A Prospective, Multi-center, Randomized, Parallel-group Controlled Trial to Compare Conservative Versus Surgical Treatment of Foot Drop in Peroneal Nerve Entrapment.
Phase: NA
Conditions: Peroneal Nerve Entrapment
Sponsor: Universitaire Ziekenhuizen KU Leuven

 
 
 
 
FULL/LONG TITLE OF THE TRIAL:  
A PROSPECTIVE, MULTI-CENTER, RANDOMIZED, 
PARALLEL-GROUP CONTROLLED TRIAL TO COMPARE 
CONSERVATIVE VERSUS SURGICAL TREATMENT OF FOOT 
DROP IN PERONEAL NERVE ENTRAPMENT.  
 
SHORT STUDY TITLE / ACRONYM: 
FOOT DROP (Follow-up and Outcome of Operative Treatment with Decompressive Release Of The 
Peroneal nerve) 
PROTOCOL VERSION NUMBER AND DATE: 
Version 3.0; Date 10/03/2023 
RESEARCH REFERENCE NUMBERS 
Clinical trials.gov 
Number: 
NCT04695834 
SPONSOR Number: 
        UZ Leuven – S62895 
KCE Trials Number: 
        KCE19-1232  

 
 
◼ TABLE OF CONTENTS 
◼ 
SIGNATURE PAGE ...................................................................................................... 4 
◼ 
STUDY PROTOCOL ................................................................................................... 14 
1 
BACKGROUND .......................................................................................................... 14 
2 
RATIONALE ............................................................................................................... 18 
3 
ASSESSMENT AND MANAGEMENT OF RISK ......................................................... 20 
4 
OBJECTIVES AND ENDPOINTS / OUTCOME MEASURES ...................................... 21 
4.1 
PRIMARY OBJECTIVE ................................................................................................................. 21 
4.2 
SECONDARY OBJECTIVES ........................................................................................................ 21 
4.3 
ENDPOINTS ................................................................................................................................. 21 
4.3.1 
Primary endpoint ............................................................................................................. 21 
4.3.2 
Secondary endpoints ...................................................................................................... 22 
5 
TRIAL DESIGN ........................................................................................................... 23 
5.1 
FULL-SCALE STUDY DESIGN .................................................................................................... 23 
5.2 
FEASIBILITY PILOT STUDY DESIGN ......................................................................................... 24 
6 
STUDY SETTING ........................................................................................................ 25 
7 
ELIGIBILITY CRITERIA .............................................................................................. 26 
7.1 
INCLUSION CRITERIA ................................................................................................................. 26 
7.2 
EXCLUSION CRITERIA ................................................................................................................ 26 
8 
TRIAL PROCEDURES ................................................................................................ 27 
8.1 
RECRUITMENT ............................................................................................................................ 27 
8.1.1 
Patient identification ........................................................................................................ 27 
8.1.2 
Screening ........................................................................................................................ 28 
8.2 
CONSENT ..................................................................................................................................... 28 
8.3 
TRIAL RANDOMISATION ............................................................................................................. 30 
8.4 
BLINDING ..................................................................................................................................... 30 
8.5 
UNBLINDING OF OUTCOME ASSESSOR .................................................................................. 31 
8.6 
BASELINE DATA .......................................................................................................................... 31 
8.7 
TRIAL ASSESSMENTS ................................................................................................................ 33 
8.7.1 
Time to recovery ............................................................................................................. 34 
8.7.2 
Electrodiagnostics (EDX) ................................................................................................ 34 
8.7.3 
Muscle Power Assessment (Medical Research Council’s scale) ................................... 35 
8.7.4 
Isometric dynamometry .................................................................................................. 36 
8.7.5 
Six-minute walk test (6MWT) .......................................................................................... 37 
8.7.6 
Ankle dorsiflexion: range of motion ......................... Fout! Bladwijzer niet gedefinieerd. 
8.7.7 
Ability to walk barefoot .................................................................................................. 399 
8.7.8 
Stanmore Questionnaire ................................................................................................. 39 
8.7.9 
Need for ankle-foot orthosis............................................................................................ 40 
8.7.10 
Gait speed in the 10-meter walk test .............................................................................. 40 
8.7.11 
Sensory Changes ........................................................................................................... 41 
8.7.12 
Functional Ambulation Categories .................................................................................. 41 
8.7.13 
Quality of life questionnaires........................................................................................... 42 
8.7.14 
Surgical Complications ................................................................................................... 43 
8.7.15 
Treatment record ............................................................................................................ 43 
8.7.16 
Work Productivity and Activity Impairment Questionnaire: General Health (WPAI:GH) 44 
8.7.17 
Return to work at six weeks after randomization .......................................................... 444 
8.8 
TABLE OF TRIAL PROCEDURES ............................................................................................... 44 

 
 
8.9 
WITHDRAWAL CRITERIA ............................................................................................................ 46 
8.9.1 
Loss to follow-up ............................................................................................................. 47 
8.10 
END OF TRIAL ............................................................................................................................. 47 
9 
TRIAL INTERVENTION .............................................................................................. 48 
9.1 
SURGICAL DECOMPRESSION OF THE PERONEAL NERVE AT THE FIBULAR HEAD 
(NEUROLYSIS) ............................................................................................................................. 48 
9.2 
CONSERVATIVE TREATMENT ................................................................................................... 49 
10 
SAFETY RECORDING AND REPORTING ................................................................. 50 
10.1 
DEFINITIONS ............................................................................................................................... 50 
10.2 
RECORDING OF SAFETY FINDINGS IN FUNCTION OF THE AVAILABLE EVIDENCE .......... 50 
10.3 
DATA SAFETY MONITORING BOARD ....................................................................................... 51 
10.4 
NOTIFICATION OF DEATHS ....................................................................................................... 52 
11 
STATISTICS AND DATA ANALYSIS ......................................................................... 53 
11.1 
SAMPLE SIZE CALCULATION .................................................................................................... 53 
11.2 
SAMPLE SIZE REASSESSMENT ................................................................................................ 53 
11.3 
PLANNED RECRUITMENT RATE ............................................................................................... 53 
11.4 
STATISTICAL ANALYSIS PLAN .................................................................................................. 55 
11.4.1 
Analysis sets ................................................................................................................... 55 
11.4.2 
Summary of baseline data and flow of patients .............................................................. 55 
11.4.3 
Primary outcome analysis ............................................................................................... 56 
11.4.4 
Secondary outcome analysis .......................................................................................... 56 
11.4.5 
Procedure(s) to account for missing or spurious data .................................................... 57 
11.4.6 
Other statistical considerations. ...................................................................................... 57 
11.5 
DATA COLLECTION FOR ECONOMIC EVALUATION ............................................................... 57 
12 
DATA HANDLING ....................................................................................................... 59 
12.1 
DATA COLLECTION TOOLS AND SOURCE DOCUMENT IDENTIFICATION .......................... 59 
12.2 
DATA HANDLING AND RECORD KEEPING ............................................................................... 60 
12.3 
ACCESS TO DATA ....................................................................................................................... 60 
12.4 
ARCHIVING .................................................................................................................................. 60 
13 
MONITORING, AUDIT & INSPECTION ...................................................................... 62 
14 
ETHICAL AND REGULATORY CONSIDERATIONS .................................................. 63 
14.1 
ETHICS COMMITTEE (EC) REVIEW & REPORTS ..................................................................... 63 
14.2 
PUBLIC AND PATIENT INVOLVEMENT ..................................................................................... 63 
14.3 
REGULATORY COMPLIANCE..................................................................................................... 67 
14.4 
PROTOCOL COMPLIANCE ......................................................................................................... 67 
14.5 
NOTIFICATION OF SERIOUS BREACHES TO GCP AND/OR THE PROTOCOL ..................... 68 
14.6 
DATA PROTECTION AND PATIENT CONFIDENTIALITY .......................................................... 68 
14.7 
FINANCIAL AND OTHER COMPETING INTERESTS FOR THE CHIEF INVESTIGATOR, PIS 
AT EACH SITE AND COMMITTEE MEMBERS FOR THE OVERALL TRIAL MANAGEMENT .. 68 
14.8 
INDEMNITY................................................................................................................................... 68 
14.9 
ACCESS TO THE STUDY DATA BY KCE AND SIMILAR INSTITUTES IN THE EU .................. 69 
14.10 
ACCESS TO THE FINAL TRIAL DATASET BY OTHER PARTIES ............................................. 70 
15 
DISSEMINATION POLICY .......................................................................................... 70 
15.1 
DISSEMINATION POLICY ............................................................................................................ 70 
15.2 
AUTHORSHIP ELIGIBILITY GUIDELINES AND ANY INTENDED USE OF PROFESSIONAL 
WRITERS ...................................................................................................................................... 70 
15.3 
COMMUNICATION PLAN ............................................................................................................. 71 
16 
REFERENCES ............................................................................................................ 72 

 
Protocol FOOT DROP (S62895)        Version: V3.0       Version date: 10-03-2023 
4 
◼ SIGNATURE PAGE 
 
The undersigned confirms that the following protocol has been agreed and accepted and that the Chief 
Investigator agrees to conduct the trial in compliance with the approved protocol and will adhere to the 
principles outlined in the requirements for the conduct of clinical trials in the EU as provided for in " Directive 
2001/20/EC”, ),  and any subsequent amendments, GCP guidelines, the Belgian law of May 7th 2004 
regarding experiments on the human person, the Sponsor’s SOPs, and other regulatory requirements as 
amended. 
I agree to ensure that the confidential information contained in this document will not be used for any other 
purpose other than the evaluation or conduct of the clinical investigation without the prior written consent 
of the Sponsor. 
I also confirm that I will make the findings of the study publically available through publication or other 
dissemination tools without any unnecessary delay and that an honest accurate and transparent account 
of the study will be given; and that any discrepancies from the study as planned in this protocol will be 
explained. 
 
For and on behalf of the Study Sponsor, Chief Investigator: 
Signature:  
...................................................................................................... 
 
Date: 
....../....../...... 
Name (please print): 
...................................................................................................... 
 
 
Position: 
...................................................................................................... 
 
 
 
Statistician: 
 
 
Signature: 
...................................................................................................... 
 
Date: 
....../....../...... 
Name: (please print): 
...................................................................................................... 
 
 
 
Position: 
...................................................................................................... 
 
 
 
For acknowledgement on behalf of the funder (KCE): 
Signature:  
...................................................................................................... 
 
Date: 
....../....../...... 
Name (please print): 
...................................................................................................... 
 
 
Position: 
...................................................................................................... 
 
 
 
Principal Investigator Participating Site: 
Signature:  
...................................................................................................... 
 
Date: 
....../....../...... 
Name (please print): 
...................................................................................................... 
 
 
Position: 
...................................................................................................... 
 
 
 
 
 
 

 
Protocol FOOT DROP (S62895)        Version: V3.0       Version date: 10-03-2023 
5 
KEY TRIAL CONTACTS 
 
Chief Investigator 
Tom Theys – UZ Leuven Department of Neurosurgery 
Herestraat 49, 3000 Leuven 
tom.theys@uzleuven.be 
+32 16 34 42 90  
Trial Coordinator 
Christophe Oosterbos  – Departement of Neurosurgery 
Herestraat 49, 3000 Leuven 
christophe.oosterbos@uzleuven.be 
+32 16 34 52 60 
Blinded Researcher 
A blinded researcher will be appointed in every participating center. Preferably, 
the outcome assessor will be an independent physician. This will be finalized in 
the delegation logs.  
Sponsor 
Universitaire Ziekenhuizen Leuven  
Herestraat 49, 
3000 Leuven 
CTC@uzleuven.be  
+32 16 34 19 98 
 
Although KCE provides funding for the trial, KCE shall under no circumstances 
be considered as sponsor of the Study or assume any responsibilities or 
liabilities in connection therewith, and sponsor or co-sponsor shall make no 
representations whatsoever in this respect. 
Funder(s) 
Belgian Health Care Knowledge Centre (KCE) 
Administrative Centre Botanique, Doorbuilding, Boulevard du Jardin Botanique 
55, B-1000 Brussels, Belgium  
Trials@kce.fgov.be  
00 32 2 287 33 88 
Clinical Trials Unit 
Ellen Nijs  
Ine Vanopdenbosch 
Clinical Trial Center UZ Leuven 
Herestraat 49, 3000 Leuven 
ctc@uzleuven.be 
+32 16 34 19 98 
Statistician 
Kris Bogaerts - L-BioStat 
Kapucijnenvoer 35 bus 7001, 3000 Leuven 
Kris.Bogaerts@kuleuven.be 
+32 16 37 33 43 
 

 
Protocol FOOT DROP (S62895)        Version: V3.0       Version date: 10-03-2023 
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Data Manager 
Jill Claes - Clinical Trial Center UZ Leuven 
Herestraat 49, 3000 Leuven  
ctc.datamanagement@uzleuven.be 
+32 16 34 43 91 
Committees 
Trial Steering Committee 
Trial Management Group 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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TRIAL SUMMARY 
 
Trial Title 
A PROSPECTIVE, MULTI-CENTER, RANDOMIZED, PARALLEL-
GROUP CONTROLLED TRIAL TO COMPARE CONSERVATIVE 
VERSUS SURGICAL TREATMENT IN PERONEAL NERVE 
ENTRAPMENT 
 
Short title 
FOOT DROP: Follow-up and Outcome of Operative Treatment with 
Decompressive Release Of the Peroneal nerve 
 
Trial Design 
This is a prospective, multi-center, randomized, parallel-design study. 
This is a superiority trial: the goal is to prove superiority of surgery to 
maximal conservative treatment. 
Subjects will be randomized 1:1 to surgery or to conservative 
treatment. No cross-over is allowed until the primary endpoint is 
assessed at 9 months after randomization. After the primary endpoint 
is assessed, cross-over to surgery is allowed, with extended follow-up 
at 18 months after randomization (equals 9 months after primary 
endpoint).  
Trial Participants and setting 
Patients with electrodiagnostic (EDX)-documented peroneal nerve 
entrapment with persisting foot drop 10 +/- 4 weeks after onset of 
symptoms will be included in the trial. Imaging to exclude a 
compressive mass at the level of the fibular head is required, since 
these patients are excluded from the trial. Included patients will be 
allocated to either surgical decompression of the peroneal nerve or 
maximal conservative treatment. 
Intervention 
Decompressive release of the peroneal nerve at the level of the fibular 
head. 
Control 
Maximal (prolonged) conservative treatment with physiotherapy 
aiming at muscle strengthening and gait rehabilitation.  
Allowed: use of foot-ankle orthosis / electrostimulation and other 
therapies reflecting daily practice.  
Primary Endpoint 
Difference in distance (in meters) covered during the six-minute walk 
test between baseline and 9 months after randomization  
Secondary Endpoint(s) 
Key secondary endpoint:  
- 
Time to recovery (defined as the time necessary to cover the 
minimal age- and sex-specific normal 6MWD AND the time 
necessary for foot drop recovery to an MRC-score ≥ 4 for 
ankle dorsiflexion 
Secondary endpoints: 
- 
Ankle dorsiflexion strength at 10 days (surgical group), 6 
weeks, 3 months, 6 months, 9 months and 18 months after 
randomization. 
- 
Gait assessment at 6 weeks, 3 months, 6 months, 9 months 
and 18 months after randomization. 
- 
Complications and  neurological deficits at 10 days (surgical 
group), 6 weeks, 3 months, 6 months, 9 months and 18 
months after randomization.  

 
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- 
Health-economic assessment at 6 weeks and 6 months after 
randomization.  
- 
Electrodiagnostics (EDX) at 3 months and 9 months after 
randomization. 
- 
Patient-reported outcome measures at 10 days (surgical 
group), 6 weeks, 3 months, 6 months, 9 months and 18 
months after randomization.  
Planned Sample Size 
Overall, the study will enrol 182 subjects in 2 treatment arms, 91 
subjects per arm.  
The statistical analysis plan will contain a blinded sample size 
reassessment to verify if the planned sample size is sufficient to show 
the minimal clinical important difference. 
 In phase 1, the study will be conducted in 19 centers in Belgium and 
1 center in the Netherlands. If the predefined, minimal yearly number 
of randomizations is not reached, additional centers can be initiated in 
phase 2. 
Treatment duration 
The duration of treatment in the conservative arm of the trial is 9 
months. 
Surgery can be performed in day-care setting or through short 
hospitalisation (up to 2 nights). Postoperative physiotherapy can be 
variable.  
If cross-over occurs after 9 months, postoperative treatment is 
standard of care and depending on the treating physician. 
Follow up duration 
Primary endpoint is assessed at 9 months.  
Extended follow-up at 18 months. 
Duration of the trial (FPI-CSR) 
All patients will be included within 4 years after the last site initiation 
visit in the phase 1 study centers. Maximal trial duration is 5.5 years. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ROLE OF STUDY SPONSOR AND FUNDER 
 
UZ Leuven as mentioned in KEY TRIAL CONTACT shall act as sponsor of the Study, as defined in the Law 
of 2004, and shall assume all responsibilities and liabilities in connection therewith and procure the 
mandatory liability insurance coverage in accordance with the Law of 2004. UZ Leuven shall ensure that it 
shall be mentioned in the Protocol, the Informed Consent Forms and in other relevant communication with 

 
Protocol FOOT DROP (S62895)        Version: V3.0       Version date: 10-03-2023 
9 
the Study Subjects or the Regulatory Authorities as sponsor of the Study. UZ Leuven acknowledges and 
agrees for the avoidance of doubt that KCE shall under no circumstances be considered as sponsor of the 
Study or assume any responsibilities or liabilities in connection therewith, and UZ Leuven shall make no 
representations whatsoever in this respect.  
 
 

 
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10 
ROLES AND RESPONSIBILITIES OF TRIAL MANAGEMENT 
COMMITEES 
Trial Steering Committee (TSC) 
The role of the Trial Steering Committee (TSC) is to provide the overall supervision of the trial. The TSC 
monitors trial progress, conduct and advise on scientific credibility. The TSC will consider and act, as 
appropriate, and ultimately carries the responsibility for deciding whether a trial needs to be stopped on 
grounds of safety or efficacy. 
 
The TSC will meet on average 3 times per year the first year and twice a year thereafter. The TSC is 
composed of the Chief Investigator (CI), the trial statistician, the trial Project Manager (PM), an independent 
expert, a representative of other participating centres or groups, up to 2 patients or members of the public, 
1 representative of the sponsor, and 1 representative of the funder. 
 
Members of the TSC: 
 
1. Tom Theys, M.D., PhD. Department of neurosurgery, UZ Leuven (Chief Investigator) 
2. Robin Lemmens, M.D., PhD. Department of neurology, UZ Leuven 
3. Johannes van Loon, M.D., PhD. Chairman of the department of neurosurgery, UZ Leuven 
4. Frank Weyns, M.D. Chairman of the department of neurosurgery, ZOL Genk (Representative 
participating center) 
5. Annie Dubuisson, M.D., PhD. Department of neurosurgery, CHU de Liège (Co-chief Investigator)  
6. Justus Groen, M.D. Department of neurosurgery, Leids Universitair Medisch Centrum 
(Representative participating center) 
7. Kris Bogaerts, PhD. L-Biostat (Trial statistician) 
8. Ine Vanopenbosch, Clinical Trial Center UZ Leuven 
9. Nelle Stocquart (Representative KCE) 
10. Magdalena Zabrzeska-Schmitt, physiotherapist, UZ Leuven  
11. Philip Van Damme, M.D., PhD. Department of neurology, UZ Leuven (Independent expert) 
12. Lukas Rasulic, M.D., PhD. Department of neurosurgery, Clinical center of Serbia (Independent 
expert) 
13. Jan Goffin, M.D., PhD. Emeritus professor, former head of the department of neurosurgery, UZ 
Leuven (Independent expert) 
14. Irena Vicchio: Patient representative: ongoing process 
 
There is no need for a true data safety monitoring board (see section 10.3). However, the independent 
experts (experts that are not directly involved in the trial) will act as an ‘extern advisory board’ to follow up 
on possible harm (e.g. related to late cross-over to surgery) and to follow up on blinding and accidental 
unblinding. 
 
 
 
 
 
 
 
 
 
 

 
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Trial Management Group (TMG) 
The day-to-day management of the study will be performed by the Trial Management Group (TMG), 
which is distinct from the TSC.  
Members of the TMG: 
 
1. Tom Theys, M.D., PhD. Department of neurosurgery, UZ Leuven (chief investigator) 
2. Christophe Oosterbos, M.D. Department of neurosurgery, UZ Leuven (project manager) 
3. Jill Claes, Clinical Trial Center, UZ Leuven (data manager) 
4. Annie Dubuisson, M.D., PhD. Department of neurosurgery, CHU de Liège (co-chief investigator) 
5. Kris Bogaerts, PhD. L-BioStat (trial statistician)  
6. Sophie Hoornaert, Clinical Trial Assistant, UZ Leuven 
 
LIST OF ABBREVIATIONS 
 
ABBREVIATION 
DEFINITION 
AE 
Adverse Event 
CA 
Competent Authority 
CI 
Chief Investigator 
CMAP 
Compound Motor Action Potential 
CRF 
Case Report Form 
CRO 
Contract Research Organisation 
DMC 
Data Monitoring Committee 
DSUR 
Development Safety Update Report 
EC 
Ethics Committee 
EDB 
Extensor Digitorum Brevis Muscle 
EDX 
Electrodiagnostics 
EMG 
Electromyography 
EU 
European Union 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice  
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation of technical requirements for 
registration of pharmaceuticals for human use. 
IDMC 
Independent Data Monitoring Committee 
ISF 
Investigator Site File 
KCE 
Belgian Healthcare Knowledge Centre 
MCID 
Minimal clinically important difference 
MRC 
Medical Research Council 

 
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MS 
Member State 
MS 
Multiple Sclerosis 
NCS 
Nerve Conduction Studies 
PI 
Principal Investigator 
PIS 
Participant Information Sheet 
PM 
Project Manager 
QA 
Quality Assurance 
QC 
Quality Control 
QoL 
Quality of Life 
RCT 
Randomised Control Trial 
SAE 
Serious Adverse Event 
SAR 
Serious Adverse Reaction 
SDV 
Source Data Verification 
SNAP 
Sensory Nerve Action Potential 
SOP 
Standard Operating Procedure  
SSI 
Site Specific Information 
SUSAR 
Suspected Unexpected Serious Adverse Reaction  
TMG 
Trial Management Group 
TSC 
Trial Steering Committee 
TMF 
Trial Master File 
WPAI:GH 
Work Productivity and Activity Impairment Questionnaire: General Health 
6MWT 
Six-minute walk test 
6MWD 
Distance covered during the six-minute walk test in meters (six-minute 
walk distance) 
 
 
 
 

 
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TRIAL FLOW CHART 
 
 
SCREENING VISIT (SOC)
Diagnosis (clinical, imaging, EDX)
Informed Consent
schedule surgery
RANDOMIZATION VISIT (DAY 0)
Clinical re-evaluation
Blinded baseline assessment by clinical 
researcher
CONSERVATIVE TREATMENT (SOC)
FOLLOW UP VISIT 6 WEEKS  (SOC)
Clinical evaluation by treating physician
Blinded evaluation by clinical researcher
(key) secondary endpoints
FOLLOW UP VISIT 3 MONTHS
Blinded evaluation by clinical researcher
(key) secondary endpoints (EDX)
FOLLOW UP VISIT 6 MONTHS
Blinded evaluation by clinical researcher
(key) secondary endpoints 
FOLLOW UP VISIT 9 MONTHS
Blinded evaluation by clinical researcher
Primary endpoint (6MWD)
(key) secondary endpoints (EDX)
SURGICAL DECOMPRESSION (SOC)
max. 1 week after randomization
6-14 weeks after onset of symptoms
FOLLOW UP VISIT 10 DAYS (SOC)
Postoperative control
Ankle dorsiflexion strength / QOL / 
Complications & neurological deficits
FOLLOW UP VISIT 6 WEEKS  (SOC)
Clinical evaluation by treating physician
Blinded evaluation by clinical researcher
(key) secondary endpoints
FOLLOW UP VISIT 3 MONTHS
Blinded evaluation by clinical researcher
(key) secondary endpoints (EDX)
FOLLOW UP VISIT 6 MONTHS
Blinded evaluation by clinical researcher
(key) secondary endpoints
FOLLOW UP VISIT 9 MONTHS
Blinded evaluation by clinical researcher
Primary endpoint (6MWD)
(key) secondary endpoints (EDX)
 
FINAL STUDY VISIT 18 MONTHS 
Cross-over to surgery is only allowed after the primary endpoint at 9 months is reached.  
Assessment of secondary outcome by clinical researcher 
1:1 

 
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◼ STUDY PROTOCOL 
1 BACKGROUND 
Peroneal neuropathy is the most common neuropathy in the lower limbs(1-4) and represents the third most 
common focal neuropathy, after median and ulnar nerve pathology (5, 6). Epidemiologic data on peroneal 
neuropathy are scarce. Studies from Egypt (7, 8) found a prevalence of symptomatic peroneal neuropathy 
of 40 per 100.000 inhabitants in a population-based survey, and 19 per 100000 in a community-based 
study of 42633 subjects. Based on the data from the Egyptian studies (7, 8), 0.6% to 1.2% of all 
neuropathies are peroneal neuropathies. The reported percentage of 0.6% in the Kandil series is probably 
an underestimation of the total number of peroneal neuropathies, since all idiopathic neuropathies were 
reported as a separated category. Cruz-Martinez et al. (9) however, found 150 peroneal neuropathies in a 
patient database of 1000 neuropathies (15%), contrasting the percentages of Khedr and Kandil. According 
to Katirji et al.(10), 10% of peroneal neuropathies are bilateral. Motor deficits are frequent and even patients 
with subclinical peroneal mononeuropathy are at increased risk of falling (11-13). There is no data on the 
number of subjects with peroneal nerve entrapment suffering from foot drop. 
The etiology of peroneal neuropathy is very broad. The nerve can be compressed by cysts and tumors 
(14), or due to muscle herniation (15). The peroneal nerve is also sensitive to external compression which 
can result from bracing, wearing a tight cast, habitual crossing of the legs, squatting and kneeling. Peroneal 
neuropathy is frequently associated with excessive weight loss, as seen after bariatric surgery (3, 16-19) 
or anorexia nervosa (20); some authors believe that the loss of subcutaneous fat tissue in the area of the 
fibular head causes increased susceptibility to compression (6, 21). Long-term bedridden patients are also 
prone to peroneal neuropathy (1, 22, 23). Iatrogenic damage can occur after surgery of the hip, knee and 
ankle, or even after thoracic-abdominal surgery due to patient positioning. Other potential causes are 
trauma (23-25) and metabolic disorders (e.g. diabetes mellitus, hypothyroidism) (26). 
Given the broad range of causes of peroneal neuropathy, treatment strategies are likely to vary for different 
subtypes of peroneal nerve pathology. Peroneal neuropathies can be classified as idiopathic, idiopathic 
with established risk factors (e.g. leg crossing, squatting, weight loss, kneeling, metabolic disorders, 
bracing, …) and non-idiopathic peroneal neuropathies (e.g. trauma, iatrogenic, cysts and tumors, …). In 
this proposal, non-idiopathic peroneal neuropathies are not discussed, since these ‘subtypes’ will be 
excluded from the trial. The pathology of interest will be referred to as peroneal nerve entrapment. Peroneal 
nerve pathology in general will be referred to as peroneal neuropathy. 
The peroneal nerve is especially vulnerable to compression at the level of the fibular head, due to its 
superficial course. Here, the nerve dives in the fibular tunnel, defined by the fibular neck, peroneus longus 
muscle and soleus muscle(27). Figure 1 illustrates the anatomy at the level of the fibular head. 
 
 

 
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15 
Figure 1 Anatomy of the peroneal nerve at the level of the fibular nerve (Illustration by Irene Caprara). 
 
Conservative treatment of peroneal nerve entrapment consists of physiotherapy using stretching of the 
calf muscles to prevent contractures, muscle strengthening and gait rehabilitation (28). Physiotherapy 
exercises are sometimes combined with functional electrical stimulation and electrostimulation has been 
applied for denervated muscles after peripheral nerve lesions (29-31). Ankle foot orthoses can improve gait 
parameters and functional ambulation in patients with foot drop (28, 32-34). The available literature on the 
conservative treatment mainly consists of retrospective series (22, 24, 35-39) describing a very 
heterogeneous patient population including traumatic and iatrogenic peroneal nerve lesions. The number 
of patients with peroneal nerve entrapment was low varying between 14 and 33 with a follow-up ranging 
between three months and three years. Outcome of these retrospective series is summarized in table 1. 
One multicenter prospective study of 46 patients (28) documented follow-up data in conservatively treated 
patients including 13 patients who did not receive any treatment at all due to mild symptoms. After a mean 
follow-up of 6 months, 39% of the conservatively treated patients (n = 33) needed a foot orthosis to be able 
to walk and 53% had a normal gait pattern. In patients in whom no conservative treatment was initiated 
25% needed a foot orthosis and 63% had a normal gait pattern. Overall, 79% of patients with peroneal 
nerve entrapment reported improvement of ankle dorsiflexion at 6 months (n = 34). Taking all available 
literature into consideration, good outcome after conservative treatment for peroneal nerve entrapment 
varies between 53% and 100% in the literature. When interpreting these range of outcome percentages, 
one should realize that outcome measures differ between the studies. If data was available, good outcome 
was translated to an MRC-score ≥ 4 for ankle dorsiflexion. If data was not available, outcome measure of 
the study was documented.   
Sangwan et al. (40) reported the results of conservative treatment of foot drop due to prolonged squatting 
in a prospective case series of 30 patients (34 limbs). Thirty-two foot drops fully recovered after 3 to 9 
weeks. The other 2 patients recovered fully after 16 and 20 weeks (100%). Cruz-Martinez (9) prospectively 
documented the clinical evolution of foot drop in 30 patients receiving no or conservative treatment. Twenty-
six patients fully recovered after a period of 3 weeks to 3 months, three other patients reported minimal 
weakness (97%). The severe muscle weakness in 1 patient did not improve after 6 months (but recovered 
within 2 weeks after neurolysis). Although these findings are not confirmed in other case studies, these 
series describe possible recovery of foot drop in an early stage with conservative therapy. These findings 
are important regarding the timing of randomization (see 5.1 full-scale study design).  
Fares et al. (41) reviewed foot drop after bariatric surgery in 21 cases. Seven patients were treated 
conservatively and improved (100%). Two other foot drops resolved spontaneously. Since the degree of 
recovery was often not specified, this study was not included in Table 1. 
 
 
Author 
Type of study 
Number 
of 
patients 
Outcome 
measure 
Good 
outcome 
(%) 
Follow-up 
Aprile (24) 
Retrospective  
 
14 
Improvement 
ankle dorsiflexion 
or 
absence 
of 
gait difficulties  
71% 
3 months – 3 years 
Berry (37) 
Retrospective  
14 
MRC-score ankle 
dorsiflexion ≥ 4 
64% 
up to 1 year 
Bsteh (38) 
Retrospective  
25 
MRC-score ankle 
dorsiflexion ≥ 4 
88% 
9.3 months (mean) 
Sipahioglu (39) 
Retrospective 
14 
(16 
limbs) 
MRC-score ankle 
dorsiflexion ≥ 4 
87.5% 
Until 
full 
recovery 
(max. 13 weeks) 
Aprile (28) 
Prospective 
 
33* 
 
34 
Absence of gait 
difficulties 
53% 
 
79% 
6 months 

 
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Improvement of 
ankle dorsiflexion 
Sangwan (40) 
Prospective 
30 
(34 
limbs) 
MRC-score ankle 
dorsiflexion ≥ 4 
100% 
Mean: 28.2 months 
Cruz-Martinez 
(9) 
Prospective 
30 
MRC-score ankle 
dorsiflexion ≥ 4 
97% 
Until recovery (max. 
7 months) 
Table 1 Outcome after conservative treatment. Good outcome is defined as an MRC grade ≥ 4 for ankle 
dorsiflexion. * Patients with mixed etiology of peroneal neuropathy.  
 
The surgical approach for entrapment at the fibular head aims at decompressing the peroneal nerve as it 
dives under the peroneus longus muscle. Similar to the literature on conservative treatment most studies 
on the surgical management concerned retrospective patient series (3, 31, 42-54). Some studies had a 
very heterogeneous patient population hampering extraction of required data, or did not discuss patients 
with peroneal nerve entrapment (31, 46, 48, 52-54). Most series suffered from a low sample size (the 
smallest study included only 12 patients) with a great variability in timing between symptom onset and 
surgery ranging from weeks to years. On average patients were operated after 4.6 months (range:1 month 
-27 months for the included case series) with a follow-up duration ranging from 11 months to 7 years. 
We identified 2 prospective studies, one describing 14 patients with a follow-up of one year after surgery 
(55) recording improvement of ankle dorsiflexion in 13 of 14 patients (93%), with half of the patients having 
normal ankle dorsiflexion at one year. The prospective series of Nirenberg (56) described the outcome of 
17 patients with peroneal neuropathy (of unknown etiology) and a follow-up of minimum 4 months. Seven 
of 17 patients (41%) reported an MRC grade ≥ 4 for hallux dorsiflexion. All patients reported improvement 
of ankle dorsiflexion and sensory changes within one week after surgery.   
Broekx et al. (3) described a large retrospective series of neurolysis after excessive weight loss. In total, 
200 patients were included and on average patients were operated 4 months after symptom onset. Of all 
included patients, 85% had a good outcome, defined as an MRC scale for muscle strength grade ≥ 4 for 
ankle dorsiflexion. Complications after peroneal nerve are unusual(3). In the largest retrospective patient 
series, 7 out of 200 patients suffered from wound problems, 1 out of 200 patients suffered from 
postoperative abscess formation and subsequent bacterial sepsis (3). Overall, good outcome after 
decompressive surgery for peroneal nerve entrapment varies between 43% and 100% in the literature. 
When interpreting these range of percentages, one should realize that outcome measures differ between 
the studies. If data was available, good outcome was translated to an MRC-score ≥ 4 for ankle dorsiflexion. 
If data was not available, outcome measure of the study was documented.   
 
Fares et al. (41) reviewed foot drop after bariatric surgery in 21 cases. Twelve patients were operated and 
improved (100%). The degree of recovery is often not specified. Table 2 gives an overview of the literature 
discussed. (Fares et al. was not included in the table, due to the aforementioned reasons.)  
 
 
Author 
Type of study 
Number 
of 
patients 
Outcome measure 
Good 
outcome 
(%)  
Follow-up 
Broekx (3) 
Retrospective  
200 
MRC-score 
ankle 
dorsiflexion ≥ 4 
85% 
N.A. 
Maalla (44) 
Retrospective 
12 
MRC-score 
ankle 
dorsiflexion ≥ 4 
92% 
42 months (mean) 
Mitra (47) 
Retrospective  
12 
MRC-score 
ankle 
dorsiflexion ≥ 4 
100% 
11 months – 7 years 
Lale (57) 
Retrospective 
9 
MRC-score 
ankle 
dorsiflexion ≥ 4 
100% 
Until recovery, max. 60 
days 

 
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Ramanan (50) Retrospective  
10 
MRC-score 
ankle 
dorsiflexion ≥ 4 
40% 
2 – 60 months (mean 
19 months) 
Wilson (58) 
Retrospective  
14 
Improvement 
of 
ankle dorsiflexion 
71% 
29 months (median) 
Nirenberg 
(56) 
Prospective* 
17* 
MRC-score 
ankle 
dorsiflexion ≥ 4 
41% 
Minimum 4 months 
Tarabay (55) 
Prospective  
14 
MRC-score 
ankle 
dorsiflexion ≥ 4 
86% 
1 year 
Table 2 Outcome after surgical treatment. *Inclusion of patients with peroneal neuropathy of mixed etiology.  
 
Comparative studies or randomized controlled trials are not available in the literature. Hence, the foot drop 
trial will be the first, randomized controlled trial to compare both conservative treatment and surgery in a 
prospective manner.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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2 RATIONALE  
The rationale for this study is to explore whether a surgical approach to peroneal nerve entrapment is 
warranted i.e. does a foot drop, caused by peroneal nerve entrapment, recover faster and better after 
surgical release? This question is relevant, given the fact that the actual treatment strategy varies greatly 
between and even within different centers, depending on the consulting physician.  
Since peroneal nerve entrapment represents one of the most common entrapments, and no practice 
guidelines exist on its preferred treatment, this prospective study will provide important outcome data after 
conservative treatment (current data very limited), as well as surgical treatment (current data very biased, 
retrospective in nature and uncontrolled). The impact on quality of life will be assessed and the 
complications (surgical, chronic pain, sensory changes, …) of both treatments will be recorded. These data 
will define future treatment guidelines for this mononeuropathy and is thus relevant for all physicians treating 
entrapment neuropathies (neurology, neurosurgery, physical medicine, orthopaedic surgery, …).  
There is indeed insufficient data in the available literature to make any recommendations. No studies have 
compared surgical versus conservative treatment in a prospective manner and currently no guidelines are 
available. Even data on the prevalence and the spontaneous evolution of peroneal neuropathy are virtually 
non-existent. 
The lack of prospective studies on this topic is remarkable since most patient series on both the 
conservative and surgical treatment are retrospective in nature. Most patient series are very heterogeneous 
given the fact that patients with peroneal nerve damage due to different causes were included, which makes 
it difficult to draw conclusions on the clinical management. Based on the current literature, the percentage 
of patients with good outcome after conservative treatment varies between 53% and 100% (9, 22, 24, 28, 
36-40). Data concerning the spontaneous evolution of peroneal nerve entrapment (without any intervention) 
is almost absent, except for 15 patients (28, 41). Furthermore, studies discussing prevalence, report 
contrasting percentages (7-9).  
 
After reviewing the current literature, we identified several methodological issues when comparing the 
various studies. Good outcome was not uniformly defined and duration of follow-up differed not only 
between, but even within studies (where follow-up could range from 5 months to 3 years (36)). Additionally, 
the number of patients was low to very low in most studies.   
Most studies on decompressive surgery for the treatment of peroneal entrapment were retrospective in 
nature and for most studies the sample size was small. Similar to the studies on the conservative treatment, 
they involved a heterogeneous patient population and variable follow-up durations. The percentage of 
patients with good outcome varied between 40% and 100% (see Table 2). A meta-analysis of 136 patients 
(58) undergoing neurolysis demonstrated that surgery after more than 12 months of symptoms was 
associated with poorer outcomes, however there was no difference in outcome between surgery before 
and after 6 months of symptom onset. Overall, patients in the included studies were operated on average 
4.6 months after the onset of symptoms (average ranging between 1 month and 27 months). This seems 
quite late since several authors propose an early release (1, 3, 50, 57), although a recommendation on the 
exact time interval between onset of treatment and intervention is lacking. 
Overall there seems to be a tendency towards better outcome after surgery although this has to be 
cautiously interpreted. Indeed, no direct comparison between the two treatment modalities exists and most 
likely, certain surgical patients could have recovered spontaneously as well.  
 
The literature, mostly the lack of it, reflects the current practice in Belgium and the Netherlands. Current 
practice varies greatly between (and even within) centers. Treatment is mostly based on the personal 
experience of the physician. Many centers tend to follow a conservative treatment, while other centers tend 
to operate these patients after varying time windows. This issue became very apparent when different 
physicians were asked to participate in the trial. Responses ranged from ‘We unfortunately cannot 
participate to the study because we do not operate on patients with a peroneal nerve entrapment. We think 
it would not be ethical to start performing surgery on these patients’ to ‘We want to participate to the trial, 

 
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but we do not want to randomize patients with a foot drop after weight loss. These patients should always 
be operated on, as soon as possible, and it would therefore not be ethical to refrain from surgery’.  
 
Patients were involved in the trial design and were interviewed for feasibility reasons as well. In total, 31 
patient interviews were conducted. These interviews were conducted in a very biased population, given the 
fact that all patients had undergone surgery. Nevertheless, 74% of patients would be willing to 
participate in the proposed trial. The most frequent reason to refuse was related to their profession. 
Many patients needed to be able to walk safely and often (for example a construction worker). They feared 
that, if they were not operated on, recovery would take longer, and they would not be able to return to work. 
Taking this bias into account, 74% of inclusions represents a substantial number. In 90% of patients, the 
success of treatment could be measured by improvement in gait. For 74% good outcome was 
considered as being able to walk long distances (either for professional or recreational purposes). In 16% 
of patients, a decrease in frequency of falling was essential for their recovery.  
 
In conclusion, there are various good reasons to conduct the FOOT DROP trial: 
1. The optimal treatment for peroneal nerve entrapment (the most common neuropathy in the lower 
limbs) is unknown. The foot drop trial compares both treatment modalities in order to establish the 
optimal treatment. This will allow for the development of future guidelines.  
2. Impact on quality of life and health economics will be assessed. 
3. Useful prospective data, including long-term follow-up data on both treatment modalities will be 
gathered. Both treatment modalities are considered standard of care at the moment.  
4. The study has potential for return on investment, in terms of QALYs, by reducing the number of 
surgeries (if conservative treatment deems favorable) or by reducing the costs of failed 
conservative treatment (foot-ankle orthosis, physiotherapy, medications, …) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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3 ASSESSMENT AND MANAGEMENT OF RISK  
The additional diagnostic or monitoring procedures do not pose more than minimal additional risk or burden to 
the safety of the subjects compared to normal clinical practice.  
Therefore, this trial is categorised as a low intervention clinical trial.  
The risk of adverse events occurring as a consequence of the intervention in this trial is unlikely, therefore 
safety reporting will be limited to the safety reporting that is necessary in routine care.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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4 OBJECTIVES AND ENDPOINTS / OUTCOME MEASURES  
4.1 Primary objective 
The primary research question of the trial is to assess whether foot drop, caused by peroneal nerve 
entrapment in adult patients* recovers better within 9 months after decompressive surgery compared to 
prolonged standard conservative treatment.  
* Exclusion of iatrogenic or traumatic peroneal nerve palsies. Exclusion of peroneal nerve compression caused by cysts 
or tumours. Exclusion of patients with polyneuropathy. Exclusion of other surgical techniques than neurolysis.  
 
Intervention A: Decompressive release of the peroneal nerve at the level of the fibular head in patients with 
foot drop due to peroneal nerve entrapment.  
Intervention B: Prolonged conservative treatment of foot drop due to peroneal nerve entrapment. 
Null hypothesis: There is no difference in recovery of foot drop due to peroneal nerve entrapment after 
intervention A or intervention B.  
Alternative hypothesis: Recovery of foot drop due to peroneal nerve entrapment is superior after 
intervention A compared to intervention B. 
 
4.2 Secondary objectives 
The secondary objectives of the foot drop trial are:  
- 
To collect pathology-related data in peroneal nerve entrapment.  
- 
To evaluate and compare quality of life data of patients with foot drop due to peroneal nerve 
entrapment and to assess the evolution of quality of life during conservative/surgical treatment 
- 
To assess and compare follow-up electrophysiological data in patients with peroneal nerve 
entrapment 
- 
To assess the evolution of gait impairment in patients with foot drop due to peroneal nerve 
entrapment through a broad range of questionnaires/gait assessments. 
- 
To assess long-term follow-up (18 months after randomization) data after cross-over is allowed (to 
collect prospective data on long term follow-up). 
- 
To evaluate the cost-effectiveness of both treatment strategies. 
 
4.3 Endpoints  
4.3.1 Primary endpoint 
The primary endpoint is the difference in distance covered in meters during the six-minute walk test 
(6MWD) between baseline and 9 months after randomization.  Based on a literature analysis and patient 
feedback on the trial design, gait analysis and recovery of a normal gait pattern are crucial in the recovery 
of foot drop. In 88% of interviewed patients, success of treatment was related to gait improvement. The 
distance covered during the six-minute walk test (6MWD) is validated and clinically used in gait analysis.  
 
 

 
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4.3.2 Secondary endpoints  
Key secondary endpoint: time to recovery.  
Very limited data is available regarding time to recovery after surgical or conservative treatment in peroneal 
nerve entrapment (35, 55). Time to recovery is defined as: the time necessary to cover the minimal age- 
and sex-specific normal 6MWD AND the time necessary for foot drop recovery to an MRC-score ≥ 4 for 
ankle dorsiflexion. The minimal age- and sex-specific normal 6MWD is defined as 82% of the applied 
reference equations for prediction of the 6MWD (59, 60). The reference value that will be used is 
6MWDpred(m) = 868.8 – (ageyears x 2.99) – (gender x 74.7). The value for gender is 0 in male subjects and 
1 in female subjects (60).The reference values and equation are added to the study protocol in Appendix 
5. 
Other Secondary outcomes 
1. Ankle dorsiflexion strength: measured by the MRC-score and isometric dynamometry at 10 
days, 6 weeks, 3 months, 6 months, 9 months and 18 months after randomization. Ankle 
dorsiflexion strength will also be assessed after 10 days in the surgical arm of the trial. 
2. Gait assessment at 6 weeks, 3 months, 6 months, 9 months and 18 months after randomization 
with  
a. Functional ambulation categories, Stanmore questionnaire 
b. Gait speed during the 10-meter walk test 
c. The proportion of patients in both groups who reach minimal normal age- and sex-specific 
reference values for 6MWD, 9 months after randomization.  
d. Difference in distance covered in meters during the six-minute walk test between baseline 
and 6 weeks, 3 months, 6 months and 18 months after randomization 
3. Complications and neurological deficits : 
a. Motor changes including MRC-score for ankle eversion and hallux extension at 6 weeks, 
3 months, 6 months, 9 months and 18 months after randomization. Motor function will also 
be assessed after 10 days in the surgical arm of the trial.  
b. Sensory changes at 6 weeks, 3 months, 6 months, 9 months and 18 months after 
randomization. Sensory changes will also be assessed after 10 days in the surgical arm of 
the trial.  
c. Surgical complications at 10 days, 6 weeks and 18 months after surgery: a list of possible 
complications is composed to score in a uniform way in all centers.  
4. Health-economic assessment: 
a. Work productivity and Activity Impairment Questionnaire at 6 weeks and 6 months after 
randomization.  
b. Return to work at 6 weeks after randomization. 
5. Electrodiagnostics (EDX) at 3 months and 9 months after randomization. 
6. Patient-reported outcome measures: health-related quality of life (EQ5D-5L) at 6 weeks, 3 
months, 6 months, 9 months and 18 months after randomization. Patient-reported outcome 
measurements will also be assessed after 10 days in the surgical arm of the trial.  
For all secondary endpoints, baseline measurements will be obtained if applicable.  
 
 
 
 

 
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5 TRIAL DESIGN 
5.1 Full-scale study design 
The overall objective of the foot drop trial is to test the superiority of surgical release of the peroneal nerve 
at 10 +/- 4 weeks after symptom onset to maximal conservative treatment. The FOOTDROP trial is 
designed as a prospective, multicenter, randomized, parallel-design study. A double-blind design is not 
possible, given the fact that both the treating physician and the patient will always know the allocated 
treatment strategy. The clinical researcher (= outcome assessor) will be blinded for treatment.  
Subjects will be randomized 1:1 to surgery or conservative treatment (simple randomization based solely 
on a single, constant 1:1 allocation ratio). If a patient, that signed the informed consent form (ICF), cannot 
be randomised because the foot drop has recovered, this will be documented in the eCRF. After 
randomization, the patients allocated to conservative treatment will enter a treatment period of 
approximately 9 months (individualised physiotherapy program). Patients allocated to the surgical arm will 
undergo surgery as soon as feasible after randomization (maximum within 1 week, preferably within 2 
days). For all participating patients that signed the informed consent at the screening visit, an operation day 
will be scheduled, maximum one week after the randomization visit (due to practical scheduling reasons). 
At the moment of scheduling, the patient will be unaware of this date to prevent bias (and orientation of the 
mindset of patients toward surgery). If a patient is allocated to the conservative arm of the trial, the 
scheduled operation date will be cancelled, without knowledge of the patient. To facilitate signing of the 
informed consent form at the screening visit, patients will be informed prior to the consultation about the 
study (by telephone, through the patient brochure). 
Patients in the surgical arm of the trial, are allowed to follow physiotherapy after surgery. The frequency 
and intensity are to be determined by the treating physician. All participants are allowed to use an ankle-
foot orthosis. The use of electrostimulation is not advised, although not forbidden.  
The endpoints will be evaluated at fixed time-points: 6 weeks, 3 months, 6 months and 9 months after 
randomization. Extended follow-up is scheduled 9 months after the primary endpoint is reached i.e. 18 
months after randomization. Most trial assessments will be performed by the site-specific blinded 
researcher, ideally an independent physiotherapist. Patients allocated to the surgical arm of the trial will be 
evaluated 10 days after neurolysis. A postoperative control is considered standard of care. Sensorimotor 
function, quality of life and complications will be assessed during this postoperative control. Assessment of 
MRC-scores for ankle dorsiflexion and ankle eversion is considered standard of care and shall be 
performed by the treating physician. The treating physician can also assess ankle dorsiflexion strength 
measured by isometric dynamometry. This cannot be done by the outcome assessor because this would 
lead to unblinding. 
A list of standard assessments (clinical records, considered daily practice = SOC; including motor and 
sensory function,  ability to walk (barefoot), need for orthosis, treatment) will be composed for uniformity 
across centers. Standard assessments will be conducted at each study visit.  
 
Cross-over is not allowed until the primary endpoint at 9 months is assessed. After the primary endpoint is 
assessed, cross-over from the conservative arm to surgery is allowed and patients will be treated according 
to standard of care (decision between treating physician and patient). Extended follow-up for all patients 
will be organised, 18 months after randomization. All primary and secondary endpoints, with the exception 
of electrodiagnostics, WPAI and return to work, will be assessed at 18 months. The End-of-Study (EOS) 
visit will take place at 18 months post-randomization. Cross-over patients will be followed-up as per 
protocol. All participating physicians and trial sites have the responsibility to guide patients throughout the 
study visits and are expected to follow protocol and to inform patients in a correct, objective manner. If the 
TSC documents an unusual high percentage of cross-over in a specific trial site, this trial site can be 
excluded from the foot drop trial.  
 
Ninety-one patients will be enrolled in each arm of the trial, so that in total 182 patients will be enrolled in 
the foot drop trial. A blinded sample size reassessment by the trial statistician is planned when 50% of the 
planned patients have reached their 9 month visit or one month before the final patient would be 

 
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randomized, whichever occurs first. A dropout rate of 5% is anticipated, based on a large randomised trial 
with similar design (61, 62). 
The foot drop trial is a multicenter trial. The number of participating centers will vary in function of the 
recruitment rate. In a first phase, 14 additional centers will be initiated apart from the pilot study centers. If 
recruitment is slower than expected, an additional 6 centers can be initiated. In other words; the study will 
run in 20 to 26 centers in Belgium and the Netherlands. The number of Dutch centers will be limited to 4 
(phase 1 + phase 2). 
 
 
 
Subgroup analysis 
A literature search was performed to identify predictors of good and bad outcome after surgical or 
conservative treatment. There is only limited data available and the data discussed come from several 
retrospective patient series (3, 38, 39, 43, 44, 63), one prospective conservative multicenter trial (28), one 
prospective case series (40) and one meta-analysis (58). Based on the cited articles, the following 
predictors of outcome will be used for further analysis:  
 
1. Diabetes 
2. Smoking (No, history, current) 
3. Rapid/significant weight loss (> 5% of total body weight (18, 64)) 
4. High age (> 60 years) 
5. Prolonged squatting 
 
These predictors will be used in an exploratory analysis for the primary and key secondary endpoint (see 
Section 11). In this way, interactions between the predictor and a possible treatment effect can be identified 
and several new hypothesises can be generated to be investigated in further trials (were several subgroups 
could be studied in further detail).  
 
- 
 
 

 
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6 STUDY SETTING 
 
The foot drop trial is a multicenter study.. In function of the recruitment rate, up to 23 Belgian centers and 
5 Dutch centers will participate in the trial. 
 
In each participating centre, there should be a department of neurosurgery, neurology and physical 
medicine/rehabilitation. The departments of orthopaedic surgery and plastic and reconstructive surgery will 
be involved as well if they are routinely involved in this patient care. To accentuate the multidisciplinary 
collaboration throughout the study, an non-surgical adjunct principal investigator should be appointed in 
each centre. There needs to be at least one neurologist/rehabilitation physician that is thoroughly trained 
in electrodiagnostics and has experience with the interpretation of electrophysiological investigations in 
patients with peripheral nerve entrapment. Since all patients are diagnostic using electrodiagnostics, the 
adjunct principal investigator is preferably the local electrophysiologist. 
The surgical procedure is not considered very complex. Therefore, every general neurosurgeon is qualified 
to perform the procedure in participating patients. A neurolysis can also be performed by an orthopaedic 
surgeon with experience in peripheral nerve surgery. Preferentially, every participating centre has an 
experienced peripheral nerve surgeon. The rehabilitation program can be organised within the participating 
center or in an ambulant setting, with physiotherapists working according to the proposed guidelines 
(designed to be a mirror of current daily practice).   
The blinded researcher (or outcome assessor), can be a site-specific clinical trial assistant, study-nurse, 
physiotherapist, resident or other qualified medical professional. The blinded assessor is preferably an 
independent physiotherapist. At each participating site, the (blinded) researchers will be trained in certain 
clinical assessments including isometric dynamometry and MRC-scoring for ankle dorsiflexion, hallux 
extension and ankle eversion. Training videos will be made available, so that a uniform assessment can be 
made in the different centers and inter-observer variability can be reduced to the minimum. These training 
videos will be shown at the site initiation visit and will be accompanied by a questionnaire. In this way, it 
can be guaranteed that the training has been followed.  
The majority of patients with peroneal nerve entrapment and foot drop present in an emergency setting. 
Most often, these patients are referred by general practitioners because of sudden gait difficulties and an 
increased risk of falling. Sometimes the reason for referral is further diagnostics since foot drop has a broad 
differential diagnosis, and some diagnoses require (semi-)urgent treatment (for example L5 radiculopathy 
with foot drop due to lumbar disc herniation). In other cases, patients present at the emergency department 
without referral because of the paralysis of the foot and associated gait difficulties. A small group of patients 
presents in private clinics of neurologists and physical medicine and rehabilitation physicians. With the 
exception of some unique cases, almost all patients present in the acute setting. The first medical 
examination is almost never conducted more than three months after onset of symptoms. The statements 
above are based on experience and conducted patient interviews.  
In every peroneal nerve entrapment case, diagnosis is made at the electrophysiology department. Involving 
the local electrophysiologist is therefore key to trial success. Ideally, the local electrophysiologist should be 
appointed as the non-surgical adjunct principal investigator. 
 
 
 
 
 
 
 
 
 

 
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7 ELIGIBILITY CRITERIA 
 
7.1 Inclusion criteria 
For inclusion in the study, the subject must fulfil the following inclusion criteria: 
• 
Written informed consent to participate in the study must be obtained from the subject or proxy / 
legal representative prior to initiation of any study-mandated procedure 
• 
EDX-documented peroneal nerve entrapment with persisting (10 ± 4 weeks) foot drop (MRC-
score ≤ 3)  
• 
Imaging (ultrasound/MRI) performed to exclude a compressive mass  
• 
Age ≥ 18 years 
 
7.2 Exclusion criteria 
• 
Subjects with posttraumatic or iatrogenic peroneal nerve injury  
• 
Subjects with peroneal neuropathy due to a compressive mass (e.g. cyst, tumour)  
• 
Peroneal nerve entrapment at other sites than the fibular head 
• 
Bilateral peroneal nerve entrapment 
• 
Patients with mental or physical problems that incapacitate them to participate in a 
physiotherapy program  
• 
Psychiatric illness  
• 
Pregnancy  
• 
Planned (e)migration within 1 year after randomization to another country  
• 
Subjects with previous foot drop  
• 
Permanently bedridden subjects 
• 
Subjects with neurological or musculoskeletal history which could impact foot drop assessment 
and/or gait analysis (e.g. polyneuropathy, hereditary neuropathy with pressure palsies, critical 
illness polyneuropathy, previous stroke, ankle surgery, ankle sprain, …). 
 
 
 
 
 
 
 
 
 
 

 
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8 TRIAL PROCEDURES  
8.1 Recruitment 
All patients with foot drop due to peroneal nerve entrapment will be screened for eligibility at the screening 
visit. If a patient does not meet the inclusion criteria, or if a patient declines to participate, this will be 
documented in the screening log (ineligibility). Reasons for refusal to participate will also be documented 
in the screening log. Data will be anonymised. If a patient does not receive the allocated treatment after 
randomisation, the reason will be documented in the screening log and the reason will be communicated 
to the trial co-ordinator. In summary, the following information will be collected in the screening log:  
- 
Screening number (not allowed to use initials, patient identification codes, not allowed to use any 
combination of elements that might allow the patient to be identified (GDPR) 
- 
Date of consent (if applicable) 
- 
Version of consent (if applicable) 
- 
Date screened 
- 
Eligible for enrolment?  
- 
Study specific number (only to be completed for enrolled subjects) 
- 
Date of randomization (if applicable)  
- 
Ineligibility reasons (if applicable). If a patient enrolled in the study but cannot be randomized due 
to recovery, this will be clearly documented.  
 
This allows for data collection in accordance with the 2010 CONSORT statement (Consolidated Standards 
of Reporting Trials) (65).  
 
8.1.1 Patient identification 
Most patients, if not all, present within 3 months, due to the acute onset of paralysis. A significant 
percentage of patients with foot drop is referred (by the general practitioner) to the emergency department 
and will be detected in a very early stage. The reason for early referral is caused by the functional deficit 
resulting in difficulties walking and also due to the fact that the differential diagnosis of foot drop is broad, 
and certain diagnoses require urgent treatment. Other patients will seek medical attention without referral 
because of sudden gait problems.  All but one interviewed patients sought medical attention within six 
weeks after the onset of symptoms, 63% presented in the first week.  
The patient will be seen by a neurosurgeon, an orthopaedic surgeon, a neurologist or a physical medicine 
doctor. These departments will thus be heavily involved in this trial. . In every peroneal nerve entrapment 
case, diagnosis is made at the electrophysiology department. Involving the local electrophysiologist is 
therefore key to trial success. Ideally, the local electrophysiologist should be appointed as the non-surgical 
adjunct principal investigator. 
The treating physician will recruit the patient. At this stage, only the existing clinical care team has access 
to the patient records and therefore the treating physician will evaluate if the subject is a suitable candidate 
for the study based on the inclusion and exclusion criteria. There will be no recruitment through publicity 
(posters, leaflets, adverts or websites). Patient or disease registers will not be used to identify potential 
participants.  
A small percentage of patients with foot drop due to peroneal nerve entrapment will present to neurologists 
and rehabilitation physicians in private practice, who do not always refer these patients to hospitals or 
surgical departments because they prefer a prolonged conservative treatment. An informative letter about 
the foot drop trial will be made to sensitize this group of treating physicians to refer their patients to a 
participating centre. These letters will be distributed through the representative national societies of both 

 
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specialisations. Furthermore, a manuscript reviewing the literature on peroneal nerve entrapment and 
discussing the foot drop study design was published in TNN (Tijdschrift voor Neurologie en Neurochirurgie). 
8.1.2 Screening 
Peroneal nerve entrapment will be confirmed by EDX after clinical investigation which is standard of care. 
The electrodiagnostic protocol will include motor nerve conduction studies [nerve conduction velocities, 
distal motor latencies, amplitudes of compound motor action potentials (CMAPs)], sensory nerve 
conduction studies and electromyography (EMG) evaluation during rest and voluntary contraction. EDX 
can identify other neuropathies/polyneuropathies or entrapment at other sites than the fibular head 
Imaging (MRI or/and ultrasound) will be performed to document a compressive mass at the level of the 
fibular head (cysts/tumours). Through patient history and clinical investigation, the treating physician can 
identify posttraumatic or iatrogenic nerve injury, as well as subjects under the age of 18 years, previous 
foot drops and permanently bedridden patients. Eligibility screening procedures involve no investigations 
that emit ionising radiation. A knee X-ray is optional and warranted in traumatic peroneal nerve injury, but 
these patients are excluded. In a traumatic peroneal neuropathy, an x-ray of the knee is considered 
standard of care.  
After the diagnosis of an EDX confirmed peroneal nerve entrapment at the level of the fibular head is made, 
the patient can be considered for inclusion in the trial, provided that ICF is obtained, and all other in- and 
exclusion criteria are fulfilled.  
After the ICF has been signed, the local investigator or delegate contacts the clinical coordinator to allocate 
a subject number to the subject.  
There are no intended payments to participants except reimbursement of reasonable travel expenses for 
any visits additional to normal care and reimbursement of expenses of extra investigations. There will be 
no extra payments to avoid a financial incentive to participate in the trial.  Details on the amount of payment 
will be included in the informed consent form.  
 
8.2 Consent  
 
The Principal Investigator (PI) retains overall responsibility for the informed consent of participants at their 
site and must ensure that any person delegated responsibility to participate in the informed consent process 
is duly authorised, trained and competent to participate according to the ethically approved protocol, 
principles of Good Clinical Practice (GCP) and Declaration of Helsinki. If delegation of consent is acceptable 
then details should be provided. 
Informed consent must be obtained prior to the participant undergoing procedures that are specifically for 
the purposes of the trial and are out-with standard routine care at the participating site. Data can only be 
collected if informed consent form is signed at the screening visit. In daily practice, this is often not the case 
since patients want to overthink participation. Throughout the pilot study, several patients that were willing 
to participate but recovered before informed consent form was signed. This data is lost.  
To tackle this issue, we will train and encourage centers to contact patients about the study prior to the 
study visit by telephone. Information about the trial is given and the patient brochure is sent to the patient. 
In this way, patients are already informed about the study at the screening visit and informed consent form 
can be signed. 
The right of a participant to refuse participation without giving reasons must be respected.   
The participant must remain free to withdraw at any time from the trial without giving reasons and without 
prejudicing his/her further treatment and must be provided with a contact point where he/she may obtain 
further information about the trial. Where a participant is required to re-consent or new information is 
required to be provided to a participant it is the responsibility of the PI to ensure this is done in a timely 
manner.  

 
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The PI takes responsibility for ensuring that all vulnerable subjects are protected and participate voluntarily 
in an environment free from coercion or undue influence. 
The participant population is not likely to include a significant proportion of participants who cannot read or 
write, require translators or have cognitive impairment (the patient must be a suited candidate for 
physiotherapy in order to participate in the trial). However, if present, appropriate alternative methods for 
supporting the informed consent process should be employed. This may include allowing a witness to sign 
on a participant’s behalf (in the case of problems with reading or writing), designate a legal representative, 
or providing Participant Information Sheets in other languages or in a format easily understood by the 
participant population (in the case of minors or cognitive impairment) providing they are approved by the 
Ethics Committee (EC). 
Informed consent will be signed by the patient or a legal representative. In the foot drop trial, the ICF will 
be discussed and signed at the screening visit. This process will involve: 
 
• 
discussion between the potential participant or his/her legally acceptable representative and an 
individual knowledgeable about the research, the nature and objectives of the trial and possible 
risks associated with their participation 
• 
the presentation of written material (e.g., information leaflet and consent document which must 
be approved by the EC and be in compliance with GCP, local regulatory requirements and legal 
requirements) 
• 
the opportunity for potential participants to ask questions 
• 
assessment of capacity. For consent to be ethical and valid in law, participants must be capable 
of giving consent for themselves. A capable person will:  
o understand the purpose and nature of the research.  
o understand what the research involves, its benefits (or lack of benefits), risks and burdens.  
o understand the alternatives to taking part.  
o be able to retain the information long enough to make an effective decision. 
o be able to make a free choice.  
o be capable of making this particular decision at the time it needs to be made (though their 
capacity may fluctuate, and they may be capable of making some decisions but not others 
depending on their complexity). 
o where participants are capable of consenting for themselves but are particularly susceptible 
to coercion, it is important to explain how their interests will be protected. 
General good practice in research (and the basis of legal frameworks) require that persons incapable of 
giving legal consent should be given special protection.  
A person is assumed to have the mental capacity to make a decision unless it is shown to be absent. Mental 
capacity is considered to be lacking if, in a specific circumstance, a person is unable to make a decision for 
him or herself because of impairment or a disturbance in the functioning of their mind or brain. In practice 
for participants with mental incapacity this means that they should not be included in clinical trials if the 
same results can be obtained using persons capable of giving consent and should only be included where 
there are grounds for expecting that their taking part will be of direct benefit to that participant, thereby 
outweighing the risks.  
If subjects, who lacks the capacity to consent for themselves, are considered for inclusion, the PI should 
determine if the patient is incapacitated to participate in a physiotherapy program. If not, the patient is not 
suited to be included in the trial (inclusion and exclusion criteria).  
Where a participant is able to consent for a clinical trial but later becomes incapacitated (for example 
progressive cancerous disease), in all such cases the original consent given endures the loss of capacity, 

 
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providing that the trial has not significantly altered and the patient can continue the physiotherapy program. 
If cessation of any further clinical intervention or follow-up is mandatory, patients will be analysed according 
to the intention-to-treat principle (i.e. all patients randomized included in the analyses and analysed in the 
group to which they were randomized). 
 
8.3 Trial randomisation 
Trial randomization is mandatory and affords an unbiased comparison between groups as it controls for 
both known and unknown variables. Through randomization both the conservative and surgical treated 
group will be balanced regarding prognostic variables. Both treatment groups will be prognostically 
balanced (with exception of the intervention), so that if a difference in outcome is observed, a sound 
argument can be made attributing the difference in result to the intervention under study. Simple 
randomization based solely on a single, constant 1:1 allocation ratio will be used in the foot drop trial.  
The Randomization Module within REDCap will be used to assign participants to specific groups (web-
based randomisation/treatment allocation system). In this way, an unpredictable allocation sequence will 
be generated so that the treatment allocation is concealed from the randomizing treating physician. 
Randomization will be documented by e-mail. Since peroneal nerve entrapment is not a medical 
emergency, randomization will not be done outside of the office hours. Randomization will not be stratified 
by centre because of the risk of selection bias due to treatment predictability in centers with low inclusion 
rates. Furthermore, due to the anticipated low inclusion rate in several centers, an imbalance in the number 
of patients per study arm can be created when working with stratification by centre. Therefore, 
randomization will be global over all participating centers. The PI of the local centre, as well as all the 
treating physicians, and the study coordinator will receive User Rights for the Randomization Module. The 
study coordinator should have an overview of all the randomizations made in each centre.  
 
8.4 Blinding 
Blinding of trial participants and care providers is not possible because of obvious differences between both 
treatment groups: one group will be surgically treated whereas the other group will receive maximal 
conservative treatment until the primary endpoint is assessed. However, the clinical investigator in the foot 
drop trial (= outcome assessor) can be blinded to treatment. All participants will be asked to wear long 
trousers to cover a potential scar at the level of the knee. Furthermore, all patients will be asked to apply a 
bandage at the site of the operation (or the site of entrapment if there was no operation). Participants are 
not allowed to discuss their treatment with the outcome assessor. A preassessment contact between the 
patient and an unblinded member should be organized prior to the study assessments, to remind and 
instruct patients of the blinding precautionary measures. 
 
Patients in the surgical arm of the trial will be evaluated after 10 days. A postoperative control is considered 
standard of care. Assessments cannot be performed by the outcome assessor at this stage, as this will 
cause unblinding.  
 
Since all health care providers have access to the electronic health record, measures should be taken to 
prevent unblinding of the outcome assessors. Several precautions should be considered: 
- 
Data of assessments will be documented on a separate worksheet, outside the electronic health 
record so that there will be no need to access the electronic health record.  
- 
If the outcome assessor thinks the electronic health record should be accessed, the treating 
physician should be consulted. Since the treating physician is not blinded, he/she can access the 
electronic health record if deemed necessary.  
To avoid errors, the outcome assessor must be aware of the identity of the patient during the assessments. 
Therefore, anonymization during assessment is not possible. 
 

 
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Blinding the outcome assessor will create the opportunity to make an objective assessment of primary and 
(key) secondary outcome parameters, without increasing the risk of bias.  
Until the time of unblinding for final data analysis, the randomization list is kept strictly confidential. The 
randomization list is accessible only by the REDCap data manager to prevent further selection bias. The 
statistician should neither have access to randomized treatments (or randomization list) nor even to the full 
database until the database has been locked for analysis. 
 
8.5 Unblinding of outcome assessor 
Full randomization information will be made available for data analysis only after database lock. Given the 
fact that both the care providers and patients aren’t blinded, situations that require unblinding of the 
outcome assessor during the trial will be rare. Surgical complications can occur in the postoperative period, 
during which the patient is followed by the treating physician. In situations where the patient signals 
treatment related problems during the examination by the outcome assessor, the treating physician should 
be consulted. The treating physician, who is not blinded can assess the problems of the patient and can 
decide if unblinding of the outcome assessor is necessary. Where possible, the outcome assessor should 
remain blinded.  
Accidental unblinding of outcome assessors can happen. Measures will be taken to anticipate the 
occurrence of such event. A preassessment contact with an unblinded member of the study team will be 
scheduled prior to the study visit, to remind patients of the blinding and help them with placing the bandage 
or other blinding material. In all participating centers, at least 2 outcome assessors should be trained and 
deployable. In case of accidental unblinding of one outcome assessor, the other outcome assessor can 
follow-up on the particular patient during the remaining study visits. 
The study code should only be broken for valid medical or safety reasons e.g. in the case of a severe 
adverse event where it is necessary for the investigator or treating health care professional to know which 
treatment the patient is receiving before the participant can be treated. In the foot drop trial, these situations 
will be virtually non-existent, since the treating physician is not blinded.  
The occurrence of any emergency unblinding during the study must be clearly justified and explained by 
the investigator. In all cases, the sponsor personnel must be informed about the reason for unblinding as 
soon as possible before or after the event. The circumstances leading to unblinding must be documented 
in the hospital charts, the Investigator Site File (ISF) and in the eCRF. If unblinding occurs, all assessments 
as defined in the study protocol must still be performed, unless the subject withdraws consent to participate 
in the study. 
 
8.6 Baseline data 
Baseline data can be collected by the treating physician during the screening visit and will be recorded 
in the eCRF. 
• 
EDX characteristics (see also 8.7.2.) 
• 
Sex (male/female) 
• 
Height in centimetres 
• 
Age in years 
• 
Site of entrapment (left/right/bilateral) 
• 
Time since onset of foot drop in weeks 
• 
MRC score for ankle dorsiflexion and ankle eversion at presentation 
• 
Subacute onset (>2days) of foot drop 
• 
Weight loss during last 6 months: 

 
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o 
Weight loss in kg 
o 
Current weight 
o 
BMI (kg/m2) 
o 
Is weight loss intentional?  
o 
Weight loss after bariatric surgery? 
o 
Rapid onset? 
• 
Postural neuropathy  
o 
Habitual leg crossing?  
o 
Prolonged squatting? 
o 
Frequent kneeling?  
• 
Exercise (dynamic compression) 
• 
Onset after childbirth? 
• 
Previous lumbar surgery? 
• 
Trauma 
o 
Sharp/blunt 
o 
Inversion trauma of the ankle 
o 
Knee dislocation 
o 
Other 
• 
Iatrogenic causes of peroneal neuropathy  
o 
Surgery of the hip/knee/ankle 
o 
Other surgery (e.g. wrong positioning during thoracic surgery) 
o 
Recent bracing/ pneumatic compression device/ compression wrapping  
o 
Other 
• 
Metabolic/systemic disease  
o 
Diabetes mellitus  
o 
Thyroid disease  
o 
Vitamin deficiencies e.g. B12  
o 
Oncological history 
o 
Other 
• 
Prolonged bedrest  
• 
Professional occupation  
• 
Use of alcohol in units/week 
• 
Tinel sign at the level of the fibular head 
• 
History of neuromuscular diseases 
• 
Professional disability  
o 
Currently employed/working?  
o 
Ability to continue working? (last day of work if the patient is unable to work) 

 
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Baseline assessment for the primary and secondary endpoints analyses will be collected at the 
randomisation visit by the outcome assessor (blinded researcher), this will reduce inter-observer 
variability during follow-up. The limited baseline assessments conducted by the treating physician should 
be conducted before the actual randomization to avoid bias. The EQ5D-5L is only to be registered if the 
patient did not complete the online survey or if the patient chose to not use the online system.  
Baseline primary and secondary endpoint data will include:  
- 
MRC-score for ankle dorsiflexion, hallux extension and ankle eversion  
- 
Gait assessment:  
o 
Distance covered during the six-minute walk test (primary outcome) 
o 
Gait speed during the 10 meter walk test 
o 
Ability to walk barefoot  
o 
Stanmore questionnaire 
o 
Need for foot-ankle-orthosis 
o 
Functional ambulation categories 
- 
Sensory changes 
- 
Quality of life questionnaire 
o 
EQ-5D 5L 
- 
Work and Productivity Impairment Questionnaire (WPAI) 
 
8.7 Trial assessments 
In the section below, all study procedures and trial assessments are described, as well as their timing. 
Several assessments will be performed by the treating physicians, others by the outcome assessor (blinded 
researcher). The study assessments are listed in the visit and assessment schedule (see Section 8.8).  
A list of standard assessments (clinical records, considered daily practice; including motor and sensory 
function, ability to walk (barefoot), need for orthosis, treatment) will be composed for uniformity across 
centers. These data will be collected at every study visit and will be recorded in the eCRF. The list of 
standard assessments is included in appendix 4. 
Several questionnaires (EQ-5D 5L, WPAI) will be made available as an online survey (REDCap) for 
patients. All other questionnaires completed by the subject or proxy are entered into the corresponding 
eCRF form by the study coordinator. The original paper copies of the questionnaires that are not available 
online will be filed in the ISF and made available for verification by the site monitor. If patients fail to 
complete the survey online, the blinded researchers can make sure that the questionnaires are complete 
during follow-up. If the patient is unable to return to the investigative site for study specific follow-up, the 
questionnaires will be sent to the patient’s home (and the clinical evaluation will be recorded as missing 
data). Patients will receive a message prior to each evaluation moment, to remind them of the upcoming 
assessments. At every assessment, the schedule of the assessments to come will be discussed with the 
patients as an extra reminder.  
If visits or data collection time-points are missed, despite previous mentioned efforts, following measures 
will be taken:  
- 
The outcome assessor will inform the treating physician, PI, clinical trial assistant or any other non-
blinded study personnel. The patient will be contacted to reschedule the visit as soon as possible. 
This cannot be done by the outcome assessor to guarantee blinding.  
- 
If the patient is not able to reschedule, the reason will be documented in the eCRF. If possible, 
certain assessments will be evaluated through telephone:  
o 
EQ-5D 5L questionnaire 

 
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o 
WPAI questionnaire 
o 
Sensory changes  
o 
Ability to walk barefoot  
o 
Need for foot-ankle orthosis  
o 
Return to work  
o 
Registration of treatment  
- 
The scheduling of the following appointments will be checked with the subject, to be sure that 
further follow-up is guaranteed.  
The site and study team must take preventive measures to avoid a subject being lost to follow-up (at least 
3 contacts (e.g., telephone calls or e-mails) must be placed to the last available telephone number or e-
mail address) and 1 registered letter must be sent by post to the last available home address. If the subject 
is still unreachable after all contact attempts listed above, he/she will be considered to be lost to follow-up. 
If a patient decides to not attend to some follow-up visits (for example a patient with fast recovery after 
surgery), efforts should be made to convince the patient to agree to the study visit at 9 months after 
randomization. The visit at 9 months is the most important study visit due to assessment of the primary 
endpoint. In this way, the patient is not lost to follow-up and the other visits will be marked as ‘missed data 
collection time-points’.  
For protocol non-adheres, all endpoints will be assessed according to protocol if the patient chooses to 
remain included in the trial.    
 
8.7.1 Time to recovery 
Limited data are available in the literature regarding time to recovery after surgical or conservative treatment 
in peroneal nerve entrapment (35, 55). Time to recovery is defined as: the time necessary to cover the 
minimal age- and sex-specific normal distance in meters during the six-minute walk test AND the time 
necessary for foot drop recovery to an MRC-score ≥ 4 for ankle dorsiflexion. The minimal age- and sex-
specific normal 6MWD is defined as 82% of the applied reference equation for prediction of the distance 
covered in the six-minute walk test (59, 60). The reference value that will be used is 6MWDpred(m) = 868.8 
– (ageyears x 2.99) – (gender x 74.7). The value for gender is 0 is the patient is male and 1 if the patient is 
female (60) .The reference values and equation are added to the study protocol in Appendix 5.  
The reference equation of Gibbons et al. is used, because this is based on the 6MWD in healthy Caucasian 
patients aged between 20 and 80. Troosters et al. stresses the variability in 6MWD in a healthy population 
and therefore proposes to consider a 6MWD smaller than 82% of the predicted 6MWD as abnormal (59). 
The reference equation proposed by Troosters et al. is not used, despite the inclusion of Belgian healthy 
subjects, due to the fact that no patients younger than 50 years old were included in this trial. However, the 
average difference between the predicted 6MWD derived from the study of Troosters et al. and predicted 
6MWD according to Gibbons et al. was only 8.8 meters (standard deviation 73.6 meters) (60). Other 
publications on reference values of 6MWD in healthy subjects were discarded because of inclusion of 
restricted age categories (66-69) or different ethnic groups (70, 71). 
 
8.7.2 Electrodiagnostics (EDX) 
Electrodiagnostic testing will be performed at baseline (screening visit, standard of care). After 
randomization, EDX will be repeated after 3 months and 9 months. EDX will be conducted by a trained 
neurologist/rehabilitation physician (see Section 6. Study Setting). EDX after randomization is not 
considered standard of care. The diagnosis of peroneal nerve entrapment is based on the screening EMG 
and falls outside the scope of the trial. However, electrophysiologists in the participating centers are advised 
to follow the ‘guidelines’ below. 
 

 
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In 2005, the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) published a 
practice parameter for the use of EMG (electromyography) and NCS (nerve conduction studies) in 
evaluating patients with peroneal neuropathy (72), based on a thorough review of the literature. These 
recommendations however were based on Class III and IV evidence and classified as level C 
recommendations, reflecting the paucity of the literature on this topic (72, 73). Nevertheless, EDX was 
considered useful in making and/or confirming the diagnosis of peroneal neuropathy and in providing 
prognostic information. Following recommendations for electrodiagnostic techniques for diagnosing 
peroneal neuropathy were formulated:  
- 
Peroneal motor NCS with assessment of conduction velocity through the fibular head and in the 
leg with recording from the anterior tibial (TA) muscle and extensor digitorum brevis muscle (EDB). 
- 
Orthodromic and antidromic superficial peroneal sensory NCS 
- 
At least one additional motor or sensory NCS in the same limb with normal findings (expert opinion) 
The role of needle EMG in making a diagnosis remained questionable. However, experts suggest that 
abnormalities on needle examination outside of the distribution of the peroneal nerve should suggest 
alternative or additional diagnoses (6, 72).  
No limits for abnormality were suggested in the literature, so following criteria were designed based on 
experience and previous trials in the literature (6, 10, 21, 74-76): 
- 
Difference in motor nerve conduction velocity across the fibular head of more than 10 m/s  
AND/OR 
- 
Presence of a motor conduction block: delta CMAP (compound motor action potential) amplitude 
across fibular head > 30%  
Furthermore, the presence of and extent of axonal damage and mixed involvement needs to be studied, 
since these patients are expected to improve later and slower (1, 23). 
Following data will be collected in the eCRF (a paper source document is available to the local 
electrophysiologist):  
- 
Difference in conduction velocity across the fibular head (m/s) 
- 
Motor nerve conduction velocity (proximal and distal to the fibular head) 
- 
CMAP distal motor latency  
- 
Superficial peroneal sensory potential 
- 
Conduction block: drop in amplitude (%)  
- 
EDB-CMAP (in mV) (proximal and distal to the fibular head) 
- 
Rest EMG abnormalities  
- 
EMG during voluntary contraction abnormalities  
- 
Evaluation of axonal damage 
- 
Evaluation of mixed damage 
 
8.7.3 Muscle Power Assessment (Medical Research Council’s scale) 
The MRC-score is a clinical assessment. A score from 0 to 5 is used to grade the power of a muscle group 
in relation to the maximum expected for that muscle. The score was first published in a manuscript called 
‘Aids to the investigation of peripheral nerve injuries’ (77) and has since been used in many clinical trials 
and publications. The MRC-score is a widely used tool to assess muscle strength in peripheral nerve 
pathology and used on a daily basis around the world to assess strength of foot dorsiflexion in patients with 
foot drop.  Training videos for the trial investigators will be made available, so the MRC-scoring will be more 
rigorously applied and inter-observer variability will be reduced a strict minimum. Several modified MRC-
scores are available, taking range of motion or more subtle changes in muscle strength into account (78). 
However, there are several disadvantages in using modified scales. There are more possible 
measurements and there will be more inter-observer variability. Furthermore, the MRC-score as depicted 
below is more representative for daily practice.  
The MRC score will be noted at every visit: 

 
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- 
Screening visit: treating physician  
- 
Randomization visit:treating physician* and outcome assessor (before, during or after 
randomization) 
- 
10 days after surgery: treating physician 
- 
6 weeks after randomization: outcome assessor  
- 
3 months after randomization: outcome assessor  
- 
6 months after randomization: outcome assessor  
- 
9 months after randomization: outcome assessor  
- 
18 months after randomization: outcome assessor  
* before the actual randomization to avoid bias.  
MRC-score will be determined for ankle dorsiflexion, hallux extension and ankle eversion. Good outcome 
corresponds to an MRC-score ≥ 4 for ankle dorsiflexion.  Assessment of muscle strength using the MRC-
score is considered standard of care in the follow-up of patients with foot drop.  
 
 
 
8.7.4 Isometric dynamometry  
Recovery of ankle dorsiflexion strength is essential in patients with foot drop. The use of dynamometry 
allows to document ankle dorsiflexion strength in an objective manner. Dynamometry has frequently been 
used to assess muscle strength in patients with foot drop (79-81). Won et al. (81) used a handheld 
dynamometer to assess ankle dorsiflexion strength in 52 patients with peroneal neuropathy (47 traumatic 
peroneal neuropathies and 3 idiopathic peroneal neuropathies). During the foot drop trial, results will be 
obtained and reported according to the same method.  
 
Patients are asked to lay in a supine position, with the knees extended. The test pad of the dynamometer 
is placed on the dorsal head of the first metatarsal bone. The patient is instructed to perform ankle 
dorsiflexion with maximal muscle strength. The best of three attempts is registered.  Ankle dorsiflexion is 
measured and reported for both ankles (in Newton). The ankle dorsiflexion strength ratio, defined as the 
ratio of ankle dorsiflexion strength in the affected ankle over ankle dorsiflexion strength in the healthy ankle 
will be calculated and reported in the eCRF. Training videos for the trial investigators will be made available, 
so that the inter-observer variability will be reduced to a strict minimum. 
 
Based on the experience with isometric dynamometry throughout the FOOTDROP pilot study, following 
instructions are proposed to collect data in the most uniform way:  
1. The ankle joint is placed in neutral position (90°). Aid the patient if necessary.  Register the best of 
three attempts. If a patient is not able to generate any dorsiflexion strength, do not apply resistance, 
to avoid registering passive resistance.  
2. The ankle joint is placed in ‘natural position’. The natural position is defined as the position of the 
ankle joint in the sagittal plain when the patient is neither actively dorsiflexing of plantarflexing the 
ankle joint. Since the natural position is depending on muscle tone in both the dorsiflexion and 
plantarflexion muscles, this is patient (and time) dependent. Register the best of three attempts. If 
a patient is not able to generate any dorsiflexion strength, do not apply resistance, to avoid 
registering passive resistance.  

 
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3. Register normal strength in both positions at the contralateral healthy site in order to calculate the 
two relevant ankle dorsiflexion strength ratios (in neutral (90°) and natural position). 
 
The use of isometric dynamometry is not considered standard of care. The treating physician will perform 
dynamometric measurements at 10 days in the surgical group to avoid unblinding. The blinded outcome 
assessor will perform dynamometric measurements at baseline, six weeks, 3 months, 6 months, 9 months 
and 18 months. The MicroFet 2 dynamometer, distributed by ProCare, will be used in all participating 
centers.  
 
8.7.5 Six-minute walk test (6MWT) 
The primary endpoint is the difference in distance covered in meters during the six-minute walk test 
(6MWD) between baseline and 9 months after randomization.  The distance in meters covered during 
the six-minute walk test at 6 weeks, 3 months, 6 months and 18 months will be recorded as secondary 
endpoint. Including a six-minute walk test at earlier time points will allow us to assess the 6MWD before 
any possible cross-over could have occurred. Moreover, a quicker improvement in gait as measured by the 
6MWT may also represent an important outcome parameter. Each assessment will be performed by the 
outcome assessor. Performing the six-minute walk test is not considered standard of care. 
Based on a literature analysis and patient feedback on the trial design, gait analysis and recovery of a 
normal gait pattern are crucial in the recovery of foot drop. In 88% of interviewed patients, success of 
treatment was related to improvement in gait. The distance covered during the six-minute walk test (6MWD) 
is validated and clinically used in gait analysis. Several advantages exist in daily practice when using the 
6MWT. There is no need for expensive equipment and the test can be performed in every hospital. It is 
possible to work in a very standardized manner and patient instructions can be easily understood. Since 
we measure speed and distance over a period of 6 minutes, we get much more information about gait than 
during a shorter version of the test. It is also possible to detect fatigability. Since we look at differences 
between baseline values and values after 9 months, the influence of comorbidities (such as age, pulmonary 
or cardiac problems, …) can be limited. 
The 6MWT has been used in other studies examining foot drop due to other pathologies including multiple 
sclerosis and stroke (32-34, 82-85). Baseline values for these pathologies are therefore available. 
Unfortunately, direct baseline values from previous trials of patients with foot drop due to peroneal nerve 
entrapment are non-existent. Moreover, the data available from other trials concerning foot drop due to 
different pathology are expected to differ from the foot drop trial study population because of the following 
reasons: 
- 
The available data on foot drop are extracted from a population with either multiple sclerosis or 
ischemic stroke. These neurological conditions differ greatly from a peripheral, focal neuropathy. 
In these patients, the neurologic deficits are caused by lesions in the brain resulting in other clinical 
presentations which are more generalized compared to an isolated foot drop. Our trial will be able 
to provide better quantitative measures related to foot drop in this patient population. Currently we 
only have qualitative evidence based on interviews that walking is hampered in patients with foot 
drop due to peroneal nerve entrapment.  
- 
Based on our review of the literature, we expect large numbers of patients to recover partially or 
fully after peroneal nerve entrapment, regardless of the treatment modality. Good outcome after 
surgical treatment varied between 41% and 100% and good outcome after conservative treatment 
varied between 53% and 100% (see Section 1 and 2). This rate of recovery is different from 
recovery in patients with multiple sclerosis or stroke.  
- 
Extrapolation of data is further complicated when MS or stroke patients are allowed to use a foot-
ankle orthosis during the 6MWT. 
Since the 6MWT is a widely used test, reference data about distance covered in the normal population are 
available (59, 60, 66-71). We can only provide data on healthy subjects which can serve as surrogate 

 
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markers for the optimal outcome for patients. As mentioned before (see Section 8.7.1: time to recovery), 
the reference equation of Gibbons et al. (60) will be used to predict the normal 6MWD for each subject. 
Minimal normal 6MWD is defined as 82% of the predicted 6MWD (59).  Information on the minimal clinically 
important difference (MCID) in 6MWD is important to assess the clinical relevance of the primary endpoint. 
These data are available from previous cited trials, including patients with foot drop due to central pathology 
(stroke, MS).  
- 
The minimal clinically important difference was estimated at 50 meters in the study of 
Sankaranayan et al. (82).  
- 
McLoughlin (83) estimated that a clinically meaningful increase in 6MWD by MS-patients is 100 
meters (n=40). This number is based on the difference in 6MWD in patients with mild and moderate 
MS (defined using the Expanded Disability Status Scale (EDSS)) in Goldman’s paper (86). 
- 
Fulk (84) estimated the minimal important difference in 6MWD for stroke patients 2 months post-
stroke. Fulk performed a secondary analysis of the data of the LEAPS rehabilitation trial 
(n=265)(87). Two anchors of important change were used: the modified Rankin Scale (mRS) and 
the Stroke Impact Scale (SIS). The estimated MCID of the 6MWD was 71 meters with the mRS as 
the anchor and 65 meters with the SIS as the anchor. For participants with initial gait speed (IGS) 
<0.40 m/s, the estimated MCID was 44 meters with the mRS as the anchor and 34 meters with the 
SIS as the anchor. For participants with IGS ≥0.40 m/s, the estimated MCID was 71 meters with 
the mRS as the anchor and 130 meters with the SIS as the anchor. 
- 
In another publication, Fulk (85) determined the minimal detectable change (MDC90) in 
rehabilitating stroke patients (n=37) defined as the amount of change that must be observed before 
the change can be considered to exceed the measurement error and variability at the 90% 
confidence level. For people who could walk without physical assistance, the MDC90 was 61 meters 
and for people requiring physical assistance, the MDC90 was 39 meters. Overall MDC90 was 54.1 
meters. 
The 6MWT is widely used to assess functional exercise capacity in cardiovascular and respiratory 
pathology (88). Bohannon (89) published a systematic review of reported MCID on the 6MWD in adults 
with pathology. They concluded that a change of 14.0 to 30.5 meters may be clinically important across 
multiple patient groups.  
Based on the available data in the stroke and MS literature, the reference values in a normal population 
and the work of Bohannon, we estimate the minimal clinically important difference in 6MWD in 
patients with foot drop due to peroneal nerve entrapment to be 10% of the minimal predicted age- 
and sex-specific reference value for that patient (see Appendix 5). This value corresponds to a certain 
level with the range of MCID documented in stroke pathology. The MCID will be taken into account to 
determine relevance of the difference in 6MWD between the two patient groups. An example: 
Suppose the baseline mean 6MWD is 300 meters in the conservative arm and surgical arm of the trial (no difference 
due to randomization). Mean difference in 6MWD in the surgical arm between baseline and 9 months is 120 meters 
and mean difference in 6MWD in the conservative arm between baseline and 9 months is 100 meters. Therefore, the 
difference between both groups is 20 meters. Apart from the assessment of statistical significance, the clinically relevant 
difference will be defined as the minimum of 10% of the mean minimal predicted age- and sex specific reference value 
of all patients in the conservative and surgical arm. E.g. assuming an average age of 55 years and 42% of the patients 
being female(3), the minimal mean predicted 6MWD would be 551.86 meters, resulting in a MCID of 55.2 meters. The 
actual value applied will be determined by the trial population.  
Standardized 6MWT methodology is essential for reproducible and reliable results. The test should be 
performed in a minimally trafficked area along a flat, straight corridor ideally ≥ 30 meters in length (90, 91). 
Although the procedural guidelines, formulated in 2002, were made to address patients with respiratory 
pathology, several items can make the 6MWT in the foot drop trial more standardized: 
1. Mark the starting line with brightly colored tape. 
2. Mark the length of the hallway every 3m. 
3. Mark turn around with a cone. 

 
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4. Patients should be wearing comfortable clothing and use their usual walking aids. The use of a foot-
ankle orthosis is prohibited. 
5. The patient should rest for at least 10 min prior to commencement of testing. 
6. Patients should not have exercised vigorously within 2 hours of beginning the test. 
7. All patients will be instructed to cover as much distance as possible during six minutes.  
8. Subjects will be encouraged every minute. The remaining time will be communicated every minute. 
An example: When the timer shows 3 minutes remaining, tell the patient the following: “You are 
doing well. You have only 3 minute left.” 
9. If the patient stops during testing, the timer should not be stopped. The time at which the patient 
stopped, and recommenced walking should be noted.  
10. Walk distance is measured by counting the number of full laps and rounding to the nearest meter 
for the partial final lap. 
The 6MWD will be evaluated twice at each visit (as first and last assessment), taking the ‘learning effect’ 
into account. Furthermore, the applied reference values are based on repeated 6MWD. Best 6MWD will be 
documented in the eCRF. 
 
8.7.6 Ability to walk barefoot 
Outcome based on patient interview/experience (yes / no). The ability to walk barefoot will be noted by the 
outcome assessor using the list of standard assessments at baseline, six weeks, 3 months, 6 months, 9 
months and 18 months after randomization. 
 
8.7.7 Stanmore Questionnaire 
Through the Stanmore questionnaire, functional outcome can be assessed. The Stanmore questionnaire 
has been used in the literature to assess functional outcome in patients with foot drop due to peroneal 
nerve injury (94-96). Seven sections (pain, need for orthosis, normal shoes, functional outcome, muscle 
power, degree of active dorsiflexion and foot posture) add up to a sum score of 100 points.  All cited studies 
used the same classification system for excellent, good, fair and poor:  
- 
Excellent outcome: 85 to 100 points 
- 
Good outcome: 70 to 84 points 
- 
Fair outcome: 55 to 69 points 
- 
Poor outcome: < 55 points  
Gait assessment through the Stanmore Questionnaire is not considered standard of care. The Stanmore 
Questionnaire will be assessed by the outcome assessor at randomization, 6 weeks, 3 months, 6 months, 
9 months and 18 months after randomization.  

 
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The Stanmore questionnaire, as used in Yeap et al.(96)  
8.7.8 Need for ankle-foot orthosis 
The need for ankle-foot orthosis will be scored as part of the Stanmore questionnaire, but will be recorded 
separately as well (baseline, 6 weeks, 3 months, 6 months, 9 months and 18 months). The outcome 
assessor will document the need for an ankle-foot orthosis at each visit in the list of standard assessments 
and the eCRF.  
 
8.7.9 Gait speed in the 10-meter walk test  
Walking speed is an important aspect of gait and is often used as an objective measure of functional 
mobility. The 10-meter walk test is a commonly used and validated tool to assess gait speed. 
To our knowledge, gait speed during the 10-meter walk test has not been mentioned in the assessment of 
foot drop due to peroneal nerve entrapment in the available literature. However, the test is used to assess 
gait speed in stroke literature (32, 82, 97) since gait velocity is a powerful indicator of function and prognosis 
after stroke (97) and the most efficient in predicting ambulation classification (98). In stroke literature, gait 
velocity is often interpreted in the context of community ambulation, broadly defined as locomotion outdoors 
to encompass activities such as visits to the supermarket, shopping mall and bank, social outings, vacations 
and pursuit of leisure activities (98, 99). Extrapolation of these data to patients with foot drop due to peroneal 
nerve entrapment needs to be done with caution, for the same reasons as mentioned in the discussing of 
the six-minute walk test. Lord (99) defined 4 ‘community ambulation groups’ in a sample of 130 post-stroke 
patients. Only patients discharged to a private home were included, which means that outcome after stroke 
was rather good. This improves the resemblance to patients with foot drop due to peroneal nerve 
entrapment.  
 
- 
Community ambulation group 1 (not ambulant outside their home): 0.52 m/s (mean) 
- 
Community ambulation group 2 (ambulant as far as the letterbox): 0.66 m/s (mean) 
- 
Community ambulation group 3 (ambulant in the immediate environment): 0.82 m/s (mean) 
- 
Community ambulation group 4 (ambulant in a shopping center and/or places of special interest): 
1.14 m/s (mean) 

 
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Apart from the data from the stroke literature, reference values are available in the literature (100). Samson 
(101) defined reference values in a Dutch patient sample based on age and sex (see Appendix 6). 
Bohannon reported the MCID for change in comfortable gait speed measurements in patients with 
pathology in his systematic review (102). He concluded that changes in gait speed of 0.10 to 0.20 m/s may 
be important across multiple patient groups. Sankaranarayan estimated the MCID in gait speed in stroke 
patients to be 0.16 m/s (82). 
Based on these data, good outcome in terms of gait speed (m/s), as measured by the 10-meter walk 
test, is defined as gait speed ≥ 1.14 m/s. The MCID for gait speed in patients with foot drop due to 
peroneal nerve entrapment is estimated to be 0.15 m/s.  
 
In the 10-meter walk test, patients are instructed to walk at their usual, comfortable pace. Time is measured 
after a 5 meter stroke for acceleration (at the end there is a 5 meter stroke for deceleration (103). 
Determining gait speed through the 10-meter walk test is not considered standard of care. The 10-meter 
walk test will be carried out by the outcome assessor as baseline assessment, at 6 weeks, 3 months, 6 
months, 9 months and 18 months after randomization.  
 
 
Figure 2. Set-up of the 10-meter walk test as described by Peters et al.(104). 
 
Determining gait speed with the 10-meter walk test is not considered standard of care.  
 
8.7.10 Sensory Changes 
In a large retrospective patient series on peroneal nerve decompression after weight loss, Broekx et al. 
(2018) examined the recovery of sensory deficits (64). Symptoms qualified as sensory included the 
presence of hypoesthesia and/or paresthesia. They used the following system to assess sensory 
symptoms:  
a. Complete recovery: the absence of any sensory symptoms 
b. Partial recovery: patients with a minimum of sensory symptoms  
c. No recovery: patients with no improvement 
The same system will be used to assess and compare the evolution of sensory symptoms in the foot drop 
trial. Sensory changes will be evaluated at baseline and at the visits at 6 weeks, 3 months, 6 months, 9 
months and 18 months after randomization by the outcome assessor. Sensory changes at 10 days will be 
assessed by the treating physician. Documenting sensory function is considered standard of care.  
8.7.11 Functional Ambulation Categories 
Functional ambulation categories (FAC) (105) is a useful scale to assess gait in patients with foot drop. It 
is a six point scale, that is used in stroke literature (99, 106-109) and can help determine how much 
assistance a patient requires. A FAC ≥ 3 has been considered a surrogate of general walk ability in 
assessing mobility in stroke patients (108, 110). Mehrholz (111) showed a strong correlation between FAC 
and commonly used indicators of progress in gait performance. A FAC ≥ 4 could predict community 
ambulation with high sensitivity and specificity. Lord (99) assessed mobility in stroke patients. The highest 

 
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FAC was achieved by 72.3% of all 130 subjects and median FAC was 5. Again, extrapolation of these data 
is not ideal. However, taking all data into account, good outcome correlates with a FAC of 5. 
Gait assessment through functional ambulation score is not considered standard of care. The FAC will be 
determined by the outcome assessor at baseline, 6 weeks, 3 months, 6 months, 9 months and 18 months 
after randomization. 
 
Functional ambulation categories (FAC) 
FAC 0 
Nonfunctional 
- No ambulation  
- Ambulation only in parallel 
bars 
- 
Requires 
supervision 
or 
physical assistance from > 1 
person 
FAC 1 
Dependent (level II) MCID 
- Requires manual contact of 
one person during ambulation 
on level surfaces 
- Manual contact is continuous 
and necessary to support body 
weight 
and/or 
to 
maintain 
balance and coordination 
FAC 2 
Dependent (level I) 
- Requires manual contact of 
one person during ambulation 
on level surfaces 
- Manual contact is continuous 
or intermittent light touch to 
maintain balance/coordination 
FAC 3 
Dependent, supervision 
- Ambulation occurs on level 
surfaces 
without 
manual 
contact of another person 
- Requires stand-by guarding of 
one person because of the need 
for verbal guidance or poor 
judgement 
or 
questionable 
cardiac status 
FAC 4 
Independent, 
level 
surfaces 
only 
- Ambulation is independent on 
level surfaces 
- Requires supervision/physical 
assistance 
to 
walk 
stairs, 
inclinations 
or 
non-level 
surfaces 
FAC 5 
Independent, level and non-
level surfaces 
Ambulation is independent on 
non-level surfaces, inclinations 
and stairs. 
 
 
8.7.12 Quality of life: the EQ5D-5L questionnaire 
We will use the validated and commonly used EQ5D-5L (5 Level EUROQoL – 5 Dimensions) 
questionnaires to assess patient reported outcome measures (PROM). The EQ5D-5L questionnaires is 
attached to the protocol in Appendix 8. Assessing quality of life through the EQ5D-5L questionnaire is not 
considered standard of care. The questionnaire will be available as an online survey (REDCap) for the 
patients. If patients forget or don’t want to use the online system, the outcome assessor will provide the 
questionnaire at the randomization visit, at 10 days (surgical group), 6 weeks, 3 months, 6 months, 9 
months and 18 months after randomization and data will be collected in the eCRF. The treating physician 

 
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will provide the EQ5D-5L  questionnaire at 10 days (surgical group) if a patient does not use the online 
system. This can only be done by the treating physician to guarantee blinding. 
The EQ-5D 5L is a generic measure of health-related quality of life developed by the EuroQol Group. It is 
a validated measurement of quality of life widely used in different pathologies. The questionnaire is made 
up of two parts. The first part is descriptive and uses five different dimensions to score quality of life. These 
five dimensions are mobility, self-care, activities of the daily life, pain/discomfort and anxiety/depression. 
There are five different answer possibilities within each dimension, i.e. “no problem”, “slight problem”, 
“moderate problem”, “severe problem” and “unable to”. This renders 3125 different answer possibilities. 
The second part uses a visual analogue scale (VAS) to score the current health status of the patient, 
ranging from zero to one hundred. Zero corresponds to death and one hundred corresponds to a 
(subjective) perfect health status.  
N.B.: Based on patient feedback throughout the pilot study, the SF-36 questionnaire will no longer be used. 
Patients experienced the questionnaire as too extensive. Furthermore, quality of life questionnaires were 
among the least popular trial assessments.  
 
8.7.13 Surgical Complications 
Overall, neurolysis of the peroneal nerve is considered a low-risk surgery (113). Surgical complications will 
be assessed by the treating physician at 10 days and 6 weeks. This is considered standard of care. We will 
use a list of possible complications based on the available literature (1, 3, 43, 44, 47, 48, 50, 51, 55) and 
our own experience. In this way, surgical complications can be uniformly scored throughout all participating 
centers. Unforeseen complications will be recorded as free-text.  After cross-over, surgical complications 
will be assessed by the outcome assessor at the extended follow-up visit (18 months).  
List of predefined possible surgical complications: 
 
 
8.7.14 Treatment record 
At every visit after the randomization visit (6 weeks, 3 months, 6 months, 9 months and 18 months), the 
outcome assessor should record several parameters of the ongoing physiotherapy program:  
- 
Frequency of training  
- 
Duration of training  
- 
Home exercises 
- 
Use of electrostimulation  
- 
Total number of physiotherapy sessions 
- 
Other therapies (vitamin substitution, acupuncture, …) 
Other therapies are allowed, as long as they reflect daily practice. These therapies should be thoroughly 
noted in the eCRF. This registration is not considered standard of care.  
 

 
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8.7.15 Work Productivity and Activity Impairment Questionnaire: General Health (WPAI:GH) 
Health economic aspects of foot drop will be evaluated through the Work Productivity and Activity 
Impairment Questionnaire (WPAI). The WPAI is widely used and validated in multiple languages. The WPAI 
allows for assessment of employment and professional productivity among other features. Participants will 
fill in the WPAI at baseline, 6 weeks and 6 months. WPAI will be available online. If the patient receives 
allowances, the amount will be noted for economic analysis. This is not considered standard of care. The 
English version of the WPAI is included in Appendix 7. 
 
8.7.16 Return to work at six weeks after randomization 
Health economic aspects will also be evaluated through the assessment of return to work. We expect 
subgroups of patients with foot drop to be unable to work. Once the foot drop has improved (or fully 
recovered), we expect patients to be able to return to work and to not experience any more related problems 
(after their initial recovery). In this trial population foot drop does in general not represent a chronic condition 
with periods of relapse. Either the foot drop recovers enough to be able to work again, or the foot drop does 
not sufficiently recover to resume previous professional activities.  
Taking this into account, return to work seems to represent a very important measure. Patients will be 
asked about return to work at the study visit six weeks after randomization. To avoid recall bias, patients 
will be asked in advance to record the date of return to work. During baseline assessments, subjects will 
be questioned if they are incapacitated to work due to the foot drop and the last working day will be recorded 
in the eCRF. 
We anticipate the biggest difference in return to work between the two groups at six weeks after 
randomization. We except patients to recover faster after neurolysis. Therefore, we expect that a significant 
majority in the surgically treated group will be able to return to work six weeks after randomization (equals 
five to six weeks after surgery), whereas recovery could be slower in the conservative group. Recovery 
from surgery itself is generally fast, thus we do not expect that surgical recovery has a big impact on return 
to work but of course this issue will also be tackled in the trial. 
 
8.8 
Table of trial procedures

 
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TABLE 
 OF 
 TRIAL PROCEDURES 
SCREENING 
RANDOMIZATION! 
 
TREATMENT PERIOD 
EXTENDED FU 
PERIOD CROSS-
OVER PATIENTS 
DAY 0 
FU  10D  
(+4D) 
 surgery 
FU  6W 
 (+ 1W) 
FU  3M  
(+ 2W) 
FU  6M 
 (+ 2W) 
FU  9M 
 (+ 3W) 
FU 18M 
 (+ 3w) 
INFORMED CONSENT 
TP 
 
MEDICAL HISTORY 
TP 
 
ELIGIBILITY CRITERIA 
TP 
 
CONTRIBUTING FACTORS  
TP 
 
EDX 
TP* 
 
* 
* 
ISOMETRIC DYNAMOMETRY 
 
BR 
TP 
BR 
BR 
BR 
BR 
BR 
6MWT 
BR 
 
BR 
BR 
BR 
BR 
BR 
10MWT 
BR 
 
BR 
BR 
BR 
BR 
BR 
RETURN TO WORK 
 
BR/P 
FUNCTIONAL AMBULATION 
CATEGORIES 
BR 
 
BR 
BR 
BR 
BR 
BR 
NEED FOR ORTHOSIS 
BR 
 
BR 
BR 
BR 
BR 
BR 
ABILITY TO WALK BAREFOOT 
BR 
 
BR 
BR 
BR 
BR 
BR 
STANMORE QUESTIONNAIRE 
BR 
 
BR 
BR 
BR 
BR 
BR 
EQ5D-5L QUESTIONNAIRE 
BR/P 
TP/P 
BR/P 
BR/P 
BR/P 
BR/P 
BR/P 
SURGICAL COMPLICATIONS 
TP 
TP 
TP 
SENSORY CHANGES 
TP 
TP/BR 
TP 
BR 
BR 
BR 
BR 
BR 
TREATMENT RECORD 
BR 
 
BR 
BR 
BR 
BR 
BR 
WPAI  
 
BR/P 
 
BR/P 
 
BR/P 
 
 
ADVERSE EVENTS 
 
TP 
SERIOUS ADVERSE EVENTS 
 
TP 
LEGEND 
 
 
TP = treating physician; BR = blinded researcher (outcome assessor); bold = standard of care; P = patient (online survey); red = 
primary endpoint; FU = follow-up; D = days; W = weeks; M= months, YR = year 
*investigation performed by neurologist / rehabilitation physician, data collection in eCRF by study coordinator  
Some assessments are done by both the treating physician and blinded researcher to prevent bias/unblinding 
! = surgery maximum one week after randomization, preferably within 2 days 
 

 
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8.9 Withdrawal criteria 
Participants may voluntarily discontinue from Trial treatment and/or prematurely end their participation in 
the Trial for any reason at any time. In such case, the Investigator must make a reasonable effort to contact 
the participant (e.g. via telephone, e-mail, letter) in order to document the primary reason for this decision. 
  
The Investigator may also decide at any time during the course of the Trial, to temporarily interrupt or 
permanently discontinue the Trial treatment if it is deemed that continuation would be detrimental to, or not 
in the best interest of the participant. 
  
Similarly, the Sponsor, Ethics Committee or authorized regulatory authority can decide to halt or 
prematurely terminate the Trial when new information becomes available whereby the rights, safety and 
well-being of Trial participants can no longer be assured, when the integrity of the Trial has been 
compromised, or when the scientific value of the Trial becomes obsolete and/or unjustifiable. 
The study design does not allow any cross-over to the other treatment arm until the primary endpoint is 
reached (9 months after randomization). Conservative care patients have the opportunity to undergo 
surgery after 9 months.  
Subjects are considered withdrawn from the study if they: 
- 
Are not willing to be followed up for the purposes of the trial at any further visits. 
- 
State an intention to withdraw further participation in all components of the study. 
- 
Are lost for follow-up (if all repeated attempts by the study-team to communicate with the individual 
have failed. The site and study team must take preventive measures to avoid a subject being lost 
to follow-up (at least 3 contacts (e.g., telephone calls, or e-mails) must be placed to the last 
available telephone number or e-mail address) and 1 registered letter must be sent by post to the 
last available home address. If the subject is still unreachable after all contact attempts listed above, 
he/she will be considered to be lost to follow-up.) In the source documents will be documented 
which steps have been taken to contact the participant. 
Subjects are considered withdrawn from treatment if: 
- 
The patient and/or patient’s guardian does not wish to continue with further trial intervention.  
- 
Choose for treatment in other arm (cross-over from conservative treatment to surgery). 
A patient withdrawn from further treatment should remain in follow-up  
Subjects are considered withdrawn from consent if:  
- 
He/she withdraws consent to take part in the study without having to give a reason, and that may 
mean withdrawing his/her consent to the processing of health data.  
If a subject withdraws consent, no further data will be collected in the eCRF from the date of withdrawal 
onward.  
The details of withdrawal should be clearly documented in the patient’s medical records and in the eCRF. 
In the sample size of 182 subjects, there is an expected 5% dropout of patients (n=9). These subjects will 
not be replaced.  
The sponsor reserves the right to terminate the study at any time globally or locally.  
If a study is prematurely suspended or terminated, the sponsor will promptly inform the investigators and 
the Ethics Committee and provide the reasons for the suspension or termination. If the study is suspended 
or prematurely terminated for any reason, the investigator — in agreement with the sponsor — must 
promptly inform all enrolled subjects who are still in the study and/or their proxies/legal representatives (as 
applicable) and ensure appropriate treatment and follow-up. 
 

 
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8.9.1 Loss to follow-up 
If a patient is lost to follow-up, every effort should be made to contact the patient’s primary physician (GP) 
to obtain information on the patient’s status. Similarly, if a patient’s care is transferred to another clinician, 
every effort should be made so that follow-up information be obtained. 
 
8.10 End of trial 
The sponsor must notify the main EC of the end of a clinical trial within 90 days of its completion. End of 
trial is the date of the last visit/data item of the last patient in the trial.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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9 TRIAL INTERVENTION 
  
9.1 Surgical decompression of the peroneal nerve at the fibular head (neurolysis) 
Surgical decompression of the peroneal nerve can be performed under local, locoregional or general 
anaesthesia. Pneumatic compression to restrict blood flow in the operation area during surgery can be 
used (and will be recorded in the surgery report). 
The surgical approach for entrapment at the fibular head is usually through a curvilinear incision just distal 
to the fibular head. The length of the incision can vary between 3 and 10 centimeters. The subcutaneous 
tissue is bluntly dissected, and the common peroneal nerve is identified proximal to the peroneus longus 
muscle. The peroneal nerve is then released from the surrounding fibrous tissue and fascia. The anterior 
intermuscular septum is usually not cut, but this can be done if deemed necessary. The nerve is 
decompressed distally as it dives under the peroneus longus muscle. The decompression at this site is 
essential. Certain authors state that an adequate decompression should extend beyond the bifurcation in 
the deep and superficial peroneal nerve and should involve cutting the intermuscular septa (1, 114). It is up 
to the surgeon to decide if decompression beyond the bifurcation is necessary, based on intraoperative 
findings (recorded in the surgery report). Figure 3 illustrates the incision and decompression at the fibular 
head.  
 
 
Figure 3. Surgical decompression of the peroneal nerve at the fibular head. Courtesy of dr. F. Weyns.  
 
The patient will be hospitalized for up to 2 nights or can be operated on in an ambulatory day-care surgery 
setting. Postoperative treatment follows standard of care and can include physiotherapy and medication, a 
decision that is left to the treating physician.  
A template for reporting the surgical procedure is made and included in appendix 9. All surgeons are 
advised to use this standardized template, since some technical aspects will be included in the eCRF 
(length of incision, cutting of the intermuscular septum, decompression beneath the fibular tunnel, 
decompression beyond the bifurcation, damage to the nerve).  
 
 

 
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9.2 Conservative treatment 
Evidence on the conservative management of foot drop is scarce. Willerslev-Olsen et al. (115) found a 
significant improvement of foot and great toe dorsiflexion in children with cerebral palsy and foot drop after 
1 month of gait training. Despite the lack of studies on training to improve foot drop of peripheral origin (as 
in peroneal neuropathy), a training program is recommended for every patient with foot drop (116). Goals 
of the treatment are to reduce muscle fiber atrophy, to preserve ankle mobility and to improve gait in 
general. 
A basic standard protocol for physiotherapy is proposed. However, the protocol should be adapted to the 
clinical presentation and needs of every individual patient. So, if the trial should be mirroring daily practice, 
some degree of freedom in the conservative treatment should be allowed.  
Standard instructions for the physiotherapist will be provided:  
• 
Mobilization of ankle and foot, stretching of the calf muscles (prevention of contractures)  
• 
Tonification of the dorsiflexion- and eversion muscles of the ankle   
• 
Proprioceptive training  
• 
Gait rehabilitation  
• 
Home exercise schedule 
Intensity: 60 sessions (F-pathology, Belgium) at a frequency of 1/2 sessions per week, with a possibility of 
a higher frequency during the first months.  
The training program should be progressive. To evaluate the compliance, the patients will be asked to 
complete a training diary.  
We do not advice to use electrostimulation because of the lack of training of younger physiotherapists and 
the lack of good equipment. The use of electrostimulation is not prohibited. We do not routinely support the 
use of an orthosis during the first six weeks. Most patients receive a prefabricated orthosis at this stage. 
However, this does not always meet the requirements of the patients at later stages. When the foot drop is 
irreversible, an ankle foot orthosis can help to improve everyday mobility. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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10 SAFETY RECORDING AND REPORTING 
10.1 Definitions 
Term 
Definition 
Adverse Event (AE) 
An AE is any untoward medical occurrence in a patient or subject during an 
experiment, and which does not necessarily have a causal relationship with 
this treatment. 
An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom or disease temporally associated with 
the use of a product, whether or not considered related to the product. Any 
worsening (i.e., any clinically significant adverse change in the frequency or 
intensity of a pre-existing condition) should be considered an AE. 
 
Adverse Reaction (AR) 
 
An AR is any untoward and unintended responses to an investigational 
medicinal product or to an experiment and, when an investigational product 
is concerned, related to any dose administered. 
 
Serious Adverse Event 
(SAE) 
A serious adverse event is any untoward medical occurrence that: 
• results in death 
• is life-threatening 
• requires 
inpatient 
hospitalisation 
or 
prolongation 
of 
existing 
hospitalisation 
• results in persistent or significant disability/incapacity 
• consists of a congenital anomaly or birth defect 
Other ‘important medical events’ may also be considered serious if 
they jeopardise the participant or require an intervention to prevent 
one of the above consequences. 
NOTE: The term "life-threatening" in the definition of "serious" refers 
to an event in which the participant was at risk of death at the time of 
the event; it does not refer to an event which hypothetically might have 
caused death if it were more severe. 
NB: to avoid confusion or misunderstanding of the difference between the terms “serious” and “severe”, the 
following note of clarification is provided: “Severe” is often used to describe intensity of a specific event, 
which may be of relatively minor medical significance. “Seriousness” is the regulatory definition supplied 
above. 
 
10.2 Recording of safety findings in function of the available evidence 
The participant will be asked to report any adverse event related to the study-specific intervention to the 
study team. These reported events will be documented by the investigator in the source documents. 
The following minimum information should be recorded for each adverse reaction (AR) by the reporting 
investigator: 
- 
AE description 
- 
Start and stop date of the AR 
- 
Severity 
- 
Seriousness 
- 
Causality assessment to the study interventions 

 
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- 
Outcome 
 
The sponsor will keep detailed records of all AEs reported to him by the investigators and will perform an 
evaluation with respect to seriousness, causality and expectedness. 
 
A Serious Adverse Event (SAE) is an untoward medical occurrence that results in any of the following: 
- 
Death 
- 
A life-threatening experience 
- 
In patient hospitalisation or prolongation of existing hospitalisation 
- 
A persistent or significant disability or incapacity  
- 
A congenital anomaly or birth defect.  
 
- 
Important medical events that may be considered an SAE when - based on appropriate medical 
judgement - they may jeopardise the subject and may require medical or surgical intervention to prevent 
one of the above outcomes 
 
The term “life threatening” in the definition of SAE refers to an event in which the subject was at risk of 
death at the time of the event. It does not refer to an event which hypothetically might have caused death 
if it was more severe. 
 
When reporting adverse events to the sponsor, the investigator will protect confidentiality by excluding the 
names of individual subjects, personal identification numbers (e.g. social security numbers) or addresses. 
The unique code number assigned to the trial subject will be used in the report and the investigator 
retains the code to facilitate data verification by the sponsor and any medical follow-up which may be 
warranted. The name of the investigator reporting the adverse events will be stated. 
After the trial has been completed or terminated, all recorded adverse events will be listed, evaluated and 
discussed in the final report. 
 
Reporting to the Ethics Committee 
The sponsor will assess whether any relevant safety information that becomes available during the study 
should be reported ad hoc to the EC. 
The sponsor has the obligation to, once a year throughout the clinical trial (or on request), submit a 
progress report to the EC containing an overview of all SARs (Serious Adverse Reactions) occurred 
during the reporting period and taking into account all new available safety information received during 
the reporting period. 
 
 
10.3 Data Safety Monitoring Board 
Based on the European Medicines Agency (EMA) guidelines on data monitoring committees, the 
organisation of a Data Safety Monitoring Board is not necessary in the foot drop trial due to following 
reasons:  
1. Peroneal nerve entrapment is no life-threatening disease.  
2. The targeted patient population is to be expected to be able to signal any potential harm in an early 
stage in an appropriate manner.  
3. There is no prior knowledge or strong suspicion that a treatment under consideration has the 
potential to harm patients.  
4. The study design gives no reason for setting up a data safety monitoring board 
5. The foot drop trial is a study in non-critical indications and both treatment modalities are well 
characterised, considered daily practice and known for not harming patients. 

 
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The independent experts in the TSC will act as an ‘extern advisory board’ to follow up on possible harm 
(e.g. related to late cross-over to surgery) and to follow up on blinding and accidental unblinding. 
 
10.4 Notification of deaths 
All deaths will be reported without delay to the EC (irrespective of whether the death is related to disease 
progression, study procedure or is an unrelated event).  
 
 
 

 
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11 STATISTICS AND DATA ANALYSIS 
11.1 Sample size calculation 
Given that no reliable estimates of the 6MWD are available in this population, the sample size calculation 
is performed assuming a moderate effect size (mean difference divided by the standard deviation). Based 
on an effect size of 0.5, 172 patients would have 90% power to show a significant difference at a two-sided 
significant level of 5% in the change in the 6MWD from baseline to 9 months after randomization using a t-
test. The sample size calculation was performed with G*Power, version 3.1.9.4. To compensate for an 
expected 5% dropout, a total of 182 patients (91 patients per group) will be included. The expected dropout 
rate of 5% is based on the results of patients interviews and a large, multicenter, randomised controlled 
trial comparing surgery versus non-surgery (or delayed surgery) with a design very similar to the foot drop 
trial (61, 62). 
11.2 Sample size reassessment 
A blinded sample size reassessment by the trial statistician is planned when 50% of the planned patients 
has reached their 9 month visit or one month before the final patient would be randomized, whichever 
occurs first. It will be based on the estimation of the overall variance of the primary outcome for the patients 
for which the primary endpoint data are available and the minimal clinical difference determined from all 
the patients randomized at that point. The maximum number of patients to be potentially added will be 
determined before the analysis will take place. It will among others be based on the recruitment rate. Full 
details of the analysis will be described in an interim analysis plan, which will be finalised after the pilot 
study and before the analysis will take place. Among others, it will contain the timing, the maximal number 
of potential extra number of patients to be recruited and the exact methods to be applied. Given that a blind 
analysis will be performed, the type I error will be preserved and no adjustment to the alpha level for the 
final analysis will be necessary. The trial will only potentially be extended but never terminated early based 
on this analysis. 
11.3 Planned recruitment rate 
A recruitment rate and recruitment strategy (table 3 and figure 4) was established for the full-scale study 
based on the following principles:  
- 
A realistic inclusion rate for pilot study centers was established throughout the pilot study. This was  
taken into account to estimate a realistic recruitment potential for new centers.  
- 
Based on additional retrospective data analysis in UZ Leuven and the recruitment rate in UZ 
Leuven during the pilot study, we do not expect any centre to randomize more than 10 patients per 
year 
- 
All principal investigators were asked to estimate potential recruitment rate based on the number 
of patients treated in the past and their own experience.  
- 
Centers will be initiated in two phases (see table 3). In a second phase, extra centers can be 
initiated if recruitment is going slower than expected. In a first phase we would like to start in centers 
that fulfil following criteria (based on the lessons learned during the pilot study): 
o 
Established multidisciplinary collaboration with all disciplines involved 
o 
Motivated study team  
o 
Centers from Brussels, Flanders and Wallonia  
- 
The possibility of several new COVID-19 pandemic waves should be taken into account. This can 
slow patient recruitment and site initiating and therefore prolong patient inclusion 
- 
Extra time should be taken into account since a sample size reassessment is planned during the 
course of the trial 
Figure 4 visualises the recruitment strategy for the full-scale study. For every year of the full-scale study, 
we defined the (expected) maximal recruitment potential based on the estimated recruitment rate of the 
pilot study centers and phase 1 study centers. We also defined the number of patients that we minimally 
expect to randomize in the study. If this specific threshold is not reached, we can escalate by initiating the 
study in the phase 2 study centers. The start of the first year of the trial is defined as the date of the site 
initiating visit in the last participating phase 1 study centre (for simplicity it has been defined as the year 
2023 in figure 5).   
 

 
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FOOTDROP PILOT STUDY CENTERS:  
25 patients / year  
Centre 
Principal investigator 
Estimated recruitment rate / year 
UZ Leuven 
Prof. dr. Tom Theys 
10 patients 
ZOL Genk 
Dr. Frank Weyns 
5 patients 
LUMC Leiden 
Dr. Justus Groen 
5 patients 
AZ Groeninge Kortrijk 
Dr. Jeroen Ceuppens 
2 patients 
CHU Liège 
Prof. Dr. Annie Dubuisson 
2 patients 
ULB Erasme 
Dr. Sophie Schuind 
1 patient  
 
FOOTDROP PHASE 1: 
 
55 patients / year 
Centre 
Principal investigator 
Estimated recruitment rate / year 
ZAS Antwerpen 
Dr. Tony Van Havenbergh 
5 patients 
AZ Sint-Jan Brugge  
Dr. Nikolaas Vantomme 
5 patients 
AZ Damiaan Oostende 
Dr. Adinda De Pauw 
5 patients 
AZ Sint-Maarten Mechelen 
Dr. Pieter Jan Van Dyck-
Lippens 
3 patients 
AZ Turnhout 
Dr. Jens Deckers 
3 patients 
AZ Alma 
Dr. Kristel Vanchaze 
3 patients 
AZ Sint-Lucas  
Dr. Kristel Vanchaze 
3 patients 
AZ Delta Roeselare 
Dr. Jeroen Van Lerbeirghe 
3 patients 
AZ Vesalius Tongeren 
Dr. Eveleen Buelens 
3 patients 
PHASE 1- CENTER 16 
XXX 
3-5 PATIENTS PER YEAR 
PHASE 1 – CENTER 17 
XXX 
3-5 PATIENTS PER YEAR 
PHASE 1 – CENTER 18 
XXX 
3-5 PATIENTS PER YEAR 
PHASE 1 – CENTER 19 
XXX 
3-5 PATIENTS PER YEAR 
PHASE 1 – CENTER 20 
XXX 
3-5 PATIENTS PER YEAR 
 
 
 
 
FOOTDROP PHASE 2: 
 
30 patients / year 
Centre 
Principal investigator 
Estimated recruitment rate / year 
PHASE 2 – CENTER 1 
XXX 
3 -5 PATIENTS PER YEAR 
PHASE 2 – CENTER 2 
XXX 
3-5 PATIENTS PER YEAR 
PHASE 2 – CENTER 3 
XXX 
3-5 PATIENTS PER YEAR 
PHASE 2  - CENTER 4 
XXX 
3-5 PATIENTS PER YEAR 
PHASE 2 – CENTER 5 
XXX 
3-5 PATIENTS PER YEAR 
PHASE 2 – CENTER 6 
XXX 
3-5 PATIENTS PER YEAR 
 
 
 
 
 
 
Table 3 – FOOTDROP study centers 
 
 
 

 
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Figure 4 – Recruitment strategy 
 
 
11.4 Statistical analysis plan 
11.4.1 Analysis sets 
The primary analysis will be the full analysis set (FAS) which will include all patients randomized. Patients 
will be analyzed in the group to which they were randomized, irrespectively which treatment was received, 
if any. In addition, a per protocol analysis set (PPS) will be used for sensitivity analyses. These will exclude 
patients or measurements from the FAS with major protocol violations like e.g., receiving surgery for 
patients randomized to the conservative arm within 9 months after randomization. All major protocol 
deviations that lead to exclusion from the PPS will be fully documented in the Analysis Sets Specification 
Document that will be dated and signed prior to database lock.  
11.4.2 Summary of baseline data and flow of patients 
Continuous variables will be summarized by treatment group by the number of non-missing data points, 
mean, standard deviation, median and interquartile range.  

 
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Categorical and ordinal variables will be summarized by treatment group by observed frequencies and 
percentages relative to the total number of non-missing items.  
A CONSORT flow diagram (http://www.consort-statement.org/) will be produced to describe the flow of 
patients (65). 
 
11.4.3 Primary outcome analysis 
The distance covered during the six-minute walk test in meters (6MWD) at 9 months will be evaluated at 
each visit. A constrained longitudinal data analysis (cLDA) will be performed taking the correlation between 
these measurements into account. The value at baseline and all follow-up measurements will be taken as 
responses.   
Indicators for baseline, follow-up visits, treatment group and the interaction between follow-up visits and 
treatment group will be included in the model. Missing data are appropriately taken into account with this 
model under the missing at random assumption. This is applicable to no-shows (patients that don’t show 
up at study visits). For patients, refusing to participate in the 6MWT, zero as value will be recorded. We do 
not expect patients to not be able to perform the 6MWT due to peroneal nerve entrapment. All patients 
should be able to stand and walk a limited distance (if only the foot drop is taking into account). The primary 
analysis is the comparison between the two treatment groups of the difference in 6MWD between 9 months 
and baseline.  
We will report the mean difference between the two treatment groups with a 95% confidence interval and 
a two-sided p-value. Superiority of surgery above conservative treatment will be claimed if p < 0.05 and the 
patients in the surgery arm improved more than the patients in the conservative arm.  
Several sensitivity analyses will be performed. The first sensitivity analysis is similar to the primary analysis 
but with follow-up measurements after surgery not being used in the analysis for patients randomized to 
conservative treatment but who underwent surgery within 9 months. Similarly, follow-up measurements of 
patients randomized to surgery who did not undergo surgery will not be used in the analysis. This will allow 
to estimate the treatment effect most honestly. In the unlikely event that in the conservative treatment arm 
more than 10% cross-overs are observed, this sensitivity analysis will become the primary analysis and the 
primary analysis the first sensitivity analysis. 
A second sensitivity analysis will be a multiple imputation analysis in which missing follow measurements 
will be imputed according to the conservative treatment arm for both the surgical and conservative treatment 
arm. 
Full details will be made available in a statistical analysis plan (SAP), which will be finalized before database 
lock.  
11.4.4 Secondary outcome analysis 
The key secondary endpoint is the timing of recovery (defined as as the time necessary to cover the minimal 
age- and sex-specific normal distance in meters during the six-minute walk test AND the time necessary 
for foot drop to recover to a MRC-score ≥ 4 for ankle dorsiflexion). However, the study will be only powered 
for the primary endpoint but if the primary endpoint should show a significant difference, it is anticipated 
that also the timing of recovery might yield a significant effect. Motor strength will also be assessed at the 
following time points: at 6 weeks, 3 months, 6 months and 9 months. The time of recovery will be analysed 
using a generalized log-rank test with constant weights over time for interval-censored data. In addition, 
the Turnbull estimator with 95% confidence intervals will be produced. The estimated proportion of patients 
which are recovered will be estimated at 6 weeks, 3 months, 6 months and 9 months. We do not anticipate 
any mortality due to the pathology. In case a patient should die, the patient will be censored at his day of 
death.   
 
Full details on the analysis of the key secondary endpoint and the analysis of the other secondary endpoints 
will be described in the SAP.  

 
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11.4.5 Procedure(s) to account for missing or spurious data  
Real time data checks will be built into the data collection tool (eCRF) and further data management queries 
including missing data, out of range values, will be emailed to the centres on a regular basis, in accordance 
with the data management plan.  Outstanding data queries will be reviewed on a regular basis by the trial 
coordinating and data management teams. Feedback will be provided to all centres on a regular basis.  
Protocol deviations will be reviewed and classified (major/minor) on a regular basis by the trial co-ordinating 
team and will be escalated if recurring issues emerge.  Major deviations will be flagged to the trial statistician 
and the trial Sponsor. 
The handling of missing data will be described in the statistical analysis plan (SAP).  
 
11.4.6 Other statistical considerations. 
The analysis of the economic evaluation will be described in a separate analysis plan.  
 
11.5 Data collection for economic evaluation 
One of the goals of the KCE Trials programme is to improve the efficiency of the healthcare system. This 
protocol has been designed with a later possible economic analysis in mind. The economic analysis itself 
is however not part of this protocol. Several characteristics of the foot drop trial make an economic 
analysis more feasible(117):  
a. During the foot drop trial, there will be protocol-driven resource use that will bias costs in both 
treatment groups. There will be more hospital visits and technical investigations (EDX) than in 
standard of care. However, these extra costs are the same in both treatment arms and these 
costs are known. Bias will be very limited.  
b. The comparator (prolonged conservative therapy) is relevant and considered daily practice.  
c. We expect the recruiting centers to be representative of the larger population, given the large 
number of participating centers.  
d. Compliance is not artificially enhanced.  
e. The trial is designed to be naturalistic and to evaluate the effectiveness of interventions in real-life 
routine practice conditions.  
Participation of Dutch centers can complicate economic analyses, since costs can differ substantially 
between different health care systems.  
In a recent review Poage et al. (1) state that if a peroneal neuropathy is not treated properly the percentage 
of people with permanent motor weakness ranges from 30 to 35 %. The percentage of invalidity for a 
complete paralysis of the peroneal nerve is estimated at 22 % (European physical and mental disability 
rating scale for medical purposes (https://www.ecb.europa.eu/careers/pdf/annex_II_staff_rules_ft.pdf). De 
Bruijn (118) et al. reported on the economic impact of peroneal neuropathy in 19 patients. Nine of these 
patients (47%) with a paid job experienced some restrictions in work. Work adaptations were reported by 
two patients. No jobs were lost because of the nerve injury. In the OBSI (officiële Belgische schaal ter 
bepaling van de graad van invaliditeit), the acknowledged percentage of invalidity due to severe limitations 
in 
ankle 
dorsiflexion 
(and/or 
plantar 
flexion) 
is 
10 
to 
20% 
(http://www.ejustice.just.fgov.be/cgi_loi/change_lg.pl?language=nl&la=N&cn=2006020831&table_name=
wet). During the pilot trial, the foot drop trial will assess the feasibility of documenting the percentage of 
invalidity, acknowledged by health care insurances. 
Health-related Quality of Life data will be collected in both trial arms at baseline, 10 days, 6 weeks, 3 
months, 6 months, 9 months and 18 months. Cost-effectiveness will be calculated as cost per quality-
adjusted life-year (QALY) gained. Cost and utility impact will be derived from the analysis of individual 
patient data. Since peroneal neuropathy represents a common neuropathy and people with a permanent 
motor deficit will suffer from gait abnormalities (with the need for an orthosis and physiotherapy), as well as 

 
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chronic pain and possible skin problems due to sensory and autonomic deficits, we believe that this 
condition will have an important impact on quality of life. In addition to quality of life measures, the work 
productivity and impairment questionnaire (WPAI) will be used to assess employment and professional 
productivity. The WPAI will be collected at baseline, 6 weeks and 6 months. The professional occupation 
of patients will be collected as baseline data. Return to work will be assessed six weeks after randomization. 
We expect patients to be able to return to work after improvement (of recovery) of foot drop. Relapse of 
foot drop is not expected in the majority of cases (see also Section 8.7.16). 
The proposed trial will provide the ideal opportunity to collect data about quality of life, surgical 
complications, employment and professional productivity in patients with a foot drop due to peroneal nerve 
entrapment. In addition, these data will provide further insights into the quality of life of people with a foot 
drop resulting from other aetiologies (such as lumbar disc herniation), and even about patients with other 
entrapment neuropathies.  
The economic evaluation will be conducted from a healthcare payer (base case) and societal perspective. 
The aim of the economic evaluation is to measure, value and analyse total costs of patients in both groups 
and to relate the difference in costs between the two treatment groups to the difference in clinical effects. 
The time horizon of the economic evaluation is 18 months, after collection of all clinical data that can be 
used for the cost evaluation of the intervention. Sensitivity analysis will be performed to assess the 
robustness of the results using different assumptions regarding costs and effects. 
Effect measures in the economic evaluation will be calculated by the available QOL-questionnaires (EQ-
5D 5L at baseline, 6weeks, 3 months, 6 months, 9 months and 18 months). EQ-5D 5L is a sensitive QOL 
instrument in this trial, since mobility is one of the five dimensions of the EQ-5D 5L questionnaire. Therefore, 
we expect differences in outcome to be reflected in differences in EQ-5D 5L. EQ-5D 5L value sets are 
expected to be available at the end of the trial. If not, the EQ-5D-5L Crosswalk Index Value Calculator can 
be used. We expect to see a higher QOL for the surgical management of the foot drop. 
To facilitate a later cost-utility analysis, quality of life data is collected during the trial (EQ-5D 5L). After the 
completion of the study the Sponsor will transfer the pseudonymised study data set to KCE. KCE will 
request approval from the competent chamber of the Information Security Committee (ISC) to have the 
relevant study data linked with e.g. IMA data by a trusted third party (TTP, eHealth platform) using the 
patient national number (see also 14.10 access to the study data by KCE and similar institutes in the EU).  
This will allow to know the exact costs in both treatment arms, in which an important difference is to be 
expected. These costs are the costs of surgery, anaesthesia and hospitalisation in the surgical arm of the 
trial and costs of physiotherapy (F-pathology) in the conservative (and surgical) trial of the arm. The exact 
number of physiotherapy sessions will be recorded for all participants (treatment record). The costs of a 
foot-ankle orthosis will be documented as well (need for ankle-foot orthosis). If there is an unforeseen 
severe surgical complication, leading to hospitalization, these costs can be retrospectively determined 
through the national number of the patient. Other anticipated health care expenses are general practitioner 
care, costs of visits to other primary care providers, ambulatory and inpatient hospital care, medication and 
home care. The expected difference in these costs are expected to be relative minor and some of them are 
difficult to determine (home care), therefore, the economic analysis will not focus on these costs. Indirect 
costs include absenteeism from paid and unpaid work and presentism.  
The incremental cost (ICER) will be calculated by dividing the difference in total costs between the treatment 
groups by the difference in mean effects (QOL) to compare both treatments. 
 
 
 

 
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12 DATA HANDLING 
12.1 Data collection tools and source document identification 
 
Source Data 
ICH E6 section 1.51, defines source data as "All information in original records and certified copies of 
original records or clinical findings, observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial. Source data are contained in source documents (original records 
or certified copies)." 
 
Source Documents 
ICH E6 1.52, defines source documents as "Original documents, data and records (e.g., hospital records, 
clinical and office charts, laboratory notes, memoranda, subjects' diaries of evaluation checklists, pharmacy 
dispensing records, recorded data from automated instruments, copies or transcriptions certified after 
verification as being accurate and complete, microfiches, photographic negatives, microfilm or magnetic 
media, x-rays, subject files, and records kept at the pharmacy, at the laboratories, and at medico-technical 
departments involved in the clinical trial)." 
Investigators must keep accurate separate records (other than the eCRFs) of all subjects' visits, being sure 
to include all pertinent study related information. A statement should be made indicating that the subjects 
have been enrolled in Protocol and have provided written Informed Consent. Any and all side effects and 
adverse events must be thoroughly documented. Results of any diagnostic tests conducted during the study 
should also be included in the source documentation. Telephone conversations with the subjects 
concerning the study must also be recorded. The Investigator is responsible for maintaining a Subject 
Identification Log, which will include all subjects who provided informed consent (i.e. to include randomized 
subjects and screening failures). This confidential subject identification provides the link between named 
subject source records in the subject file and pseudonymized eCRF data provided to sponsor. The 
Investigator must retain all study related documentation until at least 25 years after completion of the study. 
If regional regulations differ, the investigator must retain study related documents by whichever is longer. 
Study documents should not be destroyed without prior written agreement between the Investigator and 
sponsor. The sponsor must be notified if the Investigator wishes to assign the study records to another 
party or move them to another location. 
Entries recorded by the subject on the paper copies of the Stanmore questionnaire and functional 
ambulation categories are considered source data (WPAI, SF-36, EQ-5D 5L and sensory changes will be 
filled in online through REDCap). Site personnel will review and ensure completeness of the subjects’ 
entries. 
Case report forms 
A case report form (CRF) is a form on which individual patient data required by the trial protocol are 
recorded. REDCap will be utilized by trial site personnel to transfer trial data from source records (medical 
records and/or source document worksheets) onto common eCRFs (electronic Case Report Forms). This 
system is a web-based, secure electronic software application and will ensure that adequate collection of 
data has been performed: 
• 
proper trails can be kept demonstrating the validity of the trial (both during and after the trial) 
• 
only the data required by the protocol are captured in the CRF (using the CRF to capture 
secondary data not required for the study may be a criminal beach of the Data Protection Act, 
makes the CRF unnecessarily complicated, and can make it more difficult to extract the primary 
data for analysis) 
• 
an annotated CRF is developed with coding convention as will be used in the database 
 

 
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12.2 Data handling and record keeping 
All data relating to the Trial must be prepared and validated by the Investigator. Any (e)CRF entries, 
corrections and alterations must be made by the Investigator or other authorized Trial staff. 
Proper audit trails must be available to demonstrate the validity of the Trial data collected. This includes 
historical records of original data entries, by whom and when the data was entered, as well as detailed 
records of any corrections or additions made to the original data entry (i.e. who made the 
correction/addition, when and why), without obliterating the original data entry information. 
The Trial Data Manager will perform extensive consistency checks on the received data. Queries will be 
issued in case of inconsistencies in accordance with internal procedures. A Data Management Plan will be 
developed to map data flows, data validation measures that will be taken and how (interim) database lock(s) 
will be managed.  
Any participant records or datasets that are transferred to the Sponsor or any partners of the Sponsor will 
contain the Trial-specific participant identifier only; participant names or any information which would make 
the participant identifiable will not be transferred. All pseudonymized data relating to the Trial must be 
transmitted in a secure manner to the Sponsor. 
All source data will be kept at a secured location with restricted access at all times. These data must be 
collected and processed with adequate precautions to ensure confidentiality and compliance with 
applicable data protection laws and regulations and more in particular the EU General Data Protection 
Regulation 2016/679 (GDPR) and relevant national laws implementing the GDPR. Appropriate technical 
and organizational measures to protect the data against unauthorized disclosure or access, accidental or 
unlawful destruction, or accidental loss or alteration must be established. Trial staff whose responsibilities 
require access to personal data agree to keep the data confidential. 
The Investigator and the Participating Site(s) (as applicable) shall treat all information and data relating to 
the Trial disclosed to them as confidential and shall not disclose such information to any third parties or use 
such information for any purpose other than the objectives of the Trial as described in this protocol. The 
collection, processing and disclosure of personal data, such as participant health and medical information 
is subject to compliance with applicable laws and regulations regarding personal data protection and the 
processing of personal data. 
Transfer of the pseudonymized data will be performed via a secured method of transfer taking into account 
all applicable security arrangements and regulations (such as the European General Data Protection 
Regulation). The receiving party will be bound by contractual agreement to keep the transferred data 
confidential at all times and to only process the data for the purpose of the Trial. To this end, appropriate 
Data Transfer Agreements (DTAs) will be established. 
 
12.3 Access to Data 
Direct access will be granted to authorised representatives from the Sponsor, host institution and the 
regulatory authorities to permit trial-related monitoring, audits and inspections. 
 
12.4 Archiving 
Archiving will be authorised by the Sponsor following submission of the end of study report. The ISF and 
subjects’ source documents must be kept by the investigator for as long as is necessary to comply with the 
sponsor’s requirements (i.e., as specified in the clinical study agreement), and national and/or international 
regulations, whichever would be the longest period. If the investigator cannot guarantee this archiving 
requirement at the site for any or all of the documents, special arrangements, respecting the data 
confidentiality, must be made between the investigator and the sponsor to store these documents outside 
the site, so that they can be retrieved in the event of a regulatory inspection. No study document should be 
destroyed without prior written approval from the sponsor. Should the investigator wish to assign the study 
records to another party, or move them to another location, the sponsor must be notified in advance. 

 
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All essential documents will be archived for 25 years.  
 
 

 
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13 MONITORING, AUDIT & INSPECTION 
Trial monitoring aims to verify that: 
- 
the rights and well-being of human subjects are protected 
- 
the reported trial data are accurate, complete and verifiable from source documents 
- 
the conduct of the trial is in compliance with the currently approved protocol and amendment, with GCP 
and with the applicable regulatory requirements. 
 
Prior to the start of the study, all required approvals must be obtained. During the study a monitor can 
contact and visit the site and must be permitted, on request, to access the study facilities and all source 
documents needed to verify adherence to the protocol and the completeness, consistency and accuracy of 
the data being entered in the CRF. The processes reviewed can relate to participant enrolment, consent, 
eligibility, and allocation to trial groups; adherence to trial interventions and policies to protect participants, 
including reporting of harm and completeness, accuracy, and timelines of data collection. Monitoring can 
be done by exploring the trial dataset or by performing site visits. 
 
The monitoring standards require full verification that informed consent has been provided, verification of 
adherence to the inclusion/exclusion criteria, documentation of SAEs and the recording of the main 
endpoints. Additional checks of the consistency of the source data with the CRF will be performed according 
to the study-specific monitoring guidelines. 
The requested subject files (ICF, medical notes, other documentation verifying the activities conducted for 
the study) should be available for review. The required study site personnel (see delegation log) must be 
available during monitoring visits and allow adequate time to meet with the monitor to discuss study-related 
issues.  
 
The investigator agrees to cooperate with the monitor to ensure that any issues detected in the course of 
these monitoring visits are resolved.  
The frequency of visits will be specified in the trial monitoring plan.  
 
The Investigator (and head of institution, if required by regional regulations) will make source data and 
documents for this study available to an appropriately qualified quality assurance auditor mandated by 
Sponsor or to regulatory authority inspectors, after appropriate notification. 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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14 ETHICAL AND REGULATORY CONSIDERATIONS 
14.1 Ethics Committee (EC) review & reports 
The trial will be conducted in compliance with the principles of the Declaration of Helsinki (current version), 
the principles of GCP and in accordance with all applicable regulatory requirements. This protocol and 
related documents will be submitted for review and approval to Ethics Committee: 
• 
before the start of the trial, approval will be sought from a EC for the trial protocol, informed 
consent forms and other relevant documents e.g. advertisements and GP information letters 
• 
substantial amendments that require review by EC will not be implemented until the EC grants a 
favourable opinion for the study (note that amendments may also need to be reviewed and 
accepted by the FAMHP before they can be implemented in practice at sites) 
• 
all correspondence with the EC will be retained in the Trial Master File/Investigator Site File  
• 
an annual progress report (APR) will be submitted to the EC within 30 days of the anniversary 
date on which the favourable opinion was given, and annually until the trial is declared ended 
• 
it is the Chief Investigator’s responsibility to produce the annual reports as required. 
• 
the Chief Investigator will notify the EC of the end of the study 
• 
if the study is ended prematurely, the Chief Investigator will notify the EC, including the reasons 
for the premature termination 
• 
within one year after the end of the study, the Chief Investigator will submit a final report with the 
results, including any publications/abstracts, to the EC 
 
The Study can and will be conducted only on the basis of prior informed consent by the Subjects, or their 
legal representatives, to participate in the Study. The Participating Site shall obtain an ICF for all patients 
prior to their enrollment and participation in the Study in compliance with all applicable laws, regulations 
and the approval of the (local) Ethics Committee, if required. The Participating Site shall retain such ICFs 
in accordance with the requirements of all applicable regulatory agencies and laws. 
The Investigator and the Participating Site shall treat all information and data relating to the Study disclosed 
to Participating Site and/or Investigator in this Study as confidential and shall not disclose such information 
to any third parties or use such information for any purpose other than the performance of the Study. The 
collection, processing and disclosure of personal data, such as patient health and medical information is 
subject to compliance with applicable data protection laws and regulations and more in particular the EU 
General Data Protection Regulation 2016/679 (GDPR) and relevant national laws implementing the GDPR. 
Data are anonymous if no one, not even the researcher, can connect the data to the individual who 
provided it. No identifying information is collected from the individual. 
When data are coded, there continues to be a link between the data and the individual who provided it. 
The research team is obligated to protect the data from disclosure outside the research according to the 
terms of the research protocol and the informed consent document. The subject’s name or other identifiers 
should be stored separately (site file) from their research data and replaced with a unique code to create a 
new identity for the subject. Note that coded data are not anonymous.   
 
14.2 Public and Patient Involvement 
Patient involvement in the design of the research  
Overall, 41 patients were involved in the trial design. All but one patient underwent treatment and were 
therefore biased. In total 32 patients were operated on and 9 patients were treated conservatively. One of 
the surgically treated patients underwent late neurolysis after extensive conservative treatment. 
Nevertheless, the reported information proved to be very useful. The information was collected in patient 

 
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interviews (almost exclusively by telephone given the COVID-19 pandemic). A single video-evaluation has 
been conducted. The purpose of patient involvement was to receive feedback on the design of the trial with 
the focus on choosing the primary and secondary endpoints relevant to patients. Furthermore, we wanted 
to assess willingness to participate in the trial. Treatment-related (e.g. would you undergo the same 
treatment again? Would you recommend this treatment to your family or a friend?), work-related (return to 
work) and health-related information (comorbidities) allowed for assessment of the impact of the disease 
and treatment on daily activities. Currently, no patient support groups and/or public initiatives exist for this 
pathology.  
The following feedback from the patients was used in the design of the trial:  
 
Choice of the primary outcome: a measure for gait analysis  
In 93% of all patients, the success of treatment could be measured by improvement in gait. Improvement 
of gait could be measured as being able to walk long distances (either for professional or recreational 
purposes) or as a decreased risk of falling. Given the importance of gait impairment, the distance covered 
during the six-minute walk test was chosen as the primary outcome measurement. Several types of gait 
assessment were included as secondary endpoints.  
 
Assessment of standard of care in peroneal nerve entrapment  
Surgery was experienced as a safe procedure. Patient satisfaction was very high in the surgical group 
(93%), and complications rare (4%). Patient satisfaction in the conservative group was very high as well, 
with 90% of patients reporting to be satisfied with their treatment. All patients but one sought medical 
attention within six weeks after the onset of symptoms. 68% presented within the first week. A large 
proportion of patients followed intense physiotherapy. All patients, treated conservatively, followed at least 
18 sessions. A high percentage of surgical treated patients followed physiotherapy, both pre- and 
postoperative. Ankle foot orthoses were not regularly used (in both treatment groups). Follow-up with EDX 
was more common in the conservative group (half of the patients underwent two electrodiagnostic 
evaluations) than in the surgical group (almost none had more than one EDX). Almost all patients were 
evaluated once after surgery. All patients were evaluated at least once during the conservative treatment. 
Half of these patients were evaluated at least two times. 
Taking this information into account, the visits at three months, six months, 9 months and 18 months cannot 
be considered as standard of care. EDX after randomization cannot be considered standard of care.  
 
Assessment of trial feasibility  
71% of patients would be willing to participate in the proposed trial. The most frequent reason to refuse 
participation was related to the patient’s profession. Many patients needed to be able to walk safely and 
often (for example a construction worker). They feared that, if they were not operated on, recovery would 
take longer, and they would not be able to return to work. Of course, these patients were biased, as most 
of them experienced fast and good recovery after surgery. The most frequent reasons to refuse participation 
in the conservative group were fear of the surgical procedure and the existence of significant comorbidities. 
However, even patients that would refuse to participate themselves, thought that other patients could 
certainly be interested as well. Taking into account that a biased patient sample was interviewed, 71% of 
inclusions represents a substantial number. In 97% of patients, a longer follow-up (with more investigations) 
would not be a reason to abstain from entering such trial. 
During the pilot study we will have the opportunity to receive feedback from our subjects about the further 
trial.  
Patients will be involved in the further set-up of the study, during the course of the trial and during the 
dissemination of the project results. We will also ask for feedback on the ICF. Patients will be involved in 
the development of the online tools for patients and will be asked to evaluate the different trial assessments 
for feasibility and relevance. (Online) patient meetings will be organised to collect feedback during the trial.  
Patient feedback throughout the pilot study  

 
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Study assessments were evaluated by patients through a pilot study questionnaire, obtained at 6 weeks 
and 3 months after randomization. Opinions about different study assessments that are not considered 
standard of care are discussed below. Nine patients answered the pilot study questionnaire at 6 weeks and 
3 months. Analysis is based on the data available from the start of the pilot study until the 7th of September 
2022 (total of 18 questionnaires).   
 
 
The six-minute walk test (6MWT)  
Overall, the 6MWT was considered relevant, useful and completed without difficulties. At three months after 
randomization, two patients considered the 6MWT not useful (figure 5). From a patient perspective, the 
6MWT seems to be a relevant and well chosen primary endpoint.  
Figure 5 – The six-minute walk test during the pilot study  
 
The 10 meter walk test (10MWT).  
The 10-meter walk test was considered relevant by most patients. At 3 months, progressively more patients 
considered the 10MWT to be relevant compared to 6 weeks (figure 6).  
Figure 6 – The 10 meter walk test during the pilot study (figure 7)  
 
 
Repeated electrodiagnostics 
No patients considered EDX to be irrelevant. EDX is experienced as relevant by all patients at 3 months 
after randomization. (figure 7). We can conclude that patients find electrodiagnostics important in the follow-
up of foot drop.  

 
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Figure 7 – Electrodiagnostics  
 
 
Isometric dynamometry 
An absolute majority of participants considered the assessment of motor function through isometric 
dynamometry to be relevant (see figure 8).  
Figure 8 – Isometric dynamometry  
 
 
Quality of life questionnaires (QoL) 
Opinions regarding the quality of life questionnaires were more divided (figure 9). A little more than half of 
the participants considered the QoL questionnaires to be relevant at both evaluation moments. However, 
compared to the trial assessments discussed above, more patients considered QoL questionnaires to be 
less useful at both 6 weeks and 3 months.  One patient in Leuven thought the SF-36 to be excessively long 
without any additional value over the EQ5D questionnaire.  
Figure 9 – Quality of life questionnaires  
 
Work productivity and activity impairment questionnaire (WPAI) 
Comparable to the quality of life questionnaires, opinions regarding the WPAI questionnaire were divided. 
However, the largest group of participants still considered the questionnaire to be relevant at both 
evaluation moments (figure 10).  

 
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Figure 10 – Professional disability questionnaire 
 
 
Other relevant pilot study questionnaire information 
All patients understood the goal of the study and all patients acknowledged that they received enough 
information about the trial and the trial flow. All patients agreed that the instructions during the assessments 
were clear and understandable. The statements above were true both at  6 weeks and 3 months (1 
questionnaire was incomplete regarding this topics). At 6 weeks after randomization, all patients (8), did 
not consider the study visits to be too time consuming. At 3 months, one patient thought the study visits 
were too time consuming. At 6 weeks, completion of the trial assessments took 71.25 minutes on average 
(minimum of 60 minutes, maximum of 90 minutes). At 3 months, completion of the trial assessments took 
76.25 minutes on average (minimum of 30 minutes, maximum of 120 minutes).  
 
Patients had the possibility to give other feedback in the questionnaire as well. A summary:  
- 
“Due to the multiple appointments in a short period of time, the difference is really noticeable.” 
- 
“I am happy with the evolution of my foot.” 
- 
“It is important that there is a good connection between the patient and the physiotherapist. My 
physiotherapist gives me a good feeling!” 
- 
“Surprised that there was no need for an operation, but all the better.” 
- 
“Since there is no progress, I do not think that it is useful to repeat the investigations this often. I 
am not making any staps forwards. I do not have pain, only hindrance. With pain I would not be 
able to complete all the assessments.” 
Apart from patient feedback from the questionnaire, we learned from one of our patients in UZ Leuven that 
perhaps too many questionnaires need to be completed repeatedly. Currently, patients need to complete 
4 questionnaires: EQ5D-5L, SF-36, WPAI and the pilot study feedback questionnaire. This was discussed 
during the second Trial Steering Committee of 25-11-2021. The committee proposed to consider to exclude 
the SF-36 from the full-scale trial.After completion of the pilot study, the SF-36 questionnaire was omitted 
from the full-scale study.  
 
14.3 Regulatory Compliance  
The trial will not commence until a favourable opinion is obtained from the EC. The protocol and trial conduct 
will comply with applicable legislation, including but not limited to the Belgian law of May 7th 2004 regarding 
experiments on the human person and any relevant amendments. 
 
14.4 Protocol compliance  
The investigator must conduct the study in compliance with the EC and/or the regulatory authority-approved 
version of the protocol and must not implement any deviation/change from the protocol, except when 
deviation is necessary to eliminate an immediate hazard to the subject.  
Accidental protocol deviations can happen at any time. Deviations from the protocol which are found to 
frequently recur are not acceptable, will require immediate action and could potentially be classified as a 
serious breach. If a protocol deviation occurs, the investigator/delegate will inform the sponsor or its 
representative in a timely manner. The investigator/delegate must document and explain any deviation from 
the approved protocol. Deviations considered to be a violation of ICH-GCP must be reported to the EC and 
regulatory authorities according to the sponsor or (overruling) local requirements.  

 
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All protocol deviations will be reported in the clinical study report. IECs/IRBs will be provided with listings 
of protocol deviations as per local requirements. 
Prospective, planned deviations or waivers to the protocol are not allowed and must not be used e.g. it is 
not acceptable to enrol a subject if they do not meet the eligibility criteria or restrictions specified in the trial 
protocol.  
All participating physicians and trial sites have the responsibility to guide patients throughout the study visits 
and are expected to follow protocol and to inform patients in a correct, objective manner. If the TSC 
documents an unusual high percentage of cross-over in a specific trial site, this trial site can be excluded 
from the foot drop trial.  
 
14.5 Notification of Serious Breaches to GCP and/or the protocol  
It is understood that “a serious violation” is likely to affect to a significant degree: 
- 
the safety or physical or mental integrity of the Trial participants; or 
- 
the scientific validity of the Trial 
In that case, the Sponsor should be notified immediately upon becoming aware of a serious breach 
during the study conduct phase. The sponsor of a clinical will notify the licensing authority in writing of any 
serious breach of the conditions and principles of GCP in connection with that trial, or the protocol relating 
to that trial, as amended from time to time, within 7 days of becoming aware of that breach.  
 
14.6 Data protection and patient confidentiality  
All investigators and trial site staff must comply with the requirements of the Belgian and European Privacy 
legislation (http://www.dataprotectionauthority.be/legislation-and-standards) on the protection of privacy in 
relation to the processing of personal data, with regards to the collection, storage, processing and 
disclosure of personal information.  
The investigator/delegate must ensure that data/patient confidentiality is maintained. On eCRFs or other 
documents (e.g., documents submitted to the EC or those attached to SAE forms) submitted to the sponsor, 
subjects must be identified only by number and never by their name or initials, date of birth, hospital 
numbers, or any other personal identifier. The investigator/delegate must keep a subject identification code 
list at the site, showing the subject number, the subject’s name, date of birth, and address or any other 
locally accepted identifiers. Documents identifying the subjects (e.g., signed ICFs) must not be sent to the 
sponsor, and must be kept in strict confidence by the investigator/delegate. 
 
14.7 Financial and other competing interests for the chief investigator, PIs at each site 
and committee members for the overall trial management  
The Chief Investigator and PIs at each site and committee members of the overall trial management have 
no competing interest.  
 
14.8 Indemnity 
The Participating Site, the Investigator and Sponsor shall have and maintain in full force and effect during 
the term of this Trial, and for a reasonable period following termination of the Trial, adequate insurance 
coverage for: (i) medical professional and/or medical malpractice liability, and (ii) general liability. 
For Belgian Participating Sites 
Art 29 of the Belgian Law relating to experiments on human persons dated May 7th, 2004 applies. 
Prior to the start of the Trial, the Sponsor shall enter into an insurance contract in order to adequately cover 
Trial participants from Belgian sites in accordance with art. 29 of the said law. 

 
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For non-Belgian Participating Sites 
The Participating Site shall have and maintain in full force and effect during the term of this Trial (and for 
a reasonable period following termination of the Trial, adequate insurance coverage for other possible 
damages resulting from the Trial at the Participating Site, as required by local law. Each such insurance 
coverage shall be in amounts appropriate to the conduct of the services of the Participating Site under this 
Trial. The Participating Site and Sponsor shall be solely responsible for any deductible or self-insured 
retention under any such policies. 
 
14.9 Access to the Study Data by KCE and similar institutes in the EU 
This section should be read in conjunction with the research agreement, which supersedes the protocol in 
case of contradictory statements. 
A distinction is to be made by access by KCE (and similar institutes in Europe) and access by other parties. 
 
Access to Study Data by KCE is fully defined in the contract between KCE and the Sponsor and the 
research 
agreement 
template 
is 
publicly 
available 
on 
the 
KCE 
website. 
Link: 
https://kce.fgov.be/en/resources-for-investigators 
After the completion of the study the Sponsor will transfer the pseudonymised study data set to KCE. KCE 
will request approval from the competent chamber of the Information Security Committee (ISC) to have the 
relevant study data linked with e.g. IMA data by a trusted third party (TTP, eHealth platform) using the 
patient national number. 
 
The patient information and consent includes wording that the national number will be recorded on site by 
the investigator for later data linkage, but will not be included in trial database available to the sponsor or 
any other third party. The patient information and consent will also include that in case the patient is 
randomized, it is planned that a trusted third party (TTP, eHealth platform) will receive and use the national 
number to link with IMA administrative data. To this end, KCE will receive the link between the study number 
and the national number under pseudonymised form. KCE will never be able to use the link without 
authorisation of the ISC and the intervention of the TTP. This data linkage is planned to obtain a more 
complete data set containing costs related to health care paid by the compulsory health insurance and the 
patient that will be used for the analysis of effectiveness and cost-effectiveness of the intervention by KCE. 
The processing of personal data for this analysis is necessary for the performance of a task carried out in 
the public interest, as specified in the law defining KCE’s missions and tasks. To the extent the personal 
data is related to health, the processing is necessary for scientific or statistic purposes, as specified in the 
law defining KCE’s missions and tasks. For all processing related to the analysis of effectiveness and cost-
effectiveness of the intervention, KCE is the controller. 
 
KCE and Sponsor have entered into a research agreement detailing the roles and responsibilities of each 
party, as well as other legal aspects of this collaboration, including the right to use and access of KCE to 
the Study Data. 
  
“Background” means any intellectual property (IP), data, materials, information owned or controlled by the 
Sponsor or a Site, and required to run this Study. Sponsor will identify such Background including the legal 
restrictions of which Sponsor or Sites are aware that may affect the use of the Background for the purpose 
of the Study or the rights granted to KCE under this Agreement. 
  
The Study Data consist of this protocol, including amendments, the electronic forms for data capture, 
including the annotations and guidance for use, the electronic database of the pseudonymized clinical and 
non-clinical data collected using data capture, including the log of changes from data entry to database 

 
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lock, study reports based on these pseudonymized data, and any data or reports generated at a later stage, 
e.g. based on exploratory analyses or stored samples. 
  
“Foreground” means any Study Data, and any tangible biological, chemical and physical material and 
inventions, that are generated, acquired, discovered, conceived, developed, created, exemplified or derived 
as a result of carrying out the Clinical Study, whatever its form or nature, whether it can be protected or not, 
as well as any Foreground IP. Sponsor acknowledges that the main purpose of the research performed 
under this Agreement is to generate results that will serve the general public interests, and specifically the 
interests of the patients and public healthcare decision making bodies, and, therefore, undertakes not to 
exploit the Foreground in any way that is or could be detrimental to such interests. 
 
The Sponsor owns the Study Data, but provides KCE with a copy of the pseudonymized database after 
database lock as well as a royalty-free unrestricted license to use the Study Data for non-commercial public 
health related purposes as detailed in the Agreement between KCE and <<Institution>> (details will be 
documented in the appropriate juridical documents). If judged appropriate, KCE will introduce the request 
to the competent chamber of the Information Security Committee and arrange for the data linkage. For the 
sake of clarity, the linked data are not part of the Study Data. However, KCE will discuss with the Sponsor 
the results of the analyses and the reporting of the linked data. 
 
 
14.10 Access to the final trial dataset by other parties 
The study results will be owned by the party who generates them. The Sponsor will have access to the 
study data. At the end of the study, KCE will receive from Sponsor specific study data. This will only be 
anonymous study data or, where requested by KCE, coded personal data are made available to KCE. 
The study data shall not be provided to a third party without the prior written approval of KCE, which 
approval KCE shall not unreasonably withhold or delay and which KCE may subject to specific conditions 
in order to ensure that the provision of said study data does not have a negative impact on the further 
performance of the study, the rights granted to KCE under the research agreement and/or the benefit of 
the Study for the patients and/or the public payers. 
15 DISSEMINATION POLICY 
15.1 Dissemination policy 
This section should be read in conjunction with the research agreement, which supersedes the protocol in 
case of contradictory statements. 
The Declaration of Helsinki (latest version) and European and Belgian regulations require that every 
research Trial involving human participants be registered in a publicly accessible database before 
recruitment of the first participant. The CI is responsible for registering the Trial.  
In addition, the CI will fulfil their ethical obligation to disseminate and make the research results publicly 
available. As such the CI is accountable for the timeliness, completeness and accuracy of the reports. 
Researchers, authors, Sponsors, editors and publishers must adhere to accepted guidelines for ethical 
reporting. Negative and inconclusive, as well as positive results must be published or otherwise made 
publicly available. Sources of funding, institutional affiliations and conflicts of interest must be declared in 
publication.  
 
15.2 Authorship eligibility guidelines and any intended use of professional writers 
Publications will be coordinated by the CI. Authorship to publications will be determined in accordance with 
the requirements published by the International Committee of Medical Journal Editors and in accordance 
with the requirements of the respective medical journal.  

 
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For multicentre Trials, it is anticipated that the primary results of the overall Trial shall be published in a 
multicentre publication. 
Participating Sites are not allowed to publish any subset data or results from the Trial prior to such 
multicentre publication. 
Any publication by a Participating Site must be submitted to the Sponsor for review at least thirty (30) 
calendar days prior to submission or disclosure. Sponsor shall have the right to delay the projected 
publication for a period of up to three (3) months from the date of first submission to the Sponsor in order 
to enable the Sponsor to take steps to protect its intellectual property rights and know-how. 
 
15.3 Communication plan 
There is a consensus among experts that the results of clinical trials should be made available to 
participants and suggested that providing participants with results, both positive and negative, should be 
considered the “ethical norm”(119). This practice is being encouraged because it is a way of showing 
respect for research participants and to acknowledge the central role of participants in the completion of 
research studies. Communicating results avoids treating the participants as a means to an end (120). 
Although there are no strict guidelines formulated to share the results of trials with patients (121), the 
development of a communication plan is important. Therefore, a plan to communicate the results of the foot 
drop trial with all participants will be developed. Several barriers are taken into account:  
 
1. Some patients might not want to know the results. Reactions to results may be influenced by an 
individual’s coping style, how well he or she dealt with the foot drop. The response of the participant 
can also be affected by how the patient fared with the treatment. Patients may not want to know 
that they were allocated to the inferior arm of the trial. To address this concern, patients will be 
asked at the time of study enrollment if they wish to be offered trial results in the future. The 
informed consent form should both discuss potential benefits and risks of receiving results of the 
trial (122).  
2. If the study participant has died or is not capable anymore of receiving the results himself or herself, 
psychosocial repercussions have to be anticipated when the family of the participant is contacted 
to discuss the results of the trial. Death or mental deterioration due to peroneal entrapment is not 
anticipated and highly unlikely.  
3. The primary goal of clinical research is to seek generalizable knowledge. Physicians need to be 
aware that the results of the trial could not be beneficial for his/her own individual patient with whom 
he has a therapeutic relationship.  
4. A fourth barrier is the absence of patient’s groups. Therefore it is not possible to distribute trial 
specific information through patient group websites or patient communities, something that has 
been done in other trials (123). 
Following guidelines to determine the appropriate time at which results would be offered to participants and 
to disseminate the plans are proposed. The proposed guidelines are partially based on the guidelines 
formulated by Fernandez et al. (124). 
 
Willingness to receive trial related information.  
Patients will be asked at the time of study enrollment if they wish to be offered trial results in the future.  
This will be included in the informed consent form. Both potential benefits and risks of receiving results of 
the trial will be discussed. If a patient chooses to not receive the trial results, this will be documented in the 
electronic case report form (eCRF). If a patient wants to receive the trial results, the patient can choose if 
he wants to be informed through e-mail or through a postal letter. If patients change their mind during the 
trial and choose to not receive the trial results, the study team can be addressed and the changes can be 
documented in the eCRF. 
 
 
Trial results of full-scale trial  
The results of the research will be communicated with the participants after all participants have reached 
the primary endpoint. This data will not be shared with participants until the data interpretation has 
undergone peer review. Research results should be offered in a timely manner and will therefore be 

 
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communicated within 1 month after the data are peer reviewed. Participants will receive an e-mail or postal 
letter that will address the following bullet points:  
- 
The context and goals of the study will be documented, without the use of medical jargon.  
- 
Major findings of the trial. The analyzed endpoints will be discussed.  
- 
Limitations of the study.  
- 
Any anticipated long-term effects 
- 
Contact information of the site-specific clinical trial assistant will be provided to give participants 
the opportunity to ask for more / individualized information. This will also allow participants to 
receive additional information provided by the treating physician. This will allow to address medical 
or psychological needs of the research participants.  
- 
The opportunity for patients will be provided to enlist to receive information on the extended follow-
up period of 18 months. Only participants that want to receive additional information will receive 
this information. Results of the extended follow-up visit of 18 months will be communicated after 
the end of the trial, when all data have been analyzed and peer reviewed. These results will be 
made available within 3 months after this process.  
- 
Gratitude towards the participants will be stressed in the communication.  
Communication of results of the trial towards patients can be time consuming. Since the anticipated number 
of inclusions in the most centers is rather small, this should be feasible. The PI will be responsible for patient 
communication but can involve other staff or employees in a site-specific manner. In exceptional and 
unforeseen circumstances, bad information should always be discussed with the patient by the treating 
physician or PI.  
 
 
 
 
 
 
 
 
 
 
 
 
16 REFERENCES 
 
1. 
Poage C, Roth C, Scott B. Peroneal Nerve Palsy: Evaluation and Management. The Journal of 
the American Academy of Orthopaedic Surgeons. 2016;24(1):1-10. 
2. 
Greenberg M. Peripheral nerves, entrapment neuropathies.  Handbook of neurosurgery. 1. New 
York: Thieme; 2010. p. 515-40. 
3. 
Broekx S, Weyns F. External neurolysis as a treatment for foot drop secondary to weight loss: a 
retrospective analysis of 200 cases. Acta neurochirurgica. 2018;160(9):1847-56. 
4. 
Masakado Y, Kawakami M, Suzuki K, Abe L, Ota T, Kimura A. Clinical neurophysiology in the 
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◼ APPENDICES 
APPENDIX 1. RISK ASSESSMENT OF THE TRIAL 
INTERVENTION(S) 
Risks associated with trial interventions 
 A ≡ Comparable to the risk of standard medical care 
 B ≡ Somewhat higher than the risk of standard medical care 
 C ≡ Markedly higher than the risk of standard medical care 
 
 
Justification:  Briefly justify the risk category selected and your conclusions below (where the table is 
completed in detail the detail need not be repeated, however a summary should be given): 
 
Both treatment arms are currently applied in daily clinical practice and application in this trial do not pose 
more than minimal additional risk or burden to the safety of the subjects compared to normal clinical 
practice. 
 
 
 

 
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APPENDIX 2. AUTHORISATION OF PARTICIPATING SITES  
Appendix 2.1. Required documentation  
- 
CV of the research team  
- 
Certificate of good clinical practice (physicians)  
- 
Confirmation of training of blinded researchers  
- 
Confirmation of successful in training in REDCap data management  
Appendix 2.2. Procedure for initiating/opening a new site  
If the go criterion is met during the feasibility pilot study, the foot drop trial will be extended to a full-scale 
study. More than 20 centers in Belgium and several centers in the Netherlands will be included.  
Appendix 2.3. Principal Investigator responsibilities  
The PI’s legal responsibilities will be listed in the clinical study agreement.  
A PI is expected to:  
- 
Attend the initiation meeting/teleconference  
- 
Supervise the training of the team members / blinded outcome assessors 
- 
Ensure that the ISF is accurately maintained 
- 
Report safety within the timelines  
- 
Disseminate important safety or trial related information to all stakeholders within their sites 

 
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APPENDIX 3. AMENDMENT HISTORY 
 
Amendment 
No. 
Protocol 
version no. 
Date issued 
Author(s) of 
changes 
Details of changes made 
1 
V.2.0 
### 
Christophe 
Oosterbos 
Adaptation of protocol based on pilot 
study results. This amendment 
concers minor protocol adaptations:  
- 
Deletion of SF-36 as QOL 
questionnaire 
- 
Deletion of ankle dorsiflexion 
range of motion as study 
assessment  
The new recruitment strategy is 
included as well.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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APPENDIX 4. LIST OF STANDARD ASSESSMENTS 
 
MOTOR ASSESSMENT: MRC score for ankle dorsiflexion, ankle eversion and hallux-extension  
Please use a score from 0 to 5 to grade the power of the muscle group in relation to the maximum expected 
for that muscle (compare to the contralateral healthy side). 
Muscle group 
 
 
MRC score (/5) 
 
Ankle dorsiflexion 
…. 
Ankle eversion 
…. 
Hallux extension 
…. 
 
 
SENSORY FUNCTION 
Symptoms qualified as sensory included the presence of hypoesthesia and/or paresthesia. Please use 
following system to assess sensory symptoms (compare to the contralateral healthy side):  
a. Complete recovery: the absence of any sensory symptoms 
b. Partial recovery: patients with a minimum of sensory symptoms  
c. No recovery: patients with no improvement 
 
…….            …………………………………           recovery 
 
 
 
 
Ability to WALK BAREFOOT?  
          YES 
 
 
 
 
NO 
 
 
 
Need for FOOT-ANKLE ORTHOSIS?  
          YES 
 
 
 
 
NO 

 
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TREATMENT RECORD 
Physiotherapy: frequency 
 
………………………………. / week 
 
Physiotherapy: duration per session 
………………………………… minutes 
Additional Home exercises 
 
Yes  /  No 
……. / week (frequency) 
Use of electrostimulation 
Yes  /  No 
……. / week (frequency) 
Total number of physiotherapy sessions 
…………………………….. sessions 
Other therapies (e.g. vitamin substitution, 
acupuncture, …) 
 
…………………………………………………… 
 
 
 

 
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APPENDIX 5. REFERENCE VALUES FOR 6-MINUTE WALK 
DISTANCE (6MWD) IN A NORMAL HEALTHY 
POPULATION  
 
Appendix 5.1. Reference values for 6MWD in a healthy population aged 20 to 80 
years 
 
 
 
 
 
Reference values for the 6MWD per age-category as published by Gibbons et al. (60). 
 
 
 
 

 
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APPENDIX 6. AGE AND SEX-BASED REFERENCE VALUES 
FOR GAIT SPEED  
 
 
Mean estimate of walking speed (m/s) presented by gender and decade of age (101). 
 
 
 
 
 
 
 
 
 
 
 
 

 
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APPENDIX 7. WORK PRODUCTIVITY AND ACTIVITY 
IMPAIRMENT QUESTIONNAIRE: GENERAL 
HEALTH 
 
 
 
 
 
 
 

 
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APPENDIX 8. QUALITY OF LIFE QUESTIONNAIRE 
Appendix 8.1. EQ-5D 5L 
 
The foot drop trial was registered at the EuroQol website with registration ID 39666. Included in Appendix 
8 is the English version of the Health Questionnaires. The French and Dutch (for Belgium and the 
Netherlands) version are available as well.  
 
 
 
 

 
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Under each heading, please tick the ONE box that best describes your health 
TODAY. 
MOBILITY 
 
I have no problems in walking about 
❑ 
I have slight problems in walking about 
❑ 
I have moderate problems in walking about 
❑ 
I have severe problems in walking about 
❑ 
I am unable to walk about 
❑ 
SELF-CARE 
 
I have no problems washing or dressing myself 
❑ 
I have slight problems washing or dressing myself 
❑ 
I have moderate problems washing or dressing myself 
❑ 
I have severe problems washing or dressing myself 
❑ 
I am unable to wash or dress myself 
❑ 
USUAL ACTIVITIES (e.g. work, study, housework, family or leisure 
activities) 
 
I have no problems doing my usual activities 
❑ 
I have slight problems doing my usual activities 
❑ 
I have moderate problems doing my usual activities 
❑ 
I have severe problems doing my usual activities 
❑ 
I am unable to do my usual activities 
❑ 
PAIN / DISCOMFORT 
 
I have no pain or discomfort 
❑ 
I have slight pain or discomfort 
❑ 
I have moderate pain or discomfort 
❑ 
I have severe pain or discomfort 
❑ 
I have extreme pain or discomfort 
❑ 
ANXIETY / DEPRESSION 
 
I am not anxious or depressed 
❑ 
I am slightly anxious or depressed 
❑ 
I am moderately anxious or depressed 
❑ 
I am severely anxious or depressed 
❑ 
I am extremely anxious or depressed 
❑ 
 
 

 
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The worst health 
you can imagine 
 
 
 
 
 
• We would like to know how good or bad your health is TODAY. 
• This scale is numbered from 0 to 100. 
• 100 means the best health you can imagine. 
0 means the worst health you can imagine. 
• Please mark an X on the scale to indicate how your health is TODAY. 
• Now, write the number you marked on the scale in the box below. 
 
  
 
 
 
 
 
 
 
 
 
The best health you 
can imagine 
YOUR HEALTH TODAY = 
10
0
20
30
40
50
60
80
70
90
100
5
15
25
35
45
55
75
65
85
95

 
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APPENDIX 9. TEMPLATE FOR SURGICAL PROCEDURE 
 
Surgical procedure: 
Neurolysis of the right/left peroneal nerve at the level of the fibular head 
 
Anaesthesia: Local / locoregional / general anaesthesia 
 
Surgical report:  
Patient positioning: supine/lateral with/without pneumatic compression device. 
Disinfection and sterile draping.  
Curvilinear/linear incision of approximately ### centimetres beneath the fibular head.  
The subcutaneous tissue is bluntly dissected, and the common peroneal nerve is identified proximal to the 
peroneus longus muscle. The peroneal nerve is then released from the surrounding fibrous tissue and 
fascia.  
The anterior intermuscular septum is/ is not cut.  
The peroneal nerve is decompressed distal to the fibular tunnel.  
Decompression does/does not extend beyond the bifurcation in the superficial and deep peroneal 
branches.  
The peroneal nerve was/was not damaged during the procedure.  
Hemostasis.  
Closure of the wound. 
Estimated time of procedure (skin-to-skin: … mins).