B-lymphocyte Depletion Using Rituximab in Chronic Fatigue Syndrome/ Myalgic Encephalopathy (CFS/ME). A Randomized Phase-III Study.

The hypothesis is that a subgroup of patients with Chronic Fatigue Syndrome/ Myalgic Encephalopathy (CFS/ME) have a chronically activated immune system and may benefit from B-lymphocyte treatment using the monoclonal anti-CD20 antibody rituximab with induction and maintenance treatment.

We have published a case series of pilot patient observations with B-cell depletion in Chronic Fatigue Syndrome/ Myalgic Encephalopathy (CFS/ME) (Fluge and Mella, BMC Neurol, 2009). Subsequently, we published a small randomized and double-blind phase II study using rituximab induction two infusions two weeks apart (Fluge et al, Plos One, 2011).

We have completed an open label phase II study with 29 patients using rituximab induction and maintenance treatment (six rituximab infusions over 15 months, with follow-up for three years, unpublished).

We hypothesize that a subgroup of patients with Chronic Fatigue Syndrome/ Myalgic Encephalopathy (CFS/ME) have a chronically activated immune system involving B-lymphocytes, possibly a variant of an autoimmune disease, and that patients may benefit from B-cell depletion therapy.

Three substudies will be performed:

Endothelial function: assessment of Flow-Mediated Dilation and skin microcirculation at baseline and repeated during the time interval 17-21 months.

Cardiopulmonary exercise test for two following days: assessment at baseline and repeated during the time interval 17-21 months.

Gastrointestinal function: assessment at baseline and repeated during the time interval 17-21 months.

Eligibility Criteria:
Inclusion Criteria:

* Patients with Chronic Fatigue Syndrome/ Myalgic Encephalopathy (CFS/ME) according to Canadian diagnostic criteria (Carruthers, 2003)
* Duration of CFS/ME disease 2-15 years. For patients with mild CFS/ME duration of disease must be 5-15 years.
* Mild, Mild/Moderate, Moderate, Moderate/Severe and Severe CFS/ME may be included
* Signed informed consent

Exclusion Criteria:

* Patients with fatigue, who do not comply with Canadian diagnostic criteria (2003)
* Duration of CFS/ME \< 2 years or \>15 years
* Patients with very severe CFS/ME
* Pregnancy or lactation.
* Previous malignant disease (except basal cell carcinoma in skin or uterine cervical dysplasia)
* Previous treatment with B-lymphocyte depleting therapeutic monoclonal antibodies, such as rituximab
* Previous long-term systemic immunosuppressive treatment, including drugs such as cyclosporine, azathioprine, mycophenolate mofetil, but except steroid treatment e.g. for obstructive lung disease or for other autoimmune diseases such as ulcerative colitis
* Severe endogenous depression
* Lack of ability to adhere to protocol
* Known multi-allergy with clinically assessed risk from rituximab infusion
* Reduced kidney function (serum creatinine \> 1,5x upper normal level)
* Reduced liver function (serum bilirubin or transaminases \> 1,5x upper normal level)
* Known HIV positivity, previous hepatitis B or hepatitis C
* Evidence of ongoing, active and clinically relevant infection
* Known immunodeficiency with risk from therapeutic B-cell depletion, such as hypogammaglobulinemia