Clinical trial NCT01001832: Efficacy, Pharmacokinetics, Safety, and Immunogenicity Study of Abatacept Administered Subcutaneously to Treat Rheumatoid Arthritis in Japanese Patients
Official title: A Phase II/III, Multicenter, Randomized, Double-Blind, Double-Dummy Study to Assess Similarity of the Efficacy, Pharmacokinetics, Safety and Immunogenicity of Abatacept Administered Subcutaneously or Intravenously in Japanese Subjects With Rheumatoid Arthritis, Receiving Background Methotrexate, and Experiencing an Inadequate Response to Methotrexate
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Rheumatoid Arthritis
Lead sponsor: Bristol-Myers Squibb
Sponsor class: INDUSTRY
First posted: 2009-10-27
Enrollment: 118
Sex: ALL
Minimum age (years): 20
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to assess the efficacy, pharmacokinetics, safety, and immunogenicity of abatacept after subcutaneous and intravenous administration in Japanese participants with active rheumatoid arthritis and inadequate response to methotrexate.


Eligibility criteria: Key Inclusion Criteria:

* Meeting criteria of the American Rheumatism Association for the diagnosis of rheumatoid arthritis (RA) and the American College of Rheumatology functional Classes I, II, or III.
* Inadequate response (as deemed by investigator) to methotrexate taken for at least 3 months (12 weeks) at a stable dose (6 to 8 mg/week) for 28 days prior to randomization (Day 1).
* Stabilization requirements for concomitant therapy: Oral corticosteroid treatment reduced to the equivalent of ≤10 mg prednisolone daily for 28 days and stabilized for at least 25 of 28 days prior to treatment (Day 1). No intra-articular, intravenous, or intramuscular injections of corticosteroids were permitted within 28 days prior to randomization (Day 1.)
* Washout requirements: Participants receiving combination RA therapy had to discontinue the following therapies at least 28 days prior to treatment (Day 1):

disease-modifying antirheumatic drugs (DMARDs), such as gold (auranofin and aurothiomalate sodium), actarit, bucillamine, azathioprine, salazosulfapyridine, lobenzarit disodium, D-penicillamine, cyclophosphamide, mycophenolate mofetil, mizoribine; cyclosporin, tacrolimus, and other calcineurin inhibitors; and immunoadsorption columns.

* Disease Activity Requirements: At randomization (Day 1), participants had to meet the following disease activity criteria: Swollen joint count: 10 or more swollen joints (66 joint count); tender joint count: 12 or more tender joints (68 joint count); C reactive protein (CRP): ≥0.8 mg/dL (result from screening visit).
* For participants receiving methotrexate plus other DMARDs(washout of a combination therapy required): At screening visit, participants had to meet the following disease activity criteria: Swollen joint count: 6 or more swollen joints (66 joint count); tender joint count: 8 or more tender joints (68 joint count); CRP: no restriction on CRP (not applicable).
* After washout, at randomization (Day 1), participants must meet the following disease activity criteria: Swollen joint count-10 or more swollen joints (66 joint count) and tender joint count-12 or more tender joints (68 joint count) and CRP: ≥0.8 mg/dL (result from screening visit). For those whose screening period were longer than 4 weeks, CRP test needed to be performed on Day
* 28 to Day -3 (prior to treatment Day 1) to verify eligibility.

Key Exclusion Criteria:

* Current symptoms of severe, progressive, or uncontrolled renal, hepatic, hematologic, gastrointestinal, pulmonary, cardiac, neurologic, or cerebral disease. Concomitant medical conditions that, in the opinion of the investigator, might place the participant at unacceptable risk for participation in this study.
* Female participants who had undergone breast cancer screening that was suspicious for malignancy, and in whom the possibility of malignancy could not be reasonably excluded following additional clinical, laboratory, or other diagnostic evaluations.
* History of cancer within the last 5 years (other than nonmelanoma skin cell cancers cured by local resection)
* Existing nonmelanoma skin cell cancers had been removed prior to the first administration. Participants with carcinoma in situ, treated with definitive surgical intervention prior to study entry were allowed to participate.
* Clinically significant drug or alcohol abuse
* Any serious acute bacterial infection (such as pneumonia or pyelonephritis unless treated and completely resolved with antibiotics)
* Serious, chronic, or recurrent bacterial infections (such as recurrent pneumonia, chronic bronchiectasis)
* Those at risk for tuberculosis (TB). Specifically, those with current clinical, radiographic, or laboratory evidence suggestive of active TB; history of active TB within the last 3 years, even if treated; history of active TB more than 3 years ago unless there was documentation that the prior anti-TB treatment was appropriate in type and duration; latent TB that was not successfully treated. Participants with a positive result on TB screening test indicative of latent TB were not eligible for the study unless active TB infection had been ruled out and treatment for latent TB with isoniazid had been initiated for at least 4 weeks prior to administration of the study drug and the participant had a negative finding for TB on a chest X-ray film at enrollment.
* Herpes zoster resolving less than 2 months prior to enrollment
* Current evidence (as assessed by the investigator) suggestive of active or latent bacterial or viral infections, including human immunodeficiency virus infection.
* Physical examination and laboratory test findings: Hepatitis B surface antigen-positive status; hepatitis C antibody-positive status. Any of the following laboratory values: Hemoglobin concentration: \<.5 g/dL; white blood cell count: \<3,000/μL (3\*10\^9/L); platelet count: \<100,000/mm\^3(100\*10\^9/L); serum creatinine: \>2 times upper limit of normal (ULN); serum alanine aminotransferase: \>2 ULN; serum aspartate aminotransferase: \>2 ULN.
* Prohibited treatments and/or therapies: Prior exposure to abatacept (CTLA4-Ig); prior RA treatment with any biologics, such as anti-tumor necrosis factor therapy; prior exposure to any investigational biologic not currently approved in Japan; exposure to any study medication in any other previous study within 4 weeks or 5 half-lives, whichever was longer; receipt of any live vaccines within 3 months of administration of study medication or scheduled to receive live vaccines.

Primary outcomes:
measure: Percentage of Participants With an American College of Rheumatology (ACR) 20 Response at Day 169 in Short Term Period
timeFrame: Day 169
measure: Percentage of Participants With Sustained American College of Rheumatology (ACR) Response at Day 533 in Long Term Period - All Randomized and Treated Participants During the Long Term Period
timeFrame: Day 533
measure: Mean Change From Baseline in HAQ-DI Score at Day 533 in Long Term Period
timeFrame: Baseline to Day 533
measure: Percentage of Participants With Health Assessment Questionnaire (HAQ) Response at Day 533 in Long Term Period
timeFrame: Day 533
measure: Mean Change in DAS28-CRP From Baseline at Day 533 in Long Term Period
timeFrame: Baseline to Day 533
Secondary outcomes:
measure: Percentage of Participants With American College of Rheumatology 50 (ACR50) and American College of Rheumatology 70 (ACR70) Responses at Day 169 in Short Term Period
timeFrame: Day 169
measure: Mean Change From Baseline in HAQ-DI Score at Day 169 in Short Term Period
timeFrame: Baseline to Day 169
measure: Percentage of Participants With HAQ Response at Day 169 in the Short Term Period
timeFrame: Day 169
measure: Mean Change From Baseline at Six Months in DAS28-CRP - All Treated Participants
timeFrame: Baseline to 6 Months
measure: Percentage of Participants With European League Against Rheumatism (EULAR)-Defined Low Disease Activity Score (LDAS) and EULAR-defined Remission (REM) at Day 169 in Short Term Period
timeFrame: Day 169
measure: Percentage of Participants With European League Against Rheumatism (EULAR)-Defined Low Disease Activity Score (LDAS) and EULAR-defined Remission (REM) at Day 533 in Long Term Period
timeFrame: Day 533
measure: Short-term Period: Number of Participants With Death as Outcome, Serious Adverse Events (SAEs), Treatment-related SAEs, Discontinuations Due to SAEs, Adverse Events (AEs), Treatment-related AEs, and Discontinuations Due to AEs
timeFrame: Baseline to Day 169
measure: Long-term Period: Number of Participants With Death as Outcome, Serious Adverse Events (SAEs), Treatment-related SAEs, Discontinuations Due to SAEs, Adverse Events (AEs), Treatment-related AEs, and Discontinuations Due to AEs
timeFrame: Baseline to Day 533 and up to 56 days following last dose in Long-Term period
measure: Short-term Period: Number of Participants With Hematology Laboratory Values Meeting the Criteria for Marked Abnormality
timeFrame: Baseline to Day 169
measure: Long-term Period: Number of Participants With Hematology Laboratory Values Meeting the Marked Abnormality Criteria
timeFrame: Baseline to Day 533
measure: Short-term Period: Number of Participants With Liver and Kidney Function Laboratory Values Meeting the Criteria for Marked Abnormality
timeFrame: Baseline to Day 169
measure: Short-term Period: Number of Participants With Electrolyte Laboratory Values Meeting the Criteria for Marked Abnormality
timeFrame: Baseline to Day 169
measure: Long-term Period: Number of Participants With Liver and Kidney Function Laboratory Values Meeting the Criteria for Marked Abnormality
timeFrame: Baseline to Day 533
measure: Long-term Period: Number of Participants With Electrolyte Laboratory Values Meeting the Criteria for Marked Abnormality
timeFrame: Baseline to Day 533
Other outcomes:
Locations:
city: Narita-Shi
country: Japan
facility: Local Institution
state: Chiba
city: Fukuoka-Shi
country: Japan
facility: Local Institution
state: Fukuoka
city: Kitakyushu-Shi
country: Japan
facility: Local Institution
state: Fukuoka
city: Kurume-Shi
country: Japan
facility: Local Institution
state: Fukuoka
city: Maebashi-Shi
country: Japan
facility: Local Institution
state: Gunma
city: Takasaki-Shi
country: Japan
facility: Local Institution
state: Gunma
city: Higashi-Hiroshima-Shi
country: Japan
facility: Local Institution
state: Hiroshima
city: Sapporo-Shi
country: Japan
facility: Local Institution
state: Hokkaido
city: Sapporo-Shi
country: Japan
facility: Local Institution
state: Hokkaido
city: Sapporo-Shi
country: Japan
facility: Local Institution
state: Hokkaido
city: Sapporo
country: Japan
facility: Local Institution
state: Hokkaido
city: Kanzaki-Gun
country: Japan
facility: Local Institution
state: Hyogo
city: Kato-Shi
country: Japan
facility: Local Institution
state: Hyogo
city: Kobe-Shi
country: Japan
facility: Local Institution
state: Hyogo
city: Hitachi-Shi
country: Japan
facility: Local Institution
state: Ibaraki
city: Kagoshima-Shi
country: Japan
facility: Local Institution
state: Kagoshima
city: Sagamihara-Shi
country: Japan
facility: Local Institution
state: Kanagawa
city: Yokohama-Shi
country: Japan
facility: Local Institution
state: Kanagawa
city: Yokohama-Shi
country: Japan
facility: Local Institution
state: Kanagawa
city: Nagano-Shi
country: Japan
facility: Local Institution
state: Nagano
city: Kurashiki-Shi
country: Japan
facility: Local Institution
state: Okayama
city: Hannan-Shi
country: Japan
facility: Local Institution
state: Osaka
city: Iruma-Gun
country: Japan
facility: Local Institution
state: Saitama
city: Kawagoe-Shi
country: Japan
facility: Local Institution
state: Saitama
city: Kitamoto-Shi
country: Japan
facility: Local Institution
state: Saitama
city: Tokorozawa-Shi
country: Japan
facility: Local Institution
state: Saitama
city: Hamamatsu-Shi
country: Japan
facility: Local Institution
state: Shizuoka
city: Shizuoka-Shi
country: Japan
facility: Local Institution
state: Shizuoka
city: Shimotsuke-Shi
country: Japan
facility: Local Institution
state: Tochigi
city: Utsunomiya-Shi
country: Japan
facility: Local Institution
state: Tochigi
city: Bunkyo-Ku
country: Japan
facility: Local Institution
state: Tokyo
city: Nakano-Ku
country: Japan
facility: Local Institution
state: Tokyo
city: Shinjuku-Ku
country: Japan
facility: Local Institution
state: Tokyo
Study officials:
affiliation: Bristol-Myers Squibb
name: Bristol-Myers Squibb
role: STUDY_DIRECTOR
References:
citation: Amano K, Matsubara T, Tanaka T, Inoue H, Iwahashi M, Kanamono T, Nakano T, Uchimura S, Izumihara T, Yamazaki A, Karyekar CS, Takeuchi T; Japan Abatacept Study Group. Long-term safety and efficacy of treatment with subcutaneous abatacept in Japanese patients with rheumatoid arthritis who are methotrexate inadequate responders. Mod Rheumatol. 2015 Sep;25(5):665-71. doi: 10.3109/14397595.2015.1012786.