NCT03041025 - Proof of Mechanism Study of GSK2330811 in Diffuse Cutaneous Systemic Sclerosis | Crick

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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.

Outcomes

Primary Outcomes

Number of Participants With Non-serious Adverse Events (Non-SAEs) and Serious Adverse Events (SAEs)

An adverse event (AE) is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. An SAE is defined as any untoward medical occurrence that: results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, is a congenital anomaly/birth defect, other situations judged by physician. SAEs were collected up to Day 197, but the protocol also allowed investigators to report SAEs occurring after participants had completed the study. This outcome measure includes two SAEs reported after participants had completed the study, occurring on Day 306 and Day 603 following first dose. Safety Population consisted of all randomized participants who have taken at least 1 dose of study treatment.

Time frame: Up to Day 197, but protocol allowed for additional events to be collected; up to Day 603 post first dose

Change From Baseline in Hematology Parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils, Platelet Count, White Blood Cell (WBC) Count

Blood samples were collected to analyze the hematology parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils, Platelet Count and WBC count. Baseline was defined as the pre-dose Day 1 assessment, unless unavailable, in which case it was the latest pre-dose assessment. Change from Baseline was calculated by subtracting the Baseline value from the post-dose visit value.

Time frame: Baseline (Day 1: Pre-dose), Days 15, 29, 43, 57, 71, 85, 113, 155 and 197

Change From Baseline in Hematology Parameters: Hemoglobin, Mean Corpuscle Hemoglobin Concentration (MCHC)

Blood samples were collected to analyze the hematology parameters: hemoglobin and MCHC. Baseline was defined as the pre-dose Day 1 assessment, unless unavailable, in which case it was the latest pre-dose assessment. Change from Baseline was calculated by subtracting the Baseline value from the post-dose visit value.

Time frame: Baseline (Day 1: Pre-dose), Days 15, 29, 43, 57, 71, 85, 113, 155 and 197

Change From Baseline in Hematology Parameter: Hematocrit

Blood samples were collected to analyze the hematology parameter: hematocrit. Baseline was defined as the pre-dose Day 1 assessment, unless unavailable, in which case it was the latest pre-dose assessment. Change from Baseline was calculated by subtracting the Baseline value from the post-dose visit value.

Time frame: Baseline (Day 1: Pre-dose), Days 15, 29, 43, 57, 71, 85, 113, 155 and 197

Change From Baseline in Hematology Parameter: Mean Corpuscle Hemoglobin (MCH)

Blood samples were collected to analyze the hematology parameter: MCH. Baseline was defined as the pre-dose Day 1 assessment, unless unavailable, in which case it was the latest pre-dose assessment. Change from Baseline was calculated by subtracting the Baseline value from the post-dose visit value.

Time frame: Baseline (Day 1: Pre-dose), Days 15, 29, 43, 57, 71, 85, 113, 155 and 197

Change From Baseline in Hematology Parameters: Mean Corpuscle Volume (MCV), Mean Platelet Volume (MPV)

Blood samples were collected to analyze the hematology parameters: MCV and MPV. Baseline was defined as the pre-dose Day 1 assessment, unless unavailable, in which case it was the latest pre-dose assessment. Change from Baseline was calculated by subtracting the Baseline value from the post-dose visit value.

Time frame: Baseline (Day 1: Pre-dose), Days 15, 29, 43, 57, 71, 85, 113, 155 and 197

Change From Baseline in Hematology Parameters: Red Blood Cell (RBC) Count, Reticulocyte Count

Blood samples were collected to analyze the hematology parameters: RBC count and reticulocyte count. Baseline was defined as the pre-dose Day 1 assessment, unless unavailable, in which case it was the latest pre-dose assessment. Change from Baseline was calculated by subtracting the Baseline value from the post-dose visit value.

Time frame: Baseline (Day 1: Pre-dose), Days 15, 29, 43, 57, 71, 85, 113, 155 and 197

Change From Baseline in Hematology Parameter: Red Cell Distribution Width (RDW)

Blood samples were collected to analyze the hematology parameter: RDW. Baseline was defined as the pre-dose Day 1 assessment, unless unavailable, in which case it was the latest pre-dose assessment. Change from Baseline was calculated by subtracting the Baseline value from the post-dose visit value.

Time frame: Baseline (Day 1: Pre-dose), Days 15, 29, 43, 57, 71, 85, 113, 155 and 197

Change From Baseline in Reticulocyte Production Index

Blood samples were collected to analyze the hematology parameter: Reticulocyte Production Index. Baseline was defined as the pre-dose Day 1 assessment, unless unavailable, in which case it was the latest pre-dose assessment. Change from Baseline was calculated by subtracting the Baseline value from the post-dose visit value. Reticulocyte Production Index (RPI) was calculated as 'Reticulocyte Production Index = Reticulocyte Count (percent \[%\]) multiply by (x) (hematocrit \[%\] divided by \[/\] 45) x 1/ reticulocyte maturation time'.

Time frame: Baseline (Day 1: Pre-dose), Days 15, 29, 43, 57, 71, 85, 113, 155 and 197

Change From Baseline Hematology Parameter: Reticulocytes

Blood samples were collected to analyze the hematology parameter: reticulocytes. Baseline was defined as the pre-dose Day 1 assessment, unless unavailable, in which case it was the latest pre-dose assessment. Change from Baseline was calculated by subtracting the Baseline value from the post-dose visit value.

Time frame: Baseline (Day 1: Pre-dose), Days 15, 29, 43, 57, 71, 85, 113, 155 and 197

Number of Participants With Worst-Case Chemistry Results Relative to Potential Clinical Importance (PCI) Criteria Post-Baseline Relative to Baseline

Blood samples were collected for analysis of clinical chemistry parameters. PCI ranges were low: \<30 grams per liter (g/L) (albumin), high: \>44.2 micromoles per liter (µmol/L) increase from Baseline (creatinine), low: \<3 or high: \>9 mmol/L (glucose), low: \<3 or high: \>5.5 mmol/L (potassium), and low: \<130 or high: \>150 mmol/L (sodium). Participants were counted in the worst case category that their value changes to (low, within range or no change, or high), unless there was no change in their category. Participants whose laboratory value category was unchanged (e.g. High to High), or whose value became within range, were recorded in the "To within Range or No Change" category. Participants were counted twice if the participant had values that changed 'To Low' and 'To High', so the percentages may not add up to 100%.

Time frame: Up to Day 197

Change From Baseline in Chemistry Parameter: Total Protein

Blood samples were collected to analyze chemistry parameter: total protein. Baseline was defined as the pre-dose Day 1 assessment, unless unavailable, in which case it was the latest pre-dose assessment. Change from Baseline was calculated by subtracting the Baseline value from the post-dose visit value.

Time frame: Baseline (Day 1: Pre-dose), Days 15, 29, 43, 57, 71, 85, 113, 155 and 197

Change From Baseline in Chemistry Parameters: Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Lactate Dehydrogenase (LDH)

Blood samples were collected to analyze chemistry parameters: ALP, ALT, AST and LDH. Baseline was defined as the pre-dose Day 1 assessment, unless unavailable, in which case it was the latest pre-dose assessment. Change from Baseline was calculated by subtracting the Baseline value from the post-dose visit value.

Time frame: Baseline (Day 1: Pre-dose), Days 15, 29, 43, 57, 71, 85, 113, 155 and 197

Change From Baseline in Chemistry Parameters: Total Bilirubin, Direct Bilirubin

Blood samples were collected to analyze chemistry parameters: total bilirubin and direct bilirubin. Baseline was defined as the pre-dose Day 1 assessment, unless unavailable, in which case it was the latest pre-dose assessment. Change from Baseline was calculated by subtracting the Baseline value from the post-dose visit value.

Time frame: Baseline (Day 1: Pre-dose), Days 15, 29, 43, 57, 71, 85, 113, 155 and 197

Change From Baseline in Chemistry Parameters: Cholesterol, Direct High-density Lipoprotein (HDL) Cholesterol, Low-density Lipoprotein (LDL) Cholesterol, Triglycerides

Blood samples were collected to analyze chemistry parameters: cholesterol, direct HDL cholesterol, LDL cholesterol and triglycerides. Baseline was defined as the pre-dose Day 1 assessment, unless unavailable, in which case it was the latest pre-dose assessment. Change from Baseline was calculated by subtracting the Baseline value from post-dose visit value.

Time frame: Baseline (Day 1: Pre-dose) and Day 85

Change From Baseline in Chemistry Parameter: Corrected Calcium, Urea

Blood samples were collected to analyze chemistry parameters: corrected calcium and urea. Baseline was defined as the pre-dose Day 1 assessment, unless unavailable, in which case it was the latest pre-dose assessment. Change from Baseline was calculated by subtracting the Baseline value from the post-dose visit value.

Time frame: Baseline (Day 1: Pre-dose), Days 15, 29, 43, 57, 71, 85, 113, 155 and 197

Change From Baseline in Chemistry Parameter: Estimated Glomerular Filtration Rate

Blood samples were collected to analyze chemistry parameter: estimated glomerular filtration rate. Baseline was defined as the pre-dose Day 1 assessment, unless unavailable, in which case it was the latest pre-dose assessment. Change from Baseline was calculated by subtracting the Baseline value from the post-dose visit value.

Time frame: Baseline (Day 1: Pre-dose), Days 15, 29, 43, 57, 71, 85, 113, 155 and 197

Number of Participants With Emergent Worst Case Urinalysis Results by Dipstick

Urine samples were collected for the assessment of potential of hydrogen, specific gravity, glucose, ketones, occult blood and protein by dipstick method. The dipstick test gave results in a semi-quantitative manner, and results for urinalysis parameters: potential of hydrogen, specific gravity, glucose, ketones, occult blood and protein were categorized as 'any increase from Baseline', which imply any increase in their concentrations in the urine sample. Only participants with emergent worst case any increase from Baseline values are presented.

Time frame: Up to Day 197

Number of Participants With Vital Signs Relative to Change From Baseline by Potential Clinical Importance (PCI) Criteria

Systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR) were measured in a seated or semi-supine position after 5 minutes of rest using a completely automated device. PCI ranges were: SBP (increase or decrease from Baseline of \>=40 millimeter of mercury \[mmHg\]), DBP (increase or decrease from Baseline of \>=20 mmHg), and HR (increase or decrease from Baseline of \>=30 beats per minute). Baseline was defined as the pre-dose Day 1 assessment, unless unavailable, in which case it was the latest pre-dose assessment.

Time frame: Baseline (Day 1: Pre-dose) and up to Day 197

Change From Baseline in Body Temperature

Body temperature was measured in a seated or semi-supine position after 5 minutes of rest. Baseline was defined as the pre-dose Day 1 assessment, unless unavailable, in which case it was the latest pre-dose assessment. Change from Baseline was calculated by subtracting the Baseline value from the post-dose visit value.

Time frame: Baseline (Day 1: Pre-dose), Days 15, 29, 43, 57, 71, 85, 113, 155 and 197

Number of Participants With Worst-case Post-Baseline Abnormal Electrocardiogram (ECG) Findings

Twelve lead ECGs were obtained using an ECG machine that automatically calculated the heart rate and measured PR, QRS, QT, and corrected QT intervals. Abnormal findings were categorized as clinically significant and not clinically significant. Clinically significant abnormal findings were those which were not associated with the underlying disease, unless judged by the investigator to be more severe than expected for the participant's condition. Data for number of participants with worst case post-Baseline abnormal ECG findings have been presented.

Time frame: Up to Day 57

Secondary Outcomes

Plasma Concentrations of GSK2330811

Blood samples were collected at the indicated time points for pharmacokinetic analysis of GSK2330811. Pharmacokinetic (PK) Population was defined as participants in the 'Safety' population who received an active dose and for whom a PK sample was obtained and analyzed.

Time frame: Days 1, 15, 29, 57, 85, 113, 155 and 197

Concentration at the End of the Dosing Interval (Ctrough) of GSK2330811

Blood samples were collected at the indicated time points for PK analysis of GSK2330811.

Time frame: Days 1, 15, 29, 57, 85, 113, 155 and 197

Apparent Clearance (CL/F) of GSK2330811

Blood samples were collected at the indicated time points for PK analysis of GSK2330811. Data was analyzed by population pharmacokinetic methods using a non-linear mixed-effects modelling approach.

Time frame: Days 1, 15, 29, 57, 85, 113, 155 and 197

Apparent Volume of Distribution (Vss/F) of GSK2330811

Blood samples were collected at the indicated time points for PK analysis of GSK2330811. Data was analyzed by population pharmacokinetic methods using a non-linear mixed-effects modelling approach.

Time frame: Days 1, 15, 29, 57, 85, 113, 155 and 197

Serum Level of Total Oncostatin M (OSM)

Blood samples were collected at indicated timepoints for analysis of total OSM levels in serum. Per Protocol Population comprised of participants in the 'Safety' population who complied with the protocol.

Time frame: Days 1, 15, 29, 57, 85, 113, 155 and 197

Serum Level of Free OSM

Blood samples were collected at indicated timepoints for analysis of free OSM levels in serum.

Time frame: Days 1, 15, 29, 57, 85, 113, 155 and 197

Number of Participants With Positive Anti-GSK2330811 Antibodies

Proof of Mechanism Study of GSK2330811 in Diffuse Cutaneous Systemic Sclerosis

Overview

Conditions

Interventions

Eligibility

Locations (14)

Outcomes

Primary Outcomes

Secondary Outcomes