B-Cell Depleting Therapy (Rituximab) as a Treatment for Fatigue in Primary Biliary Cirrhosis

NCT02376335 | Completed Phase 2 DMC

• 2 other identifiers: 59972012-000145-12
• Study Type: interventional
• Target: 71
• Locations: 1 country
• Sites: 1

Brief Summary

Primary Biliary Cirrhosis (PBC) is a liver disease that predominantly affects females, can present for the first time at any age and which develops over many years. It is caused by the immune system attacking the body's own tissues. People with PBC frequently experience profound fatigue or tiredness which they liken to their "batteries running down" and although people still want to undertake normal activities they often lack the energy to be able to do them. This reduces quality of life, makes it difficult for people to work and can end up with them becoming isolated in the community. At present the investigators have no treatment for fatigue in PBC. Finding a treatment for fatigue in PBC is one of the highest research priorities identified by patient groups. The aim of this study is to undertake a clinical trial to examine the effects of a treatment ("Rituximab") on severe fatigue in PBC to help us understand whether this will be a potentially useful treatment. The information that this will give us about how energy generation changes in patients with PBC with and without the treatment will also help us to develop new treatments for fatigue in other diseases. The study has the potential to improve the quality of life of many patients with PBC, for whom there is currently no hope of improvement. The investigators will perform a randomised controlled study of Rituximab therapy in PBC compared to placebo (1:1 ratio). The study will be performed in a specialised clinical research environment at Clinical Research Facility Royal Victoria Infirmary. The investigators have, for many years, worked closely with PBC patient groups to focus on the problems that are important to our patients. This study is fully supported by Liver North, a liver disease charity and patient support group. The study will take place over one year and will involve between 9 and 20 visits although a number of these will be telephone visits. Blood tests and quality of life questionnaires will be performed at the start of the study and after three, six, nine and twelve months. At baseline and 12 weeks follow up physical activity will be monitored using monitors, and an exercise test and MRI scan will be performed.

Conditions

Fatigue; Primary Biliary Cirrhosis

Keywords

Fatigue; Primary Biliary Cirrhosis; Rituximab; PBC-40

Outcome Measures

Primary Outcomes (1)

• Fatigue severity in PBC patients, assessed using the fatigue domain of the PBC-40, a fully validated, psychometrically robust, disease specific quality of life measure

  Between baseline and 12 week assessment

Secondary Outcomes (4)

• Improvement in physical activity assessed using seven day physical activity monitoring

  12 weeks

• Assessment of improvement in daytime somnolence, vasomotor autonomic symptoms, functional status, reduction in depressive and anxiety-related symptoms

  12 weeks

• Reduction in serum anti-pyruvate dehydrogenase complex antibody levels and in numbers of peripheral blood B-cells

  12 months

• Improvement in peripheral muscle bio-energetic function on exercise

  12 weeks

Study Arms (2)

Rituximab infusion

ACTIVE COMPARATOR

Participants will be randomised to Rituximab therapy (1000 mg IV on days 1 and 15) or placebo (0.9% Sodium Chloride 250mls) control.

Biological: Rituximab

Placebo infusion

PLACEBO COMPARATOR

Participants will be randomised to Rituximab therapy (1000 mg IV on days 1 and 15) or placebo (0.9% Sodium Chloride 250mls) control.

Other: Placebo

Interventions

Rituximab BIOLOGICAL

The Rituximab dosing regimen identified is that used in the proof of concept study, which is also the established treatment regimen for Rituximab use in rheumatoid arthritis. All interventions will be administered with a clinician present throughout the infusion in participants who have been encouraged to have adequate oral hydration in the 24 hours prior to attendance. Resuscitation equipment will be immediately available during the infusion period. Blood pressure, heart rate and temperature will be monitored during the infusion. Participants will continue to be observed in the Clinical Research Facility for at least 1 hour after the infusion.

Also known as: MabThera

Rituximab infusion

Placebo OTHER

Participants will be randomised to Rituximab therapy (1000 mg IV on day 1 and 15) or placebo (0.9% Sodium Chloride 250 mls) control

Also known as: 0.9% Sodium Chloride 250 mls

Placebo infusion

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• age ≥ 18 years
• 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 \< 7
• ECOG performance status \< 2
• adequate renal function; Cockroft and Gault estimation \> 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. Acceptable forms of effective contraception include:
• established use of oral, injected or implanted hormonal methods of contraception
• placement of an intrauterine device (IUD) or intrauterine system (IUS)
• barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository
• male sterilisation (with the appropriate post-vasectomy documentation of the absence of sperm in the ejaculate)

You may not qualify if:

• 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 study entry
• vaccination within 4 weeks of study entry; patients requiring seasonal flu or travel vaccines will be required to wait a minimum of 4 weeks post vaccination to enrol in the study
• 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

Sponsors & Collaborators

• Newcastle-upon-Tyne Hospitals NHS Trust: lead
• National Institute for Health Research, United Kingdom: collaborator
• Department of Health, United Kingdom: collaborator
• Newcastle University: collaborator

Study Sites (1)

Newcastle Clinical Trials Unit

Newcastle upon Tyne, Tyne and Wear, NE2 4AE, United Kingdom

Location

Related Publications (1)

• Khanna A, Jopson L, Howel D, Bryant A, Blamire A, Newton JL, Jones DE. Rituximab Is Ineffective for Treatment of Fatigue in Primary Biliary Cholangitis: A Phase 2 Randomized Controlled Trial. Hepatology. 2019 Nov;70(5):1646-1657. doi: 10.1002/hep.30099. Epub 2018 Sep 22.

  PMID: 29790196 DERIVED

MeSH Terms

Conditions

Fatigue; Liver Cirrhosis, Biliary

Interventions

Rituximab

Condition Hierarchy (Ancestors)

Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Cholestasis, Intrahepatic; Cholestasis; Bile Duct Diseases; Biliary Tract Diseases; Digestive System Diseases; Liver Diseases; Liver Cirrhosis; Fibrosis; Pathologic Processes

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• David EJ Jones, BA, BM, MRCP, PhD, FRCP

  Faculty of Medical Sciences, Newcastle University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 24, 2015
• First Posted: March 3, 2015
• Study Start: October 1, 2012
• Primary Completion: March 1, 2016
• Study Completion: September 1, 2016
• Last Updated: January 13, 2017

Record last verified: 2017-01

Locations

GB (1)