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

• Sponsor: Actelion (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01474109
• Collaborator: (none)
• Enrollment: 289
• Locations: 77
• Arms: 3
• Duration (Months): 23
• Patients Per Site: 3.8
• Patients Per Site Per Month: 0.2

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Systemic Sclerosis; Ulcers	Drug: macitentan 3mg; Drug: macitentan 10mg; Drug: placebo	Phase 3

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

• Study Type: Interventional
• Actual Enrollment: 289 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, 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
• Study Start Date: Dec 1, 2011
• Actual Primary Completion Date: Nov 1, 2013
• Actual Study Completion Date: Nov 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: macitentan 3mg macitentan 3mg tablet once daily	Drug: macitentan 3mg; macitentan 3mg tablet once daily; Other Names: ACT-064992
Active Comparator: macitentan 10mg macitentan 10mg tablet once daily	Drug: macitentan 10mg; macitentan 10mg tablet once daily; Other Names: ACT-064992
Placebo Comparator: placebo matching placebo once daily	Drug: placebo; matching placebo once daily

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

2. Percentage of Participants With at Least One DU Complication [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.

3. 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).

4. 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).

5. 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)

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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 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

Locations

	Site	City	State	Country	Postal Code
1	University of Arizona Arthritis Center	Tucson	Arizona	United States	85724
2	UCLA Medical School - Rheumatology Division Rehabilitation Center	Los Angeles	California	United States	90095
3	Arthritis & Rheumatic Disease Specialties	Aventura	Florida	United States	33180
4	Sarasota Arthritis Research Center	Sarasota	Florida	United States	34239
5	Ochsner Medical Center	New Orleans	Louisiana	United States	70121
6	The Johns Hopkins University School of Medicine	Baltimore	Maryland	United States	21224-6801
7	University of Michigan - Scleroderma Program	Ann Arbor	Michigan	United States	48109
8	Michigan State University	Grand Rapids	Michigan	United States	49546
9	University of Medicine & Dentistry of New Jersey, UMDNJ Scleroderma Program	New Brunswick	New Jersey	United States	08903-0010
10	The Center for Rheumatology	Albany	New York	United States	12206
11	Shanahan Rheumatology and Immunotherapy, PLLC	Raleigh	North Carolina	United States	27617-7884
12	The Cleveland Clinic Foundation	Cleveland	Ohio	United States	44195
13	Altoona Center for Clinical Research	Duncansville	Pennsylvania	United States	16635
14	University of Pittsburgh Department of Rheumatology	Pittsburgh	Pennsylvania	United States	15261
15	Medical University of South Carolina	Charleston	South Carolina	United States	29425-8905
16	Royal Adelaide Hospital	Adelaide		Australia	5000
17	Wesley Hospital, Thoracic Department	Auchenflower		Australia	4066
18	Royal Prince Alfred Hospital	Camperdown		Australia	2050
19	St Vincent's Hospital	Fitzroy		Australia	3065
20	Menzies Research Institute	Hobart		Australia	7000
21	Gomel Regional Clinical Hospital	Gomel		Belarus	246029
22	Healthcare Institution "Minsk City Hospital #1"	Minsk		Belarus	220013
23	Healthcare Institution "Minsk Clinical Hospital #9"	Minsk		Belarus	220116
24	Multiprofile Hospital for Active Treatment "Sveti Pantaleymon"	Pleven		Bulgaria	5800
25	MHAT "Kaspela" EOOD Plovdiv - Rheumatology Ward	Plovdiv		Bulgaria	4002
26	MHAT "Sv. Ivan Rilski" EAD Sofia - Clinic of Rheumatology	Sofia		Bulgaria	1612
27	Rheumatology Research Associates	Edmonton	Alberta	Canada	T5M 0H4
28	St. Paul's Hospital	Vancouver	British Columbia	Canada	V6Z 1Y6
29	St. Joseph's Health Care	London	Ontario	Canada	N6A 4V2
30	Mount Sinai Hospital	Toronto	Ontario	Canada	M5G 1X5
31	CHUS Hopital Fleurimont	Sherbrooke	Quebec	Canada	J1H 5N4
32	Prosalud	Santiago		Chile	7510047
33	Private Office Marta Aliste	Santiago		Chile	7510186
34	Hospital San Juan de Dios	Santiago		Chile	8500000
35	Centro de Estudios Clinicos V	Vina del Mar		Chile	2570017
36	Medicity S.A.S.	Bucaramanga		Colombia
37	Servimed E.U.	Bucaramanga		Colombia
38	Klinicki Bolnicki Centar Osijek	Osijek		Croatia	31000
39	University Hospital Centre Rijeka	Rijeka		Croatia	51000
40	Klinički bolnički centar Split	Split		Croatia	21000
41	Klinicka Bolnica "Svety Duh"	Zagreb		Croatia	10000
42	Klinička bolnica Dubrava	Zagreb		Croatia	10000
43	University Hospital Centre Zagreb	Zagreb		Croatia	10000
44	Lekarna FN Brno	Brno		Czech Republic	62500
45	Faculty Hospital Hradec Králové	Hradec Králové		Czech Republic	500 05
46	Revmatologický ústav Praha	Praha		Czech Republic	12000
47	Bispebjerg Hospital København	Copenhagen		Denmark	2400
48	Odense Universitetshospital	Odense		Denmark	5000
49	Helsingin yliopistollinen keskussairaala (HYKS), Meilahden kolmiosairaala, Reumatologian klinikka	Helsinki		Finland	00290
50	Universitätsmedizin Berlin Medizinische Klinik mit Schwerpunkt Rheumatologie und Klinische Immunologie	Berlin		Germany	10117
51	Klinik für Dermatologie und Allergologie der Ruhr-Universität Bochum	Bochum		Germany	44791
52	Medizinische Universitätsklinik Freiburg, Abt. Rheumatologie und klinische Forschung	Freiburg		Germany	79106
53	Asklepios Westklinikum Hamburg Abteilung für Gefäßmedizin, Angiologie und Diabetologie	Hamburg		Germany	22559
54	Rheumatologie, klinische Immunologie, Nephrologie Asklepios Rheumazentrum Hamburg Asklepios Klinik Altona	Hamburg		Germany	22763
55	Akademie für Gefäßkrankheiten eV.	Karlsbad		Germany	76307
56	Klinik und Poliklinik für Dermatologie und Venerologie der Universität zu Köln	Koln		Germany	50937
57	Universitäts-Hautklinik Tübingen	Tuebingen		Germany	72076
58	Budai Irgalmasrendi Kórház	Budapest		Hungary	1023
59	Debreceni Egyetem Orvos- és Egészségtudományi Centrum	Debrecen		Hungary	4032
60	Pécsi Tudományegyetem Klinikai Központ, Reumatológiai és Immunológiai Klinika	Pécs		Hungary	7632
61	Advance Rheumatology Clinic	Hyderabad		India	500082
62	Krishna Institute of Medical Sciences	Secunderabad		India	500 003
63	Christian Medical College	Vellore		India	632004
64	Azienda Ospedaliera Careggi	Firenze		Italy	50139
65	Azienda Ospedaliera Policlinico di Modena	Modena		Italy	41100
66	Complesso Integrato Columbus	Rome		Italy	00168
67	Uniwersyteckie Centrum Kliniczne	Gdańsk		Poland	80-952
68	NZOZ Reumed	Lublin		Poland	20-607
69	Centralny Szpital Kliniczny MSWiA	Warszawa		Poland	02-507
70	Akademicki Szpital Kliniczny im. Jana Mikulicza-Radeckiego we Wrocławiu	Wrocław		Poland	50-566
71	State Healthcare Institution "Sverdlovsk Regional Clinical Hospital #1"	Ekaterinburg		Russian Federation	620102
72	State Healthcare Institution "Penza Regional Clinical Hospital named after N.N. Burdenko"	Penza		Russian Federation	440026
73	Vladimir Regional State Institution of Healthcare, "Regional Clinical Hospital"	Vladimir		Russian Federation	600023
74	Dinpropetrovsk Regional Clinical Hospital named after I. Mechnykova	Dnipropetrovsk		Ukraine	49005
75	Municipal Institution of Kyiv Regional Council, Kyiv Regional Clinical Hospital	Kyiv		Ukraine	04107
76	Lviv Regional Clinical Hospital	Lviv		Ukraine	79010
77	Internal disease chair of Ukrainian medical dentist academy based on therapy department of Poltava Poltava City Clinical Hospital #1	Poltava		Ukraine	36039

Sponsors and Collaborators

• Actelion

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Actelion
• ClinicalTrials.gov Identifier: NCT01474109
• Other Study ID Numbers: AC-055C301
• First Posted: Nov 18, 2011
• Last Update Posted: Jan 6, 2015
• Last Verified: Jan 1, 2015

• Keywords provided by Actelion: systemic sclerosis; digital ulcers
• Additional relevant MeSH terms: Scleroderma, Systemic; Scleroderma, Diffuse; Sclerosis; Ulcer; Macitentan

Study Results

Participant Flow

Recruitment Details	Conducted at 70 centers in 17 countries. First patient randomized was 11 January 2012 and last patient, last visit was 29 November 2013.
Pre-assignment Detail	A screening visit was performed between Day -14 and Day -1 of the study. Of the 327 patients screened for the study, 38 were screen failures.

Arm/Group Title	Macitentan 3mg	Macitentan 10mg	Placebo
Arm/Group Description	macitentan 3mg tablet once daily macitentan 3mg: macitentan 3mg tablet once daily	macitentan 10mg tablet once daily macitentan 10mg: macitentan 10mg tablet once daily	matching placebo once daily placebo: matching placebo once daily
Period Title: Period 1: Baseline to Week 16
STARTED	95	97	97
COMPLETED	88	91	95
NOT COMPLETED	7	6	2
Period Title: Period 1: Baseline to Week 16
STARTED	88	91	95
COMPLETED	70	73	83
NOT COMPLETED	18	18	12

Baseline Characteristics

Arm/Group Title	Macitentan 3mg	Macitentan 10mg	Placebo	Total
Arm/Group Description	macitentan 3mg tablet once daily macitentan 3mg: macitentan 3mg tablet once daily	macitentan 10mg tablet once daily macitentan 10mg: macitentan 10mg tablet once daily	matching placebo once daily placebo: matching placebo once daily	Total of all reporting groups
Overall Participants	95	97	97	289
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	77 81.1%	84 86.6%	84 86.6%	245 84.8%
>=65 years	18 18.9%	13 13.4%	13 13.4%	44 15.2%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	51.4 (14.44)	51.6 (11.10)	50.6 (12.12)	51.2 (12.58)
Sex: Female, Male (Count of Participants)
Female	84 88.4%	81 83.5%	83 85.6%	248 85.8%
Male	11 11.6%	16 16.5%	14 14.4%	41 14.2%
Race/Ethnicity, Customized (participants) [Number]
White	86 90.5%	82 84.5%	88 90.7%	256 88.6%
Black or African American	0 0%	3 3.1%	1 1%	4 1.4%
Asian	5 5.3%	6 6.2%	4 4.1%	15 5.2%
Hispanic	3 3.2%	4 4.1%	3 3.1%	10 3.5%
Other	1 1.1%	2 2.1%	1 1%	4 1.4%
Region of Enrollment (participants) [Number]
Australia	10 10.5%	9 9.3%	9 9.3%	28 9.7%
Belarus	3 3.2%	3 3.1%	5 5.2%	11 3.8%
Bulgaria	13 13.7%	16 16.5%	17 17.5%	46 15.9%
Canada	1 1.1%	3 3.1%	2 2.1%	6 2.1%
Chile	6 6.3%	7 7.2%	4 4.1%	17 5.9%
Colombia	0 0%	2 2.1%	1 1%	3 1%
Croatia	3 3.2%	1 1%	6 6.2%	10 3.5%
Czech Republic	6 6.3%	3 3.1%	5 5.2%	14 4.8%
France	0 0%	0 0%	1 1%	1 0.3%
Germany	9 9.5%	7 7.2%	11 11.3%	27 9.3%
Hungary	4 4.2%	7 7.2%	3 3.1%	14 4.8%
India	4 4.2%	5 5.2%	4 4.1%	13 4.5%
Italy	3 3.2%	3 3.1%	2 2.1%	8 2.8%
Poland	5 5.3%	3 3.1%	3 3.1%	11 3.8%
Russian Federation	6 6.3%	7 7.2%	8 8.2%	21 7.3%
Ukraine	10 10.5%	5 5.2%	7 7.2%	22 7.6%
United States	12 12.6%	16 16.5%	9 9.3%	37 12.8%

Outcome Measures

1. Primary Outcome

Title	Incidence Rate of New Digital Ulcers (DUs) up to Week 16
Description	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

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	Macitentan 3mg	Macitentan 10mg	Placebo
Arm/Group Description	macitentan 3mg tablet once daily macitentan 3mg: macitentan 3mg tablet once daily	macitentan 10mg tablet once daily macitentan 10mg: macitentan 10mg tablet once daily	matching placebo once daily placebo: matching placebo once daily
Measure Participants	95	97	97
Number [number of new DUs/observation days]	0.9082	0.9567	0.8115

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Macitentan 3mg, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.706
	Comments
	Method	negative binomial-2 regression (NB-2)
	Comments
Method of Estimation	Estimation Parameter	NB-2 estimate of new DUs per patient
	Estimated Value	1.103
	Confidence Interval	(2-Sided) 95%; 0.663 to 1.834
	Parameter Dispersion	Type: Value:
	Estimation Comments	The estimated value corresponds to the treatment effect i.e. the ratio between the estimated number of new DUs in Macitentan 3 mg and in Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Macitentan 10mg, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.360
	Comments
	Method	negative binomial-2 regression (NB-2)
	Comments
Method of Estimation	Estimation Parameter	NB-2 estimate of new DUs per patient
	Estimated Value	1.268
	Confidence Interval	(2-Sided) 95%; 0.763 to 2.106
	Parameter Dispersion	Type: Value:
	Estimation Comments	The estimated value corresponds to the treatment effect i.e. the ratio between the estimated number of new DUs in Macitentan 10 mg and in Placebo

2. Secondary Outcome

Title	Percentage of Participants Without a New DU Up To Week 16
Description	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

Outcome Measure Data

Analysis Population Description

Modified intent-to-treat set. Eleven patients were excluded from the modified intent-treat set due to protocol violations.

Arm/Group Title	Macitentan 3mg	Macitentan 10mg	Placebo
Arm/Group Description	macitentan 3mg tablet once daily macitentan 3mg: macitentan 3mg tablet once daily	macitentan 10mg tablet once daily macitentan 10mg: macitentan 10mg tablet once daily	matching placebo once daily placebo: matching placebo once daily
Measure Participants	92	92	94
Number [Percentage of participants]	64.1 67.5%	63.0 64.9%	67.0 69.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Macitentan 3mg, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.6670
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.875
	Confidence Interval	(2-Sided) 95%; 0.477 to 1.606
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Macitentan 10mg, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5518
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.832
	Confidence Interval	(2-Sided) 95%; 0.454 to 1.524
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Percentage of Participants With at Least One DU Complication
Description	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 approximately 90 weeks

Outcome Measure Data

Analysis Population Description

Modified intent-to-treat set. Eleven patients were excluded from the modified intent-treat set due to protocol violations.

Arm/Group Title	Macitentan 3mg	Macitentan 10mg	Placebo
Arm/Group Description	macitentan 3mg tablet once daily macitentan 3mg: macitentan 3mg tablet once daily	macitentan 10mg tablet once daily macitentan 10mg: macitentan 10mg tablet once daily	matching placebo once daily placebo: matching placebo once daily
Measure Participants	92	92	94
Number [percentage of participants]	14.1 14.8%	19.6 20.2%	19.1 19.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Macitentan 3mg, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3625
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.696
	Confidence Interval	(2-Sided) 95%; 0.319 to 1.518
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Macitentan 10mg, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9362
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.030
	Confidence Interval	(2-Sided) 95%; 0.498 to 2.133
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Change in Hand Functionality Health Assessment Questionnaire - Disability Index (HAQ-DI) Hand Component From Baseline to Week 16
Description	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

Outcome Measure Data

Analysis Population Description

Modified intention-to-treat set. Eleven patients were excluded from the modified intent-treat set due to protocol violations.

Arm/Group Title	Macitentan 3mg	Macitentan 10mg	Placebo
Arm/Group Description	macitentan 3mg tablet once daily macitentan 3mg: macitentan 3mg tablet once daily	macitentan 10mg tablet once daily macitentan 10mg: macitentan 10mg tablet once daily	matching placebo once daily placebo: matching placebo once daily
Measure Participants	92	92	94
Baseline	1.3 (0.73)	1.4 (0.70)	1.3 (0.68)
Week 16	1.2 (0.79)	1.2 (0.66)	1.2 (0.73)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Macitentan 3mg, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.863
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.0
	Confidence Interval	(2-Sided) 95%; -0.1 to 0.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Macitentan 10mg, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.649
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.0
	Confidence Interval	(2-Sided) 95%; -0.2 to 0.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Health Assessment Questionnaire - Disability Index (HAQ-DI) Overall Score From Baseline to Week 16
Description	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

Outcome Measure Data

Analysis Population Description

Modified intention-to-treat set. Eleven patients were excluded from the modified intent-treat set due to protocol violations.

Arm/Group Title	Macitentan 3mg	Macitentan 10mg	Placebo
Arm/Group Description	macitentan 3mg tablet once daily macitentan 3mg: macitentan 3mg tablet once daily	macitentan 10mg tablet once daily macitentan 10mg: macitentan 10mg tablet once daily	matching placebo once daily placebo: matching placebo once daily
Measure Participants	92	92	94
Baseline	1.1 (0.71)	1.2 (0.66)	1.1 (0.62)
Week 16	1.1 (0.73)	1.1 (0.64)	1.1 (0.67)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Macitentan 3mg, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.456
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.1
	Confidence Interval	(2-Sided) 95%; -0.2 to 0.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Macitentan 10mg, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.440
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.1
	Confidence Interval	(2-Sided) 95%; -0.2 to 0.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Change in Hand Functionality - Hand Disability in Systemic Sclerosis - Digital Ulcers (HDISS-DU) Score From Baseline to Week 16
Description	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

Outcome Measure Data

Analysis Population Description

Modified intention-to-treat set. Eleven patients were excluded from the modified intent-treat set due to protocol violations.

Arm/Group Title	Macitentan 3mg	Macitentan 10mg	Placebo
Arm/Group Description	macitentan 3mg tablet once daily macitentan 3mg: macitentan 3mg tablet once daily	macitentan 10mg tablet once daily macitentan 10mg: macitentan 10mg tablet once daily	matching placebo once daily placebo: matching placebo once daily
Measure Participants	92	92	94
Baseline	3.0 (1.15)	3.0 (1.09)	3.0 (1.09)
Week 16	2.7 (1.14)	2.6 (0.99)	2.7 (1.10)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Macitentan 3mg, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.464
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.1
	Confidence Interval	(2-Sided) 95%; -0.3 to 0.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Macitentan 10mg, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.342
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.1
	Confidence Interval	(2-Sided) 95%; -0.3 to 0.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	From start of study treatment up to 30 days after treatment discontinuation, up to approximately 90 weeks
Adverse Event Reporting Description	Safety analysis set. One patient was excluded in the safety analysis set as they did not receive study drug after randomisation.
Arm/Group Title	Macitentan 3mg		Macitentan 10mg		Placebo
Arm/Group Description	macitentan 3mg tablet once daily macitentan 3mg: macitentan 3mg tablet once daily		macitentan 10mg tablet once daily macitentan 10mg: macitentan 10mg tablet once daily		matching placebo once daily placebo: matching placebo once daily
All Cause Mortality
	Macitentan 3mg		Macitentan 10mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Macitentan 3mg		Macitentan 10mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	17/94 (18.1%)		14/97 (14.4%)		13/97 (13.4%)
Blood and lymphatic system disorders
ANAEMIA	1/94 (1.1%)		0/97 (0%)		0/97 (0%)
Cardiac disorders
ACUTE CORONARY SYNDROME	0/94 (0%)		1/97 (1%)		0/97 (0%)
CARDIAC ARREST	0/94 (0%)		1/97 (1%)		0/97 (0%)
PLEUROPERICARDITIS	0/94 (0%)		1/97 (1%)		0/97 (0%)
VENTRICULAR EXTRASYSTOLES	2/94 (2.1%)		0/97 (0%)		0/97 (0%)
ANGINA PECTORIS	1/94 (1.1%)		0/97 (0%)		0/97 (0%)
ANGINA UNSTABLE	1/94 (1.1%)		0/97 (0%)		0/97 (0%)
ATRIAL FIBRILLATION	1/94 (1.1%)		0/97 (0%)		0/97 (0%)
ATRIAL FLUTTER	1/94 (1.1%)		0/97 (0%)		0/97 (0%)
MYOCARDIAL FIBROSIS	1/94 (1.1%)		0/97 (0%)		0/97 (0%)
MYOCARDIAL ISCHAEMIA	1/94 (1.1%)		0/97 (0%)		0/97 (0%)
PERICARDIAL EFFUSION	1/94 (1.1%)		0/97 (0%)		0/97 (0%)
PERICARDITIS	1/94 (1.1%)		0/97 (0%)		0/97 (0%)
Gastrointestinal disorders
ABDOMINAL DISTENSION	0/94 (0%)		1/97 (1%)		0/97 (0%)
GASTRITIS	0/94 (0%)		0/97 (0%)		1/97 (1%)
General disorders
OEDEMA PERIPHERAL	0/94 (0%)		1/97 (1%)		0/97 (0%)
CHEST PAIN	1/94 (1.1%)		0/97 (0%)		0/97 (0%)
FATIGUE	1/94 (1.1%)		0/97 (0%)		0/97 (0%)
PYREXIA	1/94 (1.1%)		0/97 (0%)		0/97 (0%)
Hepatobiliary disorders
CHOLECYSTITIS ACUTE	0/94 (0%)		1/97 (1%)		0/97 (0%)
CHOLELITHIASIS	0/94 (0%)		1/97 (1%)		0/97 (0%)
Infections and infestations
INFECTED SKIN ULCER	0/94 (0%)		3/97 (3.1%)		1/97 (1%)
PNEUMONIA	2/94 (2.1%)		1/97 (1%)		0/97 (0%)
BACTERIAL SEPSIS	0/94 (0%)		1/97 (1%)		0/97 (0%)
CLOSTRIDIUM DIFFICILE COLITIS	0/94 (0%)		1/97 (1%)		0/97 (0%)
CLOSTRIDIUM DIFFICILE INFECTION	0/94 (0%)		1/97 (1%)		0/97 (0%)
SEPSIS	0/94 (0%)		1/97 (1%)		0/97 (0%)
GANGRENE	3/94 (3.2%)		0/97 (0%)		0/97 (0%)
BRONCHOPNEUMONIA	1/94 (1.1%)		0/97 (0%)		0/97 (0%)
CELLULITIS	1/94 (1.1%)		0/97 (0%)		0/97 (0%)
ERYSIPELAS	1/94 (1.1%)		0/97 (0%)		0/97 (0%)
PNEUMOCOCCAL SEPSIS	1/94 (1.1%)		0/97 (0%)		0/97 (0%)
SINUSITIS	1/94 (1.1%)		0/97 (0%)		0/97 (0%)
OESOPHAGEAL CANDIDIASIS	0/94 (0%)		0/97 (0%)		1/97 (1%)
Injury, poisoning and procedural complications
FALL	1/94 (1.1%)		0/97 (0%)		0/97 (0%)
POST PROCEDURAL HAEMORRHAGE	0/94 (0%)		0/97 (0%)		1/97 (1%)
Metabolism and nutrition disorders
DIABETES MELLITUS INADEQUATE CONTROL	1/94 (1.1%)		0/97 (0%)		0/97 (0%)
FAILURE TO THRIVE	1/94 (1.1%)		0/97 (0%)		0/97 (0%)
HYPOGLYCAEMIA	1/94 (1.1%)		0/97 (0%)		0/97 (0%)
Musculoskeletal and connective tissue disorders
INTERVERTEBRAL DISC PROTRUSION	1/94 (1.1%)		1/97 (1%)		0/97 (0%)
LUMBAR SPINAL STENOSIS	0/94 (0%)		1/97 (1%)		0/97 (0%)
PAIN IN EXTREMITY	0/94 (0%)		1/97 (1%)		1/97 (1%)
SYSTEMIC SCLEROSIS	1/94 (1.1%)		0/97 (0%)		0/97 (0%)
OSTEOARTHRITIS	0/94 (0%)		0/97 (0%)		1/97 (1%)
OSTEONECROSIS	0/94 (0%)		0/97 (0%)		1/97 (1%)
RHEUMATOID ARTHRITIS	0/94 (0%)		0/97 (0%)		1/97 (1%)
SCLERODERMA	0/94 (0%)		0/97 (0%)		1/97 (1%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
METASTATIC BRONCHIAL CARCINOMA	1/94 (1.1%)		0/97 (0%)		0/97 (0%)
B-CELL LYMPHOMA	0/94 (0%)		0/97 (0%)		1/97 (1%)
Nervous system disorders
LOSS OF CONSCIOUSNESS	1/94 (1.1%)		0/97 (0%)		0/97 (0%)
NEURALGIA	1/94 (1.1%)		0/97 (0%)		0/97 (0%)
Psychiatric disorders
CONFUSIONAL STATE	1/94 (1.1%)		0/97 (0%)		0/97 (0%)
Renal and urinary disorders
RENAL FAILURE	1/94 (1.1%)		0/97 (0%)		0/97 (0%)
URINARY INCONTINENCE	1/94 (1.1%)		0/97 (0%)		0/97 (0%)
NEPHROTIC SYNDROME	0/94 (0%)		0/97 (0%)		1/97 (1%)
RENAL DISORDER	0/94 (0%)		0/97 (0%)		1/97 (1%)
SCLERODERMA RENAL CRISIS	0/94 (0%)		0/97 (0%)		1/97 (1%)
Reproductive system and breast disorders
UTERINE PROLAPSE	0/94 (0%)		1/97 (1%)		0/97 (0%)
Respiratory, thoracic and mediastinal disorders
PNEUMONIA ASPIRATION	0/94 (0%)		1/97 (1%)		0/97 (0%)
HYDROTHORAX	1/94 (1.1%)		0/97 (0%)		0/97 (0%)
PULMONARY CONGESTION	1/94 (1.1%)		0/97 (0%)		0/97 (0%)
PULMONARY EMBOLISM	1/94 (1.1%)		0/97 (0%)		0/97 (0%)
RESPIRATORY FAILURE	1/94 (1.1%)		0/97 (0%)		0/97 (0%)
Skin and subcutaneous tissue disorders
SKIN ULCER	3/94 (3.2%)		2/97 (2.1%)		3/97 (3.1%)
LEUKOCYTOCLASTIC VASCULITIS	0/94 (0%)		1/97 (1%)		0/97 (0%)
DRY GANGRENE	1/94 (1.1%)		0/97 (0%)		0/97 (0%)
HYPERKERATOSIS	0/94 (0%)		0/97 (0%)		1/97 (1%)
Surgical and medical procedures
PROSTATIC OPERATION	0/94 (0%)		0/97 (0%)		1/97 (1%)
Vascular disorders
GRANULOMATOSIS WITH POLYANGIITIS	1/94 (1.1%)		0/97 (0%)		0/97 (0%)
HYPERTENSION	1/94 (1.1%)		0/97 (0%)		0/97 (0%)
HYPOTENSION	1/94 (1.1%)		0/97 (0%)		0/97 (0%)
NECROSIS ISCHAEMIC	1/94 (1.1%)		0/97 (0%)		0/97 (0%)
PERIPHERAL ARTERIAL OCCLUSIVE DISEASE	1/94 (1.1%)		0/97 (0%)		0/97 (0%)
PERIPHERAL ISCHAEMIA	1/94 (1.1%)		0/97 (0%)		0/97 (0%)
RAYNAUD'S PHENOMENON	1/94 (1.1%)		0/97 (0%)		1/97 (1%)
EXTREMITY NECROSIS	0/94 (0%)		0/97 (0%)		1/97 (1%)
Other (Not Including Serious) Adverse Events
	Macitentan 3mg		Macitentan 10mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	61/94 (64.9%)		73/97 (75.3%)		69/97 (71.1%)
Blood and lymphatic system disorders
ANAEMIA	4/94 (4.3%)		8/97 (8.2%)		7/97 (7.2%)
Gastrointestinal disorders
GASTROOESOPHAGEAL REFLUX DISEASE	0/94 (0%)		6/97 (6.2%)		5/97 (5.2%)
DIARRHOEA	6/94 (6.4%)		5/97 (5.2%)		7/97 (7.2%)
NAUSEA	5/94 (5.3%)		4/97 (4.1%)		6/97 (6.2%)
General disorders
OEDEMA PERIPHERAL	7/94 (7.4%)		12/97 (12.4%)		6/97 (6.2%)
Infections and infestations
INFECTED SKIN ULCER	7/94 (7.4%)		12/97 (12.4%)		11/97 (11.3%)
UPPER RESPIRATORY TRACT INFECTION	3/94 (3.2%)		7/97 (7.2%)		4/97 (4.1%)
BRONCHITIS	7/94 (7.4%)		1/97 (1%)		5/97 (5.2%)
Investigations
ALANINE AMINOTRANSFERASE INCREASED	2/94 (2.1%)		6/97 (6.2%)		1/97 (1%)
ASPARTATE AMINOTRANSFERASE INCREASED	3/94 (3.2%)		5/97 (5.2%)		1/97 (1%)
Musculoskeletal and connective tissue disorders
BACK PAIN	3/94 (3.2%)		5/97 (5.2%)		3/97 (3.1%)
ARTHRALGIA	6/94 (6.4%)		4/97 (4.1%)		7/97 (7.2%)
PAIN IN EXTREMITY	4/94 (4.3%)		4/97 (4.1%)		6/97 (6.2%)
Nervous system disorders
HEADACHE	14/94 (14.9%)		19/97 (19.6%)		12/97 (12.4%)
DIZZINESS	4/94 (4.3%)		5/97 (5.2%)		2/97 (2.1%)
Skin and subcutaneous tissue disorders
SKIN ULCER	6/94 (6.4%)		8/97 (8.2%)		9/97 (9.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.