Chronic Fatigue Syndrome/ Myalgic Encephalitis (CFS/ME)
Conditions
Keywords
Chronic Fatigue Syndrome (CFS), Myalgic Encephalitis (ME), Rituximab, B-lymphocyte depletion, B-cell depletion
Brief summary
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.
Detailed description
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rituximab induction and maintenance treatment (six rituximab infusions over 15 months, with follow-up for three years, unpublished).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.
Interventions
DRUGRituximab
Induction with two infusions two weeks apart, rituximab 500 mg/m2 (max 1000 mg). Maintenance with rituximab infusions (500 mg fixed dose) at 3, 6, 9 and 12 months.
DRUGPlacebo
Saline (NaCl 0,9%) added human albumin (Flexbumin) 0,4 mg/ml, two infusions two weeks apart. Maintenance infusions after 3,6, 9 and 12 months.
Sponsors
The Research Council of Norway
Norwegian Department of Health and Social Affairs
The Kavli Foundation
Oslo University Hospital
Trondheim University Hospital
University Hospital of North Norway
Sykehuset Telemark
MEandYou Foundation
The Norwegian ME association
Haukeland University Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Fatigue score, selfreported. | Course of Fatigue score during 24 months follow-up. | Selfreported Fatigue score is registered every second week, as the mean score for the four symptoms: Post-exertional malaise, Fatigue, Need for rest, Daily functioning (scale 0-6). Mean Fatigue scores for the time intervals 0-4, 4-8, 8-12, 12-16, 16-20, 20-24 months are recorded for each patient. These data are used for statistical analysis. The difference in course of Fatigue score during 24 months follow-up, between the rituximab and placebo groups, will constitute the primary endpoint. Overall response is recorded as the effect on CFS/ME symptoms during 24 months follow-up. The overall response is not predefined to a specific time interval, but is defined as mean Fatigue score at least 4.5 for at least 8 consecutive weeks for moderate response, and mean Fatigue score at least 5.0 for at least 8 consecutive weeks for major response. Single response periods and the sum of response periods during 24 months follow-up will be recorded. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Short Form-36 (SF-36) | Changes in SF-36 scores during 24 months follow-up | SF-36 (ver 1.2) are selfreported by patients at baseline, and at 3, 6, 9, 12, 15, 18, 21 and 24 months follow-up. Changes in Physical health summary score, Physical function, and Mean of five subdimensions (Physical function, Bodily pain, Vitality, Social function, General health) are recorded. The difference in course during 24 months follow-up, between the rituximab and placebo groups, will constitute secondary endpoints. Also, the difference between rituximab and placebo groups, in changes from baseline to recording at 18 months, for Physical health summary score, Physical function, and mean of five SF-36 subdimensions, constitute secondary endpoints. |
| Physical activity (Sensewear armband) | Analyzed at baseline and at interval 17-21 months | The patients' physical activity level, in a home setting for 7 consecutive days, is recorded using Sensewear armbands, with registration at baseline and repeated in the time interval 17-21 months follow-up. Changes from baseline to analysis during the time interval 17-21 months, for mean number of steps per 24h, maximum number of steps per 24h, mean duration per 24h with activity level at least 3.5 METs, max duration per 24h with activity level at least 3.5 METs, are recorded. The difference between rituximab and placebo groups will constitute secondary endpoints. |
| Self-recorded Function level | Course during 24 months follow-up | Self-recorded Function level (scale 0-100, compared to healthy state, according to a set of examples) are registered every second week. Mean Function level for the time intervals 0-4, 4-8, 8-12, 12-16, 16-20, 20-24 months are calculated. The difference in course of Function level, between the rituximab and placebo groups, constitute a secondary endpoint. Also, the differences between the rituximab and placebo groups, for changes in selfreported Fatigue score and in selfreported Function level, calculated from baseline to the mean value during the time interval 16-20 months, constitute secondary endpoints. |
| Clinical response duration | During 24 months follow-up | Clinical response periods, defined as consecutive self-recorded Fatigue score at least 4.5 (scale 0-6) for a minimum of 8 weeks, during 24 months follow-up, are recorded. The difference in the longest consecutive clinical response period, between rituximab and placebo groups, constitutes a secondary endpoint. |
| Sustained clinical response at 24 months | Assessment at 24 months | The difference between rituximab and placebo groups, in fraction of patients with sustained clinical response (defined as Fatigue score of at least 4.5) at 24 months, constitute a secondary endpoint. |
| Fatigue Severity Scale | 24 months | Fatigue Severity Scale (FSS) is self-recorded at baseline and at 6, 12, 18, 24 months. The difference between the rituximab and placebo groups, in changes in FSS from baseline to 18 months follow-up, constitutes a secondary endpoint. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Toxicity and side-effects | During 24 months follow-up | Toxicity and side effects will be recorded throughout 24 months follow-up, as specified in the protocol. |
Countries
Norway
Outcome results
None listed