E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Ischemic digital ulcers associated with systemic sclerosis |
Úlceras digitales isquémicas asociadas a esclerosis sistémica |
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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) |
Dificultad para cicatrizar úlceras abiertas en dedos (Úlceras Digitales) asociadas a enfermedad (Esclerosis Sistémica) que conduce a endurecimiento de la piel, vasos sanguíneos y a organos internos |
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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 | 14.0 |
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 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 and ongoing digital ulcer (DU) disease. |
Demostrar el efecto de macitentan sobre la reducción del número de nuevas úlceras digitales en la Semana 16 en pacientes con esclerosis sistémica y enfermedad de ulceras digitales (DU) en curso. |
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E.2.2 | Secondary objectives of the trial |
-To evaluate the efficacy of macitentan on hand functionality an dDU 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. |
- Evaluar la eficacia de macitentan sobre la funcionalidad de la mano y la carga de UD en la Semana 16 en pacientes con esclerosis sistémica (SSc) con enfermedad de DUs en curso. - Evaluar la seguridad y tolerabilidad de macitentan en pacientes con SSc con UDs en curso. -Evaluar la eficacia de macitentan en el momento de primera complicación de UD durante el periodo completo de tratamiento. |
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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) [Subcommittee for scleroderma criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee 1980], or having ever met criteria for CREST syndrome (with sclerodactyly and 2 out of the 4 remaining criteria: calcinosis, Raynaud?s phenomenon, esophageal dysmotility, and telangiectasia). -At least one visible, active ischemic digital ulcer (DU) at baseline, located at or distal to the PIP joints 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 (Visit 1). |
- Diagnóstico de SSC de acuerdo a los criterios de clasificación del Colegio Americano de Reumatología (ACR) [Subcommittee for scleroderma criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee 1980], o haber cumplido alguna vez criterios para el síndrome CREST (con esclerodactilia y 2 de los 4 criterios restantes: calcinosis, fenómeno de Raynaud, disfunción esofágica y telangiectasia. - Al menos una úlcera digital (DU) isquémica activa y visible en la visita basal, localizada en o distal a las articulaciones PIP o en el extremo digital, y que se desarrolló o empeoró dentro de las 8 semanas antes de la selección. - Historia de al menos una DU isquémica activa adicional dentro de 6 meses, o al menos dos dentro de 12 meses antes de la Selección (Visita 1) |
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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 at Screening (Visit 1) and Randomization (Visit 2). 7. Severe malabsorption, defined as greater than 15% unintentional loss of body weight in the last 6 months prior to randomization; 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, within 12 months prior to Screening (Visit 1) or tobacco use at any level within the past 6 months prior to Screening (Visit 1). 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, such as calcium channel blockers, ACE-inhibitors, nitroglycerin, alpha adrenergic blockers, or angiotensin II receptor antagonists, 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) within 3 months prior to Screening (Visit 1). 18. Systemic antibiotics (oral and IV) to treat infected DU(s) within 4 weeks prior to Screening (Visit 1). 19. Use of topical growth factors, hyperbaric oxygen. 20. Local injection of botulinum toxin in an affected finger within 4 weeks prior to Screening (Visit 1). 21. Surgical sympathectomy of the upper limbs or surgical wound debridement within 1 month prior to Screening (Visit 1). 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 (Visit 1). 23. Known hypersensitivity to drugs of the same class as the study drug, or any of their excipients. 24. Planned treatment, or treatment with another investigational drug within 4 weeks prior to Screening (Visit 1). 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. |
1.DUs debidos a otros motivos distintos de SSc. 2.Hipertensión arterial pulmonar sintomática (PAH). 3.Índice de masa corporal (BMI: kg/m2) <18. 4.Aspartato aminotransferasa (AST) y/o alanino aminotransferasa (ALT) sérica > 1.5 veces el límite superior del valor normal (ULN). 5.Hemoglobina < 75% del límite inferior de los rangos normales. 6.Presión arterial sistólica < 95 mmHg o presión arterial diastólica < 50 mmHg. 7.Malabsorción grave, cualquier fallo orgánico grave (ej., pulmón, riñón), o cualquier condición de peligro para la vida. 8.Comorbilidades, distintas al SSc, que pudiesen afectar seriamente la evaluación de la funcionalidad de la mano 9.Mujeres que estén embarazadas o lactantes o tengan planeado realizarlo durante el curso de este estudio. 10.Abuso o dependencia de sustancias o alcohol o tabaco. 11.Tratamiento con inhibidores de la PDE5 (ej., sildenafilo, tadalafilo). 12.Pacientes con estatinas (ej., atorvastatina, simvastatina), que hayan recibido tratamiento durante menos de 3 meses antes de la Selección (Visita 1) o cuyo tratamiento no haya sido estable durante este periodo. 13.Pacientes con vasodilatadores, N-acetilcisteína, terapia de agregación antiplaquetaria y heparina de bajo peso molecular, que hayan recibido tratamiento durante menos de 2 semanas antes de la Selección (Visita 1) o cuyo tratamiento no haya sido estable durante este periodo. 14.Tratamiento con prostanoides. 15. Tratamiento con agentes modificadores de la enfermedad como methotrexato y ciclofosfamida si se administra al menos tres meses antes de la elección (Visita 1) o cuyo tratamiento no ha sido estable durante al menos 1 mes antes de la selección (Visita 1 ) 16. Tratamiento con corticoides orales(> 10 mg/día con prednisona o equivalente). 17.Tratamiento con antagonistas de los receptores de la endotelina (ERAs). 18.Antibióticos sistémicos (oral y i.v.) para tratar DU(s) infectadas. 19.Utilización de factores de crecimiento tópicos, oxígeno hiperbárico. 20.Inyección local de toxina botulínica en un dedo afectado dentro de las 4 semanas anteriores a la Selección. 21. Simpactectomía quirúrgica de los miembros superiores o desbridamiento quirúrgico de la herida dentro de 1 mes antes de la Selección. 22.Tratamiento con inductores del citocromo P450 3A (CYP3A4), como la rifabutina, rifampicina, rifapentina, carbamacepina, fenobarbital, fenitoína, hierba de San Juan, dentro de las 4 semanas anteriores a la Selección. 23.Hipersensibilidad conocida a fármacos de la misma clase que el fármaco del estudio, o a alguno de sus excipientes. 24.Tratamiento programado, o tratamiento con otro fármaco en investigación en las 4 semanas anteriores a la Selección. 25. Cualquier otra situación que impida el cumplimiento con el protocolo del estudio o adherencia a la terapia, incluyendo la incapacidad para hablar, leer, o entender el idioma local suficientemente bien como para completar todas las evaluaciones del estudio. |
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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. |
Objetivo principal (evaluado durante el Periodo 1) Número total de nuevas DUs hasta la Semana 16. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
End-of-Period 1 (Week 16) |
Final-del-Periodo 1 (Semana 16) |
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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. |
? Funcionalidad de la mano: i. HDISS-DU ii. HAQ-DI ? Carga de DU: i. Respuesta binaria de pacientes sin una nueva DU ii. Respuesta binaria de pacientes con más de 1, 2, 3, etc., nuevas DU(s) iii. Número total de DUs observadas iv. Tiempo hasta aparición de cada nueva DU (1a, 2da, 3ra, 4a, etc., DU) ? Complicaciones de DU: Un evento de complicaciones de DU se define como la composición de lo siguiente: i. Crisis isquémica crítica que requiere hospitalización. ii. Gangrena, (auto)amputación. iii. Fallo del manejo conservador: Simpatectomía quirúrgica y química, reconstrucciones vasculares, o cualquier cirugía no programada en el manejo de la(s) manifestación(es) de la mano. iv. Utilización de prostanoides parenterales. v. Uso de antagonistas del receptor de la endotelina. vi. Requerir narcóticos clase II, III o IV o incremento de la dosis existente de > 50% comparado con la situación basal. vii. Inicio de antibióticos sistémicos para el tratamiento de infecciones atribuidas a la ulceración digital. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
-Period 1: 4 visits (week 4, 8, 12 and 16) -Period 2: varialble number of visits every 3 months |
-Periodo 1: 4 visitas (semanas 4, 8, 12 and 16) -Periodo 2: número variable de visitas cada 3 meses |
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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 | 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 |
Último Paciente Último Seguimiento de Seguridad: 30 días después de LPLV. |
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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 | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
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 |