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

Fatigue Clinical Trial

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

Status Completed

Clinical Trial 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.

Clinical Trial Description

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 simply 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 we 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.

We have shown that PBC patients with fatigue have an abnormality in the way they generate energy within their muscles. This appears to be associated with the presence of an antibody in the blood which is directed against an important protein which normal cells in the body use to generate energy. In recent years new drug treatments have been developed which allow us to safely suppress the part of the immune system which produces antibodies of the type that seem to cause energy production problems in PBC. As yet, however, the extent to which these medicines can improve fatigue through removal of antibodies in PBC has not been tested.

The aim of this study is to undertake a clinical trial to examine the effects of this treatment ("Rituximab") on severe fatigue in PBC to help us understand whether this will be a potentially useful treatment. This will give us information about how energy generation changes in patients with PBC and 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 licensed treatment.

We will perform a randomised controlled trial of Rituximab therapy in PBC compared to placebo with the primary end point of fatigue severity. The study will be performed in a specialised PBC clinical centre.

Our hypothesis is that the B-cell-directed immunotherapeutic agent Rituximab will improve fatigue in PBC (an important and disabling symptom) through its effect on B-cells producing antibodies which inhibit the function of pyruvate dehydrogenase (PDH) an important energy generating enzyme.

Fatigue is a common and debilitating symptom which frequently impacts significantly on quality of life and ability to function in patients with PBC. There are currently no effective treatments for fatigue in PBC and new approaches are urgently required to address this unmet need. Rituximab, a B-cell depleting agent, holds specific promise (with evidence from a small-scale proof-of-concept pilot trial) as a therapy for fatigue in PBC, given the strong evidence linking the antibody response to PDH in the pathogenesis of fatigue in this disease. We also believe, given the robust diagnostic criteria and the availability of validated clinical tools, that PBC is an important and useful human model in which to study the pathogenesis and treatment of fatigue.

There are currently no treatments for fatigue in PBC and we are not aware of any other treatments under evaluation.

A pilot study performed in Canada exploring the use of Rituximab in PBC (in 13 patients) has provided proof-of-concept, showing that the agent is safe and well-tolerated in patients, and is associated with a clinically significant reduction in fatigue. Fatigue severity was assessed using the Fatigue Severity Scale (FSS) (potential range 9-63 points) with a fall being seen from pre-treatment (median FSS=36, range 11-59) to post-treatment (median=29, range 12-55). Taking into account the floor value for the FSS, this represents a median fall in fatigue severity over 6 months of 26%. This compares with our own case-control study of fatigue in PBC which suggests that fatigue severity in age and sex matched normal controls is 30% lower than in PBC patients1 suggesting the potential for Rituximab therapy to return PBC patients to close to normal with regards to their perceived fatigue. However, this pilot study did not attempt to explore the mechanism of the effect, and since it did not use severe fatigue as an inclusion criteria, the extent of possible improvement for such patients is unclear; moreover, the study was not optimised for the study of fatigue (fatigue was a secondary outcome and only some of the patients who participated had fatigue potentially under-estimating the clinical effect). Patients showed a sustained reduction in anti-PDH antibody levels of all isotypes, supporting the concept that Rituximab has a beneficial effect on fatigue through depletion of PDH-reactive antibody.

The importance of severe fatigue in PBC and the current lack of treatments, the strong theoretical basis for the approach, and the supportive pilot trial proof-of-concept data all, we believe, justify a formal clinical trial of Rituximab targeting fatigue in PBC. Data from animal models of PBC implicating activated B-cells in promoting autoreactivity, from human in vitro studies showing increased TLR-mediated B-cell activation in PBC, from human genetic studies showing disease associations with loci implicated in regulation of the B-cell pool size and the pilot trial data showing improvement in liver biochemistry in PBC patients treated with Rituximab all point to the potential for an additional, more generic benefit for this treatment in terms of underlying liver inflammation further justifying a substantive clinical trial in PBC. ;

Related Conditions & MeSH terms

• Fatigue
• Fibrosis
• Liver Cirrhosis
• Liver Cirrhosis, Biliary
• Primary Biliary Cirrhosis

• NCT number: NCT02376335
• Study type: Interventional
• Source: Newcastle-upon-Tyne Hospitals NHS Trust
• Status: Completed
• Phase: Phase 2
• Start date: October 2012
• Completion date: September 2016