E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Skin and Connective Tissue Diseases [C17] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10042953 |
E.1.2 | Term | Systemic sclerosis |
E.1.2 | System Organ Class | 10028395 - Musculoskeletal and connective tissue disorders |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the safety and tolerability of repeat subcutaneous doses of GSK2330811 in participants with dcSSc |
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E.2.2 | Secondary objectives of the trial |
- 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
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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 dosing period and for at least 126 days (18 weeks) after the last dose of study treatment. If more stringent contraception requirements are necessary for any concomitant medications the participant may be taking then these must still continue whilst participating in this study.
Informed Consent
13. Capable of giving signed informed consent as described in Appendix 3 which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. |
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E.4 | Principal 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/Concurrent Clinical Study Experience
27. Current enrolment or past participation within the last 30 days before signing of consent in any other clinical study involving an investigational study treatment.
28. Exposure to more than 4 new chemical entities within 12 months prior to the first dosing day (Day 1).
Diagnostic assessments
29. Any of the following at screening:
• Haemoglobin <110 g/L
• Platelet count <150x109/L
• Estimated glomerular filtration rate (GFR) (MDRD calculation) of <45 mL/min/1.73m2
30. A positive human immunodeficiency virus (HIV) antibody test at screening.
31. Presence of Hepatitis B surface antigen (HBsAg) at screening.
32. Positive Hepatitis B core antibody (HBcAb) test at screening.
33. Positive Hepatitis C antibody test result at screening or within 3 months prior to starting study treatment.
34. Positive Hepatitis C RNA test result at screening or within 3 months prior to first dose of study treatment.
Contraindications
35. 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.
36. Where participation in the study would result in donation of blood or blood products in excess of a volume of 500mL during the study.
37. A history of drug and alcohol misuse. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Safety and tolerability: Adverse event reporting, Laboratory safety data, Vital signs and 12 lead ECG. |
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E.5.1.1 | 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.
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E.5.2 | 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.
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E.5.2.1 | 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).
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |