Efficacy, Pharmacokinetics, Safety, and Immunogenicity Study of Abatacept Administered Subcutaneously to Treat Rheumatoid Arthritis in Japanese Patients

Rheumatoid Arthritis Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01001832
• Other study ID #: IM101-250
• Status: Completed
• Phase: Phase 2/Phase 3
• First received: October 26, 2009
• Last updated: January 2, 2014
• Start date: December 2009
• Est. completion date: October 2012

Study information

• Verified date: January 2014
• Source: Bristol-Myers Squibb
• Contact: n/a
• Is FDA regulated: No
• Health authority: Japan: Institutional Review BoardJapan: Pharmaceuticals and Medical Devices Agency
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 118
• Est. completion date: October 2012
• Est. primary completion date: February 2011
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 20 Years and older

Eligibility

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.

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Arthritis
• Arthritis, Rheumatoid
• Rheumatoid Arthritis

Intervention

Drug:
• Intravenous (IV) abatacept
IV vial, 125-mg infusions on Days 1, 15, and 29, and every 28 days thereafter until Day 141.
• Subcutaneous (SC) abatacept
Solution in prefilled syringes, SC, 125 mg, once weekly, for 169 days and then for 52 weeks

Locations

Country	Name	City	State
Japan	Local Institution	Bunkyo-Ku	Tokyo
Japan	Local Institution	Fukuoka-Shi	Fukuoka
Japan	Local Institution	Hamamatsu-Shi	Shizuoka
Japan	Local Institution	Hannan-Shi	Osaka
Japan	Local Institution	Higashi-Hiroshima-Shi	Hiroshima
Japan	Local Institution	Hitachi-Shi	Ibaraki
Japan	Local Institution	Iruma-Gun	Saitama
Japan	Local Institution	Kagoshima-Shi	Kagoshima
Japan	Local Institution	Kanzaki-Gun	Hyogo
Japan	Local Institution	Kato-Shi	Hyogo
Japan	Local Institution	Kawagoe-Shi	Saitama
Japan	Local Institution	Kitakyushu-Shi	Fukuoka
Japan	Local Institution	Kitamoto-Shi	Saitama
Japan	Local Institution	Kobe-Shi	Hyogo
Japan	Local Institution	Kurashiki-Shi	Okayama
Japan	Local Institution	Kurume-Shi	Fukuoka
Japan	Local Institution	Maebashi-Shi	Gunma
Japan	Local Institution	Nagano-Shi	Nagano
Japan	Local Institution	Nakano-Ku	Tokyo
Japan	Local Institution	Narita-Shi	Chiba
Japan	Local Institution	Sagamihara-Shi	Kanagawa
Japan	Local Institution	Sapporo	Hokkaido
Japan	Local Institution	Sapporo-Shi	Hokkaido
Japan	Local Institution	Sapporo-Shi	Hokkaido
Japan	Local Institution	Sapporo-Shi	Hokkaido
Japan	Local Institution	Shimotsuke-Shi	Tochigi
Japan	Local Institution	Shinjuku-Ku	Tokyo
Japan	Local Institution	Shizuoka-Shi	Shizuoka
Japan	Local Institution	Takasaki-Shi	Gunma
Japan	Local Institution	Tokorozawa-Shi	Saitama
Japan	Local Institution	Utsunomiya-Shi	Tochigi
Japan	Local Institution	Yokohama-Shi	Kanagawa
Japan	Local Institution	Yokohama-Shi	Kanagawa

Sponsors (1)

Lead Sponsor	Collaborator
Bristol-Myers Squibb

Country where clinical trial is conducted

Japan, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of Participants With an American College of Rheumatology (ACR) 20 Response at Day 169 in Short Term Period	The ACR score of 20 indicates the degree of improvement in a patient's rheumatoid arthritis (RA), based on ACR guidelines (ACR20). The ACR score represents a percentage. To qualify for an ACR20 score, the patient must have >=20% fewer tender joints and >=20% fewer swollen joints and show 20% improvement in at least 3 of: patient overall assessment of his/her RA, physician global assessment of the patient's RA, patient self-assessment of pain, patient self-assessment of physical functioning, and results of an erythrocyte sedimentation rate or C-reactive protein test (to assess inflammation). Percentage is calculated n/N with n=number of participants with ACR score of 20 and N= all randomized participants who received at least one dose of study drug.	Day 169	No
Primary	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	The ACR score indicates the degree of improvement in a patient's rheumatoid arthritis (RA), based on ACR guidelines. The ACR score= a percentage. To qualify for a score of 20, 50 or 70 (ACR20, ACR50 or ACR70), the patient must have >=20%, >=50% or >=70%, respectively, fewer tender joints and >=20%, >=50% or >=70%, respectively, fewer swollen joints and show 20%, 50% or 70%, respectively, improvement in at least 3 of the following: patient overall assessment of his/her RA, physician global assessment of the patient's RA, patient self-assessment of pain, patient self-assessment of physical functioning, and results of an erythrocyte sedimentation rate or C-reactive protein test (to assess inflammation). Treatment groups represent treatment received in the short term period. Percentage calculated as n/m with n=number of paticipants with sustained ACR response at Day 533; m= long term participants who received at least one dose of drug and were ACR responders in the short term period.	Day 533	No
Primary	Mean Change From Baseline in HAQ-DI Score at Day 533 in Long Term Period	Adjusted mean. The Health Assessment Questionnaire Disability Index (HAQ-DI) assesses patients' functional ability by rating their abilities over the previous week. At least 2 questions are asked from each of 8 categories: dressing and grooming, hygiene, arising, reach, eating, grip, walking, and common daily activities. Patients rate difficulty performing specific tasks: 0=without difficulty, 1=with some difficulty, 2=with much difficulty, and 3=unable to do. The sum of the categories score (the highest scored item in the category) is divided by the number of categories answered, yielding a score from 0-3. Treatment groups represent treatment received in the short term period. Baseline is Day 1 of the study or last non-missing pre-treatment value.	Baseline to Day 533	No
Primary	Percentage of Participants With Health Assessment Questionnaire (HAQ) Response at Day 533 in Long Term Period	The Health Assessment Questionnaire (HAQ) disability index assesses patients' functional ability by rating their abilities over the previous week. At least 2 questions are asked from each of 8 categories: dressing and grooming, hygiene, arising, reach, eating, grip, walking, and common daily activities. Patients rate difficulty performing specific tasks: 0=without difficulty, 1=with some difficulty, 2=with much difficulty, and 3=unable to do. The higher the number the worse the outcome. The sum of the categories score (the highest scored item in the category) is divided by the number of categories answered, yielding a score from 0-3. HAQ response=reduction of at least 0.30 units in HAQ score from baseline. The percentage of participants with a reduction of at least 0.30 units in their HAQ score from baseline is presented. Baseline is Day 1 of the study or last non-missing pre-treatment value. Treatment groups represent treatment received in the short term period.	Day 533	No
Primary	Mean Change in DAS28-CRP From Baseline at Day 533 in Long Term Period	The Disease Activity Score 28 using C-Reactive Protein (DAS28-CRP) is a measure of disease activity in rheumatoid arthritis (RA) and assesses the 28 joints RA commonly affects; the score includes the number of tender and swollen joints (out of 28), CRP level (a measure of inflammation in the blood), and the patient's global assessment of health (ranging from very good to very bad). An overall DAS >5.1 implies active disease; <3.2, well controlled disease; and <2.6, remission.). Treatment groups represent treatment received in the short term period. Baseline is Day 1 of the study or last non-missing pre-treatment value.	Baseline to Day 533	No
Secondary	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	The American College of Rheumatology (ACR) scores of 50 and 70 indicates the degree of improvement in a patient's rheumatoid arthritis (RA), based on ACR guidelines. The ACR score represents a percentage. To qualify for an ACR50 or ACR70 scores, the patient must have >=50% or >=70%, respectively, fewer tender joints and >=50% or >=70%, respectively, fewer swollen joints and show 50% or 70%, respectively, improvement in at least 3 of the following: patient overall assessment of his/her RA, physician global assessment of the patient's RA, patient self-assessment of pain, patient self-assessment of physical functioning, and results of an erythrocyte sedimentation rate or C-reactive protein test (to assess inflammation).	Day 169	No
Secondary	Mean Change From Baseline in HAQ-DI Score at Day 169 in Short Term Period	Adjusted mean. The Health Assessment Questionnaire Disability Index (HAQ-DI) assesses patients' functional ability by rating their abilities over the previous week. At least 2 questions are asked from each of 8 categories: dressing and grooming, hygiene, arising, reach, eating, grip, walking, and common daily activities. Patients rate difficulty performing specific tasks: 0=without difficulty, 1=with some difficulty, 2=with much difficulty, and 3=unable to do. The sum of the categories score (the highest scored item in the category) is divided by the number of categories answered, yielding a score from 0-3.	Baseline to Day 169	No
Secondary	Percentage of Participants With HAQ Response at Day 169 in the Short Term Period	The Health Assessment Questionnaire Disability Index (HAQ-DI) assesses patients' functional ability by rating their abilities over the previous week. At least 2 questions are asked from each of 8 categories: dressing and grooming, hygiene, arising, reach, eating, grip, walking, and common daily activities. Patients rate difficulty performing specific tasks: 0=without difficulty, 1=with some difficulty, 2=with much difficulty, and 3=unable to do. The sum of the categories score (the highest scored item in the category) is divided by the number of categories answered, yielding a score from 0-3. The HAQ-DI response is defined as a reduction of at least 0.30 units in HAQ score from baseline.	Day 169	No
Secondary	Mean Change From Baseline at Six Months in DAS28-CRP - All Treated Participants	The Disease Activity Score 28 using C-Reactive Protein (DAS28-CRP) is a measure of disease activity in rheumatoid arthritis (RA) and assesses the 28 joints RA commonly affects; the score includes the number of tender and swollen joints (out of 28), CRP level (a measure of inflammation in the blood), and the patient's global assessment of health (ranging from very good to very bad). An overall DAS >5.1 implies active disease; <3.2, well controlled disease; and <2.6, remission.). Baseline is Day 1 or last non-missing pre-treatment value.	Baseline to 6 Months	No
Secondary	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	EULAR defines LDAS as DAS28-CRP less than, equal to (=) 3.2 and defines REM as DAS28-CRP less than (<) 2.6.	Day 169	No
Secondary	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	EULAR defines LDAS as DAS28-CRP=3.2 and defines REM as DAS28-CRP<2.6.	Day 533	No
Secondary	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	AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Treatment-related=related or missing relationship to study medication.	Baseline to Day 169	No
Secondary	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	AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Treatment-related=related or missing relationship to study medication.	Baseline to Day 533 and up to 56 days following last dose in Long-Term period	Yes
Secondary	Short-term Period: Number of Participants With Hematology Laboratory Values Meeting the Criteria for Marked Abnormality	lower limit of normal(LLN); upper limit of normal(ULN); pretreatment(preRX). Hemoglobin (g/dL): >3 g/dL decrease from preRX; hematocrit (%): <0.75*preRX; erythrocytes (*10^6 c/uL): <0.75*preRX; platelet count (*10^9 c/uL): <0.67*LLN or >1.5*ULN, of if preRX	Baseline to Day 169	Yes
Secondary	Long-term Period: Number of Participants With Hematology Laboratory Values Meeting the Marked Abnormality Criteria	LLN=lower limit of normal; ULN=upper limit of normal; preRX=pretreatment. Hemoglobin (g/dL): >3 g/dL decrease from preRX; hematocrit (%): <0.75*preRX; erythrocytes (*10^6 c/uL): <0.75*preRX; platelet count (*10^9 c/uL): <0.67*LLN or >1.5*ULN, of if preRX	Baseline to Day 533	Yes
Secondary	Short-term Period: Number of Participants With Liver and Kidney Function Laboratory Values Meeting the Criteria for Marked Abnormality	ULN=upper limit of normal; LLN=lower limit of normal; preRX=pretreatment. alkaline phosphatase (ALP) (U/L): >2*ULN, or if preRX>ULN, use >3*preRX; aspartate aminotransferase (AST) (U/L): >3*ULN, or if preRX>ULN, use >4*preRX; alanine aminotransferase(ALT) (U/L): >3*ULN, or if preRX>ULN, use >4*preRX; Gamma glutamyltransferase(GGT) (U/L): >2*ULN, or if preRX>ULN, use >3*preRX; bilirubin (mg/dL): >2*ULN, or if preRX>ULN, use >4*preRX; blood urea nitrogen (mg/dL): >2*preRX; creatinine (mg/dL): >1.5*preRX.	Baseline to Day 169	Yes
Secondary	Short-term Period: Number of Participants With Electrolyte Laboratory Values Meeting the Criteria for Marked Abnormality	LLN=lower limit of normal; ULN=upper limit of normal; preRX=pretreatment. Sodium (mEq/L): <0.95*LLN or >1.05*ULN, or if preRX	Baseline to Day 169	Yes
Secondary	Long-term Period: Number of Participants With Liver and Kidney Function Laboratory Values Meeting the Criteria for Marked Abnormality	ULN=upper limit of normal; LLN=lower limit of normal; preRX=pretreatment. ALP (U/L): >2*ULN, or if preRX>ULN, use >3*preRX; AST (U/L): >3*ULN, or if preRX>ULN, use >4*preRX; ALT (U/L): >3*ULN, or if preRX>ULN, use >4*preRX; GGT (U/L): >2*ULN, or if preRX>ULN, use >3*preRX; bilirubin (mg/dL): >2*ULN, or if preRX>ULN, use >4*preRX; blood urea nitrogen (mg/dL): >2*preRX; creatinine (mg/dL): >1.5*preRX.	Baseline to Day 533	Yes
Secondary	Long-term Period: Number of Participants With Electrolyte Laboratory Values Meeting the Criteria for Marked Abnormality	LLN=lower limit of normal; ULN=upper limit of normal; preRX=pretreatment. Sodium (mEq/L): <0.95*LLN or >1.05*ULN, or if preRX	Baseline to Day 533	Yes

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