SYNOPSIS. 2-Year (0.5 DB OL) Addendum to Clinical Study Report

Transcription

1 Name of Sponsor/Company: Bristol-Myers Squibb Name of Finished Product: Abatacept () Name of Active Ingredient: Abatacept () Individual Study Table Referring to the Dossier (For National Authority Use Only) SYNOPSIS TITLE OF STUDY: Protocol Open-label Period up to 10-Jan-2006: A Phase III, Multi-center, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy and Safety of vs Placebo in Subjects with Active Rheumatoid Arthritis on Background DMARDS Who Have Failed Anti-TNF Therapy INVESTIGATORS/STUDY CENTERS AND COUNTRIES: 85 sites worldwide: 59 sites in the United States; 20 sites in Europe (Belgium, France, Italy, Spain, Poland, Russia); and 6 sites in Canada. PUBLICATIONS: Genovese, MC, Becker, JC, Schiff M, et al. Abatacept for rheumatoid arthritis refractory to tumor necrosis factor α inhibition. N Engl J Med 2005;353: STUDY PERIOD: Double-blind Period: 18-Nov-2002 to 01-Jun-2004 Open-label Period (First Subject, First Visit): 09-Jun-2003 Data Cutoff: 10-Jan-2006 CLINICAL PHASE: Phase III OBJECTIVES: Primary Objective: The primary objective of the open-label period was to assess the safety and long-term tolerability of abatacept in combination with background disease-modifying anti-rheumatic drugs (DMARDs) or anakinra in subjects with active rheumatoid arthritis (RA) who completed the initial 6-month, double-blind treatment period. Secondary Objectives: Secondary objectives were to assess efficacy, pharmacodynamic (PD) marker activity, and immunogenicity of abatacept in combination with background DMARDs during the open-label period. Immunogenicity data will be summarized in a separate report. METHODOLOGY: All subjects who completed the 6-month, double-blind period of Study, continued to meet the inclusion criteria and none of the exclusion criteria, and provided informed consent could enter the open-label period. At the time of enrollment into the open-label period (Day 169), all subjects (active and placebo) were re-allocated to a fixed dose of abatacept that approximated 10 mg/kg. During the open-label period, adjustments in background DMARD therapy and other concomitant medications were permitted at the discretion of the investigator based on the subject s clinical status. As of June 2005, investigators were requested to discontinue all marketed biologic therapy including TNF-blocking agents and anakinra in subjects receiving abatacept. The purpose of this report is to present safety, tolerability, efficacy, and PD marker activity data for subjects treated with abatacept in combination with background DMARDs during the uncontrolled,

2 open-label period through 10-Jan As of the data cut off date, subjects electing to continue into the open label period received at least 2 years of study therapy; those initially randomized to abatacept in the double-blind received at least 2 years of treatment with abatacept while those initially randomized to placebo in the double-blind phase received at least 18 months of treatment with abatacept. NUMBER OF SUBJECTS: 317 of the 322 subjects who completed the double-blind period were enrolled and treated in the open-label period. DIAGNOSIS AND MAIN CRITERIA FOR INCLUSION/EXCLUSION: Adult subjects with active RA who completed the 6-month double-blind period of Protocol were eligible to continue into the open-label period. Subjects had to continue to meet the inclusion criteria (with the exception of tender and swollen joint counts, C-reactive protein [CRP] value, and dose of background DMARDs) and none of the exclusion criteria (other than receiving abatacept) as outlined in Protocol and all subsequent amendments. TEST PRODUCT, DOSE AND MODE OF ADMINISTRATION, BATCH NUMBERS: Abatacept (fixed dose that approximated 10 mg/kg) was administered intravenously (IV) monthly beginning on Day 169. Batch numbers were 2J59315, 2J62804, 2J62805, 2J62806, 2J62801, 3A64965, 3A64967, 3D66861, 3E75222, 3H65127, 3M60521, 4A75209, 4A79855, 4B80782, 4J88292, 4J88331, 4K84062, 4K84065, 4K88013, 4K88014, 5C10527, 5D01056, 5D01057, 5D05853, 5D05859, and 5M CRITERIA FOR EVALUATION: Efficacy: All subjects who received at least 1 dose of abatacept at any time during the open-label period were evaluated for efficacy. The American College of Rheumatology (ACR) 20 response criteria were defined as a 20% improvement over baseline (Day 1) in tender and swollen joint counts and a 20% improvement in 3 of the remaining 5 ACR core assessments (subject assessment of pain, subject global assessment of disease activity, physician assessment of disease activity, subject assessment of physical function, and 1 acute phase reactant (CRP) value). ACR 50 and ACR 70 responses were similarly defined with 50% and 70% improvements required, respectively. Other efficacy measures included improvements (changes from baseline [Day 1]) in ACR core components, disease activity as measured by the Disease Activity Score (DAS 28), physical function as measured by the health assessment questionnaire (HAQ), health-related quality of life based on the short form questionnaire (SF-36), sleep quality based on the Medical Outcomes Study Sleep Module (MOS-Sleep), fatigue assessments using a visual analogue scale (VAS), activity limitations using a 2-item questionnaire, and pharmacodynamic markers (rheumatoid factor [RF], soluble interleukin-2 receptor [sil-2r], CRP, and erythrocyte sedimentation rate [ESR]). Safety: All subjects who received at least 1 dose of abatacept at any time during the open-label period were evaluated for safety. Adverse events (AEs), serious adverse events (SAEs) including deaths, discontinuations due to AEs, clinical laboratory test abnormalities, changes in vital signs, and physical examinations, and reported up to 10-Jan-2006 were included in this report. Some subjects received open-label treatment for up to 33 months. As part of the comprehensive safety evaluation of abatacept, the sponsor identified AEs that may be associated with the use of immunomodulatory drugs. Specific events within the categories of infections, autoimmune symptoms and disorders, neoplasms, and AEs following infusion were prospectively identified and classified as AEs of special interest. These AEs are a subset of all AEs and include serious and non-serious events. Immunogenicity data will be described in a separate report. STATISTICAL METHODS: Efficacy: No formal statistical testing was done on the efficacy data for the open-label period. Efficacy analyses were performed by the subject s double-blind period treatment group assignment, ie, abatacept 10 mg/kg or placebo plus background DMARDs or anakinra therapy. All efficacy analyses were conducted on as-observed data subject to the conventions that follow for missing data. ACR responses and HAQ

3 scores were imputed for subjects who had missing data at a given visit; missing data post discontinuation for subjects who discontinued were imputed as a non-response. Safety: Subjects who entered the open-label period were re-allocated to active abatacept treatment and pooled as 1 group. No formal statistical testing was performed on the safety data. SUBJECT POPULATION RESULTS: A total of 322 subjects completed the 6-month double-blind period, of whom 317 were enrolled and treated during the open-label period. As of 10-Jan-2006, a total of 95 of the 317 subjects (30.0%) entering the open-label period discontinued and 222 subjects (70.0%) were still participating in the study. The most common reasons for discontinuation in the open-label period were lack of efficacy (16.4%) and AEs (7.6%). The mean total duration of exposure to abatacept across the double-blind and open-label periods was 24.5 months. The mean duration of exposure to abatacept in the open-label period was 20.6 months (range, 1.9 to 32.9 months). Baseline Demographic and Disease Characteristics Abatacept Placebo Total N = 218 N = 99 N = Age (years) Mean SD Gender Male 51 (23.4%) 20 (20.2%) 71 (22.4%) Female 167 (76.6%) 79 (79.8%) 246 (77.6%) Race White 211 (96.8%) 92 (92.9%) 303 (95.6%) Black 7 ( 3.2%) 4 ( 4.0%) 11 ( 3.5%) American Indian or Alaska Native 0 1 ( 1.0%) 1 ( 0.3%) Asian 0 1 ( 1.0%) 1 ( 0.3%) Other 0 1 ( 1.0%) 1 ( 0.3%) Duration of RA (yrs) Mean SD Population: All treated subjects who entered the open-label period. EFFICACY RESULTS: Data from the double-blind period reported in this addendum reflect only subjects who entered the open-label period. The following is a brief summary of efficacy: ACR, DAS 28, and HAQ responses were maintained from the end of the double-blind period (Day 169) to Day 729 (1.5 years of open-label treatment) in the cohort of subjects who received abatacept at a fixed dose approximating 10 mg/kg (plus background DMARDs) during both the double-blind and open-label periods. During the open-label period, subjects in the original double-blind abatacept group also maintained the improvements in the SF-36 physical and mental component summary scores and sleep index, fatigue VAS, and activity limitation scores seen at the end of double-blind period. Subjects who originally received placebo during the double-blind period and fixed-dose abatacept during the open-label period experienced improvements in ACR, HAQ, and DAS 28 responses, and in

4 all health outcomes measures (SF-36, sleep index, fatigue VAS, and activity limitation scores) during the open-label period. As early as Day 365, response rates for efficacy measures were similar to those for the original double-blind abatacept group, and the improvements were maintained through Day 729 (1.5 years of the open-label period). The improvements (ie, seroconversion or reduction) in pharmacodynamic markers (RF, sil-2r, CRP, ESR) after 1.5 years of the open-label period in both cohorts of subjects were comparable to the improvements seen after 6 months of double-blind treatment with abatacept. SAFETY RESULTS: The following is a brief summary of safety: Up through the CRF lock date of 10-Jan-2006, the incidence of AEs, SAEs, and discontinuations due to AEs during the open-label period was 93.7%, 30.9%, and 6.6%. The incidence of AEs, SAEs, and discontinuations due to AEs in the abatacept group during the 6-month double-blind period was 76.7%, 10.7%, and 3.3%, respectively. Overview of Safety During Open-label Period ----Number (%) of Subjects---- All Abatacept (N=317) Deaths 1 (0.3) SAEs a 98 (30.9) Related SAEs b 15 (4.7) Discontinued due to SAEs 13 (4.1) AEs 297 (93.7) Related AEs b 162 (51.1) Discontinued due to AEs 21 (6.6) a SAEs include hospitalizations for elective surgeries. b Related AEs or SAEs defined as investigator assessment of certain, probable, possible or missing. Population: All treated subjects who entered the open-label period. MEDDRA VERSION: 8.1 The types and intensity of AEs occurring during the open-label periods generally appeared to be similar to those observed during the double-blind period. The most frequently reported AEs during the open-label period were in the SOC of infections and infestations (68.5% of subjects). The most commonly reported AEs by PT during the open-label period were upper respiratory infection (21.1%), back pain (12.9%), bronchitis (12.3%), nasopharyngitis (12.3%), and urinary tract infection (12.0%). The majority of reported AEs were mild or moderate in intensity. One subject died during in the open-label period as the result of Enterobacter pneumonia complicated by sepsis, retroperitoneal bleed, and respiratory failure after approximately 1.5 years in the study (6 months on double-blind placebo and 11 months on open-label abatacept). The investigator reported the relationship to the investigational drug as possible for the events of respiratory failure, Enterobacter pneumonia, and septicemia, and as unrelated for the event of retroperitoneal bleed. SAEs (including hospitalizations for surgical procedures) were reported for 98 subjects (30.9%, with a corresponding incidence rate of 29.44/100 person-years) during the open-label period; this is similar to

5 the incidence rate for the double-blind period with abatacept (36.56 per 100 person-years). The most frequently reported SAEs by SOC during the open-label period involved musculoskeletal and connective tissue disorders (13.6%). These included RA (including worsening RA: 33 subjects, 10.4% and osteoarthritis: 7 subjects, 2.2%). For most of these subjects, the SAEs were considered unrelated or unlikely related to abatacept. Infection and infestations was the second most frequent SOC in which SAEs were reported, with 20 (6.3%) subjects experiencing serious infections or infestations. Within this SOC, the most frequently reported individual SAE was pneumonia (1.9%). The rate of the SAEs did not appear to increase during the open-label period relative to the double-blind period. Infections of interest were pre-specified and these were reported by 57 subjects (18.0%, with a corresponding incidence rate of 12.30/100 person-years) during the open-label period (compared with per 100 person-years for the double-blind period with abatacept). The most common were cellulitis (3.8%), herpes simplex (3.5%), and tooth abscess (3.5%). Most of these infections were mild or moderate in intensity. Fourteen subjects (4.4%) developed pre-specified infections that were serious. The serious pre-specified infection resolved following treatment for 13 of the 14 subjects, only one (pneumonia) resulted in discontinuation. The rate of pre-specified infections overall, pneumonia, and viral infections did not appear to increase in the open-label period, although the rate of cellulitis appeared to be higher than that seen during the double-blind period. All but one case of cellulitis was mild or moderate in intensity, none were serious, and none resulted in treatment discontinuation. Neoplasms (benign, malignant or unspecified) were reported in 22 subjects (6.9%) during the open-label period. Malignancies were reported for 11 of these subjects (3.5%, with a corresponding incidence rate of 2.24/100 person-years vs 2.61 per 100 person-years for the double-blind period with abatacept). Six subjects had non-melanomatous skin cancers; the other were gastric cancer, breast cancer, ovarian epithelial cancer, uterine cancer and T-cell lymphoma. Two additional malignancies (lung cancer, rectal cancer) were reported > 56 days after the last dose of study medication (60 days and 124 days, respectively). By data convention, these latter 2 malignancies were not included in the calculation of incidence rates. Pre-specified autoimmune symptoms or disorders were reported in 11 subjects (3.5%, with a corresponding incidence rate of 2.05/100 person-years), all of which were mild (0.9%) or moderate (2.5%) in intensity. One of the pre-specified autoimmune symptoms or disorders (autoimmune hepatitis) resulted in premature discontinuation. The most common individual event reported was psoriasis (0.9% of subjects). The rate of pre-specified autoimmune symptoms or disorders during the double-blind period with abatacept was 0.77/100 person-years. Sponsor-defined acute infusional AEs (within 1 hour following dosing) were reported in 15 (4.7%) subjects. Sponsor-defined peri-infusional AEs (within 24 hours following dosing) were reported for a total of 49 subjects (15.5%). With the exception of 1 case each of severe urticaria and severe headache, all peri-infusional AEs were mild or moderate in intensity. The clinical laboratory data were generally unremarkable, and no safety issues were identified. Mean IgA, IgG, and IgM values decreased from baseline (Day 1), but with the exception of IgA, were within the normal range at Day 729. Mean IgA values were above the upper limit of the normal range at Day 729.

6 CONCLUSIONS: In subjects with RA who had an inadequate efficacy response to TNF-blocking agents: A fixed dose of abatacept approximating 10 mg/kg (IV) administered monthly for up to 33 months after the 6-month double-blind period was generally well tolerated. The overall pattern and intensity of AEs during the open-label period was not different from that observed during the double-blind period. The incidence of SAEs, serious infections, pre-specified infections of interest and malignancies reported by subjects treated with abatacept during the open-label period did not appear to increase relative to the rates in the double-blind period. Continued treatment with abatacept fixed dose during the open-label period was effective in maintaining improvements in disease symptoms, physical function, and quality of life. Efficacy responses for the cohort of subjects in the original placebo group improved during the open-label period after being switched to abatacept and were similar to those in the original abatacept group as early as Day 365; these improvements were generally maintained through Day 729 (1.5 years of the open-label period). DATE OF REPORT: 16-Oct-2006