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

Study Overview
=================
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rituximab induction and maintenance treatment (six rituximab infusions over 15 months, with follow-up for three years, unpublished).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.

Official Title
-----------------
B-lymphocyte Depletion Using the Monoclonal Anti-CD20 Antibody Rituximab in Chronic Fatigue Syndrome/ Myalgic Encephalopathy (CFS/ME). A Multicentre, Randomized, Double-blind and Placebo Controlled Phase-III Study With Rituximab Induction and Maintenance Treatment.

Conditions
-----------------
Chronic Fatigue Syndrome/ Myalgic Encephalitis (CFS/ME)

Intervention / Treatment
-----------------
* Drug: Rituximab
* Drug: Placebo


Participation Criteria
=================
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Rituximab<br>Rituximab induction (two infusions two weeks apart) and maintenance (infusions at 3, 6, 9 and 12 months) | Drug: Rituximab<br>* 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.<br>* Other names: Mabthera;|
| Placebo Comparator: Placebo<br>Saline (with added albumin), two infusions two weeks apart, followed by infusions at 3, 6, 9 and 12 months. | Drug: Placebo<br>* 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.<br>* Other names: Saline;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Fatigue score, selfreported. | 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. | Course of Fatigue score during 24 months follow-up. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Short Form-36 (SF-36) | 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. | Changes in SF-36 scores during 24 months follow-up | 
| Physical activity (Sensewear armband) | 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. | Analyzed at baseline and at interval 17-21 months | 
| Self-recorded Function level | 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. | Course during 24 months follow-up | 
| Fatigue Severity Scale | 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. | 24 months | 
| Clinical response duration | 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. | During 24 months follow-up | 
| Sustained clinical response 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. | Assessment at 24 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Chronic Fatigue Syndrome (CFS), Myalgic Encephalitis (ME), Rituximab, B-lymphocyte depletion, B-cell depletion