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

NCT03028467 | Completed Phase 1 Results

• 1 other identifier: 201789
• Study Type: interventional
• Target: 15
• Locations: 1 country
• Sites: 32

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.

Conditions

Arthritis, Rheumatoid

Keywords

GSK3196165; Active Rheumatoid Arthritis; Methotrexate; Monoclonal Antibody; Efficacy; Electrocardiogram; Tolerability; Pharmacokinetics; Japanese Subjects

Outcome Measures

Primary Outcomes (5)

• Maximum Observed Concentration (Cmax) of GSK3196165

  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.

  Pre-dose on Days 1, 8, 15, 29, 57 and 71; anytime during visit on Days 3, 74, 85, 106, 127 and 155

• 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

  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.

  Pre-dose on Days 1, 8, 15, 29, 57 and 71; anytime during visit on Days 3, 74, 85, 106, 127 and 155

• Time to Reach Cmax (Tmax) of GSK3196165

  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).

  Pre-dose on Days 1, 8, 15, 29, 57 and 71; anytime during visit on Days 3, 74, 85, 106, 127 and 155

• Terminal Half-life (t1/2) of GSK3196165

  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.

  Pre-dose on Days 1, 8, 15, 29, 57 and 71; anytime during visit on Days 3, 74, 85, 106, 127 and 155.

• Number of Participants With Any Adverse Event (AE), Serious AE (SAE) and Adverse Events of Special Interest (AESI)

  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.

  Up to 22 weeks

Secondary Outcomes (10)

• 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

• Number of Participants With Abnormal 12-lead Electrocardiogram (ECG) Findings

  At Week 12

Study Arms (4)

GSK3196165 Dose 1

EXPERIMENTAL

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.

Drug: GSK3196165 Dose 1; Drug: Methotrexate; Drug: Folic acid

GSK3196165 Dose 2

EXPERIMENTAL

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.

Drug: GSK3196165 Dose 2; Drug: Methotrexate; Drug: Folic acid

GSK3196165 Dose 3

EXPERIMENTAL

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.

Drug: GSK3196165 Dose 3; Drug: Methotrexate; Drug: Folic acid

Placebo

PLACEBO COMPARATOR

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; Drug: Placebo; Drug: Folic acid

Interventions

GSK3196165 Dose 1 DRUG

GSK3196165 is supplied as liquid and will be administered as SC injection.

GSK3196165 Dose 1

GSK3196165 Dose 2 DRUG

GSK3196165 is supplied as liquid and will be administered as SC injection.

GSK3196165 Dose 2

GSK3196165 Dose 3 DRUG

GSK3196165 is supplied as liquid and will be administered as SC injection.

GSK3196165 Dose 3

Methotrexate DRUG

Methotrexate capsule/tablet 8-16 mg per week is given orally.

GSK3196165 Dose 1; GSK3196165 Dose 2; GSK3196165 Dose 3; Placebo

Placebo DRUG

Placebo is supplied as liquid as sterile 0.9% sodium chloride solution and will be administered as SC injection.

Placebo

Folic acid DRUG

Folic acid tablet 5 mg per week is given orally.

GSK3196165 Dose 1; GSK3196165 Dose 2; GSK3196165 Dose 3; Placebo

Eligibility Criteria

• Age: 20 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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)

You may not qualify if:

• 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

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (32)

GSK Investigational Site

Aichi, 440-8510, Japan

Location

GSK Investigational Site

Aichi, 440-85, Japan

Location

GSK Investigational Site

Aichi, 455-8530, Japan

Location

GSK Investigational Site

Aichi, 455-85, Japan

Location

GSK Investigational Site

Aichi, 457-8511, Japan

Location

GSK Investigational Site

Aichi, 457-85, Japan

Location

GSK Investigational Site

Chiba, 260-8712, Japan

Location

GSK Investigational Site

Chiba, 260-87, Japan

Location

GSK Investigational Site

Chiba, 270-2296, Japan

Location

GSK Investigational Site

Chiba, 270-22, Japan

Location

GSK Investigational Site

Fukuoka, 810-8563, Japan

Location

GSK Investigational Site

Fukuoka, 810-85, Japan

Location

GSK Investigational Site

Fukuoka, 814-0180, Japan

Location

GSK Investigational Site

Fukuoka, 814-01, Japan

Location

GSK Investigational Site

Hyōgo, 665-0827, Japan

Location

GSK Investigational Site

Hyōgo, 665-08, Japan

Location

GSK Investigational Site

Hyōgo, 673-1462, Japan

Location

GSK Investigational Site

Hyōgo, 673-14, Japan

Location

GSK Investigational Site

Ibaraki, 312-0057, Japan

Location

GSK Investigational Site

Ibaraki, 312-00, Japan

Location

GSK Investigational Site

Kanagawa, 222-0036, Japan

Location

GSK Investigational Site

Kanagawa, 240-8521, Japan

Location

GSK Investigational Site

Kanagawa, 240-85, Japan

Location

GSK Investigational Site

Kanagawa, 245-8575, Japan

Location

GSK Investigational Site

Kanagawa, 245-85, Japan

Location

GSK Investigational Site

Nagasaki, 857-1195, Japan

Location

GSK Investigational Site

Nagasaki, 857-11, Japan

Location

GSK Investigational Site

Osaka, 543-8555, Japan

Location

GSK Investigational Site

Osaka, 543-85, Japan

Location

GSK Investigational Site

Osaka, 586-8521, Japan

Location

GSK Investigational Site

Wakayama, 649-2211, Japan

Location

GSK Investigational Site

Wakayama, 649-22, Japan

Location

Related Links

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

MeSH Terms

Conditions

Arthritis, Rheumatoid

Interventions

Methotrexate; Folic Acid

Condition Hierarchy (Ancestors)

Arthritis; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Skin and Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Aminopterin; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

GSKClinicalSupportHD@gsk.com

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

• GSK Clinical Trials

  GlaxoSmithKline (for GlaxoSmithKline; Human Genome Sciences Inc., a GSK Company; Sirtris, a GSK Company; Stiefel, a GSK Company; ViiV Healthcare)

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 10, 2017
• First Posted: January 23, 2017
• Study Start: January 24, 2017
• Primary Completion: December 20, 2017
• Study Completion: December 20, 2017
• Last Updated: June 26, 2019
• Results First Posted: June 26, 2019

Record last verified: 2019-04

Data Sharing

• IPD Sharing: Will share
• Shared Documents: 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.

Locations

JP (32)