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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02376335
Recruitment Status : Completed
First Posted : March 3, 2015
Last Update Posted : January 13, 2017
Sponsor:
Collaborators:
National Institute for Health Research, United Kingdom
Department of Health, United Kingdom
Newcastle University
Information provided by (Responsible Party):
Newcastle-upon-Tyne Hospitals NHS Trust

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.


Condition or disease Intervention/treatment Phase
Fatigue Primary Biliary Cirrhosis Biological: Rituximab Other: Placebo Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 71 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: B-Cell Depleting Therapy (Rituximab) as a Treatment for Fatigue in Primary Biliary Cirrhosis
Study Start Date : October 2012
Actual Primary Completion Date : March 2016
Actual Study Completion Date : September 2016


Arm Intervention/treatment
Active Comparator: Rituximab infusion
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
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.
Other Name: MabThera

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




Primary Outcome Measures :
  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 [ Time Frame: Between baseline and 12 week assessment ]

Secondary Outcome Measures :
  1. Improvement in physical activity assessed using seven day physical activity monitoring [ Time Frame: 12 weeks ]
  2. Assessment of improvement in daytime somnolence, vasomotor autonomic symptoms, functional status, reduction in depressive and anxiety-related symptoms [ Time Frame: 12 weeks ]
    All assessments will be using questionnaires that currently are used in the routine clinical setting.

  3. Reduction in serum anti-pyruvate dehydrogenase complex antibody levels and in numbers of peripheral blood B-cells [ Time Frame: 12 months ]
    This is to confirm whether any clinical effect is directly related to antibody modulation.

  4. Improvement in peripheral muscle bio-energetic function on exercise [ Time Frame: 12 weeks ]
    This is to confirm whether any clinical effect is directly related to effects on muscle bioenergetic function.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 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)
    • true abstinence: when this is in line with the preferred and usual lifestyle of the subject

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 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
  • any other medical condition that, in the opinion of the investigator would interfere with safe completion of the study
  • 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 study
  • any contraindication to Rituximab therapy not covered by other exclusions

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02376335


Locations
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United Kingdom
Newcastle Clinical Trials Unit
Newcastle upon Tyne, Tyne and Wear, United Kingdom, NE2 4AE
Sponsors and Collaborators
Newcastle-upon-Tyne Hospitals NHS Trust
National Institute for Health Research, United Kingdom
Department of Health, United Kingdom
Newcastle University
Investigators
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Principal Investigator: David EJ Jones, BA, BM, MRCP, PhD, FRCP Faculty of Medical Sciences, Newcastle University
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Newcastle-upon-Tyne Hospitals NHS Trust
ClinicalTrials.gov Identifier: NCT02376335    
Other Study ID Numbers: 5997
2012-000145-12 ( EudraCT Number )
First Posted: March 3, 2015    Key Record Dates
Last Update Posted: January 13, 2017
Last Verified: January 2017
Keywords provided by Newcastle-upon-Tyne Hospitals NHS Trust:
Fatigue
Primary Biliary Cirrhosis
Rituximab
PBC-40
Additional relevant MeSH terms:
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Liver Cirrhosis
Liver Cirrhosis, Biliary
Fatigue
Fibrosis
Pathologic Processes
Liver Diseases
Digestive System Diseases
Cholestasis, Intrahepatic
Cholestasis
Bile Duct Diseases
Biliary Tract Diseases
Rituximab
Antineoplastic Agents, Immunological
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents