Proof of Mechanism Study of GSK2330811 in Diffuse Cutaneous Systemic Sclerosis

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.