A Multi-centre, Double-blind Randomised Controlled Trial to Compare Modafinil Versus Placebo Over 12 Weeks in Patients With Severe Fatigue and Inflammatory Bowel Disease (MFI): a Feasibility Study
Phase: PHASE2
Conditions: Crohn Disease (CD), Ulcerative Colitis (UC), Fatigue
Sponsor: Imperial College London

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Feasibility trial of modafinil for severe fatigue in IBD (MFI) protocol v1.0, dated 10/10/2025, IRAS 
number 344329 
A multi-centre, double-blind randomised controlled trial to 
compare Modafinil versus placebo over 12 weeks in patients with 
severe Fatigue and Inflammatory bowel disease (MFI): a feasibility 
study 
 
Protocol Short Title/Acronym: Modafinil for fatigue in IBD (MFI) 
 
 
MAIN SPONSOR: Imperial College London 
FUNDER: Crohn’s and Colitis UK and Jon Moulton Charity Trust 
 
Clinicaltrials.gov number:  
REC Number: 25/LO/0719 
IRAS Project ID: 344329 
 
Version: 1.0; 10/10/2025 
 
 
 
Funding to conduct the trial is provided by Crohn’s and Colitis UK and the Jon Moulton Charity Trust. 
 
Clinical Queries 
 
Clinical queries should be directed to Dr Calum Moulton (c.moulton@imperial.ac.uk) who will direct 
the query to the appropriate person. 
 
 
Sponsor 
 

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Feasibility trial of modafinil for severe fatigue in IBD (MFI) protocol v1.0, dated 10/10/2025, IRAS 
number 344329 
Imperial College London/Imperial College Healthcare NHS Trust (delete as applicable) is the main 
research Sponsor for this study.  For further information regarding the sponsorship conditions, 
please contact the Head of Regulatory Compliance at: 
 
 
 
Research Governance and Integrity Team 
Imperial College London and Imperial College Healthcare NHS Trust 
Room 215, Level 2, Medical School Building 
Norfolk Place 
London, W2 1PG 
Tel: 0207 594 9480 
Imperial College - Research Governance and Integrity Team (RGIT) Website 
 
 
 
3. Study synopsis 
 
Title of clinical trial 
A multi-centre, double-blind randomised controlled trial to 
compare Modafinil versus placebo over 12 weeks in patients 
with severe Fatigue and inflammatory bowel disease (MFI): a 
feasibility study  
Protocol Short Title/Acronym
MD-IBD
Study Phase, if not mentioned in title
Phase II Feasibility 
Sponsor name
Imperial College London
Chief Investigator
Dr Calum Moulton
REC number
TBC
Medical condition or disease under 
investigation 
Fatigue 
Intervention of interest
Modafinil
Purpose of clinical trial 
To test the feasibility of a definitive trial of modafinil versus 
placebo for the treatment of severe fatigue in patients with 
IBD. 
Primary objective 
To evaluate the feasibility of an RCT design by measuring 
recruitment rates, retention rates, adherence rates and 
patient acceptability, in order to inform the design of a 
phase 3 trial. 
Secondary objective(s) 
To assess the acceptability of the proposed data measures, as 
estimated using completeness of data. This will comprise 

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Feasibility trial of modafinil for severe fatigue in IBD (MFI) protocol v1.0, dated 10/10/2025, IRAS 
number 344329 
questionnaire measures of mental health, quality of life and 
IBD control; measures of other gastrointestinal symptoms; 
blood measures of dopamine; and faecal sampling for 
calprotectin 
Trial Design  
Parallel group, double-blind, randomised, placebo-
controlled, phase II feasibility design. 
Endpoints 
Primary endpoints (feasibility)
1) Recruitment rates 
2) Attrition rates at 12 weeks post-randomisation 
3) Treatment adherence: % of participants taking at 
least 75% of prescribed medication  
4) Acceptability scores at 12-weeks post-randomisation
5) Study procedures acceptability and compliance: % of 
questionnaire data collected at primary endpoint (12 
weeks) 
 
The questionnaire measures at 12 weeks are:  
I. 
IBD Fatigue Assessment Score (first 5 questions) 
II. 
FACIT Fatigue scale 
III. 
Chalder Fatigue Questionnaire 
IV. 
PHQ-9 depression 
V. 
GAD-7 anxiety  
VI. 
IBD control scale 
VII. 
Pittsburgh Sleep Quality Index  
VIII. 
Maudsley 3-item Visual Analogue Scale 
IX. 
Harvey Bradshaw Index for Crohn’s disease patients 
(baseline and 12 weeks only) 
X. 
Simple Clinical Colitis Activity Index for patients with 
ulcerative colitis (baseline and 12 weeks only) 
XI. 
Dietary Screener Questionnaire (baseline and 12 
weeks only) 
XII. 
EQ-5D-5L (quality of life) 
 
2. Blood measures at 12 weeks:  
Serum dopamine 
 
3. Faecal calprotectin measurement at 12 weeks 
 
Secondary feasibility endpoints  
Completeness and variance of the above questionnaire 
measures (except the HBI and SCCAI) at 6 weeks post-
randomisation, as well as post-treatment at 18 weeks post-
randomisation 
 
Sample Size
N=70 (35 modafinil, 35 placebo)
Summary of Eligibility Criteria
 
 
 
Inclusion criteria: 
1) Established diagnosis of Crohn’s disease (CD) or ulcerative 
colitis (UC) according to clinical notes 
2) Reported fatigue duration of 6 months or more 

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Feasibility trial of modafinil for severe fatigue in IBD (MFI) protocol v1.0, dated 10/10/2025, IRAS 
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3) Aged 18 years or over
4) Current IBD Fatigue Assessment Scale score ≥11/20 
5) Use of contraception if female and of childbearing age. 
Female participants of childbearing age will require a negative 
serum/urine pregnancy test before starting the study and will 
also need to agree to use an acceptable form of contraception 
throughout the intervention period, e.g. long-acting 
reversible contraceptive. 
6) Faecal calprotectin <250mcg/g within the last 3 months 
7) Normal haemoglobin concentration (≥130g/L [men] and 
≥120g/L [women]) within the last 3 months 
8) Thyroid stimulating hormone (TSH) level 0.4-4.0 mU/L 
within last 3 months 
9) Serum total B12 concentration (≥180 nanograms/L) within 
last 3 months 
10) Able to provide written informed consent to enter the 
trial. 
 
Exclusion criteria:  
1) Diagnosis of drug or alcohol dependence syndrome 
according to patient report or GP record. 
2) Diagnosis of any dementia according to patient report or 
GP record. 
3) Diagnosis of psychosis or schizophrenia according to 
patient report or GP record. 
4) Diagnosis of bipolar disorder according to patient report or 
GP record. 
5) Current active suicidal ideation on clinical assessment by 
study psychiatrist. 
6) Current treatment with stimulant medication (e.g. 
methylphenidate), dopamine agonist (e.g. ropinirole), levo-
dopa (L-DOPA), antipsychotic (e.g. olanzapine), avacopan, 
avaritinib, bosutinib, doravirine, grazoprevir, leniosilib, 
moboceritinib, Osimertinib, sofosbuvir, velpatasvir or  
voxilapravir 
7) Contraindications to the administration of modafinil, as per 
the current SmPC. 
8) Patient-reported hypersensitivity to modafinil 
9) Non-registration with a GP or failure to consent to sharing 
of the GP summary care record and any psychiatric 
assessments held. 
10) Currently enrolled in another drug trial or psychological 
therapy trial. 

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Feasibility trial of modafinil for severe fatigue in IBD (MFI) protocol v1.0, dated 10/10/2025, IRAS 
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11) Currently hospitalised for the treatment of IBD.
12) Currently being prescribed a course of budesonide or 
reducing course of prednisolone for IBD. 
13) Planned change in IBD treatment within the next 12 
weeks. 
14) Currently breastfeeding, pregnant or planning pregnancy.
15) Diagnosis of indeterminate colitis 
Medication, dosage and route of 
administration 
Modafinil capsule total daily dose 100-300mg daily for 12 
weeks (dose increased according to clinical response) 
Comparator product(s) 
Placebo capsules for 12 weeks (dose increased according to 
clinical response) 
Maximum duration of treatment of a 
subject 
12 weeks followed by 1-week tapering off dose 
Follow up Duration 
18 weeks post-randomisation (12 weeks of blinded 
treatment followed by 6 weeks of post-treatment follow-up) 
Planned Trial Period
November 2025-November 2027
Funding 
Jon Moulton Charity Trust
Crohn’s and Colitis UK 
Version and Date of Final Protocol
Version 1.0, 10/10/25
 

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Feasibility trial of modafinil for severe fatigue in IBD (MFI) protocol v1.0, dated 10/10/2025, IRAS 
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 4. Abbreviations list 
5-HT 
5-hydroxytryptamine 
AE 
Adverse Event 
BMI 
Body mass index 
CD 
Crohn's disease 
CFQ 
Chalder Fatigue Questionnaire 
CFS 
Chronic fatigue syndrome 
CONSORT 
Consolidated Standards of Reporting Trials 
CTA 
Clinical Trials Authorisation 
CTU 
Clinical Trials Unit 
DSM 
Diagnostics and Statistical Manual  
GAD-7 
Generalised Anxiety Disorder-7 
GP 
General Practitioner 
HBI 
Harvey Bradshaw Index 
HRA 
Health Research Authority 
IBD Control 
Inflammatory Bowel Disease Control Questionnaire 
IBD-Fatigue 
Inflammatory Bowel Disease Fatigue Scale 
M3VAS 
Maudsley 3-item Visual Analogue Scale 
ME 
Myalgic encephalomyelitis 
MedDRA 
Medical Dictionary for Drug Regulatory Activities 
MINI 
MINI Neuropsychiatric Interview 
NICE 
National Institute for Health and Care Excellence 
ON 
Once at night 
PAGI-SYM 
Patient Assessment of Gastrointestinal Disorders Symptom 
Severity Index 
PSQI 
Pittsburgh Sleep Quality Index 
QIDS-SR-16 
Quick Inventory of Depressive Symptomatology-16 
SAE 
Serious Adverse Event 
SAR 
Serious Adverse Reaction 
SCCAI 
Short Clinical Colitis Activity Index 
SNRI 
Serotonin and noradrenaline reuptake inhibitor 
SOP 
Standard Operating Procedure 
SSRI 
Selective serotonin reuptake inhibitor 
TAU 
Treatment-as-usual 
UC 
Ulcerative colitis 
USAR 
Unexpected Serious Adverse Reaction 
 
 

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Feasibility trial of modafinil for severe fatigue in IBD (MFI) protocol v1.0, dated 10/10/2025, IRAS 
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Funder 
 
Crohn’s and Colitis UK 
Helios Court, 1 Bishops Court, Hatfield Business Park, Herts 
AL10 9NE 
 
 
 
This protocol describes the study and provides information about procedures for entering participants.  
Every care was taken in its drafting, but corrections or amendments may be necessary. These will be 
circulated to investigators in the study.  Problems relating to this study should be referred, in the first 
instance, to the Chief Investigator.  
 
This study will adhere to the principles outlined in the UK Policy Frame Work for Health and Social Care 
Research. It will be conducted in compliance with the protocol, the Data Protection Act and other 
regulatory requirements as appropriate.  
 
 
Contents 
A multi-centre, double-blind randomised controlled trial to compare Modafinil versus placebo 
over 12 weeks in patients with severe Fatigue and Inflammatory bowel disease (MFI): a 
feasibility study ..................................................................................................................................... 1 
Protocol Short Title/Acronym: Modafinil for fatigue in IBD (MFI) ........................................................ 1 
3. Study synopsis .................................................................................................................................. 2 
4. Abbreviations list .............................................................................................................................. 6 
5. Roles and responsibilities ............................................................................................................. 11 
5.1. Sponsor ......................................................................................................................................... 11 
5.2. Chief Investigator ......................................................................................................................... 11 
5.3. Co-Investigators ........................................................................................................................... 11 

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Feasibility trial of modafinil for severe fatigue in IBD (MFI) protocol v1.0, dated 10/10/2025, IRAS 
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5.4. Trial statistician ............................................................................................................................ 12 
5.5. Committees ................................................................................................................................... 12 
5.5.1. Trial steering committee .......................................................................................................... 12 
5.6. Role of sponsor and funder ........................................................................................................ 13 
6. Introduction ..................................................................................................................................... 14 
6.1. Background and rationale ........................................................................................................... 14 
7. Study objectives and design ......................................................................................................... 14 
7.1. Aim................................................................................................................................................. 14 
7.2. Objectives ..................................................................................................................................... 14 
8. Study design .................................................................................................................................... 15 
Methods: Participants, Interventions and Outcomes ...................................................................... 16 
9.  Study setting .................................................................................................................................. 16 
10. Eligibility criteria ........................................................................................................................... 16 
10.2. Exclusion criteria ....................................................................................................................... 16 
11. Intervention .................................................................................................................................... 17 
11.1. Treatment arm ............................................................................................................................ 17 
11.1.1. Modifications (treatment arm) ............................................................................................... 17 
11.2. Control arm ................................................................................................................................. 17 
11.2.2 Modifications (placebo arm) ................................................................................................... 18 
11.5. Concomitant medications ......................................................................................................... 18 
11.6. Medication risks ......................................................................................................................... 19 
11.7. Medication manufacture, packaging and labelling ................................................................. 19 
11.8. Medication storage and dispensing ......................................................................................... 19 
11.9. Treatment stopping rules .......................................................................................................... 19 
11.9.1. Suicidality protocol ................................................................................................................. 20 
11.10. Withdrawal ................................................................................................................................ 20 
12. Outcomes ....................................................................................................................................... 20 
12.1. Feasibility and acceptability ..................................................................................................... 20 
12.2. Measures collected at baseline ................................................................................................ 21 

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Feasibility trial of modafinil for severe fatigue in IBD (MFI) protocol v1.0, dated 10/10/2025, IRAS 
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12.3. Secondary feasibility outcomes (baseline, 6 weeks, 12 weeks and 18 weeks post-
randomisation) .................................................................................................................................... 22 
12.4. Exploratory outcomes ............................................................................................................... 23 
13. Participant timeline ....................................................................................................................... 23 
13.1. Summary of procedures by visit .............................................................................................. 23 
13.2. Pre-screening ............................................................................................................................. 25 
13.3. Setting of visits .......................................................................................................................... 25 
13.5. Week 6  (+/- 7 days) .................................................................................................................... 25 
13.6. Week 12 visit (+/- 7 days) ........................................................................................................... 26 
13.7. Week 18 (+/- 7 days) ................................................................................................................... 26 
13.8. End of study definition .............................................................................................................. 26 
13.9. Flow diagram .............................................................................................................................. 26 
14. Sample size .................................................................................................................................... 27 
15. Recruitment ................................................................................................................................... 27 
Methods: Assignment of interventions ............................................................................................ 28 
16. Allocation ....................................................................................................................................... 28 
16.1. Sequence generation ................................................................................................................. 28 
16.2. Concealment mechanism .......................................................................................................... 28 
16.3. Implementation ........................................................................................................................... 28 
17. Blinding .......................................................................................................................................... 28 
Methods: Data collection, management, and analysis ................................................................... 29 
18. Data collection methods............................................................................................................... 29 
19. Data management ......................................................................................................................... 29 
Methods: Monitoring ........................................................................................................................... 31 
21. Data monitoring ............................................................................................................................. 31 
22. Assessment of safety ................................................................................................................... 31 
23. Auditing .......................................................................................................................................... 35 
24. Research ethics approval ............................................................................................................ 35 
26. Consent .......................................................................................................................................... 36 
27. Confidentiality ............................................................................................................................... 36 

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Feasibility trial of modafinil for severe fatigue in IBD (MFI) protocol v1.0, dated 10/10/2025, IRAS 
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28. Declaration of interests ................................................................................................................ 36 
29. Access to data ............................................................................................................................... 36 
30. Ancillary and post-trial care ......................................................................................................... 36 
31. Dissemination policy .................................................................................................................... 37 
32. Sample handling ........................................................................................................................... 37 
33. Timeframe ...................................................................................................................................... 37 
34. Study participant support and reimbursement .......................................................................... 37 
35. Insurance/indemnity ..................................................................................................................... 38 
36. Signatures ...................................................................................................................................... 38 
37. References ..................................................................................................................................... 38 
 

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Feasibility trial of modafinil for severe fatigue in IBD (MFI) protocol v1.0, dated 10/10/2025, IRAS 
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5. Roles and responsibilities 
5.1. Sponsor  
Imperial College London 
 
5.2. Chief Investigator  
Name: Dr Calum Moulton 
Address: Division of Psychiatry, 2nd Floor Commonwealth Building, Hammersmith Campus, W12 0NN 
Telephone: 07384 799297 
Email: c.moulton@imperial.ac.uk 
 
5.3. Co-Investigators 
Name: Professor Allan Young 
Address: Division of Psychiatry, Department of Brain Sciences, 2nd Floor Commonwealth Building, 
Du Cane Road, London, W12 0NN  
Tel: 0207 594 1069  
Email: a.young@imperial.ac.uk 
 
 
Name: Dr James Alexander  
Address: Department of Metabolism, Digestion & Reproduction, Imperial College London, W12 0NN 
Email: james.l.alexander@imperial.ac.uk  
 
Name: Dr Polychronis Pavlidis 
Address: Dept of Gastroenterology, King’s College Hospital, SE5 9RS 
Telephone: +44 (0)20 3299 8306 
Email: ppavlidis@nhs.net 
 
 
Name: Dr Joel Mawdsley 
Address: Dept of Gastroenterology, St Thomas’ Hospital, Westminster Bridge Road, London, SE1 7EH 
Email: joel.mawdsley@gstt.nhs.uk 

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Feasibility trial of modafinil for severe fatigue in IBD (MFI) protocol v1.0, dated 10/10/2025, IRAS 
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Name: Professor Ailsa Hart 
Address: IBD Unit, St Mark’s Hospital, London, NW10 7NS 
Email: ailsa.hart@nhs.net 
 
5.4. Trial statistician 
Name: Professor Ben Carter  
Address: S2.04, Department of Biostatistics and Health Informatics, Institute of Psychiatry, 
Psychology & Neuroscience, King's College London, 16 De Crespigny Park, London SE5 8AF, United 
Kingdom 
Telephone: 02078480305 
Fax: 02078480298 
Email: ben.carter@kcl.ac.uk 
 
 
5.5. Committees 
A trial management group will meet regularly to review trial progress. An independent trial steering 
committee (TSC) will meet between 6 months to 1 year during the duration of the trial. 
5.5.1. Trial steering committee 
We will follow NIHR Research Governance Guidelines (https://www.nihr.ac.uk/documents/research-
governance-guidelines/)  in setting up the Trial Steering Committee (TSC). As per NIHR guidance, the 
TSC will meet at least once per year and will be set up to monitor, review and supervise the progress 
of the trial. This will have an independent chair. We will invite 2-4 service user representatives onto 
the TSC. Alongside our statistical expertise, the Steering Committee review will ensure that conduct 
and reporting standards (e.g. stipulated by the Nature Publishing Group) are adhered to. This will 
include use of appropriate methodology and subsequent reporting (i.e. CONSORT checklist items, 
design, recruitment, allocation, blinding, ethics, trial registration), and statistical procedures (i.e. 
stating assumptions, comprehensive reporting of results and providing clearly labelled descriptive 
statistics and figures, along with a CONSORT flowchart). In accordance with NIHR guidelines, 67% of 
appointed members must attend TSC meetings to be deemed quorate. 
The role of the TSC will be to provide overall supervision for the trial on behalf of the Trial Sponsor 
and Trial Funder and to ensure that the trial is conducted to the rigorous standards set out in the 
Department of Health’s Research Governance Framework for Health and Social Care and the 
Guidelines for Good Clinical Practice. We will carefully monitor adverse events and patient safety, and 
any concerns in this regard will be promptly taken to the CI and TSC. The main roles of the TSC are as 
follows: 

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Feasibility trial of modafinil for severe fatigue in IBD (MFI) protocol v1.0, dated 10/10/2025, IRAS 
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 
To provide advice, through its Chair, to the Chief Investigator, the Trial -sponsor, the Trial 
Funder and the Host Institution on all appropriate aspects of the trial 
 
To concentrate on progress of the trial, adherence to the protocol, patient safety and the 
consideration of new information of relevance to the research question 
 
The rights, safety and well-being of the trial participants are the most important 
considerations and should prevail over the interests of science and society 
 
To ensure appropriate ethical and other approvals are obtained in line with the project plan 
 
To agree proposals for substantial protocol amendments and provide advice to the sponsor 
and funder regarding approvals of such amendments 
 
To provide advice to the investigators on all aspects of the trial 
 
In accordance with NIHR guidelines, at least 67% of the TSC will be independent. The independent 
members will sign the TSC terms of reference. 
 
5.6. Role of sponsor and funder 
The Funder was not involved in the design of the study and will not be involved in the management 
of the study. The sponsor helped to revise the protocol for clarity. The sponsor will provide overall 
oversight of the study. The Chief Investigator will take full responsibility for the decision to submit for 
publication.  
 
 
 

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Feasibility trial of modafinil for severe fatigue in IBD (MFI) protocol v1.0, dated 10/10/2025, IRAS 
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6. Introduction 
 
6.1. Background and rationale 
Fatigue is highly prevalent in patients with IBD, affecting 72% of patients with active IBD and 47% in 
remission, and associated with poor quality of life and significant wider costs.1 However, effective 
treatments are lacking.2 Drug trials for IBD fatigue have been very few and unsuccesful.2–4 As such, 
novel pharmacological treatments for IBD fatigue are needed. Modafinil is a central nervous system 
stimulant used since the 1980s to promote wakefulness in narcolepsy, producing a rapid benefit that 
wears off late in the day.5 Modafinil primarily induces wakefulness by increasing available dopamine 
in the brain.5 Modafinil can be used off-licence in patients with depression, producing improvement 
in depression and fatigue,6 and such use is supported by clinical guidelines.7 Modafinil also enhances 
cognitive performance.8 Modafinil is safe with long-term use and has a low risk of adverse effects or 
dependence.5 With no serotonergic and minimal noradrenergic effects, it is not expected to worsen 
any gut symptoms. To date, however, there are no trials of modafinil for fatigue in IBD. 
 
Preliminary data: We recently published a case series of 10 patients with IBD and severe fatigue 
treated with modafinil. In this series, we found 58% improvement in fatigue and good tolerability.9 
Although the results presented were at 6-month follow-up, we found the same benefit only 2 months 
after starting treatment, which was sustained. Overall, in our clinical IBD fatigue service, we have used 
modafinil in 36 patients with IBD fatigue. Despite the cohort having very refractory IBD (56% already 
treated with multiple biologic therapies), modafinil produced a mean 41.4% improvement in fatigue 
severity after 3 months and was well tolerated.10 Whereas all were in the severe fatigue range at 
baseline, only 36.1% remained so after modafinil treatment. 
Summary: Our preliminary findings suggest that dopamine deficiency may be a key pathway to IBD 
fatigue. This complements growing genetic, epidemiological and mechanistic evidence of gut-brain 
dopamine deficiency in IBD.7 However, measuring brain dopamine levels directly would require 
invasive and hugely expensive methods, such as positron emission technology (PET) imaging. Using 
modafinil – a dopamine reuptake inhibitor – provides a therapeutic test of this mechanism. Given that 
modafinil has never been trialled in patients with IBD, the necessary first step is a feasibility trial 
testing modafinil in patients with IBD. 
 
 
7. Study objectives and design 
 
7.1. Aim 
To test whether it is feasible to carry out a trial of modafinil versus placebo – both in addition to 
treatment-as-usual – for the treatment of severe fatigue in patients with IBD, in order to inform the 
design of a subsequent powered multi-centre randomised controlled trial (RCT). 
 
7.2. Objectives 
The primary objective of the research is to test the feasibility of a definitive trial of modafinil + 
treatment-as-usual (TAU) against matched placebo + TAU for severe fatigue in adults with IBD.  This 
study will: 
1) Establish recruitment, retention, and adherence rates (see section 20.1 for feasibility outcomes with 
green/amber/red ranges) 

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Feasibility trial of modafinil for severe fatigue in IBD (MFI) protocol v1.0, dated 10/10/2025, IRAS 
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2) Measure acceptability using treatment adherence (see section 20.1) and qualitative interview (see 
sections 13.9 and 20.3) 
3) Test the assessment methods and procedures for measuring variables for use in a full trial, including 
the acceptability and completion rate of outcome measures (see section 12.4) 
 
Secondary objectives 
We will also estimate the completeness and variance (spread) in the following secondary outcomes:  
1) Questionnaires:  
I. General fatigue severity using the first 5 questions of the Inflammatory Bowel Disease-Fatigue 
questionnaire 
(https://crohnsandcolitis.org.uk/info-support/information-about-crohns-and-
colitis/measure-your-fatigue)  
II. The FACIT-F fatigue scale: a 13-item measure that assesses self-reported fatigue and its impact upon 
daily activities and function  
III. Depression using the PHQ-9 questionnaire (1999 version), which has been validated in patients 
with IBD  
IV. Anxiety using the GAD-7 questionnaire (1999 version), which has been validated in patients with 
IBD  
V. IBD control measured using the IBD-Control questionnaire (2014 version)  
VI. Mental and physical fatigue symptoms using the 11-item Chalder Fatigue Scale (1993 version)  
VII. Sleep disturbance and quality using the Pittsburgh Sleep Quality Index (1989 version)  
VIII. Core depressive symptoms using the Maudsley 3-item Visual Analogue Scale, which we previously 
validated (for participants being seen in person only)  
IX. Harvey Bradshaw Index for Crohn’s disease patients (baseline and week 12 only)21  
X. Simple Clinical Colitis Activity Index for ulcerative colitis patients (baseline and week 12 only)  
XI. Dietary Screener Questionnaire (baseline and week 12 only) from the NHANES 2009-10 study  
XII. EQ-5D-5L (5-item quality of life questionnaire)  
 
2) Blood levels of dopamine at baseline and 12 weeks  
 
3) Faecal calprotectin level at baseline and 12 weeks  
 
4) Hand grip strength at baseline and 12 weeks 
 
8. Study design 
The study is a parallel group, 1:1 feasibility randomised controlled trial (RCT). Participants will be 
randomised to one of the two treatment arms (modafinil + treatment-as-usual (TAU) or matched 
placebo + TAU) and will complete measures at baseline, 6 weeks and 12-weeks post randomisation. 
Blinded treatment will last for 12 weeks, followed by the offer of a 1-week tapering off dose. A post-
treatment follow-up will take place at 18 weeks post-randomisation. This feasibility trial is designed 
to test “can this trial be done” and is not designed to assess clinical efficacy or safety of modafinil 

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against placebo. Assessment of safety is for participating adverse events and not to measure drug 
safety. 
 
 
Methods: Participants, Interventions and Outcomes 
 
9.  Study setting 
Patients will be recruited from outpatient gastroenterology services at King’s College Hospital, St 
Mark’s Hospital, Imperial College Healthcare NHS Foundation Trust, and Guy’s and St Thomas’ Hospital 
NHS Foundation Trust. For participants wishing to be reviewed in person, study visits will take place 
at the NIHR/Wellcome Clinical Research Facility at King’s College Hospital, at St Mark’s Hospital, Guy’s 
and St Thomas’ Hospital, and Imperial College Healthcare NHS Foundation Trust. Participants can also 
be reviewed online via MS Teams videolink if they prefer, with the exception of the baseline visit, 
which must be conducted in person. 
 
 
10. Eligibility criteria  
 
10.1. Inclusion criteria 
Inclusion criteria: 
1) Established diagnosis of Crohn’s disease (CD) or ulcerative colitis (UC) according to clinical notes. 
2) Reported fatigue duration of 6 months or more. 
3) Aged 18 years or over. 
4) Current IBD Fatigue Assessment Scale score ≥11/20. 
5) Use of contraception if female and of childbearing age. Female participants of childbearing age will 
require a negative serum/urine pregnancy test before starting the study and will also need to agree 
to use an acceptable form of contraception throughout the intervention period, e.g. long-acting 
reversible contraceptive. 
6) Faecal calprotectin <250mcg/g within the last 3 months. 
7) Normal haemoglobin concentration (≥130g/L [men] and ≥120g/L [women]) within the last 3 
months. 
8) Thyroid stimulating hormone (TSH) level 0.4-4.0 mU/L within last 3 months. 
9) Serum total B12 concentration (≥180 nanograms/L) within last 3 months. 
10) Able to provide written informed consent to enter the trial. 
 
10.2. Exclusion criteria 
1) Diagnosis of drug or alcohol dependence syndrome according to patient report or GP record. 
2) Diagnosis of any dementia according to patient report or GP record. 
3) Diagnosis of psychosis or schizophrenia according to patient report or GP record. 
4) Diagnosis of bipolar disorder according to patient report or GP record. 
5) Current active suicidal ideation on clinical assessment by study psychiatrist. 

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6) Current treatment with stimulant medication (e.g. methylphenidate), dopamine agonist (e.g. 
ropinirole), antipsychotic (e.g. olanzapine), L-DOPA, avacopan, avaritinib, bosutinib, doravirine, 
grazoprevir, leniosilib, moboceritinib, Osimertinib, sofosbuvir, velpatasvir or  voxilapravir 
7) Contraindications to the administration of modafinil, as per the current SmPC. 
8) Patient-reported hypersensitivity to modafinil 
9) Non-registration with a GP or failure to consent to sharing of the GP summary care record and any 
psychiatric assessments held. 
10) Currently enrolled in another drug trial or psychological therapy trial. 
11) Currently hospitalised for the treatment of IBD. 
12) Currently being prescribed a course of budesonide or reducing course of prednisolone for IBD. 
13) Planned change in IBD treatment within the next 12 weeks. 
14) Currently breastfeeding, pregnant or planning pregnancy 
15) Diagnosis of indeterminate colitis 
 
11. Intervention 
11.1. Treatment arm 
Half of the cohort (n=35) will be randomised to 12 weeks of treatment with modafinil, which will be 
blinded through over-encapsulation. The starting dose will be 100mg once in the morning. Treatment 
with modafinil will occur in addition to treatment-as-usual, which is antidepressant treatment or any 
psychological therapy the patient wishes to access through NHS services or private therapy services, 
although a typical wait for psychological therapy on the NHS is 3-6 months. The patient and assessor 
will remain blinded to treatment allocation throughout the 12 weeks of treatment. In order to avoid 
serious confounding of the findings in any confirmatory trial, patients will be asked not to change any 
IBD treatment or start any new antidepressants during the 12-week treatment period. If they do 
require a change in their IBD treatment, they will be withdrawn from the trial. 
 
11.1.1. Modifications (treatment arm) 
After 2 weeks, participants will be asked to increase to 100mg morning and 100mg lunchtime if they 
feel they need a higher dose and they are tolerating the treatment. After a further 2 weeks, 
participants will be asked to increase to the maximum dose of 200mg morning and 100mg lunchtime 
if they feel they need a higher dose and they are tolerating the treatment. Participants can increase 
their dose at longer intervals if they prefer, but will be asked not to increase to the maximum dose 
before 4 weeks. 
 
11.2. Control arm 
The other half of the cohort (n=35) will be randomised to a matched placebo, which is a matched 
capsule filled with lactose. Treatment with placebo will occur in addition to treatment-as-usual, which 
is antidepressant treatment or any psychological therapy the patient wishes to access through NHS 
services or private therapy services, although a typical wait for psychological therapy on the NHS is 3-
6 months. The patient and assessor will remain blinded to treatment allocation throughout the 12 
weeks of treatment. In order to avoid serious confounding of the findings in any confirmatory trial, 

18 
 
Feasibility trial of modafinil for severe fatigue in IBD (MFI) protocol v1.0, dated 10/10/2025, IRAS 
number 344329 
patients will be asked not to change any IBD treatment or start any new antidepressants during the 
12-week treatment period. If they do require a change in their IBD treatment, they will be withdrawn 
from the trial. For procedures after the 12 weeks of treatment, see section 11.4. 
 
 
11.2.2 Modifications (placebo arm) 
After 2 weeks, participants will be asked to increase to 1 capsule in the morning and 1 capsule at 
lunchtime if they feel they need a higher dose and they are tolerating the treatment. After a further 2 
weeks, participants will be asked to increase to the maximum dose of 2 capsules morning and 1 
lunchtime if they feel they need a higher dose and they are tolerating the treatment. Participants can 
increase their dose at longer intervals if they prefer, but will be asked not to increase to the maximum 
dose before 4 weeks. 
 
 
11.3. Adherence (both arms) 
Adherence will be monitored through patient report and through pill counts. We will also capture 
reasons for non-adherence. Adherence reminders will take place at the initial product dispensing 
and each study visit thereafter. This session will include: 
 
The importance of following study guidelines for adherence to the dosing advice 
 
Instructions about taking study pills including dose timing, storage, and importance 
of taking pills whole, and what to do in the event of a missed dose (do not double-
dose) 
 
Importance of calling the study team if experiencing problems possibly related to 
study product such as symptoms or lost pills 
11.4. Continuity of care 
Modafinil is not a licensed treatment for IBD fatigue and so routine continuation of care through 
primary care will not be offered to patients. All participants will be given a 1-week tapering supply 
with which to reduce their dose gradually and stop after the 12 weeks of treatment. Modafinil is not 
associated with discontinuation or withdrawal on cessation. Patients will be offered advice on 
alternative treatments they may be able to access for fatigue. 
 
11.5. Concomitant medications 
Modafinil can be combined with antidepressants or used without.11 As such, prescription of these 
medications does not preclude participation in the study. However, patients taking stimulant 
medications will be excluded, owing to mechanistic overlap with modafinil. Likewise, patients will be 
excluded if they are taking antipsychotics, dopamine agonists or L-DOPA. 
During the trial itself, changes in any depression medication or IBD medication could seriously 
confound the findings. Participants will therefore agree not to start any other antidepressants during 
the trial. In order to avoid serious confounding of the findings in any confirmatory trial, patients will 
be asked not to change any IBD treatment during the 12-week treatment period. To minimise the risk 
of this happening, we will exclude participants where there is a planned or expected change in IBD 
treatment in the next 12 weeks.  
 

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Feasibility trial of modafinil for severe fatigue in IBD (MFI) protocol v1.0, dated 10/10/2025, IRAS 
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11.6. Medication risks 
Summary of Product Characteristics (SmPC) for modafinil 100mg are the reference safety information 
(RSI) documents which detail the medication risks. Specifically, section 4.8 will be used to assess the 
relativeness of an adverse event with the medication.    
 
11.7. Medication manufacture, packaging and labelling 
Modafinil and placebo capsules will be manufactured by Newcastle Specials Pharmacy. Modafinil will 
be packaged into HDPE containers containing, respectively, 35 x 100mg modafinil. Participants will 
receive 7 of these containers to cover the maximum dose that could be required for the whole trial, 
in addition to a post-trial tapering supply. Placebo capsules will be packaged into identical containers 
containing 35 capsules and participants will be given 7 of these containers also. The placebo and 
modafinil capsules will be visually identical and in identical packaging Annex 13-compliant labels will 
be provided by Newcastle Specials Pharmacy. As pharmacy staff will not be blinded, the study product 
will be supplied to pharmacy in containers that will be clearly differentiated and then dispensed to 
researchers and participants in a blinded fashion. Tear-off labels will be used for pharmacy staff to 
identify the modafinil and the placebo. Medication will be sent to King’s College Hospital by dedicated 
courier with temperature-controlled vehicles tracked from site to site. 
 
11.8. Medication storage and dispensing 
All study products will be stored at King’s College Hospital Pharmacy according to manufacturer 
instructions (at room temperature). King’s College Hospital Pharmacy will dispense the correct 
treatment arm to each participant against the unblinded kit number list provided by the KCTU. Refer 
to the Pharmacy Manual for further instructions. There will be one dispensing episodes: at baseline 
after baseline after baseline data collection and randomisation.  
 
 
11.9. Treatment stopping rules 
Treatment will be stopped for an individual participant if they develop any of the following: 
 
Active suicidal thoughts. Specifically, any participant who scores 2 or 3 on item 9 (suicidal 
thoughts) of the Patient Health Questionnaire-9 (PHQ-9) at any point in the trial or before, 
will undergo a clinical assessment of suicide risk by one of the trial psychiatrists. If such a 
participant is assessed as having active suicidal thoughts according to clinical assessment, they 
will be excluded from the trial or their treatment stopped 
 
Pregnancy 
 
Any Serious Adverse Event (SAE), Serious Adverse Reaction (SAR) or Unexpected Serious 
Adverse Reaction (USAR), which, in the view of the investigators, necessitates treatment 
cessation. For these events, the modafinil/placebo should be paused until resolution of the 
event. After this, the CI will make a clinical decision on the safety of re-introducing the 
modafinil/placebo 
 
Treatment will also be stopped if requested by any participant at any time. The trial may be 
prematurely discontinued by the sponsor, Chief Investigator or Regulatory Authority on the basis of 
new safety information or for other reasons given by the regulatory authority or ethics committee 
concerned. If the trial is prematurely discontinued, active participants will be informed and no further 
participant data will be collected. The Research Ethics Committee will be informed within 15 days of 
the early termination of the trial. 

20 
 
Feasibility trial of modafinil for severe fatigue in IBD (MFI) protocol v1.0, dated 10/10/2025, IRAS 
number 344329 
 
Every effort will be made to ensure the patient outcomes are continued to be collected even if their 
treatment has been stopped.  
 
11.9.1. Suicidality protocol 
 
Anyone scoring 2/3 or 3/3 on item 9 on the PHQ-9 questionnaire (“Have you had thoughts that you 
would be better off dead, or of hurting yourself in some way?”) will be asked the following question 
by the research team: “You mentioned you’ve been having thoughts that life is not worth living. Is that 
right?” If the patient replies yes or is unsure, they will be asked, “have you had any thoughts about 
taking your own life?” and “do you feel hopeless about the future?” If a patient replies yes to these 
questions or is not sure, one of the study team will contact the patient’s GP and/or local crisis mental 
health services on the same day to report their concerns. A study psychiatrist will assess the patient 
and recommend trial treatment discontinuation if the patient is deemed actively suicidal. The research 
team will explain this to the patient. The study team will follow-up within 1 week to ensure that 
appropriate clinical follow-up has taken place. 
 
In the very unlikely event that a patient is actively suicidal but refuses to let the research team contact 
their GP or local mental health services, a study psychiatrist will perform a more detailed assessment. 
They will explain their concerns to the patient and that most patients can be cared for in the 
community. If, however, the psychiatrist believes that the patient is at high risk of suicide yet they 
continue to refuse follow-up, the psychiatrist will advise that they will have to contact the police. If 
appropriate, the police can convey an actively suicidal patient to a place of safety under the Mental 
Health Act.  
 
11.10. Withdrawal 
Participants have the right to withdraw from the study at any time for any reason. The right to 
withdraw is clearly explained in the participant information sheet and consent form. The investigator  
also has the right to withdraw participants from the study in the event of inter-current illness, AEs, 
protocol or treatment non-compliance or administrative reasons. As an excessive rate of withdrawals 
can render the study uninterpretable, unnecessary withdrawal of participants should be avoided. 
Should a participant decide to withdraw from the study, all efforts will be made to report the reason 
for withdrawal as thoroughly as possible. Should a participant withdraw from the intervention, efforts 
will be made to continue to obtain follow-up data, with the permission of the patient. 
 
12. Outcomes 
12.1. Feasibility and acceptability 
1. Recruitment feasibility: participants randomised overall, % of target 
2. Trial adherence: % of participants completing 12 weeks of treatment 
3. Treatment adherence: % of participants taking at least 75% of prescribed mediation  
4. Study procedures acceptability and compliance: % of planned data and samples collected at primary 
endpoint (12 weeks) 
5. Overall acceptability: % participants describing the treatment as acceptable (≥6/10 on 0-10 scale) 
 

21 
 
Feasibility trial of modafinil for severe fatigue in IBD (MFI) protocol v1.0, dated 10/10/2025, IRAS 
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12.2. Measures collected at baseline 
The research team will collect the following data at the baseline visit: 
 
Socio-demographic variables: data on age, sex, ethnicity (white, black, South Asian/other), 
occupational status, marital status (Married /Civil partnership, Living with a partner, Widowed, 
Divorced/Separated, Single, with a partner but not living together), current employment status 
(Employed full-time, Employed part-time, Full or part-time education, Full-time domestic 
responsibilities, Retired, Unemployed current/previous smoking status (number of cigarettes, cigars 
or vapes per day), and current alcohol use (none, 1-14 units per day, 15 or more units per day). 
 
Psychiatric history: participants will be asked about previous episodes of depression or anxiety, 
medication history (including current and previous antidepressants), previous psychological therapies 
(Graded Exercise Therapy, Group-based Cognitive Behavioural Therapy, Individual Cognitive 
Behavioural Therapy, Counselling, [Short-term] psychodynamic therapy, Mindfulness Based Cognitive 
Therapy), and psychiatric comorbidities. Patients will also be asked about previous diagnoses of 
ME/CFS or long covid. 
 
Other medical conditions: we will ask about conditions associated with fatigue, including liver disease, 
rheumatoid arthritis, coeliac disease. Pain syndromes: patients will be asked about previous diagnoses 
of fibromyalgia, migraine, chronic headache, chronic pelvic pain, temporomandibular joint 
dysfunction, endometriosis 
Criteria for ME/CFS: patients will be assessed for NICE criteria for ME/CFS, which is diagnosed if all of 
the following are present for at least 6 weeks:   
• Debilitating fatigue that is worsened by activity, is not caused by excessive cognitive, physical, 
emotional or social exertion, and is not significantly relieved by rest.  
• Post-exertional malaise after activity in which the worsening of symptoms:  
－ is often delayed in onset by hours or days  
－ is disproportionate to the activity  
－ has a prolonged recovery time that may last hours, days, weeks or longer.  
• Unrefreshing sleep or sleep disturbance (or both), which may include:  
－ feeling exhausted, feeling flu-like and stiff on waking  
－ broken or shallow sleep, altered sleep pattern or hypersomnia.  
• Cognitive difficulties (sometimes described as 'brain fog'), which may include problems finding words 
or numbers, difficulty in speaking, slowed responsiveness, short-term memory problems, and 
difficulty concentrating or multitasking. 
 
The person's ability to engage in occupational, educational, social or personal activities is 
significantly reduced from pre-illness level 
 
IBD variables: from the clinical notes, we will record IBD diagnosis, disease type using the Montreal 
classification, IBD duration, current medications, current analgesia, presence/absence of fistulae, 
current stoma, current parenteral nutrition or intravenous fluid support, and previous surgery 
(number of operations). Where these data are not available, we will ask patients. If not available within 
the last 3 months, participants will be asked to provide a faecal sample for calprotectin, which provides 
a measure of IBD disease activity. 

22 
 
Feasibility trial of modafinil for severe fatigue in IBD (MFI) protocol v1.0, dated 10/10/2025, IRAS 
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Hand-grip strength (HGS) will be quantified using a Hand Dynamometer that measures isometric 
muscular strength of the hand and forearm. Participants will be seated with back, pelvis, and knees as 
close to 90 degrees as possible. The shoulder will be abducted and neutrally rotated with the elbow 
flexed at 90 degrees, the forearm neutral, and the wrist held between 0 and 15 degrees of ulnar 
deviation. The dynamometer will be presented vertically, in line with the forearm, to the participant's 
dominant hand. Participants will be instructed to squeeze the hand grip as hard as they can for 3 
seconds, in three successive trials with 30 s in between each, with the best reading taken. 
Bloods: where possible, if not completed in the last 3 months, a blood sample will be taken for CRP, 
serum micronutrient concentrations, including selenium, copper, zinc and a vitamin screen. 
Hand-grip strength: Questionnaires: Participants will complete a questionnaire schedule that includes 
key psychological measures, typically completed within 30 minutes by patients themselves, and can 
therefore be completely remotely online if preferred (see section 12.4: ‘secondary feasibility 
outcomes’). For this feasibility study, the primary aim is to assess the acceptability, spread and 
completeness of these questionnaire data.  
Anthropometrics: Height and weight will be obtained.  
 
12.3. Secondary feasibility outcomes (baseline, 6 weeks, 12 weeks and 18 weeks post-randomisation) 
 
We will also estimate the completeness and variance in the following secondary outcomes: 
1) Questionnaires (all reported as continuous scores):  
I. 
General fatigue severity using the first 5 questions of the Inflammatory Bowel 
Disease-Fatigue 
questionnaire 
(https://crohnsandcolitis.org.uk/info-
support/information-about-crohns-and-colitis/measure-your-fatigue)12  
II. 
The FACIT-F fatigue scale: a 13-item measure that assesses self-reported fatigue and 
its impact upon daily activities and function 
III. 
Depression using the PHQ-9 questionnaire (1999 version), which has been validated 
in patients with IBD13,14 
IV. 
Anxiety using the GAD-7 questionnaire (1999 version), which has been validated in 
patients with IBD14,15 
V. 
IBD control measured using the IBD-Control questionnaire (2014 version)16  
VI. 
Mental and physical fatigue symptoms using the 11-item Chalder Fatigue Scale (1993 
version)17,18  
VII. 
Sleep disturbance and quality using the Pittsburgh Sleep Quality Index (1989 
version)19  
VIII. 
Core depressive symptoms using the Maudsley 3-item Visual Analogue Scale, which 
we previously validated20 (for participants being seen in person only) 
IX. 
Harvey Bradshaw Index for Crohn’s disease patients (baseline and week 12 only)21 
X. 
Simple Clinical Colitis Activity Index for ulcerative colitis patients (baseline and week 
12 only)22 
XI. 
Dietary Screener Questionnaire (baseline and week 12 only) from the NHANES 2009-
10 study 
XII. 
EQ-5D-5L (quality of life) 
 
Assessments will be conducted either in person or remotely, according to patient 
preference.  
 

23 
 
Feasibility trial of modafinil for severe fatigue in IBD (MFI) protocol v1.0, dated 10/10/2025, IRAS 
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2) Blood tests at baseline and 12 weeks post-randomisation (reported as continuous scores): We will 
draw blood and measure plasma dopamine.  
 
3) Faecal calprotectin at baseline and 12 weeks post-randomisation (reported as continuous 
measurement and as proportion with cut-off ≥150µg/g; note that this is different from the 250µg/g; 
cut-off used for inclusion) 
4) Hand-grip strength (HGS) will be repeated at 12 weeks, as per the baseline protocol. 
 
12.4. Exploratory outcomes 
A further sample will be extracted in a lithium tube to be used for global metabolomic analysis using 
full-length 16S rRNA gene sequencing. The results of this will be reported outside of this trial. 
Participant will also be asked to provide an additional faecal sample at baseline and at 12 weeks for 
analysis of faecal microbiome and metabolome. The results will also be reported outside of this trial. 
As well as being measured as outcomes, the following questionnaires (see section 12.4) will be 
collected as potential mediators of modafinil treatment response in a future powered trial: change 
in sleep quality (PSQI score), changes in plasma dopamine, and change in depression (PHQ-9 score). 
 
13. Participant timeline 
13.1. Summary of procedures by visit 
Visit 
Pre-
screening 
Baseline 
Week 6 
Week 12 
Week 18 
 
Pre-
Screening 
(Day -14 
to Day 0) 
Consent & 
baseline 
measures 
(Day 0) 
6 weeks (+/- 
7 days) after 
random-
isation) 
12 weeks 
(+/-7 days) 
after 
random-
isation) 
18 
weeks 
(+/-7days) 
after 
random-
isation) 
Administrative 
 
 
 
 
 
Informed 
consent** 
 
X 
 
 
 
Randomisation 
 
X 
 
 
 
Dispensing 
modafinil 
/placebo 
 
X* 
 
 
 
Screening 
 
 
 
 
 
Demographics 
 
X 
 
 
 
MINI depression 
interview 
 
X 
 
 
 
IBD history 
X 
X 
 
 
 
Psychiatric 
history 
 
X 
 
 
 
NICE diagnostic 
criteria 
for 
ME/CFS 
 
X 
 
 
 
Eligibility 
assessment 
X 
X 
 
 
 
IBD 
Fatigue 
Scale 
(first 
5 
questions) 
X 
X 
 
 
 
Assessments 
 
 
 
 
 

24 
 
Feasibility trial of modafinil for severe fatigue in IBD (MFI) protocol v1.0, dated 10/10/2025, IRAS 
number 344329 
0-10 
acceptability 
score 
 
 
 
X 
 
Chalder Fatigue 
Questionnaire 
 
X 
X 
X 
X 
Dietary screener 
 
X 
 
X 
 
EQ-5D-5L 
 
X 
X 
X 
 
FACIT-F scale 
 
X 
X 
X 
X 
GAD-7 
  
X 
X 
X 
X 
Hand 
Grip 
Strength 
 
X 
 
X 
 
Height 
(to 
calculate BMI) 
  
X 
  
  
  
IBD Control 
  
X 
X 
X 
X 
IBD-Fatigue 
Scale 
(first 
5 
questions) 
  
X 
X 
X 
X 
M3VAS*** 
  
X 
X 
X 
X 
PHQ-9 
 
X 
X 
X 
X 
PSQI 
  
X 
X 
X 
X 
Short 
Clinical 
Colitis 
Activity 
Index (UC) or 
Harvey 
Bradshaw index 
(CD) 
  
X 
 
X 
 
Weight 
  
X 
 
X*** 
 
Biological 
samples 
 
 
 
 
 
Faecal 
calprotectin*** 
 
X 
 
X 
 
Serum cytokines 
and CRP*** 
 
X 
 
X 
 
Blood 
for 
metabolomic 
analysis*** 
 
X 
 
X 
 
Blood (plasma) 
dopamine 
 
X 
 
X 
 
Faecal 
sample 
for microbiome/ 
metabolomic 
analysis 
 
X 
 
X 
 
Monitoring 
 
 
 
 
 
Adverse events 
 
 
X 
X 
X 
Concomitant 
medication 
 
X 
X 
X 
X 
Pill count 
 
 
 
X 
 
*The first medication dispensing can happen on the same day as the baseline visit or within 
the following 4 days. If necessary, the medication can be sent via secure post; **Informed 
consent will be taken prior to the baseline measures being collected; ***Not for 
participants being reviewed remotely. 
 
 

25 
 
Feasibility trial of modafinil for severe fatigue in IBD (MFI) protocol v1.0, dated 10/10/2025, IRAS 
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13.2. Pre-screening 
If interested in taking part, patients will be asked a small set of basic pre-screening questions either in 
the clinic, over the phone or over videolink (IBD diagnosis, duration of fatigue, current medications, 
whether they are planned to change any IBD treatments in the next 12 weeks) to determine their 
suitability for the study before being asked to attend a screening visit. If they have not yet completed 
the IBD-Fatigue scale, they will be asked this over the phone to ensure their score is 11 or more. Before 
pre-screening, the research team will advise patients that the fatigue information they provide will be 
passed onto their clinical team - with their permission - even if they decide not to take part in the 
study. They will be advised that any other information about their IBD will not be retained by the study 
team if they do not wish to take part. If anyone has an elevated fatigue score but does not wish to 
take part in the study, the research team will seek the patient’s permission to relay the fatigue score 
to their clinical team. 
 
13.3. Setting of visits 
For participants wishing to be reviewed in person, study visits will take place at King’s College Hospital, 
Imperial College Healthcare NHS Foundation Trust, Guy’s and St Thomas’ Hospital or at St Mark’s 
Hospital. Participants can also be reviewed online videolink (MS Teams or NHS attend anywhere) if 
they prefer, with the exception of the baseline visit, which will only be conducted in person. 
 
13.4. Baseline visit 
In person, full informed consent will be obtained and an assessment of eligibility will be performed 
according to the eligibility criteria outlined. The participant will complete the baseline study 
questionnaires. The MINI interview for depression will be performed and the NICE criteria for ME/CFS 
used (these two diagnostic assessments will not be repeated after the baseline visit). The participant 
will also be invited to provide a blood sample and have height and weight measured. If determined 
eligible, the participant will be randomized to modafinil or placebo. 
 
At this visit or within the next 4 days, patients will be given their medication supply for the trial and 
given the dosing instructions. The patients will be given contact details for the investigator team. If 
patients are unable to receive the medication the same day, they will be sent medication via recorded 
post within 4 days of the baseline visit. Two weeks after starting the medication, the participant will 
receive a phonecall from the research team to reiterate the dosing instructions and to answer any 
questions that may have arisen. 
 
13.5. Week 6  (+/- 7 days) 
At these visits, we will collect the following measures, which can be done in person or online according 
to patient preference: 
 
All the baseline psychiatric questionnaires (except the HBI/SCCAI or dietary screener) 
 
All baseline questionnaires of IBD disease activity 
 
Concomitant medications for IBD or mental health (strong or weak opioids) 
 
Adverse events/reactions, coded according to the Medical Dictionary for Drug Regulatory 
Activities [MedDRA] version 14.1) 
 
 

26 
 
Feasibility trial of modafinil for severe fatigue in IBD (MFI) protocol v1.0, dated 10/10/2025, IRAS 
number 344329 
13.6. Week 12 visit (+/- 7 days) 
We will collect the following measures: 
 
All the baseline psychiatric questionnaires  
 
All baseline questionnaires of IBD disease activity 
 
Concomitant medications for IBD or mental health  
 
Hand grip strength 
 
Averse events/reactions, coded according to the Medical Dictionary for Drug Regulatory 
Activities [MedDRA] version 14.1).  
 
Weight (for participants attending in person) 
 
Repeat blood testing for plasma dopamine and metabolomic analysis 
 
Repeat faecal calprotectin and additional faecal sample for microbiome and metabolomic 
analysis 
 
Count of unused medication 
 
0-10 overall acceptability scores of the trial 
 
 
13.7. Week 18 (+/- 7 days) 
We will collect the following measures: 
 
All the baseline questionnaires (except the HBI/SCCAI and Dietary Screener) 
 
Concomitant medications for IBD or mental health 
 
Averse events/reactions, coded according to the Medical Dictionary for Drug Regulatory 
Activities [MedDRA] version 14.1).  
 
13.8. End of study definition 
The end of the trial will be defined as the date when all participants have made their final visits. 
 
13.9. Flow diagram 

27 
 
Feasibility trial of modafinil for severe fatigue in IBD (MFI) protocol v1.0, dated 10/10/2025, IRAS 
number 344329 
 
 
14. Sample size 
As a feasibility study, power calculations for a treatment effect are not applicable. The target sample 
size is 70 participants (35 per group), which is sufficient to generate robust variance estimates.23 To 
account for an estimated 15% attrition, we will recruit 70 participants to the study. Based on this 
sample size, a two-sided confidence interval will extend no more than 12% of the observed 
proportion.24 
 
15. Recruitment  
Consecutive patients aged ≥18 and diagnosed with IBD, confirmed using clinical notes, with self-
reported fatigue will be identified. Where possible, they will be screened for severe fatigue using the 
first 5 questions of the IBD Fatigue Scale (the fatigue assessment component) as part of outpatient 
clinical care. For those with suspected severe fatigue, the clinical team will seek the patient’s 
permission to be contacted by the research team. If they agree, the research team will then contact 
the patient – either in the clinic or over the phone – and provide the patient information sheet. Those 
who are deemed to be potentially eligible will be invited for a screening assessment with a member 
of the study team. Final study inclusion and consent will be taken by a member of the study team. 
 
Recruitment will be maximised, where possible, by active psychological screening within clinical care 
at some of the participating centres. If necessary, further patients will be identified from screening of 
endoscopy schedules and IBD multidisciplinary team meetings. In addition, regular meetings will be 
held between the CI and research assistant/associate to scrutinise recruitment rates and enact 
contingency plans if necessary, including 1. Wider advertising about the study; 2. Widening 
recruitment to other sites; 3. Increased support from the Clinical Research Network; and 4. 
Recruitment through the My IBD Care app, which uses the PHQ-9 and for which several hundred 
patients at King’s College Hospital are registered. 
 
 
Modafinil (n=35) 
Placebo (n=35) 
Screening 
phase
Treatment phase: 
12 weeks 
Post-treatment
follow-up
Week 0
Week 6
Week 12
Randomisation 
Week 18

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Feasibility trial of modafinil for severe fatigue in IBD (MFI) protocol v1.0, dated 10/10/2025, IRAS 
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Methods: Assignment of interventions  
16. Allocation 
Participants will be randomised into the study after providing informed consent and meeting the study 
selection criteria. Each participant will be assigned a unique identification number and randomised at 
the individual level prior to starting treatment.  
 
16.1. Sequence generation 
Participants will be randomly assigned to either modafinil or placebo with a 1:1 allocation as per a 
computer-generated randomisation schedule, which will use a varying permuted block design 
stratified by diagnosis (CD/UC) and sex assigned at birth (male/female). The block sizes will not be 
disclosed to ensure concealment. Participants will be randomised by the clinical team using a web 
based online the KCL Clinical Trials Unit (KCTU) randomisation system. 
 
16.2. Concealment mechanism 
Allocation concealment will be ensured, as the KCU randomisation service will not release the 
randomisation code which takes place after all baseline measurements have been completed. 
 
16.3. Implementation 
All patients who give consent for participation and who fulfil the inclusion criteria will be randomised 
before starting any treatment. Randomisation will be requested by the research team. The central 
randomisation service will send a form to the dispensing pharmacy that includes a randomisation 
number. In the pharmacy, closed envelopes with printed randomisation numbers will be available. For 
every randomisation number, the corresponding code for the treatment group of the randomisation 
list will be found inside the envelopes. The pharmacist will open the envelope and will find the 
treatment (modafinil or placebo) to be allocated to this patient. They will then dispense the 
medication to the patient. The study team and patient will not receive information about the group 
allocation. Throughout the study, the randomisation will be conducted by the KCTU in order to keep 
the data management and the statistician blind against the study condition as long as the data bank 
is open. The randomisation list remains with the KCTU for the whole duration of the study. Thus, 
randomisation will be conducted without any influence of the study team. Unblinding will occur after 
completion of all data analysis, on approval by the Chief Investigator.  
 
17. Blinding 
Participants and researchers will be blind to treatment allocation. The blinding will be maintained by 
opaque over-encapsulation of the modafinil/placebo. Assessments regarding clinical outcomes will be 
conducted by an assessor blind to treatment allocation. The trial statistician will become unblind after 
the first version of the Statistical Analysis Plan is signed. KCH pharmacy will provide blinded labelling 
and kit number allocation.  
 
This is a low-risk intervention and we do not foresee any circumstances under which emergency 
unblinding would be required. Nevertheless, if the patient’s clinician or study team believe that 
emergency unblinding is required, the Chief Investigator will contact the KCH trials pharmacy team 
and ask them to reveal the patient’s treatment allocation. Such a participant would be removed from 
the trial.  
 
 
 

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Methods: Data collection, management, and analysis 
 
18. Data collection methods 
Subjects will be initially screened for possible severe fatigue using the IBD Fatigue questionnaire, using 
a cut-off score of 11 or more. This cut-off is validated in patients with IBD. Participants will be assessed 
for diagnostic criteria for ME/CFS using the NICE Guideline criteria, though inclusion is based on the 
IBD-Fatigue scale and not the NICE criteria. Participants will also undergo diagnostic interview for 
major depression using the MINI Neuropsychiatric Interview. This is a structured clinical interview that 
diagnoses MDD according to diagnostic criteria. It performs comparably with much longer semi-
structured interviews,25 yet can be completed in around 5-10 minutes, thereby minimising participant 
burden. The remaining questionnaires are self-report. 
 
Anyone collecting data will be trained centrally in the study requirements, standardized measurement 
of height and weight, requirements for laboratory specimen collection, and the eliciting of information 
from study participants in a uniform reproducible manner. 
 
Every effort will be made to ensure the patient outcomes are continued to be collected even if their 
treatment has been stopped.  
 
 
19. Data management 
Data will be collected on paper case report form (CRF) – this will be the source data - and then 
transferred to the MACRO electronic case report form (eCRF). Referential data rules, valid values, range 
checks, and consistency checks against data already stored in the database (i.e., longitudinal checks) are supported 
by the MACRO eCRF. The study team will resolve any queries identified by the eCRF checking function, cross-
referencing with the source data. Where the original value is ambiguous, the data will be marked as absent. Data 
entered into the database will be retrievable for viewing through the data entry applications. The type of activity 
that an individual user may undertake is regulated by the privileges associated with his/her user identification code 
and password. All forms and tapes related to study data will be kept in locked cabinets. Access to the study data 
will be restricted. The database will be password-protected.  
 
20. Statistical methods 
A statistical analysis plan (SAP) will be drafted using KCTU SOPs prior to database lock (ST:02, SAP) and approved 
by a blinded senior statistician and the TSC independent statistician. The results will be reported following 
CONSORT guidelines. The analysis population will use intention-to-treat principles. A recruitment plot of predicted 
vs. actual recruitment will be generated on a monthly basis.  
 
20.1. Feasibility outcomes analyses 
The milestones for progression to a full efficacy clinical trial will be as follows: 
 
Outcome 
Green (go) 
Amber (amend) 
Red (no-go) 

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Feasibility trial of modafinil for severe fatigue in IBD (MFI) protocol v1.0, dated 10/10/2025, IRAS 
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N=70 
N=70 
N=70 
Recruitment feasibility: participants randomised 
overall, % of target 
80% (≥56) 
60-79% (42-55) 
<60% (<42) 
Trial adherence: % of participants completing 
12 weeks of treatment 
75% (≥53) 
60-74% (42-52) 
<60% (<42) 
Treatment adherence: % of participants taking 
at least 75% of prescribed mediation  
75% (≥53) 
50-74% (35-52) 
<50% (<35) 
Study procedures acceptability and compliance: 
% of questionnaire data collected at primary 
endpoint 
80% (≥56) 
60-79% (42-55) 
<60% (<42) 
Overall acceptability for both arms: % 
participants describing the treatment as 
acceptable (≥6/10 on 0-10 scale) 
70% (≥49) 
50-69% (35-48) 
<50% (<35) 
 
 
 
 
20.2. Quantitative data analysis 
Quantitative data analysis will be primarily descriptive to aid the planning of a future RCT. Participant 
flow through the study will be presented following CONSORT guidelines. Descriptive data will be 
presented in the form of means and standard deviations; medians and ranges; or percentages with 
95% confidence intervals, as appropriate depending on the data being described.  
We will use linear mixed models to estimate the between group adjusted mean difference (aMD) 
between modafinil and placebo groups at week 12 after adjustment for baseline scores, time, and a 
treatment-by-time-interaction. Associated 95% confidence intervals will be presented alongside the 
aMD without p-values.26  More details will be provided in the SAP. 
As the study is not powered to find treatment differences, the analysis will be preliminary and only 
used to inform the design of a full trial.  
 
20.4. Exploratory analysis 
To explore potential mediators of treatment response in a future powered trial (reduction in plasma 
dopamine, improvement in sleep quality [PSQI score], improvement in depression), exploratory 
analysis will report the mediation analysis. A directed acyclic graph (DAG) will be proposed to support 

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the causal inference. Significant findings will be interpreted cautiously, acknowledging the issue of 
multiple testing, need for replication and low statistical power. 
 
Methods: Monitoring 
21. Data monitoring 
As this is a feasibility study using a low-risk intervention, no data monitoring committee will be formed 
for this trial. No interim analyses will be performed. 
 
Harms 
22. Assessment of safety 
Data on Adverse Events will be collected with open ended questions and recorded systematically. Any 
reported events will be reviewed by the Investigator. The standard definitions of Adverse events/ 
Serious Adverse Events for medicinal products will be used, as follows:  
 
Adverse Event (AE): any untoward medical occurrence in a patient or clinical study subject.   
 
Serious Adverse Event (SAE): any untoward medical occurrence or effect that: 
 
Results in death 
 
Is life-threatening – 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 
 
 
Requires hospitalisation, or prolongation of existing inpatients’ hospitalisation 
 
Results in persistent or significant disability or incapacity 
 
Is a congenital anomaly or birth defect 
 
All adverse events should be reported.  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.   
 
Medical judgement will be exercised in deciding whether an AE is serious in other situations.  
Important AEs that are not immediately life-threatening or do not result in death or hospitalisation 
but may jeopardise the subject or may require intervention to prevent one of the other outcomes 
listed in the definition above, will also be considered serious. 
 
22.1. Assessments of Adverse Events  
Each adverse event will be assessed for severity, causality, seriousness and expectedness as described 
below. 
Severity  
Category 
Definition 
Mild 
The adverse event does not interfere with the participant’s daily routine, and does 
not require further procedure; it causes slight discomfort 
Moderate 
The adverse event interferes with some aspects of the participant’s routine, or 
requires further procedure, but is not damaging to health; it causes moderate 
discomfort 

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Severe 
The adverse event results in alteration, discomfort or disability which is clearly 
damaging to health 
 
 
Causality 
The assessment of relationship of adverse events to the procedure is a clinical decision based on all 
available information at the time of the completion of the case report form.   
The following categories will be used to define the causality of the adverse event: 
Category 
Definition 
Definitely 
There is clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out. 
Probably 
There is evidence to suggest a causal relationship, and the influence of other 
factors is unlikely 
Possibly 
There is some evidence to suggest a causal relationship (e.g. the event occurred 
within a reasonable time after administration of the study procedure). However, 
the influence of other factors may have contributed to the event (e.g. the 
participant’s clinical condition, other concomitant events). 
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 study procedure). 
There is another reasonable explanation for the event (e.g. the participant’s 
clinical condition). 
Not related 
There is no evidence of any causal relationship. 
 
 
 
Expectedness 
Category 
Definition 
Expected 
An adverse event which is consistent with the available information about the 
intervention/treatment/procedure in use in this study.   
Unexpected 
An adverse event which is not consistent with the available information about the 
intervention/treatment/procedure in use in this study* 
* this includes listed events that are more frequently reported or more severe than previously 
reported 
22.2. Procedures for recording adverse events  
All such events, whether expected or not, should be recorded. 
All Adverse events will be recorded in the CRF and in the medical notes following consent. 
All adverse events will be recorded with clinical symptoms and accompanied with a simple, brief 
description of the event, including dates as appropriate.  
 
22.3. Procedures for recording and reporting Serious Adverse Events  

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An SAE form should be completed and emailed to the Chief Investigator within 24 hours.  However, 
hospitalisations for elective treatment of a pre-existing condition do not need reporting as SAEs. 
 
All SAEs should be reported to the REC where in the opinion of the Chief Investigator, the event was: 
 
‘related’, ie resulted from the administration of any of the research procedures; and 
 
‘unexpected’, ie an event that is not listed in the protocol as an expected occurrence 
 
Reports of related and unexpected SAEs should be submitted within 15 days of the Chief Investigator 
becoming aware of the event, using the NRES SAE form for non-IMP studies.  The Chief Investigator 
must also notify the Sponsor of all related and unexpected SAEs. 
 
Local investigators should report any SAEs as required by their Local Research Ethics Committee, 
Sponsor (RGIT@imperial.ac.uk) and/or Research & Development Office. 
All serious adverse events will be recorded in the medical records and the CRF.   
All SAEs must be recorded on a serious adverse event (SAE) form. The PI or designated individual will 
complete an SAE form and the form will be preferably emailed to the Chief Investigator 
(c.moulton@imperial.ac.uk) within 1 working day of becoming aware of the event. The Chief 
Investigator must also notify the Sponsor of all related and unexpected SAEs.within 5 working 
days.  
 
22.4. Reporting Urgent Safety Measures  
If any urgent safety measures are taken the CI/ PI 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, Health Research 
Authority and R&I office of the measures taken and the circumstances giving rise to those measures. 
 
22.5. Protocol deviations and notification of protocol violations 
A deviation is usually an unintended departure from the expected conduct of the study protocol/SOPs, 
which does not need to be reported to the sponsor.   The CI will monitor protocol deviations. 
 
 A protocol violation is a breach which is likely to effect to a significant degree – 
(a) the safety or physical or mental integrity of the participants of the study; or 
(b) the scientific value of the study. 
The CI (with guidance from the trial statistician) and R&I Office should be notified immediately of any 
case where the above definition applies during the study conduct phase.   

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Feasibility trial of modafinil for severe fatigue in IBD (MFI) protocol v1.0, dated 10/10/2025, IRAS number 344329 
Flow Chart for SAE reporting  
AE occurs
Assign Severity Grade 
Was the event Serious? 
No 
Yes 
Submit SAE form to: 
Chief Investigator 
 Sponsor within 5 working days 
 
Record in medical records
and CRF 
Record in medical records, CRF  
Complete an SAE report form 
Submit SAE form to 
Sponsor office 
 

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Feasibility trial of modafinil for severe fatigue in IBD (MODIFI) protocol v1.0, dated 10/10/2025, IRAS 
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22.6. Trust incidents and near misses 
An incident or near miss is any unintended or unexpected event that could have or did lead to harm, 
loss or damage that contains one or more of the following components: 
a. It is an accident or other incident which results in injury or ill health. 
b. It is contrary to specified or expected standard of patient care or service. 
c. It places patients, staff members, visitors, contractors or members of the public at unnecessary risk. 
d. It puts the Trust in an adverse position with potential loss of reputation. 
e. It puts Trust property or assets in an adverse position or at risk. 
Incidents and near misses must be reported to the Trust through DATIX as soon as the individual 
becomes aware of them. 
 
22.7. Incidental findings 
In this study, a likely incidental finding is of depression or suicidal ideation. This will be identified using 
the MINI interview and PHQ-9 questionnaire. These findings will be communicated by the study team 
to the patient’s GP (see section 11.9.1 for suicidality protocol). The other likely incidental finding is of 
a raised faecal calprotectin or CRP concentration. These will be communicated to the patient’s 
gastroenterology clinical team. 
 
23. Auditing 
According to the UK Policy Framework for Health and Social Care Research (section 9.2), part of the 
Chief Investigators responsibilities involves “adhering to the agreed procedures and arrangements for 
reporting (e.g. progress reports, safety reports) and for monitoring the research, including its conduct, 
the participants’ safety and well-being and the ongoing suitability of the approved proposal or 
protocol in light of adverse events or other developments”.  The Chief Investigator will therefore 
ensure there are adequate quality and number of monitoring activities conducted by the study team. 
This will include at least annual monitoring visits at each site. Monitoring will include adherence to 
the protocol, procedures for consenting and ensure adequate data quality.  
The Chief Investigator will inform the sponsor should he have concerns which have arisen from 
monitoring activities, and/or if there are problems with oversight/monitoring procedures. 
As sponsor, Imperial R&D carry out audits of studies and check how studies are performing during 
quarterly portfolio review meetings. 
Ethics and Dissemination 
 
 24. Research ethics approval 
The trial will be conducted in compliance with the principles of the Declaration of Helsinki (1996), the 
principles of Good Clinical Practice in research (GCP), the CONSORT statement and in accordance with 
all applicable regulatory requirements including but not limited to the Research Governance 
Framework and the Medicines for Human Use (Clinical Trial) Regulations 2004, as amended in 2006 
and any subsequent amendments. The Chief Investigator will ensure that REC Favourable Opinion, 
HRA approval is in place before recruitment for the study begins. They will also ensure that 

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Feasibility trial of modafinil for severe fatigue in IBD (MODIFI) protocol v1.0, dated 10/10/2025, IRAS 
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Confirmation of Capacity and Capability is in place at the relevant recruitment sites before recruitment 
at that site study begins. This protocol and other study documents have been submitted for review to 
the Queen’s Square Research Ethics Committee.  
25. Protocol amendments 
Any modifications to the protocol which may impact on the conduct of the study, potential benefit of 
the patient or may affect patient safety, including changes of study objectives, study design, patient 
population, sample sizes, study procedures, or significant administrative aspects will require a formal 
amendment to the protocol. Such amendment will be agreed upon by the Trial Management Group 
and sponsor and approved by the Ethics Committee/HRA.  
 
26. Consent 
The Principal Investigator, or appropriately trained psychiatrist or gastroenterologist delegated by the 
Principal Investigator as documented in the site delegation log, will obtain written informed consent 
from each participant prior to any study specific procedures. Informed consent will be taken in person. 
The Informed Consent procedure will be preceded by an adequate explanation of the aims, methods, 
anticipated benefits and potential risks of the study. The participant will be given ample time to 
consider giving their consent for the study. It will be explained to the potential participant that they 
are free to refuse participation or alternatively withdraw their consent at any point during the study 
and for any reason. All participants who are actively enrolled on the study will be informed of any 
updated safety information which may result in significant changes in the risk/benefit analysis and will 
be re-consented to confirm their wish to continue the study.  
 
27. Confidentiality 
The Chief Investigator will act as custodian for the study data. All participant data written on paper 
will be anonymised and stored in password-protected files. Paper forms of participant data will be 
stored securely on site in locked filing cabinets. Information with regards to study subjects will be kept 
confidential and managed in accordance with the Data Protection Act, NHS Caldicott Guardian, The 
Research Governance Framework for Health and Social Care and Research Ethics Committee Approval. 
Data will be stored for 5 years after study completion and will be archived according to Imperial 
College London policy. During study visits, data will be collected on paper Case Report Forms (CRFs) 
and then transferred to a secure web-based electronic database (MACRO). All electronic data entries 
will be regularly verified with source data. 
 
28. Declaration of interests 
The Chief Investigator and co-investigators have no conflicts of interests to declare that are relevant 
to this trial. 
 
29. Access to data 
The Chief Investigator will act as custodian for the study data. Access to anonymised data will be 
granted to other researchers upon reasonable request. 
 
30. Ancillary and post-trial care 

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Feasibility trial of modafinil for severe fatigue in IBD (MODIFI) protocol v1.0, dated 10/10/2025, IRAS 
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Although stopping modafinil is not associated with any withdrawal, we will provide patients with an 
extra 1-week supply that enables them to stop their dose gradually at the end of the trial. As modafinil 
is not a licensed treatment for fatigue, we are not routinely able to offer ongoing treatment after the 
trial. We will advise patients of any other treatments that may help their fatigue, such as 
antidepressants, and liaise with their GP as appropriate.  
 
31. Dissemination policy 
Findings of this feasibility study will be disseminated through international conferences, peer-
reviewed journals, charities and educational seminars in acute trusts. If the study is feasible, it will 
support an application for a powered trial of modafinil for depression in IBD, for example through the 
NIHR Efficacy and Mechanism Evaluation Scheme. An expert IBD patient panel will advise on this 
Fellowship and on the dissemination of the study findings and developing future grant applications.  
32. Sample handling 
Blood samples will be collected at baseline and week 12. Blood samples will be collected by a 
phlebotomy-trained nurse or member of the research team and labelled with a unique barcode that 
includes the participant number and study identifier. The samples will then be taken directly to the 
Affinity Biolabs Laboratory. Those taken from other hospitals will be transported by validated courier. 
The analyses will be performed by the Affinity Biolabs laboratory and the results returned to the study 
team via email. Samples will be stored and processed in accordance with strict health and safety 
guidelines and under the requirements of the Human Tissue Act. The samples will only be used for the 
purposes of this study and then discarded.  
Prior to the baseline visit, participants will be given a faecal sample pot and asked to provide a faecal 
sample for calprotectin (a measure of IBD disease activity). They will bring this sample with them on 
the day of the baseline visit. The sample will be analysed by Affinity Biolabs using an enzyme 
immunoassay. Participants will be provided with a second sample pot and asked to repeat the sample 
on the day of 12-week visit. This will also be analysed by Affinity Biolabs. 
Participants may also be asked to provide an additional blood sample (taken in a lithium heparin tube) 
for metabolomic analysis, as well as a faecal sample for future microbiome and metabolomic analysis 
in the laboratory of Professor Julian Marchesi and Professor Nick Powell, Imperial College London.  
 
 
33. Timeframe 
This 24-month study includes up to 5 months for setup and approval, 12 months for recruitment (plus 
3 months’ contingency), 4 months for follow-up visits (including post-treatment follow-ups and 
qualitative interviews) and 3 months for write-up and dissemination.  
 
34. Study participant support and reimbursement 
Participants can contact the study team on a dedicated phone for 24 hours per day, for example to 
report adverse effects. Participants can choose to have questionnaire/interview assessments in 
person or virtually. Participants will receive a voucher of £40 each to compensate for inconvenience, 
as well as reimbursement of reasonable travel expenses. Individual researchers will not receive any 
personal payment over and above normal salary, or any other benefits or incentives, for taking part in 
this research. 

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Feasibility trial of modafinil for severe fatigue in IBD (MODIFI) protocol v1.0, dated 10/10/2025, IRAS 
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35. Insurance/indemnity 
Imperial College London holds insurance against claims from participants for harm caused by their 
participation in this clinical study. Participants may be able to claim compensation if they can prove 
that Imperial College has been negligent. However, if this clinical study is being carried out in a 
hospital, the hospital continues to have a duty of care to the participant of the clinical study. Imperial 
College London does not accept liability for any breach in the hospital’s duty of care, or any negligence 
on the part of hospital employees. This applies whether the hospital is an NHS Trust or otherwise. 
 
 
 
36. Signatures 
 
 
__________ ______  
 
 
____13/10/2025_____ 
Chief Investigator 
 
 
 
 
 
Date  
Print Name: Dr Calum Moulton 
 
 
 
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