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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01474109
Recruitment Status : Completed
First Posted : November 18, 2011
Results First Posted : January 6, 2015
Last Update Posted : January 6, 2015
Sponsor:
Information provided by (Responsible Party):
Actelion

Tracking Information
First Submitted Date  ICMJE October 31, 2011
First Posted Date  ICMJE November 18, 2011
Results First Submitted Date  ICMJE December 3, 2014
Results First Posted Date  ICMJE January 6, 2015
Last Update Posted Date January 6, 2015
Study Start Date  ICMJE December 2011
Actual Primary Completion Date November 2013   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 2, 2015)
Incidence Rate of New Digital Ulcers (DUs) up to Week 16 [ Time Frame: 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.
Original Primary Outcome Measures  ICMJE
 (submitted: November 15, 2011)
cumulative number of digital ulcers up to week 16 [ Time Frame: Period1: baseline (visit 2) to week 16. Period2: week 16 to end of study (which will occur when the last randomized patient, not prematurely withdrawn, has completed Period 1 and a 30 day safety follow-up period) ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 2, 2015)
  • Percentage of Participants Without a New DU Up To Week 16 [ Time Frame: 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 [ Time Frame: Up to approximately 90 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.
  • Change in Hand Functionality Health Assessment Questionnaire - Disability Index (HAQ-DI) Hand Component From Baseline to Week 16 [ Time Frame: 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).
  • Health Assessment Questionnaire - Disability Index (HAQ-DI) Overall Score From Baseline to Week 16 [ Time Frame: 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 [ Time Frame: 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)
Original Secondary Outcome Measures  ICMJE
 (submitted: November 15, 2011)
Hand functionality assessed though the HDISS-DU PRO and HAQ-DI [ Time Frame: Period1: baseline (visit 2) to week 16. Period2: week 16 to end of study (which will occur when the last randomized patient, not prematurely withdrawn, has completed Period 1 and a 30 day safety follow-up period) ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Macitentan for the Treatment of Digital Ulcers in Systemic Sclerosis Patients
Official Title  ICMJE 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
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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Condition  ICMJE
  • Systemic Sclerosis
  • Ulcers
Intervention  ICMJE
  • Drug: macitentan 3mg
    macitentan 3mg tablet once daily
    Other Name: ACT-064992
  • Drug: macitentan 10mg
    macitentan 10mg tablet once daily
    Other Name: ACT-064992
  • Drug: placebo
    matching placebo once daily
Study Arms  ICMJE
  • Active Comparator: macitentan 3mg
    macitentan 3mg tablet once daily
    Intervention: Drug: macitentan 3mg
  • Active Comparator: macitentan 10mg
    macitentan 10mg tablet once daily
    Intervention: Drug: macitentan 10mg
  • Placebo Comparator: placebo
    matching placebo once daily
    Intervention: Drug: placebo
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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: June 12, 2013)
289
Original Estimated Enrollment  ICMJE
 (submitted: November 15, 2011)
285
Actual Study Completion Date  ICMJE November 2013
Actual Primary Completion Date November 2013   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Australia,   Belarus,   Bulgaria,   Canada,   Chile,   Colombia,   Croatia,   Czech Republic,   Denmark,   Finland,   Germany,   Hungary,   India,   Italy,   Poland,   Russian Federation,   Ukraine,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01474109
Other Study ID Numbers  ICMJE AC-055C301
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Actelion
Study Sponsor  ICMJE Actelion
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account Actelion
Verification Date January 2015

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP