Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Efficacy of Repeat Doses of GSK2982772 in Subjects With Psoriasis
Condition: Psoriasis
MeSH terms: Psoriasis
Intervention: GSK2982772; Placebo
Intervention description: GSK2982772 will be supplied as a white to almost white, round, film coated 30 mg oral tablets; two tablets to be taken in the morning and two in the evening, as directed for Cohort 1 and for Cohort 2 two tablets to be taken three times daily as directed.; Matching placebo will be supplied as a white to almost white, round film coated tablets; two tablets to be taken in the morning and two in the evening, as directed for Cohort 1 and for Cohort 2 two tablets to be taken three times daily as directed.
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 65.0
Sex: All
Minimum age: 18 Years
Maximum age: 75 Years
Healthy volunteers: No
Keywords: tolerability; safety; GSK2982772; RIP1 kinase inhibitor; psoriasis

Summary:

      This is the first study with GSK2982772, a receptor-interacting protein-1 (RIP1) kinase
      inhibitor, in subjects with active plaque-type psoriasis (PsO). The primary objective will be
      to investigate the safety and tolerability of repeat oral doses of GSK2982772 60 milligram
      (mg) twice daily (BID) for 84 days in Cohort 1 and 60 mg thrice daily (TID) for 84 days in
      Cohort 2. In addition, a number of experimental and clinical endpoints will be employed to
      obtain information on the pharmacokinetics, pharmacodynamics, and efficacy in subjects with
      active PsO. There will be two Cohorts of subjects. In Cohort 1 after a screening period of up
      to 30 days, approximately 30 subjects will be randomized to receive either GSK2982772 60 mg
      BID or placebo for 84 days (12 Weeks), followed by a follow-up period (28 days). In Cohort 2
      after a screening period of up to 30 days, approximately 24 subjects will be randomized to
      receive either GSK2982772 60 mg TID or placebo for 84 days (12 Weeks), followed by a
      follow-up period (28 days). The total duration of participation is approximately 20 Weeks
      from screening to the last study visit.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Between 18 and 75 years of age inclusive, at the time of signing the informed consent.

          -  Subjects who do not have any medical conditions, other than active plaque-type
             psoriasis, that in the opinion of the Investigator put the subject at unacceptable
             risk or interfere with study assessments or integrity of the data. All medical
             conditions must be stable for the duration of the study.

          -  Presence of active chronic plaque-type psoriasis as determined by the Investigator for
             at least 6 months (confirmed by the subject or medical record) before first dose of
             study treatment (Day 1).

          -  Subject has psoriasis plaques involving Body Surface Area >=3% assessed at screening
             and before dosing on Day 1.

          -  Physician Global Assessment >=3.

          -  Subject must agree to avoid prolonged exposure to natural sunlight, tanning beds or
             phototherapy devices for the duration of the study

          -  Subject has at least two stable plaques assessed at screening and before dosing on Day
             1:

        Both must be of a suitable size (>=3 centimeter [cm] by 3 cm) and one in a site suitable
        for repeat biopsy, and one in a site suitable for index lesion PLSS scoring.

        Both plaques must have a PLSS lesional score >=2 for the induration component (moderate or
        above), >=1 for erythema and scaling with a total score of >=5.

        The biopsy lesion must not be on the face, groin, scalp, knees, elbows, or on the
        palmar/plantar surfaces of the hands/feet, and must be shielded from natural light with
        clothing.

          -  Subject is naive to any biologic therapies for psoriasis, OR has had previous exposure
             to a single anti- TNF biologic agent in the context of a previous clinical trial. The
             anti-TNF biologic agent must have been discontinued more than 8 weeks prior to
             screening visit (12 Weeks or 5 half lives whichever is longer from first dose).

          -  A body mass index within the range of 18.5-35 kilogram per meter square (kg)/m^2
             (inclusive).

          -  Male and Female subjects:

        Males: Male subjects with female partners of child bearing potential must comply with the
        pre specified contraception requirements.

        Females: A female subject is eligible to participate if she is not pregnant (as confirmed
        by a negative serum or urine human chorionic gonadotropin test), not lactating, and is
        either of non-reproductive potential or reproductive potential. If of reproductive
        potential, then the subject should agree to follow one of the options listed per GSK
        Modified List of Highly Effective Methods for Avoiding Pregnancy in Females of Reproductive
        Potential from 30 days prior to the first dose and until 30 days after the last dose of
        study medication The Investigator is responsible for ensuring that subjects understand how
        to properly use these methods of contraception.

          -  Capable of giving signed informed consent

        Exclusion Criteria:

          -  Subjects with clinically overt concurrent psoriatic arthritis who are receiving
             chronic disease-modifying anti-rheumatic medications therapy (other than non-steroidal
             anti-inflammatory drug), as judged by the Investigator.

          -  Has nonplaque forms of psoriasis (e.g. erythrodermic, guttate, or pustular), as judged
             by the Investigator.

          -  Has current drug-induced psoriasis (e.g., a new onset of psoriasis or an exacerbation
             from beta blockers, calcium channel blockers, or lithium).

          -  Subject with current history of Suicidal Ideation Behaviour as measured using the
             Columbia Suicide Severity Rating Scale or a history of attempted suicide.

          -  An active infection, or a history of infections as follows:

        Hospitalization for treatment of infection within 60 days before first dose (Day 1).

        Currently on any suppressive therapy for a chronic infection (such as pneumocystis,
        cytomegalovirus, herpes simplex virus, herpes zoster and atypical mycobacteria).

        Use of parenteral (intravenous or intramuscular) antibiotics (antibacterials, antivirals,
        antifungals, or antiparasitic agents) within 60 days before first dose.

        A history of opportunistic infections within 1 year of screening (e.g. pneumocystis
        jirovecii, cytomegalovirus, pneumonitis, aspergillosis). This does not include infections
        that may occur in immunocompetent individuals, such as fungal nail infections or vaginal
        candidiasis, unless it is of an unusual severity or recurrent nature.

        Recurrent or chronic infection or other active infection that, in the opinion of the
        Investigator might cause this study to be detrimental to the subject.

        History of tuberculosis (TB), irrespective of treatment status. A positive diagnostic TB
        test at screening defined as a positive QuantiFERON-TB Gold test or T-spot test.

        In cases where the QuantiFERON or T-spot test is indeterminate, the subject may have the
        test repeated once, but they will not be eligible for the study unless the second test is
        negative.

        In cases where the QuantiFERON or T-spot test is positive, but a locally-read follow up
        chest X-ray, shows no evidence of current or previous pulmonary tuberculosis, the subject
        may be eligible for the study at the discretion of the Investigator and medical monitor.

          -  ECG for heart rate QTc >450 milliseconds (msec) or QTc >480 msec in subjects with
             bundle branch block.

          -  Alanine aminotransferase >2×upper limit of normal (ULN) and bilirubin >1.5×ULN
             (isolated bilirubin >1.5×ULN 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).

          -  Current or history of renal disease or estimated glomerular filtrate rate by Chronic
             Kidney Disease Epidemiology Collaboration equation <60 mL/min/1.73 m^2.

          -  Hereditary or acquired immunodeficiency disorder, including immunoglobulin deficiency.

          -  A major organ transplant (e.g., heart, lung, kidney, liver) or hematopoietic stem
             cell/marrow transplant.

          -  A planned surgical procedure that, in the opinion of the Investigator, makes the
             subject unsuitable for the study.

          -  A history of malignant neoplasm within the last 5 years, except for adequately treated
             cancers of the skin (basal or squamous cell carcinoma) or carcinoma in situ of the
             uterine cervix that has been fully treated and shows no evidence of recurrence.

          -  A history of hypertrophic scarring or keloid formation, or known allergy to lidocaine
             or other local anaesthetics.

          -  The subject has received treatment with the specified therapies listed in the
             protocol, or changes to those treatments, within the specified timeframe.

        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 alcohol or drug abuse that would interfere with the ability to comply with
             the study.

          -  Subject intends to sunbathe or use a tanning device (sun bed or solarium) within 14
             days prior to Day 1 and until completion of the follow up visit (Day 112).

          -  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.

          -  Received a live or attenuated vaccine within 30 days of randomization OR plan to
             receive a vaccination during the study until completion of the follow-up visit.

          -  The subject has participated in a clinical trial and has received an investigational
             product within 30 days or 5 half-lives, whichever is longer before the first dose of
             study medication, or plans to take part in another clinical trial at the same time as
             participating in this clinical trial. Subjects who were randomized into Cohort 1 are
             not eligible to be re-randomized into Cohort 2.

          -  Hemoglobin <11 g/deciliter (dL); hematocrit <30%, white blood cell count
             =<3,000/millimeter (mm)^3 (<=3.0×10^9/L) ; platelet count <=100,000/microliter (µL)
             (<=100 × 10^9/L); absolute neutrophil count <=1.5×10^9/L at the screening visit.

          -  Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody test
             result at screening or within 3 months prior to first dose of study treatment. As
             potential for and magnitude of immunosuppression with this compound is unknown,
             subjects with presence of hepatitis B core antibody (HBcAb) should be excluded.
             Subjects positive for HBsAg and/or positive for anti-HBcAb (regardless of anti-HBs
             antibody status) are excluded.

          -  A positive serology for human immunodeficiency virus 1 or 2 at screening.

          -  Where participation in the study would result in donation of blood or blood products
             in excess of 500 mL within 3 months.

          -  Exposure to more than 4 investigational medicinal products within 12 months prior to
             the first dosing day