Proof of Mechanism Study of GSK2330811 in Diffuse Cutaneous Systemic Sclerosis

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.