Compression Hosiery to Avoid Post-Thrombotic Syndrome (CHAPS)
Phase: NA
Conditions: Deep Vein Thrombosis, Deep Vein Thrombosis Leg, Post Thrombotic Syndrome
Sponsor: Imperial College London

Sponsor: Imperial College London 
Sponsor Reference Number: 19CX5434 
IRAS: 263041 
PROTOCOL 
CHAPS 
 
 
CHAPS Protocol v8.0, 15/02/2022 
Confidential              
 
 
Page 1 of 47 
 
 
 
 
 
 
 
Compression Hosiery to Avoid 
Post-Thrombotic Syndrome 
 
(CHAPS) 
 
 
CLINICAL STUDY PROTOCOL 
 
 
 
 
Sponsor:  
Imperial College London 
IRAS ID: 
263041 
REC Reference Number: 
19/LO/1585 
Indications: 
Deep venous thrombosis (DVT) 
Sponsor’s Reference Number: 
19CX5434  
Funder’s Reference Number: 
NIHR HTA 17/147/47 
Protocol Version: 
8.0 
 
Protocol Date: 
15/02/2022 
This study/project is funded by the National Institute for Health Research (NIHR) Health Technology 
Assessment programme (project reference 17/147/47). The views expressed are those of the author(s) and 
not necessarily those of the NIHR or the Department of Health and Social Care. 
 
 

Sponsor: Imperial College London 
Sponsor Reference Number: 19CX5434 
IRAS: 263041 
PROTOCOL 
CHAPS 
 
 
CHAPS Protocol v8.0, 15/02/2022 
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REVISION HISTORY 
Protocol 
Version 
Date  
Amendments 
V8.0 
15/02/2022 
- 
Clarification regarding the reporting of Serious 
Adverse Events (SAEs): All ‘related’ and ‘unexpected’ 
SAEs will be reported to the Sponsor 
An update to the process evaluation methodology (including 
the addition of a questionnaire in the control arm; 
questionnaires administered at additional timepoints in the 
intervention arm; confirmation that the qualitative interviews 
can be conducted via telephone, online video call or in-
person) 
V7.0 
31/JAN/2022 
- 
Inclusion criteria to be changed from:                    
•Symptomatic presentation of first deep vein thrombosis, 
<2 weeks from diagnosis 
to                                                
•Symptomatic presentation of first deep vein thrombosis, 
<3 weeks from diagnosis.            
                                                 
This change has been made to aid recruitment.  
V6.0 
05/AUG/2021 
- 
The eligibility criteria has been updated to confirm that 
participants who score C4 on the CEAP classification are 
eligible to participate. Only patients who score C5 and C6 
on the CEAP classification will be excluded. 
V5.0 
05/OCT/2020 
- 
An update has been provided to page 27 of the protocol to 
indicate that sites should collect and report adverse events 
related to the study intervention. 
V 4.0  
25/JUN/2020 
- 
The Covid-19 pandemic has led to a long pause in study 
set up and recruitment which has enabled the authors to 
re-evaluate the protocol in detail. Although previous 
versions of the protocol were written with a pragmatic 
approach to the level of compression i.e. supplying UK 
Class II (18-24 mm Hg). The authors re-evaluated this 
decision and have amended the protocol to standardise 
the study intervention with other recently published trials. 
Stockings provided to trial patients randomised to the 
intervention arm should be the Class II European variety 
which have a slightly higher level of compression (23- 32 
mm Hg). The stockings will be provided by a Medi UK. 

Sponsor: Imperial College London 
Sponsor Reference Number: 19CX5434 
IRAS: 263041 
PROTOCOL 
CHAPS 
 
 
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Confidential              
 
 
Page 3 of 47 
 
 
This change will allow the results of the trial to be more 
widely generalisable to the international community. 
 
- 
Addition of updated NICE guideline [NG158] (reference 
21) which replaces NICE guideline [CG144] (reference 
20).  
 
- 
New citation (reference) 1 to provide clarity on the 
definition of the exclusion criteria- contraindication to 
graduated compression stockings.  
 
- 
Update in the protocol to say the 2 week visit can be 
performed over the phone or via video call if restrictions 
prevent the participant attending in person. 
 
- 
The correct disclaimer for the funding body has been 
added to the title page.  
 
V 3.0 
02/JAN/2020 
- 
Addition of information detailing the CHAPS Process 
Evaluation procedures.  
 
v 2.0 
21/NOV/2019 
- 
Correction of typographical errors throughout the 
document to ensure that all stockings are Class II, 18-
24mmHg  
- 
Correction of typographical errors to correct the name of 
the BMQ questionnaire to the BSQ questionnaire 
- 
Addition of a ‘patient letter’ to send to participants asking 
them to complete the health related quality of life 
questionnaires and a ‘patient reminder letter’ to send if the 
participant has not responded to the first letter. 
- 
Clarification of adverse event reporting procedures  
 
v 1.0  
02/SEP/2019 
Protocol submitted to HRA/Ethics 
 
 

Sponsor: Imperial College London 
Sponsor Reference Number: 19CX5434 
IRAS: 263041 
PROTOCOL 
CHAPS 
 
 
CHAPS Protocol v8.0, 15/02/2022 
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Page 4 of 47 
 
 
CONTACT LIST 
 
Chief Investigator  
Professor Alun H Davies 
Professor of Vascular Surgery & Consultant Surgeon 
Department of Vascular Surgery 
4th Floor, East Wing 
Charing Cross Hospital 
Fulham Palace Road 
London, W6 8RF 
 
Tel: 
+44 (0)203 311 7309 
Fax: 
+44 (0)203 311 7362 
 
Sponsor 
Imperial College London 
Contact: Head of Research Governance and Integrity Team (RGIT) 
Research Governance and Integrity Team (RGIT) 
Imperial College London and Imperial College Healthcare NHS Trust 
Room 215, Level 2 Medical School Building 
Norfolk Place 
London, W2 1PG 
 
Tel: 
+44 (0)207 594 1872 
 
Funder 
National Institute for Health Research (NIHR) 
Health Technology Assessment (HTA) Programme (# 17/147/47) 
 
University of Southampton 
Alpha House 
Enterprise Road 
Southampton, SO16 7NS 
 
Study Manager 
Rebecca Lawton 
Department of Vascular Surgery 
Room 14, 4th Floor, East Wing 
Charing Cross Hospital 
Fulham Palace Road 
London, W6 8RF 
 
Tel: 
+44 (0)203 311 5204 
 
 
 
 

Sponsor: Imperial College London 
Sponsor Reference Number: 19CX5434 
IRAS: 263041 
PROTOCOL 
CHAPS 
 
 
CHAPS Protocol v8.0, 15/02/2022 
Confidential              
 
 
Page 5 of 47 
 
 
 
Senior Statistician 
Professor John Norrie 
Chair of Medical Statistics and Trial Methodology 
Director of Edinburgh Clinical Trials Unit 
Usher Institute- University of Edinburgh 
9 Little France Road 
Nine Edinburgh BioQuarter 
Edinburgh, EH16 4UX 
Tel: 
+44 (0)131 651 7895 
 
Study Statistician 
Imad Adamestam 
Clinical Trials Statistician 
Edinburgh Clinical Trials Unit 
Usher Institute- University of Edinburgh 
9 Little France Road, Nine Edinburgh BioQuarter 
Edinburgh, EH16 4UX 
Email:  
Tel: 
 
 
Health Economist  
Dr David Epstein  
Department of Applied Economics  
Faculty of Economics and Business Sciences  
University of Granada  
Email: davidepstein@ugr.es  
 
Process Evaluation  
Professor Robert Horne 
Director, Centre for Behavioural Medicine 
School of Pharmacy 
University College London  
Email: r.horne@ucl.ac.uk 
 
Clinical Trial Unit 
Edinburgh Clinical Trials Unit 
Level 2, Nine Edinburgh BioQuarter 
9 Little France Road 
Edinburgh, EH16 4UX 
Tel: 
+44 (0)131 651 7895 
Fax: 
+44 (0)131 537 3581 
 

Sponsor: Imperial College London 
Sponsor Reference Number: 19CX5434 
IRAS: 263041 
PROTOCOL 
CHAPS 
 
 
CHAPS Protocol v8.0, 15/02/2022 
Confidential              
 
 
Page 6 of 47 
 
 
ABBREVIATIONS 
 
ABPI 
Ankle Brachial Pressure Index 
AE 
Adverse Event 
ATTRACT 
Acute Venous Thrombosis: Thrombus Removal with Adjunctive 
Catheter-Directed Thrombolysis trial 
B-IPQ 
The Brief Illness Perception Questionnaire 
BMI 
Body Mass Index 
BSQ 
The Beliefs about Stocking Questionnaire 
CACE 
Complier Average Causal Estimation 
CEAP 
Clinical Etiological Anatomical Pathophysiological 
CG 
Clinical Guideline 
CHAPS 
Compression Hosiery to Avoid Post-Thrombotic Syndrome 
CHEERS 
Consolidated guidelines for economic evaluation 
CI 
Confidence Interval 
CRF 
Case Report Form 
CTU 
Clinical Trials Unit 
DMC 
Data Monitoring and Ethical Committee 
DVT 
Deep venous thrombosis 
eCRF 
Electronic Case Report Form 
ECTU 
Edinburgh Clinical Trials Unit 
EQ-5D-5L 
Euroqol 5D instrument for measuring generic health status 
GCS 
Graduated compression stocking 
HRA 
Health Research Authority 
HTA 
Health Technology Assessment 
ICMJE 
International Committee of Medical Journal Editors 
ICH GCP 
International Conference on Harmonisation-Good Clinical Practice 
ICTU 
Imperial Clinical Trials Unit 
NHS 
National Health Service 
NICE 
National Institute for Health and Care Excellence 
NIHR 
National Institute for Health Research 
NNT 
Number needed to treat 
PPI 
Patient and public involvement 

Sponsor: Imperial College London 
Sponsor Reference Number: 19CX5434 
IRAS: 263041 
PROTOCOL 
CHAPS 
 
 
CHAPS Protocol v8.0, 15/02/2022 
Confidential              
 
 
Page 7 of 47 
 
 
PTS 
Post-thrombotic syndrome 
QA 
Quality Assurance 
QALY 
Quality-adjusted life year 
QC 
Quality Control  
QoL 
Quality of Life 
RCT 
Randomised Controlled Trial 
REC 
Research Ethics Committee 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SARS 
Stockings Adherence Reporting Scale 
SIMS 
The Satisfaction with Information about Medicines Scale 
SMS 
Short Messaging Service 
SOP 
Standard Operating Procedure 
SOX 
Compression Stockings to Prevent the Post-Thrombotic Syndrome Trial 
TIQ-A 
Treatment Intrusiveness Questionnaire_Adapted (TIQ_A) 
TMG 
Trial Management Group  
TSC 
Trial Steering Committee 
VEINES 
QoL/Sym 
Instrument to measure quality of life in deep venous thrombosis 
VTE 
Venous thromboembolism 
 
 

Sponsor: Imperial College London 
Sponsor Reference Number: 19CX5434 
IRAS: 263041 
PROTOCOL 
CHAPS 
 
 
CHAPS Protocol v8.0, 15/02/2022 
Confidential              
 
 
Page 8 of 47 
 
 
Table of Contents  
CONTACT LIST ............................................................................................................................ 4 
ABBREVIATIONS ........................................................................................................................ 6 
TRIAL SUMMARY ....................................................................................................................... 9 
 
BACKGROUND ............................................................................................................................. 11 
1.1 
Epidemiology of post-thrombotic syndrome .................................................................. 11 
1.2 
Impact of preventing post-thrombotic syndrome .......................................................... 11 
1.3 
Summary of current research ......................................................................................... 12 
1.4 
Rationale for the study ................................................................................................... 12 
1.5 
Risk / Benefit Assessment ............................................................................................... 12 
 
OBJECTIVES AND OUTCOMES .................................................................................................. 13 
2.1 
Primary Objective ........................................................................................................... 13 
2.2 
Secondary Objectives ..................................................................................................... 13 
2.3 
Primary Endpoint ............................................................................................................ 13 
2.4 
Secondary Endpoints ...................................................................................................... 13 
 
STUDY DESIGN ......................................................................................................................... 14 
3.1 
Design ............................................................................................................................. 14 
3.2 
Figure 1. Study Flowchart ............................................................................................... 15 
 
PARTICIPANT ENTRY ............................................................................................................... 17 
4.1 
Study setting and population ......................................................................................... 17 
 
DETAILS OF INTERVENTIONS ......................................................................................................... 18 
5.1 
Study Arms...................................................................................................................... 18 
5.2 
Permanent Discontinuation of Study Intervention and Change of status...................... 19 
 
PROCEDURES AND MEASUREMENTS ..................................................................................... 20 
6.1 
Identification and recruitment of patients ..................................................................... 20 
6.2 
Screening and pre-randomisation evaluations .............................................................. 20 
6.3 
Study Assessments ......................................................................................................... 20 
6.4 
Randomisation and Blinding .......................................................................................... 21 
6.5 
Stocking ordering/re-ordering and fitting: ..................................................................... 21 
6.6 
Follow up ........................................................................................................................ 21 
6.7 
Code-breaking/ Unblinding ............................................................................................ 22 
 
SAFETY REPORTING ....................................................................................................................... 27 
7.1 
Adverse Event (AE) ......................................................................................................... 27 
7.2 
Adverse Event recording ................................................................................................. 27 
7.3 
Serious Adverse Events (SAE) ......................................................................................... 28 
7.4 
Reporting of SAEs ........................................................................................................... 29 
7.5 
Reporting urgent safety measures ................................................................................. 30 
 
STATISTICS AND DATA ANALYSIS ................................................................................................... 31 
8.1 
Sample Size and power considerations .......................................................................... 31 
8.2 
Planned Data Analysis .................................................................................................... 31 
 
REGULATORY, ETHICAL AND LEGAL ISSUES ............................................................................ 33 
9.1 
Declaration of Helsinki ................................................................................................... 33 
9.2 
Good Clinical Practice ..................................................................................................... 33 
9.3 
Independent Ethics Committee Approval ....................................................................... 33 
9.4 
HRA approval .................................................................................................................. 33 
9.5 
Non-Compliance and Serious Breaches .......................................................................... 33 

Sponsor: Imperial College London 
Sponsor Reference Number: 19CX5434 
IRAS: 263041 
PROTOCOL 
CHAPS 
 
 
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9.6 
Insurance and Indemnity ................................................................................................ 34 
9.7 
Trial Registration ............................................................................................................ 34 
9.8 
Informed Consent ........................................................................................................... 34 
9.9 
Contact with General Practitioner .................................................................................. 35 
9.10 
Subject Confidentiality.................................................................................................... 35 
9.11 
Data Protection and Patient Confidentiality .................................................................. 35 
9.12 
End of Trial...................................................................................................................... 35 
9.13 
Study Documentation and Data Storage ....................................................................... 35 
 
DATA MANAGEMENT ......................................................................................................... 36 
10.1 
Source Data .................................................................................................................... 36 
10.2 
Language ........................................................................................................................ 36 
10.3 
Database ........................................................................................................................ 36 
10.4 
Data Collection ............................................................................................................... 36 
10.5 
Archiving ......................................................................................................................... 36 
 
STUDY MANAGEMENT STRUCTURE ................................................................................... 37 
11.1 
Trial Steering Committee ................................................................................................ 37 
11.2 
Trial Management Group ............................................................................................... 37 
11.3 
Data Monitoring Committee .......................................................................................... 37 
11.4 
Early Discontinuation of the Study ................................................................................. 37 
11.5 
Risk Assessment .............................................................................................................. 37 
11.6 
Monitoring ...................................................................................................................... 38 
11.7 
Quality Control and Quality Assurance .......................................................................... 38 
11.8 
Peer review ..................................................................................................................... 38 
11.9 
Patient and Public Involvement ...................................................................................... 38 
11.10 
Publication and Dissemination policy......................................................................... 38 
 
REFERENCES ....................................................................................................................... 40 
SIGNATURE PAGE 1 (CHIEF INVESTIGATOR) .............................................................................. 43 
SIGNATURE PAGE 2 (SPONSOR) ................................................................................................ 44 
SIGNATURE PAGE 3 (STATISTICIAN) .......................................................................................... 45 
SIGNATURE PAGE 4 (PRINCIPAL INVESTIGATOR) ....................................................................... 46 
APPENDIX 1- VILLALTA’S SCORE ............................................................................................... 47 
APPENDIX 2- SCHEDULE OF ASSESSMENTS ................................................................................. 1 
 
 
 
 
 
 
 
TRIAL SUMMARY 
 

Sponsor: Imperial College London 
Sponsor Reference Number: 19CX5434 
IRAS: 263041 
PROTOCOL 
CHAPS 
 
 
CHAPS Protocol v8.0, 15/02/2022 
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Page 10 of 47 
 
 
TITLE 
Compression Hosiery to Avoid Post-Thrombotic Syndrome (CHAPS) 
 
OBJECTIVE 
To measure the difference in incidence of post-thrombotic syndrome at a median of 18 months 
follow up after first, acute DVT between standard clinical care (anticoagulation) and the intervention 
arm (a graduated compression stocking and the standard clinical care (anticoagulation)). 
 
DESIGN 
Multi-centre, pragmatic, blinded outcome assessment, randomised controlled trial. The trial will 
follow patients up for a median of 18 months (range 6 – 30 months) and will be conducted in 
approximately 11 secondary care Trusts in the United Kingdom. 
 
SAMPLE SIZE 
A total of 864 patients will be recruited, in 1:1 allocation between the two randomised arms. 
 
ELIGIBILITY CRITERIA 
 
Inclusion Criteria 
• Symptomatic presentation of first deep vein thrombosis, <3 weeks from diagnosis 
• Imaging confirmed, lower limb deep vein thrombosis (popliteal, femoral, iliac or 
combination)  
• Ability to give informed consent  
• Age 18 or over 
 
Exclusion Criteria 
• Life expectancy < 2 years 
• Contraindication to wearing graduated compression stockings (in line with 
International consensus statement(1))  
• Previously intolerant of or already wearing graduated compression stockings for 
more than 1 month. 
• Ankle brachial pressure index (ABPI) <0.8 or pedal pulses absent 
• Bilateral deep vein thrombosis 
• Previous chronic venous insufficiency (patients with existing chronic skin changes or 
ulceration, defined as C5 or C6 by CEAP classification). 
• Pre-existing post thrombotic syndrome, significant leg pain (e.g. knee arthritis, spinal 
claudication) or oedema (e.g. lymphoedema). 
• Newly diagnosed cancer, metastatic cancer, or cancer undergoing active treatment 
or palliation 
• Contraindication to anticoagulation  
• Known allergy to fabric in compression stockings 
 
 
 
 
 
PRIMARY ENDPOINT 

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Sponsor Reference Number: 19CX5434 
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Page 11 of 47 
 
 
The primary outcome is any incidence of Post Thrombotic Syndrome (PTS) using the validated 
Villalta criteria (Appendix 1) over a median 18 month follow up (range 6 to 30 months). The primary 
outcome will be assessed on up to three occasions (6 and 12 months post randomisation, and at 
study end) depending on an individual participant’s length of follow up (minimum 6 and maximum 
30 months)  
 
SECONDARY ENDPOINTS 
• Venous ulceration incidence as measured by the validated Villalta criteria 
• Employment status-(change in number of days working from baseline) 
• Change in disease-specific and generic quality of life- VEINES-QoL and EuroQoL EQ5D scales 
from baseline over 6m, 12m and end of study visit 
• Adherence to stockings and anticoagulants- patient self-report 
• Cost-effectiveness of stocking prescription- Incremental cost-effectiveness ratio (ICER) from 
the EQ-5D questionnaire, with appropriate sensitivity analysis 
 
 BACKGROUND 
 
Deep venous thrombosis (DVT) occurs in approximately 1-2 per 1000 adults in the UK (2) and just 
under half will go on to develop lifelong disability from post-thrombotic syndrome (PTS) (3). PTS is 
defined as “chronic venous symptoms or signs secondary to deep vein thrombosis” e.g. lifelong leg 
pain, oedema and skin changes, progressing in 5% to venous ulceration (4). The pathophysiology of 
post- thrombotic syndrome is sustained venous hypertension from venous outflow obstruction and 
valvular incompetence (5). Three clinical scales are widely used to diagnose PTS after objectively‐
diagnosed DVT, Brandjes scale (6), Ginsberg measure (7) and Villalta scale (8) with the Villalta 
considered the “gold standard” for the diagnosis and classification of post-thrombotic syndrome (9).  
The average age of patients developing PTS is 55 years (10), meaning that around half of patients 
work to support a family. Of patients having a lower limb DVT, around 30% of patients will develop 
mild PTS, 10% moderate and 5% severe PTS (3, 10). Severe PTS is characterised by leg ulceration. 
The incidence of DVT rises markedly with age (2) and the severity of PTS increases with age and 
body mass index (3) . With an older, heavier UK population in the future, the burden of PTS is set to 
rise. 
 
 
PTS is a lifelong condition that affects men and women of working age. On average, patients with 
PTS have difficulty walking and staying in active employment; and have levels of disability 
comparable to other chronic diseases such as chronic obstructive pulmonary disease (11). The 15-
year direct healthcare costs of PTS have been estimated at £3000 per patient (12). Reducing the 
rates of venous ulceration are a key outcome as these increase costs from £3000 to £20,000 per 
patient (13, 14), due to the nursing time involved in twice-weekly compression bandaging and 
hospital admissions for management of infection. For those who work, there are personally incurred 
costs such as the use of taxis or the loss of earnings through days off sick and unemployment. 
 

Sponsor: Imperial College London 
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IRAS: 263041 
PROTOCOL 
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Systematic reviews of the literature (15-17) highlight the need for a large definitive trial to settle the 
discrepancies between the earlier positive Brandjes (18) and Prandoni (19) RCTs and the later 
negative SOX trial (10). Furthermore, in the UK (20, 21) and USA (22) stockings are not 
recommended, however in Europe they are (23). 
 
The ATTRACT trial evaluated the benefit of thrombolysis for acute DVT and showed no significant 
benefit in the prevention of post-thrombotic syndrome (47% v 48% at 2 years) (18). This has called 
into question the current DVT thrombolysis strategy recommended by NICE (15). Thrombolysis costs 
approximately £10,000 (19), requires an inpatient stay in a high dependency unit and has important 
safety risks such as intracranial haemorrhage. However, more importantly only 1 in 40 patients were 
actually eligible for thrombolysis in ATTRACT, meaning that 39/40 could not be offered thrombolysis 
(18). These issues are not encountered with stockings.  
 
 
Until 2015, graduated compression stockings were recommended as standard of care by NICE. Key 
barriers to stocking use are evidence of effect, demonstration to Clinical Commissioning Groups that 
they are cost-effective and that adherence can be improved with low cost measures that are widely 
applicable. They also have to be seen as patient friendly and part of patient self-care for the 
condition. 
 
Previous studies evaluating the effectiveness of graduated compression stockings (GCS) in 
preventing PTS have been inconsistent due to high heterogeneity. Further evidence is needed to 
determine the benefit of GCS in the incidence of PTS. 
 
CHAPS includes an internal pilot study and process evaluation that acts as an adherence checkpoint 
at 1 year follow-up. In previous trials, 74% of patients allocated to stockings actually wore stockings 
for more than half of waking hours (24). Stockings are a medical device that are required to be used 
by patients regularly to exert a therapeutic effect on venous haemodynamics. As such, patients need 
to be trained and motivated in order for them to be used effectively. This was an important criticism 
of the SOX trial.  Following recommendations from a previous study of the critical components to 
patient adherence (25), aids to adherence have also been incorporated into CHAPS. 
 
 
Graduated compression stockings, when used in patients with an adequate arterial circulation 
(palpable foot pulse or ABPI0.8), have no major side effects.  There is a small risk that if not worn 
properly, GCS can cause excess pressure on the skin. GCS must be worn smoothly on the skin with 
no folding. There is also a risk that GCS can cause skin irritation, itching, redness or rash.  Therefore, 
it is important patients are examined by a trained health professional before use. 
 
In terms of benefit, prevention of long-term disability that results in 50% of patients following DVT 
is being examined. The CHAPS study group feel this is an acceptable risk/benefit balance. 
 

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Page 13 of 47 
 
 
 OBJECTIVES AND OUTCOMES 
 
To measure the difference in incidence of post-thrombotic syndrome at a median of 18 months 
follow up after first, acute DVT between standard clinical care (anticoagulation) and the intervention 
arm (a graduated compression stocking and the standard clinical care (anticoagulation)). 
 
 
• To compare specific and generic quality of life at the end of the trial  
• To compare employment status at the end of the trial  
• To evaluate whether the use of stockings to prevent PTS is cost effective 
• To perform a detailed process evaluation to understand barriers to adherence 
• To measure adherence in detail over the initial first year and at the end of the trial 
• To capture off-label stocking use in the standard care arm 
 
 
 
The primary outcome measure is any incidence of PTS using the validated Villalta’s score over a 
median 18 month follow up (range 6 to 30 months). The primary outcome will be recorded at fixed 
time points for all those randomised; at 6 and 12 months post randomisation and at study end 
(estimated to be a median of 18 months, range 6-30 months). 
 
 
• Venous ulceration incidence as measured by the validated Villalta’s score 
• Employment status-(change in number of days working from baseline) 
• Change in disease-specific and generic quality of life- VEINES-QoL and EuroQoL EQ5D scales 
from baseline over 6m, 12m and end of study visit 
• Adherence to stockings and anticoagulants- patient self-report 
• Cost-effectiveness of stocking prescription- Incremental cost-effectiveness ratio (ICER) from 
the EQ-5D questionnaire, with appropriate sensitivity analysis 
 
 
 

Sponsor: Imperial College London 
Sponsor Reference Number: 19CX5434 
IRAS: 263041 
PROTOCOL 
CHAPS 
 
 
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Page 14 of 47 
 
 
 STUDY DESIGN   
 
CHAPS is a UK, multi-centre, pragmatic, blinded outcome assessment, randomised controlled trial. 
The 45-month trial will follow up patients with first, acute lower limb DVT for a median of 18 months 
(range 6 – 30 months) and will be conducted in approximately 11 secondary care Trusts in the United 
Kingdom. 
Participants (n=864) will be randomised 1:1 to standard care (anticoagulation as per local hospital 
guidelines) or intervention (anticoagulation as per local hospital guidelines and regular use of a 
graduated compression stocking). 
 
CHAPS has an internal pilot study which will follow the first 200 patients (100 intervention, 100 
control) for one year and provide detailed information on stocking use in both arms. At six months 
median follow up, the criteria for continuing CHAPS is 70% of participants wearing stockings (self-
reported patient adherence) for 4 days per week in the intervention arm, along with a documented 
reorder of stockings within the last 6 months. 
 
A parallel process evaluation will complement the main CHAPS trial with the aim to better 
understand how and why the educational elements of the intervention were effective or ineffective. 
We will identify contextually relevant strategies for successful implementation through detailed 
descriptions of the participants’ views and experiences of wearing graduated compression 
stockings. We will assess patients’ perspectives of the stockings by applying a mixed-methods 
approach to identify the salient perceptions and practicalities influencing patients’ motivation and 
ability to use the stockings as recommended..  
 
 
 

Sponsor: Imperial College London 
Sponsor Reference Number: 19CX5434 
IRAS: 263041 
PROTOCOL 
CHAPS 
 
 
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Page 15 of 47 
 
 
 
 
 

Sponsor: Imperial College London 
Sponsor Reference Number: 19CX5434 
IRAS: 263041 
PROTOCOL 
CHAPS 
 
 
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Page 16 of 47 
 
 
 
 
 

Sponsor: Imperial College London 
Sponsor Reference Number: 19CX5434 
IRAS: 263041 
PROTOCOL 
CHAPS 
 
 
CHAPS Protocol v8.0, 15/02/2022 
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Page 17 of 47 
 
 
 
 PARTICIPANT ENTRY 
 
This study is open to all patients who are 18 years or older at the participating NHS sites with a 
diagnosis of first, acute DVT meeting specific inclusion and exclusion criteria. 
(i) 
Inclusion criteria 
• Symptomatic presentation of first deep vein thrombosis, <3 weeks from diagnosis 
• Imaging confirmed, lower limb deep vein thrombosis (popliteal, femoral, iliac or 
combination)  
• Ability to give informed consent  
• Age 18 or over 
 
Exclusion Criteria 
• Life expectancy < 2 years 
• Contraindication to wearing graduated compression stockings 
• Previously intolerant of or already wearing graduated compression stockings for 
more than 1 month. 
• Ankle brachial pressure index (ABPI) <0.8 or pedal pulses absent 
• Bilateral deep vein thrombosis 
• Previous chronic venous insufficiency (patients with existing chronic skin changes or 
ulceration, defined as C5 or C6 by CEAP classification) 
• Pre-existing post thrombotic syndrome, significant leg pain (e.g. knee arthritis, spinal 
claudication) or oedema (e.g. lymphoedema). 
• Newly diagnosed cancer, metastatic cancer, or cancer undergoing active treatment 
or palliation 
• Contraindication to anticoagulation  
• Known allergy to fabric in compression stockings 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Sponsor: Imperial College London 
Sponsor Reference Number: 19CX5434 
IRAS: 263041 
PROTOCOL 
CHAPS 
 
 
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Page 18 of 47 
 
 
 DETAILS OF INTERVENTIONS 
 
 
(i) ARM 1: STANDARD OF CARE 
Anticoagulation as per standard care, usually for a minimum of 3 months (as per NICE CG 144). 
Anticoagulation is usually prescribed as standard of care for a minimum of 3 months, however is 
variable on an individual patient basis. During this study, participants’ anticoagulation regime will 
be recorded, as will be the adherence to prescription. The type and duration of anticoagulation 
will be left to the discretion of the treating clinician. 
 
(ii) ARM 2: INTERVENTION/STUDY ARM 
Anticoagulation as per standard care, usually for a minimum of 3 months (as per NICE CG 144) and 
a fitted, below knee stocking providing  23- 32 mm Hg pressure ( Class II) worn during waking 
hours. Stockings will be supplied by Medi UK. 
 
Regularly wearing stockings requires behavioural change, therefore a number of low cost 
behavioural aids will be made available to patients in the intervention arm to aid adherence: 
• A patient education video at their first or second visit, detailing what post-thrombotic 
syndrome is, how it can affect a patient’s life and their beliefs regarding wearing stockings 
• A patient and carer training session at recruitment of how to don stockings, reinforced by 
up to 2 follow up fitting appointments at 2 weeks and again if necessary 
• Free provision of a donning aid at 2 weeks if the participant is struggling to wear the 
stockings regularly 
• An SMS reminder to wear their stockings including a motivational SMS reminder to wear 
their stockings and fill out their adherence questionnaire. A number for stocking re-order 
will be provided 
• An anonymous web forum to provide peer to peer support regarding the best types of 
stockings and tips and tricks for use 
• A variety of below knee stockings including cotton stockings for the summer months to 
mitigate the effects of heat, and dress stockings for social occasions. Once a good fit has 
been established, patients will be provided with 2 pairs of stockings (one summer one 
winter pair) to minimise the number of times that washes are required. Every 6 months, 
patients will be asked to reorder stockings by telephone or text, as per their instructions 
for use (26).   
 
 
 
 
 
 
 
 
 
 

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(i) 
Permanent discontinuation of study intervention 
Subjects may discontinue study intervention for the following reasons: 
• At the request of the subject. 
• Adverse event/ Serious Adverse Event 
• If the investigator considers that a subject's health will be compromised due to adverse 
events or concomitant illness that develop after entering the study, e.g. development of 
peripheral arterial disease or leg amputation. 
(ii) 
Change of status 
A change of status refers to discontinuation of study intervention and study procedures and can 
occur for the following reasons: 
• Subject decision to withdraw 
• Loss to follow-up 
• Death 
• New diagnosis of metastatic cancer 
• Venoplasty or venous stenting for post-thrombotic syndrome  
 
 
(iii) 
Procedures for Withdrawal from Study 
Participants who meet the above criteria will be free to withdraw from the study. Participants will 
be free to withdraw from the study without any effect on their usual medical care. The reason for 
their withdrawal will be recorded in the CRF/eCRF and medical records if offered. All randomised 
patients will be followed up for between 6 – 30 months (median 18 months) unless they 
specifically ask to be withdrawn as per intention to treat. In line with this analysis, patients lost to 
follow up or withdrawn from the study will not be replaced. 
 
 
 
 
 
 
 
 
 
 
 

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 PROCEDURES AND MEASUREMENTS  
 
 
Recruitment will primarily be from vascular or haematology clinics and A&E but in addition may be 
from inpatient and maternity wards in approximately 11 secondary care UK hospitals. The largest 
sites see around 240 proximal DVTs per year, whereas the smaller sites see around 120. Hence, the 
total number of potential participants would be just under 3000 per year, across 11 sites. From this 
pool, recruitment of 864 participants is planned over 30 months. In summary, it is anticipated that 
1 in 6 participants will be eligible and willing to join CHAPS. 
 
 
 
Adults with first, acute DVT presenting to participating NHS organisations will be pre- screened by a 
member of the direct care team and invited to speak to a research nurse. With permission of the 
participant, the reasons for non-inclusion will be logged anonymously along with a minimum data 
set of age, sex and reason for exclusion. The anonymised pre-screening logs will be transferred to 
the Trial Coordinating Centre for the purposes of monitoring recruitment.  
 
Participants will have pedal pulses palpated by a trained health professional. If pedal pulses are 
absent (score=0) the participant will not be eligible to take part in the trial. If the research team are 
unable to assess the pedal pulses an ankle-brachial pressure measurement should be taken prior to 
entry into the study. An ABPI of <0.8 is an exclusion criteria.  
 
Research personnel can take informed consent if the patient is eligible at the baseline visit. If the 
patient requires more time to consider the study, a baseline assessment can be arranged for another 
time but must be ≤ 3 weeks after imaging confirmed diagnosis of DVT. 
 
 
Baseline visit  
Following consenting and screening procedures, patients will undergo a series of baseline 
assessments or questionnaires to record the following: 
• Demographic data- date of birth, gender and ethnicity 
• Employment status 
• Height, weight and Body Mass Index (BMI) 
• Lifestyle data- smoking status, alcohol consumption, physical activity level 
• Comprehensive Classification System for Chronic Venous Disorders (CEAP). A score between 
C5-C6 indicates that the patient is ineligible for the study.  
• Villalta’s score 
• Medical history 
• Concomitant medication 
• Quality of life assessments- EQ-5D-DL, VEINES-QoL and B-IPQ 

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Details about the patients DVT including symptom onset, extent and location will be recorded at 
baseline. A copy of the anonymised imaging report confirming the DVT diagnosis will be securely 
transferred to the Trial Manager (Imperial College London) using the Imperial College File 
Exchange.  For full details of the study assessments see Appendix 2.  
 
 
 
Participants will undergo 1:1 web based randomisation to either standard care or the intervention 
via an automated system linked to the eCRF setup via the Study Data Centre at the Edinburgh Clinical 
Trials Unit (ECTU), University of Edinburgh (a fully registered UKCRC Clinical Trials Unit, registration 
number 15). 
 
An independent researcher at each site will perform leg assessments blind to participant allocation. 
This researcher will not have been involved in recruitment, stocking provision, adherence 
monitoring or behavioural interventions. Participants will be encouraged to remove their stockings 
on the day prior to their clinic visit, they will be asked not to discuss the stockings with the 
independent assessor. Blinding will be assessed by asking the assessors whether the patient 
attended study visits wearing a stocking, and whether the patient made it known that they had been 
wearing a stocking or not.  
  
 
Participants randomised to the stocking arm will have their index leg measured for stockings at 
baseline by the local research nurse.  Once the participant’s legs have been measured the research 
nurse will contact Medi UK Ltd to request a pair of Class II stockings (23-32mmHg). The 
participant’s leg measurements will be provided to the manufacturer, along with their study ID to 
ensure the stockings are supplied to the correct participant. No other information will be sent to 
the supplier.  Medi UK will send the stockings to the local hospital site. The research nurse will 
then send the stockings to the participant in the post or the participant will be able to collect them 
in person. The level of compression must be between 23- 32 mm Hg (Class II) and knee-length or 
thigh length depending on patient preference. They should be worn on the DVT-affected leg daily, 
applied upon waking and removed upon retiring to bed, beginning as early as possible within 21 
days after DVT diagnosis and continued for the duration of the study. Patients will be reminded by 
the research nurse at each face-to-face follow up visit to wear their stockings daily in addition to 
receiving SMS reminders.  
 
Medi UK Ltd will act as stocking supplier for the study. A proportion of the stockings will be 
donated free of charge for the use of participants randomised into the study. Medi UK Ltd will not 
have access to any data during the study or prior to publication of the anonymised results of the 
study.  
 
Participants in both arms will be followed up face to face at 6 months 12 months and at the final 
visit which may be between 18 and 30 months depending on when the patient was recruited into 
the trial. Visits will be performed in clinic so that a blinded clinical assessment of both legs can be 
performed using the Villalta’s score. 

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In addition, participants randomised to wear stockings will be seen in clinic at 2 weeks for a 
stocking training session. This can be performed over the phone or via video call if restrictions 
mean the participant cannot attend hospital. The research nurse will discuss any barriers to 
wearing the stockings, check the size and position and provide training in the use of a donning aid 
if required. The stocking video will be shown to the patient again to motivate them to adhere to 
the intervention. Participants randomised to the stocking arm will also receive a monthly online 
stocking usage questionnaire (Stockings Adherence Reporting Scale [SARS]) which will be 
completed remotely by the patient via the electronic database who will receive an email from 
ECTU with login details. Participants can opt to receive this via phone call or the post if they prefer. 
Participants in both arms will receive questionnaires at follow-up visits. The adapted_BMQ 
is administered to both the standard care and intervention arms at baseline, 1 month, 3 
months, 6 months, 12 months and final study visit. The BIPQ is also administered to both 
study arms at baseline, 6 months, 12 months and final study visit. The BSQ is administered 
to the intervention arm only at baseline, 1 month, 3 months, 6 months, 12 months and final 
study visit. The TIQ is also administered to the intervention arm only at 1 month, 3 months, 
6 months, 12 months and final study visit.  
 
Study research nurses will complete three items on the Case Report Form (CRF) relating to 
the GCS training they provide to participants. First, they will record the length of time it takes 
to conduct the training. Second, research nurses will rate their confidence in the patient’s 
ability to use the stockings as prescribed on a visual analogue scale (VAS) ranging from “not 
at all confident” to “completely confident”. The third optional item is an open-text box where 
the research nurses can choose to record any comments regarding their answer to item 2.  
Nurses will also record information about stocking provision, as this may influence 
adherence. This includes information regarding the number of stocking pairs provided to 
the patient, the type of stockings provided (i.e., style and length), and colour. All of these 
items will be answered at stocking provision and each follow-up visit.  
 
Monthly online stocking usage questionnaire:  
Participants in the intervention arm will receive a monthly web survey regarding their use of 
stockings, to assess adherence to the intervention. This can also be administered via the phone or 
post if the participant chooses.  
 
Further Follow-Up 
• Face to face follow up at the end of the follow up period will be performed with an 
independent blind assessor who has been trained in the use of the Villalta’s scoring system 
for PTS. Participants will be followed for between 6 – 30 months (median 18 months). 
• If a patient develops a leg ulcer, they will be advised to attend their local vascular service for 
treatment according to standard care. 
 
 
It is not possible to mask participants or the research to the intervention and a sham stocking was 
deemed impractical to administer. The primary outcome assessment (incidence of PTS) will be 

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completed by an independent clinical assessor trained in the use of the Villalta’s score, who will 
have no previous involvement with, or knowledge of, the participant’s treatment allocation and as 
such will be blind. Participants will be reminded to remove their stockings prior to any face to face 
clinic visit or assessment with the blinded clinician. 
 
 
 
The aim of the process evaluation is to complement the main CHAPS trial, to better understand 
how and why the educational elements of the intervention were effective or ineffective. We will 
identify contextually relevant strategies for successful implementation through detailed 
descriptions of the participants’ views and experiences of wearing graduated compression 
stockings. We will assess patients’ perspectives of the stockings by applying a mixed-methods 
approach to identify the salient perceptions and practicalities influencing patients’ motivation and 
ability to use the stockings as recommended.  
 
6.8.1 Process evaluation design 
The overall design is a mixed-methods study using quantitative and qualitative data. 
Quantitative methods will include: 
• self-report patient questionnaires: Brief Illness Perceptions Questionnaire 
(BIPQ), Beliefs about Stockings Questionnaire (BSQ), the adapted Beliefs 
about Medicines Questionnaire (adapted_BMQ), and Treatment Intrusiveness 
Questionnaire (TIQ) 
• self-report nurse data on patient stocking training and use. 
Qualitative methods will include: 
• One-to-one patient interviews with a post-doctoral qualitative researcher at 
University College London (UCL). 
 
Patients randomised to the intervention will receive behavioural aids designed around a 
Perceptions and Practicalities Approach (PAPA™) (27) for supporting adherence. As non-adherence 
may be linked to ideas around patient beliefs about the development of PTS the necessity of 
wearing stockings and concerns about the potential side effects, confidence building and 
constructive feedback through interactions with the research nurse are designed to improve self-
mastery and ultimately adherence to GCS throughout the study. 
Adherence is considered to be a modifiable trait and the process evaluation aims to understand if 
adherence has been enhanced by the education package over the course of the trial. Definitions of 
adequate adherence will be described in detail in the CHAPS statistical analysis plan. 
At baseline participants will be randomised 1:1 to receive either standard care 
(anticoagulation alone), or the intervention (anticoagulation plus graduated compression 
stockings). Participants randomised to the intervention will be told of their treatment 
allocation and provided with stockings and the behavioural aids. 

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The overarching concept of the adherence-promoting package created for CHAPS is that 
by targeting and increasing patient’s motivation and ability to use GCS, adherence will reach 
a level of adequacy to provide a robust and conclusive answer to the main CHAPS research 
question. 
 
 
The Perceptions and Practicalities framework suggests that non-adherence to 
recommended therapies is a complex human behaviour which can be broadly categorised 
as:  
Unintentional non-adherence 
Occurring when patients want to take the recommended treatment but are prevented 
in doing so by external barriers beyond their control. For example, patients may 
forget to apply GCS, they may not be physically able to get them on, or the 
healthcare practitioner may not have communicated that they need to be worn every 
day.  
  
Intentional non-adherence 
Occurs when the patient decides not to adhere. Intentional non-adherence is best 
explained in terms of the perceptions that shape the patient’s motivation to start and 
continue with treatment. For example, patients may not display any symptoms of PTS for 
many months so could perceive compression therapy as unnecessary. As around 50% of 
people will go on to develop PTS after first acute DVT, some patients may decide to take 
their chance. 
 
 
Two sets of in-depth qualitative interviews (via telephone, online video call or face to 
face) will take place as part of the process evaluation. These will be with a sample (n= 
20) of participants enrolled in the trial at around 2 weeks after receiving the 
intervention, and another sample of participants (n= 20) who have at least 6 months 
experience of wearing stockings. 
Participants will be invited to attend an interview via the research nurse. If the patient 
agrees to being included in the process evaluation, they will be contacted by a 
qualitative researcher.  
The interviews will be audio-recorded, transcribed, and textual coding will be 
undertaken. Lower-level codes will be grouped into themes and analysis will be 
undertaken through a process of constant comparison. Two members of the process 
evaluation team will participate in data analysis to reduce bias in the identification and 
interpretation of themes. Any emerging themes from either the early or late interviews 
that may be relevant to future participants enrolled in the trial, will be communicated   
back to the trial coordination team, to provide the opportunity to adapt the intervention. 
 
Once recruitment has commenced, participants enrolled into the study will be 
contacted by the research nurse and invited to take part in an in-depth interview with 

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IRAS: 263041 
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a qualitative researcher. If the participant agrees, the qualitative researcher will make 
contact with the patient and explain the purpose of the interviews. The patient will 
receive a gift voucher and travel expenses for taking part.  
The 1:1 interviews with the researcher will take place either at a convenient public 
location or remotely (via phone or video call), after the patient has read the information 
sheet and signed a consent form.  
The interview will be conducted using a conversational manner with probes, facilitation, 
and clarification of responses as required by the interviewer. There will be two parts to 
the interview. The first part is semi-structured, where participants will discuss their 
perceptions of and adherence to GCS. This includes describing any barriers or 
facilitators to wearing the GCS. The second part of the interview is a structured 
questionnaire where participants will be asked about their experience of the 
behavioural aids (the video, nurse training, text messages, donning aids, and online 
support group) in the CHAPS trial, including whether and in what ways they have 
continued to make use of these.  
  
 
The late interviews will be conducted with participants who have at least 6 months 
experience of using GCS. The rationale behind the late interviews is to capture the 
experiences of participants who have been wearing GCS for at least 6 months and 
across different seasons. The effect of seasonal changes upon adherence to GCS is 
something that was considered to be important in previous trials and was anecdotally 
reported in interviews conducted with lay patients at the grant application stage. 
Late interviews will follow the same two-part structure and topic guide as the early 
interviews, with additional questioning around experiences of using GCS across 
seasons.  
 
 
1. Patient questionnaires 
 
Adapted questionnaires [BSQ, adapted BMQ, TIQ, BIPQ] will be used to assess the 
key perceptions and practicalities likely to influence participants’ motivation and ability 
to adhere to their stockings, as well as their perceptions of their DVT. 
  
Appendix 1 outlines the assessment schedule for the process evaluation 
questionnaires. The BMQ is administered to both the standard care and intervention 
arms at baseline, 1 month, 3 months, 6 months, 12 months and final study visit. The 
BIPQ is also administered to both study arms at baseline, 6 months, 12 months and 
final study visit. The BSQ is administered to the intervention arm only at baseline, 1 
month, 3 months, 6 months, 12 months and final study visit. The TIQ is also 
administered to the intervention arm only at 1 month, 3 months, 6 months, 12 months 
and final study visit.  

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Participants will complete questionnaires either at scheduled study visits or online, in 
accordance with the CHAPS study protocol.  
 
2. Nurse self-report items 
 
Study research nurses will complete three items on the Case Report Form (CRF) 
relating to the GCS training they provide to participants. First, they will record the length 
of time it takes to conduct the training. Second, research nurses will rate their 
confidence in the patient’s ability to use the stockings as prescribed on a visual 
analogue scale (VAS) ranging from “not at all confident” to “completely confident”. The 
third optional item is an open-text box where the research nurses can choose to record 
any comments regarding their answer to item 2.  
 
Nurses will also record information about stocking provision, as this may influence 
adherence. This includes information regarding the number of stocking pairs provided 
to the patient, the type of stockings provided (i.e., style and length), and colour. All of 
these items will be answered at stocking provision and each follow-up visit.  
 
 
 
1. Qualitative analysis:  
The interviews conducted with the researchers will be audio-recorded (with consent) 
and transcribed. The analysis will proceed alongside data collection and will be based 
on a framework approach (13). This is suitable for small numbers of cases and ensures 
that each case is fully taken into account in the analysis. Initial themes will be identified 
that are then grouped into main and subthemes. This is applied to the raw transcript 
data for each interview, and a thematic “chart” is created that summarises information 
for each theme and allows cross-case and within-case analysis through a process of 
comparison. 
2. Quantitative analysis:  
Data from the BSQ, BMQ, BIPQ and TIQ will be analysed descriptively. We will also 
use within-group tests to investigate whether these variables change across the study 
period. As the BMQ and BIPQ are answered in both study arms, we will conduct 
between-groups analyses to see whether there are differences in beliefs about 
anticoagulation medicines and DVT between those who do and those who do not wear 
stockings. 
In regard to process variables, we will analyse whether scores on the BSQ, BMQ, BIPQ 
and TIQ are associated with adherence to stockings. We will also analyse whether the 
items related to stocking provision and the nurse’s confidence in the patient’s ability to 
wear stockings are associated with adherence to stockings.  
 
 
Investigators at each recruiting centre will retain the original consent form for the process 
evaluation until notified by the Sponsor, and for at least ten years after study completion. A copy of 

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PROTOCOL 
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the consent form will be securely transferred to the researcher at UCL which will be destroyed after 
it has been checked.  
 
Documents will be stored in such a way that they can be accessed/data retrieved at a later date. No 
study document will be destroyed without prior written agreement between the Sponsor and the 
investigator. Should the investigator wish to assign the study records to another party or move them 
to another location, written agreement must be obtained from the Sponsor. 
 
Study data gathered by UCL during the process evaluation will be kept in a secure location and in 
accordance with the terms of the Data Protection Act 2018. Participant confidentiality will be 
maintained at all times and all study records will be kept in pseudonymised form identifying 
participants by a pseudonym rather than name, or hospital number. 
 
Any paper interview transcripts or notes made by the UCL researcher during the interview will be 
kept in locked filing cabinets in locked rooms at UCL, only accessible by authorised personnel and 
destroyed at the end of the study. The key to the participant code list will be kept separately to 
these documents and destroyed at the end of the study.  
 
Electronic data of pseudonymised interview transcripts, the final coding frame and coding tables 
may be transferred via the Imperial College File Exchange, password protected and encrypted where 
possible. Any data that is stored on Imperial College London networked computers will be stored in 
an anonymised form with no identifiable information. The electronic pseudonymised transcript will 
be retained by UCL until the end of the study, it will then be archived for up to 10 years in line with 
Imperial College Sponsor requirements. 
 
 SAFETY REPORTING 
 
An AE is any untoward medical occurrence in a patient or clinical trial subject. An AE can therefore 
be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, 
whether or not considered related to the trial protocol.  
For the purposes of the study, only AEs related to the study intervention (graduated compression 
stockings) will be recorded. The adverse events listed below are expected to be related and should 
be reported: 
- 
GCS-related complications (e.g. discomfort, skin breaks, skin ulcers, skin necrosis, blistering 
of the skin, rash, limb ischaemia) 
Please note this is not an exhaustive list, if you suspect an event is related to treatment please 
contact the Trial Manager. 
 
 
 

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For the purposes of the study, all AEs will be followed up according to local practice until the event 
has stabilised or resolved, whichever the sooner is. It is essential that all AEs that occur during the 
course of the study are appropriately reported in order to ensure the participants continuing safety. 
Of particular importance is the assessment of any event for causality and expectedness in relation 
to the stockings.  All adverse events whether expected or not should be recorded.  Depending on 
the nature of the event the reporting procedures below should be followed.  Any questions 
concerning adverse event reporting should be directed to the Chief Investigator in the first instance.   
 
(i) 
Severity of Adverse Events 
Definitions for assessment of severity: 
 
Mild:  
Awareness of event but easily tolerated 
Moderate: 
Discomfort enough to cause some interference with usual activity 
Severe: 
Inability to carry out usual activity 
(ii) 
Causality of Adverse Events 
Definitions for assessment of causality: 
 
Unrelated: 
No evidence of any causal relationship 
Unlikely: 
There is little evidence to suggest there is a causal relationship (e.g. the 
 
 
event did not occur within a reasonable time after administration of the trial 
 
 
device). There is another reasonable explanation for the event (e.g. 
 
 
the patient’s clinical condition, other concomitant treatment). 
Possible: 
There is some evidence to suggest a causal relationship (e.g. because the 
 
 
event occurs within a reasonable time after administration of the trial 
 
 
device). However, the influence of other factors may have contributed 
 
 
to the event (e.g. the patient’s clinical condition, other concomitant 
 
 
treatments). 
Probable: 
There is evidence to suggest a causal relationship and the influence of 
 
 
other factors is unlikely. 
Definite: 
There is clear evidence to suggest a causal relationship and other possible 
 
 
contributing factors can be ruled out. 
 
(i) 
Definition of SAE 
An SAE is defined as any event that  
• Results in death;  
• Is life-threatening*; 
• Requires hospitalisation or prolongation of existing inpatient’s hospitalisation**; 
• Results in persistent or significant disability or incapacity; 
• Is a congenital abnormality or birth defect; 
 

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* “Life-threatening” in the definition of “serious” 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 were more severe. 
** “Hospitalisation” means any unexpected admission to a hospital department. It does not usually 
apply to scheduled admissions that were planned before study inclusion or visits to casualty 
(without admission).  
 
Medical judgement should be exercised in deciding whether an adverse event/reaction is serious in 
other situations. Important adverse events/reactions that are not immediately life-threatening, or 
do not result in death or hospitalisation but may jeopardise a subject, or may require intervention 
to prevent one of the other outcomes listed in the definition above should also be considered 
serious. 
 
 
Rapid reporting of all SAEs i.e. within 24 hours, occurring during the study must be performed as 
detailed in SAE reporting instructions. If the investigator becomes aware of safety information that 
appears to be related to the trial, involving a subject who participated in the study, even after an 
individual subject has completed the study, this should be reported to the Sponsor. 
 
All SAEs will be reviewed by the Chief Investigator or a designated medically qualified representative 
to confirm expectedness and causality. 
 
Reporting of SAEs and review by the CI will be via the trial data collection system (CRF/eCRF).  
 
All related and unexpected SAEs will be reported to the JRCO as soon as possible after becoming 
aware of the event. 
 
(i) 
Related SAEs 
Related: resulted from administration of any of the research procedures 
(ii) 
Unexpected SAEs 
Unexpected: type of event is not listed in the protocol as an expected occurrence 
(iii) 
 Reporting of SAEs that are related and unexpected 
SAEs that are related and unexpected should be notified to the relevant REC and the Sponsor in 
accordance with local requirements. 
 
Follow up of patients who have experienced a related and unexpected SAE should continue until 
recovery is complete or the condition has stabilised.  
 
(iv) 
Annual reporting of Serious Adverse Events 
Annual Safety reports will be submitted to the Sponsor and the Ethics Committee in accordance 
with local requirements. 

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If any urgent safety measures are taken the CI/Sponsor shall immediately and in any event no later 
than 3 days from the date the measures are taken, give written notice to the relevant REC of the 
measures taken and the circumstances giving rise to those measures. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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 STATISTICS AND DATA ANALYSIS 
 
The sample size calculation for this study was based on the primary endpoint of incidence of PTS. 
With improvements in anticoagulation since the previously mentioned SOX trial, it is anticipated 
that 30% of the control arm will develop PTS at some point during the follow up (median 18 months, 
range 6 to 30 months), rather than the 40% observed in SOX. In smaller trials, the number needed 
to treat varied from 1 in 2 (18), to 1 in 4 (19), however SOX demonstrated no benefit. As smaller 
trials tend to overestimate treatment effect and because the use of a stocking means investment 
into a behavioural change for each patient, the number needed to treat (NNT) for CHAPS has been 
set at 1 in 10. 
 
With 864 participants, the study will have 90% power at a 5% level of significance using a test of 
binomial proportions to detect an absolute reduction in the incidence of PTS of 10% (from 30% in 
the standard care arm to 20% in the stockings plus standard care arm), allowing for 10% loss to 
follow up.  
 
 
Quantitative analysis and oversight will be performed in conjunction with the Edinburgh Clinical 
Trials Unit (ECTU). ECTU will work closely with the CI and trial manager on the delivery of the data 
management and statistical aspects of the study, in compliance with the applicable regulations. 
 
(i) 
Primary Endpoint Analysis 
At a median of 18 months (range 6-30 months) patients will be seen by an independent, blinded 
observer to assess their degree of post-thrombotic syndrome using the validated semi-
quantitative Villalta scoring system. 
The primary analysis will be an intention-to-treat analysis that does not adjust for adherence to 
stockings. This will tell us the treatment effect given the observed adherence, which is appropriate 
to gauge real-world performance.  
We will use a time-to-first-event approach since it is possible that the treatment effect may be a 
combination of averting PTS, but also in those that develop PTS the onset may be delayed. 
 
(ii) 
Secondary Endpoints Analysis 
Secondary analysis will determine how much the behavioural components affect adherence; firstly 
whether behavioural components change participants knowledge, beliefs and intentions regarding 
stocking usage. Secondly, to determine what extent compliance has indeed mediated outcome 
using Complier Average Causal Estimation (CACE) causal modelling through instrumental variable 
regression i.e. does better compliance improve outcomes; and looking ahead, whether future 
development of behavioural components is likely to be beneficial.  
 
Full rationale and methodological details of the intention to treat compliance-unadjusted, 
supplementary compliance based analyses and secondary endpoint analyses will be detailed in the 
comprehensive Statistical Analysis Plan. 
 
 
(iv) Adjusted Analysis (missing, unused and spurious data) 

Sponsor: Imperial College London 
Sponsor Reference Number: 19CX5434 
IRAS: 263041 
PROTOCOL 
CHAPS 
 
 
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(v) Health Economic Analysis 
A within-trial analysis and a decision model will be constructed. In both cases, the main analyses 
will be performed from the perspective of the NHS and Personal Social Services. Secondary 
analyses will be performed from a societal perspective. The price year will be 2018. Discounting 
will be applied according to UK Government guidelines. The study will be reported according to 
consolidated guidelines for economic evaluation (CHEERS). 
The within-trial analysis will compare the treatment strategies within the 18-month time horizon 
of the clinical trial. Data will be collected by case note review and questionnaires completed at 
baseline and follow-ups. Resource use items in hospital and community care, adverse events or 
complications will be recorded for each patient at each follow-up. Resource use will be multiplied 
by UK unit costs obtained from published literature, Healthcare Resource Groups, and 
manufacturers’ list prices to calculate overall costs. Utilities (QALYs) will be calculated from the 
EQ-5D questionnaire. The extent of missing data will be assessed and appropriate methods to 
handle missing data will be applied. The incremental cost-effectiveness ratio will be calculated and 
compared to current UK decision making thresholds. Sensitivity analysis will be carried out to test 
the robustness of results to alternative assumptions (for example, about missing data, or using 
per-protocol estimates of treatment effect). Probabilistic sensitivity analysis will be carried out 
using bootstrapping. Subgroup analyses consistent with the protocol of the clinical trial will be 
considered. 
The decision model provides a framework to incorporate evidence from other relevant studies and 
to extrapolate outcomes beyond the trial reporting period. The Markov model will include the key 
health states and events that may occur during the lifetime of the patient (PTS, venous leg ulcer, 
deep venous stenting, etc.) A literature review will be conducted to identify other economic 
studies and other trials in comparable populations. The data to support extrapolation may be 
taken from the trial (e.g. fitting parametric time-to-event functions to the trial data) or may come 
from external sources (such as observational data). 
The results of the analyses will be presented as estimates of mean incremental costs, effects, and, 
incremental cost per QALY. Sensitivity analysis will be conducted to test the robustness of the 
results to alternative assumptions about model structure, assumptions and input data. 
Probabilistic sensitivity analysis will be conducted using Monte-Carlo simulation. 
 
 
 
 

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IRAS: 263041 
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 REGULATORY, ETHICAL AND LEGAL ISSUES 
 
The investigator will ensure that this study is conducted in the spirit of the 1964 Declaration of 
Helsinki, adopted by the 18th World Medical Assembly, and all later revisions. 
 
 
The study will be conducted in accordance with the guidelines laid down by the International 
Conference on Harmonisation for Good Clinical Practice (ICH GCP E6 guidelines).  
 
 
 
(i) 
Initial Approval 
Prior to the enrolment of subjects, the REC must provide written approval of the conduct of the 
study at named sites, the protocol and any amendments, the Subject Information Sheet and Consent 
Form, any other written information that will be provided to the subjects, any advertisements that 
will be used and details of any subject compensation.  
 
(ii) Approval of Amendments 
Proposed amendments to the protocol and aforementioned documents must be submitted to the 
REC for approval as instructed by the Sponsor. Amendments requiring REC approval may be 
implemented only after a copy of the REC’s approval letter has been obtained.  
 
Amendments that are intended to eliminate an apparent immediate hazard to subjects may be 
implemented prior to receiving Sponsor or REC approval. However, in this case, approval must be 
obtained as soon as possible after implementation. 
 
(iii) Annual Progress Reports and End of Trial Notification 
The REC will be sent annual progress reports in accordance with national requirements and will also 
be informed about the end of the trial, within the required timelines.  
 
 
Health Research Authority (HRA) approval will be obtained prior to starting the study. Each 
participating site will confirm capacity and capability prior to commencing. 
The HRA and all participating sites also need to be notified of all protocol amendments to assess 
whether the amendment affects the institutional approval for each site.  
 
 
 
All protocol deviations and protocol violations will be reported via the eCRF/CRF and reviewed by 
the Chief Investigator on a monthly basis. Protocol violations will be reported to the Sponsor. 

Sponsor: Imperial College London 
Sponsor Reference Number: 19CX5434 
IRAS: 263041 
PROTOCOL 
CHAPS 
 
 
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An assessment of whether the protocol deviation/violation constitutes a serious breach will be 
made.  
A serious breach is defined as: 
A breach of the conditions and principles of GCP in connection with a trial or the trial protocol, 
which is likely to affect to a significant degree:  
• The safety or physical or mental integrity of the UK trial subjects; or 
• The overall scientific value of the trial 
 
The Sponsor will be notified within 24 hours of identifying a likely Serious Breach. If a decision is 
made that the incident constitutes a Serious Breach, this will be reported to the REC within 7 days 
of becoming aware of the serious breach. 
 
 
Imperial College London holds negligent harm and non-negligent harm insurance policies which 
apply to this trial. Imperial College Healthcare NHS Trust holds standard NHS Hospital Indemnity and 
insurance cover with NHS Litigation Authority for NHS Trusts in England, which apply to this trial. 
 
 
The study is registered on a trial database in accordance with requirements of the International 
Committee of Medical Journal Editors (ICMJE) regulations. 
The study will be registered on ISCTRN. 
 
 
 
Consent will be through standard GCP measures including a patient information sheet and signed 
informed consent form.  No minors are eligible to join CHAPS. 
Consent to enter the study will be sought from each participant only after a full verbal explanation 
has been given, and an information leaflet offered. The consent will be informed, voluntary and 
participants will be given an appropriate amount of time to consider participation and to ask 
questions. There will be no set minimum time to consider the trial as this will be determined on a 
case by case basis, this is usually 24 hours but could be less if there is agreement from both the 
researcher and participant that the consent is fully informed.  
 
Signed participant consent will be obtained and participants will be asked to consent for their data 
to be linked with appropriate databases including Hospital Episode Statistics (HES), and the 
National Vascular Database as well as for longer term follow-up in the event the trial is extended. 
A copy of the signed Participant Information Sheet/Informed Consent Form document will be 
provided to the patient and the original Informed Consent Form should be retained with the 
source documents. 
 
The right of the participant to refuse to participate without giving reasons will be respected, 
although if the participate is willing a reason for declining will be recorded. After the participant has 
entered the trial the clinician remains free to give alternative treatment to that specified in the 
protocol at any stage if he/she feels it is in the participant’s best interest, but the reasons for doing 

Sponsor: Imperial College London 
Sponsor Reference Number: 19CX5434 
IRAS: 263041 
PROTOCOL 
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so should be recorded. In these cases, the participants remain within the study for the purposes of 
follow-up and data analysis. All participants are free to withdraw at any time from the protocol 
treatment without giving reasons and without prejudicing further treatment. Participants will be 
asked to consent to long term follow up to allow for linkage to routine datasets including Hospital 
Episode Statistics (HES) and the National Vascular Database. 
 
The investigator will inform the subject’s General Practitioner by letter that the subject is taking part 
in the study provided the subject agrees to this, and information to this effect is included in the 
Subject Information Sheet and Informed Consent. A copy of the letter will be filed in the Investigator 
Site File.  It is possible that the GP will be contacted to obtain trial information in the event that the 
patient cannot be contacted. 
 
 
The investigator will ensure that the subject’s confidentiality is maintained. On the CRF or other 
documents submitted to the Sponsors, subjects will be identified by a subject ID number only. 
Documents that are not submitted to the Sponsor (e.g., signed informed consent form) will be kept 
in a strictly confidential file by the investigator. 
 
The investigator shall permit direct access to subjects’ records and source document for the 
purposes of monitoring, auditing, or inspection by the Sponsor, authorised representatives of the 
Sponsor and RECs. 
 
The investigator will preserve the confidentiality of all participants taking part in the study, which 
will be conducted in accordance with the Data Protection Act 
 
 
The end of trial is defined as the last subject, last visit.  
 
 
The investigator will retain essential documents until notified by the Sponsor, and for at least ten 
years after study completion. Subject files and other source data (including copies of protocols, 
CRFs, original reports of test results, correspondence, records of informed consent, and other 
documents pertaining to the conduct of the study) will be retained. Documents will be stored in 
such a way that they can be accessed/data retrieved at a later date. Consideration will be given to 
security and environmental risks. 
 
No study document will be destroyed without prior written agreement between the Sponsor and 
the investigator. Should the investigator wish to assign the study records to another party or move 
them to another location, written agreement must be obtained from the Sponsor. 
 

Sponsor: Imperial College London 
Sponsor Reference Number: 19CX5434 
IRAS: 263041 
PROTOCOL 
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DATA MANAGEMENT 
 
Data will be written directly into the CRF (source data) and then transcribed into the eCRF. Source 
documents include original documents related to the trial, to medical treatment and to the history 
of the participant, and adequate source documentation must be maintained to allow reliable 
verification and validation of the trial data.  
 
CRFs will be in English. Generic names for concomitant medications should be recorded in the CRF 
wherever possible. All written material to be used by subjects must use vocabulary that is clearly 
understood, and be in the language appropriate for the study site. 
 
The principal means of data collection from participant visits will be Electronic Data Capture (EDC) 
in the bespoke database system via the internet. Data is entered into the EDC system via site 
personnel. All source data recorded in the CRF will be signed by the Investigator or his/her 
appropriate designee. All changes made following the electronic signing will have an electronic audit 
trail with a username and date. Specific instructions and further details will be outlined in SOPs 
and/or manuals. 
 
 
Details of procedures for CRF/eCRF completion will be provided in a study manual. 
 
All trial documentation, including that held at participating sites and the trial coordinating centre, 
will be archived for a minimum of 10 years (amend as per Sponsor requirements) following the end 
of the study.  
 
 

Sponsor: Imperial College London 
Sponsor Reference Number: 19CX5434 
IRAS: 263041 
PROTOCOL 
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STUDY MANAGEMENT STRUCTURE  
The study will be coordinated by a trial manager who will report to the Chief Investigator. The trial 
manager will liaise with local principal investigators to ensure that the trial is conducted locally 
according to protocol and in an expeditious manner. The organisational structure and 
responsibilities are outlined below. 
 
 
A Trial Steering Committee (TSC) will be convened including as a minimum an independent Chair, 
independent clinician, the Chief Investigator and Trial Manager. The role of the TSC is to provide 
overall supervision of trial conduct and progress. Details of membership, responsibilities and 
frequency of meetings will be defined in a separate Charter. 
A trial steering committee meeting will be held at the start of CHAPS prior to commencement of 
recruitment and at least annually as per NIHR guidelines, with the lay applicant invited to attend 
each convening. 
 
 
A Trial Management Group (TMG) will be convened including the Chief Investigator, co-investigators 
and key collaborators, trial statistician and trial manager. The TMG will be responsible for day-to-
day conduct of the trial and operational issues. Details of membership, responsibilities and 
frequency of meetings will be defined in separate terms of Reference.  
 
 
A data monitoring committee meeting will be held prior to first patient first visit, following 
completion of the pilot study, and will then be held one month prior to each TSC meeting. Further 
details will be defined in the separate DMC Charter.  
After the results of the 100-patient adherence pilot are available in June 2020, the data monitoring 
committee will submit the pilot study adherence results to NIHR. 
 
 
If one year adherence is <70% of participants in the intervention arm wearing the stocking for <4 
days per week the trial will stop after the 1 year adherence pilot phase.  There will be no further 
follow up. 
 
 
 
A study-specific risk assessment will be performed prior to the start of the study by the study 
sponsor. The risk assessment will consider all aspects of the study and will be updated as required 
during the course of the study. The risk assessment will consider all aspects of the study and will be 
updated as required during the course of the study. 
 

Sponsor: Imperial College London 
Sponsor Reference Number: 19CX5434 
IRAS: 263041 
PROTOCOL 
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The study will be monitored periodically by the trial manager to assess the progress of the study, 
verify adherence to the protocol, ICH GCP E6 guidelines and other national/international 
requirements and to review the completeness, accuracy and consistency of the data. 
 
Monitoring procedures and requirements will be documented in a Monitoring Plan, in accordance 
with the risk assessment. 
 
 
Quality Control will be performed according to Imperial College internal procedures. The study may 
be audited by a Quality Assurance representative of the Sponsor. All necessary data and documents 
will be made available for inspection. 
The study may be subject to inspection and audit by regulatory bodies to ensure adherence to GCP 
and the UK Policy Framework for Health and Social Care.  
 
 
CHAPS has been peer reviewed by NIHR and international experts. 
 
 
 
Patients, their carers’ and relatives were involved in a 3-stage consultation process during the trial 
development stage, incorporating the INVOLVE methodology. This consisted of a series of semi-
structured interviews, a survey run via Thrombosis UK, and review of the CHAPS research plan and 
lay summary. Responses and feedback were incorporated into the design and budget of CHAPS. 
 
The Imperial Vascular PPI group has contributed 4 patients and 2 members of the public who are 
available for the duration of CHAPS. These individuals had the opportunity to review the detailed 
research plan and will be available to review patient information sheets, newsletters and informed 
consent forms for CHAPS. The expert patients will help select appropriate brands and types of 
stockings for use in summer and winter months, along with donning aids that they have found to be 
beneficial. A patient applicant will be invited to join the TSC and attend trial meetings.  
The patient applicant will moderate and feedback from the patient Facebook group, for example, if 
there are technical or scientific queries, or problems with reordering stockings. 
 
 
 
The final results of CHAPS, the process evaluation and the cost-effectiveness analysis will be 
published in a high impact journal and presented at international and national vascular and 
haematology conferences. The results will be presented to the National Institute for Health and Care 
Excellence, and at UK, European and American vascular, venous and haematology societies. This will 
lead to the generation of altmetric data. 
Dissemination will be via the Thrombosis UK Facebook group to patients, Imperial College London 
website to the public, via peer reviewed publication for health professionals, and an email summary 
will be sent to all trial participants. 
 

Sponsor: Imperial College London 
Sponsor Reference Number: 19CX5434 
IRAS: 263041 
PROTOCOL 
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All information obtained as a result of the study will be regarded as CONFIDENTIAL, at least until 
appropriate analysis and review by the investigator(s) are completed.  
 
A Clinical Study Report summarising the study results will be prepared and submitted to the REC 
within a year of the end of study. 
 
 
 
 

Sponsor: Imperial College London 
Sponsor Reference Number: 19CX5434 
IRAS: 263041 
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REFERENCES 
1. 
Rabe E, Partsch H, Morrison N, Meissner MH, Mosti G, Lattimer CR, et al. Risks and 
contraindications of medical compression treatment – A critical reappraisal. An 
international consensus statement. Phlebology. 2020:0268355520909066. 
2. 
Raskob GE AP, Blanco AN, Buller H, Gallus A, Hunt BJ, Hylek EM, Kakkar A, 
Konstantinides SV, McCumber M, Ozaki Y, Wendelboe A, Weitz JI. Thrombosis: a major 
contributor to the global disease burden. J Thromb Haemost. 2014;12(10):1580-90. 
3. 
Kahn SR, Shrier I, Julian JA, Ducruet T, Arsenault L, Miron MJ, et al. Determinants 
and time course of the postthrombotic syndrome after acute deep venous thrombosis. 
Annals of internal medicine. 2008;149(10):698-707. 
4. 
Kahn SR, Partsch H, Vedantham S, Prandoni P, Kearon C. Definition of post-
thrombotic syndrome of the leg for use in clinical investigations: a recommendation for 
standardization. Journal of thrombosis and haemostasis : JTH. 2009;7(5):879-83. 
5. 
Kahn SR, Ginsberg JS. The post-thrombotic syndrome: current knowledge, 
controversies, and directions for future research. Blood reviews. 2002;16(3):155-65. 
6. 
Brandjes DPM, Büller HR, Heijboer H, Huisman MV, de Rijk M, Jagt H, et al. 
Randomised trial of effect of compression stockings in patients with symptomatic proximal-
vein thrombosis. The Lancet. 1997;349(9054):759-62. 
7. 
Ginsberg JS, Turkstra F, Buller HR, MacKinnon B, Magier D, Hirsh J. Postthrombotic 
syndrome after hip or knee arthroplasty: a cross-sectional study. Archives of internal 
medicine. 2000;160(5):669-72. 
8. 
Villalta S BP, Piccioli A, Lensing A, Prins MH. Assessment of validity and 
reproducibility of a clinical scale for the post-thrombotic syndrome. Haemostasis. 1994. 
9. 
Soosainathan A, Moore HM, Gohel MS, Davies AH. Scoring systems for the post-
thrombotic syndrome. Journal of Vascular Surgery. 2013;57(1):254-61. 
10. Kahn SR, Shapiro S, Wells PS, Rodger MA, Kovacs MJ, Anderson DR, et al. 
Compression stockings to prevent post-thrombotic syndrome: a randomised placebo-
controlled trial. Lancet (London, England). 2014;383(9920):880-8. 
11. Kahn SR, Shbaklo H, Lamping DL, Holcroft CA, Shrier I, Miron MJ, et al. 
Determinants of health-related quality of life during the 2 years following deep vein 
thrombosis. Journal of thrombosis and haemostasis : JTH. 2008;6(7):1105-12. 
12. Caprini JA, Botteman MF, Stephens JM, Nadipelli V, Ewing MM, Brandt S, et al. 
Economic burden of long-term complications of deep vein thrombosis after total hip 
replacement surgery in the United States. Value in health : the journal of the International 
Society for Pharmacoeconomics and Outcomes Research. 2003;6(1):59-74. 
13. Epstein D, Gohel M, Heatley F, Davies AH. Cost-effectiveness of treatments for 
superficial venous reflux in patients with chronic venous ulceration. BJS open. 
2018;2(4):203-12. 
14. Olin JW, Beusterien KM, Childs MB, Seavey C, McHugh L, Griffiths RI. Medical costs 
of treating venous stasis ulcers: evidence from a retrospective cohort study. Vascular 
medicine (London, England). 1999;4(1):1-7. 
15. Berntsen CF, Kristiansen A, Akl EA, Sandset PM, Jacobsen EM, Guyatt G, et al. 
Compression Stockings for Preventing the Postthrombotic Syndrome in Patients with Deep 
Vein Thrombosis. The American journal of medicine. 2016;129(4):447.e1-.e20. 

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16. Skervin AL, Thapar A, Franchini AJ, Prandoni P, Shalhoub J, Davies AH. Systematic 
Review and Meta-Analysis of Utility of Graduated Compression Stockings in Prevention of 
Post-Thrombotic Syndrome. European journal of vascular and endovascular surgery : the 
official journal of the European Society for Vascular Surgery. 2016;51(6):838-45. 
17. Subbiah R, Aggarwal V, Zhao H, Kolluri R, Chatterjee S, Bashir R. Effect of 
compression stockings on post thrombotic syndrome in patients with deep vein 
thrombosis: a meta-analysis of randomised controlled trials. The Lancet Haematology. 
2016;3(6):e293-300. 
18. Brandjes DP, Buller HR, Heijboer H, Huisman MV, de Rijk M, Jagt H, et al. 
Randomised trial of effect of compression stockings in patients with symptomatic proximal-
vein thrombosis. Lancet (London, England). 1997;349(9054):759-62. 
19. Prandoni P, Lensing AW, Prins MH, Frulla M, Marchiori A, Bernardi E, et al. Below-
knee elastic compression stockings to prevent the post-thrombotic syndrome: a 
randomized, controlled trial. Ann Intern Med. 2004;141(4):249-56. 
20. Excellence. NIfHaC. Venous thromboembolic diseases: diagnosis, management and 
thrombophilia testing CG144. NICE. 2015. 
21. Excellence NIfHaC. National Institute for Health and Care Excellence. Venous 
thromboembolic diseases: diagnosis, management and thrombophilia testing [NG158] 
NICE; 2020. 
22. Kearon C, Akl EA, Ornelas J, Blaivas A, Jimenez D, Bounameaux H, et al. 
Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report. 
Chest. 2016;149(2):315-52. 
23. Rabe E, Partsch H, Hafner J, Lattimer C, Mosti G, Neumann M, et al. Indications for 
medical compression stockings in venous and lymphatic disorders: An evidence-based 
consensus statement. Phlebology. 2018;33(3):163-84. 
24. Soosainathan A, Moore HM, Gohel MS, Davies AH. Scoring systems for the post-
thrombotic syndrome. J Vasc Surg. 2013;57(1):254-61. 
25. Bouman AC, Ten Cate-Hoek AJ, Dirksen CD, Joore MA. Eliciting patients' 
preferences for elastic compression stocking therapy after deep vein thrombosis: potential 
for improving compliance. J Thromb Haemost. 2016;14(3):510-7. 
26. Mediven. mediven® Instructions for Use. 2020. p. 1-8. 
27. Mahler C, Hermann K, Horne R, Ludt S, Haefeli WE, Szecsenyi J, et al. Assessing 
reported adherence to pharmacological treatment recommendations. Translation and 
evaluation of the Medication Adherence Report Scale (MARS) in Germany. Journal of 
evaluation in clinical practice. 2010;16(3):574-9. 
28. Broadbent E, Petrie KJ, Main J, Weinman J. The brief illness perception 
questionnaire. Journal of psychosomatic research. 2006;60(6):631-7. 
29. Horne R, Hankins M, Jenkins R. The Satisfaction with Information about Medicines 
Scale (SIMS): a new measurement tool for audit and research. Quality in health care : 
QHC. 2001;10(3):135-40. 
30. Horne R, Weinman J, Hankins M. The beliefs about medicines questionnaire: The 
development and evaluation of a new method for assessing the cognitive representation of 
medication AU - Horne, Robert. Psychology & health. 1999;14(1):1-24. 

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31. Ritchie J SL, O'Connor W Carrying out qualitative analysis. Ritchie J LJ, editor. New 
York: Sage; 2003. 

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SIGNATURE PAGE 1 (CHIEF INVESTIGATOR) 
 
The signature below constitutes approval of this protocol by the signatory and provides the 
necessary assurances that this study will be conducted according to all stipulations of the protocol 
including all statements regarding confidentiality. 
 
 
Study Title: 
 
 
Compression Hosiery to Avoid Post-Thrombotic Syndrome  
 
Protocol Version Number: 
 
8.0 
 
 
 
Signed: 
___________________________________________ 
 
 
 
 
Professor Alun Huw Davies 
 
 
 
 
Date:  
 
_____________________ 
  
 
 
 
 
 
 
 
 
 
 
 
 

Sponsor: Imperial College London 
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SIGNATURE PAGE 2 (SPONSOR) 
 
The signatures below constitute approval of this protocol by the signatory.  
 
 
Study Title: 
 
 
Compression Hosiery to Avoid Post-Thrombotic Syndrome  
 
Protocol Version Number: 
 
8.0 
 
Sponsor Reference Number:               19CX5434 
 
 
 
Signed: 
___________________________________________ 
 
 
 
 
Becky Ward 
 
 
 
Research Governance Manager  
 
 
 
Imperial College London 
 
 
 
 
 
 
Date:  
 
_____________________ 

Sponsor: Imperial College London 
Sponsor Reference Number: 19CX5434 
IRAS: 263041 
PROTOCOL 
CHAPS 
 
 
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Page 45 of 47 
 
 
SIGNATURE PAGE 3 (STATISTICIAN) 
 
The signatures below constitute approval of this protocol by the signatory.  
 
 
Study Title: 
 
 
Compression Hosiery to Avoid Post-Thrombotic Syndrome  
 
Protocol Number: 
 
8.0 
 
 
 
 
Signed: 
___________________________________________ 
 
 
 
 
Name of Statistician 
 
 
 
Title 
 
 
 
Organisation/Company 
 
 
Date:  
 
_____________________ 
 
 

Sponsor: Imperial College London 
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SIGNATURE PAGE 4 (PRINCIPAL INVESTIGATOR) 
 
The signature of the below constitutes agreement of this protocol by the signatory and provides the 
necessary assurance that this study will be conducted at his/her investigational site according to all 
stipulations of the protocol including all statements regarding confidentiality. 
 
 
Study Title: 
 
 
Compression Hosiery to Avoid Post-Thrombotic Syndrome  
 
Protocol Number: 
 
8.0 
 
 
Address of Institution:  
____________________________________________ 
 
 
 
 
 
 
 
 
 
 
____________________________________________ 
 
 
 
 
 
 
____________________________________________ 
 
 
 
Signed: 
 
____________________________________________ 
 
 
Print Name and Title: ____________________________________________ 
 
 
Date:  
 
 
_____________________ 
 

Sponsor: Imperial College London 
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APPENDIX 1- VILLALTA’S SCORE 
Villalta’s score is a disease specific clinical measure that can be used to both diagnose and 
categorise the severity of PTS (8). (Five patient-rated symptoms (pain, cramps, heaviness, pins and 
needles, itching) and six physical signs (pretibial edema, skin induration, hyperpigmentation, pain 
during calf compression, venous ectasia, redness)are graded for intensity (0 points=absent, 1 
point=mild, 2 points=moderate, 3 points=severe). The points are summed into a total score. The 
range of scores for symptoms is 0-15, for signs is 0-18, and for total score is 0-33. The presence of 
a venous leg ulcer is also documented and classified as severe regardless of the presence or 
absence of other signs or symptoms. The patient is diagnosed as having PTS if the Vilallta score is 
≥5 or if a venous ulcer was present. A score of 5-9 signifies mild disease, 10-14 moderate disease, 
and ≥15 severe disease. The Villalta’s scale can be administered at any time during follow up if 
there is clinical suspicion of PTS or the patient reports symptoms outside the face to face follow up 
visits.  
Villalta Score 
 
 
 
 
Symptoms/clinical signs 
None 
Mild 
Moderate 
Severe 
Symptoms 
 Pain 
0 points 
1 point 
2 points 
3 points 
 Cramps 
0 points 
1 point 
2 points 
3 points 
 Heaviness 
0 points 
1 point 
2 points 
3 points 
 Paresthesia 
0 points 
1 point 
2 points 
3 points 
 Pruritus 
0 points 
1 point 
2 points 
3 points 
Clinical signs 
 Pretibial edema 
0 points 
1 point 
2 points 
3 points 
 Skin induration 
0 points 
1 point 
2 points 
3 points 
 Hyperpigmentation 
0 points 
1 point 
2 points 
3 points 
 Redness 
0 points 
1 point 
2 points 
3 points 
 Venous ectasia 
0 points 
1 point 
2 points 
3 points 
 Pain on calf compression 
0 points 
1 point 
2 points 
3 points 
Venous ulcer 
Absent 
Present 
 
Total Score: 
 
 
 
 
 
 
 
 
 

 
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APPENDIX 2- SCHEDULE OF ASSESSMENTS  
 
Baseline Visit  
Follow up visits 
Assessment  
Day 0 
2 weeks 
Months 1-5 
Month 6 
Months 7-11 
Month 12 
Final visit (18 or 30 months) 
Informed Consent 
X 
 
Inclusion/exclusion Criteria 
X 
 
Screening assessments  
X 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
Working status  
X 
 
X 
X 
X 
Height/weight 
X 
 
 
 
 
 
 
Lifestyle  
X 
 
 
 
 
CEAP clinical examination  
X 
 
 
X 
 
X 
X 
Medical History 
X 
 
 
 
 
 
 
EQ-5D-DL and VEINES-QoL  
X 
 
 
X 
 
X 
X 
Villalta’s Score# 
X 
 
 
X 
 
X 
X 
Concomitant medication 
X 
 
 
X 
 
X 
X 
Randomisation 
X 
 
GP letter issued 
X 
 
 
 
 
 
 
SMS reminder set up* 
X 
 
 
 
 
 
 
Stocking fitting* 
X 
 
 
 
 
 
 
Education package:  educational video, nurse led training* 
X 
X 
 
 
 
 
 
Online self-report stocking questionnaire (SARS)1 
 
X 
X 
X 
X 
X 
Stocking re-fitting/ provision of donning aid* 
 
X 
 
 
 
 
 
Adapted BSQ* 
X 
 
1 and 3 months 
X 
X 
X 
Adapted TIQ* 
 
 
1 and 3 months 
X 
 
X 
X 
Adapted BMQa 
X 
 
1 and 3 months 
X 
 
X 
X 
BIPQb 
X 
 
 
X 
 
X 
X 

 
CHAPS Protocol v8.0, 15/02/2022 
Confidential              
 
 
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Resource Use Information 
X 
X 
X 
Adverse Event Assessment 
X 
X 
X 
X 
*BSQ in Stocking arm only,  #can be measured at any time if the patient reports symptoms of PTS or there is clinical suspicion 
1SARS administered in the stockings arm only from 1M to 12M and at final visit 
a Adapted BMQ administered in both arms at Baseline, 1M, 3M, 6M, 12M and final visit 
b BIPQ administered in both arms at baseline, 6M, 12M and final visit