Digital Ulcers
Conditions
Keywords
digital ulcers, systemic sclerosis
Brief 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. 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.
Interventions
DRUGMacitentan 3 mg
Macitentan 3-mg tablet once daily
DRUGMacitentan 10 mg
Macitentan 10-mg tablet once daily
DRUGPlacebo
Placebo tablet matching macitentan tablet, once daily
Sponsors
Actelion
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence Rate of New Digital Ulcers (DUs) up to Week 16 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Without a New DU up to Week 16 | 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 | Up to 95 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 | 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 | 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 | 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) |
Participant flow
Recruitment details
Conducted at 73 centers in 20 countries.The first patient randomized was 9 Feb 2012 and last patient, last visit was 6 Feb 2014.
Pre-assignment details
A screening visit was performed between Day -14 and Day -1 of the study. Of the 324 patients screened for the study, 59 were screen failures.
Participants by arm
| Arm | Count |
|---|---|
| Macitentan 3mg Patients received macitentan once daily at a dose of 3 mg. | 88 |
| Macitentan 10mg Patients received macitentan once daily at a dose of 10 mg. | 88 |
| Placebo Patients received placebo once daily. | 89 |
| Total | 265 |
Baseline characteristics
| Characteristic | Macitentan 3mg | Total | Placebo | Macitentan 10mg |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 12 Participants | 31 Participants | 14 Participants | 5 Participants |
| Age, Categorical Between 18 and 65 years | 76 Participants | 234 Participants | 75 Participants | 83 Participants |
| Age, Continuous | 50.6 years STANDARD_DEVIATION 13.2 | 49.6 years STANDARD_DEVIATION 13.06 | 50.6 years STANDARD_DEVIATION 12.88 | 47.4 years STANDARD_DEVIATION 13.02 |
| Race/Ethnicity, Customized Asian | 6 participants | 16 participants | 6 participants | 4 participants |
| Race/Ethnicity, Customized Black or African American | 2 participants | 2 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Hispanic | 12 participants | 35 participants | 9 participants | 14 participants |
| Race/Ethnicity, Customized Other | 6 participants | 19 participants | 6 participants | 7 participants |
| Race/Ethnicity, Customized White | 62 participants | 193 participants | 68 participants | 63 participants |
| Region of Enrollment Argentina | 12 participants | 18 participants | 3 participants | 3 participants |
| Region of Enrollment Belgium | 0 participants | 1 participants | 0 participants | 1 participants |
| Region of Enrollment China | 3 participants | 11 participants | 5 participants | 3 participants |
| Region of Enrollment Colombia | 3 participants | 14 participants | 6 participants | 5 participants |
| Region of Enrollment Germany | 2 participants | 7 participants | 2 participants | 3 participants |
| Region of Enrollment Greece | 2 participants | 11 participants | 5 participants | 4 participants |
| Region of Enrollment Ireland | 1 participants | 4 participants | 1 participants | 2 participants |
| Region of Enrollment Israel | 5 participants | 24 participants | 12 participants | 7 participants |
| Region of Enrollment Mexico | 6 participants | 21 participants | 6 participants | 9 participants |
| Region of Enrollment Netherlands | 3 participants | 6 participants | 1 participants | 2 participants |
| Region of Enrollment New Zealand | 2 participants | 6 participants | 3 participants | 1 participants |
| Region of Enrollment Poland | 7 participants | 23 participants | 5 participants | 11 participants |
| Region of Enrollment Portugal | 1 participants | 7 participants | 4 participants | 2 participants |
| Region of Enrollment Puerto Rico | 1 participants | 2 participants | 0 participants | 1 participants |
| Region of Enrollment Russian Federation | 5 participants | 16 participants | 7 participants | 4 participants |
| Region of Enrollment South Africa | 3 participants | 9 participants | 2 participants | 4 participants |
| Region of Enrollment Turkey | 0 participants | 1 participants | 1 participants | 0 participants |
| Region of Enrollment Ukraine | 9 participants | 20 participants | 4 participants | 7 participants |
| Region of Enrollment United Kingdom | 7 participants | 16 participants | 6 participants | 3 participants |
| Region of Enrollment United States | 16 participants | 48 participants | 16 participants | 16 participants |
| Sex: Female, Male Female | 75 Participants | 217 Participants | 71 Participants | 71 Participants |
| Sex: Female, Male Male | 13 Participants | 48 Participants | 18 Participants | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 73 / 88 | 73 / 87 | 70 / 89 |
| serious Total, serious adverse events | 10 / 88 | 21 / 87 | 13 / 89 |
Outcome results
Primary
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.
Time frame: Baseline to Week 16
Population: Full analysis set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Macitentan 3mg | Incidence Rate of New Digital Ulcers (DUs) up to Week 16 | 1.4413 new DUs/16 weeks |
| Macitentan 10mg | Incidence Rate of New Digital Ulcers (DUs) up to Week 16 | 1.3636 new DUs/16 weeks |
| Placebo | Incidence Rate of New Digital Ulcers (DUs) up to Week 16 | 1.1049 new DUs/16 weeks |
p-value: 0.43495% CI: [0.766, 1.861]negative binomial-2 regression (NB-2)
p-value: 0.40795% CI: [0.773, 1.886]NB-2
Secondary
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)
Time frame: Baseline to Week 16
Population: Modified intention to treat set. Ten patients were excluded from the modified intent to treat set due to protocol violations.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Macitentan 3mg | Change in Hand Functionality - Hand Disability in Systemic Sclerosis - Digital Ulcers (HDISS-DU) Score From Baseline to Week 16 | Baseline | 3.0 Units on a scale | Standard Deviation 1.08 |
| Macitentan 3mg | Change in Hand Functionality - Hand Disability in Systemic Sclerosis - Digital Ulcers (HDISS-DU) Score From Baseline to Week 16 | Week 16 | 2.8 Units on a scale | Standard Deviation 1.17 |
| Macitentan 10mg | Change in Hand Functionality - Hand Disability in Systemic Sclerosis - Digital Ulcers (HDISS-DU) Score From Baseline to Week 16 | Baseline | 2.9 Units on a scale | Standard Deviation 1.05 |
| Macitentan 10mg | Change in Hand Functionality - Hand Disability in Systemic Sclerosis - Digital Ulcers (HDISS-DU) Score From Baseline to Week 16 | Week 16 | 2.7 Units on a scale | Standard Deviation 1.11 |
| Placebo | Change in Hand Functionality - Hand Disability in Systemic Sclerosis - Digital Ulcers (HDISS-DU) Score From Baseline to Week 16 | Baseline | 2.9 Units on a scale | Standard Deviation 1.14 |
| Placebo | Change in Hand Functionality - Hand Disability in Systemic Sclerosis - Digital Ulcers (HDISS-DU) Score From Baseline to Week 16 | Week 16 | 2.9 Units on a scale | Standard Deviation 1.12 |
p-value: 0.31995% CI: [-0.4, 0.1]ANCOVA
p-value: 0.22195% CI: [-0.4, 0.1]ANCOVA
Secondary
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).
Time frame: Baseline to Week 16
Population: Modified intention to treat set. Ten patients were excluded from the modified intent to treat set due to protocol violations.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Macitentan 3mg | Change in Hand Functionality Health Assessment Questionnaire - Disability Index (HAQ-DI) Hand Component From Baseline to Week 16 | Baseline | 1.4 Units on a scale | Standard Deviation 0.73 |
| Macitentan 3mg | Change in Hand Functionality Health Assessment Questionnaire - Disability Index (HAQ-DI) Hand Component From Baseline to Week 16 | Week 16 | 1.2 Units on a scale | Standard Deviation 0.75 |
| Macitentan 10mg | Change in Hand Functionality Health Assessment Questionnaire - Disability Index (HAQ-DI) Hand Component From Baseline to Week 16 | Baseline | 1.3 Units on a scale | Standard Deviation 0.7 |
| Macitentan 10mg | Change in Hand Functionality Health Assessment Questionnaire - Disability Index (HAQ-DI) Hand Component From Baseline to Week 16 | Week 16 | 1.1 Units on a scale | Standard Deviation 0.76 |
| Placebo | Change in Hand Functionality Health Assessment Questionnaire - Disability Index (HAQ-DI) Hand Component From Baseline to Week 16 | Baseline | 1.4 Units on a scale | Standard Deviation 0.72 |
| Placebo | Change in Hand Functionality Health Assessment Questionnaire - Disability Index (HAQ-DI) Hand Component From Baseline to Week 16 | Week 16 | 1.3 Units on a scale | Standard Deviation 0.77 |
p-value: 0.34795% CI: [-0.2, 0.1]ANCOVA
p-value: 0.16595% CI: [-0.3, 0]ANCOVA
Secondary
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).
Time frame: Baseline to Week 16
Population: Modified intention to treat set. Ten patients were excluded from the modified intent to treat set due to protocol violations.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Macitentan 3mg | Health Assessment Questionnaire - Disability Index (HAQ-DI) Overall Score From Baseline to Week 16 | Baseline | 1.2 Units on a scale | Standard Deviation 0.67 |
| Macitentan 3mg | Health Assessment Questionnaire - Disability Index (HAQ-DI) Overall Score From Baseline to Week 16 | Week 16 | 1.1 Units on a scale | Standard Deviation 0.7 |
| Macitentan 10mg | Health Assessment Questionnaire - Disability Index (HAQ-DI) Overall Score From Baseline to Week 16 | Baseline | 1.1 Units on a scale | Standard Deviation 0.65 |
| Macitentan 10mg | Health Assessment Questionnaire - Disability Index (HAQ-DI) Overall Score From Baseline to Week 16 | Week 16 | 1.0 Units on a scale | Standard Deviation 0.71 |
| Placebo | Health Assessment Questionnaire - Disability Index (HAQ-DI) Overall Score From Baseline to Week 16 | Baseline | 1.2 Units on a scale | Standard Deviation 0.66 |
| Placebo | Health Assessment Questionnaire - Disability Index (HAQ-DI) Overall Score From Baseline to Week 16 | Week 16 | 1.2 Units on a scale | Standard Deviation 0.68 |
p-value: 0.33995% CI: [-0.2, 0.1]ANCOVA
p-value: 0.31295% CI: [-0.2, 0.1]ANCOVA
Secondary
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.
Time frame: Up to 95 weeks
Population: Modified intention to treat set. Ten patients were excluded from the modified intent to treat set due to protocol violations.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Macitentan 3mg | Percentage of Participants With at Least One DU Complication | 21.4 Percentage of participants |
| Macitentan 10mg | Percentage of Participants With at Least One DU Complication | 19.0 Percentage of participants |
| Placebo | Percentage of Participants With at Least One DU Complication | 18.4 Percentage of participants |
p-value: 0.611795% CI: [0.572, 2.582]Chi-squared
p-value: 0.904795% CI: [0.485, 2.264]Chi-squared
Secondary
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.
Time frame: Baseline to Week 16
Population: Modified intention to treat set. Ten patients were excluded from the modified intent to treat set due to protocol violations.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Macitentan 3mg | Percentage of Participants Without a New DU up to Week 16 | 56.0 Percentage of participants |
| Macitentan 10mg | Percentage of Participants Without a New DU up to Week 16 | 54.8 Percentage of participants |
| Placebo | Percentage of Participants Without a New DU up to Week 16 | 59.8 Percentage of participants |
p-value: 0.566895% CI: [0.442, 1.564]Chi-squared
p-value: 0.462495% CI: [0.42, 1.484]Chi-squared