Macitentan for the Treatment of Digital Ulcers in Systemic Sclerosis Patients

Systemic Sclerosis Clinical Trial

— DUAL-2  

Official title:

Prospective, Randomized, Placebo-controlled, Double-blind, Multicenter, Parallel Group Study to Assess the Efficacy, Safety and Tolerability of Macitentan in Patients With Ischemic Digital Ulcers Associated With Systemic Sclerosis

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01474122
• Other study ID #: AC-055C302
• Status: Terminated
• Phase: Phase 3
• First received: October 31, 2011
• Last updated: January 19, 2015
• Start date: December 2011
• Est. completion date: February 2014

Study information

• Verified date: January 2015
• Source: Actelion
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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 will continue on their original randomized treatment into Period 2, until the last randomized patient has completed Period 1.

Patients will be 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.

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 information / eligibility

• Status: Terminated
• Enrollment: 265
• Est. completion date: February 2014
• Est. primary completion date: February 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria :

• Patients = 18 years of age

• Women of childbearing potential must use two reliable methods of contraception

• Diagnosis of SSc according to the classification criteria of the American College of Rheumatology (ACR)

• At least one visible, active ischemic DU at baseline

• History of at least one additional recent active ischemic digital ulcer

Exclusion Criteria :

• DUs due to condition other than SSc

• Symptomatic pulmonary arterial hypertension (PAH)

• Body mass index (BMI) < 18 kg/m^2

• Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 1.5 x upper limit of normal (ULN)

• Hemoglobin < 75% of the lower limit of the normal range

• Systolic blood pressure < 95 mmHg or diastolic blood pressure < 50 mmHg

• Severe malabsorption; any severe organ failure (e.g., lung, kidney), or any life-threatening condition

• Females who are pregnant or breastfeeding or plan to do so during the course of this study

• Substance or alcohol abuse or dependence, or tobacco use at any level

• Treatment with phosphodiesterase-5 (PDE5) inhibitors

• Patients on statins, who have received treatment for less than 3 months prior to Screening or whose treatment has not been stable during this period

• Patients on vasodilators, who have received treatment for less than 2 weeks prior to Screening or whose treatment has not been stable during this period

• Treatment with prostanoids within 3 months

• Treatment with disease modifying agents if present for less than 3 months prior to Screening or whose treatment has not been stable for at least 1 month prior to Screening

• Treatment with oral corticosteroids (> 10 mg/day of prednisone or equivalent).

• Treatment with endothelin receptor antagonists (ERAs) within 3 months

• Systemic antibiotics to treat infected DU(s) within 4 weeks

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Scleroderma, Diffuse
• Scleroderma, Systemic
• Sclerosis
• Systemic Sclerosis
• Ulcer
• Ulcers

Intervention

Drug:
• macitentan 3mg
macitentan tablet 3mg once daily
• macitentan 10mg
macitentan tablet 10mg once daily
• placebo
matching placebo once daily

Locations

Country	Name	City	State
Argentina	Centro de Educacion Medica e Investigaciones Clinicas - CEMIC	Buenos Aires
Argentina	Hospital Britanico de Buenos Aires	Buenos Aires
Argentina	Hospital Italiano de Buenos Aires	Buenos Aires
Argentina	Sanatorio San Jose	Caba
Argentina	Hospital Italiano de Cordoba	Cordoba
Argentina	Hospital Privado Centro Medico de Cordoba S.A.	Cordoba
Belgium	Clinique Universitaires Saint Luc	Brussels
Belgium	Cliniques universitaires UCL Mont-Godinne	Yvoir
China	Peking Union Medical College Hospital	Beijing
China	Guangdong General Hospital	Guangzhou
China	Renji Hospital, Shanghai Jiaotong University	Shanghai
China	First Affiliated Hospital of the Forth Military University	Xi'an
Colombia	Centro Integral de Reumatologia y Inmunologia CIREI SAS	Bogota
Colombia	Fundacion Instituto du Reumatologia Fernando Chalem	Bogota
Colombia	Hospital Pablo Tobon Uribe	Medellin	Antioquia
Germany	Kerckhoff-Klinik GmbH	Bad Nauheim
Germany	Universitätsklinikum der Technischen Universität Dresden	Dresden
Germany	Hautklinik Universitätsklinikum Erlangen	Erlangen
Germany	Department of Dermatology University Hospital Johannes Gutenberg	Mainz
Germany	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
Greece	General University Hospital LAIKO/A' Propaideftiki Pathology Clinic	Athens
Greece	EUROMEDICA - Kyanos Stavros	Thessaloniki
Greece	General University Hospital AHEPA	Thessaloniki
Ireland	Cork University Hospital	Cork
Ireland	Beaumont Hospital	Dublin
Ireland	St. Vincents University Hospital	Dublin
Ireland	Mid-Western Regional Hospital	Limerick
Israel	Sheba Medical Center	Tel-Hashomer
Israel	Asaf Harofe Medical Center	Zerifin
Mexico	Christus Muguerza del Parque Hospital	Chihuahua
Mexico	Clinica Diagnostico y Tratamiento de las Enfermedades Reumaticas	Distrito Federal
Mexico	Hospital Civil de Guadalajara - Fray Antonio Alacade Hospital No. 278	Guadalajara
Mexico	Unidad de Investigacion en Enfermedades Cronico Degeneratives SC	Guadalajara	Jalisco
Mexico	Hospital Aranda de la Parra Leon	Leon
Mexico	Hospital Angeles Lindavista	Madero
Mexico	Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubrian	Mexico D.F.
Netherlands	VU University Medical Center	Amsterdam
Netherlands	UMC St Radboud	GA Nijmegen
New Zealand	Middlemore Hospital	Auckland
New Zealand	Dunedin Hospital	Dunedin
New Zealand	Waikato Hospital	Hamilton
New Zealand	North Shore Hospital, STAR (Shore Trials and Research) Unit	North Shore
New Zealand	Wellington Hospital	Wellington South
Poland	Prywatna Praktyka Lekarska Prof. UM dr hab. med. Pawel Hrycaj	Poznan
Poland	SPSK Nr 1 PUM Szczecin	Szczecin
Poland	Reumatika - Centrum Reumatologii NZOZ	Warszawa
Poland	Wojskowy Instytut Medyczny CSK MON	Warszawa
Poland	SPSK Nr 1 Wroclaw	Wroclaw
Portugal	Instituto Português de Reumatologia	Lisboa
Puerto Rico	University of Puerto Rico	San Juan
Russian Federation	State Institution, "Institute of Rheumatology of RAMS"	Moscow
Russian Federation	Municipal Treatment and Prevention Institution, "City Clinical Hospital #5"	Nizhniy Novgorod
Russian Federation	State Educational Institution of High Professional Education "Voronezh State Medical Academy named after N.N.Burdenko of Roszdrav"	Voronezh
South Africa	Groote Schuur Hospital, University of Cape Town	Cape Town
South Africa	Louis Pasteur Medical Centre	Pretoria
South Africa	Chris Hani Baragwanath Hospital	Soweto
Spain	HOSPITAL Universitario VALL D'HEBRON - Servicio Medicina Interna	Barcelona
Spain	Hospital Universitari i Politecnic La Fe	Valencia
Turkey	Çukurova Üniversitesi Tip Fakültesi ROMATOLOJI BILIM DALI	Adana
Turkey	Dokuz Eylul Universitesi Tip Fakultesi Romatoloji Bilim Dali	Izmir
Ukraine	Municipal Healthcare Institution "Donetsk Regional Clinical Hospital of Occupational Diseases"	Donetsk
Ukraine	National scientific centre "Institute of Cardiology named after M. Strazheska"	Kyiv
Ukraine	Crimean Republican Institution 'Clinical territorial medical union 'University Clinic	Simferopol
Ukraine	Vinnytsia Regional Clinical Hospital named after M. Pyrogov	Vinnytsia
Ukraine	Scientific and Research Institute of Handicapped Rehabilitation of Vinnitsa National Medical University named after M. Pirogova	Vinnytsya
United Kingdom	Royal National Hospital	Bath
United Kingdom	Addenbrooke's Hospital - University of Cambridge School of Clinical Medicine	Cambridge
United Kingdom	University Hospital Aintree - Rheumatology Department	Liverpool
United Kingdom	Royal Free & University College Medical School	London
United Kingdom	University of Manchester School of Translational Medicine Musculoskeletal Research Group	Manchester
United Kingdom	Ninewells Hospital & Medical School	Scotland
United Kingdom	Torbay Hospital	Torbay
United States	Boston University School of Medicine	Boston	Massachusetts
United States	Northwestern University - Feinberg School of Medicine Department of Rheumatology	Chicago	Illinois
United States	University of Connecticut Health Center - Division of Rheumatic Diseases	Farmington	Connecticut
United States	University of Texas - Houston Medical School	Houston	Texas
United States	North Shore Long Island Jewish Health System - Div. of Rheumatology & Allergy-Clinical Immunology	Lake Success	New York
United States	Medical College of Wisconsin	Milwaukee	Wisconsin
United States	The Hospital for Special Surgery	New York	New York
United States	Millennium Research	Ormond Beach	Florida
United States	Stanford Univ. School of Medicine - Palo Alto VA Health Care System	Palo Alto	California
United States	The University of Pennsylvania	Philadelphia	Pennsylvania
United States	University of Utah	Salt Lake City	Utah
United States	Arthritis Northwest PLLC	Spokane	Washington
United States	Washington University School of Medicine	St Louis	Missouri
United States	Ruppert Health Center	Toledo	Ohio
United States	Georgetown University	Washington	District of Columbia
United States	Cleveland Clinic Florida	Weston	Florida
United States	Florida Medical Clinic-PA	Zephyrhills	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Actelion

Countries where clinical trial is conducted

United States,  Argentina,  Belgium,  China,  Colombia,  Germany,  Greece,  Ireland,  Israel,  Mexico,  Netherlands,  New Zealand,  Poland,  Portugal,  Puerto Rico,  Russian Federation,  South Africa,  Spain,  Turkey,  Ukraine,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Incidence Rate of New Digital Ulcers (DUs) up 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.	Baseline to Week 16	No
Secondary	Percentage of Participants Without a New DU Up 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.	Baseline to Week 16	No
Secondary	Percentage of Participants With at Least One DU Complication	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.	Up to 95 weeks	No
Secondary	Change in Hand Functionality Health Assessment Questionnaire - Disability Index (HAQ-DI) Hand Component From 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).	Baseline to Week 16	No
Secondary	Health Assessment Questionnaire - Disability Index (HAQ-DI) Overall Score From 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).	Baseline to Week 16	No
Secondary	Change in Hand Functionality - Hand Disability in Systemic Sclerosis - Digital Ulcers (HDISS-DU) Score From 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)	Baseline to Week 16	No