Clinical trial NCT01474109: Macitentan for the Treatment of Digital Ulcers in Systemic Sclerosis Patients
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Systemic Sclerosis
Ulcers
Keywords: systemic sclerosis
digital ulcers
Lead sponsor: Actelion
Sponsor class: INDUSTRY
First posted: 2011-11-18
Enrollment: 289
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The DUAL-1 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.

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.

Eligibility criteria: 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 digital ulcers (DU) at baseline
* History of at least one additional recent active ischemic DU

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 the normal range (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 type-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 ERAs within 3 months.
* Systemic antibiotics to treat infected DU(s) within 4 weeks.

Primary outcomes:
measure: Incidence Rate of New Digital Ulcers (DUs) up to Week 16
timeFrame: Baseline to week 16
Secondary outcomes:
measure: Percentage of Participants Without a New DU Up To Week 16
timeFrame: Baseline to week 16
measure: Percentage of Participants With at Least One DU Complication
timeFrame: Up to approximately 90 weeks
measure: Change in Hand Functionality Health Assessment Questionnaire - Disability Index (HAQ-DI) Hand Component From Baseline to Week 16
timeFrame: Baseline to week 16
measure: Health Assessment Questionnaire - Disability Index (HAQ-DI) Overall Score From Baseline to Week 16
timeFrame: Baseline to week 16
measure: Change in Hand Functionality - Hand Disability in Systemic Sclerosis - Digital Ulcers (HDISS-DU) Score From Baseline to Week 16
timeFrame: Baseline to week 16
Other outcomes:
Locations:
city: Tucson
country: United States
facility: University of Arizona Arthritis Center
state: Arizona
city: Los Angeles
country: United States
facility: UCLA Medical School - Rheumatology Division Rehabilitation Center
state: California
city: Aventura
country: United States
facility: Arthritis & Rheumatic Disease Specialties
state: Florida
city: Sarasota
country: United States
facility: Sarasota Arthritis Research Center
state: Florida
city: New Orleans
country: United States
facility: Ochsner Medical Center
state: Louisiana
city: Baltimore
country: United States
facility: The Johns Hopkins University School of Medicine
state: Maryland
city: Ann Arbor
country: United States
facility: University of Michigan - Scleroderma Program
state: Michigan
city: Grand Rapids
country: United States
facility: Michigan State University
state: Michigan
city: New Brunswick
country: United States
facility: University of Medicine & Dentistry of New Jersey, UMDNJ Scleroderma Program
state: New Jersey
city: Albany
country: United States
facility: The Center for Rheumatology
state: New York
city: Raleigh
country: United States
facility: Shanahan Rheumatology and Immunotherapy, PLLC
state: North Carolina
city: Cleveland
country: United States
facility: The Cleveland Clinic Foundation
state: Ohio
city: Duncansville
country: United States
facility: Altoona Center for Clinical Research
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh Department of Rheumatology
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
city: Auchenflower
country: Australia
facility: Wesley Hospital, Thoracic Department
city: Camperdown
country: Australia
facility: Royal Prince Alfred Hospital
city: Fitzroy
country: Australia
facility: St Vincent's Hospital
city: Hobart
country: Australia
facility: Menzies Research Institute
city: Gomel
country: Belarus
facility: Gomel Regional Clinical Hospital
city: Minsk
country: Belarus
facility: Healthcare Institution "Minsk City Hospital #1"
city: Minsk
country: Belarus
facility: Healthcare Institution "Minsk Clinical Hospital #9"
city: Pleven
country: Bulgaria
facility: Multiprofile Hospital for Active Treatment "Sveti Pantaleymon"
city: Plovdiv
country: Bulgaria
facility: MHAT "Kaspela" EOOD Plovdiv - Rheumatology Ward
city: Sofia
country: Bulgaria
facility: MHAT "Sv. Ivan Rilski" EAD Sofia - Clinic of Rheumatology
city: Edmonton
country: Canada
facility: Rheumatology Research Associates
state: Alberta
city: Vancouver
country: Canada
facility: St. Paul's Hospital
state: British Columbia
city: London
country: Canada
facility: St. Joseph's Health Care
state: Ontario
city: Toronto
country: Canada
facility: Mount Sinai Hospital
state: Ontario
city: Sherbrooke
country: Canada
facility: CHUS Hopital Fleurimont
state: Quebec
city: Santiago
country: Chile
facility: Prosalud
city: Santiago
country: Chile
facility: Private Office Marta Aliste
city: Santiago
country: Chile
facility: Hospital San Juan de Dios
city: Vina del Mar
country: Chile
facility: Centro de Estudios Clinicos V
city: Bucaramanga
country: Colombia
facility: Medicity S.A.S.
city: Bucaramanga
country: Colombia
facility: Servimed E.U.
city: Osijek
country: Croatia
facility: Klinicki Bolnicki Centar Osijek
city: Rijeka
country: Croatia
facility: University Hospital Centre Rijeka
city: Split
country: Croatia
facility: Klinički bolnički centar Split
city: Zagreb
country: Croatia
facility: Klinicka Bolnica "Svety Duh"
city: Zagreb
country: Croatia
facility: Klinička bolnica Dubrava
city: Zagreb
country: Croatia
facility: University Hospital Centre Zagreb
city: Brno
country: Czech Republic
facility: Lekarna FN Brno
city: Hradec Králové
country: Czech Republic
facility: Faculty Hospital Hradec Králové
city: Praha
country: Czech Republic
facility: Revmatologický ústav Praha
city: Copenhagen
country: Denmark
facility: Bispebjerg Hospital København
city: Odense
country: Denmark
facility: Odense Universitetshospital
city: Helsinki
country: Finland
facility: Helsingin yliopistollinen keskussairaala (HYKS), Meilahden kolmiosairaala, Reumatologian klinikka
city: Berlin
country: Germany
facility: Universitätsmedizin Berlin Medizinische Klinik mit Schwerpunkt Rheumatologie und Klinische Immunologie
city: Bochum
country: Germany
facility: Klinik für Dermatologie und Allergologie der Ruhr-Universität Bochum
city: Freiburg
country: Germany
facility: Medizinische Universitätsklinik Freiburg, Abt. Rheumatologie und klinische Forschung
city: Hamburg
country: Germany
facility: Asklepios Westklinikum Hamburg Abteilung für Gefäßmedizin, Angiologie und Diabetologie
city: Hamburg
country: Germany
facility: Rheumatologie, klinische Immunologie, Nephrologie Asklepios Rheumazentrum Hamburg Asklepios Klinik Altona
city: Karlsbad
country: Germany
facility: Akademie für Gefäßkrankheiten eV.
city: Koln
country: Germany
facility: Klinik und Poliklinik für Dermatologie und Venerologie der Universität zu Köln
city: Tuebingen
country: Germany
facility: Universitäts-Hautklinik Tübingen
city: Budapest
country: Hungary
facility: Budai Irgalmasrendi Kórház
city: Debrecen
country: Hungary
facility: Debreceni Egyetem Orvos- és Egészségtudományi Centrum
city: Pécs
country: Hungary
facility: Pécsi Tudományegyetem Klinikai Központ, Reumatológiai és Immunológiai Klinika
city: Hyderabad
country: India
facility: Advance Rheumatology Clinic
city: Secunderabad
country: India
facility: Krishna Institute of Medical Sciences
city: Vellore
country: India
facility: Christian Medical College
city: Firenze
country: Italy
facility: Azienda Ospedaliera Careggi
city: Modena
country: Italy
facility: Azienda Ospedaliera Policlinico di Modena
city: Rome
country: Italy
facility: Complesso Integrato Columbus
city: Gdańsk
country: Poland
facility: Uniwersyteckie Centrum Kliniczne
city: Lublin
country: Poland
facility: NZOZ Reumed
city: Warszawa
country: Poland
facility: Centralny Szpital Kliniczny MSWiA
city: Wrocław
country: Poland
facility: Akademicki Szpital Kliniczny im. Jana Mikulicza-Radeckiego we Wrocławiu
city: Ekaterinburg
country: Russian Federation
facility: State Healthcare Institution "Sverdlovsk Regional Clinical Hospital #1"
city: Penza
country: Russian Federation
facility: State Healthcare Institution "Penza Regional Clinical Hospital named after N.N. Burdenko"
city: Vladimir
country: Russian Federation
facility: Vladimir Regional State Institution of Healthcare, "Regional Clinical Hospital"
city: Dnipropetrovsk
country: Ukraine
facility: Dinpropetrovsk Regional Clinical Hospital named after I. Mechnykova
city: Kyiv
country: Ukraine
facility: Municipal Institution of Kyiv Regional Council, Kyiv Regional Clinical Hospital
city: Lviv
country: Ukraine
facility: Lviv Regional Clinical Hospital
city: Poltava
country: Ukraine
facility: Internal disease chair of Ukrainian medical dentist academy based on therapy department of Poltava Poltava City Clinical Hospital #1
Study officials:
References:
citation: Khanna D, Denton CP, Merkel PA, Krieg T, Le Brun FO, Marr A, Papadakis K, Pope J, Matucci-Cerinic M, Furst DE; DUAL-1 Investigators; DUAL-2 Investigators. Effect of Macitentan on the Development of New Ischemic Digital Ulcers in Patients With Systemic Sclerosis: DUAL-1 and DUAL-2 Randomized Clinical Trials. JAMA. 2016 May 10;315(18):1975-88. doi: 10.1001/jama.2016.5258.