A Study to Evaluate the Safety and Efficacy of Rituximab in Combination With Methotrexate Compared to Methotrexate Alone in Patients With Active Rheumatoid Arthritis

Rheumatoid Arthritis Clinical Trial

— SERENE  

Official title:

A Randomized, Placebo Controlled, Double-blind, Parallel Group, International Study to Evaluate the Safety and Efficacy of Rituximab in Combination With Methotrexate, Compared to Methotrexate Monotherapy, in Patients With Active Rheumatoid Arthritis

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00299130
• Other study ID #: U2973g
• Secondary ID: WA17045
• Status: Completed
• Phase: Phase 3
• First received: March 3, 2006
• Last updated: January 11, 2016
• Start date: October 2005
• Est. completion date: July 2013

Study information

• Verified date: January 2016
• Source: Genentech, Inc.
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

This study evaluated the efficacy and safety of rituximab in patients with active rheumatoid arthritis (RA).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 511
• Est. completion date: July 2013
• Est. primary completion date: June 2008
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 80 Years

Eligibility

Inclusion criteria:

• Adult patients 18-80 years of age.

• Rheumatoid arthritis (RA) for = 6 months, diagnosed according to the revised 1987 American College of Rheumatology (ACR) criteria for the classification of rheumatoid arthritis.

• Receiving outpatient treatment for RA.

• Swollen joint count (SJC) = 8 (66 joint count), and tender joint count (TJC) = 8 (68 joint count) at screening and baseline.

• At screening, either

• C-reactive protein (CRP) = 0.6 mg/dL (6 mg/L), or

• Erythrocyte sedimentation rate (ESR) = 28 mm/hour.

• Inadequate response to methotrexate, having received and tolerated at a dose of 10-25 mg/week it for = 12 weeks.

Exclusion criteria:

• Rheumatic autoimmune disease other than RA, or significant systemic involvement secondary to RA.

• Inflammatory joint disease other than RA, or other systemic autoimmune disorder.

• Diagnosis of juvenile rheumatoid arthritis, or RA before the age of 16.

• Surgery within 12 weeks of study or planned within 24 weeks of randomization.

• Previous treatment with any approved or investigational biological agent for RA, an anti-alpha4-integrin antibody or co-stimulation modulator, or cell-depleting therapy.

Study Design

Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Arthritis
• Arthritis, Rheumatoid
• Rheumatoid Arthritis

Intervention

Drug:
• Folate
A stable dose, = 5 mg/week given as either a single dose or as a divided weekly dose, orally.
• Methotrexate
A stable dose of between 10-25 mg/week, oral or parenteral, as prescribed by the treating physician.
• Methylprednisolone
Intravenous infusion
• Placebo
Placebo to rituximab intravenous infusion
• Rituximab
Intravenous infusion

Locations

Country	Name	City	State
n/a

Sponsors (2)

Lead Sponsor	Collaborator
Genentech, Inc.	Hoffmann-La Roche

References & Publications (1)

Emery P, Deodhar A, Rigby WF, Isaacs JD, Combe B, Racewicz AJ, Latinis K, Abud-Mendoza C, Szczepanski LJ, Roschmann RA, Chen A, Armstrong GK, Douglass W, Tyrrell H. Efficacy and safety of different doses and retreatment of rituximab: a randomised, placebo — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of Participants With American College of Rheumatology (ACR) 20 Response at Week 24	To achieve an ACR20 required at least a 20% improvement compared with Baseline in both tender joint counts (68 joints assessed for tenderness) and swollen joint counts (66 joints assessed for swelling), as well as a 20% improvement in three of the following five additional measurements: Physician's global assessment of disease activity (assessed using a 100 mm Visual Analog Scale [VAS]); Patient's global assessment of disease activity (assessed using a 100 mm VAS); Patient's assessment of pain (assessed using a 100 mm VAS); Health Assessment Questionnaire (HAQ; a patient completed questionnaire consisting of 20 questions, scored from 0-3); Acute phase reactant: C-reactive protein (CRP) or, if CRP was missing, erythrocyte sedimentation rate (ESR).; Participants who withdrew prematurely from the study prior to Week 24, who received rescue therapy or had insufficient data in order to calculate a clinical response were considered to be non-responders.	Baseline and Week 24	No
Secondary	Percentage of Participants With an ACR50 Response at Week 24	To achieve an ACR50 required at least a 50% improvement compared with Baseline in both tender joint counts (68 joints assessed for tenderness) and swollen joint counts (66 joints assessed for swelling), as well as a 50% improvement in three of the following five additional measurements: Physician's global assessment of disease activity (assessed using a 100 mm Visual Analog Scale [VAS]); Patient's global assessment of disease activity (assessed using a 100 mm VAS); Patient's assessment of pain (assessed using a 100 mm VAS); Health Assessment Questionnaire (HAQ; a patient completed questionnaire consisting of 20 questions, scored from 0-3); Acute phase reactant: C-reactive protein (CRP) or, if CRP was missing, erythrocyte sedimentation rate (ESR).; Participants who withdrew prematurely from the study prior to Week 24, who received rescue therapy or had insufficient data in order to calculate a clinical response were considered to be non-responders.	Baseline and Week 24	No
Secondary	Percentage of Participants With an ACR70 Response at Week 24	To achieve an ACR70 required at least a 70% improvement compared with Baseline in both tender joint counts (68 joints assessed for tenderness) and swollen joint counts (66 joints assessed for swelling), as well as a 70% improvement in three of the following five additional measurements: Physician's global assessment of disease activity (assessed using a 100 mm Visual Analog Scale [VAS]); Patient's global assessment of disease activity (assessed using a 100 mm VAS); Patient's assessment of pain (assessed using a 100 mm VAS); Health Assessment Questionnaire (HAQ; a patient completed questionnaire consisting of 20 questions, scored from 0-3); Acute phase reactant: C-reactive protein (CRP) or, if CRP was missing, erythrocyte sedimentation rate (ESR).; Participants who withdrew prematurely from the study prior to Week 24, who received rescue therapy or had insufficient data in order to calculate a clinical response were considered to be non-responders.	Baseline and Week 24	No
Secondary	Change From Baseline in Disease Activity Score (DAS28-ESR) at Week 24	The DAS28 is a composite score to measure disease activity in patients with rheumatoid arthritis, derived from the following variables: The number of swollen and tender joints assessed using the 28-joint count; Erythrocyte sedimentation rate (ESR); Patient's global assessment of disease activity measured on a 100 mm visual analog scale.; The DAS28 score ranges from zero to ten. A DAS28 score above 5.1 means high disease activity whereas a DAS28 less than or equal to 3.2 indicates low disease activity. Remission is achieved by a DAS28 lower than 2.6.	Baseline and Week 24	No
Secondary	Percentage of Participants With European League Against Rheumatism (EULAR) Response at Week 24	A EULAR response reflects an improvement in disease activity and an attainment of a lower degree of disease activity based on the DAS28 score. The DAS28 score ranges from 0-10, with higher scores indicating more disease activity.; A Good Response is defined as an improvement (decrease) in the DAS28 of more than 1.2 compared with Baseline and attainment of a DAS28 score of less than or equal to 3.2.; A Moderate Response is defined as either: an improvement (decrease) in the DAS28 of greater than 0.6 and less than or equal to 1.2 from Baseline and attainment of a DAS28 score of less than or equal to 5.1 or,; an improvement (decrease) in the DAS28 of more than 1.2 from Baseline and attainment of a DAS28 score of greater than 3.2.; No Response is defined as either an improvement (decrease) in the DAS28 of less than or equal to 0.6, or an improvement (decrease) in the DAS28 of greater than 0.6 and less than or equal to 1.2 and attainment of a DAS28 of more than 5.1.	Baseline and Week 24	No
Secondary	Percent Change From Baseline in Swollen Joint Count	Sixty-six joints were assessed and classified as swollen/not swollen by pressure and joint manipulation on physical examination.; The percentage change from baseline at each post-baseline visit was calculated as: [(post-baseline value minus baseline value) divided by Baseline value]*100.; A negative percentage change from baseline score indicates an improvement.	Baseline, Week 24 and Week 48	No
Secondary	Percent Change From Baseline in Tender Joint Count	Sixty-eight joints were assessed and classified as tender/not tender by pressure and joint manipulation on physical examination.; The percentage change from baseline at each post-baseline visit was calculated as: [(post-baseline value minus baseline value) divided by Baseline value]*100.; A negative percentage change from baseline score indicates an improvement.	Baseline, Week 24 and Week 48	No
Secondary	Percent Change From Baseline in Patient's Global Assessment of Disease Activity	The participant's overall assessment of their current disease activity measured on a 100 mm horizontal visual analog scale (VAS). The left-hand extreme of the line (0 mm) was described as "no disease activity" (symptom-free and no arthritis symptoms) and the right-hand extreme (100 mm) as "maximum disease activity" (maximum arthritis disease activity).; The percentage change from baseline at each post-baseline visit was calculated as: [(post-baseline value minus baseline value) divided by Baseline value]*100.; A negative percentage change from baseline score indicates an improvement.	Baseline, Week 24 and Week 48	No
Secondary	Percent Change From Baseline in Patient's Pain Assessment	The participant's assessment of their current level of pain on a 100 mm horizontal visual analog scale (VAS), where the left-hand extreme of the line (0 mm) was described as "no pain" and the right-hand extreme (100 mm) as "unbearable pain".; The percentage change from baseline at each post-baseline visit was calculated as: [(post-baseline value minus baseline value) divided by Baseline value]*100.; A negative percentage change from baseline score indicates an improvement.	Baseline, Week 24 and Week 48	No
Secondary	Percent Change From Baseline in Physician's Global Assessment of Disease Activity	The physician's assessment of the participant's current disease activity on a 100 mm horizontal VAS, where the left-hand extreme of the line (0 mm) was described as "no disease activity" (symptom-free and no arthritis symptoms) and the right-hand extreme (100 mm) as "maximum disease activity".; The percentage change from baseline at each post-baseline visit was calculated as: [(post-baseline value minus baseline value) divided by Baseline value]*100.; A negative percentage change from baseline score indicates an improvement.	Baseline, Week 24 and Week 48	No
Secondary	Percent Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) Score	The Stanford Health Assessment Questionnaire disability index is a patient-reported questionnaire specific for rheumatoid arthritis. It consists of 20 questions referring to eight domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and daily activities. Participants choose from four response categories, ranging from 'without any difficulty' (Score=0) to 'unable to do' (Score=3). The overall score is the average of each of the 8 category scores and ranges from 0 to 3, where zero represents no disability and three very severe, high-dependency disability.; The percentage change from baseline at each post-baseline visit was calculated as: [(post-baseline value minus baseline value) divided by Baseline value]*100.; A negative percentage change from baseline score indicates an improvement.	Baseline, Week 24 and Week 48	No
Secondary	Percent Change From Baseline in C-Reactive Protein	C-Reactive Protein (CRP) was measured from blood samples by a central laboratory as a marker for inflammation.; The percentage change from baseline at each post-baseline visit was calculated as: [(post-baseline value minus baseline value) divided by Baseline value]*100.; A negative percentage change from baseline score indicates an improvement.	Baseline, Week 24 and Week 48	No
Secondary	Percent Change From Baseline in Erythrocyte Sedimentation Rate	Erythrocyte sedimentation rate (ESR) indirectly measures how much inflammation is in the body. A higher ESR is indicative of increased inflammation.; The percentage change from baseline at each post-baseline visit was calculated as: [(post-baseline value minus baseline value) divided by Baseline value]*100.; A negative percentage change from baseline score indicates an improvement.	Baseline, Week 24 and Week 48	No
Secondary	Percent Change From Baseline in Short Form 36 Health Survey (SF-36) Summary Scores (Physical and Mental Components)	The SF-36 measures the impact of disease on overall quality of life and consists of 36 questions split into two major components: physical health and mental health. Under physical health are the following four domains: physical health, bodily pain, physical functioning and physical role limitations. Under the mental health domain there are four domains; mental health, vitality, social functioning, and emotional role limitation. The individual domain scores are aggregated to derive a physical-component summary score and a mental-component summary score which range from 0 to 100, with higher scores indicating a better level of functioning.; The percentage change from baseline at each post-baseline visit was calculated as: [(post-baseline value minus baseline value) divided by Baseline value]*100.; A positive percentage change from baseline score indicates an improvement.	Baseline, Week 24 and Week 48	No
Secondary	Change From Baseline in Short Form 36 Health Survey (SF-36) General Health Domain Score	The SF-36 measures the impact of disease on overall quality of life and consists of 36 questions in eight domains (physical function, pain, general and mental health, vitality, social function, physical and emotional health). The individual domain scores are calculated and transformed to range from 0 to 100, with higher scores indicating a better level of functioning.; A positive change from baseline score indicates an improvement.	Baseline, Week 24 and Week 48	No
Secondary	Change From Baseline in Short Form 36 Health Survey (SF-36) Bodily Pain Domain Score	The SF-36 measures the impact of disease on overall quality of life and consists of 36 questions in eight domains (physical function, pain, general and mental health, vitality, social function, physical and emotional health). The individual domain scores are calculated and transformed to range from 0 to 100, with higher scores indicating a better level of functioning.; A positive change from baseline score indicates an improvement.	Baseline, Week 24 and Week 48	No
Secondary	Change From Baseline in Short Form 36 Health Survey (SF-36) Physical Functioning Domain Score	The SF-36 measures the impact of disease on overall quality of life and consists of 36 questions in eight domains (physical function, pain, general and mental health, vitality, social function, physical and emotional health). The individual domain scores are calculated and transformed to range from 0 to 100, with higher scores indicating a better level of functioning.; A positive change from baseline score indicates an improvement.	Baseline, Week 24 and Week 48	No
Secondary	Change From Baseline in Short Form 36 Health Survey (SF-36) Physical Role Limitations Domain Score	The SF-36 measures the impact of disease on overall quality of life and consists of 36 questions in eight domains (physical function, pain, general and mental health, vitality, social function, physical and emotional health). The individual domain scores are calculated and transformed to range from 0 to 100, with higher scores indicating a better level of functioning.; A positive change from baseline score indicates an improvement.	Baseline, Week 24 and Week 48	No
Secondary	Change From Baseline in Short Form 36 Health Survey (SF-36) Mental Health Domain Score	The SF-36 measures the impact of disease on overall quality of life and consists of 36 questions in eight domains (physical function, pain, general and mental health, vitality, social function, physical and emotional health). The individual domain scores are calculated and transformed to range from 0 to 100, with higher scores indicating a better level of functioning.; A positive change from baseline score indicates an improvement.	Baseline, Week 24 and Week 48	No
Secondary	Change From Baseline in Short Form 36 Health Survey (SF-36) Vitality Domain Score	The SF-36 measures the impact of disease on overall quality of life and consists of 36 questions in eight domains (physical function, pain, general and mental health, vitality, social function, physical and emotional health). The individual domain scores are calculated and transformed to range from 0 to 100, with higher scores indicating a better level of functioning.; A positive change from baseline score indicates an improvement.	Baseline, Week 24 and Week 48	No
Secondary	Change From Baseline in Short Form 36 Health Survey (SF-36) Social Functioning Domain Score	The SF-36 measures the impact of disease on overall quality of life and consists of 36 questions in eight domains (physical function, pain, general and mental health, vitality, social function, physical and emotional health). The individual domain scores are calculated and transformed to range from 0 to 100, with higher scores indicating a better level of functioning.; A positive change from baseline score indicates an improvement.	Baseline, Week 24 and Week 48	No
Secondary	Change From Baseline in Short Form 36 Health Survey (SF-36) Emotional Role Limitations Domain Score	The SF-36 measures the impact of disease on overall quality of life and consists of 36 questions in eight domains (physical function, pain, general and mental health, vitality, social function, physical and emotional health). The individual domain scores are calculated and transformed to range from 0 to 100, with higher scores indicating a better level of functioning.; A positive change from baseline score indicates an improvement.	Baseline, Week 24 and Week 48	No
Secondary	Change From Baseline in Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) Scores	The FACIT-Fatigue questionnaire is a self-administered patient questionnaire that consists of 13 questions designed to measure the degree of fatigue experienced by participants in the previous 7 days. Participants respond to the questions using a value in the range of 0 (not at all) to 4 (very much). The scale score is computed by summing the item scores, after reversing those items that are worded in the negative direction. The FACIT-Fatigue subscale score ranges from 0 to 52, where higher scores represent less fatigue.; A positive change from baseline score indicates an improvement.	Baseline, Week 24 and Week 48	No
Secondary	Percentage of Participants With DAS28-ESR Low Disease Activity Score and Clinical Remission at Week 24	The DAS28 is a composite score to measure disease activity in patients with rheumatoid arthritis, derived from the following variables: The number of swollen and tender joints assessed using the 28-joint count; Erythrocyte sedimentation rate (ESR); Patient's global assessment of disease activity measured on a 100 mm visual analog scale.; The DAS28 score ranges from zero to ten. DAS28 above 5.1 indicates high disease activity.; Low disease activity is defined by a DAS28 score less than or equal to 3.2. Remission is defined by a DAS28 score less than 2.6.	Week 24	No
Secondary	Percentage of Participants With HAQ-DI Improved, Unchanged or Worsened at Week 24	The Stanford Health Assessment Questionnaire disability index is a patient-reported questionnaire specific for rheumatoid arthritis. It consists of 20 questions referring to eight domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and daily activities. Participants choose from four response categories, ranging from 'without any difficulty' (Score=0) to 'unable to do' (Score=3). The overall score is the average of each of the 8 category scores and ranges from 0 to 3, where zero represents no disability and three very severe, high-dependency disability. A negative change from baseline score indicates an improvement.; Improved HAQ-DI is defined as a change from Baseline score less than or equal to -0.22.; An Unchanged HAQ-DI is defined as a change from Baseline score greater than -0.22 and less than 0.22.; A worsened HAQ-DI score is defined as a change from Baseline score of greater than or equal to 0.22.	Baseline and Week 24	No
Secondary	Percentage of Participants With HAQ-DI Improved, Unchanged or Worsened at Week 48	The Stanford Health Assessment Questionnaire disability index is a patient-reported questionnaire specific for rheumatoid arthritis. It consists of 20 questions referring to eight domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and daily activities. Participants choose from four response categories, ranging from 'without any difficulty' (Score=0) to 'unable to do' (Score=3). The overall score is the average of each of the 8 category scores and ranges from 0 to 3, where zero represents no disability and three very severe, high-dependency disability. A negative change from baseline score indicates an improvement.; Improved HAQ-DI is defined as a change from Baseline score less than or equal to -0.22.; An Unchanged HAQ-DI is defined as a change from Baseline score greater than -0.22 and less than 0.22.; A worsened HAQ-DI score is defined as a change from Baseline score of greater than or equal to 0.22.	Baseline and Week 48	No
Secondary	Percentage of Participants With European League Against Rheumatism (EULAR) Response at Week 48	A EULAR response reflects an improvement in disease activity and an attainment of a lower degree of disease activity based on the DAS-28 score.; A Good Response is defined as an improvement (decrease) in the DAS28 of more than 1.2 compared with Baseline and attainment of a DAS28 score less than or equal to 3.2.; A Moderate Response is defined as either: an improvement (decrease) in the DAS28 of greater than 0.6 and less than or equal to 1.2 and attainment of a DAS28 score of less than or equal to 5.1 or,; an improvement (decrease) in the DAS28 of more than 1.2 and attainment of a DAS28 score of greater than 3.2.; No Response is defined as either an improvement (decrease) in the DAS28 of less than or equal to 0.6, or an improvement (decrease) in the DAS28 of greater than 0.6 and less than or equal to 1.2 and attainment of a DAS28 score of 5.1 or higher.	Baseline and Week 48	No
Secondary	Percentage of Participants With DAS28-ESR Low Disease Activity Score and Clinical Remission at Week 48	The DAS28 is a composite score to measure disease activity in patients with rheumatoid arthritis, derived from the following variables: The number of swollen and tender joints assessed using the 28-joint count; Erythrocyte sedimentation rate (ESR); Patient's global assessment of disease activity measured on a 100 mm visual analog scale.; The DAS28 score ranges from zero to ten. DAS28 above 5.1 indicates high disease activity.; Low disease activity is defined by a DAS28 score less than or equal to 3.2. Remission is defined by a DAS28 score less than 2.6.	Week 48	No
Secondary	Percentage of Participants With an ACR50 Response at Week 48	To achieve an ACR50 required at least a 50% improvement compared with Baseline in both tender joint counts (68 joints assessed for tenderness) and swollen joint counts (66 joints assessed for swelling), as well as a 50% improvement in three of the following five additional measurements: Physician's global assessment of disease activity (assessed using a 100 mm Visual Analog Scale [VAS]); Patient's global assessment of disease activity (assessed using a 100 mm VAS); Patient's assessment of pain (assessed using a 100 mm VAS); Health Assessment Questionnaire (HAQ; a patient completed questionnaire consisting of 20 questions, scored from 0-3); Acute phase reactant: C-reactive protein (CRP) or, if CRP was missing, erythrocyte sedimentation rate (ESR).; Participants who withdrew prematurely from the study prior to week 48, who received rescue therapy or had insufficient data in order to calculate a clinical response were considered to be non-responders.	Baseline and Week 48	No
Secondary	Percentage of Participants With an ACR70 Response at Week 48	To achieve an ACR70 required at least a 70% improvement compared with baseline in both tender joint counts (68 joints assessed for tenderness) and swollen joint counts (66 joints assessed for swelling), as well as a 70% improvement in three of the following five additional measurements: Physician's global assessment of disease activity (assessed using a 100 mm Visual Analog Scale [VAS]); Patient's global assessment of disease activity (assessed using a 100 mm VAS); Patient's assessment of pain (assessed using a 100 mm VAS); Health Assessment Questionnaire (HAQ; a patient completed questionnaire consisting of 20 questions, scored from 0-3); Acute phase reactant: C-reactive protein (CRP) or, if CRP was missing, erythrocyte sedimentation rate (ESR).; Participants who withdrew prematurely from the study prior to Week 48, who received rescue therapy or had insufficient data in order to calculate a clinical response were considered to be non-responders.	Baseline and Week 48	No