About
Introduction
The BiP study investigates a potential new treatment for RA called BiP. BiP is a normal human protein found in every person. We have found that higher levels of BiP, given like a drug, reduced arthritis in animal models of arthritis like RA. BiP also reduced inflammation in cells taken from joint tissue of people with RA. We believe these effects suggest it may help RA in humans. This study will be giving BiP to humans for the first time.
About BiP
BiP is a human protein found in every human cell. It is therefore a natural protein. Inside the cell, BiP protects cells from stress. If stress increases then BiP is released from the cell in small amounts. Patients with rheumatoid arthritis tend to release slightly less BiP than healthy people. Dr Valerie Corrigall and Professor Gabriel Panayi, the Medical School, King’s College, London, produced BiP in large amounts and showed that it had potent anti-inflammatory activities.
In the first instance a single intravenous injection of BiP suppressed ongoing collagen induced arthritis (CIA) in the mouse. CA is the experimental model of rheumatoid arthritis (RA) used to develop and test new therapies. This single injection had a prolonged therapeutic effect. Calculations based on the life spans of mice and men suggest that, if BiP were to have the same therapeutic effect in humans as in mice, a single inject in a patient should last for about a year.
BiP had a prolonged therapeutic effect in the CA model because it induced the formation of cells, probably T cells, that have the ability to control immune responses and hence inflammation. Joint pain and swelling experienced by people with RA is due to immune mediated inflammation. Laboratory studies show that BiP also induces similar human T cells suggesting a similar effect may be seen when treating patients.
Is there any evidence that BiP will inhibit the inflammation seen in rheumatoid synovial membrane before the clinical trial? Severe combined immuno-deficient (SCID) mice have a non-functioning immune system. They will accept grafts of human tissue indefinitely without rejecting them. Corrigall and Panayi have grafted pieces of RA synovial membranes from the joints of people with RA, into SCID mice. After the joint tissue grafts had joined up with the mouse blood vessels, they injected intravenously a single small dose of BiP in some mice or a control protein in other mice. The joint tissue grafts were then taken out and examined.
Those taken from mice injected with control protein showed continued, full blown rheumatoid arthritis inflammation. By contrast those taken from the mice injected with BiP, had significant reduction in all aspects RA inflammation. This experiment, which is the nearest to a clinical trial without actually dosing a patient, has been used to test other biologics that are currently in use in the clinic for the treatment of RA.
About the BiP 001 Study
The purpose of this study is to see if BiP might be a new treatment for rheumatoid arthritis. We will be giving BiP to people for the first time. The study has three aims:
- Is BiP safe? In order to ensure safety you will be closely monitored during the course of the study for any possible side effects.
- What effect does it have on the blood? We will take blood tests regularly during the study to check for safety and also to see if BiP is changing the inflammation tests associated with rheumatoid arthritis.
- Does BiP improve Rheumatoid Arthritis? During your follow-up the activity of your arthritis will be closely monitored.
Key Inclusion Criteria
Patients to be included must meet the following criteria:
- Patients older than 18 and less than 75 years of age, with active RA.
- Active RA is defined as six or more tender and swollen joints and ESR greater than 20 mm or C-reactive protein greater than 5 mg/dL
- Patients enrolled into the study must have failed at least one DMARD
- Duration of RA ≥ 6 months prior to screening visit.
- Patients taking DMARD’s such as methotrexate, hydroxychloroquine or sulphasalazine must be on a stable dose for 6 weeks before commencement of trial medication.
- Patient must be able to adhere to the study visit schedule and other protocol requirements.
- Able and willing to give informed consent to provide clinical data and blood samples at defined time points for the duration of the study
Key Exclusion Criteria
- Women who are pregnant or breast-feeding
- Use of any investigational drug within 1 month prior to screening Pregnant
- Treatment with any biologic drug within 3 months of screening, such as TNF inhibitors, Infliximab (Remicaide), Adalimumab (Humira), Etanercept (Enbrel), Golimumab (Simponi) and Certolizumab Pegol (Cimzia). Other biologic drugs include Rituximab and Tocilizumab infusions (RoActemra) and Abatacept (Orencia) injections. People should also not be taking more than 10 mg of Prednisolone daily. Other significant active medical problems
- Known recent substance abuse (drug or alcohol).
Study Treatment
The study consists of 4 groups of eight patients. The dose increases with each group.
In each group of 8 patients there is a random selection of 6 patients who will receive BiP, and 2 patients who will receive an infusion not containing BiP called the placebo.
There is a single infusion of BiP or placebo and patients are followed for 12 weeks.
Researchers and patients do not know which patient will receive BiP until the end of the trial, unless there are important reasons to find out.
Sample Size
32 patients.
Study duration
Patients will be in the study for 12 weeks after the infusion.
Assessments:
- 1 visit for a screening check-up and blood test one week before the infusion;
- 1 or 2 nights in the infusion suite at our partner, Quintiles. Quintiles are experts in first in human studies. The infusion takes 1 hour. The overnight stay after the infusion is for observation. There is an option for people to stay the night before the infusion as well if this is easier for the patient
- 1 blood test between 3-5 days post infusion;
- Weekly visits and blood tests for 4 weeks; two more visits and blood tests every four weeks.
About Rheumatoid Arthritis
Rheumatoid arthritis (RA) is a symmetrical inflammatory polyarthritis. It usually begins in the small joints of the hands and feet. The inflamed synovium erodes the articular cartilage and underlying bone, and eventually causes joint deformity and progressive disability. RA is more common in women than men (Arthritis Research UK). RA is the commonest autoimmune disease in the United Kingdom. The overall prevalence is 0.8% (0.4% in men and 1.1% in women). The highest prevalence is in the elderly group of 75 years and above (2.2% in males and 2.7% in females). Having RA increases ones chances of early death mainly due to a greater risk of cardiovascular death from heart attacks and strokes. The economic cost of RA is difficult to calculate but the direct health care costs in 2009 in England amounted to £560 million although these are probably higher now due to increase use of biologics. If the cost of sick leave and lost employment is included this rises to£1.8 billion per annum.