Severe fatigue in Primary Biliary Cirrhosis MedDRA version: 18.0 Level: PT Classification code 10004661 Term: Biliary cirrhosis primary System Organ Class: 10019805 - Hepatobiliary disorders
Conditions
Interventions
Trade Name: MabThera®
Product Name: MabThera®
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: Rituximab
Sponsors
The Newcastle upon Tyne Hospitals NHS Foundation Trust
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: • Age 18 years or over • Patient has capacity and provided written informed consent for participation in the study prior to any study specific procedures • Moderate or severe fatigue as assessed using previously designated cut-offs of the PBC-40 fatigue domain (i.e. fatigue domain score >33) • Presence of AMA (anti-PDH antibody) at a titre of >1:40 • Adequate haematological function Hb >9g/L, absolute neutrophil count >1.5x109/L, platelet count > 50x109/L • Bilirubin = 50 µmol • INR = 1.5 • Child-Pugh score 40ml/min • Women of childbearing potential should have a negative pregnancy test prior to study entry AND be using an adequate contraception method, which must be continued for 12 months after completion of treatment Are the trial subjects under 18? no Number of subjects for this age range: 0 F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 29 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 29
Exclusion criteria
Exclusion criteria: • Advanced or decompensated disease (variceal bleed, hepatic encephalopathy or ascites) • History or presence of other concomitant liver diseases (including hepatitis due to hepatitis B (surface antigen positive or core antibody positive) or C or evidence of chronic viraemia on baseline screening), primary sclerosing cholangitis or biopsy proven non-alcoholic steatohepatitis) • Average alcohol ingestion >21 units/week (male) or >14 units / week (female) • Chronic sepsis or intercurrent condition likely to predispose to chronic sepsis during the study • Previous treatment with B-cell depleting therapy • Previous history of aberrant response or intolerance to immunological agents • Presence of significant untreated intercurrent medical condition itself associated with fatigue • Presence of significant risk of depressive illness (HADS score indicating caseness) • Current statin therapy or statin use within 3 months of enrolment • Ongoing participation in other clinical trials or exposure to any investigational agent 4 weeks prior to baseline or within <5 half lives of the investigational drug • Major surgery within 4 weeks of trial entry • Vaccination within 4 weeks of trial entry, patients requiring seasonal flu or travel vaccines will be required to wait a minimum of 4 weeks post vaccination to enroll in the trial • Pregnant or lactating women • Psychiatric or other disorder likely to impact on informed consent • Patient is unable and/or unwilling to comply with treatment and study instructions • Any other medical condition that, in the opinion of the investigator would interfere with safe completion of the trial • Hypersensitivity to the active substance (Rituximab) or to any of the excipients (sodium citrate, polysorbate 80, sodium chloride, sodium hydroxide, hydrochloric acid, water (for infusion)) or to murine proteins • Active, severe infections (e.g. tuberculosis, sepsis or opportunistic infections) • Known HIV infection • Clinical history of Latent TB infection unless the patient has completed adequate antibiotic prophylaxis • AST/ALT 4 x Upper Limit of Normal • Severe immune-compromised state • Severe heart failure (NYHA Class IV) or severe uncontrolled cardiac disease • Malignancy (other than basal cell carcinoma) within the last 10 years • Demyelinating disease • Previous participation in this trial • Any contraindication to Rituximab therapy not covered by other exclusions
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: 1. Does Rituximab therapy significantly improve the fatigue experienced by patients with PBC? 2. Does any improvement in fatigue result from a reduction in the PDH-directed antibody response in PBC and the effects that these antibodies have on muscle cell energy generation? 3. What is the safety profile of Rituximab therapy in patients with PBC? 4. How sustained is any effect of Rituximab on fatigue? ; Secondary Objective: 1. To undertake a proof of efficacy clinical intervention study of B-cell depleting therapy in PBC patients with anti-PDH antibody (>95% of patients) who experience significant fatigue. The primary endpoint is reduction of fatigue severity assessed using a disease specific quality of life measure. 2. To explore the extent to which any such improvement in fatigue is related to reduction in the level of anti-PDH antibody in PBC patients and any associated effect on biomarkers of bioenergetic function assessed using unique MRS protocols developed by the CI and co-investigators. 3. To further explore the safety of Rituximab in PBC. ;Primary end point(s): Change in PBC-40 fatigue domain score between baseline and 12 week assessment in patients with severe fatigue (PBC-40 fatigue domain score >33 at study outset: a value validated against a control population in a now validated normal population version of the PBC-40. Change in the other domains of the PBC-40 will be assessed on the same basis as secondary outcome measures.;Timepoint(s) of evaluation of this end point: The primary endpoint is severity of fatigue as assessed using PBC-40, a disease-specific quality of life measure and will be evaluated at baseline, 12 weeks, and three monthly thereafter up to 12 months. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): The breadth of the clinical effect of Rituximab in PBC, exploring impact on other symptoms, functional status and mood, as well as the nature and severity of underlying liver injury. The mechanism of action of Rituximab in terms of its effects on anti-PDH antibody of all isotypes and the B-cells producing it and the associated impact on muscle bioenergetic and cardiorespiratory function. The acceptability of Rituxmab therapy for patients in terms of tolerability and safety. ;Timepoint(s) of evaluation of this end point: Evaluation of the secondary endpoints will be at baseline and 12 weeks. | — |
Countries
United Kingdom
Contacts
Public ContactDr Alison Steel
Newcastle Clincial Trials Unit, Newcastle University
Outcome results
None listed