Clinical trial NCT00603525: Investigating Clinical Efficacy of Ofatumumab in Adult Rheumatoid Arthritis (RA) Patients Who Had an Inadequate Response to TNF-α Antagonist Therapy
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Arthritis, Rheumatoid
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2008-01-29
Enrollment: 169
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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Patients who have completed the Open-label Period or have been withdrawn will then enter a maximum 2 year Follow-up Period, or until there B-cells return to normal or to baseline levels, whichever occurs earlier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 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.

Primary outcomes:
measure: Number of Participants With a 20% Improvement From Baseline in Their American College of Rheumatology (ACR) Score (ACR20) at Week 24
timeFrame: Baseline and Week 24
Secondary outcomes:
measure: 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
timeFrame: Baseline and Weeks 4, 8, 12, 16, and 20
measure: Number of Participants With a 50% Improvement From Baseline in Their ACR Score (ACR50) at Weeks 4, 8, 12, 16, 20, and 24
timeFrame: Baseline and Weeks 4, 8, 12, 16, 20, and 24
measure: Number of Participants With a 70% Improvement From Baseline in Their ACR Score (ACR70) at Weeks 4, 8, 12, 16, 20, and 24
timeFrame: Baseline and Weeks 4, 8, 12, 16, 20, and 24
measure: 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)
timeFrame: Weeks 4, 8, 12, 16, 20, and 24
measure: Change From Baseline in DAS28 at Weeks 4, 8, 12, 16, 20, and 24 Using CRP as the Acute Phase Reactant
timeFrame: Baseline and Weeks 4, 8, 12, 16, 20, and 24
measure: Mean DAS28 at Weeks 4, 8, 12, 16, 20, and 24 Using Erythrocyte Sedimentation Rate (ESR) as the Acute Phase Reactant (ARP)
timeFrame: Weeks 4, 8, 12, 16, 20, and 24
measure: Change From Baseline in DAS28 at Weeks 4, 8, 12, 16, 20, and 24 Using ESR as the Acute Phase Reactant
timeFrame: Baseline and Weeks 4, 8, 12, 16, 20, and 24
measure: 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
timeFrame: Baseline and Weeks 4, 8, 12, 16, 20, and 24
measure: 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
timeFrame: Baseline and Weeks 4, 8, 12, 16, 20, and 24
measure: 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
timeFrame: Weeks 4, 8, 12, 16, 20, and 24
measure: Change From Baseline in the Health Assessment Questionnaire Disability Index (HAQ-DI) Score at Weeks 4, 8, 12, 16, 20, and 24
timeFrame: Weeks 4, 8, 12, 16, 20, and 24
measure: Change From Baseline in Tender Joint Count at Week 24
timeFrame: Baseline and Week 24
measure: Change From Baseline in Swollen Joint Count at Week 24
timeFrame: Baseline and Week 24
measure: Change From Baseline in CRP at Week 24
timeFrame: Baseline and Week 24
measure: Change From Baseline in ESR at Week 24
timeFrame: Baseline and Week 24
measure: Change From Baseline in the Participant-assessed Pain Score Using Visual Analogue Scale (VAS) at Week 24
timeFrame: Baseline and Week 24
measure: Change From Baseline in Participant-assessed Global Disease Score Using VAS at Week 24
timeFrame: Baseline and Week 24
measure: Change From Baseline in the Physician-assessed Global Disease Score Using VAS at Week 24
timeFrame: Baseline and Week 24
measure: Change From Baseline in the Functional Assessment of Chronic Illness Therapy (FACIT) Questionnaire Score at Week 24
timeFrame: Baseline and Week 24
measure: Change From Baseline in the Short-Form 36 (SF-36v2) Norm-based Scores for Physical Component Summary and Physical Items at Week 24
timeFrame: Baseline and Week 24
measure: Change From Baseline in the SF-36v2 Norm-based Scores for Mental Component Summary and Mental Items at Week 24
timeFrame: Baseline and Week 24
measure: Biomarker Levels for Anti-CCP, RF-IgA, RF-IgG, and RF-IgM at Baseline and Week 4
timeFrame: Baseline and Week 4
measure: Number of Participants With Positive Human Anti-human Antibodies (HAHA) at Week 24
timeFrame: Baseline and Week 24
measure: Change From Baseline in Levels of IgA, IgG and IgM at Week 12 and Week 24
timeFrame: Baseline, Week 12, and Week 24
measure: Minimum DAS28-ESR Score During the DB and OL Periods, by Ofatumumab Treatment Course
timeFrame: First 24 weeks of each treatment course (assessed up to Week 144)
measure: Minimum DAS28-CRP Score During the DB and OL Periods, by Ofatumumab Treatment Course
timeFrame: First 24 weeks of each treatment course (assessed up to Week 144)
measure: Minimum Change From Baseline DAS28-ESR Score, During the DB and OL Periods, by Ofatumumab Treatment Course
timeFrame: First 24 weeks of each treatment course (assessed up to Week 144)
measure: Minimum Change From Baseline DAS28-CRP Score, During the DB and OL Periods, by Ofatumumab Treatment Course
timeFrame: First 24 weeks of each treatment course (assessed up to Week 144)
measure: Time to Retreatment, by Ofatumumab Treatment Course
timeFrame: From Baseline up to Week 144
measure: 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
timeFrame: First 24 weeks of each treatment course (assessed up to Week 144)
measure: 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
timeFrame: First 24 weeks of each treatment course (assessed up to Week 144)
measure: Number of Participants With Any On-treatment Adverse Event or Serious Adverse Event, During the DB and OL Periods, by Ofatumumab Treatment Course
timeFrame: First treatment (Day 0) until the participant terminated the trial, assessed up to Week 144
measure: Number of Participants With the Indicated Electrocardiogram (ECG) Findings, During the OL Period
timeFrame: From DB Period completion (Week 24) until the completion of the OL Period, assessed up to Week 144
measure: Number of Participants With a CD19+ Cell Count Greater Than or Equal to the Lower Limit of Normal or the Baseline Value at Indicated the Time Point, During the DB and OL Periods, by Ofatumumab Treatment Course
timeFrame: From baseline up to Week 144
measure: 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
timeFrame: From baseline up to Week 144
measure: 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
timeFrame: From baseline up to Week 144
measure: 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
timeFrame: From baseline up to Week 144
measure: 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
timeFrame: From baseline up to Week 144
measure: 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
timeFrame: From baseline up to Week 144
measure: 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
timeFrame: From baseline up to Week 144
measure: Number of Participants With Immunoglobulin Values Outside the Reference Range at Baseline or Any Visit Post-baseline, During the DB and OL Periods, by Ofatumumab Treatment Course
timeFrame: From baseline up to Week 144
measure: Number of Participants With Positive John Cunningham (JC) Virus Test Results at Baseline or Any Visit Post-baseline During the DB and OL Periods
timeFrame: From basline up to Week 144
measure: Number of Participants With Any Serious Adverse Event During the Follow-up Period
timeFrame: 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])
measure: Number of Participants With Immunoglobulin Values Outside the Reference Range During the Follow-up Period
timeFrame: 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)
measure: Time to First CD19+ B-cell Repopulation Relative to the First Dose and Last Dose of Ofatumumab
timeFrame: From the first dose of ofatumumab until the last Follow-up Period visit (up to Week 248)
measure: Number of Participants With a Positive JC Virus Test Result During the Follow-up Period
timeFrame: 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)
measure: Number of Participants With the Indicated Clinical Chemistry Values of Potential Clinical Concern During the Follow-up Period
timeFrame: 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)
measure: Number of Participants With the Indicated Hematology Values of Potential Clinical Concern During the Follow-up Period
timeFrame: 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)
Other outcomes:
Locations:
city: Ciudad Autónoma de Buenos Aires
country: Argentina
facility: GSK Investigational Site
state: Buenos Aires
city: Rosario
country: Argentina
facility: GSK Investigational Site
state: Santa Fe
city: Cordoba
country: Argentina
facility: GSK Investigational Site
city: Tucuman
country: Argentina
facility: GSK Investigational Site
city: Herlev
country: Denmark
facility: GSK Investigational Site
city: Silkeborg
country: Denmark
facility: GSK Investigational Site
city: Amiens
country: France
facility: GSK Investigational Site
state: Picardie
city: Cahors cedex 9
country: France
facility: GSK Investigational Site
city: Corbeil Essonnes Cedex
country: France
facility: GSK Investigational Site
city: Echirolles
country: France
facility: GSK Investigational Site
city: Strasbourg
country: France
facility: GSK Investigational Site
city: Toulouse
country: France
facility: GSK Investigational Site
city: Heidelberg
country: Germany
facility: GSK Investigational Site
state: Baden-Wuerttemberg
city: Erlangen
country: Germany
facility: GSK Investigational Site
state: Bayern
city: Potsdam
country: Germany
facility: GSK Investigational Site
state: Brandenburg
city: Hannover
country: Germany
facility: GSK Investigational Site
state: Niedersachsen
city: Osnabrueck
country: Germany
facility: GSK Investigational Site
state: Niedersachsen
city: Magdeburg
country: Germany
facility: GSK Investigational Site
state: Sachsen-Anhalt
city: Leipzg
country: Germany
facility: GSK Investigational Site
state: Sachsen
city: Berlin
country: Germany
facility: GSK Investigational Site
city: Berlin
country: Germany
facility: GSK Investigational Site
city: Hamburg
country: Germany
facility: GSK Investigational Site
city: Hamburg
country: Germany
facility: GSK Investigational Site
city: Napoli
country: Italy
facility: GSK Investigational Site
state: Campania
city: Telese Terme (BN)
country: Italy
facility: GSK Investigational Site
state: Campania
city: Roma
country: Italy
facility: GSK Investigational Site
state: Lazio
city: Genova
country: Italy
facility: GSK Investigational Site
state: Liguria
city: Milano
country: Italy
facility: GSK Investigational Site
state: Lombardia
city: Milano
country: Italy
facility: GSK Investigational Site
state: Lombardia
city: Milano
country: Italy
facility: GSK Investigational Site
state: Lombardia
city: Varese
country: Italy
facility: GSK Investigational Site
state: Lombardia
city: Prato
country: Italy
facility: GSK Investigational Site
state: Toscana
city: Padova
country: Italy
facility: GSK Investigational Site
state: Veneto
city: Incheon
country: Korea, Republic of
facility: GSK Investigational Site
city: Seoul
country: Korea, Republic of
facility: GSK Investigational Site
city: Seoul
country: Korea, Republic of
facility: GSK Investigational Site
city: Seoul
country: Korea, Republic of
facility: GSK Investigational Site
city: Seoul
country: Korea, Republic of
facility: GSK Investigational Site
city: Amsterdam
country: Netherlands
facility: GSK Investigational Site
city: Enschede
country: Netherlands
facility: GSK Investigational Site
city: Zwolle
country: Netherlands
facility: GSK Investigational Site
city: Haugesund
country: Norway
facility: GSK Investigational Site
city: Levanger
country: Norway
facility: GSK Investigational Site
city: Lillehammer
country: Norway
facility: GSK Investigational Site
city: Trondheim
country: Norway
facility: GSK Investigational Site
city: Lima
country: Peru
facility: GSK Investigational Site
city: Getafe/Madrid
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Mérida (Badajoz)
country: Spain
facility: GSK Investigational Site
city: Santander
country: Spain
facility: GSK Investigational Site
city: Sevilla
country: Spain
facility: GSK Investigational Site
city: Valencia
country: Spain
facility: GSK Investigational Site
city: Oskarström
country: Sweden
facility: GSK Investigational Site
city: Stockholm
country: Sweden
facility: GSK Investigational Site
city: Wishaw
country: United Kingdom
facility: GSK Investigational Site
state: Lanarkshire
city: Newcastle
country: United Kingdom
facility: GSK Investigational Site
state: Northumberland
city: Cannock
country: United Kingdom
facility: GSK Investigational Site
city: Dundee
country: United Kingdom
facility: GSK Investigational Site
city: Leytonstone, London
country: United Kingdom
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References: