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

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

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.

Study Overview

• Status: Completed
• Conditions: Rheumatoid Arthritis
• Intervention / Treatment: Drug: rituximab [MabThera/Rituxan]; Drug: Methotrexate

• Study Type: Interventional
• Enrollment (Actual): 246
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina, C1280AEB
  • Buenos Aires, Argentina, C1426AAL
  • Buenos Aires, Argentina, 1425
  • Córdoba, Argentina, 5000
  • San Miguel de Tucuman, Argentina, 4000
  • Tucuman, Argentina, 4000
• Brazil
  • Belem, Brazil, 66063-240
  • Brasilia, Brazil, 70322000
  • Brasilia, Brazil, 70390-904
  • Campinas, Brazil, 13015-001
  • Campinas, Brazil, 13025-141
  • Curitiba, Brazil, 80730-000
  • Florianopolis, Brazil, 88040-970
  • Fortaleza, Brazil, 60155-290
  • Fortaleza, Brazil, 60430-370
  • Goiania, Brazil, 74110010
  • Nova Lima, Brazil, 34000-000
  • Porto Alegre, Brazil, 90610-000
  • Recife, Brazil, 50000-000
  • Ribeirão Preto, Brazil, 14048-900
  • Rio de Janeiro, Brazil, 21941-590
  • Rio de Janeiro, Brazil, 20551-030
  • Rio de Janeiro, Brazil, 22050-000
  • Rio de Janeiro, Brazil, 22640102
  • Salvador, Brazil, 40050-410
  • Sao Paulo, Brazil, 05403-000
  • Sao Paulo, Brazil, 04038-002
  • Sao Paulo, Brazil, 04026-000
  • Sao Paulo, Brazil, 03128-050
  • Sao Paulo, Brazil, 04038-040
  • Sao Paulo, Brazil, 04039-004
  • Vitoria, Brazil, 29043-910
• Chile
  • Santiago, Chile
• Colombia
  • Barranquilla, Colombia
  • Bogota, Colombia
• Ecuador
  • Cuenca, Ecuador, 1394
  • Guayaquil, Ecuador
  • Quito, Ecuador, 1394
• El Salvador
  • San Salvador, El Salvador
• Mexico
  • Mexico City, Mexico, 14080
  • Mexico City, Mexico, 02990
  • Mexico City, Mexico, 06920
  • San Luis Potosi, Mexico, 78240
• Peru
  • Jesus Maria, Peru
  • Lima, Peru, 13
  • San Isidro, Peru, Lima 27
• Uruguay
  • Montevideo, Uruguay, 11600
• Venezuela
  • Barquisimeto, Venezuela, 3005
  • Caracas, Venezuela, 1010
  • Caracas, Venezuela, 1040

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Rituximab; 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: rituximab [MabThera/Rituxan]; 1g iv on days 1 and 15; Drug: Methotrexate; >=15 mg po/week

What is the study measuring?

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)

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche

Study record dates

Study Major Dates

• Study Start: February 1, 2006
• Primary Completion (Actual): December 1, 2008
• Study Completion (Actual): December 1, 2008

Study Registration Dates

• First Submitted: July 17, 2007
• First Submitted That Met QC Criteria: July 17, 2007
• First Posted (Estimate): July 18, 2007

Study Record Updates

• Last Update Posted (Estimate): October 14, 2016
• Last Update Submitted That Met QC Criteria: August 22, 2016
• Last Verified: August 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Arthritis; Arthritis, Rheumatoid; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Dermatologic Agents; Reproductive Control Agents; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Folic Acid Antagonists; Rituximab; Methotrexate
• Other Study ID Numbers: ML19385