Efficacy, Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of GSK3117391 in Subjects With Rheumatoid Arthritis
Condition: Arthritis, Rheumatoid
MeSH terms: Arthritis; Arthritis, Rheumatoid
Intervention: GSK3117391; Placebo
Intervention description: GSK3117391 (Dose A) is a white, opaque, gelatin capsule.; Placebo is a white, opaque, gelatin capsule.
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 3.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: pharmacodynamics; tolerability; GSK3117391; safety; efficacy; rheumatoid arthritis; pharmacokinetics

Summary:

      GSK3117391 has the potential to complement existing therapies in the treatment of chronic
      inflammatory disorders such as rheumatoid arthritis (RA). This study will evaluate the
      efficacy, safety and tolerability of oral GSK3117391 (Dose A) administered to subjects with
      severe RA despite treatment with disease-modifying anti-rheumatic drugs (DMARDs). This is a
      randomised, double-blind (sponsor open), multicentre, placebo-controlled, parallel group
      study. The total maximum study duration is approximately 10 weeks. Following a screening
      period of up to 28 days, subjects will be randomized (1:1) to placebo or GSK3117391 (Dose A)
      administered orally for a period of 28 days. Subjects will be followed up for 7 to 14 days
      post final dose. Approximately 40 subjects with severe RA will be randomised into the study.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Age >=18 years at the time of signing the informed consent.

          -  The subject must have a diagnosis of RA according to the 2010 ACR/ European League
             Against Rheumatism (EULAR) classification criteria for RA.

          -  Functional class I, II or III defined by the 1992 ACR Classification of Functional
             Status in RA

          -  The subject must have a EULAR DAS 28-CRP of greater than 5.1 at screening.

          -  Disease duration of >6 months (time from onset of patient-reported symptoms of either
             pain or stiffness or swelling in hands, feet or wrists).

          -  Swollen joint count of >=6 (66-joint count) and tender joint count of >=8 (68-joint
             count) at screening and at day 1

          -  The subject must have a CRP serum level of >=5 mg/L at screening

          -  The subject has had an inadequate response or intolerance of DMARDs (due to lack of
             efficacy or toxicity, after at least 8 weeks treatment).

          -  Body weight >=45 kilograms (kg) and body mass index (BMI) within the 18.5 - 35
             kg/square metre (m^2) inclusive.

          -  Male or female requirements. Males: Male subjects with female partners of child
             bearing potential must comply with contraception requirements from the time of first
             dose of study medication 91 days after the last dose of study medication. In addition,
             male subjects must not donate sperm for 91 days after the last dose of study
             medication.

        Females: A female subject is eligible to participate if she is not pregnant (as confirmed
        by a negative human chorionic gonadotrophin [hCG] test), not lactating, and at least one of
        the following conditions applies:

          -  Non-reproductive potential defined as pre-menopausal females with one of the
             following: documented tubal ligation; documented hysteroscopic tubal occlusion
             procedure with follow-up confirmation of bilateral tubal occlusion; hysterectomy;
             documented Bilateral Oophorectomy. Postmenopausal defined as 12 months of spontaneous
             amenorrhea.

          -  Females of reproductive potential must have proper and established use of a Highly
             Effective Methods for Avoiding Pregnancy in Females of Reproductive Potential (FRP)
             from 28 days prior to the first dose of study medication and until 15 weeks after the
             last dose of study medication and completion of the follow-up visit. In addition,
             subjects will be required to utilise a barrier method of contraception. A negative HCG
             pregnancy test, (serum at screening visit and urine for subsequent visits) with a
             sensitivity of at least 25 international units per litre [IU/L]) is required at the
             screening visit, between Day -7 to -4 and on Day 1 prior to dose administration.
             Further pregnancy tests are required at the weekly study visits and the follow-up
             visit.

               -  Capable of giving signed informed consent that includes compliance with the
                  requirements and restrictions listed in the consent form and in the protocol.

        Exclusion Criteria:

          -  Pregnant or lactating women.

          -  Subjects who meet diagnostic criteria for any other rheumatic disease (example [eg],
             lupus erythematosus, gout, psoriatic arthritis).

          -  Subjects who have previously been treated with more than 1 biologic agent (such as TNF
             inhibitors eg. adalimumab, etanercept, infliximab, certolizumab, golimumab or non-TNF
             inhibitors eg. abatacept, rituximab, tociluzimab) or any investigational biologic.

          -  Subjects with past history of granulomatous disease eg. leprosy, sarcoidosis.

          -  Subjects with current symptoms of severe, progressive, or uncontrolled renal, hepatic,
             haematological (including clotting disorders), gastrointestinal (including
             gastrooesophageal ulcers), pulmonary, cardiac (including ischemic heart disease),
             neurological, or cerebral disease, or other medical conditions that, in the opinion of
             the Investigator, might place the subject at unacceptable risk for participation in
             this study.

          -  Subjects with any values for monocytes are below the lower limit of normal (LLN) at
             screening.

          -  Haemoglobin <11 grams (g)/decilitre (dL); haematocrit <30%, white blood cell count
             <=3,000/cubic millimeter (mm^3) (<=3.0 x 10^9/litre [L]) or >=14,000/mm^3 (>=14 x
             10^9/L); platelet count <= 100,000/microlitre (μL) (<=100x10^9/L); absolute neutrophil
             count <=2x10^9/L; lymphocyte count <1x10^9/L at screening.

          -  Alanine transaminase (ALT) and bilirubin >1.5xupper limit of normal (ULN) (isolated
             bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin
             <35%) at screening.

          -  Current or chronic history of liver disease, or known hepatic or biliary abnormalities
             (with the exception of Gilbert's syndrome or asymptomatic gallstones).

          -  Corrected QT interval (QTc) by Fridericia's correction formula (QTcF) or QTc by
             Bazett's correction formula (QTcB) >450 milliseconds (msec) (based on the average of
             triplicate electrocardiograms [ECGs]) at screening.

          -  Abnormal findings on ECG considered clinically significant by the investigator.

          -  A history of carcinoma in situ and malignant disease, except for adequately treated
             non-invasive cancers of the skin (basal or squamous cell) or carcinoma in situ of the
             uterine cervix.

          -  Hereditary or acquired immunodeficiency disorder, including immunoglobulin deficiency.

          -  Abnormal chest X-ray within 12 weeks of Day 1 (locally read and reported by a
             radiologist) judged by the investigator as clinically-significant.

          -  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).

               -  Hospitalisation for treatment of infection within 12 weeks of Day 1.

               -  Use of parenteral (intravenous [IV] or intramuscular [IM]) antimicrobials
                  (antibacterials, antivirals, antifungals, or antiparasitic agents) within 12
                  weeks of Day 1 or oral antimicrobials within 14 days of Day 1.

          -  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 or follow-up
             period.

          -  A vaccination (live or attenuated) within 30 days of Day 1 or Bacillus Calmette-Guérin
             (BCG) vaccination within 365 days of Day 1, or a live vaccination planned during the
             course of the study.

          -  The subject has received treatment with the therapies prohibited or changes to those
             treatments in the prescribed timeframe. Subjects who have previously taken >1 biologic
             therapy for RA are excluded from this study.

          -  Other medications (including vitamins, herbal and dietary supplements) will be
             considered on a case-by-case basis, and will be allowed if in the opinion of the
             investigator the medication will not interfere with the study procedures or compromise
             subject safety.

          -  History of regular alcohol consumption within 6 months of the study defined as an
             average weekly intake of >21 units for males or >14 units for females. One unit is
             equivalent to 8 g of alcohol: a half-pint (~240 millilitre [mL]) of beer, 1 glass (125
             mL) of wine or 1 (25 mL) measure of spirits.

          -  Smokers who would not be able to refrain from smoking whilst in the clinic.

          -  Subjects who cannot refrain from consuming any of the following fruits or juices
             (alone or in combination): seville oranges, grapefruit, pummelos, or any citrus fruits
             from 7 days prior to the first dose of study medication until their discharge from the
             unit after their last dose of study medication.

          -  History of sensitivity to any components of the study medication, or a history of drug
             or other allergy that, in the opinion of the Investigator or Medical Monitor,
             contraindicates their participation.

          -  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 6 weeks of Day 1: Subjects positive for HBsAg
             and/or positive for anti-HBc antibody (regardless of anti-HBs antibody status) are
             excluded

          -  Hepatitis C: Positive test for Hepatitis C virus (HCV) antibody confirmed on a
             subsequent blood sample by Ribonucleic acid (RNA)-polymerase chain reaction (PCR)
             assay within 6 weeks of Day 1. Subjects who are positive for Hepatitis C antibody and
             negative for Hepatitis C RNA-PCR assay performed on a subsequent sample will be
             eligible to participate. Subjects who are positive for Hepatitis C antibody and have a
             positive result for Hepatitis C RNA-PCR assay performed on the subsequent sample,will
             not be eligible to participate.

          -  A positive test for HIV 1 or 2 at screening.

          -  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 diagnostic TB test within 28 days of baseline (Day 1) defined as: A
                  negative QuantiFERON Gold test or T-spot test (two successive indeterminate
                  QuantiFERON tests will be considered as a positive result) OR If QuantiFERON gold
                  or T-spot test not approved or registered in country of participation, then a
                  negative tuberculin skin test (TST) reaction as per local guidelines is required
                  (it is strongly recommended that subjects with a history of BCG vaccination be
                  tested with QuantiFERON gold test).

               -  Chest X-ray within 12 weeks of Day 1 with no evidence of current or previous
                  pulmonary tuberculosis, locally read by a radiologist.

          -  Glucose-6-phosphate dehydrogenase (G6PD) deficiency.

          -  Participation in a trial with any investigational drug within 3 months or 5 half-lives
             (whichever is longer) before the start of the study and within 4 months if the study
             drug was new chemical entity. Exposure to more than 3 new chemical entities in a
             clinical study setting within 12 months prior to the first dosing day.

          -  Donation of blood in excess of 500 mL within a 56 day period prior to dosing.