Macitentan for the Treatment of Digital Ulcers in Systemic Sclerosis Patients (DUAL-1)

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

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.

Study Overview

• Status: Completed
• Conditions: Systemic Sclerosis; Ulcers
• Intervention / Treatment: Drug: macitentan 3mg; Drug: macitentan 10mg; Drug: placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 289
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Adelaide, Australia, 5000
    • Royal Adelaide Hospital
  • Auchenflower, Australia, 4066
    • Wesley Hospital, Thoracic Department
  • Camperdown, Australia, 2050
    • Royal Prince Alfred Hospital
  • Fitzroy, Australia, 3065
    • St Vincent's Hospital
  • Hobart, Australia, 7000
    • Menzies Research Institute
• Belarus
  • Gomel, Belarus, 246029
    • Gomel Regional Clinical Hospital
  • Minsk, Belarus, 220013
    • Healthcare Institution "Minsk City Hospital #1"
  • Minsk, Belarus, 220116
    • Healthcare Institution "Minsk Clinical Hospital #9"
• Bulgaria
  • Pleven, Bulgaria, 5800
    • Multiprofile Hospital for Active Treatment "Sveti Pantaleymon"
  • Plovdiv, Bulgaria, 4002
    • MHAT "Kaspela" EOOD Plovdiv - Rheumatology Ward
  • Sofia, Bulgaria, 1612
    • MHAT "Sv. Ivan Rilski" EAD Sofia - Clinic of Rheumatology
• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T5M 0H4
      • Rheumatology Research Associates
  • British Columbia
    • Vancouver, British Columbia, Canada, V6Z 1Y6
      • St. Paul's Hospital
  • Ontario
    • London, Ontario, Canada, N6A 4V2
      • St. Joseph's Health Care
    • Toronto, Ontario, Canada, M5G 1X5
      • Mount Sinai Hospital
  • Quebec
    • Sherbrooke, Quebec, Canada, J1H 5N4
      • CHUS Hopital Fleurimont
• Chile
  • Santiago, Chile, 7510047
    • PROSALUD
  • Santiago, Chile, 7510186
    • Private Office Marta Aliste
  • Santiago, Chile, 8500000
    • Hospital San Juan de Dios
  • Vina del Mar, Chile, 2570017
    • Centro de Estudios Clinicos V
• Colombia
  • Bucaramanga, Colombia
    • Medicity S.A.S.
  • Bucaramanga, Colombia
    • Servimed E.U.
• Croatia
  • Osijek, Croatia, 31000
    • Klinički bolnički centar Osijek
  • Rijeka, Croatia, 51000
    • University hospital centre Rijeka
  • Split, Croatia, 21000
    • Klinički Bolnički Centar Split
  • Zagreb, Croatia, 10000
    • Klinicka Bolnica "Svety Duh"
  • Zagreb, Croatia, 10000
    • Klinicka bolnica Dubrava
  • Zagreb, Croatia, 10000
    • University Hospital Centre Zagreb
• Czech Republic
  • Brno, Czech Republic, 62500
    • Lekarna FN Brno
  • Hradec Králové, Czech Republic, 500 05
    • Faculty Hospital Hradec Králové
  • Praha, Czech Republic, 12000
    • Revmatologický ústav Praha
• Denmark
  • Copenhagen, Denmark, 2400
    • Bispebjerg Hospital København
  • Odense, Denmark, 5000
    • Odense Universitetshospital
• Finland
  • Helsinki, Finland, 00290
    • Helsingin yliopistollinen keskussairaala (HYKS), Meilahden kolmiosairaala, Reumatologian klinikka
• Germany
  • Berlin, Germany, 10117
    • Universitätsmedizin Berlin Medizinische Klinik mit Schwerpunkt Rheumatologie und Klinische Immunologie
  • Bochum, Germany, 44791
    • Klinik fur Dermatologie und Allergologie der Ruhr-Universitat Bochum
  • Freiburg, Germany, 79106
    • Medizinische Universitätsklinik Freiburg, Abt. Rheumatologie und klinische Forschung
  • Hamburg, Germany, 22559
    • Asklepios Westklinikum Hamburg Abteilung für Gefäßmedizin, Angiologie und Diabetologie
  • Hamburg, Germany, 22763
    • Rheumatologie, klinische Immunologie, Nephrologie Asklepios Rheumazentrum Hamburg Asklepios Klinik Altona
  • Karlsbad, Germany, 76307
    • Akademie für Gefäßkrankheiten eV.
  • Koln, Germany, 50937
    • Klinik und Poliklinik für Dermatologie und Venerologie der Universität zu Köln
  • Tuebingen, Germany, 72076
    • Universitäts-Hautklinik Tübingen
• Hungary
  • Budapest, Hungary, 1023
    • Budai Irgalmasrendi Korhaz
  • Debrecen, Hungary, 4032
    • Debreceni Egyetem Orvos- es Egeszsegtudomanyi Centrum
  • Pécs, Hungary, 7632
    • Pécsi Tudományegyetem Klinikai Központ, Reumatológiai és Immunológiai Klinika
• India
  • Hyderabad, India, 500082
    • Advance Rheumatology Clinic
  • Secunderabad, India, 500 003
    • Krishna Institute of Medical Sciences
  • Vellore, India, 632004
    • Christian Medical College
• Italy
  • Firenze, Italy, 50139
    • Azienda Ospedaliera Careggi
  • Modena, Italy, 41100
    • Azienda Ospedaliera Policlinico di Modena
  • Rome, Italy, 00168
    • Complesso Integrato Columbus
• Poland
  • Gdańsk, Poland, 80-952
    • Uniwersyteckie Centrum Kliniczne
  • Lublin, Poland, 20-607
    • NZOZ Reumed
  • Warszawa, Poland, 02-507
    • Centralny Szpital Kliniczny Mswia
  • Wrocław, Poland, 50-566
    • Akademicki Szpital Kliniczny im. Jana Mikulicza-Radeckiego we Wrocławiu
• Russian Federation
  • Ekaterinburg, Russian Federation, 620102
    • State Healthcare Institution "Sverdlovsk Regional Clinical Hospital #1"
  • Penza, Russian Federation, 440026
    • State Healthcare Institution "Penza Regional Clinical Hospital named after N.N. Burdenko"
  • Vladimir, Russian Federation, 600023
    • Vladimir Regional State Institution of Healthcare, "Regional Clinical Hospital"
• Ukraine
  • Dnipropetrovsk, Ukraine, 49005
    • Dinpropetrovsk Regional Clinical Hospital named after I. Mechnykova
  • Kyiv, Ukraine, 04107
    • Municipal Institution of Kyiv Regional Council, Kyiv Regional Clinical Hospital
  • Lviv, Ukraine, 79010
    • Lviv Regional Clinical Hospital
  • Poltava, Ukraine, 36039
    • Internal disease chair of Ukrainian medical dentist academy based on therapy department of Poltava Poltava City Clinical Hospital #1
• United States
  • Arizona
    • Tucson, Arizona, United States, 85724
      • University of Arizona Arthritis Center
  • California
    • Los Angeles, California, United States, 90095
      • UCLA Medical School - Rheumatology Division Rehabilitation Center
  • Florida
    • Aventura, Florida, United States, 33180
      • Arthritis & Rheumatic Disease Specialties
    • Sarasota, Florida, United States, 34239
      • Sarasota Arthritis Research Center
  • Louisiana
    • New Orleans, Louisiana, United States, 70121
      • Ochsner Medical Center
  • Maryland
    • Baltimore, Maryland, United States, 21224-6801
      • The Johns Hopkins University School of Medicine
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan - Scleroderma Program
    • Grand Rapids, Michigan, United States, 49546
      • Michigan State University
  • New Jersey
    • New Brunswick, New Jersey, United States, 08903-0010
      • University of Medicine & Dentistry of New Jersey, UMDNJ Scleroderma Program
  • New York
    • Albany, New York, United States, 12206
      • The Center for Rheumatology
  • North Carolina
    • Raleigh, North Carolina, United States, 27617-7884
      • Shanahan Rheumatology and Immunotherapy, PLLC
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • The Cleveland Clinic Foundation
  • Pennsylvania
    • Duncansville, Pennsylvania, United States, 16635
      • Altoona Center For Clinical Research
    • Pittsburgh, Pennsylvania, United States, 15261
      • University of Pittsburgh Department of Rheumatology
  • South Carolina
    • Charleston, South Carolina, United States, 29425-8905
      • Medical University of South Carolina

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: macitentan 3mg; macitentan 3mg tablet once daily	Drug: macitentan 3mg; macitentan 3mg tablet once daily; Other Names: ACT-064992
Active Comparator: macitentan 10mg; macitentan 10mg tablet once daily	Drug: macitentan 10mg; macitentan 10mg tablet once daily; Other Names: ACT-064992
Placebo Comparator: placebo; matching placebo once daily	Drug: placebo; matching placebo once daily

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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 approximately 90 weeks
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
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
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

Collaborators and Investigators

• Sponsor: Actelion

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start: December 1, 2011
• Primary Completion (Actual): November 1, 2013
• Study Completion (Actual): November 1, 2013

Study Registration Dates

• First Submitted: October 31, 2011
• First Submitted That Met QC Criteria: November 15, 2011
• First Posted (Estimate): November 18, 2011

Study Record Updates

• Last Update Posted (Estimate): January 6, 2015
• Last Update Submitted That Met QC Criteria: January 2, 2015
• Last Verified: January 1, 2015

More Information

Terms related to this study

• Keywords: systemic sclerosis; digital ulcers
• Additional Relevant MeSH Terms: Pathologic Processes; Skin Diseases; Connective Tissue Diseases; Sclerosis; Ulcer; Scleroderma, Systemic; Scleroderma, Diffuse; Molecular Mechanisms of Pharmacological Action; Endothelin Receptor Antagonists; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Macitentan
• Other Study ID Numbers: AC-055C301