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

• Register: ClinicalTrials.gov
• Last refreshed on: 12 December 2020
• Main ID: NCT03028467
• Date of registration: 10/01/2017
• Prospective Registration: Yes
• Primary sponsor: GlaxoSmithKline
• Public title: Evaluation of Pharmacokinetics and Safety of GSK3196165 in Combination With Methotrexate in Japanese Subjects With Rheumatoid Arthritis
• Scientific 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
• Date of first enrolment: January 24, 2017
• Target sample size: 15
• Recruitment status: Completed
• URL: https://clinicaltrials.gov/show/NCT03028467
• Study type: Interventional
• Study design: Allocation: Randomized. Intervention model: Parallel Assignment. Primary purpose: Treatment. Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor).
• Phase: Phase 1/Phase 2

Countries of recruitment

Japan

Contacts

• Name: GSK Clinical Trials
• Affiliation: GlaxoSmithKline (for GlaxoSmithKline; Human Genome Sciences Inc., a GSK Company; Sirtris, a GSK Company; Stiefel, a GSK Company; ViiV Healthcare)

• Name: GSK Clinical Trials
• Affiliation: GlaxoSmithKline

Key inclusion & exclusion 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 w


Age minimum: 20 Years
Age maximum: N/A
Gender: All

Health Condition(s) or Problem(s) studied

Arthritis, Rheumatoid

Intervention(s)

Drug: GSK3196165 Dose 2

Drug: Methotrexate

Drug: GSK3196165 Dose 1

Drug: Placebo

Drug: GSK3196165 Dose 3

Drug: Folic acid

Primary Outcome(s)

Terminal Half-life (t1/2) of GSK3196165 [Time Frame: 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 [Time Frame: 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 [Time Frame: 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) [Time Frame: Up to 22 weeks]

Maximum Observed Concentration (Cmax) of GSK3196165 [Time Frame: Pre-dose on Days 1, 8, 15, 29, 57 and 71; anytime during visit on Days 3, 74, 85, 106, 127 and 155]

Secondary Outcome(s)

Change From Baseline in Heart Rate (HR) [Time Frame: Baseline and up to 22 weeks]

Number of Participants With Urinalysis Dipstick Findings [Time Frame: Up to 22 weeks]

Change From Baseline in Body Temperature [Time Frame: Baseline and up to 22 weeks]

Change From Baseline in Disease Activity Score for 28 Different Joints C-reactive Protein (DAS28 [CRP]) at All Indicated Timepoints [Time Frame: Baseline, up to Week 22]

Number of Participants With Abnormal 12-lead Electrocardiogram (ECG) Findings [Time Frame: At Week 12]

Number of Participants With Anti-GSK3196165 Antibody Test Results [Time Frame: Weeks 2, 4, 12 and 22]

Change From Baseline in Respiratory Rate [Time Frame: Baseline and up to 22 weeks]

Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) [Time Frame: Baseline and up to 22 weeks]

Number of Participants With Emergent Hematology Results Relative to Normal Range [Time Frame: Up to 22 weeks]

Number of Participants With Emergent Clinical Chemistry Results Relative to Normal Range [Time Frame: Up to 22 weeks]

Secondary ID(s)

201789

Source(s) of Monetary Support

Please refer to primary and secondary sponsors

Results

• Results available: Yes
• Date Posted: 26/06/2019
• URL: https://clinicaltrials.gov/ct2/show/results/NCT03028467