0, 429.0 Preconception (within 4 months prior to conception) cumulative number of doses4

N 8 6 Mean (SD) 3.5(1.1) 3.3(1.0) Median 3.0 3.0 Min – max 2.0 – 5.0 2.0 – 5.0 Q1, Q3 3.0, 4.5 3.0, 4.0 Preconception (within 4 months prior to conception) total estimated exposure (days)4

N 8 6 Mean (SD) 183.4(26.7) 182.8(21.3) Median 177.0 177.0 Min – max 148.0 – 222.0 153.0 – 211.0 Q1, Q3 164.0, 207.5 175.0, 204.0 Pregnancy (1st, 2nd, 3rd trimesters) cumulative number of doses

N 7 5 Mean (SD) 3.4(4.2) 4.4(4.7) Median 1.0 1.0 Min – max 1.0 – 10.0 1.0 – 10.0


47


All Participants

(n=9)


(n=7) Q1, Q3 1.0, 9.0 1.0, 9.0 Pregnancy (1st, 2nd, 3rd trimesters) total estimated exposure (days)

N 7 5 Mean (SD) 188.3(116.9) 215.6(131.2) Median 120.0 120.0 Min – max 120.0 – 372.0 120.0 – 372.0 Q1, Q3 120.0, 346.0 120.0, 346.0 1st trimester cumulative number of doses N 7 5 Mean (SD) 1.9(1.5) 2.2(1.6) Median 1.0 1.0 Min – max 1.0 – 4.0 1.0 – 4.0 Q1, Q3 1.0, 4.0 1.0, 4.0 1st trimester total estimated exposure (days) N 7 5 Mean (SD) 144.3(41.5) 154.0(46.6) Median 120.0 120.0 Min – max 120.0 – 206.0 120.0 – 206.0 Q1, Q3 120.0, 204.0 120.0, 204.0 2nd trimester cumulative number of doses N 2 2 Mean (SD) 3.0(0) 3.0(0) Median 3.0 3.0 Min – max 3.0 – 3.0 3.0 – 3.0 Q1, Q3 3.0, 3.0 3.0, 3.0 2nd trimester total estimated exposure (days) N 2 2 Mean (SD) 177.0(1.4) 177.0(1.4) Median 177.0 177.0 Min – max 176.0 – 178.0 176.0 – 178.0 Q1, Q3 176.0, 178.0 176.0, 178.0 3rd trimester cumulative number of doses N 2 2 Mean (SD) 2.5(0.7) 2.5(0.7)


48


All Participants

(n=9)


(n=7) Median 2.5 2.5 Min – max 2.0 – 3.0 2.0 – 3.0 Q1, Q3 2.0, 3.0 2.0, 3.0 3rd trimester total estimated exposure (days) N 2 2 Mean (SD) 162.0(19.8) 162.0(19.8) Median 162.0 162.0 Min – max 148.0 – 176.0 148.0 – 176.0 Q1, Q3 148.0, 176.0 148.0, 176.0 Post pregnancy cumulative number of doses N 1 1 Mean (SD) 4.0(0) 4.0(0) Median 4.0 4.0 Min – max 4.0 – 4.0 4.0 – 4.0 Q1, Q3 4.0, 4.0 4.0, 4.0 Post pregnancy total estimated exposure (days) N 1 1 Mean (SD) 207(0) 207(0) Median 207.0 207.0 Min – max 207.0 – 207.0 207.0 – 207.0 Q1, Q3 207.0, 207.0 207.0, 207.0 Note: ”n” is the number of non-missing responses. Prior defined as period prior to preconception; Preconception

defined as 4 months prior to conception; Post defined as period after outcome. Max=maximum; min=minimum; Q=quartile; SD=standard deviation; SLE=systemic lupus erythematosus.

1 The first trimester begins the day after date of conception, the second trimester begins at week 14 after the date of conception or last menstrual period, and the third trimester begins at week 28.

2 Defined by the last recorded exposure with a non-missing treatment date. 3 Defined by the last recorded exposure with a non-missing treatment date plus 120 days to account for the half-life. 4 Data for one participant are excluded due to missing treatment dates during the time period greater than 4 months

prior to conception and during preconception (within 4 months prior to conception).


49

Table 9. Other Medication Exposure: All Prospectively Enrolled Participants (N=9)

All Participants

Period of Observation

Participants with Pregnancy Outcomes Period of Observation

Exposure Preconception

(n=9)

Exposure During Pregnancy

(n=9)

Exposure Preconception

(n=7)

Exposure During Pregnancy

(n=7) Corticosteroids 6(66.7%) 6(66.7%) 4(57.1%) 4(57.1%) ≥7.5 mg/day (at least one dose) 1 2(22.2%) 3(33.3%) 1(14.3%) 2(28.6%) <7.5 mg/day (at least one dose) 1 5(55.6 %) 5(55.6%) 3(42.9%) 3(42.9%) Other immunosuppressants2 5(55.6%) 0 4(57.0%) 0 Azathioprine 2(22.2%) 0 1(14.3%) 0 Cyclophosphamide 0 0 0 0 Cyclosporine 0 0 0 0 Methotrexate 2(22.2%) 0 2(28.6%) 0 Mycophenolate 1(11.1%) 0 1(14.3%) 0 Rituximab 0 0 0 0 Other medications NSAIDs 4(44.4%) 2(22.2%) 4(57.1%) 2(28.6%) Anti-malarial drugs 6(66.7%) 6(66.7%) 4(57.1%) 5(71.4%) Folate 4(44.4%) 4(44.4%) 4(57.1%) 4(57.1%) ACE inhibitors 2(22.2%) 1(11.1%) 2(28.6%) 1(14.3%) Calcium channel blockers 0 0 0 0 Beta blockers 0 0 0 0 Angiotensin II receptor antagonists 0 0 0 0 Statins 0 0 0 0 Antiretroviral therapy 0 0 0 0 Insulin 0 0 0 0 Oral hypoglycemic agent 0 0 0 0 Heparin 1(11.1%) 1(11.1%) 1(14.3%) 1(14.3%) Aspirin 2(22.2%) 2(22.2%) 2(28.6%) 2(28.6%) Epilepsy medication 0 0 0 0 Progesterone 0 0 0 0 Estrogen 0 0 0 0


50

Note: Exposure is defined as at least one dose during the period of observation (6 months prior to/during pregnancy) and does not imply continued use throughout the period of observation. Preconception is defined as six months prior to pregnancy. Denominator is the total number of participants in each column (N). Participants may be presented in one or several time points and may be exposed to one or several medications; therefore, percentages may not add to 100%. ACE inhibitors=angiotensin-converting-enzyme inhibitors; NSAIDs=non-steroidal anti-inflammatory drugs.

1 Data are not mutually exclusive. 2 Includes azathioprine, cyclophosphamide, methotrexate, mycophenolate, cyclosporine, rituximab.

Table 10. Disease Severity by Earliest Trimester of Exposure: All Prospectively Enrolled Participants (N=9)

Participants Exposed Within 4 Months Preconception

(N=9) PGA disease activity - preconception (6 months prior) 0 = None 0 1 = Mild 5(55.6%) 2 = Moderate 0 3 = Severe 1(11.1%) Missing or not done 3(33.3%) PGA disease activity (enrollment) 0 = None 1(11.1%) 1 = Mild 3(33.3%) 2 = Moderate 1(11.1%) 3 = Severe 1(11.1%) Missing or not done 3(33.3%) PGA disease activity (2nd trimester)1,2 0 = None 0 1 = Mild 3(37.5%) 2 = Moderate 0 3 = Severe 0 Missing or not done 5(62.5%) PGA disease activity (outcome)3 0 = None 1(14.3%) 1 = Mild 2(28.6%) 2 = Moderate 0 3 = Severe 0 Missing or not done 4(57.1%) SLICC/ACR Damage Index – SDI (enrollment) n=4 Mean (SD) 0 Median 0


51

Participants Exposed Within 4 Months Preconception

(N=9) Min – max 0 – 0 Q1, Q3 (0, 0) Missing or not done 5

Note: “n” is the total number of non-missing responses. ACR= American College of Rheumatology; max=maximum; min=minimum; Q=quartile; PGA=physician global assessment; SD= standard deviation;

SDI=SLICC/American College of Rheumatology Damage Index; SLICC=Systemic Lupus International Collaborating Clinics. 1 First trimester begins day after date of conception, second trimester begins at week 14 after the date of conception or last menstrual period, and the third trimester begins at week 28. 2 Denominator is number of participants completing 2nd trimester follow-up (n=8), spontaneous miscarriage deleted from denominator. 3 Denominator is number of participants with pregnancy outcomes (n=7).

Table 11. Pregnancy Outcomes: All Prospectively Enrolled Participants (N=9)

Pregnancy Outcomes

Newly Reported Outcome Data through 08 Mar 2014

(n=5)

Cumulative Reported Outcome Data from 12 Jul 2012

(n=9) Number of participants with pregnancy outcomes 5(100.0%) 7(77.8%) Live birth, n (%)1 4(80.0%) 6(85.7%) Singleton, n (%)2 4(100.0%) 6(100.0%) Twin, n (%)2 0 0 Triplet, n (%)2 0 0 Delivery method n=4 n=6 Normal vaginal, n (%)2 0 0 Caesarean, n (%)2 4(100.0%) 6(100.0%) Birth defect noted, n (%)2,3 1(25.0%) 1(16.7%) Neonatal death, n (%)2 0 0 Elective termination, n (%)1 0 0 Fetal loss, n (%)1,4 1(20.0%) 1(14.3%) Spontaneous miscarriage (<20 weeks), n (%) 5,6 1(100.0%) 1(100.0%) Stillbirth (≥20 weeks), n (%)6 0 0 Ectopic pregnancy, n (%)6 0 0 Molar pregnancy, n (%)6 0 0 Note: “n” is the total number of non-missing responses. 1 Denominator is the number of participants with pregnancy outcomes. 2 Denominator is the number of live births. Each infant of a multiple live birth will be counted separately.


52

3 Defect noted: Very mild Ebstein anomaly of the tricuspid valve. 4 Fetal loss is a combination of spontaneous miscarriage, stillbirth, ectopic pregnancy, and molar pregnancy events. 5 Participants with pregnancy outcomes at <200/7 weeks’ gestational age. 6 Denominator is the number of fetal losses.


53

Table 12. Live Birth Outcomes by Earliest Trimester of Exposure Live Birth

Characteristics: All Prospectively Enrolled Participants with Live Birth Outcomes (N=6) – Cumulative Reporting Period

Live Birth Characteristics

Live Births Exposed Within 4 Months Preconception

(n=6) Gender Male 2(33.3%) Female 4(66.7%) Gestational age at birth (weeks) n=6 Mean (SD) 366/7 (22/7) Median 376/7 Min – max 325/7 – 391/7 Q1, Q3 360/7, 382/7 Term (≥370/7 weeks) 3(50.0%) Early term (370/7 weeks – 386/7 weeks) 2(66.7%) Full term (390/7 weeks – 406/7 weeks) 1(33.3%) Late term (410/7 weeks – 416/7 weeks) 0 Post term (≥420/7 weeks) 0 Preterm1 (<370/7 weeks) 3(50.0%) Male 1(33.3%) Female 2(66.7%) Low birth weight2 (all births) 2(33.3%) Male 1(50.0%) Female 1(50.0%) Full-term low birth weight2 0 Preterm low birth weight2 2(33,3%) Male 1(50.0%) Female 1(50.0%) Small for gestational age3 0 Male 0 Female 0 Note: Each infant of a multiple live birth is counted separately. “n” is the total number of non-missing responses.

Max=maximum; min=minimum; Q=quartile; PGA=physician global assessment; SD= standard deviation; 1 Preterm is defined as delivery <370/7 gestational weeks. 2 Low birth weight is defined as a birth weight less than 2500 grams among infants. Full-term low birth weight defined

as infants born at ≥370/7 weeks’ gestational age weighing less than 2500 grams. Preterm low birth weight is defined as infants born at <370/7 weeks’ gestational age weighing less than 2500 grams.


54

3 Small for gestational age is defined as live births whose birth weight lies below the 10th percentile for that gestational age based on Williams 1982 reference data [Williams, 1982].


55

Table 13. Preterm Birth Outcomes by Earliest Trimester of Exposure - Preterm

Birth Characteristics: All Prospectively Enrolled Participants with Preterm Birth Outcomes (N=3) – Cumulative Reporting Period

Preterm Birth Characteristics

Preterm Births Exposed Within 4 Months Preconception

(n=3) Gender Male 1(33.3%) Female 2(66.7%) Gestational age at birth (weeks)1 n=3 Mean (SD) 352/7 (16/7) Median 360/7 Min – max 325/7, 366/7 Q1, Q3 342/7, 363/7 Preterm low birth weight2 2 (66.7%) Male 1(50.0%) Female 1(50.0%) Small for gestational age3 0 Male 0 Female 0 Earliest belimumab exposure4 Prior (>4 months prior to conception) 0 Preconception (within 4 months prior to conception)

3(100.0%)

1st trimester 0 2nd trimester 0 3rd trimester 0 Last belimumab exposure by treatment date5

Preconception (within 4 months prior to conception)

1(33.3%)

1st trimester 1(33.3%) 2nd trimester 0 3rd trimester 0 Post pregnancy 1(33.3%) Last belimumab exposure (treatment date + 4 months)6

Preconception (within 4 months prior


56



(n=3) to conception) 0 1st trimester 1(33.3%) 2nd trimester 1(33.3%) 3rd trimester 0 Post pregnancy 1(33.3%) Other exposures during pregnancy7 Corticosteroids 3(100.0%) NSAIDs 1(33.3%) Other immunosuppressants 0 Anti-malarial drugs 3(100.0%) PGA disease activity –preconception (6 months prior)

0 = None 0 1 = Mild 3(100.0%) 2 = Moderate 0 3 = Severe 0 PGA disease activity (enrollment) 0 = None 1(33.3%) 1 = Mild 1(33.3%) 2 = Moderate 1(33.3%) 3 = Severe 0 PGA disease activity (2nd trimester) 0 = None 0 1 = Mild 2(66.7%) 2 = Moderate 0 3 = Severe 0 Missing or not done 1(33.3%) PGA disease activity (outcome) 0 = None 1(33.3%) 1 = Mild 1(33.3%) 2 = Moderate 0 3 = Severe 0 Missing or not done 1(33.3%) Comorbidities during pregnancy8 Hyperthyroidism 1(33.3%) Hypothyroidism 1(33.3%) Placenta abruption 1(33.3%)


57



(n=3) Proteinuria 2(66.7%) Abnormal laboratory tests, ever?

Anti-ds DNA Yes 1(33.3%) Low C3/C4 Yes 2(66.7%) Anticardiolipin antibodies IgG Yes 2(66.7%) IgM Yes 1(33.3%) IgA Yes 1(33.3%) Anti-Ro+ Yes 1(33.3%) Anti-La+ Yes 0 LAC Yes 0 Note: Each infant of a multiple live birth is counted separately. “n” is the total number of non-missing responses. Anti-

ds=anti-double-stranded; LAC=lupus anticoagulant; max=maximum; min=minimum; Q=quartile; NSAIDs=non-steroidal anti-inflammatory drugs; PGA=physician global assessment; SD= standard deviation.

1Preterm is defined as delivery <370/7 weeks’ gestational age; late preterm is defined as 340/7 and 366/7 weeks’ gestational age. One infant was born at 325/7 weeks’ gestational age and two were late preterm at 360/7 weeks’ gestational age and 366/7 weeks’ gestational age.

2Low birth weight is defined as a birth weight less than 2500 grams among infants. Full-term low birth weight defined as infants born at ≥370/7 weeks’ gestational age weighing less than 2500 grams. Preterm low birth weight is defined as infants born at <370/7 weeks’ gestational age weighing less than 2500 grams.

3Small for gestational age is defined as live births whose birth weight lies below the 10th percentile for that gestational age based on Williams 1982 reference data [Williams, 1982].

4 The first trimester begins the day after date of conception, the second trimester begins at week 14 after the date of conception or last menstrual period, and the third trimester begins at week 28.

5 Defined by the last recorded exposure with a non-missing treatment date. 6 Defined by the last recorded exposure with a non-missing treatment date plus 120 days to account for the half-life. 7Includes azathioprine, cyclophosphamide, methotrexate, mycophenolate, cyclosporine, rituximab. 8Only those comorbidities present are included.


58

Table 14. Infant Outcomes – Cumulative Reporting Period

At Live Birth Outcome

(n=6)

At 4-Months Follow-Up

(n=5)

At 12-Months Follow-Up

(n=1)

Breastfeeding1 Infant ever breastfed, yes 2(33.3%) 5(100.0%) 1(100.0%) Unknown 4(66.7%) 0 0 Infant currently breastfed, yes

1(16.7%) 4(80.0%) 0

No 0 1(20.0%) 1(100.0%) Unknown 5(83.3%) 0 0 Infant exposed via breast milk, yes

0 0 0

Unknown 6(100.0%) 5(100.0%) 1(100.0%) Infant meeting appropriate developmental milestones

All live births n=5 n=1 Gross motor skills, yes -- 4(80.0%) 0 No -- 1(20.0%) 1(100.0%) Fine motor skills, yes -- 5(100.0%) 1(100.0%) Cognitive, yes -- 5(100.0%) 1(100.0%) Social/emotional, yes -- 5(100.0%) 0 No -- 0 1(100.0%) Language, yes -- 5(100.0%) 0 No -- 0 1(100.0%) Full-term births1 n=2 n=0 Gross motor skills, yes -- 2(100.0%) 0 Fine motor skills, yes -- 2(100.0%) 0 Cognitive, yes -- 2(100.0%) 0 Social/emotional, yes -- 2(100.0%) 0 Language, yes -- 2(100.0%) 0 Preterm births2 n=3 n=1 Gross motor skills, yes -- 2(66.7%) 0 No -- 1(33.3%) 1(100.0%) Fine motor skills, yes -- 3(100.0%) 1(100.0%) Cognitive, yes -- 3(100.0%) 1(100.0%) Social/emotional, yes -- 3(100.0%) 0 No 0 1(100.0%) Language, yes -- 3(100.0%) 0 No -- 0 1(100.0%) 1Full-term is defined as infants born ≥370/7 weeks’ gestational age. 2Preterm is defined as delivery <370/7 weeks’ gestational age; late preterm is defined as 340/7 and 366/7 weeks’

gestational age. One infant was born at 325/7 weeks’ gestational age and two were late preterm at 360/7 weeks’ and 366/7 weeks’ gestational age. Postmenstrual age as defined by the gestational age at outcome; the timing of the follow-up assessment was 3.1 months at the four-month assessment and 11.2 months for the infant


59

completing the registry. Post menstrual age was 2.9 months and 3.4 months for the two infants completing the four-month assessment only.

Table 15. Reports of Solicited Adverse and Serious Adverse Events: All

Prospectively Enrolled Participants (N=9) – Cumulative Reporting Period

All

Participants (N=9)

Participants With

Pregnancy Outcomes (N=7)

Number of participants with at least one solicited nonserious AE report

1(11.1%) 1(14.3%)

Number of participants with at least one solicited SAE report1

8(88.9%) 7(100.0%)

Number of participants with at least one solicited maternal SAE report1

3(88.9%) 3(43.0%)

Number of participants with at least one solicited infant SAE report1

7(77.8%) 6(85.7%)

Total number of solicited maternal SAEs 5 5 Total number of solicited infant SAEs 9 8 Note: Denominator is the total number of participants in each group (N). AE=adverse event; SAE=serious adverse

event. Solicited adverse events include the following: congenital anomaly in the infant; adverse pregnancy outcomes,

including spontaneous miscarriages; solicited SAEs in the mother or infant for which there is a definite or a reasonable possibility of attribution to belimumab.

1Not mutually exclusive of solicited nonserious AE reports (maternal or infant).


60

Table 16. Participant Status, Commercially Supplied Belimumab Exposure, and Adverse Events Reported – Cumulative Reporting Period

Registry ID

Pregnancy Status (Ongoing or Outcome)

Dosage of Commercially Supplied Belimumab

Number of Doses

Administered Preconception

Through Pregnancy1

BPR Enrollment

Date

AEs/SAEs Reported Related to Underlying

Disease

AEs/SAEs Reported Related to Pregnancy

US0001 Outcome 10 mg/kg 2 16 Jul 2012 Prematurity of infant, vomiting, nausea, and insomnia

US0002 Outcome 10 mg/kg 6 16 Oct 2012 Lupus flare

US0003 Outcome 10 mg/kg 4 28 Nov 2012

Placental abruption, prematurity 324/7 weeks’

gestational age, heavy vaginal bleeding

US0005 Outcome 10 mg/kg 12 20 Feb 2013 Ebstein anomaly3

US0008 Outcome 10 mg/kg 14 23 Apr 2013

Fetal hydrops, Non-reassuring fetal heart rate,

supraventricular tachycardia (infant) and postpartum hypertension (mother)

US0009 Outcome 10 mg/kg 3 07 May 2013 Non-reassuring fetal status

US0010 Outcome 10 mg/kg 1 01 Aug 2013 Intrauterine “fetal demise”4 at 124/7 weeks’ gestational age,

miscarriage

US0011 Ongoing 10 mg/kg 4 14 Aug 2013 Bilateral club foot2

US0012 Ongoing 10 mg/kg 6 16 Aug 2013 None None Note: SAEs are presented in bold text. AE=adverse event; BPR=Belimumab Pregnancy Registry; SAE=serious adverse event. 1 Number of doses included only those records with non-missing treatment dates. 2 Indicated during prenatal testing. Event not confirmed by HCP by time of data cut-off. 3 Defect defined as any major structural or chromosomal defect or combination of 2 or more of the conditional defects in live-born

infants, stillbirths, or fetal losses of any gestational age.4Spontaneous miscarriage: fetal death or expulsion of products of conception prior to 200/7 weeks’ gestational age


61

Additional Information

Table 17. Pregnancy Outcomes – Cumulative Reporting Period

Newly Reported Outcome Data Through

08 Mar 2014 (N=5)

Cumulative Reported Outcome Data From

12 Jul 2012 (N=7)

Completed pregnancies1

5(100.0%)

7(100.0%)

Fetal loss1,2 1(20.0%) 1(14.3%) Spontaneous miscarriage3,4 1(100.0%) 1(100.0%) Stillbirth4 0 0 Ectopic pregnancy4 0 0 Molar pregnancy4 0 0 Live birth1 4(80.0%) 6(85.7%) Preterm birth5 1(25.0%) 3(50.0%) Small for gestational age (SGA)5, 6 0 0 Birth defect5 1(25.0%) 1(16.7%) Neonatal death5 0 0 Note: “n” is the total number of non-missing responses. 1 Denominator is the number of participants with pregnancy outcomes. 2 Fetal loss is a combination of spontaneous miscarriage, stillbirth, ectopic pregnancy, and molar pregnancy events. 3 Participants with pregnancy outcomes prior to 200/7 weeks’ gestational age. 4 Denominator is the number of fetal losses. 5 Denominator is the number of live births. 6 Small for gestational age is defined as live births whose birth weight lies below the 10th percentile for that gestational

age based on Williams 1982 reference data [Williams, 1982].


62

Table 18. Preliminary Results for Completed Pregnancies as of 08 Mar 2014 –

Disease Severity

Total (n=7)

Live Births

(n=6)

Preterm Births (n=3)

Spontanous Miscarriages

(n=1)

Stillbirths

(n=0)

SGA2

(n=0) Birth Defects

(n=1)

Low Birth Weight (n=2)

Median (Q1, Q3)

Duration of SLE, years

11 (8.5, 13)

10.5 (7.8, 11.8)

10 (6, 11)

14 0 0 10 14.5 (8.75, 20.25)

n (%) Disease severity (PGA)

Preconception 0 = None 0 0 0 0 0 0 0 0 1 = Mild 5(71.4%) 5(83.3%) 3(100.0%) 0 0 0 1(100.0%) 2(100.0%) 2 = Moderate 0 0 0 0 0 0 0 0 3 = Severe 0 0 0 0 0 0 0 0 Missing 02(28.6%) 1(16.7%) 0 1(100.0%) 0 0 0 0 At enrollment 0 = None 1(14.3%) 1(16.7%) 1(33.3%) 0 0 0 0 1(50.0%) 1 = Mild 3(42.9%) 3(50.0%) 1(33.3%) 0 0 0 1(100.0%) 0 2 = Moderate 1(14.3%) 1(16.7%) 1(33.3%) 0 0 0 0 1(50.0%) 3 = Severe 0 0 0 0 0 0 0 0 Missing 2(28.6) 1(16.7%) 0 1(100.0%) 0 0 0 0 At end of second trimester1

0 = None 0 0 0 0 0 0 0 0 1 = Mild 3(50.0%) 3(50.0%) 2(66.6%) 0 0 0 1(100.0%) 1(50.0%) 2 = Moderate 0 0 0 0 0 0 0 0 3 = Severe 0 0 0 0 0 0 0 0 Missing 3(50.0%) 3(50.0%) 1(33.3%) 0 0 0 0 1(50.0%) At outcome 0 = None 1(14.3%) 1(16.7%) 1(33.3%) 0 0 0 0 1(50.0%) 1 = Mild 2(28.6%) 2(33.3%) 1(33.3%) 0 0 0 1(100.0%) 0 2 = Moderate 0 0 0 0 0 0 0 0 3 = Severe 0 0 0 0 0 0 0 0 Missing 4(57.1%) 3(50.0%) 1(33.3%) 1(100.0%) 0 0 0 1(50.0%) Note: PGA=physician global assessment; SGA=small for gestational age. 1 Second trimester begins at week 14 after the date of conception or last menstrual period to week 28, Denominator

excludes spontaneous miscarriage that occurred prior to 2nd trimester (n=6). 2 Small for gestational age is defined as live births whose birth weight lies below the 10th percentile for that gestational



63

Table 19. Preliminary Results for Completed Pregnancies as of 08 Mar 2014 – Exposure and Comorbidities

Total (n=7)

Live Births (n=6)



(n=1) Stillbirths

(n=0) SGA2 (n=0)

Birth Defects (n=1)


Median (Q1, Q3) Belimumab exposure preconception through pregnancy

Total doses 4 (3, 6)

4 (2, 12)

12 (6, 12)

1 0 0 12 3.0 (2.5, 3.5)

Cumulative exposure, days 204

(175,274) 204

(153,429) 204

(178,316) 120 0 0 429

178 (165.75, 191.25)

n (%) Belimumab dose received

Preconception 7(100.0%) 6(100.0%) 3(100.0%) 1(100.0%) 0 0 1(100.0%) 2(100.0%) During pregnancy 5(71.4%) 4(66.7%) 2(66.7%) 1(100.0%) 0 0 1(100.0%) 1(50.0%) Other exposures during pregnancy

Corticosteroids 5(71.4%) 5(83.3%) 3(100.0%) 0 0 0 1(100.0%) 2(100.0%) NSAIDs 2(28.6%) 2(33.3%) 1 (33.3%) 0 0 0 0 1(50.0%) Other Immuno-suppressants1

0 0 0 0 0 0 0 0

Anti-malarial drugs 5(71.4%) 4(66.7%) 3(100.0%) 1(100.0%) 0 0 1(100.0%) 2 (100.0%) Heparin 1(14.3%) 1(16.7%) 1(33.3%) 0 0 0 1(100.0%) 0 Comorbidities during pregnancy

Hypertension 2(28.6%) 2(33.3%) 0 0 0 0 0 0 Hyperthyroidism 1(14.3%) 1(16.7%) 1(33.3%) 0 0 0 0 1(50.0%) Hypothyroidism 2(28.6%) 1(16.7%) 1(33.3%) 1(100.0%) 0 0 1(100.0%) 0 Pregnancy induced HTN

1(14.3%) 1(16.7%) 0 N/A 0 0 0 0

Placenta abruption

1(14.3%) 1(16.7%) 1(33.3%) N/A 0 0 0 1(50.0%)

Pre-eclampsia 1(14.3%) 1(16.7%) 0 N/A 0 0 0 1(50.0%) Proteinuria 3(42.9%) 3(50.0%) 2(66.6%) 0 0 0 1(100.0%) 1(50.0%) Gestational diabetes

0 0 0 N/A 0 0 0 0

Diabetes mellitus type1/type 2

0 0 0 0 0 0 0 0

Thrombocytopenia 0 0 0 0 0 0 0 0 Thrombotic events 0 0 0 0 0 0 0 0 Chronic renal failure

0 0 0 0 0 0 0 0

Restrictive lung disease

0 0 0 0 0 0 0 0

Severe lupus flare

0 0 0 0 0 0 0 0

Note: HTN=hypertension; NSAIDs=non-steroidal anti-inflammatory drugs; SGA=small for gestational age. 1 Includes azathioprine, cyclophosphamide, methotrexate, mycophenolate, cyclosporine, and rituximab.


64

2 Small for gestational age is defined as live births whose birth weight lies below the 10th percentile for that gestational age based on Williams 1982 reference data [Williams, 1982].


65

Table 20. Preliminary Results for Completed Pregnancies as of 08 Mar 2014 –

Laboratory Results

Total (n=7)

Live Births (n=6)



(n=1) Stillbirths

(n=0) SGA1 (n=0)

Birth Defects (n=1)


n (%) Abnormal laboratory tests, ever?

Anti-ds DNA Yes 3(42.9%) 3(50.0%) 1(33.3%) 0 0 0 1(100.0%) 0

Low C3/C4

Yes 4(57.1%) 4(66.7%) 2(66.7%) 0 0 0 1(100.0%) 1(50.0%) Anticardiolipin antibodies

IgG Yes 2(28.6%) 2(33.3%) 2(66.7%) 0 0 0 1(100.0%) 1(50.0%) IgM Yes 3(42.9%) 3(50.0%) 1(33.3%) 0 0 0 1(100.0%) 1(50.0%) IgA Yes 1(14.3%) 1(16.7%) 1(33.3%) 0 0 0 1(100.0%) 0 Anti-Ro+ Yes 2(28.6%) 2(33.3%) 1(33.3%) 0 0 0 1(100.0%) 0 Anti-La+ Yes 0 0 0 0 0 0 0 0 LAC Yes 0 0 0 0 0 0 0 0 Note: Anti-ds=anti-double-stranded; C3=complement 3; C4=complement 4; LAC=lupus anticoagulant; SGA=small for

gestational age. 1 Small for gestational age is defined as live births whose birth weight lies below the 10th percentile for that gestational



66

Invalid Pregnancy Cases

The following cases reflect the period from 16 Jul 2012 through 08 Mar 2014.

Invalid Cases – Preconception Exposure

US0006 1. Participant provided consent to enroll, but all three attempts for additional participant and HCP contact were unsuccessful. Participant reported fetal swelling in the head, heart, and lungs. The pregnancy outcome was reported as fetal loss (intrauterine “fetal demise”). This case lacked confirmation from both the obstetrician and belimumab prescriber HCPs.

Invalid Cases – First Trimester Exposure

CA0007 2. Participant originally reported the pregnancy to GSK and indicated that exposure occurred in the first trimester. However, the HCP medical release was not obtained, and all attempts for additional participant contact were unsuccessful. Prior to the last attempt, it was learned from the Benlysta Monarch Program that the participant experienced a spontaneous miscarriage.

Table 21. Invalid Cases

Overall n (%)

Total invalid cases

2

Pure prospective 0 Traditional prospective 0 Retrospective 0 Unable to determine 2 (100.0%) Note: Enrollment period 16 Jul 2012 through 08 Mar 2014. Both cases are considered invalid as

they lacked confirmation from both the obstetric and prescribing health care providers to meet minimum criteria for enrollment.


67

Table 22. Drug Names and Classes

Drug Class Brand Name(s) Generic Name(s) 5-HT3 receptor antagonists Zofran Ondansetron hydrochloride Antiarrhythmics Tambocor Flecainide Antibiotics Not reported in BPR Not reported in BPR Anticoagulants Not reported in BPR Heparin Antidepressants Wellbutrin Bupropion hydrochloride Anti-malarial drugs Plaquenil Hydroxychloroquine sulfate B vitamins Not reported in BPR Folate/folic acid Glucocorticoids Not reported in BPR Prednisolone, prednisone Immunosuppressants Rheumatrex, Trexall Methotrexate Immunosuppressants Imuran, Azasan Azathioprine Immunosuppressants Cytoxan, Neosar Cyclophosphamide Immunosuppressants Gengraf, Neoral, Sandimmune Cyclosporine Immunosuppressants Rheumatrex, Trexall Methotrexate Monoclonal antibodies Benlysta Belimumab Monoclonal antibodies Rituxan Rituximab Multivitamins Not reported in BPR Prenatal vitamins Non-steroidal anti-inflammatory drugs Not reported in BPR Not reported in BPR Proton pump inhibitors Prilosec, Zegerid Omeprazole Salicylates Not reported in BPR Aspirin Selective serotonin reuptake inhibitors (SSRIs) Celexa Citalopram hydrobromide Thyroid drugs Synthroid Levothyroxine sodium Tocolytics Not reported in BPR Not reported in BPR Note: BPR=Belimumab Pregnancy Registry.


68

Appendix 2. Awareness Activities

Table 23. Awareness Activities

Awareness Activity

Health care Provider

Awareness Patient

Awareness Region Status Comments Completed, Ongoing, or In Progress

Announcement of the registry via online media (i.e., clinicaltrials.gov, AHRQ RoPR, FDA Pregnancy Registry, WHO, Center Watch, GSK Clinical Trials Register)

X X NA & EU Ongoing Initiated in 2011, will continue through study

completion

Announcement of the registry via product print materials (i.e., medication guide & prescribing information)

X NA & EU Ongoing Initiated in 2012, will continue through study

completion

Announcement of the registry via product print materials (i.e., prescribing information, health care webpage, GSKsource.com)


completion

Toll-free/free phone access to the BPR RCC


completion Combined health care provider and patient brochure


completion. Translated in local language; patient

facing when permissible by country/local laws

BPR information available via internet search engines (i.e., Google)


completion Referrals established with OTIS, GSK Medical Information/Response

X X NA Ongoing Initiated in 2012, will continue through study


69

Awareness Activity


Awareness Patient

Awareness Region Status Comments Center, Benlysta Gateway, and Motherisk Program (Canada) to BPR RCC

completion

Dedicated GSK BPR webpage (study objectives and downloadable registration/enrollment materials, brochure, etc)


completion; accessible to patients

QR Code added to all BPR posters, advertisements, and “How to Participate in the BPR” card that will allow Smartphone users to scan the QR Code and link to the dedicated GSK BPR webpage


completion

Mass mailings (i.e., BPR awareness kits, brochures, “How to Participate in the BPR” card, etc) - rheumatologic and maternal-fetal medicine health care providers

X NA Ongoing Initiated in 2013, will continue through study

completion

E-mail blasts to rheumatologists (PPD-provided list)

X NA& EU Completed Q2/Q3 20142/3Q2014 – study announcement and

contact information US MSL initiatives X NA Ongoing Initiated in 2013, will

continue through study completion

Increase awareness about BPR with rheumatology clinical researchers and external experts via dissemination of BPR awareness kits (if requested)


completion

Presence at local and regional rheumatology meetings


completion via GSK MSLs GSK Medical Information/Response Center – BPR RCC informational

X NA Ongoing Initiated in 2013; will continue through study


70

Awareness Activity


Awareness Patient

Awareness Region Status Comments slide available and dissemination of BPR awareness kits to health care providers, if requested

completion

Banner advertisements and online media advertisements (i.e., AWHONN, Alliance for Lupus Research, Reprotox)

X In progress Initiated in 2013, will continue through study

completion

BPR awareness kits belimumab clinical trial investigators and infusion centers

X NA Completed Lists provided by GSK Benlysta team, mailing completed by PPD via

third party vendor; tracking to be provided by PPD

(pending) Presence at annual national and international rheumatologic, specialty pharmacy and maternal-fetal medicine meetings and congresses

In progress

2012 ACR annual meeting – poster included in clinical trial/registry awareness exhibit; poster reprints and brochures available

X NA & EU Completed International meeting

2012 ACR annual meeting – brochure and fact sheet at Benlysta medical information booth

X NA & EU Completed International meeting; information available upon

request

2013 SMFM exhibit X NA & EU Completed International meeting – BPR awareness kit,

brochure, fact sheet and “How to Participate in

BPR” card disseminated 2013 EULAR – study description poster and brochure at Benlysta medical information recruitment



71

Awareness Activity


Awareness Patient

Awareness Region Status Comments booth 2013 International Conference on Pharmacoepidemiology & Therapeutic Risk Management – scientific abstract accepted as a poster presentation (authors: D. Covington, A. Golembesky, D. Hill, N. Hurst, P. Churchill, L. McKain)


2013 ACR annual meeting – poster included in clinical trial/registry awareness exhibit; poster reprints and brochures available


2014 SMFM late-breaking scientific abstract submitted – not accepted

X NA & EU Not accepted International meeting

BPR Steering Committee - sought awareness suggestions, reviewed data and other study-related tasks

X NA Ongoing SAC members identified 2011; annual meetings & teleconferences planned

Quarterly e-mail to SAC members X NA Ongoing First e-mail disseminated in Mar 2013; update on

study progress and reminder to refer

patients/inform physician networks

SAC chairperson announced study at the SLICC meeting

X NA & EU Ongoing First announcement in Oct 2013; will continue throughout study

SAC members to include BPR awareness slide in SLE presentations

X NA & EU Ongoing First announcement in Jan 2013; will continue throughout study

EU principal investigators with the X EU Ongoing Initiated in Aug 2013; will


72

Awareness Activity


Awareness Patient

Awareness Region Status Comments primary role to increase awareness of the BPR through physician networks and referrals of patients to the RCC

continue throughout study

2012 AHRQ nomination case example for “Registries for Evaluating Patient Outcomes”

X NA Not accepted At the time of submission, no patients had been

enrolled Planned Awareness/Outreach Activities

Presence at ACR State-of-the-Art Clinical Symposium, Chicago IL

X NA Apr 2014 GSK MSLs

2014 Congress of Clinical Rheumatology Meeting in Destin, FL (MSL attendance)

X NA May 2014 US MSLs available to address pregnancy-related queries and

dissemination awareness materials upon request

Proactive dissemination of BPR awareness kits to US Benlysta high-prescribing physicians/infusion centers

X NA Began May 2014 US MSLs will identify prescribers with at least 35 Benlysta patients (in 2013) and disseminate

BPR awareness kit 2014 ACOG – scientific abstract accepted as a poster presentation; poster reprints and brochures available (authors: Helain Landy, Marcy Powell, Deanna Hill, Amanda Eudy, Michelle Petri)

X NA Apr 2014 National meeting

The Virtual Poster Gallery – 2014 ACOG poster

X NA & EU May 2014 - -Apr 2015 Online media

2014 SMFM online newsletter “Special Delivery” article (sponsored by H. Landy)

X NA & EU May 2014 Monthly online newsletter – study description and

contact information

2014 Armada Specialty Pharmacy Conference program guide advertisement announcing the BPR

X NA May 2014 Advertisement describing BPR and RCC contact

information


73

Awareness Activity


Awareness Patient

Awareness Region Status Comments 2014 EULAR – study description poster and brochure at Benlysta recruitment booth

X NA & EU Jun 2014 International meeting

2014 EULAR – scientific abstract summarizing belimumab clinical trial studies (ph 2-4) and spontaneously reported pregnancies accepted as an oral presentation (authors: Marcy Powell, Deanna Hill, Amanda Eudy, Helain Landy, Michelle Petri)


2014 EULAR – scientific abstract summarizing belimumab external comparator cohort and preliminary data from BPR accepted as a poster presentation – poster reprints and brochures available (authors: Marcy Powell, Deanna Hill, Amanda Eudy, Qinggong Fu, Michelle Petri)


Patient BPR webpage X NA & EU Planned Target date: 2014 and continued through end of

study BPR contact information listed on Benlysta consumer webpage

X NA & EU Planned Target date: 2014 and continued through end of

study Opt-in registration form linked to dedicated GSK BPR health care provider and patient webpages

X X NA & EU Planned Target date: 2014 and continued through end of

study Liaisons with lupus patient advocacy groups (excluding LFA)

X NA & EU Planned Target date: 2014 and continued through end of

study Presence at annual international rheumatologic, specialty pharmacy, and maternal-fetal medicine meetings


74

Awareness Activity


Awareness Patient

Awareness Region Status Comments and congresses 2014 ACR annual meeting – planned submission to clinical trial/registry awareness exhibit; poster reprints and brochures available

X NA & EU Planned International meeting

2014 ACR annual meeting – planned scientific abstract submission

X NA & EU Under consideration; due Jun 2014

International meeting

2014 ACR annual meeting – brochure and fact sheet at Benlysta medical information booth

X NA & EU Under consideration; due in 2014

International meeting; Information available upon

request ;2015 SMFM scientific abstract submission

X International Under consideration; due in Aug 2014

US MSLs available to address pregnancy-related queries and

dissemination awareness materials upon request

Professional and Medical Journals Print advertisements announcing the BPR

X NA & EU Planned 2014

Rheumatology and maternal-fetal journals

Submission of peer-reviewed scientific manuscripts

X NA & EU Planned 2014/2015 Rheumatology, maternal-foetal, etc journals

Announcement of BPR in belimumab clinical trial newsletters

X NA & EU Planned 2014 Advertisement describing BPR and RCC contact

information Belimumab box-stuffer program – five copies of BPR brochure inserted in each belimumab box ordered by infusion center

X X NA Planned 2014 Target date: 2014; infusion center staff and

patient awareness

Note: ACOG=American College of Obstetrics & Genecology; ACR=American College of Rheumatology; AHRQ=Agency for Healthcare Research and Quality; AWHONN=Association of Women's Health, Obstetric and Neonatal Nurses; BPR=Belimumab Pregnancy Registry; EU=European Union; EULAR=European League Against Rheumatism; FDA=Food and Drug Administration; GSK=GlaxoSmithKline; LFA=Lupus Foundation of America; MSL=medical science liaisons; NA=North America; OTIS=Organization of Teratology Information Specialists; PI=principal investigator; QR=quick response; RCC=Research Coordination Center; RoPR=Registry of Patient Registries; SAC=Scientific Advisory Committee; SMFM=Society for Maternal-Fetal Medicine; SLICC=SLE International Coordinating Clinics; US=United States; WHO=World Health Organization.


75

Table 24. Health Care Providers and Academicians Mailing List Schedule

List Status Content SMFM: First mailing – 1st Mailing

Completed: 07 May 2013 Mailing: Dear doctor letter, brochure, how to participate card

SMFM: Second mailing – 2nd Mailing

Completed: 13 Jun 2013 Mailing: Dear doctor letter, brochure, how to participate card

SMFM: Third mailing – 3rd Mailing

Completed: 24 Jun 2013 Mailing: Postcard

ACR Dropped due to 2012 & 2013 registry poster at ACR

E-mail blast: Brochure and dear doctor letter. Follow-up with postcard to SLE specialists.

EULAR Dropped due to lack of sufficient emailing addresses

E-mail blast: Brochure and dear doctor letter. Follow-up with postcard to SLE specialists.

Genetic counselors On hold E-mail blast: Brochure and dear doctor letter. Follow-up with postcard to SLE specialists.

US Benlysta high prescribers and US belimumab clinical trial investigators

In process: Apr 2014 Awareness kit mailing

Rheumatology centers Completed: 03 Jun 2013 Mailing: Postcard Note: ACR=American College of Rheumatology; EULAR=European League Against Rheumatism; SLE=systemic lupus

erythematosus; SMFM=Society for Maternal-Fetal Medicine

Documents

Belimumab Pregnancy Registry Interim Report V12 ... - GSKpregnancyregistry.gsk.com/documents/...Annual_Interim_Report_201… · review the data and update this report and to discuss