Proof of Mechanism Study of GSK2330811 in Diffuse Cutaneous Systemic Sclerosis
Condition: Scleroderma, Systemic
MeSH terms: Scleroderma, Systemic; Scleroderma, Diffuse; Sclerosis
Intervention: GSK2330811; Placebo
Intervention description: GSK2330811 will be provided in vials and packed in 1 vial per carton. Each vial will contain 1.2 mL fill with 1 mL extractable volume at 100 mg/mL.; Normal saline (0.9 percent weight per volume sodium chloride).
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 35.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Systemic Sclerosis; Repeat-dose; Phase IIA; GSK2330811; Pharmacodynamics; Pharmacokinetics; Proof of mechanism study

Summary:

      GSK2330811 is a humanized monoclonal antibody which is in development for systemic sclerosis
      (SSc), a rare autoimmune disease with high morbidity and mortality. Currently, there are no
      approved disease modifying therapies and it is an area of high unmet medical need. GSK2330811
      has been shown to bind and neutralize Oncostatin M (OSM) that has been associated with
      fibrosis, vasculopathy and inflammation in a number of diseases. This multi-center,
      randomized, double-blind (sponsor open), placebo controlled, proof of mechanism study will be
      the first study to evaluate the safety, tolerability, pharmacokinetics (PK) and
      pharmacodynamics (PD) of repeat subcutaneous (SC) doses of GSK2330811 in male and female
      participants with diffuse cutaneous SSc (dcSSc). Participants with active disease and a
      disease duration of <= 60 months will be enrolled. Approximately 24 to 40 participants will
      be randomized across two sequential cohorts. Cohort 1 will evaluate a repeat-dose predicted
      to provide sub-maximal inhibition of OSM, leading to a dose escalation decision. Cohort 1 is
      planned to consist of at least 4 participants, randomized such that 3 participants will
      receive GSK2330811 100 milligram (mg) and 1 will receive placebo. Cohort 2 is planned to
      consist of at least 20 participants, randomized such that participants will receive
      GSK2330811 300 mg and placebo in a 3:1 ratio respectively. The duration of the study is up to
      34 weeks including a screening period of up to 6 weeks, treatment period of 12 weeks and
      follow-up period of 16 weeks.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Participants of 18 years or over, at the time of signing the informed consent.

          -  Documented diagnosis of systemic sclerosis with diffuse cutaneous involvement.

          -  Modified rodnan skin score (mRSS) >=10 and <=35 at screening.

          -  In all cases, a disease duration of <=60 months at screening, defined as time from
             onset of the first non-Raynaud's phenomenon manifestation.

          -  Active disease defined by at least one of the following criteria at screening:

               -  C-Reactive Protein (CRP) >=6 mg/liter (L) (0.6 mg/deciliter [dL]), that in the
                  opinion of the investigator is due to SSc.

               -  Disease duration <=18 months at screening, defined as time from the first
                  non-Raynaud's phenomenon manifestation.

               -  Increase of >=3 mRSS units, compared with an assessment performed within the
                  previous 6 months.

               -  Involvement of one new body area and an increase of >=2 mRSS units compared with
                  an assessment performed within the previous 6 months.

               -  Involvement of two new body areas within the previous 6 months.

          -  An area of uninvolved or mildly thickened skin that in the opinion of the investigator
             would allow subcutaneous injection either at abdomen, front or middle region of the
             thigh or at outer area of the upper arm.

          -  An area of involved skin (mRSS >=1) on the forearm suitable for repeated skin biopsies
             to be collected.

          -  Participants who are taking mycophenolate mofetil (<=3,000 mg/day) or equivalent
             mycophenolate sodium (<=2160 mg/day) are permitted in the study if the participant has
             been on a stable dose for >=3 months at the first dosing day (Day 1) and participant
             and investigator are willing to continue this dose until at least completion of the
             Day 85 (Week 12) visit. If mycophenolate was recently ceased, there must be >=3 months
             between the date mycophenolate was ceased and the first dosing day (Day 1).

          -  Participants who are taking oral corticosteroids (<=10 mg/day of prednisone or
             equivalent) are permitted in the study if the participant has been receiving a dose no
             greater than 10 mg/day for at least 4 weeks at the first dosing day (Day 1) and the
             investigator does not anticipate increasing the dose above 10 mg/day during the study.

          -  Participants who are taking phosphodiesterase 5 (PDE5) inhibitors and endothelin
             receptor antagonists (including bosentan) are permitted in the study if the
             participant has been on a stable dose for at least 4 weeks for PDE5 inhibitors and for
             at least 3 months for endothelin antagonists at the first dosing day (Day 1) and
             participant and investigator are willing to continue this dose until at least
             completion of the Day 85 (Week 12) visit.

          -  Participants who are taking non-immunosuppressive medications are permitted in the
             study (e.g. hydroxychloroquine, angiotensin converting enzyme (ACE)
             inhibitors/angiotensin II receptor (AR) blockers, calcium-channel blockers and
             proton-pump inhibitors). However no new long-term medications and no dose-changes to
             existing long term medications are permitted during the two weeks prior to the first
             dosing day (Day 1).

          -  Male participants must agree to use contraception during the dosing period and for at
             least 126 days (18 weeks) after the last dose of study treatment and refrain from
             donating sperm during this period.

          -  A female participant is eligible to participate if she is not pregnant, not
             breastfeeding, and either she is not a woman of childbearing potential (WOCBP) or she
             is a WOCBP who agrees to use contraceptives from 28 days prior to first dosing day
             (Day 1), during the dosing period and for at least 126 days (18 weeks) after the last
             dose of study treatment.

          -  Capable of giving signed informed consent which includes compliance with the
             requirements and restrictions for this study.

        Exclusion Criteria:

          -  Participants classified to the limited cutaneous SSc subset, as determined by the
             investigator.

          -  Rheumatic autoimmune disease other than dcSSc including but not limited to rheumatoid
             arthritis, systemic lupus erythematosus, mixed connective tissue disorder,
             polymyositis, dermatomyositis, systemic vasculitis and primary Sjogren's syndrome, as
             determined by the investigator.

          -  Forced vital capacity (FVC) <=50 percentage of predicted, or a diffusing capacity of
             the lung for carbon dioxide (DLCO) (corrected for hemoglobin) <=40 percentage of
             predicted at screening.

          -  Pulmonary arterial hypertension, as determined by the investigator.

          -  Clinically significant inflammatory myositis (related to SSc), as determined by the
             investigator.

          -  SSc renal crisis within 6 months of the first day of dosing (Day 1).

          -  History of clinically significant or uncontrolled cardiac, endocrinologic,
             hematologic, hepatic, immunologic, metabolic, urologic, pulmonary, neurologic,
             dermatologic, psychiatric, renal, and/or other major disease at screening not related
             to SSc and that in the opinion of the investigator would prevent participation in the
             study.

          -  Known bleeding or coagulation disorder.

          -  Major surgery (including joint surgery) within 3 months prior to screening, or planned
             during the duration of the study.

          -  Clinically significant multiple or severe drug allergies (including to humanized
             monoclonal antibodies), intolerance to topical corticosteroids, or severe
             post-treatment hypersensitivity reactions (including, but not limited to, erythema
             multiforme major, linear immunoglobulin A [IgA] dermatosis, toxic epidermal
             necrolysis, and exfoliative dermatitis).

          -  An active infection, or a history of infections as follows:

               -  History of opportunistic infections that have not resolved by 6 months prior to
                  the first day of dosing (Day1) or recurrent infection as determined by the
                  investigator. 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 frequency.

               -  A serious infection requiring treatment with intravenous antibiotics and/or
                  hospitalization, if the last dose of antibiotics or the hospital discharge date
                  was within 3 months of the first day of dosing (Day1).

               -  An acute or chronic infection requiring treatment with oral antibiotics or
                  antiviral medications, if the last dose was received within 4 weeks of the first
                  day of dosing (Day1).

               -  Any active or unresolved bacterial, viral or fungal infection present on the
                  first day of dosing (Day1), whether requiring treatment or not. This does not
                  include fungal nail infections.

               -  Active or past osteomyelitis, unless fully resolved in the opinion of the
                  investigator.

               -  Symptomatic herpes zoster that has not resolved by 3 months prior to the first
                  day of dosing (Day1).

               -  History of Tuberculosis (TB) or a positive QuantiFERON-TB Gold test or
                  QuantiFERON-TB Gold PLUS test at screening.

          -  If the QuantiFERON-TB Gold test or QuantiFERON-TB Gold PLUS test is indeterminate, it
             can be repeated once. A participant will not be eligible unless the second test is
             negative or they have a negative tuberculin skin test (defined as skin induration <5
             mm at 48 to 72 hours, regardless of Bacillus Calmette-Guerin or other vaccination
             history).

          -  There must be no other clinical evidence of TB on physical examination of the
             participant (screening examination).

          -  Alanine transferase (ALT) >2 times upper limit of normal (ULN) at screening.

          -  Bilirubin >1.5 times ULN at screening (isolated bilirubin >1.5 times ULN is acceptable
             if bilirubin is fractionated and direct bilirubin <35 percentage).

          -  Current or chronic history of liver disease, or known hepatic or biliary abnormalities
             (with the exception of gilbert's syndrome or asymptomatic gallstones). Participants
             with evidence of liver fat on imaging but who are otherwise eligible for the study
             criteria may be enrolled.

          -  QTc >480 milliseconds (msec) or QTc >500 msec in participants with bundle branch block
             at screening.

          -  A history of carcinoma in situ and malignant disease, with the exception of basal cell
             carcinoma that has been completely excised prior to the study.

          -  Treatment with methotrexate within 3 months prior to the first dosing day (Day 1).

          -  Previous or planned bone marrow transplant (e.g. autologous stem cell transplant).

          -  Treatment with a biologic within the following timeframes:

               -  Tocilizumab, abatacept or anti- tumor necrosis factor (including etanercept,
                  infliximab, certolizumab, golimumab or adalimumab) within 3 months prior to the
                  first dosing day (Day 1).

               -  Rituximab within 12 months prior to the first dosing day (Day 1).

               -  For any other biologic consult the medical monitor.

          -  Treatment with oral or intravenous cyclophosphamide within 6 months prior to the first
             dosing day (Day 1).

          -  Treatment with any other non-biologic systemic immunosuppressive medication (e.g.
             azathioprine, tacrolimus, ciclosporin) not mentioned above within 4 weeks prior to the
             first dosing day (Day 1), with the exception of mycophenolate and permitted oral
             corticosteroid.

          -  Treatment with topical immunosuppressive medications (e.g. topical corticosteroids,
             tacrolimus) within 1 week prior to the first dosing day (Day 1).

          -  Treatment with intravenous prostanoids (e.g. iloprost) within 2 weeks prior to the
             first dosing day (Day 1) or planned treatment before the Day 85 (Week 12) visit.

          -  Treatment with anti-fibrotic medications including tyrosine kinase inhibitors (e.g.
             nintedinib and imatinib) and pirfenidone within 3 months prior to the first dosing day
             (Day 1).

          -  Live vaccine(s) within 4 weeks prior to the first dosing day (Day 1), or plans to
             receive such vaccines during the study.

          -  Treatment with anti-coagulant medications, including warfarin, heparin, thrombin
             inhibitors, and factor Xa inhibitors within 2 weeks prior to the first dosing day (Day
             1).

          -  Treatment with anti-platelet medications (e.g. clopidogrel, prasugrel, ticagrelor and
             dipyridamole) within 2 weeks prior to first dosing day (Day 1). This does not include
             aspirin at doses of 150 mg or less, or non-steroidal anti-inflammatory drugs, which
             are permitted.

          -  Current enrollment or past participation within the last 30 days before signing of
             consent in any other clinical study involving an investigational study treatment.

          -  Exposure to more than 4 new chemical entities within 12 months prior to the first
             dosing day (Day 1).

          -  Any of the following at screening:

               -  Hemoglobin <110 gram (g)/L

               -  Platelet count <150x10^9/L

               -  Estimated glomerular filtration rate (GFR) (modification of diet in renal disease
                  [MDRD] calculation) of <45 mL/minute/1.73m^2

          -  A positive human immunodeficiency virus (HIV) antibody test at screening.

          -  Presence of hepatitis B surface antigen (HBsAg) at screening.

          -  Positive hepatitis B core antibody (HBcAb) test at screening.

          -  Positive hepatitis C antibody test result at screening or within 3 months prior to
             starting study treatment.

          -  Positive hepatitis C ribonucleic acid (RNA) test result at screening or within 3
             months prior to first dose of study treatment.

          -  Sensitivity to any of the study treatments or components thereof, or other allergy
             that in the opinion of the investigator, contraindicates participation in the study.

          -  Where participation in the study would result in donation of blood or blood products
             in excess of a volume of 500 mL during the study.

          -  A history of drug and alcohol misuse that could interfere with participation in the
             trial according to the protocol, or in the opinion of the investigator impacts on the
             physical or mental wellbeing of the participant.