Following is an expansion of the ME Association's Oct 20 Q&A regarding the rituximab ME/CFS trial. The update, by Tony Britton & Dr. Charles Shepherd, is reposted here with kind permission of the MEA (www.MEAssociation.org.uk). New information includes trial criticisms and responses, more details on the drug, and activities regarding development of a potential preliminary UK trial protocol.
Rituximab Clinical Trial: Questions and Answers (revised Nov 2, 2011)
This is the first updated version of our information on the rituximab clinical trial that has been carried out in Norway
What is rituximab and what is it normally used to treat?
Rituximab is a drug that is principally used to treat people with lymphoma (a cancer involving a specific type of white blood cell called lymphocytes). Rituximab has had American FDA approval since 1997 for this purpose. It can also be used to treat chronic lymphocytic leukemia.
A lymphoma involves specialist immune system cells called B lymphocytes and the drug causes lysis (= disintegration) of the malignant B cells.
One of the main functions of B cells in a healthy body is to produce antibodies.
In scientific jargon, rituximab is an anti-CD20 antibody – meaning that it acts against a protein called CD20, which is found on the surface of the B cells. Rituximab destroys both normal and cancerous B cells that have the CD20 protein present. It is therefore used in diseases where there are too many B cells, overactive B cells, or dysfunctional B cells.
Rituximab is also licensed for the treatment of severe active rheumatoid arthritis where other treatments have not been successful. In this case it acts by dampening down inflammation in the joints caused by immune chemicals called cytokines.
On an experimental unlicensed basis, it has been used to treat a number of what are called autoimmune diseases – where the body produces harmful antibodies that attack normal tissues such as muscle and thyroid. These are known as autoantibodies. Examples of immune and autoimmune diseases where rituximab has been used include SLE (systemic lupus erythematosus), MS, Sjogren’s syndrome and bullous skin diseases (e.g., pemphigoid).
The drug is co-marketed by Biogen Idec and Genentech in the US and by Hoffman La Roche in Canada and the European Union. It is sold under the trade names Rituxan and MabThera.
Are there any other drugs that act in a similar manner to Rituximab?
Yes, there are two other drugs that cause B cell depletion and have similar side-effects to rituximab. These are alemtuzumab/MabCampath (Genzyme) and ofatumumab/Arzerra (GlaxoSmithKline)
Why might rituximab be helpful in ME/CFS?
There is already plenty of sound research evidence to indicate that immune system dysfunction occurs in ME/CFS.
On current evidence, it appears that this may involve low-level activation of the immune system response, with production of immune chemicals called cytokines (which cause flu-like symptoms), rather than the type of immune system failure/deficiency that occurs in diseases such as HIV/AIDS.
Part of this activated immune response in ME/CFS may also involve the production of autoantibodies, and there is some research evidence to support this. However, it is premature to conclude that ME/CFS is an autoimmune disorder.
There is also some evidence that B cells may be involved in ME/CFS and this is a site where reactivated viruses, such as HHV-6 and Epstein Barr, are present. But the delayed response to treatment in this clinical trial suggests that viral elimination is not the mode of action here.
So there are a number of sound theoretical reasons why this drug might be helpful in at least a sub-group of people with ME/CFS.
Where and why was this trial carried out?
The trial was carried out by oncologists (cancer experts) in Norway.
A few years ago they noticed that a person with ME/CFS who had developed a lymphoma, and was then treated with rituximab, made an unexpected and significant improvement lasting five months in their ME/CFS symptoms.
A small preliminary trial was carried out and the encouraging results on three patients were published.(Abstract: www.ncbi.nlm.nih.gov/pubmed/19566965)
The encouraging findings, coupled with a sound hypothesis as to why this drug might be helpful in ME/CFS, led to what is called a phase 2 clinical trial being carried out.
What happened in the trial?
This was a double-blind (meaning neither doctors nor patients knew which treatment was being used in whom) placebo-controlled (meaning half of the group received rituximab and the other half received a placebo = saline) clinical trial.
30 patients were involved. They were assessed by a neurologist and all met the Fukuda CFS research definition. Most also met the Canadian definition.
Age range = 18 to 65. Mean age = 37.3 (80% female) in active treatment group. Mean age = 31.5 (60% female) in the placebo group.
Mean disease duration = 5.1 years in the active treatment group; 8.1 years in the placebo group.
Preceding infection identified in 73% of the active treatment group and 67% in the placebo group.
23% of patients had a previous known autoimmune disease and 40% had a first-degree relative with an autoimmune disease.
Rituximab has to be given by infusion into a vein – it is not a drug that can be taken by mouth. Two infusions at a dose of 500mg per metre2 were given two weeks apart. The patients stayed overnight in hospital.
Both groups were followed up at regular intervals for a period of 12 months.
A range of self-reported and physician-assessed measures were recorded – including fatigue, mental functioning, overall health (SF-36) – to monitor progress in both groups.
XMRV status and lymphocyte subpopulations were also measured before treatment.
At baseline 3/30 patients had a B-cell count below the normal range. All those in the active treatment group were B-cell depleted at one month after intervention.
XMRV was not detected in any of the patients.
What are the results?
Although the numbers are small for a phase 2 clinical trial, the results are very encouraging.
10/15 people who received rituximab reported a moderate or major overall response.
2/15 people who received saline reported a moderate or major overall response.
In most cases, it took several months (2 to 7/12) after starting rituximab before an improvement in symptoms occurred with response durations of 2 to 15 months. Two patients have had major lasting responses, with no relapses, and are back at work.
The drug was well tolerated and no serious side-effects were reported. Two people noticed a worsening of their pre-existing psoriasis.
Is rituximab safe?
All drugs have side-effects and anti-cancer drugs often have a potential to cause serious side effects. So this is a drug that is only given in hospital by specialists who are used to working with it.
Infusion-related side-effects are quite commonly reported. Symptoms include low grade fevers and chills, nausea and vomiting, allergic reactions, tightness of the chest and throat, and lowered blood pressure.
A rare but much more serious side effect, called a cytokine release syndrome (where immune chemicals are released), can even be fatal. This is more likely to occur in patients with a lymphoma where lymphoma cells have entered the bloodstream.
Patients are therefore given an analgesic, an antihistamine and possibly a steroid before the infusion to reduce the possibility of side-effects.
Progressive multifocal leukoencephalopathy (PML), as a result of JC virus activation, has been reported in association with more prolonged use of rituximab.
Reactivation of hepatitis virus has also been reported – so this infection should be tested for before this drug is used..
Rituximab has to be used with caution in anyone with a history of heart or lung disease.
So this is a drug that has to be used and monitored in both the short term and long term with great care.
Have there been any criticisms of the trial?
Yes. A group of doctors wrote to the journal with a number of questions and criticisms relating to:
• The theoretical basis and late response to treatment
• Blinding of the study
• Methodological concerns regarding measurement of fatigue
• Definition of improvement
• Patient and family links to autoimmune disease
• The decision to proceed with an open-label follow up study.
These criticisms were responded to in some detail by Professor Jonathan Edwards from University College London and the Norwegian researchers.
Correspondence relating to the trial results can be found here:
How much does this drug cost?
This is a fairly costly form of treatment. A 50 mL vial for infusion costs around £1,000 [$1,594].
What happens next?
The research group in Norway are following up this work with a new open-label phase 2 trial that will investigate treatment with two infusions two weeks apart followed by maintenance infusions at 3, 6, 10 and 15 months.
There is also a need to carry out further trials involving other research groups to see if they reach similar conclusions regarding efficacy and safety.
Will my doctor be able to prescribe rituximab?
No. The whole process of drug discovery and clinical trial assessment is a long and costly process – especially when it involves a drug such as rituximab which has the potential to cause very serious short-term and longer-term side effects. In simple terms, the UK drug regulator - the Medicines and Healthcare Products Regulatory Authority (MHRA) - will want to see the results of phase 2 and phase 3 clinical trials, and then be sure that the drug is both effective and safe to use in ME/CFS, before it can be granted a product license.
Phase 2 trials test a treatment in patients to find out how well it works as well as its safety.
Phase 3 trials compare the treatment in much larger numbers, gather more information on how it works, and examine safety in more detail. This a process that takes years rather than months.
Once this data is ready the MHRA in the UK, or the European Medicines Agency for the whole of the EU, can consider whether it can be given a product license for use in a specific condition.
What is the ME Association doing?
The MEA is working very closely with the UK representatives of the Norwegian research group in order to obtain media publicity for the trial results. Examples so far include coverage via the BBC, New Scientist and Daily Mail.
BBC coverage: www.bbc.co.uk/news/health-15401746
Dr Charles Shepherd briefed the All Party Parliamentary Group on ME at Westminster, and the Forward ME Group at the House of Lords, on the results last week. The Chair of the APPG is writing to the Medical Research Council.
Dr Shepherd has discussed the results, and a possible preliminary protocol for a UK clinical trial, with leading experts in the use of this drug and with the chair of the MRC Expert Group on ME/CFS research.
The MEA has made it clear that the Ramsay Research Fund would be very happy to look at funding proposals for a UK clinical trial.
A note of caution: This is one small phase 2 clinical trial. We need to see the results from further clinical trials before coming to any conclusions about the way in which this drug might work in ME/CFS and whether or not it is an effective form of treatment for what may be a sub-group of people with ME/CFS who have an autoimmune component. We do not want to see a repeat of the false hopes created by the XMRV research.
Role of the MEA Ramsay Research Fund
Further research into the use of this drug clearly needs to be carried out and Dr Shepherd has already raised the issue of rituximab at a meeting at the Medicines and Health Products Regulatory Agency (who license new drugs for use in the UK) prior to publication of the paper.
The MEA Ramsay Research Fund would be very willing to consider helping to fund a UK clinical trial if anyone in a reputable clinical unit wants to apply.
Complete paper available online:
"Benefit from B-Lymphocyte Depletion Using the Anti-CD20 Antibody Rituximab in Chronic Fatigue Syndrome. A Double-Blind and Placebo-Controlled Study" (www.plosone.org/article/info:doi/10.1371/journal.pone.0026358)
We will be updating this information in response to comments and questions - 2 November 2011 (version 2)