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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Actelion
ClinicalTrials.gov Identifier:
NCT01474109
First received: October 31, 2011
Last updated: January 2, 2015
Last verified: January 2015
  Purpose

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.

Condition Intervention Phase
Systemic Sclerosis
Ulcers
Drug: macitentan 3mg
Drug: macitentan 10mg
Drug: placebo
Phase 3

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

Resource links provided by NLM:


Further study details as provided by Actelion:

Primary Outcome Measures:
  • Incidence Rate of New Digital Ulcers (DUs) up to Week 16 [ Time Frame: Baseline to week 16 ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • Percentage of Participants Without a New DU Up To Week 16 [ Time Frame: Baseline to week 16 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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)


Enrollment: 289
Study Start Date: December 2011
Study Completion Date: November 2013
Primary Completion Date: November 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: macitentan 3mg
macitentan 3mg tablet once daily
Drug: macitentan 3mg
macitentan 3mg tablet once daily
Other Name: ACT-064992
Active Comparator: macitentan 10mg
macitentan 10mg tablet once daily
Drug: macitentan 10mg
macitentan 10mg tablet once daily
Other Name: ACT-064992
Placebo Comparator: placebo
matching placebo once daily
Drug: placebo
matching placebo once daily
Other Name: 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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01474109

  Show 77 Study Locations
Sponsors and Collaborators
Actelion
  More Information

No publications provided

Responsible Party: Actelion
ClinicalTrials.gov Identifier: NCT01474109     History of Changes
Other Study ID Numbers: AC-055C301
Study First Received: October 31, 2011
Results First Received: December 3, 2014
Last Updated: January 2, 2015
Health Authority: United States: Food and Drug Administration

Keywords provided by Actelion:
systemic sclerosis
digital ulcers

Additional relevant MeSH terms:
Scleroderma, Diffuse
Scleroderma, Systemic
Sclerosis
Ulcer
Connective Tissue Diseases
Pathologic Processes
Skin Diseases

ClinicalTrials.gov processed this record on February 25, 2015