Macitentan for the Treatment of Digital Ulcers in Systemic Sclerosis Patients (DUAL-2)

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-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.

Study Overview

• Status: Terminated
• Conditions: Digital Ulcers
• Intervention / Treatment: Drug: Macitentan 3 mg; Drug: Macitentan 10 mg; 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): 265
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina
    • Hospital Italiano de Buenos Aires
  • Buenos Aires, Argentina, C1280AEB
    • Hospital Britanico de Buenos Aires
  • Buenos Aires, Argentina, 4102
    • Centro de Educacion Medica e Investigaciones Clinicas - CEMIC
  • Caba, Argentina, C1425DUH
    • Sanatorio San Jose
  • Cordoba, Argentina, X5016KEH
    • Hospital Privado Centro Medico de Cordóba S.A.
  • Cordoba, Argentina, X5004BAL
    • Hospital Italiano de Cordoba
• Belgium
  • Brussels, Belgium, 1200
    • Clinique universitaires saint luc
  • Yvoir, Belgium, 5530
    • Cliniques Universitaires UCL Mont-Godinne
• China
  • Beijing, China, 100032
    • Peking Union Medical College Hospital
  • Guangzhou, China, 510080
    • Guangdong General Hospital
  • Shanghai, China, 200001
    • Renji hospital, Shanghai Jiaotong University
  • Xi'an, China, 710032
    • First Affiliated Hospital of the Forth Military University
• Colombia
  • Bogota, Colombia
    • Centro Integral de Reumatologia y Inmunologia CIREI SAS
  • Bogota, Colombia
    • Fundacion Instituto du Reumatologia Fernando Chalem
  • Antioquia
    • Medellin, Antioquia, Colombia
      • Hospital Pablo Tobon Uribe
• Germany
  • Bad Nauheim, Germany, 61231
    • Kerckhoff-Klinik GmbH
  • Dresden, Germany, 01307
    • Universitätsklinikum der Technischen Universität Dresden
  • Erlangen, Germany, 91054
    • Hautklinik Universitatsklinikum Erlangen
  • Mainz, Germany, 55131
    • Department of Dermatology University Hospital Johannes Gutenberg
  • Muchen, Germany, 80337
    • Ludwig-Maximilian-Universität München Abteilung Dermatologie
  • Muenchen, Germany, 80802
    • Klinik und Poliklinik für Dermatologie und Allergologie am Biderstein des Klinikums rechts der Isar der Technischen Universität München
• Greece
  • Athens, Greece, 11527
    • General University Hospital LAIKO/A' Propaideftiki Pathology Clinic
  • Thessaloniki, Greece, 54636
    • Euromedica - Kyanos Stavros
  • Thessaloniki, Greece, 54636
    • General University Hospital AHEPA
• Ireland
  • Cork, Ireland, C1
    • Cork University Hospital
  • Dublin, Ireland, 2
    • Beaumont Hospital
  • Dublin, Ireland, 4
    • St. Vincents University Hospital
  • Limerick, Ireland
    • Mid-Western Regional Hospital
• Israel
  • Tel-Hashomer, Israel, 52621
    • Sheba Medical Center
  • Zerifin, Israel, 70300
    • Asaf Harofe Medical Center
• Mexico
  • Chihuahua, Mexico, 31000
    • Christus Muguerza del Parque Hospital
  • Distrito Federal, Mexico, 06700
    • Clinica Diagnostico y Tratamiento de las Enfermedades Reumaticas
  • Guadalajara, Mexico, 44280
    • Hospital Civil de Guadalajara - Fray Antonio Alacade Hospital No. 278
  • Leon, Mexico, 37000
    • Hospital Aranda de la Parra Leon
  • Madero, Mexico, 07760
    • Hospital Angeles Lindavista
  • Mexico D.F., Mexico, 14000
    • Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubrian
  • Jalisco
    • Guadalajara, Jalisco, Mexico, 44620
      • Unidad de Investigacion en Enfermedades Cronico Degeneratives SC
• Netherlands
  • Amsterdam, Netherlands, 1081
    • VU University Medical Center
  • GA Nijmegen, Netherlands, 6525
    • UMC St Radboud
• New Zealand
  • Auckland, New Zealand, 1640
    • Middlemore Hospital
  • Dunedin, New Zealand, 9054
    • Dunedin Hospital
  • Hamilton, New Zealand, 3204
    • Waikato Hospital
  • North Shore, New Zealand, 0620
    • North Shore Hospital, STAR (Shore Trials and Research) Unit
  • Wellington South, New Zealand, 7902
    • Wellington Hospital
• Poland
  • Poznań, Poland, 61-397
    • Prywatna Praktyka Lekarska Prof. UM dr hab. med. Paweł Hrycaj
  • Szczecin, Poland, 71-752
    • SPSK Nr 1 PUM Szczecin
  • Warszawa, Poland, 02-653
    • REUMATIKA - Centrum Reumatologii NZOZ
  • Warszawa, Poland, 04-141
    • Wojskowy Instytut Medyczny CSK MON
  • Wrocław, Poland, 50-368
    • SPSK Nr 1 Wrocław
• Portugal
  • Lisboa, Portugal, 1050-034
    • Instituto Portugues de Reumatologia
• Puerto Rico
  • San Juan, Puerto Rico, 00918
    • University of Puerto Rico
• Russian Federation
  • Moscow, Russian Federation, 115552
    • State Institution, "Institute of Rheumatology of RAMS"
  • Nizhniy Novgorod, Russian Federation, 603005
    • Municipal Treatment and Prevention Institution, "City Clinical Hospital #5"
  • Voronezh, Russian Federation, 394036
    • State Educational Institution of High Professional Education "Voronezh State Medical Academy named after N.N.Burdenko of Roszdrav"
• South Africa
  • Cape Town, South Africa, 7925
    • Groote Schuur Hospital, University of Cape Town
  • Pretoria, South Africa, 0001
    • Louis Pasteur Medical Centre
  • Soweto, South Africa, 2013
    • Chris Hani Baragwanath Hospital
• Spain
  • Barcelona, Spain, 08035
    • HOSPITAL Universitario VALL D'HEBRON - Servicio Medicina Interna
  • Valencia, Spain, 46026
    • Hospital Universitari i Politecnic La Fe
• Turkey
  • Adana, Turkey, 01330
    • Çukurova Üniversitesi Tıp Fakültesi ROMATOLOJİ BİLİM DALI
  • Izmir, Turkey, 35340
    • Dokuz Eylul Universitesi Tip Fakultesi Romatoloji Bilim Dali
• Ukraine
  • Donetsk, Ukraine, 83059
    • Municipal Healthcare Institution "Donetsk Regional Clinical Hospital of Occupational Diseases"
  • Kyiv, Ukraine, 03151
    • National scientific centre "Institute of Cardiology named after M. Strazheska"
  • Simferopol, Ukraine, 95017
    • Crimean Republican Institution 'Clinical territorial medical union 'University Clinic
  • Vinnytsia, Ukraine, 21018
    • Vinnytsia Regional Clinical Hospital named after M. Pyrogov
  • Vinnytsya, Ukraine, 21029
    • Scientific and Research Institute of Handicapped Rehabilitation of Vinnitsa National Medical University named after M. Pirogova
• United Kingdom
  • Bath, United Kingdom, BA1 1RL
    • Royal National Hospital
  • Cambridge, United Kingdom, CB2 0QQ
    • Addenbrooke's Hospital - University of Cambridge School of Clinical Medicine
  • Liverpool, United Kingdom, L9 7AL
    • University Hospital Aintree - Rheumatology Department
  • London, United Kingdom, NW3 2PF
    • Royal Free & University College Medical School
  • Manchester, United Kingdom, M13 9PT
    • University of Manchester School of Translational Medicine Musculoskeletal Research Group
  • Scotland, United Kingdom, DD1 9SY
    • Ninewells Hospital & Medical School
  • Torbay, United Kingdom, TQ2 7AA
    • Torbay Hospital
• United States
  • California
    • Palo Alto, California, United States, 94304
      • Stanford Univ. School of Medicine - Palo Alto VA Health Care System
  • Connecticut
    • Farmington, Connecticut, United States, 06030-1310
      • University of Connecticut Health Center - Division of Rheumatic Diseases
  • District of Columbia
    • Washington, District of Columbia, United States, 20007
      • Georgetown University
  • Florida
    • Ormond Beach, Florida, United States, 32174
      • Millennium Research
    • Weston, Florida, United States, 33331
      • Cleveland Clinic Florida
    • Zephyrhills, Florida, United States, 33542
      • Florida Medical Clinic-PA
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University - Feinberg School of Medicine Department of Rheumatology
  • Massachusetts
    • Boston, Massachusetts, United States, 02118-2394
      • Boston University School of Medicine
  • Missouri
    • St Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • New York
    • Lake Success, New York, United States, 11042
      • North Shore Long Island Jewish Health System - Div. of Rheumatology & Allergy-Clinical Immunology
    • New York, New York, United States, 10021
      • The Hospital for Special Surgery
  • Ohio
    • Toledo, Ohio, United States, 43614
      • Ruppert Health Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • The University of Pennsylvania
  • Texas
    • Houston, Texas, United States, 77030
      • University of Texas - Houston Medical School
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • University of Utah
  • Washington
    • Spokane, Washington, United States, 99204
      • Arthritis Northwest PLLC
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Medical College of Wisconsin

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 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 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 3 mg; Oral macitentan 3 mg, once daily	Drug: Macitentan 3 mg; Macitentan 3-mg tablet once daily; Other Names: ACT-064992
Active Comparator: Macitentan 10 mg; Oral macitentan 10 mg, once daily	Drug: Macitentan 10 mg; Macitentan 10-mg tablet once daily; Other Names: ACT-064992
Placebo Comparator: Placebo; Oral placebo, once daily	Drug: Placebo; Placebo tablet matching macitentan tablet, 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 95 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): February 1, 2014
• Study Completion (Actual): February 1, 2014

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 23, 2017
• Last Update Submitted That Met QC Criteria: November 22, 2016
• Last Verified: November 1, 2016

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; Skin Ulcer; Molecular Mechanisms of Pharmacological Action; Endothelin Receptor Antagonists; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Macitentan
• Other Study ID Numbers: AC-055C302