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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
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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
m.arts@haaglandenmc.nl
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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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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
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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
m.arts@mchaaglanden.nl
Trial registration: NTR 4532
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Version 11 April 24th 2017 2
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
r.bartels@nch.umcn.nl
This study is financially supported by:
Biomet Global Supply Chain Center B.V.
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Version 11 April 24th 2017 3
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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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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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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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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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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