Evaluation of Pharmacokinetics and Safety of GSK3196165 in Combination With Methotrexate in Japanese Subjects With Rheumatoid Arthritis

• Sponsor: GlaxoSmithKline
• Information provided by (Responsible Party): GlaxoSmithKline

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Arthritis, Rheumatoid	Drug: GSK3196165 Dose 1; Drug: GSK3196165 Dose 2; Drug: GSK3196165 Dose 3; Drug: Methotrexate; Drug: Placebo; Drug: Folic acid	Phase 2

Study Design

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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

Arms and Interventions

Arm	Intervention/treatment
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.	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.	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.	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.	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.

Outcome Measures

Primary Outcome Measures :

1. 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
2. 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
3. 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
4. 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
5. 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
6. 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.
7. 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.
8. Number of subjects with any AE of special interest [ Time Frame: Up to 26 weeks ]
   AESI's will be assessed

Secondary Outcome Measures :

1. 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.
2. Number of subjects with abnormal 12-lead electrocardiogram (ECG) findings [ Time Frame: Up to 22 weeks ]
   ECG will be performed
3. Average of laboratory values [ Time Frame: Up to 22 weeks ]
   Hematology, clinical chemistry, and urinalysis parameters will be measured.
4. 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

Eligibility Criteria

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Ages Eligible for Study:	20 Years and older (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

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)

• 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

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

• 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.

• 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)

• 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 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)

Contacts and Locations

Locations

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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

Sponsors and Collaborators

GlaxoSmithKline

Investigators

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Study Director:	GSK Clinical Trials	GlaxoSmithKline

  Study Documents (Full-Text)

Documents provided by GlaxoSmithKline:

Study Protocol  [PDF] May 19, 2017

More Information

Additional Information:

IPD for this study will be made available via the Clinical Study Data Request site. 

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Responsible Party:	GlaxoSmithKline
ClinicalTrials.gov Identifier:	NCT03028467 History of Changes
Other Study ID Numbers:	201789
First Posted:	January 23, 2017
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

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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:

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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; Nutrients