Macitentan for the Treatment of Digital Ulcers in Systemic Sclerosis Patients

Systemic Sclerosis Clinical Trial

— DUAL-1  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01474109
• Other study ID #: AC-055C301
• Status: Completed
• Phase: Phase 3
• First received: October 31, 2011
• Last updated: January 2, 2015
• Start date: December 2011
• Est. completion date: November 2013

Study information

• Verified date: January 2015
• Source: Actelion
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 289
• Est. completion date: November 2013
• Est. primary completion date: November 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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.

Study Design

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

Related Conditions & MeSH terms

• Scleroderma, Diffuse
• Scleroderma, Systemic
• Sclerosis
• Systemic Sclerosis
• Ulcer
• Ulcers

Intervention

Drug:
• macitentan 3mg
macitentan 3mg tablet once daily
• macitentan 10mg
macitentan 10mg tablet once daily
• placebo
matching placebo once daily

Locations

Country	Name	City	State
Australia	Royal Adelaide Hospital	Adelaide
Australia	Wesley Hospital, Thoracic Department	Auchenflower
Australia	Royal Prince Alfred Hospital	Camperdown
Australia	St Vincent's Hospital	Fitzroy
Australia	Menzies Research Institute	Hobart
Belarus	Gomel Regional Clinical Hospital	Gomel
Belarus	Healthcare Institution "Minsk City Hospital #1"	Minsk
Belarus	Healthcare Institution "Minsk Clinical Hospital #9"	Minsk
Bulgaria	Multiprofile Hospital for Active Treatment "Sveti Pantaleymon"	Pleven
Bulgaria	MHAT "Kaspela" EOOD Plovdiv - Rheumatology Ward	Plovdiv
Bulgaria	MHAT "Sv. Ivan Rilski" EAD Sofia - Clinic of Rheumatology	Sofia
Canada	Rheumatology Research Associates	Edmonton	Alberta
Canada	St. Joseph's Health Care	London	Ontario
Canada	CHUS Hopital Fleurimont	Sherbrooke	Quebec
Canada	Mount Sinai Hospital	Toronto	Ontario
Canada	St. Paul's Hospital	Vancouver	British Columbia
Chile	Hospital San Juan de Dios	Santiago
Chile	Private Office Marta Aliste	Santiago
Chile	Prosalud	Santiago
Chile	Centro de Estudios Clinicos V	Vina del Mar
Colombia	Medicity S.A.S.	Bucaramanga
Colombia	Servimed E.U.	Bucaramanga
Croatia	Klinicki Bolnicki Centar Osijek	Osijek
Croatia	University Hospital Centre Rijeka	Rijeka
Croatia	Klinicki bolnicki centar Split	Split
Croatia	Klinicka Bolnica "Svety Duh"	Zagreb
Croatia	Klinicka bolnica Dubrava	Zagreb
Croatia	University Hospital Centre Zagreb	Zagreb
Czech Republic	Lekarna FN Brno	Brno
Czech Republic	Faculty Hospital Hradec Králové	Hradec Králové
Czech Republic	Revmatologický ústav Praha	Praha
Denmark	Bispebjerg Hospital København	Copenhagen
Denmark	Odense Universitetshospital	Odense
Finland	Helsingin yliopistollinen keskussairaala (HYKS), Meilahden kolmiosairaala, Reumatologian klinikka	Helsinki
Germany	Universitätsmedizin Berlin Medizinische Klinik mit Schwerpunkt Rheumatologie und Klinische Immunologie	Berlin
Germany	Klinik für Dermatologie und Allergologie der Ruhr-Universität Bochum	Bochum
Germany	Medizinische Universitätsklinik Freiburg, Abt. Rheumatologie und klinische Forschung	Freiburg
Germany	Asklepios Westklinikum Hamburg Abteilung für Gefäßmedizin, Angiologie und Diabetologie	Hamburg
Germany	Rheumatologie, klinische Immunologie, Nephrologie Asklepios Rheumazentrum Hamburg Asklepios Klinik Altona	Hamburg
Germany	Akademie für Gefäßkrankheiten eV.	Karlsbad
Germany	Klinik und Poliklinik für Dermatologie und Venerologie der Universität zu Köln	Koln
Germany	Universitäts-Hautklinik Tübingen	Tuebingen
Hungary	Budai Irgalmasrendi Kórház	Budapest
Hungary	Debreceni Egyetem Orvos- és Egészségtudományi Centrum	Debrecen
Hungary	Pécsi Tudományegyetem Klinikai Központ, Reumatológiai és Immunológiai Klinika	Pécs
India	Advance Rheumatology Clinic	Hyderabad
India	Krishna Institute of Medical Sciences	Secunderabad
India	Christian Medical College	Vellore
Italy	Azienda Ospedaliera Careggi	Firenze
Italy	Azienda Ospedaliera Policlinico di Modena	Modena
Italy	Complesso Integrato Columbus	Rome
Poland	Uniwersyteckie Centrum Kliniczne	Gdansk
Poland	NZOZ Reumed	Lublin
Poland	Centralny Szpital Kliniczny MSWiA	Warszawa
Poland	Akademicki Szpital Kliniczny im. Jana Mikulicza-Radeckiego we Wroclawiu	Wroclaw
Russian Federation	State Healthcare Institution "Sverdlovsk Regional Clinical Hospital #1"	Ekaterinburg
Russian Federation	State Healthcare Institution "Penza Regional Clinical Hospital named after N.N. Burdenko"	Penza
Russian Federation	Vladimir Regional State Institution of Healthcare, "Regional Clinical Hospital"	Vladimir
Ukraine	Dinpropetrovsk Regional Clinical Hospital named after I. Mechnykova	Dnipropetrovsk
Ukraine	Municipal Institution of Kyiv Regional Council, Kyiv Regional Clinical Hospital	Kyiv
Ukraine	Lviv Regional Clinical Hospital	Lviv
Ukraine	Internal disease chair of Ukrainian medical dentist academy based on therapy department of Poltava Poltava City Clinical Hospital #1	Poltava
United States	The Center for Rheumatology	Albany	New York
United States	University of Michigan - Scleroderma Program	Ann Arbor	Michigan
United States	Arthritis & Rheumatic Disease Specialties	Aventura	Florida
United States	The Johns Hopkins University School of Medicine	Baltimore	Maryland
United States	Medical University of South Carolina	Charleston	South Carolina
United States	The Cleveland Clinic Foundation	Cleveland	Ohio
United States	Altoona Center for Clinical Research	Duncansville	Pennsylvania
United States	Michigan State University	Grand Rapids	Michigan
United States	UCLA Medical School - Rheumatology Division Rehabilitation Center	Los Angeles	California
United States	University of Medicine & Dentistry of New Jersey, UMDNJ Scleroderma Program	New Brunswick	New Jersey
United States	Ochsner Medical Center	New Orleans	Louisiana
United States	University of Pittsburgh Department of Rheumatology	Pittsburgh	Pennsylvania
United States	Shanahan Rheumatology and Immunotherapy, PLLC	Raleigh	North Carolina
United States	Sarasota Arthritis Research Center	Sarasota	Florida
United States	University of Arizona Arthritis Center	Tucson	Arizona

Sponsors (1)

Lead Sponsor	Collaborator
Actelion

Countries where clinical trial is conducted

United States,  Australia,  Belarus,  Bulgaria,  Canada,  Chile,  Colombia,  Croatia,  Czech Republic,  Denmark,  Finland,  Germany,  Hungary,  India,  Italy,  Poland,  Russian Federation,  Ukraine, 

Outcome

Type	Measure	Description	Time frame	Safety issue
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.	Baseline to week 16	No
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.	Baseline to week 16	No
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.	Up to approximately 90 weeks	No
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).	Baseline to week 16	No
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).	Baseline to week 16	No
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)	Baseline to week 16	No