Proof of Mechanism Study of GSK2330811 in Diffuse Cutaneous Systemic Sclerosis

NCT03041025 | Completed Phase 2 Results FDA Drug

• 2 other identifiers: 2012472016-003417-95
• Study Type: interventional
• Target: 35
• Locations: 4 countries
• Sites: 14

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.

Conditions

Scleroderma, Systemic

Keywords

Systemic Sclerosis; Repeat-dose; Phase IIA; GSK2330811; Pharmacodynamics; Pharmacokinetics; Proof of mechanism study

Outcome Measures

Primary Outcomes (21)

• 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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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'.

  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.

  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%.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  Up to Day 57

Secondary Outcomes (7)

• Plasma Concentrations of GSK2330811

  Days 1, 15, 29, 57, 85, 113, 155 and 197

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

  Days 1, 15, 29, 57, 85, 113, 155 and 197

• Apparent Clearance (CL/F) of GSK2330811

  Days 1, 15, 29, 57, 85, 113, 155 and 197

• Apparent Volume of Distribution (Vss/F) of GSK2330811

  Days 1, 15, 29, 57, 85, 113, 155 and 197

• Serum Level of Total Oncostatin M (OSM)

  Days 1, 15, 29, 57, 85, 113, 155 and 197

Study Arms (4)

Cohort 1: GSK2330811 100 mg

EXPERIMENTAL

During Cohort 1, participants will receive a single dose of GSK2330811 100 mg by SC injection via needle and syringe in to the abdomen, thigh or upper arm by the investigator or designee at every other week from D1 to D71 (total 6 doses) for 10 weeks. Participants will be followed-up up to W28 D197.

Drug: GSK2330811

Cohort 2: GSK2330811 300 mg

EXPERIMENTAL

During Cohort 2, participants will receive a single dose of GSK2330811 300 mg by SC injection (3 vials of 1 mL each of GSK2330811 100 mg) via needle and syringe in to the abdomen, thigh or upper arm by the investigator or designee at every other week from D1 to D71 (total 6 doses) for 10 weeks. Participants will be followed-up up to W28 D197.

Drug: GSK2330811

Cohort 1: Placebo

PLACEBO COMPARATOR

During Cohort 1, participants will receive a single dose of placebo by SC injection via needle and syringe in to the abdomen, thigh or upper arm by the investigator or designee at every other week from D1 to D71 (total 6 doses) for 10 weeks. Participants will be followed-up up to W28 D197.

Drug: Placebo

Cohort 2: Placebo

PLACEBO COMPARATOR

During Cohort 2, participants will receive a single dose of placebo by SC injection (3 vials of 1 mL each) via needle and syringe in to the abdomen, thigh or upper arm by the investigator or designee at every other week from D1 to D71 (total 6 doses) for 10 weeks. Participants will be followed-up up to W28 D197.

Drug: Placebo

Interventions

GSK2330811 DRUG

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.

Cohort 1: GSK2330811 100 mg; Cohort 2: GSK2330811 300 mg

Placebo DRUG

Normal saline (0.9 percent weight per volume sodium chloride).

Cohort 1: Placebo; Cohort 2: Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (14)

GSK Investigational Site

Los Angeles, California, 90045, United States

Location

GSK Investigational Site

Stanford, California, 94304, United States

Location

GSK Investigational Site

Chicago, Illinois, 60611, United States

Location

GSK Investigational Site

Baltimore, Maryland, 21224, United States

Location

GSK Investigational Site

Boston, Massachusetts, 02118, United States

Location

GSK Investigational Site

Ann Arbor, Michigan, 48109, United States

Location

GSK Investigational Site

Toronto, Ontario, M5T 3L9, Canada

Location

GSK Investigational Site

Nijmegen, 6525 GA, Netherlands

Location

GSK Investigational Site

Salford, Greater Manchester, M6 8HD, United Kingdom

Location

GSK Investigational Site

Liverpool, Merseyside, L9 7AL, United Kingdom

Location

GSK Investigational Site

Birmingham, B15 2TH, United Kingdom

Location

GSK Investigational Site

Dundee, DD1 9SY, United Kingdom

Location

GSK Investigational Site

Leeds, LS7 4SA, United Kingdom

Location

GSK Investigational Site

London, NW3 2QG, United Kingdom

Location

Related Publications (1)

• 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.

  PMID: 35583273 DERIVED

MeSH Terms

Conditions

Scleroderma, Systemic

Condition Hierarchy (Ancestors)

Connective Tissue Diseases; Skin and Connective Tissue Diseases; Skin Diseases

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

GSKClinicalSupportHD@gsk.com

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 31, 2017
• First Posted: February 2, 2017
• Study Start: June 5, 2017
• Primary Completion: July 7, 2020
• Study Completion: July 7, 2020
• Last Updated: May 24, 2021
• Results First Posted: May 24, 2021

Record last verified: 2021-04

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: IPD will be made available within 6 months of publishing the results of the primary endpoints of the study.
• Access Criteria: Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted when justified, for up to another 12 months.

Locations

US (6); GB (6); NL (1); CA (1)