Investigating Clinical Efficacy of Ofatumumab in Adult Rheumatoid Arthritis (RA) Patients Who Had an Inadequate Response to TNF-α Antagonist 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:
NCT00603525
First received: January 16, 2008
Last updated: December 12, 2013
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 and safety of ofatumumab in reducing clinical signs and symptoms in adult RA patients who had an inadequate response to TNF-α antagonist therapy.


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 Patients With Active Rheumatoid Arthritis Who Have Previously Had an Inadequate Response to One or More TNF Antagonist Therapies

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.

  • 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 rheumatoid arthritis disease activity (DA) that combines information from swollen and tender joints, the APR, and general health (patient global assessment). 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 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 (ARP) [ 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 rheumatoid arthritis disease activity (DA) that combines information from swollen and tender joints, the APR, and general health (patient global assessment). 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 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: Baseline and 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: Baseline and 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.

  • Median of the Largest Integer n, for Which a Participant Met the ACR Criteria Requiring an Improvement of n% (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 percentage (%) 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 = min(TJC % IFBL, SJC % IFBL, composite measure % IFBL). Composite measure % IFBL is the 3rd highest value of % IFBL for the 5 parameters.

  • Change From Baseline in the Health Assessment Questionnaire Disability Index (HAQ-DI) Score at Weeks 4, 8, 12, 16, 20, and 24 [ Time Frame: Weeks 4, 8, 12, 16, 20, and 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.

  • 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 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 Participant-assessed Pain Score Using Visual Analogue Scale (VAS) 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 Using VAS 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 Using VAS 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 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 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.

  • Biomarker Levels for Anti-CCP, RF-IgA, RF-IgG, and RF-IgM at Baseline and Week 4 [ Time Frame: Baseline and Week 4 ] [ 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.

  • Number of Participants With Positive Human Anti-human Antibodies (HAHA) at Week 24 [ Time Frame: Baseline and Week 24 ] [ Designated as safety issue: No ]
    Detection of human anti-human antibodies (HAHAs) against ofatumumab was to be performed by Electrochemiluminescent (ECL) Meso-Scale Discovery (MSD) immunoassay. Positive samples from the binding antibody test were also tested in a neutralizing antibody assay.

  • Change From Baseline in Levels of IgA, IgG and IgM at Week 12 and Week 24 [ Time Frame: Baseline, Week 12, and Week 24 ] [ Designated as safety issue: No ]
    The following immunoglobulins were assessed: IgA, IgG and IgM. Immunoglobulins, or antibodies, are large proteins used by the immune system to identify and neutralize foreign particles such as bacteria and viruses. Their normal blood levels indicate proper immune status. Low levels indicate immuno-suppression.


Enrollment: 169
Study Start Date: January 2008
Study Completion Date: July 2013
Primary Completion Date: March 2011 (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 IV infusion taken 14 days apart. A total of 8 infusion 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 IV infusion taken 14 days apart. A total of 8 infusion cycles given over a 144 week period
Placebo Comparator: 1000 ml Saline
1000 mL sterile, pyrogen free 0.9% NaCl. A treatment cycle consisting of two IV infusion taken 14 days apart. Only one placebo treatment cycle provided over a 24 week period
Drug: Placebo
1000 mL sterile, pyrogen free 0.9% NaCl. A treatment cycle consisting of two IV infusion taken 14 days apart. Only one placebo treatment cycle provided over a 24 week period

Detailed Description:

This study consist 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 either ofatumumab or placebo in addition to their background methotrexate treatment. Patients who complete the 24 week Double-blind Period without receiving rescue DMARD treatment will then 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 been withdrawn will then enter a maximum 2 year Follow-up Period, or until there B-cells 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 TNF-alpha antagonist 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;
  • Exposure to TNF-alpha antagonist treatment < 12 weeks prior to visit 2;
  • 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
Please refer to this study by its ClinicalTrials.gov identifier: NCT00603525

  Show 60 Study Locations
Sponsors and Collaborators
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline
  More Information

No publications provided

Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT00603525     History of Changes
Other Study ID Numbers: 110634, GEN411
Study First Received: January 16, 2008
Results First Received: October 20, 2011
Last Updated: December 12, 2013
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 April 17, 2014