Modafinil for Debilitating Fatigue in Quiescent Inflammatory Bowel Disease MODIFI-IBD Trial)

Modafinil for Debilitating Fatigue in Quiescent Inflammatory Bowel Disease: a Multicentre,Randomised, Double-blind, Placebo-controlled, Clinical Trial (MODIFI-IBD Trial)

The goal of this clinical trial is to learn if modafinil can treat severe fatigue in adults aged 18 to 75 years with quiescent inflammatory bowel disease (IBD). The main questions it aims to answer are:

Does modafinil reduce fatigue more effectively than placebo, as measured by the mean difference in section I of the IBD-F questionnaire at week 8? Is modafinil safe and well tolerated in patients with quiescent IBD and severe fatigue?

Researchers will compare modafinil to placebo to see if modafinil improves fatigue outcomes.

Participants will:

attend one screening visit including assessment of disease activity, blood tests, stool testing, and an ECG; take modafinil or placebo for 8 weeks, starting at 100 mg daily with possible dose increases based on response and tolerability; complete online questionnaires at baseline, week 4, week 8, and week 12 about fatigue, quality of life, sleep, mood, and work productivity; be contacted regularly during the treatment period to discuss effect and side effects of the study medication; complete an online effort-based decision-making task at baseline and week 8.

Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is frequently associated with persistent fatigue, even during clinical remission. Fatigue is one of the most burdensome symptoms reported by patients with IBD and is associated with impaired quality of life, reduced daily functioning, and decreased work productivity. Despite its high prevalence and clinical relevance, there are currently no established pharmacological treatment options for fatigue in patients with quiescent IBD.

Modafinil is a centrally acting wakefulness-promoting agent approved for excessive daytime sleepiness in narcolepsy. It has been used for many years and has a well-characterized safety profile. Although its exact mechanism of action is not fully understood, available evidence suggests that modafinil enhances wakefulness and alertness through effects on central dopaminergic signalling. Because fatigue in IBD may involve central mechanisms related to motivation, alertness, and effort processing, modafinil is a biologically plausible candidate treatment for this population. Preliminary clinical observations have suggested that modafinil may reduce fatigue in patients with quiescent IBD, but controlled trial data are not available.

This study is a multicentre, randomized, double-blind, placebo-controlled, multicentre, clinical trial designed to evaluate the efficacy, safety, and tolerability of modafinil in adults with quiescent IBD and severe fatigue. Participants are randomized in a 1:1 ratio to receive modafinil or matching placebo. The treatment period is 8 weeks, followed by a 4-week post-treatment follow-up. To support tolerability and allow individualized treatment, study medication is started at 100 mg once daily and may be increased stepwise during follow-up contacts, based on clinical response and tolerability, up to a maximum daily dose of 300 mg. Participants assigned to placebo follow the same dosing schedule to maintain blinding.

After screening and baseline assessment, most study procedures are conducted remotely to minimize participant burden. Participants complete scheduled study assessments during treatment and follow-up and are contacted regularly by the study team to evaluate treatment response, dose adjustment, and adverse events. In addition to evaluating patient-reported outcomes related to fatigue and broader functioning, the trial includes an exploratory online effort-based decision-making task to assess motivational behaviour. Blood-based biomarker analyses will also be explored to investigate biological factors associated with fatigue and treatment response in IBD.

The placebo-controlled, double-blind design was selected because fatigue is a subjective outcome that is susceptible to placebo effects and expectation bias. This design is intended to allow a more reliable estimate of the specific treatment effect of modafinil. If modafinil is shown to be effective and well tolerated, the results of this trial may support the development of a pharmacological treatment option for an important unmet clinical need in IBD care.

Inclusion Criteria:

• Willing and able to provide signed informed consent at the screening visit as well as comply with all study visits and requirements through the end of the study
• Age between 18 to 75 years at screening.
• ≥1 year diagnosis of IBD, based on a combination of clinical, endoscopic, histologic and radiologic criteria
• Chronic fatigue for at least six months
• Severe fatigue as confirmed with a score of ≥11 on section I of the IBD-F
• Clinically quiescent IBD with a Harvey Bradshaw Index (HBI) <5 for CD patients or a Simple Colitis Clinical Activity Index (SCCAI) ≤2 for patients with UC or IBD-unclassified
• Faecal calprotectin <250 µg/g
• Stable IBD medication for ≥3 months before screening visit and no change in IBD medication planned for ≥3 months

Exclusion Criteria:

• Contraindications for the use of modafinil, such as:

  • Uncontrolled hypertension
  • Cardiac arrhythmia
  • A history of left ventricular hypertrophy or cor pulmonale, and in patients with mitral valve prolapse who have previously developed mitral valve prolapse syn-drome during treatment with central nervous system stimulants
  • Patients with hereditary galactose intolerance, lactase deficiency, glucose-galactose malabsorption

• Patients using medication which interacts clinically significant with modafinil, see section 3.3 'Mechanism of action & Drug class'

• Patients using pharmacological agents with similar effects to modafinil, like central nerv-ous system (CNS) stimulants or other wakefulness-promoting drugs such as methylphenidate and amphetamines

• Surgery before or during study period that impacts ability to participate in this study, per investigator judgement

• Participation in another intervention study (excl. registries and post marketing studies)

• Pregnancy or nursing at the moment of screening or planned pregnancy within two months after last dose

• People with a diagnosis of drug or alcohol dependence syndrome will be excluded

• Comorbidities or confirmed diagnoses known to cause fatigue, which may influence study outcomes, including but not limited to:

  • Anaemia (Hb <7.0 mmol/l for women and <8.0 mmol/l for men) and which is judged as clinically significant by the investigator
  • Folate deficiency (<6.0 nmol/l)
  • Iron deficiency (ferritin <20 g/l for women and <25 g/L for men)
  • Vitamin B12 deficiency (<148 pmol/l)
  • Liver insufficiency defined by an ALT or AST >2x ULN or total bilirubin > 2 mg/dL
  • Renal insufficiency defined by an estimated glomerular filtration rate < 45 mL/min, calculated using the Chronic Kidney Disease-Epidemiology Collaboration equation and/or a serum creatinine >178 μmol/L (2mg/dL)
  • Auto-immune disorders such as primary sclerosing cholangitis, rheumatoid ar-thritis, systemic lupus erythematosus or coeliac disease
  • Uncontrolled or recently diagnosed depression
  • Active suicidal ideation
  • Bipolar disorder
  • Schizophrenia or other psychotic disorders
  • Other psychiatric disorders that may interfere with the study as judged by the investigators
  • History or current anxiety or sleep disorders
  • Substance dependence disorders (e.g. alcohol, cannabis, drugs)
  • Evidence, history, or suspicion of infectious diseases that may interfere with the study as judged by the investigators
  • Active Epstein-Barr virus or cytomegalovirus infection
  • Endocrinological disorders such as uncontrolled diabetes mellitus, untreated hy-pothyroidism, hypoadrenalism or hypogonadism
  • Neurological disorders such as multiple sclerosis, dementia, Parkinson's disease or myasthenia gravis
  • Heart failure
  • Chronic obstructive pulmonary disease
  • Obstructive sleep apnoea
  • Active malignancy (exception of malignancies adequately treated with resection for non-metastatic basal cell carcinoma)
  • Long/post-COVID

• Patients who are not able to complete the Dutch questionnaires in an online form

• Has a clinically significant concurrent disease or relevant laboratory abnormality or a history of illness or medical condition that in the investigator's opinion could confound the study results or increase the participant's risk by taking part in the study