Investigating Clinical Efficacy of Ofatumumab in Adult Rheumatoid Arthritis (RA) Patients Who Had an Inadequate Response to MTX Therapy

This study has been terminated.
(Ofatumumab IV trials in RA were prematurely terminated because GSK refocused clinical development of autoimmune indications on the subcutaneous delivery.)
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline
ClinicalTrials.gov Identifier:
NCT00611455
First received: January 16, 2008
Last updated: May 8, 2014
Last verified: December 2013
  Purpose

This is a phase III, double-blind, randomized, multicenter, and parallel group trial with a duration of 24 weeks, followed by a 120 week Open-label Period. the primary purpose of the study is to demonstrate the efficacy of ofatumumab in reducing clinical signs and symptoms in adult RA patients after a single course of ofatumumab.


Condition Intervention Phase
Arthritis, Rheumatoid
Drug: ofatumumab
Drug: Placebo
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: A Double-blind, Randomized, Placebo Controlled, Parallel Group, Multi-center, Phase III Trial of Ofatumumab Investigating Clinical Efficacy in Adult Patients With Active Rheumatoid Arthritis Who Have Had an Inadequate Response to Methotrexate Therapy

Resource links provided by NLM:


Further study details as provided by GlaxoSmithKline:

Primary Outcome Measures:
  • Number of Participants With a 20% Improvement From Baseline in Their American College of Rheumatology (ACR) Score (ACR20) at Week 24 [ Time Frame: Baseline and Week 24 ] [ Designated as safety issue: No ]
    The ACR score was based on improvement from baseline in tender (TJC) and swollen joint counts (SJC). A participant had achieved ACR20 if he experienced >=20% improvement from baseline in TJC and SJC and a >=20% improvement from baseline in 3 out of 5 of the following assessments: participant pain assessment on a 100 millimeter (mm) visual analog scale (VAS), participant global assessment on a 100 mm VAS scale, physician global assessment on a 100 mm VAS scale, participant self-assessed disability, and C-reactive protein.


Secondary Outcome Measures:
  • Number of Participants With a 20% Improvement From Baseline in Their American College of Rheumatology (ACR) Score (ACR20) at Weeks 4, 8, 12, 16, and 20 [ Time Frame: Baseline and Weeks 4, 8, 12, 16, and 20 ] [ Designated as safety issue: No ]
    The ACR score was based on improvement from baseline in tender (TJC) and swollen joint counts (SJC). A participant had achieved ACR20 if he experienced >=20% improvement from baseline in TJC and SJC and a >=20% improvement from baseline in 3 out of 5 of the following assessments: participant pain assessment on a 100 millimeter (mm) visual analog scale (VAS), participant global assessment on a 100 mm VAS scale, physician global assessment on a 100 mm VAS scale, participant self-assessed disability, and C-reactive protein.

  • Number of Participants With a 50% Improvement From Baseline in Their ACR Score (ACR50) at Weeks 4, 8, 12, 16, 20, and 24 [ Time Frame: Baseline and Weeks 4, 8, 12, 16, 20, and 24 ] [ Designated as safety issue: No ]
    The ACR score was based on improvement from baseline in tender (TJC) and swollen joint counts (SJC). A participant had achieved ACR50 if he experienced >=50% improvement from baseline in TJC and SJC and a >=50% improvement from baseline in 3 out of 5 of the following assessments: participant pain assessment on a 100 millimeter (mm) visual analog scale (VAS), participant global assessment on a 100 mm VAS scale, physician global assessment on a 100 mm VAS scale, participant self-assessed disability, and C-reactive protein.

  • Number of Participants With a 70% Improvement From Baseline in Their ACR Score (ACR70) at Weeks 4, 8, 12, 16, 20, and 24 [ Time Frame: Baseline and Weeks 4, 8, 12, 16, 20, and 24 ] [ Designated as safety issue: No ]
    The ACR score was based on improvement from baseline in tender (TJC) and swollen joint counts (SJC). A participant had achieved ACR70 if he experienced >=70% improvement from baseline in TJC and SJC and a >=70% improvement from baseline in 3 out of 5 of the following assessments: participant pain assessment on a 100 millimeter (mm) visual analog scale (VAS), participant global assessment on a 100 mm VAS scale, physician global assessment on a 100 mm VAS scale, participant self-assessed disability, and C-reactive protein.

  • Median ACRn at Weeks 4, 8, 12, 16, 20, and 24 [ Time Frame: Weeks 4, 8, 12, 16, 20, and 24 ] [ Designated as safety issue: No ]
    ACRn = the largest integer n for which a participant (par.) met the criteria requiring an improvement of n%. ACRn is a measure characterizing percent (%) improvement from baseline (IFBL). A par. with an ACRn of X had an improvement of >=X% in tender/swollen joints (TJC/SJC), and an improvement of >=X% in 3 of the 5 parameters (patient [pt] pain assessment, pt global assessment [GA], physician GA, pt self-assessed disability, acute phase reactant). ACRn = minimum(TJC % IFBL, SJC % IFBL, composite measure % IFBL). Composite measure % IFBL is the 3rd highest value of % IFBL for the 5 parameters.

  • Mean Disease Activity Score Based on 28 Joints (DAS28) at Weeks 4, 8, 12, 16, 20, and 24 Using C-reactive Protein (CRP) as the Acute Phase Reactant (APR) [ Time Frame: Weeks 4, 8, 12, 16, 20, and 24 ] [ Designated as safety issue: No ]
    The DAS28 is a clinical index of rheumatoid arthritis disease activity (DA) that combines information from swollen and tender joints (jts.), the APR, and general health (patient global assessment). The following jts. were assessed on both sides of the body: shoulder, elbow, wrist, metacarpophalangeal (5 per side), proximal interphalangeal (5 per side), and knee. The level of DA can be interpreted as low (DAS28<=3.2), moderate (3.2<DAS28<=5.1), or high (DAS28>5.1); total score, 0-9.4. A DAS28 <2.6 corresponds to remission. APRs are a class of proteins that are useful markers for inflammation.

  • Change From Baseline in DAS28 at Weeks 4, 8, 12, 16, 20, and 24 Using CRP as the Acute Phase Reactant [ Time Frame: Baseline and Weeks 4, 8, 12, 16, 20, and 24 ] [ Designated as safety issue: No ]
    The DAS28 is a clinical index of RA disease activity that combines information from swollen joints, tender joints, the acute phase reactant, and general health (patient global assessment). Change from baseline in DAS28 is calculated as the Week 4, 8, 12, 16, 20, and 24 values minus the baseline value.

  • Mean DAS28 at Weeks 4, 8, 12, 16, 20, and 24 Using Erythrocyte Sedimentation Rate (ESR) as the Acute Phase Reactant [ Time Frame: Weeks 4, 8, 12, 16, 20, and 24 ] [ Designated as safety issue: No ]
    The DAS28 is a clinical index of rheumatoid arthritis disease activity (DA) that combines information from swollen and tender joints (jts.), the APR, and general health (patient global assessment). The following jts. were assessed on both sides of the body: shoulder, elbow, wrist, metacarpophalangeal (5 per side), proximal interphalangeal (5 per side), and knee. The level of DA can be interpreted as low (DAS28<=3.2), moderate (3.2<DAS28<=5.1), or high (DAS28>5.1); total score, 0-9.4. A DAS28 <2.6 corresponds to remission. APRs are a class of proteins that are useful markers for inflammation.

  • Change From Baseline in DAS28 at Weeks 4, 8, 12, 16, 20, and 24 Using ESR as the Acute Phase Reactant [ Time Frame: Baseline and Weeks 4, 8, 12, 16, 20, and 24 ] [ Designated as safety issue: No ]
    The DAS28 is a clinical index of RA disease activity that combines information from swollen joints, tender joints, the acute phase reactant, and general health (patient global assessment). Change from baseline in DAS28 is calculated as the Week 4, 8, 12, 16, 20, and 24 values minus the baseline value.

  • Number of Participants With the Indicated European League Against Rheumatism (EULAR) Response at Weeks 4, 8, 12, 16, 20, and 24 Using CRP as the Acute Phase Reactant [ Time Frame: Weeks 4, 8, 12, 16, 20, and 24 ] [ Designated as safety issue: No ]
    The DAS28-based EULAR response criteria were used to measure individual response as none, good, and moderate, depending on the extent of change from baseline and the level of disease activity reached. Good responders: change from baseline >1.2 with DAS28 <=3.2; moderate responders: change from baseline >1.2 with DAS28 <=3.2 to >5.1 or change from baseline >0.6 to <=1.2 with DAS28 <=3.2 to <=5.1); non-responders: change from baseline <=0.6 or change from baseline >0.6 and <=1.2 with DAS28 >5.1.

  • Number of Participants With the Indicated European League Against Rheumatism (EULAR) Response at Weeks 4, 8, 12, 16, 20, and 24 Using ESR as the Acute Phase Reactant [ Time Frame: Weeks 4, 8, 12, 16, 20, and 24 ] [ Designated as safety issue: No ]
    The DAS28-based EULAR response criteria were used to measure individual response as none, good, and moderate, depending on the extent of change from baseline and the level of disease activity reached. Good responders: change from baseline >1.2 with DAS28 <=3.2; moderate responders: change from baseline >1.2 with DAS28 <=3.2 to >5.1 or change from baseline >0.6 to <=1.2 with DAS28 <=3.2 to <=5.1); non-responders: change from baseline <=0.6 or change from baseline >0.6 and <=1.2 with DAS28 >5.1.

  • Number of Participants Classified as Responders at Week 24 According to the Self-Assessed Health Assessment Questionnaire Disability Index (HAQ-DI) [ Time Frame: Week 24 ] [ Designated as safety issue: No ]
    The HAQ-DI is a 20-question instrument used to assess the degree of difficulty a participant had in accomplishing tasks in 8 functional areas (FAs): dressing, arising, eating, walking, hygiene, reaching, gripping, and errands/chores. Responses for each FA were scored from 0 (no difficulty) to 3 (inability to perform a task). The total score (range of 0-3) was calculated by adding the 8 individual FA scores, then dividing this sum by the total number of components answered. Responders were defined as participants achieving an improvement from baseline in the HAQ-DI score at Week 24 of >=0.22.

  • Number of Participants With Clinical Remission at Week 24 [ Time Frame: Week 24 ] [ Designated as safety issue: No ]
    Participants achieving clinical remission were defined as those with a low disease activity, i.e., DAS28 score (using CRP) <2.6 at Week 24.

  • Change From Baseline in Tender Joint Count at Week 24 [ Time Frame: Baseline and Week 24 ] [ Designated as safety issue: No ]
    Change from baseline in tender joint count was calculated as the Week 24 count minus the baseline count. A total of 68 joints were assessed. Joints were classified as either tender or not tender by an independent assessor, who had documented experience in performing joint assessments.

  • Change From Baseline in Swollen Joint Count at Week 24 [ Time Frame: Baseline and Week 24 ] [ Designated as safety issue: No ]
    Change from baseline in swollen joint count was calculated as the Week 24 count minus the baseline count. A total of 66 joints were assessed. Joints were classified as either swollen or not swollen by an independent assessor, who had documented experience in performing joint assessments.

  • Change From Baseline in the Participant-assessed Pain Score at Week 24 [ Time Frame: Baseline and Week 24 ] [ Designated as safety issue: No ]
    A horizontal VAS of 100 mm was used to report the participant's level of joint pain. The scale ranged from 0 (no pain) to 100 (unbearable pain). Participants were instructed to draw a vertical line through the horizontal line to indicate how much joint pain they had. The distance from the "no pain" end to the vertical line drawn by the participant was the joint pain score. Change from baseline was calculated as the Week 24 value minus the baseline value.

  • Change From Baseline in Participant-assessed Global Disease Score at Week 24 [ Time Frame: Baseline and Week 24 ] [ Designated as safety issue: No ]
    The participant used a horizontal VAS of 100 mm for overall assessment of disease. The scale ranged from 0 (very well) to 100 (very poor). Participants were instructed to draw a vertical line through the horizontal line to indicate the state of the arthritis. The distance from the "very well" end to the vertical line drawn by the participant was the global disease assessment score. Change from baseline in participant-assessed global disease was calculated as the Week 24 value minus the baseline value.

  • Change From Baseline in the Physician-assessed Global Disease Score at Week 24 [ Time Frame: Baseline and Week 24 ] [ Designated as safety issue: No ]
    The physician used a horizontal VAS of 100 mm for overall assessment of disease. The scale ranged from 0 (very well) to 100 (very poor). Physicians were instructed to draw a vertical line through the horizontal line to indicate the state of the arthritis. The distance from the "very well" end to the vertical line drawn by the participant was the global disease assessment score. Change from baseline in the physician-assessed global disease was calculated as the Week 24 value minus the baseline value.

  • Change From Baseline in HAQ-DI Score at Week 24 [ Time Frame: Baseline and Week 24 ] [ Designated as safety issue: No ]
    The self-assessed HAQ-DI is a 20-question instrument used to assess the degree of difficulty a participant had in accomplishing tasks in 8 functional areas (FAs): dressing, arising, eating, walking, hygiene, reaching, gripping, and errands/chores. Responses for each FA were scored from 0 (no difficulty) to 3 (inability to perform a task). The total score (range of 0-3) was calculated by adding the 8 individual FA scores, then dividing this sum by the total number of components answered. Change from baseline was calculated as the value at Week 24 minus the baseline value.

  • Change From Baseline in CRP at Week 24 [ Time Frame: Baseline and Week 24 ] [ Designated as safety issue: No ]
    Blood samples for the determination of CRP were taken at pre-specified visits and were sent to the central laboratory for analysis. Change from Baseline in CRP was calculated as the Week 24 value minus the baseline value. CRP is an acute-phase protein whose plasma concentration increases in response to inflammation. CRP is a useful marker of inflammation.

  • Change From Baseline in ESR at Week 24 [ Time Frame: Baseline and Week 24 ] [ Designated as safety issue: No ]
    ESR is measured by a blood test that shows the rate at which red blood cells sediment in a period of 1 hour. Blood samples for the determination of ESR were taken at pre-specified visits and were measured immediately at the trial site. Change from baseline in ESR was calculated as the Week 24 value minus the baseline value.

  • Change From Baseline in the Short-Form 36 (SF-36v2) Norm-based Scores for Physical Component Summary and Physical Items at Week 24 [ Time Frame: Baseline and Week 24 ] [ Designated as safety issue: No ]
    The SF-36v2 is a standardized questionnaire used to measure overall subjective health status by measuring 8 health-related parameters (each scored from 0 [poorer health] to 100 [better health]): body pain, general mental health (MH), perception of general health, physical functioning, role limitations (RL) caused by mental condition, RL caused by a physical condition, social functioning, and vitality. It yields an 8-scale profile of functional health and well-being scores, as well as psychometrically based physical and MH summary measures and a preference-based health utility index.

  • Change From Baseline in the SF-36v2 Norm-based Scores for Mental Component Summary and Mental Items at Week 24 [ Time Frame: Baseline and Week 24 ] [ Designated as safety issue: No ]
    The SF-36v2 is a standardized questionnaire used to measure overall subjective health status by measuring 8 health-related parameters (each scored from 0 [poorer health] to 100 [better health]): body pain, general mental health (MH), perception of general health, physical functioning, role limitations (RL) caused by mental condition, RL caused by a physical condition, social functioning, and vitality. It yields an 8-scale profile of functional health and well-being scores, as well as psychometrically based physical and MH summary measures and a preference-based health utility index.

  • Change From Baseline in the Functional Assessment of Chronic Illness Therapy (FACIT) Questionnaire Score at Week 24 [ Time Frame: Baseline and Week 24 ] [ Designated as safety issue: No ]
    The FACIT-F score has a valid range of values from 0 to 52, with a higher score indicating a lower burden of fatigue. The subset determining fatigue contains 13 questions. Responses to each question were scored from 0, indicating "Not at all fatigued," to 4, indicating "Very much fatigued."

  • Change From Baseline in Levels of Anti-CCP, RF-IgA, RF-IgG, and RF-IgM at Week 24 [ Time Frame: Baseline and Week 24 ] [ Designated as safety issue: No ]
    The following biomarkers were assessed: Anti-Cyclic Citrullinated Peptide 3 antibody (Anti-CCP), Rheumatoid factor IgA (RF-IgA), RF IgG (RF-IgG), and RF IgM (RF-IgM). Measurements of RF were used to characterize participants' disease activity and immune status. Anti-CCP was used to characterize the disease type and the immune status of the participants. Assessments for which results were below the lower limit of quantification (LLQ) were reported using a value of LLQ/2. Assessments for which results were above the upper limit of quantification (ULQ) were reported using a value of ULQ.

  • Change From Baseline in Levels of IL-6 and Serum Amyloid A at Week 24 [ Time Frame: Baseline and Week 24 ] [ Designated as safety issue: No ]
    The following biomarkers were assessed: Interleukin 6 (IL-6) and Serum Amyloid A. These biomarkers were used to further characterize disease activity.

  • Minimum DAS28-ESR Score During the Double-blind (DB) and Open-label (OL) Periods, by Ofatumumab Treatment Course [ Time Frame: First 24 weeks of each treatment course (assessed up to Week 144) ] [ Designated as safety issue: No ]
    The DAS28 is a clinical index of rheumatoid arthritis disease activity that combines information from swollen and tender joints (jts.), the APR, and general health (patient global assessment). The following jts. were assessed on both sides of the body: shoulder, elbow, wrist, metacarpophalangeal (5 per side), proximal interphalangeal (5 per side), and knee. The level of disease activity can be interpreted as low (DAS28<=3.2), moderate (3.2<DAS28<=5.1), or high (DAS28>5.1); total score, 0-9.4. A DAS28 <2.6 corresponds to remission. The values summarized are the minimum DAS28 score (i.e. lowest level of disease activity) achieved by each participant within the first 24 weeks of each treatment course (TC), assessed using erythrocyte sedimentation rate (ESR; rate at which red blood cells sediment in 1 hour).

  • Minimum DAS28-CRP Score During the DB and OL Periods, by Ofatumumab Treatment Course [ Time Frame: First 24 weeks of each treatment course (assessed up to Week 144) ] [ Designated as safety issue: No ]
    The DAS28 is a clinical index of rheumatoid arthritis disease activity that combines information from swollen and tender joints (jts.), the APR, and general health (patient global assessment). The following jts. were assessed on both sides of the body: shoulder, elbow, wrist, metacarpophalangeal (5 per side), proximal interphalangeal (5 per side), and knee. The level of disease activity can be interpreted as low (DAS28<=3.2), moderate (3.2<DAS28<=5.1), or high (DAS28>5.1); total score, 0-9.4. A DAS28 <2.6 corresponds to remission. The values summarized are the minimum DAS28 score (i.e. lowest level of disease activity) achieved by each participant within the first 24 weeks of each treatment course, assessed using C-reactive Protein (CRP: used to monitor acute inflammatory phases of rheumatoid arthritis).

  • Minimum Change From Baseline in the DAS28-ESR Score, During the DB and OL Periods, by Ofatumumab Treatment Course [ Time Frame: First 24 weeks of each treatment course (assessed up to Week 144) ] [ Designated as safety issue: No ]
    The level of rheumatoid arthritis disease activity based on the DAS28 score is defined as low if DAS28 <=3.2, moderate if 3.2< DAS28 <=5.1, or high if DAS28 > 5.1. A DAS28 <2.6 corresponds to clinical remission. The values summarized are the minimum change from baseline DAS28 score (i.e. greatest change in disease activity during the treatment course) achieved by each participant within the first 24 weeks of each treatment course, assessed by using ESR. Baseline score was determined at the start of each treatment course. For change from baseline, participants had to have both a baseline DAS28 value for the treatment course (i.e., the latest value on or before the date of infusion A of the treatment course, providing it was done within a 14 day window prior to the date of infusion A) and a DAS28 value during the treatment course (i.e., during first 24 weeks of each treatment course). Change from baseline was calculated as the value during the treatment course minus the baseline value.

  • Minimum Change From Baseline in the DAS28-CRP Score, During the DB and OL Periods, by Ofatumumab Treatment Course [ Time Frame: First 24 weeks of each treatment course (assessed up to Week 144) ] [ Designated as safety issue: No ]
    The level of rheumatoid arthritis disease activity based on the DAS28 score is defined as low if DAS28 <=3.2, moderate if 3.2< DAS28 <=5.1, or high if DAS28 > 5.1. A DAS28 <2.6 corresponds to clinical remission. The values summarized are the minimum change from baseline DAS28 score (i.e. greatest change in disease activity during the treatment course) achieved by each participant within the first 24 weeks of each treatment course, assessed by using CRP. Baseline score was determined at the start of each treatment course. For change from baseline, participants had to have both a baseline DAS28 value for the treatment course (i.e., the latest value on or before the date of infusion A of the treatment course, providing it was done within a 14 day window prior to the date of infusion A) and a DAS28 value during the treatment course (i.e., during first 24 weeks of each treatment course). Change from baseline was calculated as the value during the treatment course minus the baseline value.

  • Number of Participants Who Achieved Remission or Low Disease Activity Based on DAS28 (Using ESR), During the DB and OL Periods, by Ofatumumab Treatment Course [ Time Frame: First 24 weeks of each treatment course (assessed up to Week 144) ] [ Designated as safety issue: No ]
    The DAS28 is a clinical index of rheumatoid arthritis disease activity that combines information from swollen and tender joints (jts.), the APR, and general health (patient global assessment). The following jts. were assessed on both sides of the body: shoulder, elbow, wrist, metacarpophalangeal (5 per side), proximal interphalangeal (5 per side), and knee. The level of disease activity can be interpreted as low (DAS28<=3.2), moderate (3.2<DAS28<=5.1), or high (DAS28>5.1); total score, 0-9.4. A DAS28 <2.6 corresponds to remission. Remission is defined as a DAS28 score <2.6 at any time during the first 24 weeks of each treatment course. Low disease activity is defined as a DAS28 score >=2.6 and <3.2 at any time during the first 24 weeks of each treatment course.

  • Number of Participants Who Achieved Remission or Low Disease Activity Based on DAS28 (Using CRP), During the DB and OL Periods, by Ofatumumab Treatment Course [ Time Frame: First 24 weeks of each treatment course (assessed up to Week 144) ] [ Designated as safety issue: No ]
    The DAS28 is a clinical index of rheumatoid arthritis disease activity that combines information from swollen and tender joints (jts.), the APR, and general health (patient global assessment). The following jts. were assessed on both sides of the body: shoulder, elbow, wrist, metacarpophalangeal (5 per side), proximal interphalangeal (5 per side), and knee. The level of disease activity can be interpreted as low (DAS28<=3.2), moderate (3.2<DAS28<=5.1), or high (DAS28>5.1); total score, 0-9.4. A DAS28 <2.6 corresponds to remission. Remission is defined as a DAS28 score <2.6 at any time during the first 24 weeks of each treatment course. Low disease activity is defined as a DAS28 score >=2.6 and <3.2 at any time during the first 24 weeks of each treatment course.

  • Time to Retreatment, by Ofatumumab Treatment Course [ Time Frame: From Baseline up to Week 144 ] [ Designated as safety issue: No ]
    Time to retreatment is defined as the time in days between infusion A of each treatment course and infusion A of the following treatment course. For participants randomized to ofatumumab in the Double-blind Period, Treatment Course 1 refers to the course of ofatumumab received in the Double-blind Period. The minimum period allowed per protocol before retreatment was 24 weeks (end of Double-blind Period). For participants randomized to placebo in the Double-blind Period, Treatment Course 1 refers to the first course of ofatumumab received in the Open-label Period. The minimum period allowed per protocol before retreatment during the Open-label Period was 16 weeks.

  • Number of Participants With Any On-treatment Adverse Event or Serious Adverse Event, During the DB and OL Periods, by Ofatumumab Treatment Course [ Time Frame: First treatment (Day 0) until the participant terminated the trial, assessed up to Week 144 ] [ Designated as safety issue: No ]
    An adverse event (AE) is defined as any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. A serious adverse event (SAE) is defined as any untoward medical occurrence that, at any dose: results in death; is life-threatening; requires hospitalization or prolongation of existing hospitalization; results in disability/incapacity; or is a congenital anomaly/birth defect. Medical or scientific judgment should have been exercised in other situations. Refer to the general AE/SAE module for a list of AEs (occurring at a frequency threshold >=2%) and SAEs.

  • Number of Participants With a CD19+ Cell Count Greater Than or Equal to the Lower Limit of Normal or the Baseline Value at the Indicated Time Point, During the DB and OL Periods, by Ofatumumab Treatment Course [ Time Frame: From baseline up to Week 144 ] [ Designated as safety issue: No ]
    The number of participants with a CD19+ cell count greater than or equal to the lower limit of normal (LLN; reference range 0.11 to 0.66 giga [10^9] per liter) or the baseline value (whichever was lower) is presented. The baseline assessment is defined as the start of the Double-blind Period.

  • Number of Participants With a CD3+ Cell Count Greater Than or Equal to the Lower Limit of Normal or the Baseline Value at the Indicated Time Point, During the DB and OL Periods, by Ofatumumab Treatment Course [ Time Frame: From baseline up to Week 144 ] [ Designated as safety issue: No ]
    The number of participants with a CD3+ cell count greater than or equal to the lower limit of normal (LLN; reference range 0.11 to 0.66 giga [10^9] per liter) or the baseline value (whichever was lower) is presented. The baseline assessment is defined as the start of the Double-blind Period.

  • Number of Participants With a CD4+ Cell Count Greater Than or Equal to the Lower Limit of Normal or the Baseline Value at the Indicated Time Point, During the DB and OL Periods, by Ofatumumab Treatment Course [ Time Frame: From baseline up to Week 144 ] [ Designated as safety issue: No ]
    The number of participants with a CD4+ cell count greater than or equal to the lower limit of normal (LLN; reference range 0.11 to 0.66 giga [10^9] per liter) or the baseline value (whichever was lower) is presented. The baseline assessment is defined as the start of the Double-blind Period.

  • Number of Participants With a CD8+ Cell Count Greater Than or Equal to the Lower Limit of Normal or the Baseline Value at the Indicated Time Point, During the DB and OL Periods, by Ofatumumab Treatment Course [ Time Frame: From baseline up to Week 144 ] [ Designated as safety issue: No ]
    The number of participants with a CD8+ cell count greater than or equal to the lower limit of normal (LLN; reference range 0.11 to 0.66 giga [10^9] per liter) or the baseline value (whichever was lower) is presented. The baseline assessment is defined as the start of the Double-blind Period.

  • Number of Participants With Vital Sign Data Outside the Clinical Concern Range at Baseline or Any Visit Post-baseline, During the DB and OL Periods, by Ofatumumab Treatment Course [ Time Frame: From baseline up to Week 144 ] [ Designated as safety issue: No ]
    The baseline value for a treatment course is defined as the value before infusion A of each treatment course. The post-baseline visit is defined as any assessment during or after the start of infusion A during the specified treatment course. Pre-defined limits of potential clinical concern for vital signs (Low, High) are: Diastolic blood pressure (DBP) (millimeters of mercury [mmHg]): 40, 110; Systolic blood pressure (SBP) (mmHg): 90, 170; Heart rate (beats per minute): 35, 120. LLN=lower limit of normal; ULN=upper limit of normal.

  • Number of Participants With the Indicated Electrocardiogram (ECG) Findings, During the OL Period [ Time Frame: From DB Period completion (Week 24) until the completion of the OL Period, assessed up to Week 144 ] [ Designated as safety issue: No ]
    The number of participants with normal, abnormal clinically significant (CS), and abnormal not clinically significant (NCS) ECG findings, as well as the number of participants with no results (NR), during the OL Period are presented. An overall interpretation of the ECG was made by the investigator, or the investigator could delegate this task to a cardiologist, if applicable.

  • Number of Participants With the Indicated Clinical Chemistry Values of Potential Clinical Concern at Baseline or Any Visit Post-baseline, During the DB and OL Periods, by Ofatumumab Treatment Course [ Time Frame: From baseline up to Week 144 ] [ Designated as safety issue: No ]
    Only those parameters for which at least one value of clinical concern (CC) was reported are summarized. Baseline (BL) value for a treatment course (TC) is defined as the latest value on or before the date of infusion A of the TC. The post-baseline (PBL) visit is defined as any visit after the date of infusion A during the specified TC. Pre-defined limits of potential CC (CC Low [relative to the lower limit of normal], CC High [relative to the upper limit of normal]) are: Albumin: 0.9, 1.5; Alanine amino transferase (ALT): NA, 2; Alkaline phosphatase (ALP): NA, 1.5; Aspartate amino transferase (AST): NA, 2; Bilirubin total (TBIL): NA, 1.5; Calcium: 0.85, 1.08; CO2 content/bicarbonate (BCO): 0.85/0.75, 1.2/1.3, ; Chloride: 0.9, 1.1; Creatine kinase (CK): NA, 2; Creatinine: NA, 1.2; Gamma glutamyl transferase (GGT): NA, 2; Lactate dehydrogenase (LDH): NA, 2; Potassium: 0.9, 1.1; Sodium: 0.93, 1.07; Total protein: 0.8, 1.15; Urea/blood urea nitrogen (BUN): NA, 1.5; Uric acid: NA, 1.5.

  • Number of Participants With the Indicated Hematology Values of Potential Clinical Concern at Baseline or Any Visit Post-baseline, During the DB and OL Periods, by Ofatumumab Treatment Course [ Time Frame: From baseline up to Week 144 ] [ Designated as safety issue: No ]
    Only those parameters for which at least one value of clinical concern (CC) was reported are summarized. The baseline (BL) value for a treatment course (TC) is defined as the latest value on or before the date of infusion A of the TC. The post-baseline (PBL) visit is defined as any visit after the date of infusion A during the specified TC. Pre-defined limits of potential clinical concern (CC Low [relative to lower limit of normal], CC High [relative to upper limit of normal]) are: Eosinophils: NA, 2; Hematocrit (HCT): 0.75, 1.2; Hemoglobin (Hb): 0.75, 1.2; Lymphocytes: 0.4, 2; Neutrophils total (TNUE): 0.8, 1.6; Platelet count (PC): 0.65, 1.5; Red blood cell count (RBC): 0.75, 2; White blood cell count (WBC): 0.7, 1.6.

  • Number of Participants With the Indicated Biomarker Data Outside the Reference Range at Baseline or Any Post-Baseline Visit During the DB and OL Periods by Ofatumumab Treatment Course (TC) [ Time Frame: From baseline up to Week 144 ] [ Designated as safety issue: No ]
    Only those parameters for a particular flag (<LLN or >ULN) are summarized if at least one value was outside the specified reference range. The Baseline (BL) value for a TC was defined as the latest value on or before the date of infusion A of the TC. However to be evaluable as a baseline value, assessments must have been conducted within a 14 day window prior to the date of infusion A. The post-baseline (PBL) was any visit after the date of infusion A during the specified TC. The pre-defined LLN for biomarkers are: B-lymphocyte stimulator (B-ls):<486.5 nanograms per Liter (ng/L); Interleukin-6 (IL-6):<0.31ng/L and Serum amyloid A: <1951 ng/mL. LLN was not defined for Rheumatoid factor (RF)-IgA, RF-IgG, RF-IgM or anti- cyclic citrullinated peptide (CCP) antibody and RF. The pre- defined ULN range for biomarkers (RF)-IgA: >6 units; RF-IgG:>6 units; RF-IgM:>6 units; Anti-CCP:>19.9999 units; B-ls:>1343.3 ng/L; IL-6: >5 ng/L; RF:>11.9999 kilounits (KU)/L; Serum amyloid A:>82432 ng/mL.

  • Number of Participants With Any Serious Adverse Event During the Follow-up Period [ Time Frame: From the last scheduled visit in the DB or OL Period until B-cells and circulating IgG had returned to normal or baseline levels (or maximum of 2 years from Last Subject Last Visit [LSLV]) ] [ Designated as safety issue: No ]
    A serious adverse event is defined as any untoward medical occurrence that, at any dose: results in death; is life-threatening; requires hospitalization or prolongation of existing hospitalization; results in disability/incapacity; or is a congenital anomaly/birth defect. Medical or scientific judgment should have been exercised in other situations. Refer to the general SAE module for a list of SAEs.

  • Number of Participants With Immunoglobulin Values Outside the Reference Range During the Follow-up Period [ Time Frame: From the last scheduled visit in the DB or OL Period until B-cells and circulating IgG had returned to normal or baseline levels (or maximum of 2 years from LSLV) ] [ Designated as safety issue: No ]
    The reference ranges for immunoglobulins (LLN, ULN) are defined as: IgA (grams/Liter): 0.81, 4.63; IgG (grams/Liter): 6.94, 16.18; IgM (grams/Liter): 0.48, 2.71.

  • Time to First CD19+ B-cell Repopulation Relative to the First Dose and Last Dose of Ofatumumab [ Time Frame: From the first dose of ofatumumab until the last Follow-up Period visit (up to Week 248) ] [ Designated as safety issue: No ]
    Time to first CD19+ B-cell repopulation (return to normal or baseline level) relative to the first dose was assessed only for those participants whose B-cells repopulated after receiving ofatumumab. Time to first CD19+ B-cell repopulation relative to the last dose of ofatumumab was assessed only for those participants whose B-cells repopulated during their last ofatumumab treatment course or follow-up.

  • Number of Participants With a Positive JC Virus Test Result During the Follow-up Period [ Time Frame: From the last scheduled visit in the DB or OL Period until B-cells and circulating IgG had returned to normal or baseline levels (or maximum of 2 years from LSLV) ] [ Designated as safety issue: No ]
    Blood samples were collected for analysis of plasma/white blood cell JC Virus (JCV) using the polymerase chain reaction (PCR) assay. A positive JC Virus test result indicated the presence of JC Virus.

  • Number of Participants With the Indicated Clinical Chemistry Values of Potential Clinical Concern During the Follow-up Period [ Time Frame: From the last scheduled visit in the DB or OL Period until B-cells and circulating IgG had returned to normal or baseline levels (maximum of 2 years) ] [ Designated as safety issue: No ]
    Only those parameters for which at least one value of clinical concern (CC) was reported are summarized. Pre-defined limits of potential clinical concern (CC Low [relative to the lower limit of normal], CC High [relative to the upper limit of normal]) are: ALT: NA, 2; ALP: NA, 1.5; Creatinine: N/A, 1.2; CO2/BCO: 0.85/0.75, 1.2/1.3; CK: NA, 2; GGT: NA, 2; Urea/BUN: NA, 1.5.

  • Number of Participants With the Indicated Hematology Values of Potential Clinical Concern During the Follow-up Period [ Time Frame: From the last scheduled visit in the DB or OL Period until B-cells and circulating IgG had returned to normal or baseline levels (maximum of 2 years) ] [ Designated as safety issue: No ]
    Only those parameters for which at least one value of clinical concern (CC) was reported are summarized. Pre-defined limits of potential clinical concern (CC Low [relative to lower limit of normal], CC High [relative to upper limit of normal]) are: Eosinophils: NA, 2; Total neutrophils: 0.8, 1.6; Platelet count: 0.65, 1.5.


Enrollment: 265
Study Start Date: January 2008
Study Completion Date: July 2013
Primary Completion Date: July 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: ofatumumab
1000 mL dilution of 35ml of ofatumumab in sterile, pyrogen free 0.9% NaCl. Each Treatment Cycle consisting of two 700mg IV infusions taken 14 days apart. A total of 8 infusions cycles given over a 144 week period
Drug: ofatumumab
1000 mL dilution of 35ml of ofatumumab in sterile, pyrogen free 0.9% NaCl. Each Treatment Cycle consisting of two 700mg IV infusions taken 14 days apart. A total of 8 infusions cycles given over a 144 week period
Placebo Comparator: 1000 ml Saline
1000 mL dilution of 35ml of ofatumumab in sterile, pyrogen free 0.9% NaCl. Each Treatment Cycle consisting of two IV infusions taken 14 days apart. Only one placebo treatment cycle provided over a 24 week period
Drug: Placebo
1000 mL dilution of 35ml of ofatumumab in sterile, pyrogen free 0.9% NaCl. Each Treatment Cycle consisting of two IV infusions taken 14 days apart. Only one placebo treatment cycle provided over a 24 week period

Detailed Description:

This study consists of a Double-blind , placebo controlled, and parallel group part with eligible patients enrolled into a 24 week Double-Blind Period, and randomized in a 1:1 ratio to receive ofatumumab (700mg x 2 infusions) or placebo ( saline x 2 infusions) in addition to their background methotrexate treatment. Patients who completed the 24 week Double-Blind period without receiving rescue DMARD treatment will be eligible to proceed into the 120 week Open-Label Period to receive repeat treatment courses with ofatumumab. In the Open-label Period ofatumumab treatment courses will be given at individualized time intervals only if a clinical response has been achieved following the previous treatment course, and followed by a subsequent worsening in disease activity . Patients who have completed the Open-Label Period or have withdrawn will enter a maximum 2 year Follow-up Period, or until their Bcells return to normal or to baseline levels, whichever occurs earlier.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria

  • Age ≥ 18 years;
  • Active disease at the time of screening as defined by:

    ≥ 8 swollen joints (of 66 joints assessed) and ≥ 8 tender joints (of 68 joints assessed), C-Reactive Protein (CRP) ≥ 1.0 mg/dL or Erythrocyte Sedimentation Rate (ESR) ≥ 22 mm/hour, DAS28≥3.2 (based on ESR);

  • Inadequate response to previous or current methotrexate treatment;
  • Treatment with methotrexate (MTX), 7.5-25 mg/week, for at least 12 weeks and at a stable dose for at least 4 weeks.

Exclusion Criteria

  • Patients with a history of a rheumatic autoimmune disease other than RA or with significant systemic involvement secondary to RA;
  • Previous exposure to biologic anti-rheumatic therapies, including investigational compounds;
  • Previous exposure to biologic DMARDs; Chronic or ongoing active infectious disease requiring systemic treatment;
  • Clinically significant cardiac disease; History of significant cerebrovascular disease;
  • Significant concurrent, uncontrolled medical condition including, but not limited to, renal, hepatic, hematological, gastrointestinal, endocrine, pulmonary, neurological, cerebral psychiatric disease, or evidence of demyelinating disease;
  • Known HIV positive; Serologic evidence of Hepatitis B infection; Positive test for Hepatitis C; Positive plasma / white cell JC Virus PCR;
  • Serum IgG < lower limit of normal;
  • Breast feeding women or women with a positive pregnancy test at screening;
  • Current participation in any other interventional clinical study;
  • Patients known or suspected of not being able to comply with a study protocol.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00611455

  Show 45 Study Locations
Sponsors and Collaborators
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline
  More Information

No publications provided by GlaxoSmithKline

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT00611455     History of Changes
Other Study ID Numbers: 110635, GEN410
Study First Received: January 16, 2008
Results First Received: September 21, 2011
Last Updated: May 8, 2014
Health Authority: United Kingdom: Research Ethics Committee
United Kingdom: Medicines and Healthcare Products Regulatory Agency

Additional relevant MeSH terms:
Arthritis
Arthritis, Rheumatoid
Joint Diseases
Musculoskeletal Diseases
Rheumatic Diseases
Connective Tissue Diseases
Autoimmune Diseases
Immune System Diseases

ClinicalTrials.gov processed this record on October 01, 2014