Macitentan for the Treatment of Digital Ulcers in Systemic Sclerosis Patients
- Conditions
- Digital Ulcers
- Interventions
- Registration Number
- NCT01474122
- Lead Sponsor
- Actelion
- Brief Summary
The DUAL-2 study is designed as a multicenter, double-blind two-period study with an initial fixed 16-week Period 1, followed by a Period 2 of variable duration. All patients completing Period 1 continue on their original randomized treatment into Period 2, until the last randomized patient has completed Period 1.
Patients are randomized in a 1:1:1 ratio (macitentan 3mg: macitentan 10mg: placebo).
The primary objective is to demonstrate the effect of macitentan on the reduction of the number of new digital ulcers in patients with systemic sclerosis and ongoing digital ulcers (DU).
Other objectives include:
* the evaluation of the efficacy of macitentan on hand functionality and DU burden at Week 16 in SSc patients with ongoing DU disease.
* the evaluation of the safety and tolerability of macitentan in these patients.
* the evaluation of the efficacy of macitentan on time to first DU complication during the entire treatment period.
- Detailed Description
Recurrent digital ulcers (DU) are a manifestation of vascular disease in patients with systemic sclerosis (SSc), are an important source of morbidity and lead to impaired function in these patients. In this study, we are investigating whether treatment with the endothelin receptor antagonist, macitentan, decreases the development of new digital ulcers in patients with SSc. Macitentan is a highly potent, tissue-targeting dual endothelin receptor antagonist. Through complete blockade of endothelin action, macitentan is expected to protect tissue from the damaging effect of elevated endothelin. This therapy is not approved for the treatment of systemic sclerosis, but the use of an ERA is an attractive approach in combating the structural vascular damage observed in SSc leading to complications such as DUs.
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 265
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Placebo Placebo Oral placebo, once daily Macitentan 10 mg Macitentan 10 mg Oral macitentan 10 mg, once daily Macitentan 3 mg Macitentan 3 mg Oral macitentan 3 mg, once daily
- Primary Outcome Measures
Name Time Method Incidence Rate of New Digital Ulcers (DUs) up to Week 16 Baseline to Week 16 DUs were assessed at each visit starting with the screening visit. Only DUs from the proximal interphalangeal joint (PIP) distally (both on the dorsal and volar surface of the hand, including the digital tip) were recorded. The location of each DU was noted. At each subsequent visit the location of each new DU was noted. DUs that occurred and healed between visits and were reported by patients were not recorded as new DUs. The evaluation was performed by an experienced physician or a trained rater with expertise in the assessment of DUs in systemic sclerosis (SSc). For a given patient, DUs were assessed by the same rater at each visit, whenever possible. Any DU that developed over a previously healed ulcer was recorded as a new DU. Incidence rate is adjusted for 16 weeks of observation, hence is calculated as the number of new DUs/total number of observation days.
- Secondary Outcome Measures
Name Time Method Change in Hand Functionality Health Assessment Questionnaire - Disability Index (HAQ-DI) Hand Component From Baseline to Week 16 Baseline to Week 16 HAQ-DI assesses functional ability regarding fine movements of the upper extremities, locomotor activities in the lower extremities, and movements of the upper and lower limbs. Responses were extracted from the Scleroderma Health Assessment Questionnaire covering 8 domains of functional disability (dressing and grooming, arising, eating, walking, hygiene, reach, grip, and other daily activities). A mean score ranging from 0-3 was calculated for each domain, and a composite score by dividing the summed domain scores by the number of domains. The composite score was interpreted as 0 (no impairment in function) to 3 (maximal impairment of function). Hand functionality was assessed using a composite of 4 domains (dressing and grooming, grip, hygiene, and eating).
Percentage of Participants Without a New DU up to Week 16 Baseline to Week 16 DUs were assessed at each visit starting with the screening visit. Only DUs from the proximal interphalangeal joint (PIP) distally (both on the dorsal and volar surface of the hand, including the digital tip) were recorded. The location of each DU was noted. At each subsequent visit the location of each new DU was noted. DUs that occurred and healed between visits and were reported by patients were not recorded as new DUs. The evaluation was performed by an experienced physician or a trained rater with expertise in the assessment of DUs in systemic sclerosis (SSc). For a given patient, DUs were assessed by the same rater at each visit, whenever possible. Any DU that developed over a previously healed ulcer was recorded as a new DU. Numbers of patients with no new DU at Week 16 are imputed using the last observation carried forward method.
Percentage of Participants With at Least One DU Complication Up to 95 weeks DU complications were defined as any one of the following:
resulting from DU worsening: critical ischemic crisis necessitating hospitalization; gangrene, (auto)amputation; failure of conservative management; surgical and chemical sympathectomy, vascular reconstructions, or any unplanned surgery in the management of hand SSc manifestations; use of parenteral prostanoids; use of endothelin-receptor antagonists; class II, III, or IV narcotics or a \> 50% increase in the existing dose compared with baseline; initiation of systemic antibiotics for the treatment of infection attributed to DUs.Health Assessment Questionnaire - Disability Index (HAQ-DI) Overall Score From Baseline to Week 16 Baseline to Week 16 HAQ-DI assesses functional ability regarding fine movements of the upper extremities, locomotor activities in the lower extremities, and movements of the upper and lower limbs. Responses were extracted from the Scleroderma Health Assessment Questionnaire covering 8 domains of functional disability (dressing and grooming, arising, eating, walking, hygiene, reach, grip, and other daily activities). A mean score ranging from 0-3 was calculated for each domain, and a composite score by dividing the summed domain scores by the number of domains. The composite score was interpreted as 0 (no impairment in function) to 3 (maximal impairment of function).
Change in Hand Functionality - Hand Disability in Systemic Sclerosis - Digital Ulcers (HDISS-DU) Score From Baseline to Week 16 Baseline to Week 16 Patients were asked to answer 24 questions on the use of the hand(s) affected by DUs over the past 7 days on a 6-point scale from 0 (yes without difficulty) to 5 (impossible). The HDISS-DU score is the arithmetic mean of the valid non-missing items. The scores are interpreted as 1 (better ability in completing activities) to 6 (worst ability in completing activities)
Trial Locations
- Locations (90)
Peking Union Medical College Hospital
🇨🇳Beijing, China
Sanatorio San Jose
🇦🇷Caba, Argentina
Hospital Universitari i Politecnic La Fe
🇪🇸Valencia, Spain
Renji Hospital, Shanghai Jiaotong University
🇨🇳Shanghai, China
University Hospital Aintree - Rheumatology Department
🇬🇧Liverpool, United Kingdom
Chris Hani Baragwanath Hospital
🇿🇦Soweto, South Africa
Beaumont Hospital
🇮🇪Dublin, Ireland
UMC St Radboud
🇳🇱GA Nijmegen, Netherlands
Addenbrooke's Hospital - University of Cambridge School of Clinical Medicine
🇬🇧Cambridge, United Kingdom
General University Hospital LAIKO/A' Propaideftiki Pathology Clinic
🇬🇷Athens, Greece
Royal National Hospital
🇬🇧Bath, United Kingdom
Groote Schuur Hospital, University of Cape Town
🇿🇦Cape Town, South Africa
Mid-Western Regional Hospital
🇮🇪Limerick, Ireland
HOSPITAL Universitario VALL D'HEBRON - Servicio Medicina Interna
🇪🇸Barcelona, Spain
Royal Free & University College Medical School
🇬🇧London, United Kingdom
Guangdong General Hospital
🇨🇳Guangzhou, China
First Affiliated Hospital of the Forth Military University
🇨🇳Xi'an, China
Washington University School of Medicine
🇺🇸St Louis, Missouri, United States
North Shore Long Island Jewish Health System - Div. of Rheumatology & Allergy-Clinical Immunology
🇺🇸Lake Success, New York, United States
The Hospital for Special Surgery
🇺🇸New York, New York, United States
Ruppert Health Center
🇺🇸Toledo, Ohio, United States
University of Texas - Houston Medical School
🇺🇸Houston, Texas, United States
Arthritis Northwest PLLC
🇺🇸Spokane, Washington, United States
University of Manchester School of Translational Medicine Musculoskeletal Research Group
🇬🇧Manchester, United Kingdom
Ninewells Hospital & Medical School
🇬🇧Scotland, United Kingdom
Torbay Hospital
🇬🇧Torbay, United Kingdom
Stanford Univ. School of Medicine - Palo Alto VA Health Care System
🇺🇸Palo Alto, California, United States
Georgetown University
🇺🇸Washington, District of Columbia, United States
Cleveland Clinic Florida
🇺🇸Weston, Florida, United States
Northwestern University - Feinberg School of Medicine Department of Rheumatology
🇺🇸Chicago, Illinois, United States
The University of Pennsylvania
🇺🇸Philadelphia, Pennsylvania, United States
Hospital Britanico de Buenos Aires
🇦🇷Buenos Aires, Argentina
Clinique Universitaires Saint Luc
🇧🇪Brussels, Belgium
Clinica Diagnostico y Tratamiento de las Enfermedades Reumaticas
🇲🇽Distrito Federal, Mexico
VU University Medical Center
🇳🇱Amsterdam, Netherlands
Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubrian
🇲🇽Mexico D.F., Mexico
SPSK Nr 1 PUM Szczecin
🇵🇱Szczecin, Poland
Reumatika - Centrum Reumatologii NZOZ
🇵🇱Warszawa, Poland
State Educational Institution of High Professional Education "Voronezh State Medical Academy named after N.N.Burdenko of Roszdrav"
🇷🇺Voronezh, Russian Federation
Louis Pasteur Medical Centre
🇿🇦Pretoria, South Africa
Department of Dermatology University Hospital Johannes Gutenberg
🇩🇪Mainz, Germany
University of Connecticut Health Center - Division of Rheumatic Diseases
🇺🇸Farmington, Connecticut, United States
Boston University School of Medicine
🇺🇸Boston, Massachusetts, United States
Hospital Italiano de Cordoba
🇦🇷Cordoba, Argentina
Millennium Research
🇺🇸Ormond Beach, Florida, United States
Florida Medical Clinic-PA
🇺🇸Zephyrhills, Florida, United States
Centro de Educacion Medica e Investigaciones Clinicas - CEMIC
🇦🇷Buenos Aires, Argentina
Ludwig-Maximilian-Universität München Abteilung Dermatologie
🇩🇪Muchen, Germany
Klinik und Poliklinik für Dermatologie und Allergologie am Biderstein des Klinikums rechts der Isar der Technischen Universität München
🇩🇪Muenchen, Germany
St. Vincents University Hospital
🇮🇪Dublin, Ireland
Hospital Aranda de la Parra Leon
🇲🇽Leon, Mexico
Hospital Angeles Lindavista
🇲🇽Madero, Mexico
Wellington Hospital
🇳🇿Wellington South, New Zealand
Unidad de Investigacion en Enfermedades Cronico Degeneratives SC
🇲🇽Guadalajara, Jalisco, Mexico
Medical College of Wisconsin
🇺🇸Milwaukee, Wisconsin, United States
Hospital Italiano de Buenos Aires
🇦🇷Buenos Aires, Argentina
Cliniques universitaires UCL Mont-Godinne
🇧🇪Yvoir, Belgium
Centro Integral de Reumatologia y Inmunologia CIREI SAS
🇨🇴Bogota, Colombia
Kerckhoff-Klinik GmbH
🇩🇪Bad Nauheim, Germany
Hautklinik Universitätsklinikum Erlangen
🇩🇪Erlangen, Germany
North Shore Hospital, STAR (Shore Trials and Research) Unit
🇳🇿North Shore, New Zealand
Prywatna Praktyka Lekarska Prof. UM dr hab. med. Paweł Hrycaj
🇵🇱Poznań, Poland
Wojskowy Instytut Medyczny CSK MON
🇵🇱Warszawa, Poland
University of Puerto Rico
🇵🇷San Juan, Puerto Rico
Municipal Healthcare Institution "Donetsk Regional Clinical Hospital of Occupational Diseases"
🇺🇦Donetsk, Ukraine
National scientific centre "Institute of Cardiology named after M. Strazheska"
🇺🇦Kyiv, Ukraine
University of Utah
🇺🇸Salt Lake City, Utah, United States
Hospital Privado Centro Medico de Cordoba S.A.
🇦🇷Cordoba, Argentina
Hospital Pablo Tobon Uribe
🇨🇴Medellin, Antioquia, Colombia
Fundacion Instituto du Reumatologia Fernando Chalem
🇨🇴Bogota, Colombia
Waikato Hospital
🇳🇿Hamilton, New Zealand
SPSK Nr 1 Wrocław
🇵🇱Wrocław, Poland
Instituto Português de Reumatologia
🇵🇹Lisboa, Portugal
Municipal Treatment and Prevention Institution, "City Clinical Hospital #5"
🇷🇺Nizhniy Novgorod, Russian Federation
Çukurova Üniversitesi Tıp Fakültesi ROMATOLOJİ BİLİM DALI
🇹🇷Adana, Turkey
Crimean Republican Institution 'Clinical territorial medical union 'University Clinic
🇺🇦Simferopol, Ukraine
Scientific and Research Institute of Handicapped Rehabilitation of Vinnitsa National Medical University named after M. Pirogova
🇺🇦Vinnytsya, Ukraine
Universitätsklinikum der Technischen Universität Dresden
🇩🇪Dresden, Germany
General University Hospital AHEPA
🇬🇷Thessaloniki, Greece
State Institution, "Institute of Rheumatology of RAMS"
🇷🇺Moscow, Russian Federation
EUROMEDICA - Kyanos Stavros
🇬🇷Thessaloniki, Greece
Christus Muguerza del Parque Hospital
🇲🇽Chihuahua, Mexico
Hospital Civil de Guadalajara - Fray Antonio Alacade Hospital No. 278
🇲🇽Guadalajara, Mexico
Dunedin Hospital
🇳🇿Dunedin, New Zealand
Cork University Hospital
🇮🇪Cork, Ireland
Sheba Medical Center
🇮🇱Tel-Hashomer, Israel
Asaf Harofe Medical Center
🇮🇱Zerifin, Israel
Middlemore Hospital
🇳🇿Auckland, New Zealand
Dokuz Eylul Universitesi Tip Fakultesi Romatoloji Bilim Dali
🇹🇷Izmir, Turkey
Vinnytsia Regional Clinical Hospital named after M. Pyrogov
🇺🇦Vinnytsia, Ukraine