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For peer review only

Minimally invasive surgery versus open surgery in the treatment of lumbar spondylolisthesis; study protocol of a

multicenter randomised controlled trial (MISOS trial)

Journal: BMJ Open

Manuscript ID bmjopen-2017-017882

Article Type: Protocol

Date Submitted by the Author: 29-May-2017

Complete List of Authors: Arts, Mark; Medisch Centrum Haaglanden, Wolfs, Jasper; Medisch Centrum Haaglanden Kuijlen, Jos; University Medical Center Groningen

de Ruiter, Godard; Medisch Centrum Haaglanden

<b>Primary Subject Heading</b>:

Surgery

Secondary Subject Heading: Evidence based practice, Neurology, Qualitative research, Research methods

Keywords: Spine < ORTHOPAEDIC & TRAUMA SURGERY, Back pain < ORTHOPAEDIC & TRAUMA SURGERY, NEUROSURGERY, minimally invasive spine surgery, Clinical trials < THERAPEUTICS

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml

BMJ Open


1

Minimally invasive surgery versus open surgery in the treatment of lumbar

spondylolisthesis; study protocol of a multicenter randomised controlled trial (MISOS

trial)

Mark P. Arts¹*, Jasper F.C. Wolfs¹, Jos M.A. Kuijlen² and Godard C.W. de Ruiter¹

¹Dept of Neurosurgery, Haaglanden Medical Center, The Hague, The Netherlands

²Dept of Neurosurgery, University Medical Center Groningen, The Netherlands

*corresponding author

Mark P. Arts, neurosurgeon, MD, PhD

Haaglanden Medical Center, The Hague

PO Box 432

2501 CK The Hague

The Netherlands

[email protected]

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Abstract

Introduction: Patients with symptomatic spondylolisthesis are frequently treated with nerve

root decompression in addition with pedicle screw fixation and interbody fusion. Minimally

invasive approaches are gaining attention in recent years, although there is no clear

evidence supporting the proclamation of minimally invasive spine surgery (MISS) being

better than open surgery. We present the design of the MISOS trial on the effectiveness of

MISS versus open surgery in patients with degenerative or spondylolytic spondylolisthesis.

Methods and analysis: All patients (age 18-75 years) with neurogenic claudication or

radicular leg pain based on low grade degenerative or spondylolytic spondylolisthesis with

persistent complaints for at least 3 months, are eligible. Patients will be randomised into mini-

open decompression with bilateral interbody fusion with percutaneous pedicle screw fixation

(MISS), or conventional surgery with decompression and instrumented fusion with pedicle

screws and bilateral interbody fusion (open). The primary outcome measure is visual

analogue scale (VAS) of self-reported low back pain. Secondary outcome measures include

improvement of leg pain, Oswestry Disability Index (ODI), patients’ perceived recovery,

quality of life, resumption of work, complications, blood loss, length of hospital stay,

incidence of re-operations, and documentation of fusion. This study is designed as

multicenter randomised controlled trial in which two surgical techniques are compared in a

parallel group design. Based on a 20 mm difference of low back pain score at 6 weeks

(power of 90%, assuming 8% loss to follow-up), a total of 184 patients will be needed. All

analyses will be performed according to the intention-to-treat principle.

Ethics and dissemination: The study has been approved by the Medical Ethical Review

Board Southwest Holland in August 2014 (registration number NL 49044.098.14) and

subsequently approved by the board all participating hospitals. Dissemination will include

peer-reviewed publications and presentations at national and international conferences.

Trial registration number: NTR 4532, pre-results.

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Strenghts and limitations of this study

• The Minimal Invasive Surgery versus Open Surgery (MISOS) trial evaluates the

effectiveness of percutaneous pedicle screw fixation versus open surgery in patients

with degenerative or spondylolytic spondylolisthesis.

• The trial is largest multicenter randomised trial on minimal invasive surgery versus

open surgery in patients with spondylolisthesis.

• Methodological strengths include appropriate sample size calculation based on

difference in early postoperative low back pain.

• All patients will undergo pedicle screw fixation with posterior lumbar interbody fusion

(PLIF) and alternative fusion strategies will not be performed.

• It is not feasible to blind the patients for the allocated treatment

• There is no economical evaluation.

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Introduction

Background and rationale

Patients with degenerative or spondylolytic spondylolisthesis of the lumbar spine usually

present with radicular leg pain or neurogenic claudication, with or without low back pain.

Whenever conservative management fails, patients are offered surgery. In case of stable

spondylolisthesis documented on dynamic radiographs, patients can be treated with

decompression alone and the modest difference in favour of additional instrumentation does

not justify the associated higher costs for implants and longer duration of surgery.1 In case of

instable spondylolisthesis, most patients will be treated with nerve root decompression in

addition with pedicle screw fixation and interbody fusion. However, this surgical approach

usually implies large skin incisions with detachment of the paravertebral muscles, which may

result in disabling postoperative low back pain, and higher complications with consequent

longer rehabilitation period.2

Worldwide, minimally invasive spine surgery (MISS) is becoming more and more popular.

The rationale behind minimally invasive techniques is less tissue damage, reduced back pain

leading to a shorter rehabilitation period, and faster return to work and resumption of daily

activities.3 Despite numerous studies on minimally invasive lumbar fusion techniques, level 1

evidence on outcome of MISS versus open surgery is scarce. There is no evidence

supporting the proclamation of small (minimal invasive) being better. There is only one

randomised controlled trial, of low quality, on minimally invasive lumbar fusion performed by

Wang et al.4 They reported 41 cases who underwent minimally invasive transforaminal

lumbar fusion versus 38 patients who underwent open surgery. There was no difference in

pain between both groups during the follow up of 2 years, although the Oswestry Disability

Index in patients treated with MISS was significantly better during the first 12 months. This

difference, however, diminished over time.

Recently, 2 reviews on minimally invasive fusion versus open surgery have been published

5;6, and 1 review specifically focused on spondylolisthesis.7 Overall, MISS was associated

with less blood loss and shorter hospitalisation and there was no difference in terms of

outcome, fusion rates, and complications. However, the results should be interpreted

carefully since the included studies displayed heterogeneous patient populations and neither

review contained a level 1 randomized controlled trial.

In the MISOS trial, patients with degenerative or spondylolytic spondylolisthesis will be

randomised into mini-open decompression with bilateral interbody fusion with percutaneous

pedicle screw fixation (MISS), or conventional open surgery with decompression and

instrumented fusion with pedicle screws and bilateral interbody fusion (open). We

hypothesize that patients treated with MISS have a faster speed of recovery with less low

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back pain at 2 weeks and 6 weeks after surgery, and similar outcome at 1 year after surgery,

as compared to patients treated with open surgery. We will especially focus on the short-term

results because that is the period in which possible differences in speed of recovery may

become clear in case of less invasive techniques. The presented protocol follows the

recommendations outlined in the CONSORT guidelines for randomised controlled trials.

Research aim and objectives

Despite numerous studies on minimally invasive lumbar fusion techniques, level 1 evidence

on outcome of MISS versus open surgery is scarce. The objective of our trial is to determine

whether minimally invasive lumbar fusion will result in faster recovery and less low back pain

compared to conventional open surgery in patients with degenerative or spondylolytic

spondylolisthesis. The primary outcome measure is short-term low back pain at 2 weeks and

6 weeks.

Methods and analysis

Study design and settings

This study is designed as multicenter randomised controlled trial in which patients with

symptomatic spondylolisthesis (degenerative or spondylolytic) will be allocated into minimally

invasive pedicle screw fixation versus open surgery. In order to recruit enough patients, the

study will be performed in 3 neurosurgical centers in the Netherlands; Medical Center

Haaglanden The Hague, Haga hospital in The Hague, and University Medical Center

Groningen, Groningen.

Patient selection

All patients (age between 18 and 75 years) with neurogenic claudication or radicular leg pain

based on low grade (Meyerding grade I and II) degenerative or spondylolytic

spondylolisthesis with persistent complaints for at least 3 months are eligible for the study.

Additional inclusion and exclusion criteria are shown in Table 1.

Randomisation

Randomisation will be computer generated and will be performed prior to surgery at the

outpatient clinic. A pre-defined block size will be used to ensure balanced group sizes at the

end of the inclusion period. When surgery is rescheduled the patient stays in the same

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randomisation group (intention to treat), and the original date of surgery is documented.

Blinding is not feasible because of differences in surgical wounds.

Surgical intervention

All patients in both groups will be operated with the aid of spinal navigation (O-arm

(Medtronic) or 3D-Orbic C-arm (Siemens) and will be positioned on a radiolucent spine table.

In case of the standard open procedure, a long midline skin incision (10-15 cm) is made after

which the paravertebral muscles are detached from the midline and retracted laterally in

order to expose the facet joints and pedicle entry point. After the pedicle screws are

positioned, the disc will be removed bilaterally and packed with autogeneous bone chips,

followed by bilateral placement of polyetheretherketone (PEEK) PLIF cages. In case of the

minimally invasive surgery, a small midline incision (3-5 cm) will be made to perform mini-

open decompression and placement of bilateral PEEK PLIF cages. In addition, two small

paramedian incisions will be made on both sides for percutaneous pedicle screw fixation.

All participating surgeons have performed at least 20 procedures of MISS prior to the start of

the trial.

Outcome Measurements

Primary outcome

The primary outcome is the score on the Visual Analogue Scale (VAS) of low back pain,

(ranging from 0 – 100 mm) on the short term (2 weeks and 6 weeks after surgery). Pain will

be assessed on a horizontal 100 mm scale varying from 0 mm, ‘no pain’, to 100 mm, ‘the

worst pain imaginable’. Patients do not see the results of earlier assessments and will score

the pain experienced at the visit. Reliability, validity and responsiveness of VAS have been

shown.8 The minimal clinically important difference of the visual analogue score for pain is 20

mm.9

Secondary outcome

Several secondary outcome measures will be documented:

1) Oswestry Disability index (ODI).

The Oswestry Disability Index (ODI) is one of the principal condition-specific outcome

measures used in the management of spinal disorders.10 In this study we will use the current

version 2.1a. The ODI is the most commonly used outcome measures in patients with low

back pain. It has been extensively tested, showed good psychometric properties, and

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applicable in a wide variety of settings. There are 10 questions (items), each with 6 possible

answers, each answer option receives a score of 0 to 5 points, yielding score range between

0 and 50, which is scaled to a 100% range. The questions are designed in a way to realize

how the back or leg pain is affecting the patient's ability to manage in everyday life.

2) Patients’ perceived recovery.

This is a 7-point Likert scale measuring the perceived recovery, varying from ‘complete

recovery’ to ‘worse than ever’. This outcome scale has been used in previous studies and is

regarded valid and responsive to change.11 “Complete recovery” and “almost complete

recovery” will be defined as good outcome (Likert 1 and 2).

3) Visual Analogue Scale (VAS) of leg pain.

This parameter will measure the experienced pain intensity in the leg during the week before

visiting the researcher. Pain will be assessed on a horizontal 100 mm scale varying from 0

mm, ‘no pain’, to 100 mm, ‘the worst pain imaginable’. Patients do not see the results of

earlier assessments and will score the pain experienced at the visit. Reliability, validity and

responsiveness of VAS have been shown.8

4) Quality of life (EQ-5D).

The EuroQol (EQ-5D) measures 5 dimensions (mobility, self-care, daily activities,

pain/discomfort, anxiety/depression), on a 3 point scale (no, some, or extreme problems).

For each health state described by the patients, a utility score can be calculated that reflects

society’s valuation of that health state. The Dutch tariff for the EQ-5D will be used.12

Whereas the EQ-5D provide society’s assessment of the patients’ health, the patients

themselves will also assess their own health on VAS, ranging from 0.0 (as bad as death) to

1.0 (optimal health). Both the EQ-5D and the VAS will be reported in questionnaires filled out

at home.

5) Resumption of work.

Hypothetically, MISS may result in faster recovery and earlier return to work. Therefore,

patients will be asked on every follow-up moment whether they have resumed their work

activities.

Other outcome measures that will be documented are:

6) Incidence of re-operations.

In general, re-operation is considered as bad outcome and therefore used as an outcome

measure. The incidence of re-operation in both groups will be measured.

7) Complications.

A systematic assessment of complications (including wound infection, deep venous

thrombosis, urine tract infection, hematoma, and progressive neurological deficit) will be

carried out by the surgeon. Moreover, surgeons will be asked for perioperative complications

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like cerebrospinal fluid leakage, nerve root damage, and exploration on the wrong disc level.

During the complete course of the study, all adverse events will be reported.

8) Surgical parameters.

Blood loss, time of surgery and length of hospital stay will be documented in all patients.

9) Fusion.

For the assessment of fusion we will use conventional dynamic X-ray. The flexion-extension

plane images will be analysed and quantified using FXA (Functional X-Ray Analysis). The

software allowed measurement of rotation on flexion-extension films with an accuracy of ±1º.

Absence of range of motion of the index disc level will be documented as indicator of fusion.

We defined fusion as rotation ≤ 2º and ≤ 1.25 mm translation on flexion-extension film.

Sample size

The sample size calculation is based on a difference in low back pain score of 20 mm at 6

weeks after surgery (60 mm for open surgery versus 40 mm for MIS). Assuming a standard

deviation of 40 mm, 85 patients will be needed in both groups (alpha=0.05; beta=0.10).

Including 8% loss to follow-up, a total of 184 patients will need to be randomised.

Data collection, management and analysis

All patients will be analysed pre-operatively as well as 2 weeks, 6 weeks, 3 months, 6

months, 12 months and 24 months postoperative, according to the assessment schedule in

Figure 1. The data from initial visits, hospitalization and follow-up visits will be entered into a

database via an electronic data capture system (Castor EDC). The data will be recorded and

analysed without any personal identifiers by using coded information. The source documents

and identifiers will be archived in a security facility and permission for accessing data will be

documented per investigator.

All analyses will be performed according to the intention-to-treat principle. Differences

between groups at baseline will be assessed by comparing means, medians, or percentages,

depending on the type of variable. The outcomes for function (ODI) and pain (VAS) will be

analysed with a repeated-measures analysis of variance using a first-order autoregressive

covariance matrix. The estimated consecutive scores will be expressed as means and 95%

confidence intervals. Kaplan-Meier survival analysis will be used to estimate time elapsed

between randomization and recovery, and curves will be compared using the log rank test. A

Cox model will be used to compare rates of recovery by calculation of a Hazard Ratio. The

level of significance will be P<0.05.

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Safety monitoring and adverse events

The study will be monitored by the Trial Coordinator Center of Haaglanden Medical Center.

At least one monitoring visit per year per center will be conducted. During the complete study

period, all adverse events will be reported. Adverse events are defined as any undesirable

experience occurring to a participant, whether or not related to the intervention.

Dissemination

Recently, three reviews on minimally invasive spondylodesis versus open spondylodesis

have been published of which one review specifically on spondylolisthesis.5-7 The clinical

outcome, fusion rates, and complication rates is comparable between minimally invasive

interbody fusion surgery and open fusion surgery, although MISS is associated with reduced

blood loss and shorter hospital stay. However, these results should be interpreted carefully

since the included studies displayed heterogeneous patient populations and neither review

contained a level 1 randomized controlled trial. This lack of evidence was the basis of the

MISOS trial. The objective of our trial is to determine whether minimally invasive lumbar

fusion will result in faster recovery and less low back pain compared to conventional open

surgery. We plan to disseminate our findings through presentations at national and

international spine conferences, and we will submit findings for publication in peer-reviewed

international journals. Recruitment of patients has started in September 2015 and will be

finished when all 184 patients have been followed-up for 2 years, which is expected at the

end of 2019.

Acknowledgements

The MISOS trial has been funded by Zimmer-Biomet. Furthermore, we want to thank Ditte

Varkevisser, Carolien Wolfs, Robin van Zijl, Irene van Beelen and Anne Broekema for their

work in making this trial possible.

Author’s contributions

MA designed the protocol, contributed to acquisition of data, is primary investigator and

coordinator of the trial. JW, JK and GdR have contributed to acquisition of data. All authors

read and approved the final manuscript.

Funding

The study is supported by Zimmer-Biomet.

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Competing interests

Dr. Arts, Dr. Wolfs and Dr. de Ruiter are receiving financial support from Zimmer-Biomet for

their work on this study.

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References

1. Ghogawala Z, Dziura J, Butler WE, Dai F, Terrin N, Magge SN et al. Laminectomy

plus Fusion versus Laminectomy Alone for Lumbar Spondylolisthesis. N Engl J

Med 2016; 374(15):1424-1434.

2. Fritzell P, Hagg O, Nordwall A. Complications in lumbar fusion surgery for chronic

low back pain: comparison of three surgical techniques used in a prospective

randomized study. A report from the Swedish Lumbar Spine Study Group. Eur

Spine J 2003; 12(2):178-189.

3. Foley KT, Smith MM. Microendoscopic discectomy. Techn Neurosurg 1997; 3:301-

307.

4. Wang HL, Lu FZ, Jiang JY, Ma X, Xia XL, Wang LX. Minimally invasive lumbar

interbody fusion via MAST Quadrant retractor versus open surgery: a

prospective randomized clinical trial. Chin Med J (Engl) 2011; 124(23):3868-

3874.

5. Habib A, Smith ZA, Lawton CD, Fessler RG. Minimally invasive transforaminal

lumbar interbody fusion: a perspective on current evidence and clinical

knowledge. Minim Invasive Surg 2012; 2012:657342.

6. Wu RH, Fraser JF, Hartl R. Minimal access versus open transforaminal lumbar

interbody fusion: meta-analysis of fusion rates. Spine (Phila Pa 1976) 2010;

35(26):2273-2281.

7. Lu VM, Kerezoudis P, Gilder HE, McCutcheon BA, Phan K, Bydon M. Minimally

Invasive Surgery Versus Open Surgery Spinal Fusion For Spondylolisthesis: A

Systematic Review and Meta-analysis. Spine (Phila Pa 1976) 2016.

8. Carlsson AM. Assessment of chronic pain. I. Aspects of the reliability and validity

of the visual analogue scale. Pain 1983; 16(1):87-101.

9. Ostelo RW, de Vet HC. Clinically important outcomes in low back pain. Best Pract

Res Clin Rheumatol 2005; 19(4):593-607.

10. Fairbank JC, Couper J, Davies JB, O'Brien JP. The Oswestry low back pain disability

questionnaire. Physiotherapy 1980; 66(8):271-273.

11. Bombardier C. Outcome assessments in the evaluation of treatment of spinal

disorders: summary and general recommendations. Spine 2000; 25(24):3100-3.

12. Lamers LM, Stalmeier PF, McDonnell J, Krabbe PF, van Busschbach JJ. [Measuring

the quality of life in economic evaluations: the Dutch EQ-5D tariff]. Ned Tijdschr

Geneeskd 2005; 149(28):1574-8.

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Inclusion Criteria

• Age between 18 and 75 years.

• Neurogenic claudication or radicular leg pain with or without low back pain.

• Degenerative or spondylolytic spondylolisthesis grade I or II with spinal stenosis.

• Persistent complaints for at least 3 months, regardless conservative treatments.

• Be able to understand the Dutch language and comprehend the questionnaires and

patient information.

• Written informed consent given.

Exclusion Criteria

• Previous spine fusion surgery at the same level.

• Osteoporosis.

• Active infection or prior infection at the surgical site.

• Active cancer.

• Spondylolisthesis greater than grade III.

• More than 1 symptomatic level that need fusion.

• Pregnancy.

• Contraindication for surgery.

• Severe mental or psychiatric disorder.

• Alcoholism.

• Inadequate knowledge of Dutch language.

• Morbid obesitas (BMI > 40).

Table 1.

In- and exclusion criteria.

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�

��

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Journal: BMJ Open

Manuscript ID bmjopen-2017-017882.R1

Article Type: Protocol

Date Submitted by the Author: 29-Aug-2017

Complete List of Authors: Arts, Mark; Medisch Centrum Haaglanden, Wolfs, Jasper; Medisch Centrum Haaglanden Kuijlen, Jos; University Medical Center Groningen

de Ruiter, Godard; Medisch Centrum Haaglanden

<b>Primary Subject Heading</b>:

Surgery

Secondary Subject Heading: Evidence based practice, Neurology, Qualitative research, Research methods

Keywords: Spine < ORTHOPAEDIC & TRAUMA SURGERY, Back pain < ORTHOPAEDIC & TRAUMA SURGERY, NEUROSURGERY, minimally invasive spine surgery, Clinical trials < THERAPEUTICS

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BMJ Open


Version 11 April 24th 2017 1

Study Protocol MISOS Trial

Minimally Invasive Surgery versus Open Surgery (MISOS)

in the treatment of spondylolisthesis; a randomised

controlled multicenter trial.

M.P. Arts, M.D., PhD and J.F.C. Wolfs, M.D.

Dept of Neurosurgery, Medical Center Haaglanden, The Hague, The Netherlands

Principal investigator:

Mark P. Arts, neurosurgeon, MD, PhD

Medical Center Haaglanden, The Hague

PO Box 432

2501 CK The Hague

The Netherlands

[email protected]

Trial registration: NTR 4532

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Project group

Principal investigator and responsible budget holder:

dr. M.P. Arts, neurosurgeon, Medical Center Haaglanden, The Hague

Co-investigator and trial coordinator:

J.F.C. Wolfs, neurosurgeon, Medical Center Haaglanden, The Hague

Neuroradiology:

B.F.W. van der Kallen, neuroradiologist, Medical Center Haaglanden, The Hague

Participating centers:

Medical Center Haaglanden, Westeinde and Antoniushove

Dr. M.P. Arts

J.F.C. Wolfs

Dr. G.C.W. de Ruiter

University Medical Center Groningen:

Dr. J.M.A. Kuijlen (subinvestigator)

Haga Hospital Den Haag:

Dr. M.P. Arts

Independent physician:

Prof.dr. R. H. M. A. Bartels, neurosurgeon, University Medical Center Nijmegen

Comeniuslaan 4

6525 HP Nijmegen

The Netherlands

[email protected]

This study is financially supported by:

Biomet Global Supply Chain Center B.V.

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Contents

1 Introduction ...................................................................................................................................... 4

Background.......................................................................................................................................... 4

2 Hypothesis and Study Objectives .................................................................................................... 5

Hypothesis ........................................................................................................................................... 5

Primary Objective ................................................................................................................................ 5

Secondary Objective ........................................................................................................................... 5

Study Design ....................................................................................................................................... 5

Inclusion Criteria .................................................................................................................................. 6

Exclusion Criteria ................................................................................................................................. 6

3 Surgical intervention ........................................................................................................................ 6

4 Outcome Measures ......................................................................................................................... 7

Primary outcome ................................................................................................................................. 7

Secondary outcome ............................................................................................................................. 7

Follow-up moments ............................................................................................................................. 9

Randomisation ................................................................................................................................... 10

5 STATISTICAL ANALYSIS ............................................................................................................. 10

Sample size calculation ..................................................................................................................... 10

Descriptive statistics .......................................................................................................................... 10

Subgroup analysis ............................................................................................................................. 11

Interim analysis .................................................................................................................................. 11

6 Radiological Assessment .............................................................................................................. 11

Radiography ...................................................................................................................................... 11

CT evaluation..................................................................................................................................... 11

7 Clinical Investigation Termination .................................................................................................. 11

Early discontinuation of subjects ....................................................................................................... 11

Adverse Event ................................................................................................................................... 12

Serious Adverse Events .................................................................................................................... 12

8 Ethical Considerations ................................................................................................................... 12

Ethical approval ................................................................................................................................. 13

Patient Information and Informed Consent ........................................................................................ 13

Declaration of Helsinki ....................................................................................................................... 13

Good Clinical Practice ....................................................................................................................... 13

Independent Physician ...................................................................................................................... 13

Insurance ........................................................................................................................................... 13

Contact with General practitioner ...................................................................................................... 14

Patients’ Confidentiality ..................................................................................................................... 14

Data Protection .................................................................................................................................. 14

End of Project .................................................................................................................................... 14

9 Administrative Obligations ............................................................................................................. 14

Source Data ....................................................................................................................................... 14

Data Collection and Processing ........................................................................................................ 14

Publication ......................................................................................................................................... 15

10 Duration of investigation ................................................................................................................ 15

11 Reference List ................................................................................................................................ 15

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1 INTRODUCTION

Minimally invasive spine surgery (MISS) has been popularised in recent years. Based on the

hypothesis that “small is better”, efforts have been made to decrease tissue damage through

smaller corridor approaches. In 1997, Foley and Smith introduced the muscle-splitting tubular

approach of the lumbar disc aiming at reduced muscle injury, less postoperative low back

pain and faster recovery while achieving good clinical outcome comparable to conventional

open surgery5. The worldwide introduction of MISS has been influenced by patients’

preferences, physicians’ preferences, and marketing tools. Nowadays, thousands of patients

have undergone MISS in public and private hospitals. However, the literature on MISS is

criticized as being overly optimistic and scientific proof supporting the superiority of minimally

invasive techniques is lacking1. Therefore, every new surgical procedure should be

compared with the golden standard prior to implementation of the new technique on a large

scale.

Background

Patients with degenerative or spondylolytic spondylolisthesis usually present with radicular

leg pain or neurogenic claudication with or without back pain. Whenever conservative

management fails, patients are offered surgery. Presently, the golden standard in the

treatment of instable spondylolisthesis is nerve root decompression in addition with pedicle

screw fixation and interbody fusion. However, large skin incisions and detachment of the

paravertebral muscles may result in disabling postoperative low back pain with consequent

long rehabilitation period.

Worldwide, minimally invasive spine surgery (MISS) is becoming more and more popular.

The rationale behind minimally invasive techniques is less tissue damage, reduced back pain

leading to a shorter rehabilitation period and faster return to work and resume daily

activities5.

Despite numerous studies on minimally invasive lumbar fusion techniques, level 1 evidence

on outcome of MIS versus open surgery is very scarce. There is no evidence supporting the

proclamation of small being better and only one randomised controlled trial, of low quality, on

minimally invasive lumbar fusion has been performed by Wang et al.9. They reported 41

cases who underwent minimally invasive transforaminal lumbar fusion versus 38 patients

who underwent open surgery. There was no difference in visual analogue scale (VAS)

between both groups during the follow up of 2 years, although the Oswestry Disability Index

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(ODI) in patients treated with MIS was significantly better during the first 12 months. This

difference diminished over time.

Recently, two reviews on minimally invasive TLIF versus open TLIF have been published6;12.

The clinical outcome, fusion rates, and complication rates is comparable between minimal

invasive interbody fusion surgery and open fusion surgery. However, the results should be

interpreted carefully since the included studies displayed heterogeneous patient populations

and neither review contained a level 1 randomized controlled trial.

We hypothesize that patients treated with minimally invasive spine fusion (MIS) have a faster

speed of recovery with less low back pain at 2 weeks and 6 weeks after surgery and similar

outcome at 1 year after surgery, as compared to patients treated with conventional open

surgery (OS) in an adequately power cohort.

2 HYPOTHESIS AND STUDY OBJECTIVES

Hypothesis

Patients treated with MIS will document lower back pain scores on VAS at the short-term

follow-up (2 and 6 weeks after surgery) as compared to open surgery.

Primary Objective

To evaluate the improvement of low back pain measured by the VAS after MIS compared to

open surgery.

Secondary Objective

The secondary objectives concern the effect of minimal invasive fusion on the secondary

outcome parameters of Oswestry Disability Index, VAS leg pain, quality of life (EuroQol),

patients self-reported perceived recovery, and fusion status.

Study Design

This study is designed as multi-center randomized controlled trial in which patients with

symptomatic spondylolisthesis (degenerative or spondylolytic) will be allocated into minimally

invasive pedicle screw fixation versus open surgery. Follow-up moments are preoperative, as

well as 2 weeks, 6 weeks, 3 months, 6 months, 12 months, and 24 months postoperative.

Data will be collected by local case record forms (CRF’s) .

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Inclusion Criteria

In order to be eligible for the study, the patient must meet all of the following criteria:

• Age between 18 and 75 years.

• Neurogenic claudication or radicular leg pain with or without low back pain.

• Degenerative or spondylolytic spondylolisthesis grade I or II with spinal stenosis.

• Persistent complaints for at least 3 months, regardless conservative treatments.

• Be able to understand the Dutch language and comprehend the questionnaires and

patient information.

• Written informed consent given.

Exclusion Criteria

A potential subject who meets any of the following criteria will be excluded from participation

in this study:

• Previous spine fusion surgery at the same level.

• Osteoporosis.

• Active infection or prior infection at the surgical site.

• Active cancer.

• Spondylolisthesis greater than grade II.

• More than 1 symptomatic level that need fusion.

• Pregnancy.

• Contraindication for surgery.

• Severe mental or psychiatric disorder.

• Alcoholism.

• Inadequate knowledge of Dutch language.

• Morbid obesitas (BMI > 40).

3 SURGICAL INTERVENTION

All patients will be operated with the aid of spinal navigation (O-arm) and will be positioned

on a Jackson Spine table. In case of the standard open procedure, a long midline skin

incision (10-15 cm) is made after which the paravertebral muscles are detached from the

midline and retracted laterally in order to expose the facet joints and pedicle entry. After the

pedicle screws are placed, the disc will be removed and the intervertebral space will be

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packed with autogeneous bone and bilateral PEEK PLIF cages or unilateral TLIF cage,

dependent on the preference of the surgeon.

In case of the minimally invasive surgery, 2 small paramedian incisions will be made on both

sides, followed by percutaneous navigated pedicle screw fixation. A small midline incision (5

cm) will be made to perform mini-open decompression and placement of bilateral PEEK PLIF

cages or unilateral TLIF cage, dependent on the preference of the surgeon.

All participating surgeons will perform at least 10 procedures of MIS prior to the start of the

trial.

4 OUTCOME MEASURES

Primary outcome

The primary outcome is the score on the Visual Analog Scale (VAS) of low back pain,

(ranging from 0 – 100 mm) on the short term (2 weeks and 6 weeks after surgery).

This parameter will measure the experienced pain intensity in the back during the week

before visiting the researcher. Pain will be assessed on a horizontal 100 mm scale varying

from 0 mm, ‘no pain’, to 100 mm, ‘the worst pain imaginable’. Patients do not see the results

of earlier assessments and will score the pain experienced at the visit. Reliability, validity and

responsiveness of VAS have been shown3. The minimal clinically important difference of the

visual analogue score for pain is 20 to 35 mm8.

Secondary outcome

Several secondary outcome measures will be documented:

1) Oswestry Disability index (ODI).

The Oswestry Disability Index (ODI) is one of the principal condition-specific outcome

measures used in the management of spinal disorders4. In this study we will use the current

version 2.1a. The ODI is the most commonly used outcome measures in patients with low

back pain. It has been extensively tested, showed good psychometric properties, and

applicable in a wide variety of settings. There are 10 questions (items), each with 6 possible

answers, each answer option receives a score of 0 to 5 points, yielding score range between

0 and 50, which is scaled to a 100% range. The questions are designed in a way to realize

how the back or leg pain is affecting the patient's ability to manage in everyday life.

2) Patients’ perceived recovery.

This is a 7-point Likert scale measuring the perceived recovery, varying from ‘complete

recovery’ to ‘worse than ever’. This outcome scale has been used in previous studies and is

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regarded valid and responsive to change2. Complete recovery and almost complete recovery

will be defined as good outcome.

3) Visual Analogue Scale (VAS) of leg pain.

This parameter will measure the experienced pain intensity in the leg during the week before

visiting the researcher. Pain will be assessed on a horizontal 100 mm scale varying from 0

mm, ‘no pain’, to 100 mm, ‘the worst pain imaginable’. Patients do not see the results of

earlier assessments and will score the pain experienced at the visit. Reliability, validity and

responsiveness of VAS have been shown3.

4) Quality of life (EQ-5D).

The EuroQol (EQ-5D) measures 5 dimensions (mobility, self-care, daily activities,

pain/discomfort, anxiety/depression), on a 3 point scale (no, some, or extreme problems).

For each health state described by the patients, a utility score can be calculated that reflects

society’s valuation of that health state. The Dutch tariff for the EQ-5D will be used7. Whereas

the EQ-5D provide society’s assessment of the patients’ health, the patients themselves will

also assess their own health on VAS, ranging from 0.0 (as bad as death) to 1.0 (optimal

health). Both the EQ-5D and the VAS will be reported in questionnaires filled out at home.

5) Return to work.

At every follow-up moment, patients will be asked if they have resumed their work activities.

6) Incidence of re-operations.

In general, re-operation is considered as bad outcome and therefore used as an outcome

measure. The incidence of re-operation in both groups will be measured.

7) Complications.

A systematic assessment of complications (including wound infection, deep venous

thrombosis, urine tract infection, hematoma, and progressive neurological deficit) will be

carried out by the surgeon. Moreover, surgeons will be asked for perioperative complications

like cerebrospinal fluid leakage, nerve root damage, and exploration on the wrong disc level.

8) Surgical parameters.

Blood loss, time of surgery and length of hospital stay will be documented in all patients.

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8) Fusion.

For the assessment of fusion we will use the regular computed tomography (CT) at 12

months after surgery. The assessment of fusion will be made by a neuro-radiologist. Fusion

will be defined as complete bridging of bone across the disc space on sagittal CT scans10.

Follow-up moments

All patients will be analysed pre-operatively as well as 2 weeks, 6 weeks, 3 months, 6

months, 12 months and 24 months postoperative, according to the following assessment

schedule:

Intake

Surgery

Follow-up 2 w

eeks

Follow-up 6 w

eeks

Follow-up 3

months

Follow-up 6

months

Follow-up 12

months

Follow-up 24

months

Inclusion / exclusion criteria X

Demographics & medical

history X

Basic physical examination X

Neurological examination X X

Randomisation X

X-ray X X X X X

MRI X

CT X X

VAS low back pain X X X X X X X

VAS leg pain X X X X X X X

ODI X X X X X X X

Patients’ perceived recovery X X X X X X

EQ-5D X X X X X X

Complications X X X X X X X

Re-operation X X X X X X

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Randomisation

Randomization will be computer generated and will be performed prior to induction of

anesthesia. A pre-defined block size will be used to ensure balanced group sizes at the end

of the inclusion period. When surgery is rescheduled the patient stays in the same

randomisation group, and the original date of surgery is documented. Patients data will be

coded with the acronym MISOS, complemented with the patient number in order of inclusion

(MISOS 1 till MISOS 184). Blinding is not feasible because of differences in surgical wounds.

5 STATISTICAL ANALYSIS

Sample size calculation

The sample size calculation is based on a difference in low back pain score of 20 mm at 6

weeks after surgery (60 mm for open surgery versus 40 mm for MIS). Assuming a standard

deviation of 40 mm, 85 patients will be needed in both groups (alpha=0.05; beta=0.10).

Including 8% loss to follow-up, a total of 184 patients will need to be randomised.

Descriptive statistics

All analyses will be performed according to the intention-to-treat principle. Differences

between groups at baseline will be assessed by comparing means, medians, or percentages,

depending on the type of variable. The outcomes for function (ODI and RMDQ) and pain

(VAS) will be analyzed with a repeated-measures analysis of variance using a first-order

autoregressive covariance matrix. The estimated consecutive scores will be expressed as

means and 95% confidence intervals. Kaplan-Meier survival analysis will be used to estimate

time elapsed between randomization and recovery, and curves will be compared using the

logrank test. A Cox model will be used to compare rates of recovery by calculation of a

Hazard Ratio.

The level of significance will be P<0.05.

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Subgroup analysis

Subgroup analyses will be performed for the predefined variables age, body mass index,

predominant low back pain, smoking, type and grade of spondylolisthesis, duration of

complaints, and social economic status.

Interim analysis

No interim analysis of the data is anticipated, unless the data safety board committee will

decide based on adverse events (see 7 clinical investigation termination).

6 RADIOLOGICAL ASSESSMENT

Radiography

Anterior/posterior, lateral and flexion/extension x-rays will be performed at each visit.

Instability is defined as > 3 mm displacement during flexion/extension. Absence of range of

motion (ROM) of the index disc level will be documented as indicator of fusion.

Displacement or subsidence of the PLIF/TLIF cage will be assessed by using a standard

lateral radiograph.

CT evaluation

To verify fusion, CT axial images at 2 mm slices will be taken at 12 months follow-up. Fusion

will be defined as complete bridging of bone across the disc space on sagittal CT scans10.

Moreover, positioning of the screws in relation to the pedicle will be documented in all

patients.

7 CLINICAL INVESTIGATION TERMINATION

Early discontinuation of subjects

Subjects will be informed that they are free to withdraw from the project at any time and for

any reason, without affecting their subsequent treatment. In addition, a subject may be

removed from the project if, in the investigators’ opinion, it is not in the best medical interest

of the subject to continue the project. If a subject is withdrawn from the project they will be

asked to return to the clinic as soon as possible to perform the assessments for month 24. In

addition, the date the subject is withdrawn from the project and the reason for withdrawal will

be recorded on the CRF. Subjects who discontinue will not be replaced.

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If, for any reason, the whole project is discontinued, all subjects ongoing in the project at that

time will be asked to return to the clinic as soon as possible to perform the assessments for

month 24.

Adverse Event

An “adverse event” is defined as “any untoward medical occurrence in a subject that does

not necessarily have a causal relationship with the investigational device”. An adverse event

can therefore be any unfavorable or unintended sign (including an abnormal laboratory

finding), symptom, or disease temporally associated with the use of a device. Examples of

adverse events related to spinal fusion are: dural tear, nerve root injury, epidural

hemorrhage, infection, malposition of pedicle screw, pseudarthrosis, and loosening/migration

of implants. Adverse events will be followed-up until resolved or stabilized, or until the end of

the defined follow-up period (24 months), whichever occurs first.

Serious Adverse Events

A “serious adverse event” is defined as one of the following:

• An event causing the death of the subject

• An event which leads to a serious deterioration in the health of a subject that:

a) Results in a life-threatening illness or injury

b) Results in permanent impairment of a body structure or a body function

c) Requires in-patient hospitalisation or prolongation of existing hospitalisation

d) Results in medical or surgical intervention to prevent permanent impairment to a body

structure or body function

• An event which leads to foetal distress, foetal death or a congenital abnormality or birth

defect

All adverse events and serious adverse events will be documented and send to the data

safety board committee, consisting of 2 neurosurgeons and 1 epidemiologist.

8 ETHICAL CONSIDERATIONS

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Ethical approval

Prior to initiation of the study, the investigator will submit the protocol, patient information

sheet, patient informed consent and any other documentation as required to the METC

Zuidwest Holland for review and approval.

Patient Information and Informed Consent

The investigator will obtain written Informed Consent from the patient after adequate

explanation of the aims, methods, anticipated benefits, and potential risks of the study. The

original copy of the signed and dated Informed Consent will be kept in the patient’s records.

Declaration of Helsinki

The investigator will ensure that this project is conducted in full conformity with the current

revision of the 1964 Declaration of Helsinki11.

Good Clinical Practice

The project will be conducted according to the protocol, Annex 10 of the Medical Device

Directive 93/42/EEC, ISO 14155 (Clinical Investigation of Medical Devices for Human

Subjects) and to Standard Operating Procedures (SOPs) that meet the current guidelines

laid down by the International Conference on Harmonisation (ICH) for Good Clinical Practice

(GCP) in clinical trials.

Independent Physicians are:

In any case the patient can contact the independent physicians. The assigned independent

physicians is Prof. dr. R.H.M.A. Bartels (neurosurgeon, Radboud University Medical Center)

Insurance

Clinical study insurance for patients will be obtained by Medical Center Haaglanden and

Medical Center Groningen, which is in accordance with the legal requirements in the

Netherlands (Article 7 WMO and the Measure regarding Compulsory Insurance for Clinical

Research in Humans of 23th June 2003). This insurance provides cover for damage to

research subjects through injury or death caused by the study. The sponsor has civil liability

insurance regarding the implants.

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Contact with General practitioner

The patient’s General Practitioner (GP) will be informed by letter that the patient is taking part

in the MISOS trial, provided the patient agrees to this.

Patients’ Confidentiality

The patient’s privacy is maintained at all times. On the CRF or other documents submitted to

the sponsors, patients will be identified by their subject project number only. The investigator

will permit authorized representatives of the sponsor, regulatory agencies and ethics

committees to review the portion of the subject’s medical record that is directly related to the

study.

Data Protection

All personnel involved in the project will observe or work within the confines of the European

Data Protection Directive as interpreted by each country’s laws.

End of Project

The patient’s participation in the project will end following completion of month 24.

9 ADMINISTRATIVE OBLIGATIONS

Source Data

All hospital records, laboratory reports, radiographic films, MRI and CT images, and

questionnaires are considered source data. The investigator/institution will permit trial-related

monitoring, audits and regulatory inspection providing direct access to source documents.

Data Collection and Processing

All CRFs will be completed using a black ballpoint pen, and entries must be legible. Errors

should be crossed by a single line but not obliterated, the correction inserted, and the change

initialed and dated by the investigator or an authorized member of the project staff.

The Principal Investigator or a co-investigator will sign and date at the indicated places of the

CRF. This signature will indicate a thorough inspection of the data on the CRF has been

made, and it will certify the contents of the form.

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Publication

We will submit the results of the project as a whole once all subjects have completed the

project and the project has been analyzed. The financial sponsor requires that all

publications planned for submission will be sent to the financial sponsor for comment prior to

submission. The investigators remain free to use their own data for any purpose at any time

and may submit the results of the project for publication regardless the outcome of the study.

10 DURATION OF INVESTIGATION

Start inclusion: July 2015 enrolment : 36 months

Total included patients: 184

11 REFERENCE LIST

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1. Arts MP. Commentary: Minimally invasive spine surgery: new standard or

transient fashion? Spine J 2013;13:498-500.

2. Bombardier C. Outcome assessments in the evaluation of treatment of spinal

disorders: summary and general recommendations. Spine 2000;25:3100-3.

3. Carlsson AM. Assessment of chronic pain. I. Aspects of the reliability and validity of

the visual analogue scale. Pain 1983;16:87-101.

4. Fairbank JC, Couper J, Davies JB et al. The Oswestry low back pain disability

questionnaire. Physiotherapy 1980;66:271-3.

5. Foley KT, Smith MM. Microendoscopic discectomy. Techn Neurosurg 1997;3:301-7.

6. Habib A, Smith ZA, Lawton CD et al. Minimally invasive transforaminal lumbar

interbody fusion: a perspective on current evidence and clinical knowledge.

Minim.Invasive.Surg 2012;2012:657342.

7. Lamers LM, Stalmeier PF, McDonnell J et al. [Measuring the quality of life in

economic evaluations: the Dutch EQ-5D tariff]. Ned Tijdschr Geneeskd

2005;149:1574-8.

8. Ostelo RW, de Vet HC. Clinically important outcomes in low back pain. Best Pract

Res Clin Rheumatol 2005;19:593-607.

9. Wang HL, Lu FZ, Jiang JY et al. Minimally invasive lumbar interbody fusion via

MAST Quadrant retractor versus open surgery: a prospective randomized clinical

trial. Chin Med J (Engl) 2011;124:3868-74.

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10. Williams AL, Gornet MF, Burkus JK. CT evaluation of lumbar interbody fusion:

current concepts. AJNR Am J Neuroradiol. 2005;26:2057-66.

11. WMA. Declaration of Helsinki - Ethical Principles for Medical Research Involving

Human Subjects; 2013. 2013.

12. Wu RH, Fraser JF, Hartl R. Minimal access versus open transforaminal lumbar

interbody fusion: meta-analysis of fusion rates. Spine (Phila Pa 1976)

2010;35:2273-81.

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1

SPIRIT 2013 Checklist: Recommended items to address in a clinical trial protocol and

related documents*

Section/item ItemNo

Description

Administrative information

Title 1 Descriptive title identifying the study design, population, interventions,

and, if applicable, trial acronym p1

Trial registration 2a Trial identifier and registry name. If not yet registered, name of

intended registry p1

2b All items from the World Health Organization Trial Registration Data

Set

Protocol version 3 Date and version identifier p1

Funding 4 Sources and types of financial, material, and other support p2

Roles and

responsibilities

5a Names, affiliations, and roles of protocol contributors p2

5b Name and contact information for the trial sponsor p2

5c Role of study sponsor and funders, if any, in study design; collection,

management, analysis, and interpretation of data; writing of the report;

and the decision to submit the report for publication, including whether

they will have ultimate authority over any of these activities p2

5d Composition, roles, and responsibilities of the coordinating centre,

steering committee, endpoint adjudication committee, data

management team, and other individuals or groups overseeing the

trial, if applicable (see Item 21a for data monitoring committee) p2

Introduction

Background and

rationale

6a Description of research question and justification for undertaking the

trial, including summary of relevant studies (published and

unpublished) examining benefits and harms for each intervention p4

6b Explanation for choice of comparators p4

Objectives 7 Specific objectives or hypotheses p5

Trial design 8 Description of trial design including type of trial (eg, parallel group,

crossover, factorial, single group), allocation ratio, and framework (eg,

superiority, equivalence, noninferiority, exploratory) p5

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2

Methods: Participants, interventions, and outcomes

Study setting 9 Description of study settings (eg, community clinic, academic hospital)

and list of countries where data will be collected. Reference to where

list of study sites can be obtained p5

Eligibility criteria 10 Inclusion and exclusion criteria for participants. If applicable, eligibility

criteria for study centres and individuals who will perform the

interventions (eg, surgeons, psychotherapists) p6

Interventions 11a Interventions for each group with sufficient detail to allow replication,

including how and when they will be administered p6,7

11b Criteria for discontinuing or modifying allocated interventions for a

given trial participant (eg, drug dose change in response to harms,

participant request, or improving/worsening disease) p7

11c Strategies to improve adherence to intervention protocols, and any

procedures for monitoring adherence (eg, drug tablet return,

laboratory tests) p7

11d Relevant concomitant care and interventions that are permitted or

prohibited during the trial p7

Outcomes 12 Primary, secondary, and other outcomes, including the specific

measurement variable (eg, systolic blood pressure), analysis metric

(eg, change from baseline, final value, time to event), method of

aggregation (eg, median, proportion), and time point for each

outcome. Explanation of the clinical relevance of chosen efficacy and

harm outcomes is strongly recommended p7,8

Participant

timeline

13 Time schedule of enrolment, interventions (including any run-ins and

washouts), assessments, and visits for participants. A schematic

diagram is highly recommended (see Figure) p9

Sample size 14 Estimated number of participants needed to achieve study objectives

and how it was determined, including clinical and statistical

assumptions supporting any sample size calculations p10

Recruitment 15 Strategies for achieving adequate participant enrolment to reach

target sample size p10

Methods: Assignment of interventions (for controlled trials)

Allocation:

Sequence

generation

16a Method of generating the allocation sequence (eg, computer-

generated random numbers), and list of any factors for stratification.

To reduce predictability of a random sequence, details of any planned

restriction (eg, blocking) should be provided in a separate document

that is unavailable to those who enrol participants or assign

interventions p10

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3

Allocation

concealment

mechanism

16b Mechanism of implementing the allocation sequence (eg, central

telephone; sequentially numbered, opaque, sealed envelopes),

describing any steps to conceal the sequence until interventions are

assigned p10

Implementation 16c Who will generate the allocation sequence, who will enrol participants,

and who will assign participants to interventions p10

Blinding

(masking)

17a Who will be blinded after assignment to interventions (eg, trial

participants, care providers, outcome assessors, data analysts), and

how NA

17b If blinded, circumstances under which unblinding is permissible, and

procedure for revealing a participant’s allocated intervention during

the trial NA

Methods: Data collection, management, and analysis

Data collection

methods

18a Plans for assessment and collection of outcome, baseline, and other

trial data, including any related processes to promote data quality (eg,

duplicate measurements, training of assessors) and a description of

study instruments (eg, questionnaires, laboratory tests) along with

their reliability and validity, if known. Reference to where data

collection forms can be found, if not in the protocol p9

18b Plans to promote participant retention and complete follow-up,

including list of any outcome data to be collected for participants who

discontinue or deviate from intervention protocols p9

Data

management

19 Plans for data entry, coding, security, and storage, including any

related processes to promote data quality (eg, double data entry;

range checks for data values). Reference to where details of data

management procedures can be found, if not in the protocol p9

Statistical

methods

20a Statistical methods for analysing primary and secondary outcomes.

Reference to where other details of the statistical analysis plan can be

found, if not in the protocol p10

20b Methods for any additional analyses (eg, subgroup and adjusted

analyses) p11

20c Definition of analysis population relating to protocol non-adherence

(eg, as randomised analysis), and any statistical methods to handle

missing data (eg, multiple imputation) p11

Methods: Monitoring

Data monitoring 21a Composition of data monitoring committee (DMC); summary of its role

and reporting structure; statement of whether it is independent from

the sponsor and competing interests; and reference to where further

details about its charter can be found, if not in the protocol.

Alternatively, an explanation of why a DMC is not needed p11,12

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21b Description of any interim analyses and stopping guidelines, including

who will have access to these interim results and make the final

decision to terminate the trial p11,12

Harms 22 Plans for collecting, assessing, reporting, and managing solicited and

spontaneously reported adverse events and other unintended effects

of trial interventions or trial conduct p11,12

Auditing 23 Frequency and procedures for auditing trial conduct, if any, and

whether the process will be independent from investigators and the

sponsor p11,12

Ethics and dissemination

Research ethics

approval

24 Plans for seeking research ethics committee/institutional review board

(REC/IRB) approval p13,14

Protocol

amendments

25 Plans for communicating important protocol modifications (eg,

changes to eligibility criteria, outcomes, analyses) to relevant parties

(eg, investigators, REC/IRBs, trial participants, trial registries, journals,

regulators) p13,14

Consent or assent 26a Who will obtain informed consent or assent from potential trial

participants or authorised surrogates, and how (see Item 32) p13,14

26b Additional consent provisions for collection and use of participant data

and biological specimens in ancillary studies, if applicable NA

Confidentiality 27 How personal information about potential and enrolled participants will

be collected, shared, and maintained in order to protect confidentiality

before, during, and after the trial p13,14

Declaration of

interests

28 Financial and other competing interests for principal investigators for

the overall trial and each study site p13

Access to data 29 Statement of who will have access to the final trial dataset, and

disclosure of contractual agreements that limit such access for

investigators p14

Ancillary and

post-trial care

30 Provisions, if any, for ancillary and post-trial care, and for

compensation to those who suffer harm from trial participation

Dissemination

policy

31a Plans for investigators and sponsor to communicate trial results to

participants, healthcare professionals, the public, and other relevant

groups (eg, via publication, reporting in results databases, or other

data sharing arrangements), including any publication restrictions

p13,14

31b Authorship eligibility guidelines and any intended use of professional

writers p15

31c Plans, if any, for granting public access to the full protocol, participant-

level dataset, and statistical code

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5

Appendices

Informed consent

materials

32 Model consent form and other related documentation given to

participants and authorised surrogates

Biological

specimens

33 Plans for collection, laboratory evaluation, and storage of biological

specimens for genetic or molecular analysis in the current trial and for

future use in ancillary studies, if applicable

*It is strongly recommended that this checklist be read in conjunction with the SPIRIT 2013

Explanation & Elaboration for important clarification on the items. Amendments to the

protocol should be tracked and dated. The SPIRIT checklist is copyrighted by the SPIRIT

Group under the Creative Commons “Attribution-NonCommercial-NoDerivs 3.0 Unported”

license.

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