Digital UlcersPhase 3DUAL-2NCT01474122
Macitentan for the Treatment of Digital Ulcers in Systemic Sclerosis Patients
A Phase 3 study testing Macitentan 3 mg and Macitentan 10 mg in people with Digital Ulcers, run by Actelion.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Digital Ulcers
- What is being tested?
- Macitentan 3 mg and Macitentan 10 mg
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 265 participants
- Where
- No sites listed yet
- Study dates
- Dec 2011to Feb 2014
- Phase
- Phase 3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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
Show all 17Show fewer
- 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
About this study
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
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).
Read more
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.
Read the 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.
- Conditions
- Digital Ulcers
- Being tested
- Macitentan 3 mg, Macitentan 10 mg, Placebo
- Keywords
- digital ulcers, systemic sclerosis
- Medical subject headings
- digital ulcers, Scleroderma, Systemic
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Macitentan 3 mgDrug
Also called ACT-064992
Macitentan 3-mg tablet once daily
Macitentan 10 mgDrug
Also called ACT-064992
Macitentan 10-mg tablet once daily
PlaceboDrug
Placebo tablet matching macitentan tablet, once daily
| Study group | Role | What they receive |
|---|---|---|
| Macitentan 3 mg | Active comparator | Oral macitentan 3 mg, once daily Receives: Drug: Macitentan 3 mg |
| Macitentan 10 mg | Active comparator | Oral macitentan 10 mg, once daily Receives: Drug: Macitentan 10 mg |
| Placebo | Placebo comparator | Oral placebo, once daily Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: Baseline to Week 16
Secondary outcomes (5)
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.
Measured: 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.
Measured: 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).
Measured: 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).
Measured: 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)
Measured: Baseline to Week 16
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted18 Nov 2011 (estimated)
- Study startDec 2011
- Primary completionFeb 2014
- Study completionFeb 2014
Why it stopped: company decision
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Digital UlcersStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind
- Who is masked
- Participant, Care provider, Investigator
- Enrolment
- 265 participants (actual)
Sponsor and investigators
- Lead sponsor
- Actelion
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01474122
- Sponsor's protocol ID
- AC-055C302
- Acronym
- DUAL-2
- Status last verified
- Jan 2025
- First submitted
- 31 Oct 2011
- Last updated
- 4 Feb 2025
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
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.
PubMed 27163986
Study at a glance
From the registry record, last updated by the sponsor on 4 Feb 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT01474122
- Acronym / sponsor ID
- DUAL-2 / AC-055C302
- Conditions
- Digital Ulcers
- Keywords
- digital ulcers, systemic sclerosis
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: company decision
- Enrolment
- 265 participants (actual)
- Lead sponsor
- ActelionIndustry (pharma, biotech, devices)
- Study start
- Dec 2011
- Primary completion
- Feb 2014 (actual)
- Study completion
- Feb 2014 (actual)
- First posted
- 18 Nov 2011 (estimated)
- Results
- Posted 28 Jan 2015
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, care provider, investigator)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Macitentan 3 mg | Active comparator | Drug: Macitentan 3 mgOral macitentan 3 mg, once daily |
| Macitentan 10 mg | Active comparator | Drug: Macitentan 10 mgOral macitentan 10 mg, once daily |
| Placebo | Placebo comparator | Drug: PlaceboOral placebo, once daily |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (5 listed)
- 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
Key exclusion criteria (17 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Macitentan 3 mgAlso: ACT-064992Macitentan 3-mg tablet once daily | Drug | Macitentan 3 mg |
| Macitentan 10 mgAlso: ACT-064992Macitentan 10-mg tablet once daily | Drug | Macitentan 10 mg |
| PlaceboPlacebo tablet matching macitentan tablet, once daily | Drug | Placebo |
Primary outcome
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.
5 secondary outcomes
Percentage of Participants Without a New DU up to Week 16
Time frame: Baseline to Week 16
Percentage of Participants With at Least One DU Complication
Time frame: Up to 95 weeks
Change in Hand Functionality Health Assessment Questionnaire - Disability Index (HAQ-DI) Hand Component From Baseline to Week 16
Time frame: Baseline to Week 16
Health Assessment Questionnaire - Disability Index (HAQ-DI) Overall Score From Baseline to Week 16
Time frame: Baseline to Week 16
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
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 4 Feb 2025.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Results publication: PubMed 27163986Khanna 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Macitentan 3 mg and Macitentan 10 mg in people with Digital Ulcers, run by Actelion.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 17 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 4 Feb 2025. Status can change between updates, so confirm with the study contact before making plans.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 28 Jan 2015). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Incidence Rate of New Digital Ulcers (DUs) up to Week 16 (time frame: Baseline to Week 16). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01474122, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 4 Feb 2025; AzTrials last refreshed its copy on 7 Nov 2026.