A Non-Comparative Study to Assess the Safety of MabThera (Rituximab) in Patients With Rheumatoid Arthritis.

Study Overview
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Brief Summary
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This single arm study will assess the safety of MabThera plus methotrexate in patients with rheumatoid arthritis who have had a lack of response to 1-5 DMARDs or biological agents. Patients will receive MabThera (1g i.v.) on days 1 and 15, concomitantly with methotrexate >=15mg p.o./week. The anticipated time on study treatment is 3-12 months, and the target sample size is 100-500 individuals.

Official Title
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Multicenter Non-Comparative Expanded Access Program of to Assess Safety of Rituximab (Mab Anti Cd-20) in Patients With Rheumatoid Arthritis (Ser)

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Drug: Methotrexate
* Drug: rituximab [MabThera/Rituxan]


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: adult patients, >=18 years of age; rheumatoid arthritis >=6 months; lack of response to 1-5 DMARDs or biological agents; rheumatoid factor positive. Exclusion Criteria: other chronic inflammatory articular disease or systemic rheumatic disease; joint or bone surgery during 8 weeks prior to randomization; previous treatment with any cell-depleting therapy.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Rituximab<br>Eligible participants receiving Rituximab (MabThera/Rituxan) 1 gram/dose (g/dose) intravenously (IV) on Day 1 and Day 15 followed by previous pre-medication (methylprednisolone 100 mg IV, antihistamine and antipyretic) and concomitant treatment of Methotrexate at least 15 mg per oris (PO) weekly were observed during the study period of 24 weeks. After treatment completion, participants were followed-up for safety up to 24 weeks. | Drug: Methotrexate<br>* >=15 mg po/week<br>Drug: rituximab [MabThera/Rituxan]<br>* 1g iv on days 1 and 15<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Any Adverse Event, Any Serious Adverse Event, and Death | An Adverse event (AE) was considered any unfavorable medical event in a participant of clinical research who received the study drug and that not necessarily had a causal relationship with this treatment. An AE could, therefore, being any unfavorable sign and non-intentional, symptom or disease temporarily related with the use of a medicinal product, considered or not related to the medicinal product. Pre-existing conditions that worsened during the study were reported as AEs. A serious adverse event (SAE) is any experience that suggested a significant risk, contraindication, caution, and at any dose fulfills at least one of the following criteria: adverse event considered as fatal (resulting in death), life threatening, defect of birth/congenital abnormality, required hospitalization or extension of hospital length of stay, significant medical intervention, resulted in significant disability/impairment. | Up to Week 48 | 
| Number of Participants With AEs According to Degree of Intensity | An AE is any unfavorable sign and non-intentional, symptom or disease temporarily related with the use of a medicinal product, considered or not related to the medicinal product. Pre-existing conditions that worsened during the study were reported as AEs. The Intensity of AEs was classified as Grade 1, Grade 2, Grade 3 and Grade 4. Grade 1: Discomfort was noticed, but the normal daily activity was not interrupted. Grade 2: Discomfort was enough to reduce the normal daily activity. Grade 3: There was disability for work or develop normal daily activities. Grade 4: It represented an immediate threat to life (these events were reported as SAEs). | Up to Week 48 | 
| Number of Participants With AEs Leading to Discontinuation and Any Drug Related AEs and SAEs | An AE is any unfavorable sign and non-intentional, symptom or disease temporarily related with the use of a medicinal product, considered or not related to the medicinal product. Pre-existing conditions that worsened during the study were reported as AEs. A SAE is any experience that suggested a significant risk, contraindication, caution, and at any dose, fulfills, at least, one of the following criteria: adverse event considered as fatal (resulting in death), life threatening, defect of birth/congenital abnormality, required hospitalization or extension of hospital length of stay, significant medical intervention, resulted in significant disability/impairment. Relationship between AEs and medication under investigation was evaluated through the classification Yes and No. A relationship classified as Yes implied a significant causal relationship with the medication under investigation which was evaluated based on enough evidences, facts or arguments. | Up to Week 48 | 
| Number of Participants With AEs of Special Interest During the Study | Adverse event of special interest during the study treatment and follow up period included infections. The participants with AEs of special interest were reported at Screening, End of treatment (EOT), and End of Follow-up (EOFU) visit. | Screening (Days -28 to 0), EOT (Week 24), and EOFU (Week 48) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Values of Hematology Parameters at Screening and EOT Visit (Hemoglobin and Mean Corpuscular Hemoglobin Concentration) | The values of hemoglobin (Hb) and mean corpuscular hemoglobin concentration (MCHC) for each participant were estimated at Screening and at EOT visit. | Screening (Days -28 to 0) and EOT (Week 24) | 
| Mean Values of Hematology Parameters at Screening and EOT Visit (Hematocrit, Neutrophils, Lymphocytes, Monocytes, Eosinophils, and Basophils) | The hematology parameters (hematocrit, neutrophils, lymphocytes, monocytes, eosinophils, and basophils) for each participant were estimated at Screening and at EOT. | Screening (Days -28 to 0) and EOT (Week 24) | 
| Mean Values of Hematology Parameter at Screening and EOT Visit (Mean Corpuscular Volume) | Mean corpuscular volume (MCV) is the average volume of red cells. The mean MCV concentration for each participant was estimated at Screening and EOT. | Screening (Days -28 to 0) and EOT (Week 24) | 
| Mean Values of Hematology Parameter at Screening and EOT Visit (Erythrocytes) | The mean erythrocyte concentration for each participant was estimated at Screening and at EOT. | Screening (Days -28 to 0) and EOT (Week 24) | 
| Mean Values of Hematology Parameters at Screening and EOT Visit (Leucocytes and Platelets) | The mean leucocytes and platelets concentration for each participant was estimated at Screening, at EOT visit. | Screening (Days -28 to 0) and EOT (Week 24) | 
| Mean Values of Biochemistry Parameters at Screening and Visit 8 (Albumin and Glucose) | The mean albumin and glucose concentration for each participant was estimated at Screening and at EOT visit. | Screening (Days -28 to 0) and EOT (Week 24) | 
| Mean Values of Cholesterol, Uric Acid, Urea, Creatinine, Calcium, Total Bilirubin and Serum Total Proteins at Screening and EOT Visit. | The mean concentration of cholesterol, uric acid, urea, creatinine, calcium, total bilirubin and serum total proteins (STP) for each participant was estimated at Screening and at EOT visit. | Screening (Days -28 to 0) and EOT (Week 24) | 
| Mean Values of Potassium, Chlorine, Sodium, and Phosphorus at Screening and EOT Visit | The mean concentration of potassium, chlorine, sodium and phosphorus for each participant was estimated at Screening and at EOT. | Screening (Days -28 to 0) and EOT (Week 24) | 
| Mean Values of Aspartate Transaminase, Alanine Transaminase, Alkaline Phosphatase, and Lactic Dehydrogenase at Screening and EOT Visit | The mean aspartate transaminase (AST) and alanine transaminase (ALT), Alkaline phosphatase (AP), and Lactic dehydrogenase (LDH) concentration for each participant was estimated at Screening and at EOT visit. | Screening (Days -28 to 0) and EOT (Week 24) | 
| Mean Duration of Morning Joint Stiffness | The efficacy of rituximab was assessed by evaluating mean duration of morning joint stiffness. | Screening ((Days -28 to 0), EOT (Week 24), and EOFU (Week 48) | 
| Mean Value of Painful Joints | The efficacy of rituximab was assessed by evaluating painful joints. | Screening (Days -28 to 0), EOT (Week 24), and EOFU (Week 48) | 
| Number of Participants With American College of Rheumatology (20, 50, and 70) Criteria | American College of Rheumatology (ACR) criteria improvement consisting of 20%, 50%, and 70% (ACR20, ACR50, and ACR70, respectively) reduction in tender joints and swollen joints, as well as for three of the additional five ACR core set variables: patient's assessment of pain using a Visual Analog Scale (VAS) with left end of the line 0=no pain to right end of the line 100=unbearable pain); patient's global assessment of disease activity and physician's global assessment of disease activity using a VAS (0=no disease activity to 100=maximum disease activity); health assessment questionnaire (20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip and activities, 0=without difficulty to 3=unable to do; and acute-phase reactant; C-reactive protein and globular sedimentation velocity. | Week 1, Week 12, and Week 24 | 
| Mean Value of Quality of Life (Health Assessment Questionnaire - Disease Index) | Health Assessment Questionnaire - Disease Index (HAQ-DI) indicates how the disease affected participant's activities of daily life. It consisted of 20 questions in 8 domains (dressing/grooming, arising, eating, walking, hygiene, reach, grip; common daily activities) rated on a 4-point scale, 0=without any difficulty to 3=unable to do. Sum of scores was divided by number of domains with a score for a total possible score of 0 (best/no difficulties to perform activities) to 3 (worst/ unable to perform activities at all). | Screening (Days -28 to 0), Week 1, Week 12, and Week 24 | 
| Mean Values of C Reactive Protein | C Reactive Protein (CRP) is a component of ACR. CRP is a marker of inflammation. | Screening ((Days -28 to 0), EOT (Week 24), and EOFU (Week 48) | 
| Mean Values of Globular Sedimentation Velocity | Globular sedimentation velocity is a component of ACR. | Screening ((Days -28 to 0), Week 1, Week 12, and Week 24 | 
| Mean Values of Pain and Activity Based on Visual Analogue Scale | Pain assessment was assessed by using a VAS (0=no pain to 100=unbearable pain). Disease activity was also evaluated by participants and investigators by using a VAS (0=no disease activity to 100=maximum disease activity). | Screening ((Days -28 to 0), Week 1, Week 12, and Week 24 | 
| Mean Value of Inflamed Joints | The efficacy of rituximab was assessed by evaluating inflamed joints. | Screening (Days -28 to 0), EOT (Week 24), and EOFU (Week 48) |