23
1 Continuous LNG/EE, a Low-dose Continuous-use Oral Contraceptive, Provides Similar Efficacy and Safety to a Monthly Cyclic Oral Contraceptive Alexander Teichmann, MD, PhD 1 1 Frauenklinik, Klinikum Aschaffenburg, Aschaffenburg, Germany. On behalf of: Cornelis Kluft, PhD 2 ; Gary Grubb, MD, MPH 3 ; Ginger Constantine, MD 3 ; Daniele Spielmann, MD, MSc 4 2 Gaubius Laboratory, TNO Quality of Life, Biomedical Research, Leiden, The Netherlands; 3 Research Headquarters, Wyeth Research, Collegeville, PA, USA; 4 Wyeth Research, Paris, France. Study funded by Wyeth Research, Collegeville, PA, USA.

Alexander Teichmann, MD, PhD 1 1 Frauenklinik, Klinikum Aschaffenburg, Aschaffenburg, Germany

  • Upload
    vidar

  • View
    30

  • Download
    1

Embed Size (px)

DESCRIPTION

Continuous LNG/EE, a Low-dose Continuous-use Oral Contraceptive, Provides Similar Efficacy and Safety to a Monthly Cyclic Oral Contraceptive. Alexander Teichmann, MD, PhD 1 1 Frauenklinik, Klinikum Aschaffenburg, Aschaffenburg, Germany. - PowerPoint PPT Presentation

Citation preview

Page 1: Alexander Teichmann, MD, PhD 1 1 Frauenklinik, Klinikum Aschaffenburg, Aschaffenburg, Germany

1

Continuous LNG/EE, a Low-dose Continuous-use Oral Contraceptive,

Provides Similar Efficacy and Safety to a Monthly Cyclic Oral Contraceptive

Alexander Teichmann, MD, PhD1

1Frauenklinik, Klinikum Aschaffenburg, Aschaffenburg, Germany.

On behalf of:Cornelis Kluft, PhD2; Gary Grubb, MD, MPH3;

Ginger Constantine, MD3; Daniele Spielmann, MD, MSc4

2Gaubius Laboratory, TNO Quality of Life, Biomedical Research, Leiden, The Netherlands; 3Research Headquarters, Wyeth Research,

Collegeville, PA, USA; 4Wyeth Research, Paris, France.

Study funded by Wyeth Research, Collegeville, PA, USA.

Page 2: Alexander Teichmann, MD, PhD 1 1 Frauenklinik, Klinikum Aschaffenburg, Aschaffenburg, Germany

2

Continuous LNG/EE

• Continuous levonorgestrel (LNG)/ethinyl estradiol (EE) is taken every day, 365 days a year, without a hormone-free interval

– Elimination of the hormone-free interval may reduce the total number of bleeding days

• Contains LNG (90 µg) and EE (20 µg) at the lowest combination of doses currently available in the United States

– Because of the low dose, the yearly cumulative hormone exposure is lower than that for many cyclic or extended-use oral contraceptives (OCs)

Page 3: Alexander Teichmann, MD, PhD 1 1 Frauenklinik, Klinikum Aschaffenburg, Aschaffenburg, Germany

3

Study Objectives

• Primary objective

– To evaluate the contraceptive efficacy of continuous LNG/EE

• Secondary objective

– To compare continuous LNG/EE to a similarly formulated 21/7 cyclic OC (LNG 100 µg/EE 20 µg) with respect to vaginal bleeding, safety, and metabolic effects

Page 4: Alexander Teichmann, MD, PhD 1 1 Frauenklinik, Klinikum Aschaffenburg, Aschaffenburg, Germany

4

Study Design

• Phase III, randomized, open-label, 1-year study conducted at 44 sites in Europe

– Czech Republic, Finland, Germany, Hungary, Italy, The Netherlands, Norway, Poland

• Women were randomly assigned to take 13 pill packs of either continuous LNG/EE or the LNG 100/EE 20, cyclic 21/7-day OC

Page 5: Alexander Teichmann, MD, PhD 1 1 Frauenklinik, Klinikum Aschaffenburg, Aschaffenburg, Germany

5

Key Inclusion Criteria

• Healthy women aged 18 to 49 years who were sexually active and willing to rely on a combination OC as their only means of contraception

• Regular (21- to 35-day) menstrual cycles in the previous 3 months

Page 6: Alexander Teichmann, MD, PhD 1 1 Frauenklinik, Klinikum Aschaffenburg, Aschaffenburg, Germany

6

Key Exclusion Criteria

• Standard OC contraindications

• 34 years of age and smoking 15 cigarettes per day

• Use of Depo-Provera within 10 months of screening

• Use of any of the following within 60 days of screening:– Intrauterine device, implantable contraceptive, or Lunelle

– Hepatic enzyme-inducing drugs

– Experimental drugs

– Noncontraceptive estrogens, progestins, or androgens

Page 7: Alexander Teichmann, MD, PhD 1 1 Frauenklinik, Klinikum Aschaffenburg, Aschaffenburg, Germany

7

Study Procedures

• Women were instructed to begin taking the study drug on the first day of their menstrual bleeding

• Women recorded vaginal bleeding and adverse events (AEs) on daily diary cards

• Bleeding terms were defined according to the World Health Organization

– Bleeding: required sanitary protection

– Spotting: bleeding that did not require sanitary protection

– Amenorrhea: no bleeding or spotting

• A subset of women who met predetermined criteria were also screened for 4 metabolic panels

– Included carbohydrate, fasting lipid, hemostasis, and bone maker panels

Page 8: Alexander Teichmann, MD, PhD 1 1 Frauenklinik, Klinikum Aschaffenburg, Aschaffenburg, Germany

8

Subject DispositionSubjects randomly assigned to a

treatment group N = 651

Continuous LNG/EEn = 328

LNG 100/EE 20cyclic 21/7-day OC n = 323

No drug takenn = 5 Took 1 dose of study drug

n = 641

No drug takenn = 5

Continuous LNG/EEn = 323

LNG 100/EE 20cyclic 21/7-day OC n =

318

Completed continuous LNG/EE arm

n = 216

Discontinuationsn = 69

Discontinuationsn = 107

Completed LNG 100/EE 20

cyclic 21/7-day OC arm n = 249

Page 9: Alexander Teichmann, MD, PhD 1 1 Frauenklinik, Klinikum Aschaffenburg, Aschaffenburg, Germany

9

Discontinuations

ReasonContinuous

LNG/EE, n (%)

LNG 100/EE 20 cyclic 21/7-day OC,

n (%)P value

Total 107 (33.1) 69 (21.7) 0.001

Accidental pregnancy 0 (0.0) 3 (0.9) 0.122

Investigator request 1 (0.3) 2 (0.6) 0.621

Lost to follow-up 5 (1.5) 2 (0.6) 0.451

Planning pregnancy 3 (0.9) 3 (0.9) 1.000

Protocol violation 9 (2.8) 11 (3.5) 0.656

AEs 72 (22.3) 31 (9.7) <0.001

Page 10: Alexander Teichmann, MD, PhD 1 1 Frauenklinik, Klinikum Aschaffenburg, Aschaffenburg, Germany

10

Contraceptive Efficacy

• There were no on-treatment pregnancies among women in the continuous LNG/EE group

• Women in the LNG 100/EE 20, cyclic 21/7-day OC group had 3 on-treatment pregnancies

Page 11: Alexander Teichmann, MD, PhD 1 1 Frauenklinik, Klinikum Aschaffenburg, Aschaffenburg, Germany

11

Bleeding Profile for the Continuous LNG/EE Group

0

20

40

60

80

100

1 2 3 4 5 6 7 8 9 10 11 12 13

Pill pack of continuous LNG/EE

Per

cen

tag

e o

f w

om

en

Amenorrhea Spotting only Bleeding +/- spotting

Page 12: Alexander Teichmann, MD, PhD 1 1 Frauenklinik, Klinikum Aschaffenburg, Aschaffenburg, Germany

12

Median Number of Total Bleeding/Spotting Days

0

2

4

6

8

10

1 2 3 4 5 6 7 8 9 10 11 12 13

Pill pack

Nu

mb

er

of

da

ys

Continuous LNG/EE

LNG 100/EE 20, cyclic 21/7-day OC

Page 13: Alexander Teichmann, MD, PhD 1 1 Frauenklinik, Klinikum Aschaffenburg, Aschaffenburg, Germany

13

Median Number of Bleeding and Spotting Days for Continuous LNG/EE

048

1216202428

1 2 3 4 5 6 7 8 9 10 11 12 13

Pill pack

Nu

mb

er o

f d

ays

Median number of bleeding days

Median number of spotting days

Page 14: Alexander Teichmann, MD, PhD 1 1 Frauenklinik, Klinikum Aschaffenburg, Aschaffenburg, Germany

14

Bleeding Summary

• For continuous LNG/EE, the percentage of women achieving amenorrhea generally increased with each pill pack to 53% at pill pack 13

• The median number of bleeding/spotting days decreased over time for both study groups

– The median number of unscheduled bleeding days was 0 for pill pack 2 to 13 for continuous LNG/EE

– Median number of spotting days was 0 for pill packs 8 to 13 for continuous LNG/EE

Page 15: Alexander Teichmann, MD, PhD 1 1 Frauenklinik, Klinikum Aschaffenburg, Aschaffenburg, Germany

15

Adverse Events

Continuous LNG/EE, n (%)

LNG 100/EE 20, cyclic 21/7-day OC,

n (%)

Total treatment-emergent AEs

282 (87.3) 270 (84.9)

Discontinuations due to AEs

72 (22.3) 31 (9.7)

Total serious AEs 6 (1.8) 12 (3.8)

Serious AEs related to drug

1 (0.3) 2 (0.6)

Type of serious AE 1 Cervical dysplasia1 Ovarian cyst,

1 depression

Page 16: Alexander Teichmann, MD, PhD 1 1 Frauenklinik, Klinikum Aschaffenburg, Aschaffenburg, Germany

16

Most Common Treatment Emergent AEs (5% of Patients)

0

10

20

30

40

50

Headac

he

Abdom

inal

pai

n

Met

rorrh

agia

Dysm

enorrh

ea

Nau

sea

Bac

k pai

nAcn

e

Vagin

al h

emorrh

age

Pe

rce

nta

ge

of

su

bje

cts

Continuous LNG/EE LNG 100/EE 20 cyclic 21/7-day OC

*

*

* P <0.05

Page 17: Alexander Teichmann, MD, PhD 1 1 Frauenklinik, Klinikum Aschaffenburg, Aschaffenburg, Germany

17

Differences in Treatment Emergent AEs Based on Mid-point Analyses

Vaginalbleeding*

Breastpain

Nausea

Pill packs 1 to 6

Continuous LNG/EE 105 (32.5) 22 (6.8) 23 (7.1)

LNG 100/EE 20 cyclic 21/7-day OC 38 (11.9) 22 (6.9) 31 (9.7)

P value <0.001 1.000 0.257

Pill packs 7 to 13

Continuous LNG/EE 41 (15.8) 2 (0.8) 7 (2.7)

LNG 100/EE 20 cyclic 21/7-day OC 29 (10.4) 13 (4.6) 20 (7.1)

P value 0.073 0.007 0.018

*Vaginal bleeding is a combination of COSTART terms metrorrhagia, menorrhagia, and vaginal and uterine hemorrhage.

Page 18: Alexander Teichmann, MD, PhD 1 1 Frauenklinik, Klinikum Aschaffenburg, Aschaffenburg, Germany

18

Mean Change in Body Weight

Continuous LNG/EE

LNG 100/EE 20 cyclic 21/7-day

OC

Mean weight at baseline, kg 63.5 64.2

Mean change from baseline at post-treatment, kg

+0.56* +0.39

Pairwise P value at post-treatment

0.516

*P <0.01 vs. baseline.

Page 19: Alexander Teichmann, MD, PhD 1 1 Frauenklinik, Klinikum Aschaffenburg, Aschaffenburg, Germany

19

Mean Change From Baseline in Blood Pressure

Continuous LNG/EE LNG 100/EE 20 cyclic 21/7-day OC

Pill pack 3

Post-treatment

Pill pack 3

Post-treatment

Systolic, mmHg 0.57 -0.96 0.28 0.17

Diastolic, mmHg 0.39 0.07 0.11 1.10*

*P <0.05 vs baseline.All pairwise P values not significant.

Page 20: Alexander Teichmann, MD, PhD 1 1 Frauenklinik, Klinikum Aschaffenburg, Aschaffenburg, Germany

20

Cervical Smear Results

Satisfactory for evaluation

Total epithelial cell

abnormalities— squamous cell,

n (%) ASCUS

Low grade

SIL

High grade

SIL

Pill pack 7

Continuous LNG/EE, n

226 20 (8.8%) 5 12 3

LNG 100/EE 20 cyclic 21/7 day OC, n

250 11 (4.4%) 3 6 2

Post-study

Continuous LNG/EE, n

246 10 (4.0%) 5 5 0

LNG 100/EE 20 cyclic 21/7 day OC, n

245 15 (6.1%) 7 5 3

ASCUS, atypical squamous cells of undetermined significance; SIL, squamous intraepithelial lesions.

Page 21: Alexander Teichmann, MD, PhD 1 1 Frauenklinik, Klinikum Aschaffenburg, Aschaffenburg, Germany

21

Safety Summary

• There was no statistical difference in the total number of AEs reported by each study group– Significantly more women reported metrorrhagia

(P <0.001) and vaginal hemorrhage (P = 0.011) in the continuous LNG/EE group

• The bleeding-related treatment-emergent AEs that were initially significantly higher for continuous LNG/EE in pill packs 1 to 6 were no longer different by pill packs 7 to 13

• During pill packs 7 to 13, women in the continuous LNG/EE group reported significantly less breast pain and nausea than the LNG 100/EE 20 cyclic 21/7-day OC group

Page 22: Alexander Teichmann, MD, PhD 1 1 Frauenklinik, Klinikum Aschaffenburg, Aschaffenburg, Germany

22

Summary of Metabolic Substudy

• Twenty-nine metabolic parameters were assessed and 20 were not significantly different between study groups

• Those that were statistically significantly different were not deemed clinically important

• These results have been presented elsewhere

Page 23: Alexander Teichmann, MD, PhD 1 1 Frauenklinik, Klinikum Aschaffenburg, Aschaffenburg, Germany

23

Summary and Conclusions

• Continuous LNG/EE demonstrated a similar safety profile to an established 21/7-day cyclic OC

• Over time, continuous LNG/EE offered women the ability to achieve amenorrhea and reduce the number of bleeding days

• Continuous LNG/EE did not demonstrate clinically important differences compared to the LNG 100/EE 20 cyclic 21/7-day OC in metabolic parameters commonly affected by OCs

• There were no on-treatment pregnancies in the continuous LNG/EE group and 3 in the LNG 100/EE 20 cyclic 21/7-day OC group