Title: Rituximab for the Treatment of Fatigue in Primary Biliary Cirrhosis
Funder: Department of Health (England)

Abstract: BACKGROUND: Patients with the primary biliary cirrhosis (PBC) experience profound fatigue for which there is no treatment. Fatigued PBC patients describe impaired muscle function related to abnormality in cellular bioenergetics related to the presence of serum antibodies reactive with pyruvate dehydrogenase (PDH) a key mitochondrial energy generating enzyme. The function of PDH in vitro is inhibited by PDH-reactive antibodies purified from the serum of PBC patients. Proof-of-concept studies have shown that B-cell depleting therapy (Rituximab) reduces fatigue in PBC. HYPOTHESIS & AIMS: We hypothesise that the bioenergetic abnormality underpinning fatigue in PBC is a direct consequence of the in vivo actions of anti-PDH antibody. Our aim is to explore the efficacy of Rituximab in reducing fatigue severity in PBC through reduction in the release of anti-PDH and related antibodies and associated normalisation of muscle energy generation function. This study will advance both the treatment of severe fatigue in PBC and provide insights into the role played by anti-PDH antibody in the pathogenesis of fatigue in PBC which will inform the further improvement of treatment for this important symptom. DESIGN & POPULATION: A double-blind randomized parallel group placebo-controlled clinical trial supported by an accredited CTU performed in confirmed PBC patients with severe fatigue (PBC-40 fatigue domain score > 35) recruited from a specialist disease clinic. INTERVENTIONS: Rituximab therapy in comparison to placebo (Rituximab 1000 mg iv on days 1 and 15) in patients fully established on conventional treatment (ursodeoxycholic acid). OUTCOMES: Primary: Fatigue severity assessed using the fatigue domain of the PBC-40 a fully validated disease-specific quality of life measure. Secondary: a) Clinical: 1) Safety 2) Improvement in non-fatigue domains of PBC-40 (itch cognitive social & emotional) 3) Functional capacity (Improved-HAQ) 4) Time-course of benefit 5) Patient perceptions of effect 6) Level of physical activity 7) liver biochemistry. b) Mechanistic: 1) Functional MRI-based and exercise physiology approaches to explore the mechanisms of observed effects in terms of bioenergetics and muscle acidosis 2) Immunological (antibody and B-cell assessments to confirm biological effectiveness). ASSESSMENTS: Detailed clinical fatigue physiological and mechanistic assessment at weeks 0 and 12. Clinical assessment 3 monthly to 12 months. Clinical and safety assessments the day following treatments and weekly throughout the study. SAMPLE SIZE: 78 subjects randomized to 2 groups (Rituximab & placebo). STATISTICAL ANALYSIS: The primary outcome will be analysed by analysis of covariance (ANCOVA) on the basis of intention to treat. Secondary outcomes which are continuous in nature will be analysed by ANCOVA and the use of correlation coefficients to explore the relationship between physiological/immunological measurements and fatigue. ECONOMIC BENEFIT: PBC affects c20000 patients in the UK many of whom are unable to work leading to significant social security costs and all of whom require follow-up. Amelioration of fatigue would result in significant economic benefits. RESEARCH TEAM: Leaders in PBC clinical and therapeutics research in the UK.


Research activity codes: 5.1 PHARMACEUTICALS;6.1 PHARMACEUTICALS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM