E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Ischemic digital ulcers associated with systemic sclerosis |
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E.1.1.1 | Medical condition in easily understood language |
Difficult-to-heal open sores on fingers ("Digital Ulcers") associated with a disease that leads to hardening of the skin, blood vessels and internal organs ("Systemic sclerosis") |
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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 | 14.1 |
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 demonstrate the effect of macitentan on the reduction of the cumulative number of new digital ulcers at Week 16 in patients with systemic sclerosis and ongoing digital ulcer (DU) disease. |
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E.2.2 | Secondary objectives of the trial |
_To evaluate the efficacy of macitentan on hand functionality and DU burden at Week 16 in systemic sclerosis (SSc) patients with ongoing DU disease.
_ To evaluate the safety and tolerability of macitentan in SSc patients with ongoing DU disease.
_To evaluate the efficacy of macitentan on time to first DU complication during the entire treatment period. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Diagnosis of SSc according to the classification criteria of the American College of Rheumatology (ACR), or having ever met criteria for CREST syndrome (with sclerodactyly and 2 out of the 4 remaining criteria: calcinosis, Raynaud's phenomenon, esophageal dysfunction, telangiectasia).
- At least one visible, active ischemic DU at baseline, located at or distal to the proximal interphalangeal joints (PIP) or at the digital tip, and that developed or worsened within 8 weeks prior to screening.
- History of at least one additional active ischemic DU within 6 months, or at least two within 12 months prior to Screening. |
|
E.4 | Principal exclusion criteria |
1. DUs due to condition other than SSc.
2. Symptomatic pulmonary arterial hypertension (PAH).
3. Body mass index (BMI: kg/m2) <18.
4. Serum aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 1.5 times the upper limit of normal (ULN).
5. Hemoglobin < 75% of the lower limit of the normal range.
6. Systolic blood pressure < 95 mmHg or diastolic blood pressure < 50
mmHg .
7. Severe malabsorption, any severe organ failure (e.g., lung, kidney), or any life-threatening condition.
8. Comorbidities, other than SSc, that could seriously affect the assessment of hand function.
9. Females who are pregnant or breastfeeding or plan to do so during the course of this study.
10. Substance or alcohol abuse or dependence, or tobacco use .
11. Treatment with PDE5 inhibitors (e.g., sildenafil, tadalafil).
12. Patients on statins (e.g., atorvastatin, simvastatin), who have received treatment for less than 3 months prior to Screening (Visit 1) or whose treatment has not been stable during this period.
13. Patients on vasodilators, N-acetylcysteine, antiplatelet aggregation therapy and low molecular weight heparin who have received treatment for less than 2 weeks prior to Screening (Visit 1) or whose treatment has not been stable during this period.
14. Treatment with prostanoids.
15. Treatment with disease modifying agents such as methotrexate and cyclophosphamide if present for less than 3 months prior to Screening (Visit 1) or whose treatment has not been stable for at least 1 month prior to Screening (Visit 1).
16. Treatment with oral corticosteroids (> 10 mg/day of prednisone or equivalent).
17. Treatment with endothelin receptor antagonists (ERAs).
18. Systemic antibiotics (oral and i.v.) to treat infected DU(s).
19. Use of topical growth factors, hyperbaric oxygen.
20. Local injection of botulinum toxin in an affected finger within 4 weeks prior to Screening.
21. Surgical sympathectomy of the upper limbs or surgical wound debridement within 1 month prior to Screening.
22. Treatment with cytochrome P450 3A (CYP3A) inducers, such as rifabutin, rifampin, rifapentin, carbamazepine, phenobarbital, phenytoin, St. John's wort, within 4 weeks prior to Screening.
23. Known hypersensitivity to drugs of the same class as the study drug, or any of the excipients.
24. Planned treatment, or treatment with another investigational drug within 4 weeks prior to Screening.
25. Any condition that prevents compliance with the protocol or adherence to therapy, including inability to speak, read, or understand the local language well enough to complete all study assessments. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary endpoint (assessed during Period 1) :
Cumulative number of new DUs up to Week 16. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
End-of-Period 1 (Week 16) |
|
E.5.2 | Secondary end point(s) |
• Hand Functionality:
i. HDISS-DU
ii. HAQ-DI
• DU Burden:
i. Binary response of patients without a new DU
ii. Binary response of patients with more than 1, 2, 3, etc., new DU(s)
iii. Total number of DUs observed
iv. Time to onset of each new DU (1st, 2nd, 3rd, 4th, etc., DU)
• DU Complications: An event of DU complications is defined as the composite of the following:
i. Critical ischemic crisis necessitating patient hospitalization.
ii. Gangrene, (auto)amputation.
iii. Failure of conservative management: Surgical and chemical sympathectomy, vascular reconstructions, or any unplanned surgery in the management of hand manifestation(s).
iv. Use of parenteral prostanoids.
v. Use of endothelin receptor antagonists.
vi. Requiring class II, III or IV narcotics or increase in existing dose of > 50% as compared to baseline.
vii. Initiation of systemic antibiotics for the treatment of infection attributed to digital ulceration. |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
- Period 1: 4 visits (week 4, 8, 12 and 16)
- Period 2: variable number of visits every 3 month |
|
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 | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
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 | 3 |
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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 34 |
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 |
Argentina |
Belgium |
Colombia |
Germany |
Greece |
Ireland |
Mexico |
Netherlands |
New Zealand |
Poland |
Portugal |
Puerto Rico |
Russian Federation |
South Africa |
Spain |
Turkey |
Ukraine |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
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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Last Patient Last Safety Follow-up : 30 days after LPLV |
|
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 | 2 |
E.8.9.1 | In the Member State concerned days | 15 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |