Proof of mechanism study of GSK2330811 in diffuse cutaneous systemic sclerosis.

• Register: EUCTR
• Last refreshed on: 16 November 2020
• Main ID: EUCTR2016-003417-95-NL
• Date of registration: 09/07/2018
• Prospective Registration: Yes
• Primary sponsor: GlaxoSmithKline Research & Development Ltd
• Public title: Proof of mechanism study of GSK2330811 in diffuse cutaneous systemic sclerosis.
• Scientific title: A multi-centre, 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. - Proof of mechanism study of GSK2330811 in diffuse cutaneous systemic sclerosis.
• Date of first enrolment: 18/09/2018
• Target sample size: 40
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2016-003417-95
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Canada, Netherlands, United Kingdom, United States

Contacts

• Name: Clinical Trials Helpdesk
• Affiliation: GlaxoSmithKline Research & Development Ltd

• Name: Clinical Trials Helpdesk
• Affiliation: GlaxoSmithKline Research & Development Ltd

Key inclusion & exclusion criteria

Inclusion criteria:
Participants are eligible to be included in the study only if all of the following criteria apply:
Age
1. 18 years or over, at the time of signing the informed consent. Type of Participant and Disease Characteristics
2. Documented diagnosis of systemic sclerosis as defined by the American College of Rheumatology / European League Against Rheumatism 2013 criteria (van den Hoogen, 2013), with diffuse cutaneous involvement.
3. Modified Rodnan Skin Score (mRSS) =10 and =35 at screening.
4. In all cases, a disease duration of =60 months at screening, defined as time from onset of the first non-Raynaud’s phenomenon manifestation.
5. Active disease defined by at least one of the following criteria at screening:
- CRP =6 mg/l (0.6 mg/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 (according to mRSS definitions) and an increase of =2 mRSS units compared with an assessment performed within the previous 6 months.
Involvement of two new body areas (according to mRSS definitions) within the previous 6 months.
6. An area of uninvolved or mildly thickened skin that in the opinion of the investigator would allow subcutaneous injection at one of the following locations:
- Abdomen
- Front, middle region of the thigh
- Outer area of the upper arm
7. An area of involved skin (mRSS =1) on the forearm suitable for repeated skin biopsies to be collected as described in Section 9.8.2.
8. Participants who are taking mycophenolate mofetil (=3,000 mg/day) or mycophenolate sodium (=1,440 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.
9. 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.
10. 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.
11. Participants who are taking other non-immunosuppressive medications not specifically excluded in Section 6.2 of the protocol are permitted in the study.
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).
Sex
12. Male and female participants
a. Female participants:
A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies:
(i) Not a woman of childbearing potential (WOCBP)
OR
(ii) A WOCBP who agrees to follow the contraceptive guidance in Appendix 5 from 28 days prior to first dosing day (Day 1), during the
Exclusion criteria:
Medical Conditions
1. Patients classified to the limited cutaneous SSc subset, as determined by the investigator.
2. 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.
3. FVC =50% of predicted, or a diffusing capacity of the lung for carbon dioxide (DLCO) =40% of predicted at screening.
4. Pulmonary arterial hypertension.
5. Clinically significant inflammatory myositis (related to SSc).
6. SSc renal crisis within 6 months of the first day of dosing (Day 1).
7. 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.
8. Known bleeding or coagulation disorder.
9. Major surgery (including joint surgery) within 3 months prior to screening, or planned during the duration of the study.
10. Clinically significant multiple or severe drug allergies, intolerance to topical corticosteroids, or severe post-treatment hypersensitivity reactions.
11. An active infection, or a history of infections as defined in Section 6.2 of the protocol.
12. Alanine transferase (ALT) >2x upper limit of normal (ULN) at screening.
13. Bilirubin >1.5xULN at screening (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).
14. Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
15. QTc >480 msec or QTc >500 msec in participants with Bundle Branch Block at screening.
16. 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.
Prior/Concomitant Therapy
17. Treatment with methotrexate within 3 months prior to the first dosing day (Day 1).
18. Previous or planned bone marrow transplant.
19. Treatment with a biologic within the following timeframes:
- Tocilizumab, abatacept or anti-TNF (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).
20. Treatment with oral or intravenous cyclophosphamide within 6 months prior to the first dosing day (Day 1).
21. Treatment with any other non-biologic systemic immunosuppressive medication not mentioned above within 4 weeks prior to the first dosing day (Day 1).
22. Treatment with topical immunosuppressive medications within 1 week prior to the first dosing day (Day 1).
22. Treatment with intravenous prostanoids within 2 weeks prior to the first dosing day (Day 1) or planned treatment before the Week 12 visit.
23. Treatment with anti-fibrotic medications within 3 months prior to the first dosing day (Day 1).
24. Live vaccine(s) within 4 weeks prior to the first dosing day (Day 1), or plans to receive such vaccines during the study.
25. Treatment with anti-coagulant medications within 2 weeks prior to the first dosing day (Day 1).
26. Treatment with anti-platelet medications 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.
Prior

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Skin and Connective Tissue Diseases [C17]

Systemic sclerosis
MedDRA version: 20.0 Level: LLT Classification code 10042953 Term: Systemic sclerosis System Organ Class: 100000004859

Intervention(s)

Product Name: GSK2330811 Solution for Injection, 100mg/ml
Product Code: GSK2330811
Pharmaceutical Form: Solution for injection
INN or Proposed INN: GSK2330811
CAS Number: N/A
Current Sponsor code: GSK2330811
Other descriptive name: GSK2330811
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 100-
Pharmaceutical form of the placebo: Solution for injection
Route of administration of the placebo: Subcutaneous use

Primary Outcome(s)

Timepoint(s) of evaluation of this end point: SAEs will be collected continuously from the point of signing informed consent until follow up (Day 197).

AEs will be collected continuously from the start of study treatment (Day 1) until follow up (Day 197).

Laboratory safety data and vital signs will be measured at screening, at Day 1 (predose), at Days 15, 29, 43, 57, 71, 85, 113, 155 and at follow up (Day 197).

ECGs will be measured at screening and predose on days 1, 15 and 57.

Main Objective: To evaluate the safety and tolerability of repeat subcutaneous doses of GSK2330811 in participants with dcSSc

Secondary Objective: - To evaluate the pharmacokinetic profile of repeat subcutaneous doses of GSK2330811 in participants with dcSSc
- To assess the target engagement of repeat subcutaneous doses of GSK2330811 in the blood of participants
with dcSSc
- To assess the potential for anti-drug antibody formation following repeat subcutaneous doses of GSK2330811 in participants with dcSSc
-

Primary end point(s): Safety and tolerability: Adverse event reporting, Laboratory safety data, Vital signs and 12 lead ECG.

Secondary Outcome(s)

Secondary end point(s): Pharmacokinetics: Plasma concentrations of GSK2330811 and derived pharmacokinetic parameters.
Target Engagement: Serum levels of total OSM and free OSM.
Immunogenicity: Incidence and titres of anti-GSK2330811 antibodies.

Timepoint(s) of evaluation of this end point: Pharmacokinetic and target engagement samples will be collected on Day 1 (predose), on Days 15, 29, 57, 85, 113, 155 and at follow up (Day 197).

Immunogenicity samples will be collected on Day 1 (predose), on Days 15, 57, 85 and at follow up (Day 197).

Secondary ID(s)

2016-003417-95-GB

201247

Source(s) of Monetary Support

GSK

Ethics review

Status: Approved
Approval date: 18/09/2018
Contact: