A Phase 1/2, Double-Blind, Placebo-Controlled Study of the Pharmacokinetics, Safety and Tolerability of GSK3196165 in Combination With Methotrexate Therapy, in Japanese Subjects With Active Moderate-Severe Rheumatoid Arthritis Despite Treatment With Methotrexate
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 15
- 试验地点
- 1
- 主要终点
- Maximum Observed Concentration (Cmax) of GSK3196165
研究概览
简要总结
This is a randomized, double-blind, parallel group, 3 dosage level, placebo-controlled, Phase 1/2 study designed to evaluate the pharmacokinetics, safety, tolerability, and efficacy of the monoclonal antibody GSK3196165, in Japanese subjects with active moderate-severe rheumatoid arthritis (RA) despite treatment with methotrexate(MTX). The subjects will receive GSK3196165 in combination with methotrexate therapy for the 12 weeks of treatment period. Approximately 55 subjects will be screened to achieve 40 randomized subjects, so as to have approximately 10 subjects in each treatment group.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 20 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age: >=20 years at the time of signing informed consent - Japanese rheumatoid arthritis (RA) subjects who meets American College of Rheumatology or European League Against Rheumatism (ACR/EULAR) 2010 RA Classification Criteria
- •Functional class I, II or III defined by the 1992 ACR Classification of Functional Status in RA
- •Disease duration of >=12 weeks (time from onset of subject-reported symptoms of either pain or stiffness or swelling in hands, feet or wrists).
- •Swollen joint count of >=4 (66-joint count) and tender joint count of >=4 (68-joint count) at screening and at Day 1
- •DAS28(CRP) >=3.2 at screening
- •C-Reactive Protein (CRP) >=0.5 milligrams (mg)/deciliter (dL) at screening
- •Must have previously received methotrexate (MTX) (8-16 mg weekly) orally for at least 12 weeks before screening, with a stable and tolerated dose for >=4 weeks prior to Day 1
- •>=40 kilograms (kg) - Male or female subjects are eligible to participate so long as they meet and agree to abide by the contraceptive criteria
- •Written informed consent prior to any of the screening procedures including discontinuation of prohibited medications
- •Willing to continue or initiate treatment with oral folic acid (5 mg/week) and be treated during the entire study (mandatory co-medication for MTX treatment)
- •Diffusing capacity of lung for carbon monoxide (DLCO) >=60% predicted; forced expiratory volume in 1 second (FEV1) >=70% predicted; forced vital capacity (FVC) >=80% predicted
- •For subjects with DLCO values ≥60% to <70%, a baseline chest high-resolution computed tomography (HRCT) must be performed during the screening period, and it is recommended that the subject be reviewed by a local pulmonologist to exclude significant pre-existing respiratory disease.
- •No evidence of active or latent infection with Mycobacterium tuberculosis (TB), as defined by all of the following:
- •No history of active or latent TB infection irrespective of treatment status
- •A negative T-spot test within 4 weeks of baseline (Day 1)
- •Chest X-ray within 12 weeks of Day 1, locally read by a radiologist, with no evidence of current or previous pulmonary tuberculosis
排除标准
- •Pregnant or lactating women
- •History of other inflammatory rheumatologic or autoimmune disorders, other than Sjögren's syndrome secondary to RA
- •History of any respiratory disease which (in the opinion of the investigator) would compromise subject safety or the ability of the subject to complete the study (e.g. significant interstitial lung disease, such as pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), moderate-severe asthma, bronchiectasis, previous pulmonary alveolar proteinosis (PAP)
- •Clinically-significant or unstable (in the opinion of the investigator) persistent cough or dyspnea that is unexplained
- •QT interval corrected for heart rate (QTc) >450 milliseconds (msec) or QTc >480 msec for subjects with bundle branch block. The QTc is the QT interval corrected for heart rate according to Fridericia's formula (QTcF)
- •Liver function tests: alanine aminotransferase (ALT) >=1.5x upper limit of normal (ULN); aspartate transaminase (AST) >=1.5xULN; alkaline phosphatase and bilirubin >=1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%)
- •Current active liver or biliary disease (with the exception of Gilbert's syndrome or asymptomatic gallstones or otherwise stable chronic liver disease per investigator assessment)
- •Clinically significant unstable or uncontrolled acute or chronic disease (e.g., cardiovascular including uncompensated congestive cardiac failure New York Heart Association [NYHA] III or IV, myocardial infarction within 12 months, unstable angina pectoris, uncontrolled hypertension, uncontrolled hypercholesterolemia) pulmonary, hematologic, gastrointestinal (including Crohn's Disease or ulcerative colitis), hepatic, renal, neurological, psychiatric, malignancy, endocrinological or infectious diseases, which, in the opinion of the investigator, could confound the results of the study or put the subject at undue risk
- •A history of malignant neoplasm within the last 10 years or breast cancer within the last 20 years, except for non-melanoma skin cancers that have been excised and cured or carcinoma in situ of the uterine cervix
- •Kidney disease: Current or history of renal disease, or estimated creatinine clearance <60 milliliter (mL)/minute (min)/1.73 m2 (MDRD formula) or serum creatinine >1.5xULN within 4 weeks of Day 1
- •Hereditary or acquired immunodeficiency disorder, including immunoglobulin deficiency
- •History of infected joint prosthesis at any time, with the prosthesis still in situ. History of leg ulcers, catheters, chronic sinusitis or recurrent chest or urinary tract infections
- •Active infections, or history of recurrent infections (excluding recurrent fungal infections of the nail bed), or have required management of acute or chronic infections, as follows:
- •Currently on any suppressive therapy for a chronic infection (such as tuberculosis, pneumocystis, cytomegalovirus, herpes simplex virus, herpes zoster and atypical mycobacteria)
- •OR Hospitalization for treatment of infection within 26 weeks of Day 1
- •OR Use of parenteral (Intravenous (IV) or Intramuscular (IM) antimicrobials (antibacterials, antivirals, antifungals, or antiparasitic agents) within 26 weeks of Day 1 or oral antimicrobials within 2 weeks of Day 1
- •A vaccination (live or attenuated) within 30 days of Day 1 or Bacillus Calmette-Guérin (BCG) vaccination within 1 year of Day 1, or a live vaccination planned during the course of the study (including follow-up period).
- •Any surgical procedure, including bone or joint surgery/synovectomy within 12 weeks prior to Day 1 or any planned surgery within the duration of the study (including follow-up period)
- •Use of prohibited medications Prior to AND throughout the study:
- •Any conventional DMARDs other than MTX (including sulfasalazine, bucillamine, iguratimod, tacrolimus) should be withdrawn at least 2 weeks prior to Day
- •Subjects may require longer to discontinue azathioprine or leflunomide prior to Day 1: Azathioprine must be discontinued >=4 weeks prior to randomization; Leflunomide must be discontinued >=12 weeks prior to Day 1 (or >=14 days after 11 days of standard cholestyramine or activated charcoal washout).
- •For these subjects, written informed consent for the study must be obtained prior to beginning the screening period. However, other screening assessments, other than consent, must occur within 4 weeks prior to Day
- •Any biologic agents (such as Tumor necrosis factor (TNF) inhibitors [including adalimumab, etanercept, infliximab, certolizumab pegol, golimumab] or non-TNF inhibitors [including abatacept, rituximab, tocilizumab, belimumab]).
- •Any Janus kinase (JAK) inhibitors (such as tofacitinib).
- •Any anti-rheumatic investigational compounds.
- •Any alkylating agents (such as cyclophosphamide).
- •Plasmapheresis or intravenous immunoglobulin (IVIG) within 26 weeks of Day
- •Corticosteroids:
- •Any Intramascular (IM), Intravenous (IV) or Intra-arterial (IA) corticosteroids within 8 weeks of Day
- •Oral corticosteroids:
- •Any treatment with >10 mg/day dose oral prednisolone (or equivalent) within 4 weeks of Day
- •New oral corticosteroid or changes in corticosteroid dose within the 4 weeks prior to Day
- •(New topical steroids and immunosuppressive agents (e.g., eye drops, creams) are permitted)
- •Non-steroidal anti-inflammatory drugs (NSAIDs):
- •New or change in dose of NSAID within 2 weeks of Day 1
- •Any non-anti-rheumatic investigational treatment must be discontinued for at least 4 weeks or 5 half-lives, whichever is longer, prior to Day 1
- •Have current drug or alcohol abuse or dependence, or a history of drug or alcohol abuse or dependence within a year prior to Day 1
- •History of sensitivity to any of the study treatments, or components thereof or a history of drug or other allergy that, in the opinion of the investigator or Medical Monitor, contraindicates their participation
- •Abnormal chest X-ray within 12 weeks of Day 1 (locally read and reported by a radiologist) judged by the investigator as clinically-significant
- •Any Grade 3 or 4 hematology or clinical chemistry laboratory abnormality, within 4 weeks of Day 1
- •Hemoglobin ≤9 g/dL; white blood cell count ≤3.0 x 109/L; platelet count ≤100 x 109/L; absolute neutrophil count ≤1.5 x 109/L; lymphocyte count ≤0.5 x 109/L within 4 weeks of Day 1
- •Serologic evidence of current/previous Hepatitis B virus (HBV) infection based on the results of testing for Hepatitis B surface antigen (HBsAg) and anti-Hepatitis B core (anti-HBc) antibody as follows within 4 weeks of Day 1
- •Subjects positive for HBsAg and/or positive for anti-HBc antibody (regardless of anti-HBs antibody status) are excluded
- •Subjects with positive anti-HBs antibody and HBV-DNA (>=2.1 log copies/mL) are excluded.
- •Hepatitis C: Positive test for Hepatitis C virus (HCV) antibody confirmed on a subsequent blood sample by ribonucleic acid - polymerized chain reaction (RNA-PCR) assay within 4 weeks of Day
- •Subjects who are positive for Hepatitis C antibody and negative when the Hepatitis C RNA-PCR assay is performed on a subsequent sample will be eligible to participate. Subjects who are positive for Hepatitis C antibody and have a positive result for the HCV when the Hepatitis C RNA-PCR assay is performed on the subsequent sample will not be eligible to participate
- •Positive serology for human immunodeficiency virus (HIV) 1 or 2 (within 4 weeks of Day 1)
研究组 & 干预措施
GSK3196165 Dose 1
Participants will receive GSK3196165 Dose 1 weekly as a single subcutaneous (SC) injection by an un-blinded administrator. There will be 5 weekly injections (Days 1, 8, 15, 22 and 29), then every other week (EOW) injections at Days 43, 57 and 71 (Weeks 6, 8 and 10 respectively). Participants will also receive a stable dose of methotrexate during the Treatment Period.
干预措施: GSK3196165 Dose 1 (Drug)
GSK3196165 Dose 1
Participants will receive GSK3196165 Dose 1 weekly as a single subcutaneous (SC) injection by an un-blinded administrator. There will be 5 weekly injections (Days 1, 8, 15, 22 and 29), then every other week (EOW) injections at Days 43, 57 and 71 (Weeks 6, 8 and 10 respectively). Participants will also receive a stable dose of methotrexate during the Treatment Period.
干预措施: Methotrexate (Drug)
GSK3196165 Dose 1
Participants will receive GSK3196165 Dose 1 weekly as a single subcutaneous (SC) injection by an un-blinded administrator. There will be 5 weekly injections (Days 1, 8, 15, 22 and 29), then every other week (EOW) injections at Days 43, 57 and 71 (Weeks 6, 8 and 10 respectively). Participants will also receive a stable dose of methotrexate during the Treatment Period.
干预措施: Folic acid (Drug)
GSK3196165 Dose 2
Participants will receive GSK3196165 Dose 2 weekly as a single SC injection by an un-blinded administrator. There will be 5 weekly injections (Days 1, 8, 15, 22 and 29), then EOW injections at Days 43, 57 and 71 (Weeks 6, 8 and 10 respectively). Participants will also receive a stable dose of methotrexate during the Treatment Period.
干预措施: GSK3196165 Dose 2 (Drug)
GSK3196165 Dose 2
Participants will receive GSK3196165 Dose 2 weekly as a single SC injection by an un-blinded administrator. There will be 5 weekly injections (Days 1, 8, 15, 22 and 29), then EOW injections at Days 43, 57 and 71 (Weeks 6, 8 and 10 respectively). Participants will also receive a stable dose of methotrexate during the Treatment Period.
干预措施: Methotrexate (Drug)
GSK3196165 Dose 2
Participants will receive GSK3196165 Dose 2 weekly as a single SC injection by an un-blinded administrator. There will be 5 weekly injections (Days 1, 8, 15, 22 and 29), then EOW injections at Days 43, 57 and 71 (Weeks 6, 8 and 10 respectively). Participants will also receive a stable dose of methotrexate during the Treatment Period.
干预措施: Folic acid (Drug)
GSK3196165 Dose 3
Participants will receive GSK3196165 Dose 3 weekly as a single SC injection by an un-blinded administrator. There will be 5 weekly injections (Days 1, 8, 15, 22 and 29), then EOW injections at Days 43, 57 and 71 (Weeks 6, 8 and 10 respectively). Participants will also receive a stable dose of methotrexate during the Treatment Period.
干预措施: GSK3196165 Dose 3 (Drug)
GSK3196165 Dose 3
Participants will receive GSK3196165 Dose 3 weekly as a single SC injection by an un-blinded administrator. There will be 5 weekly injections (Days 1, 8, 15, 22 and 29), then EOW injections at Days 43, 57 and 71 (Weeks 6, 8 and 10 respectively). Participants will also receive a stable dose of methotrexate during the Treatment Period.
干预措施: Methotrexate (Drug)
GSK3196165 Dose 3
Participants will receive GSK3196165 Dose 3 weekly as a single SC injection by an un-blinded administrator. There will be 5 weekly injections (Days 1, 8, 15, 22 and 29), then EOW injections at Days 43, 57 and 71 (Weeks 6, 8 and 10 respectively). Participants will also receive a stable dose of methotrexate during the Treatment Period.
干预措施: Folic acid (Drug)
Placebo
Participants will receive placebo weekly as a single SC injection by an un-blinded administrator. There will be 5 weekly injections (Days 1, 8, 15, 22 and 29), then EOW injections at Days 43, 57 and 71 (Weeks 6, 8 and 10 respectively). Participants will also receive a stable dose of methotrexate during the Treatment Period.
干预措施: Methotrexate (Drug)
Placebo
Participants will receive placebo weekly as a single SC injection by an un-blinded administrator. There will be 5 weekly injections (Days 1, 8, 15, 22 and 29), then EOW injections at Days 43, 57 and 71 (Weeks 6, 8 and 10 respectively). Participants will also receive a stable dose of methotrexate during the Treatment Period.
干预措施: Placebo (Drug)
Placebo
Participants will receive placebo weekly as a single SC injection by an un-blinded administrator. There will be 5 weekly injections (Days 1, 8, 15, 22 and 29), then EOW injections at Days 43, 57 and 71 (Weeks 6, 8 and 10 respectively). Participants will also receive a stable dose of methotrexate during the Treatment Period.
干预措施: Folic acid (Drug)
结局指标
主要结局
Maximum Observed Concentration (Cmax) of GSK3196165
时间窗: Pre-dose on Days 1, 8, 15, 29, 57 and 71; anytime during visit on Days 3, 74, 85, 106, 127 and 155
Blood samples were collected at pre-dose on Days 1, 8, 15, 29, 57 and 71; and at any time during visit on Days 3, 74, 85, 106, 127 and 155. PK parameters were calculated by non-compartmental analysis using the concentration data after last dosing (Day 71). Only those participants whose parameters could be determined were analyzed. PK Population included all GSK3196165-treated participants from whom PK samples were collected and analyzed.
Area Under the Concentration-time Curve (AUC) From Time Zero to the Time of the Last Quantifiable Concentration (AUC [0-t]), AUC From Time Zero Extrapolated to Infinity (AUC [0-inf]), AUC Over the Dosing Interval (AUCtau) of GSK3196165
时间窗: Pre-dose on Days 1, 8, 15, 29, 57 and 71; anytime during visit on Days 3, 74, 85, 106, 127 and 155
Blood samples were collected at pre-dose on Days 1, 8, 15, 29, 57 and 71; and at any time during visit on Days 3, 74, 85, 106, 127 and 155. PK parameters were calculated by non-compartmental analysis using the concentration data after last dosing (Day 71). NA indicates data was not available as geometric mean and/or 95 percent confidence interval could not be calculated when number of participant was not sufficient.
Time to Reach Cmax (Tmax) of GSK3196165
时间窗: Pre-dose on Days 1, 8, 15, 29, 57 and 71; anytime during visit on Days 3, 74, 85, 106, 127 and 155
Blood samples were collected at pre-dose on Days 1, 8, 15, 29, 57 and 71; and at any time during visit on Days 3, 74, 85, 106, 127 and 155. PK parameters were calculated by non-compartmental analysis using the concentration data after last dosing (Day 71).
Terminal Half-life (t1/2) of GSK3196165
时间窗: Pre-dose on Days 1, 8, 15, 29, 57 and 71; anytime during visit on Days 3, 74, 85, 106, 127 and 155.
Blood samples were collected at pre-dose on Days 1, 8, 15, 29, 57 and 71; and at any time during visit on Days 3, 74, 85, 106, 127 and 155. PK parameters were calculated by standard non-compartmental analysis from the concentration data after last dosing (Day 71). NA indicates data was not available as 95 percent confidence interval could not be calculated when number of participant was not sufficient.
Number of Participants With Any Adverse Event (AE), Serious AE (SAE) and Adverse Events of Special Interest (AESI)
时间窗: Up to 22 weeks
An AE is any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect, any other situation according to medical or scientific judgment that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the participant or may require medical or surgical intervention or event associated with liver injury and impaired liver function were categorized as SAE. AESI included serious infections including serious respiratory infections and tuberculosis and opportunistic infections, neutropenia (grade 3 or 4), respiratory events, pulmonary alveolar proteinosis, hypersensitivity reactions including anaphylaxis and injection site reactions.
次要结局
- Number of Participants With Abnormal 12-lead Electrocardiogram (ECG) Findings(At Week 12)
- Number of Participants With Emergent Hematology Results Relative to Normal Range(Up to 22 weeks)
- Number of Participants With Emergent Clinical Chemistry Results Relative to Normal Range(Up to 22 weeks)
- Number of Participants With Urinalysis Dipstick Findings(Up to 22 weeks)
- Number of Participants With Anti-GSK3196165 Antibody Test Results(Weeks 2, 4, 12 and 22)
- Change From Baseline in Disease Activity Score for 28 Different Joints C-reactive Protein (DAS28 [CRP]) at All Indicated Timepoints(Baseline, up to Week 22)
- Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)(Baseline and up to 22 weeks)
- Change From Baseline in Heart Rate (HR)(Baseline and up to 22 weeks)
- Change From Baseline in Body Temperature(Baseline and up to 22 weeks)
- Change From Baseline in Respiratory Rate(Baseline and up to 22 weeks)