Clinical trial NCT03041025: Proof of Mechanism Study of GSK2330811 in Diffuse Cutaneous Systemic Sclerosis
Official title: A Multi-center, Randomized, Double-blind (Sponsor Open), Placebo-controlled, Repeat-dose, Proof of Mechanism Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Explore Efficacy of GSK2330811 in Participants With Diffuse Cutaneous Systemic Sclerosis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Scleroderma, Systemic
Keywords: Systemic Sclerosis
Repeat-dose
Phase IIA
GSK2330811
Pharmacodynamics
Pharmacokinetics
Proof of mechanism study
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2017-02-02
Enrollment: 35
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Primary outcomes:
measure: Number of Participants With Non-serious Adverse Events (Non-SAEs) and Serious Adverse Events (SAEs)
timeFrame: Up to Day 197, but protocol allowed for additional events to be collected; up to Day 603 post first dose
measure: Change From Baseline in Hematology Parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils, Platelet Count, White Blood Cell (WBC) Count
timeFrame: Baseline (Day 1: Pre-dose), Days 15, 29, 43, 57, 71, 85, 113, 155 and 197
measure: Change From Baseline in Hematology Parameters: Hemoglobin, Mean Corpuscle Hemoglobin Concentration (MCHC)
timeFrame: Baseline (Day 1: Pre-dose), Days 15, 29, 43, 57, 71, 85, 113, 155 and 197
measure: Change From Baseline in Hematology Parameter: Hematocrit
timeFrame: Baseline (Day 1: Pre-dose), Days 15, 29, 43, 57, 71, 85, 113, 155 and 197
measure: Change From Baseline in Hematology Parameter: Mean Corpuscle Hemoglobin (MCH)
timeFrame: Baseline (Day 1: Pre-dose), Days 15, 29, 43, 57, 71, 85, 113, 155 and 197
measure: Change From Baseline in Hematology Parameters: Mean Corpuscle Volume (MCV), Mean Platelet Volume (MPV)
timeFrame: Baseline (Day 1: Pre-dose), Days 15, 29, 43, 57, 71, 85, 113, 155 and 197
measure: Change From Baseline in Hematology Parameters: Red Blood Cell (RBC) Count, Reticulocyte Count
timeFrame: Baseline (Day 1: Pre-dose), Days 15, 29, 43, 57, 71, 85, 113, 155 and 197
measure: Change From Baseline in Hematology Parameter: Red Cell Distribution Width (RDW)
timeFrame: Baseline (Day 1: Pre-dose), Days 15, 29, 43, 57, 71, 85, 113, 155 and 197
measure: Change From Baseline in Reticulocyte Production Index
timeFrame: Baseline (Day 1: Pre-dose), Days 15, 29, 43, 57, 71, 85, 113, 155 and 197
measure: Change From Baseline Hematology Parameter: Reticulocytes
timeFrame: Baseline (Day 1: Pre-dose), Days 15, 29, 43, 57, 71, 85, 113, 155 and 197
measure: Number of Participants With Worst-Case Chemistry Results Relative to Potential Clinical Importance (PCI) Criteria Post-Baseline Relative to Baseline
timeFrame: Up to Day 197
measure: Change From Baseline in Chemistry Parameter: Total Protein
timeFrame: Baseline (Day 1: Pre-dose), Days 15, 29, 43, 57, 71, 85, 113, 155 and 197
measure: Change From Baseline in Chemistry Parameters: Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Lactate Dehydrogenase (LDH)
timeFrame: Baseline (Day 1: Pre-dose), Days 15, 29, 43, 57, 71, 85, 113, 155 and 197
measure: Change From Baseline in Chemistry Parameters: Total Bilirubin, Direct Bilirubin
timeFrame: Baseline (Day 1: Pre-dose), Days 15, 29, 43, 57, 71, 85, 113, 155 and 197
measure: Change From Baseline in Chemistry Parameters: Cholesterol, Direct High-density Lipoprotein (HDL) Cholesterol, Low-density Lipoprotein (LDL) Cholesterol, Triglycerides
timeFrame: Baseline (Day 1: Pre-dose) and Day 85
measure: Change From Baseline in Chemistry Parameter: Corrected Calcium, Urea
timeFrame: Baseline (Day 1: Pre-dose), Days 15, 29, 43, 57, 71, 85, 113, 155 and 197
measure: Change From Baseline in Chemistry Parameter: Estimated Glomerular Filtration Rate
timeFrame: Baseline (Day 1: Pre-dose), Days 15, 29, 43, 57, 71, 85, 113, 155 and 197
measure: Number of Participants With Emergent Worst Case Urinalysis Results by Dipstick
timeFrame: Up to Day 197
measure: Number of Participants With Vital Signs Relative to Change From Baseline by Potential Clinical Importance (PCI) Criteria
timeFrame: Baseline (Day 1: Pre-dose) and up to Day 197
measure: Change From Baseline in Body Temperature
timeFrame: Baseline (Day 1: Pre-dose), Days 15, 29, 43, 57, 71, 85, 113, 155 and 197
measure: Number of Participants With Worst-case Post-Baseline Abnormal Electrocardiogram (ECG) Findings
timeFrame: Up to Day 57
Secondary outcomes:
measure: Plasma Concentrations of GSK2330811
timeFrame: Days 1, 15, 29, 57, 85, 113, 155 and 197
measure: Concentration at the End of the Dosing Interval (Ctrough) of GSK2330811
timeFrame: Days 1, 15, 29, 57, 85, 113, 155 and 197
measure: Apparent Clearance (CL/F) of GSK2330811
timeFrame: Days 1, 15, 29, 57, 85, 113, 155 and 197
measure: Apparent Volume of Distribution (Vss/F) of GSK2330811
timeFrame: Days 1, 15, 29, 57, 85, 113, 155 and 197
measure: Serum Level of Total Oncostatin M (OSM)
timeFrame: Days 1, 15, 29, 57, 85, 113, 155 and 197
measure: Serum Level of Free OSM
timeFrame: Days 1, 15, 29, 57, 85, 113, 155 and 197
measure: Number of Participants With Positive Anti-GSK2330811 Antibodies
timeFrame: Days 1, 15, 57, 85 and 197
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: GSK Investigational Site
state: California
city: Stanford
country: United States
facility: GSK Investigational Site
state: California
city: Chicago
country: United States
facility: GSK Investigational Site
state: Illinois
city: Baltimore
country: United States
facility: GSK Investigational Site
state: Maryland
city: Boston
country: United States
facility: GSK Investigational Site
state: Massachusetts
city: Ann Arbor
country: United States
facility: GSK Investigational Site
state: Michigan
city: Toronto
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Nijmegen
country: Netherlands
facility: GSK Investigational Site
city: Salford
country: United Kingdom
facility: GSK Investigational Site
state: Greater Manchester
city: Liverpool
country: United Kingdom
facility: GSK Investigational Site
state: Merseyside
city: Birmingham
country: United Kingdom
facility: GSK Investigational Site
city: Dundee
country: United Kingdom
facility: GSK Investigational Site
city: Leeds
country: United Kingdom
facility: GSK Investigational Site
city: London
country: United Kingdom
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Denton CP, Del Galdo F, Khanna D, Vonk MC, Chung L, Johnson SR, Varga J, Furst DE, Temple J, Zecchin C, Csomor E, Lee A, Wisniacki N, Flint SM, Reid J. Biological and clinical insights from a randomized phase 2 study of an anti-oncostatin M monoclonal antibody in systemic sclerosis. Rheumatology (Oxford). 2022 Dec 23;62(1):234-242. doi: 10.1093/rheumatology/keac300.