AC-055C302

Actelion Pharmaceuticals Ltd.

Gewerbestrasse 16, Allschwil, Switzerland, 4123

Clinical Trials Disclosure Desk, Actelion Pharmaceuticals Ltd., clinical-trials-disclosure@actelion.com

Clinical Trials Disclosure Desk, Actelion Pharmaceuticals Ltd., clinical-trials-disclosure@actelion.com

No

No

No

Final

26 Feb 2014

Yes

02 Feb 2014

Yes

02 Feb 2014

Yes

To demonstrate the effect of macitentan on the reduction of the number of new digital ulcers (DUs) in patients with systemic sclerosis (SSc) and ongoing DU disease

Prior to the start of the trial, each study center consulted an Independent Ethics Committee (IEC) or Institutional Review Board (IRB), i.e., a review panel that was responsible for ensuring the protection of the rights, safety, and well-being of human subjects involved in a clinical investigation. The investigator ensured that this study was conducted in full conformance with the principles of the ‘Declaration of Helsinki’ (and its amendments) and with the laws and regulations of the country in which the clinical research was conducted. The study was to be conducted according to International Committee on Harmonisation (ICH) guidelines on Good Clinical Practice (GCP) and, if applicable, the US Code of Federal Regulations (CFR) and other GCP guidelines. Documentary evidence of adequate GCP training of the investigator was collected prior to site initiation. Both Actelion and the investigator had the right to terminate the study at any time and, in such a case, were responsible for protecting the patients’ interests.

09 Feb 2012

No

Yes

Argentina: 18

Belgium: 1

China: 11

Colombia: 14

Germany: 7

Greece: 11

Ireland: 4

Israel: 24

Mexico: 21

Netherlands: 6

New Zealand: 6

Poland: 23

Portugal: 7

Puerto Rico: 2

Russian Federation: 16

South Africa: 9

Turkey: 1

Ukraine: 20

United Kingdom: 16

United States: 48

265

75

0

0

0

0

0

0

234

31

0

Baseline period

Randomised - controlled

To ensure double-blind conditions, each dose strength of the investigational drug and its matching placebo were indistinguishable with respect to appearance, taste, weight, and shape, and all medication bottles were identically packaged and labeled.

Yes

Macitentan 3 mg

Tablet

Oral use

Macitentan tablet 3 mg once daily

Placebo

Tablet

Oral use

Matching placebo once daily

Macitentan 10 mg

Tablet

Oral use

Macitentan tablet 10 mg once daily

Period 1: Baseline to Week 16

Randomised - controlled

To ensure double-blind conditions, each dose strength of the investigational drug and its matching placebo were indistinguishable with respect to appearance, taste, weight, and shape, and all medication bottles were identically packaged and labeled. IMPORTANT NOTE for "Period Milestone Achievement": Overall Period 1&2: Administrative: 1-0-2; AE nonfatal: 8-15-13; Lost to follow-up:1-0-1; Non-conformity: 0-0-1; Pat. dec.: 10-1-4; Phys. dec.: 0-3-2; Consent withdr.: 3-1-3

Yes

Macitentan 3 mg

Tablet

Oral use

Macitentan tablet 3 mg once daily

Placebo

Tablet

Oral use

Matching placebo once daily

Macitentan 10 mg

Tablet

Oral use

Macitentan tablet 10 mg once daily

Period 2: Week 16 to End of Study

Randomised - controlled

To ensure double-blind conditions, each dose strength of the investigational drug and its matching placebo were indistinguishable with respect to appearance, taste, weight, and shape, and all medication bottles were identically packaged and labeled. IMPORTANT NOTE for "Period Milestone Achievement": Overall Period 1&2: Administrative: 1-0-2; AE nonfatal: 8-15-13; Lost to follow-up:1-0-1; Non-conformity: 0-0-1; Pat. dec.: 10-1-4; Phys. dec.: 0-3-2; Consent withdr.: 3-1-3

Yes

Macitentan 3 mg

Tablet

Oral use

Macitentan tablet 3 mg once daily

Macitentan 10 mg

Tablet

Oral use

Macitentan tablet 10 mg once daily

Placebo

Tablet

Oral use

Matching placebo once daily

Macitentan 3 mg

Macitentan 10 mg

Placebo

Per-protocol (PP) set

This analysis set comprised all patients in the mITT set until the occurrence of a major protocol deviation that might affect the evaluation of the effect of study treatment on the primary endpoint. The protocol deviations affecting this set were identified before database lock. Patients were excluded from the PP set if they did not meet any of the following entry criteria: • Diagnosis of limited or diffuse SSc according to the ACR classification or met the criteria for CREST syndrome • Active DU according to protocol-defined qualifications • History of at least 1 additional active ischemic DU up to 6 months, or at least 2 up to 12 months prior to screening • No DUs due to conditions other than SSc • No comorbidities, other than SSc, that could seriously affect the assessment of hand function • Received study treatment different from that randomized Measurements after the occurrence of certain pre-defined deviations in study conduct were excluded from the PP set.

Modified intent-to-treat (mITT) set

This analysis set included all patients in the Full analysis set who received at least one dose of study treatment and had at least one post-baseline primary efficacy assessment (i.e., an on-treatment post-baseline DU assessment during Period 1). Assignment to treatment arms was as randomized, regardless of the actual treatment received.

Safety set

This analysis set included all patients who received at least one dose of study treatment. Assignment to treatment arms was as treated, regardless of the randomization allocation, according to the following algorithm: • Patients who were dispensed macitentan 10 mg at least once were assigned to the macitentan 10 mg arm. • Patients who were dispensed macitentan 3 mg at least once, but not macitentan 10 mg, were assigned to the macitentan 3 mg arm.

Full analysis set

This analysis set included all randomized patients as identified in the IVRS dataset. Assignment to treatment arms was as randomized, regardless of the treatment received. This analysis set was added in the SAP to use for the analysis of the primary endpoint, in line with the intention-to-treat principle as per ICH E9.

Macitentan 3 mg

Placebo

Macitentan 10 mg

Macitentan 3 mg

Placebo

Macitentan 10 mg

Macitentan 3 mg

Macitentan 10 mg

Placebo

Per-protocol (PP) set

This analysis set comprised all patients in the mITT set until the occurrence of a major protocol deviation that might affect the evaluation of the effect of study treatment on the primary endpoint. The protocol deviations affecting this set were identified before database lock. Patients were excluded from the PP set if they did not meet any of the following entry criteria: • Diagnosis of limited or diffuse SSc according to the ACR classification or met the criteria for CREST syndrome • Active DU according to protocol-defined qualifications • History of at least 1 additional active ischemic DU up to 6 months, or at least 2 up to 12 months prior to screening • No DUs due to conditions other than SSc • No comorbidities, other than SSc, that could seriously affect the assessment of hand function • Received study treatment different from that randomized Measurements after the occurrence of certain pre-defined deviations in study conduct were excluded from the PP set.

Modified intent-to-treat (mITT) set

This analysis set included all patients in the Full analysis set who received at least one dose of study treatment and had at least one post-baseline primary efficacy assessment (i.e., an on-treatment post-baseline DU assessment during Period 1). Assignment to treatment arms was as randomized, regardless of the actual treatment received.

Safety set

This analysis set included all patients who received at least one dose of study treatment. Assignment to treatment arms was as treated, regardless of the randomization allocation, according to the following algorithm: • Patients who were dispensed macitentan 10 mg at least once were assigned to the macitentan 10 mg arm. • Patients who were dispensed macitentan 3 mg at least once, but not macitentan 10 mg, were assigned to the macitentan 3 mg arm.

Full analysis set

This analysis set included all randomized patients as identified in the IVRS dataset. Assignment to treatment arms was as randomized, regardless of the treatment received. This analysis set was added in the SAP to use for the analysis of the primary endpoint, in line with the intention-to-treat principle as per ICH E9.

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. Note that NB-2 model estimates are presented.

Primary

Baseline to Week 16

Macitentan 3 mg v Placebo

177

Pre-specified

1.194

2-sided

Macitentan 10 mg v Placebo

177

Pre-specified

1.208

2-sided

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.

Secondary

Baseline to Week 16

Macitentan 10 mg v Placebo

171

Pre-specified

0.789

2-sided

Macitentan 3 mg v Placebo

171

Pre-specified

0.831

2-sided

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.

Secondary

Up to 95 weeks

Macitentan 3 mg v Placebo

171

Pre-specified

1.216

2-sided

Macitentan 10 mg v Placebo

171

Pre-specified

1.048

2-sided

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). Note that the last observed carried forward (LOCF) approach was applied to Week 16 data.

Secondary

Baseline to Week 16 (LOCF)

ANCOVA on mITT analysis set

Macitentan 3 mg v Placebo

171

Pre-specified

-0.1

2-sided

ANCOVA on mITT analysis set

Macitentan 10 mg v Placebo

171

Pre-specified

-0.1

2-sided

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). Note that the last observed carried forward (LOCF) approach was applied to Week 16 data.

Secondary

Baseline to Week 16 (LOCF)

ANCOVA on mITT analysis set

Macitentan 10 mg v Placebo

171

Pre-specified

-0.1

2-sided

ANCOVA on mITT analysis set

Macitentan 3 mg v Placebo

171

Pre-specified

-0.1

2-sided

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). Note that the last observed carried forward (LOCF) approach was applied to Week 16 data.

Secondary

Baseline to Week 16 (LOCF)

ANCOVA on mITT analysis set

Macitentan 10 mg v Placebo

171

Pre-specified

-0.2

2-sided

ANCOVA on mITT analysis set

Macitentan 3 mg v Placebo

171

Pre-specified

-0.1

2-sided

Adverse events occurring during treatment period, up to 95 weeks and up to 30 days after treatment discontinuation

Safety set - all treated patients

16.0

Macitentan 3 mg

Placebo

Macitentan 10 mg