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Phase II Cyclophosphamide trial for ME gets under way

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Reprinted with the kind permission of Russell Logan and Shoutout About ME.
By Russell Logan
Norwegian researchers have commenced phase II trials of the anti-cancer drug cyclophosphamide on ME patients.
Led by senior consultant Dr Øystein Fluge and Prof Olav Mella, the team is focusing on non-responders and those patients who have relapsed after treatment with rituximab, a B-cell depleting drug.
Forty patients with moderate to serious myalgic encephalomyelitis (ME) (sometimes referred to as me/cfs or chronic fatigue syndrome) are taking part in the cyclophosphamide trial, which began in March this year and is scheduled for completion by September 2016.
Patients in the cyclophosphamide study have been selected according to the Canadian criteria (2003) from those who have had the illness for at least 2 years.
Twenty-five participants have not received previous treatment with rituximab, are either rituximab non-responders, or have relapsed following rituximab treatment.
Fluge and Mella’s work is bringing hope to millions of ME sufferers, worldwide. Their research into the use of rituximab to treat ME is considered a real breakthrough after the success of an earlier trial, and they are currently undertaking a large phase III trial of rituximab on 152 ME patients running over over three years.
Mella and Fluge believe that ME is a form of autoimmune illness where the body comes under attack from its own defence system.
In this latest study, six intravenous infusions of cyclophosphamide will be administered at four-week intervals with the first at 600 mg/m2 and subsequent infusions at 700 mg/m2.
Side effects at these levels are expected to be minimal. Similar dosages are administered in the treatment of breast cancer and lymphoma as part of a multiple drugs regimen. 
Investigations into possible large vessel endothelial dysfunction and skin microvascular dysfunction will also be performed at the start of the study and during follow-up.
The Kavli Trust is contributing to funding a nursing position for 12 months and is financing laboratory work related to both the rituximab and the cyclophosphamide studies.
A chance discovery
As with many pharmaceutical developments, the possibility that cyclophosphamide might be a candidate for ME arose by chance, when two breast cancer victims with long-term ME experienced major improvements in their ME symptoms after chemotherapy.
In a subsequent small pilot study, two out of three ME patients treated with cyclophosphamide improved quite dramatically.
Before treatment, one of the pilot study participants was only able to walk an average of 326 steps per day. “After six infusions with Cyclophosphamide, she was able to take 13 000 daily paces,” Fluge explained to Teresa Grøtan.
Autoimmune response theory
Mella and Fluge believe that ME is a form of autoimmune illness where the body comes under attack from its own defence system.
“We think an autoimmune response, often after an infection, somehow disrupts the body’s ability to micro-manage the bloodstream,” said Fluge.
One indication that this might be the case is that blood vessels in ME patients do not enlarge as far as in healthy people after they have been compressed.
The researchers also believe that sufferers have a genetic predisposition to develop ME. Fluge notes that the condition tends to run in certain families.
“Members in the immediate family of 45 per cent of the participants in our first study had autoimmune illnesses. That’s a higher proportion than in the general population.”
The Nitric Oxide connection
Recent findings by Fluge and Mella have supported anecdotal evidence of ME patients receiving immediate relief after treatment with nitric oxide.
In 2014 Fluge and Mella filed a European Patent Application for the use of a nitric oxide donor in combination with a B-cell depleting agent to treat ME.
The application details a case where an ME patient experienced immediate relief from symptoms after treatment with an NO donor.
The researchers outline a strategy for the use of a B-cell depleting agent, such as rituximab, together with relatively high doses of L-Arginine 5 g twice daily and L-Citrulline 200 mg twice daily.
What is cyclophosphamide?
Cyclophosphamide dampens the immune system’s response and is used in chemotherapy to treat some forms of cancer. It is also an important treatment for serious autoimmune diseases such as systemic lupus erythematosus with severe lupus nephritis, severe rheumatoid arthritis, granulomatosis with polyangiitis and multiple sclerosis.
Haukeland University Hospital. Cyclophosphamide in Myalgic Encephalopathy/ Chronic Fatigue Syndrome (ME/CFS) (CycloME), ClinicalTrials.gov, May 2015, [Trial record]
Fluge Ø, Bruland O, Risa K, Storstein A, Kristoffersen EK, Sapkota D, Næss H, Dahl O, Nyland H, Mella O. Benefit from B-lymphocyte depletion using the anti-CD20 antibody rituximab in chronic fatigue syndrome. A double-blind and placebo-controlled study. PLoS One. 2011;6(10):e26358. doi: 10.1371/journal.pone.0026358. Epub 2011 Oct 19.[PubMed]
Fluge Ø, Mella O. Clinical impact of B-cell depletion with the anti-CD20 antibody rituximab in chronic fatigue syndrome: a preliminary case series. BMC Neurol. 2009 Jul 1;9:28. doi: 10.1186/1471-2377-9-28. [PubMed]
Grøtan Teresa. Tackling a medical mystery, Kavlifondet, April 2015 [article]
Fluge Ø, Mella O. Nitric oxide donor for the treatment of chronic fatigue syndrome, European Patent Application, 26.11.2014 Bulletin 2014/48 [PDF]
Haukeland University Hospital. B-lymphocyte Depletion Using Rituximab in Chronic Fatigue Syndrome/ Myalgic Encephalopathy (CFS/ME). A Randomized Phase-III Study. (RituxME), ClinicalTrials.gov, August 2014, [Trial record]

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