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Proof of Mechanism Study of GSK2330811 in Diffuse Cutaneous Systemic Sclerosis

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ClinicalTrials.gov Identifier: NCT03041025
Recruitment Status : Recruiting
First Posted : February 2, 2017
Last Update Posted : December 4, 2018
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline

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.

Condition or disease Intervention/treatment Phase
Scleroderma, Systemic Drug: GSK2330811 Drug: Placebo Phase 1 Phase 2

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
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
Actual Study Start Date : June 5, 2017
Estimated Primary Completion Date : September 27, 2019
Estimated Study Completion Date : September 27, 2019


Arm Intervention/treatment
Experimental: Cohort 1: GSK2330811 100 mg
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
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.

Experimental: Cohort 2: GSK2330811 300 mg
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
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.

Placebo Comparator: Cohort 1: Placebo
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
Normal saline (0.9 percent weight per volume sodium chloride).

Placebo Comparator: Cohort 2: Placebo
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
Normal saline (0.9 percent weight per volume sodium chloride).




Primary Outcome Measures :
  1. Number of participants with any adverse event (AE) and any serious adverse event (SAE) as a measure of safety and tolerability [ Time Frame: Up to Day 197 ]
    An AE is any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is defined as any untoward medical occurrence that: results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, other situations judged by physician, is associated with liver injury and impaired liver function.

  2. Hematology assessed as a measure of safety and tolerability [ Time Frame: Day 1 (pre-dose), Day 15, Day 29, Day 43, Day 57, Day 71, Day 85, Day 113, Day 155 and Day 197 ]
    Hematology parameters will be assessed.

  3. Clinical chemistry assessed as a measure of safety and tolerability [ Time Frame: Day 1 (pre-dose), Day 15, Day 29, Day 43, Day 57, Day 71, Day 85, Day 113, Day 155 and Day 197 ]
    Clinical chemistry parameters will be assessed.

  4. Urinalysis assessed as a measure of safety and tolerability [ Time Frame: Day 1 (pre-dose), Day 85 and Day 197 ]
    Routine urinalysis parameters will be assessed.

  5. Systolic and diastolic blood pressure (BP) as a measure of safety and tolerability [ Time Frame: Day 1 (pre-dose), Day 15 (pre-dose), Day 29 (pre-dose), Day 43 (pre-dose), Day 57 (pre-dose), Day 71 (pre-dose), Day 85, Day 113, Day 155 and Day 197 ]
    Systolic and diastolic BP will be measured in a seated or semi-supine position after 5 minutes of rest.

  6. Pulse rate as a measure of safety and tolerability [ Time Frame: Day 1 (pre-dose), Day 15 (pre-dose), Day 29 (pre-dose), Day 43 (pre-dose), Day 57 (pre-dose), Day 71 (pre-dose), Day 85, Day 113, Day 155 and Day 197 ]
    Pulse rate will be measured in a seated or semi-supine position after 5 minutes of rest.

  7. Body temperature as a measure of safety and tolerability [ Time Frame: Day 1 (pre-dose), Day 15 (pre-dose), Day 29 (pre-dose), Day 43 (pre-dose), Day 57 (pre-dose), Day 71 (pre-dose), Day 85, Day 113, Day 155 and Day 197 ]
    Body temperature will be measured in a seated or semi-supine position after 5 minutes of rest.

  8. Electrocardiogram (ECG) assessed as a measure of safety and tolerability [ Time Frame: Day 1 (pre-dose), Day 15 (pre-dose) and Day 57 (pre-dose) ]
    Triplicate or single 12-lead ECGs will be obtained at indicated time point during the study using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and QT corrected (QTc) intervals.


Secondary Outcome Measures :
  1. Plasma concentrations of GSK2330811 [ Time Frame: PK samples will be collected at Day 1 (pre-dose), Day 15, Day 29, Day 57, Day 85, Day 113, Day 155 and Day 197 ]
    Blood samples will be collected at indicated time points for PK analysis.

  2. Concentration at the end of the dosage interval (Ctrough) of GSK2330811 [ Time Frame: PK samples will be collected at Day 15, Day 29, Day 57, Day 85 ]
    Blood samples will be collected at indicated time points for PK analysis.

  3. Apparent clearance (CL/F) of GSK2330811 [ Time Frame: PK samples will be collected at Day 1 (pre-dose), Day 15, Day 29, Day 57, Day 85, Day 113, Day 155 and Day 197 ]
    The CL/F is defined as the apparent total clearance of the drug from plasma. CL/F will be derived from blood samples collected at indicated time points for PK analysis.

  4. Apparent volume of distribution (Vss/F) [ Time Frame: PK samples will be collected at Day 1 (pre-dose), Day 15, Day 29, Day 57, Day 85, Day 113, Day 155 and Day 197 ]
    Vss/F is defined as apparent volume of distribution at steady state after non-intravenous administration. Vss/F will be derived from blood samples collected at indicated time points for PK analysis.

  5. Serum levels of total OSM [ Time Frame: Blood samples will be collected at Day 1 (pre-dose), Day 15, Day 29, Day 57, Day 85, Day 113, Day 155 and Day 197 ]
    Blood samples will be collected for measurement of serum levels of total OSM protein at indicated time points.

  6. Serum levels of free OSM [ Time Frame: Blood samples will be collected at Day 1 (pre-dose), Day 15, Day 29, Day 57, Day 85, Day 113, Day 155 and Day 197 ]
    Blood samples will be collected for measurement of serum levels of free OSM protein at indicated time points.

  7. Incidence and titers of anti-GSK2330811 antibodies [ Time Frame: Blood samples will be collected at Day 1 (pre-dose), Day 15, Day 57, Day 85 and Day 197 ]
    Serum samples from whole blood will be collected at indicated time points.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03041025


Contacts
Contact: US GSK Clinical Trials Call Center 877-379-3718 GSKClinicalSupportHD@gsk.com

  Show 34 Study Locations
Sponsors and Collaborators
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline
Study Director: GSK Clinical Trials GlaxoSmithKline (for GlaxoSmithKline; Human Genome Sciences Inc., a GSK Company; Sirtris, a GSK Company; Stiefel, a GSK Company; ViiV Healthcare)

Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT03041025     History of Changes
Other Study ID Numbers: 201247
2016-003417-95 ( EudraCT Number )
First Posted: February 2, 2017    Key Record Dates
Last Update Posted: December 4, 2018
Last Verified: December 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by GlaxoSmithKline:
Systemic Sclerosis
Repeat-dose
Phase IIA
GSK2330811
Pharmacodynamics
Pharmacokinetics
Proof of mechanism study

Additional relevant MeSH terms:
Sclerosis
Scleroderma, Systemic
Scleroderma, Diffuse
Pathologic Processes
Connective Tissue Diseases
Skin Diseases