Evaluation of Pharmacokinetics and Safety of GSK3196165 in Combination With Methotrexate in Japanese Subjects With Rheumatoid Arthritis
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ClinicalTrials.gov Identifier: NCT03028467 |
Recruitment Status :
Completed
First Posted : January 23, 2017
Last Update Posted : August 16, 2018
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Condition or disease | Intervention/treatment | Phase |
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Arthritis, Rheumatoid | Drug: GSK3196165 Dose 1 Drug: GSK3196165 Dose 2 Drug: GSK3196165 Dose 3 Drug: Methotrexate Drug: Placebo Drug: Folic acid | Phase 2 |
Study Type : | Interventional (Clinical Trial) |
Actual Enrollment : | 15 participants |
Allocation: | Randomized |
Intervention Model: | Parallel Assignment |
Masking: | Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor) |
Primary Purpose: | Treatment |
Official Title: | 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 |
Actual Study Start Date : | January 24, 2017 |
Actual Primary Completion Date : | December 20, 2017 |
Actual Study Completion Date : | December 20, 2017 |

Arm | Intervention/treatment |
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Experimental: GSK3196165 45 mg
Participants will receive GSK3196165 45 milligram (mg) 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.
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Drug: GSK3196165 Dose 1
GSK3196165 is supplied as liquid and will be administered as SC injection. Drug: Methotrexate Methotrexate capsule/tablet 8-16 mg per week is given orally. Drug: Folic acid Folic acid tablet 5 mg per week is given orally. |
Experimental: GSK3196165 90 mg
Participants will receive GSK3196165 90 mg 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.
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Drug: GSK3196165 Dose 2
GSK3196165 is supplied as liquid and will be administered as SC injection. Drug: Methotrexate Methotrexate capsule/tablet 8-16 mg per week is given orally. Drug: Folic acid Folic acid tablet 5 mg per week is given orally. |
Experimental: GSK3196165 180 mg
Participants will receive GSK3196165 180 mg 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.
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Drug: GSK3196165 Dose 3
GSK3196165 is supplied as liquid and will be administered as SC injection. Drug: Methotrexate Methotrexate capsule/tablet 8-16 mg per week is given orally. Drug: Folic acid Folic acid tablet 5 mg per week is given orally. |
Placebo Comparator: 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.
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Drug: Methotrexate
Methotrexate capsule/tablet 8-16 mg per week is given orally. Drug: Placebo Placebo is supplied as liquid as sterile 0.9% sodium chloride solution and will be administered as SC injection. Drug: Folic acid Folic acid tablet 5 mg per week is given orally. |
- Maximum concentration (Cmax) of GSK3196165 calculated from sparse sampling concentrations [ Time Frame: Up to 22 weeks ]Blood sample will be collected at indicated time points and concentration of GSK3196165 will be determined
- Time to maximum concentration (Tmax) of GSK3196165 calculated from sparse sampling concentrations [ Time Frame: Up to 22 weeks ]Blood sample will be collected at indicated time points and concentration of GSK3196165 will be determined
- Area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time AUC (0-infinity) [ Time Frame: Up to 22 weeks ]Blood sample will be collected at indicated time points and concentration of GSK3196165 will be determined
- Area under the concentration-time curve over the dosing interval (AUCtau) of GSK3196165 calculated from sparse sampling concentrations [ Time Frame: Up to 22 weeks ]Blood sample will be collected at indicated time points and concentration of GSK3196165 will be determined
- Elimination half life (t1/2) of GSK3196165 calculated from sparse sampling concentrations [ Time Frame: Up to 22 weeks ]Blood sample will be collected at indicated time points and concentration of GSK3196165 will be determined
- Number of subjects with any adverse event (AE) [ Time Frame: Up to 26 weeks ]An AE is any untoward medical occurrence in a subject, temporarily associated with the use of a medicinal product, whether or not considered related to the medicinal product.
- Number of subjects with any serious adverse event (SAE) [ Time Frame: Up to 26 weeks ]A SAE is any untoward medical occurrence that is life threatening, requires prolonged hospitalisation, may result in death, disability and congenital anomaly.
- Number of subjects with any AE of special interest [ Time Frame: Up to 26 weeks ]AESI's will be assessed
- Change from baseline in vital sign values [ Time Frame: Up to 22 weeks ]Vital signs will be measured after 5 minutes rest and will include temperature, systolic and diastolic blood pressure, pulse rate and respiratory rate.
- Number of subjects with abnormal 12-lead electrocardiogram (ECG) findings [ Time Frame: Up to 22 weeks ]ECG will be performed
- Average of laboratory values [ Time Frame: Up to 22 weeks ]Hematology, clinical chemistry, and urinalysis parameters will be measured.
- Change from baseline in disease activity score for 28 different joints (C-reactive protein) [DAS28(CRP)] at all assessment timepoints [ Time Frame: Up to 22 weeks ]C-reactive protein will be assessed

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Ages Eligible for Study: | 20 Years and older (Adult, Older Adult) |
Sexes Eligible for Study: | All |
Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- 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)
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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.
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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
Exclusion Criteria:
- 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
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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 1.
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 1.
- 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 1.
Corticosteroids:
- Any Intramascular (IM), Intravenous (IV) or Intra-arterial (IA) corticosteroids within 8 weeks of Day 1.
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Oral corticosteroids:
- Any treatment with >10 mg/day dose oral prednisolone (or equivalent) within 4 weeks of Day 1.
- New oral corticosteroid or changes in corticosteroid dose within the 4 weeks prior to Day 1. (New topical steroids and immunosuppressive agents (e.g., eye drops, creams) are permitted)
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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
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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.
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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 1.
- 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)

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03028467
Japan | |
GSK Investigational Site | |
Aichi, Japan, 440-8510 | |
GSK Investigational Site | |
Aichi, Japan, 455-8530 | |
GSK Investigational Site | |
Aichi, Japan, 457-8511 | |
GSK Investigational Site | |
Chiba, Japan, 260-8712 | |
GSK Investigational Site | |
Chiba, Japan, 270-2296 | |
GSK Investigational Site | |
Fukuoka, Japan, 810-8563 | |
GSK Investigational Site | |
Fukuoka, Japan, 814-0180 | |
GSK Investigational Site | |
Hyogo, Japan, 665-0827 | |
GSK Investigational Site | |
Hyogo, Japan, 673-1462 | |
GSK Investigational Site | |
Ibaraki, Japan, 312-0057 | |
GSK Investigational Site | |
Kanagawa, Japan, 222-0036 | |
GSK Investigational Site | |
Kanagawa, Japan, 240-8521 | |
GSK Investigational Site | |
Kanagawa, Japan, 245-8575 | |
GSK Investigational Site | |
Nagasaki, Japan, 857-1195 | |
GSK Investigational Site | |
Osaka, Japan, 543-8555 | |
GSK Investigational Site | |
Osaka, Japan, 586-8521 | |
GSK Investigational Site | |
Wakayama, Japan, 649-2211 |
Study Director: | GSK Clinical Trials | GlaxoSmithKline |
Additional Information:
Responsible Party: | GlaxoSmithKline |
ClinicalTrials.gov Identifier: | NCT03028467 History of Changes |
Other Study ID Numbers: |
201789 |
First Posted: | January 23, 2017 Key Record Dates |
Last Update Posted: | August 16, 2018 |
Last Verified: | August 2018 |
Individual Participant Data (IPD) Sharing Statement: | |
Plan to Share IPD: | Yes |
Plan Description: | IPD for this study will be made available via the Clinical Study Data Request site. |
Supporting Materials: |
Statistical Analysis Plan (SAP) |
Time Frame: | IPD is available via the Clinical Study Data Request site (click on the link provided below) |
Access Criteria: | Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months. |
URL: | https://clinicalstudydatarequest.com |
Studies a U.S. FDA-regulated Drug Product: | No | |
Studies a U.S. FDA-regulated Device Product: | No |
Keywords provided by GlaxoSmithKline:
GSK3196165 Active Rheumatoid Arthritis Methotrexate Monoclonal Antibody Efficacy |
Electrocardiogram Tolerability Pharmacokinetics Japanese Subjects |
Additional relevant MeSH terms:
Arthritis Arthritis, Rheumatoid Joint Diseases Musculoskeletal Diseases Rheumatic Diseases Connective Tissue Diseases Autoimmune Diseases Immune System Diseases Methotrexate Folic Acid Vitamin B Complex Abortifacient Agents, Nonsteroidal Abortifacient Agents Reproductive Control Agents Physiological Effects of Drugs |
Antimetabolites, Antineoplastic Antimetabolites Molecular Mechanisms of Pharmacological Action Antineoplastic Agents Dermatologic Agents Enzyme Inhibitors Folic Acid Antagonists Immunosuppressive Agents Immunologic Factors Antirheumatic Agents Nucleic Acid Synthesis Inhibitors Hematinics Vitamins Micronutrients Growth Substances |