Clinical Trial Results:
A Long-term, Multicenter, Single-arm, Open-label Extension of the SERENADE Study, to Assess the Safety and Efficacy of Macitentan in Subjects with Heart Failure with Preserved Ejection Fraction and Pulmonary Vascular Disease
Summary
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EudraCT number |
2018-001603-37 |
Trial protocol |
BG DE HU DK SE RO |
Global end of trial date |
12 Oct 2021
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Results information
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Results version number |
v1(current) |
This version publication date |
28 Oct 2022
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First version publication date |
28 Oct 2022
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Other versions |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
AC-055G203
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT03714815 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Actelion Pharmaceuticals Ltd
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Sponsor organisation address |
Gewerbestrasse 16, Allschwil, Switzerland, 4123
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Public contact |
Clinical Registry Group, Actelion Pharmaceuticals Ltd, ClinicalTrialsEU@its.jnj.com
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Scientific contact |
Clinical Registry Group, Actelion Pharmaceuticals Ltd, ClinicalTrialsEU@its.jnj.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
10 Dec 2021
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
12 Oct 2021
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Global end of trial reached? |
Yes
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Global end of trial date |
12 Oct 2021
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Was the trial ended prematurely? |
Yes
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General information about the trial
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Main objective of the trial |
The main objective of this trial was to describe the long-term safety of macitentan 10 milligrams (mg) in subjects with heart failure with preserved ejection fraction (HFpEF) and pulmonary vascular disease (PVD).
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Protection of trial subjects |
This study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with Good Clinical Practices and applicable regulatory requirements.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
21 Dec 2018
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Argentina: 1
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Country: Number of subjects enrolled |
Austria: 2
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Country: Number of subjects enrolled |
Bulgaria: 8
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Country: Number of subjects enrolled |
Brazil: 2
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Country: Number of subjects enrolled |
Germany: 4
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Country: Number of subjects enrolled |
Denmark: 2
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Country: Number of subjects enrolled |
France: 5
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Country: Number of subjects enrolled |
United Kingdom: 3
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Country: Number of subjects enrolled |
Israel: 23
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Country: Number of subjects enrolled |
Poland: 7
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Country: Number of subjects enrolled |
Romania: 4
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Country: Number of subjects enrolled |
Russian Federation: 14
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Country: Number of subjects enrolled |
Sweden: 2
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Country: Number of subjects enrolled |
United States: 14
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Worldwide total number of subjects |
91
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EEA total number of subjects |
34
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
14
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From 65 to 84 years |
69
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85 years and over |
8
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Recruitment
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Recruitment details |
- | ||||||||||||||
Pre-assignment
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Screening details |
Out of the 91 enrolled subjects, 76 subjects completed the study. | ||||||||||||||
Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||
Arms
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Arm title
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Macitentan 10 mg | ||||||||||||||
Arm description |
Eligible subjects who remained in the main study (2016-003653-15) for at least 24 weeks after randomisation entered this open-label extension study to receive macitentan 10 milligrams (mg) tablet orally once daily until the end of the treatment (treatment exposure ranged from 0.4 to 126 weeks). | ||||||||||||||
Arm type |
Experimental | ||||||||||||||
Investigational medicinal product name |
Macitentan
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Investigational medicinal product code |
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Other name |
JNJ-67896062 ACT-064992
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Pharmaceutical forms |
Film-coated tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Macitentan 10 mg tablet was administered once daily until the end of treatment (treatment exposure ranged from 0.4 to 126 weeks).
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Baseline characteristics reporting groups
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Reporting group title |
Macitentan 10 mg
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Reporting group description |
Eligible subjects who remained in the main study (2016-003653-15) for at least 24 weeks after randomisation entered this open-label extension study to receive macitentan 10 milligrams (mg) tablet orally once daily until the end of the treatment (treatment exposure ranged from 0.4 to 126 weeks). | ||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Macitentan 10 mg
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Reporting group description |
Eligible subjects who remained in the main study (2016-003653-15) for at least 24 weeks after randomisation entered this open-label extension study to receive macitentan 10 milligrams (mg) tablet orally once daily until the end of the treatment (treatment exposure ranged from 0.4 to 126 weeks). |
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End point title |
Number of Subjects with All-cause Deaths up to 30 Days After Study Treatment Discontinuation [1] | ||||||
End point description |
Number of subjects with all-cause deaths up to 30 days after study treatment discontinuation were reported. All-cause deaths are defined as all anticipated and unanticipated deaths due to any cause. The SERENADE OL safety analysis set included all subjects who received at least 1 dose of macitentan 10 milligrams (mg).
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End point type |
Primary
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End point timeframe |
Up to 30 days after study treatment discontinuation (treatment exposure ranged from 0.4 to 126 weeks)
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Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No inferential statistics was planned for this primary endpoint. |
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No statistical analyses for this end point |
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End point title |
Number of Subjects with All-cause Hospital Admissions up to 30 Days After Study Treatment Discontinuation [2] | ||||||
End point description |
Number of subjects with all-cause hospital admissions up to 30 days after study treatment discontinuation were reported. The SERENADE OL safety analysis set included all subjects who received at least 1 dose of macitentan 10 mg.
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End point type |
Primary
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End point timeframe |
Up to 30 days after study treatment discontinuation (treatment exposure ranged from 0.4 to 126 weeks)
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Notes [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No inferential statistics was planned for this primary endpoint. |
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No statistical analyses for this end point |
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End point title |
Number of Subjects with Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) up to 30 Days After Study Treatment Discontinuation [3] | ||||||||||
End point description |
An adverse event is any untoward medical event that occurs in a subject administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product. SAE is any AE that results in: death, persistent or significant disability/incapacity, requires inpatient hospitalization or prolongation of existing hospitalization, is a suspected transmission of any infectious agent via a medicinal product, is life-threatening experience, is a congenital anomaly/birth defect and may jeopardize subject and/or may require medical or surgical intervention to prevent one of the outcomes listed above. Any AE and SAE occurring at or after the study treatment start up to 30 days after end of treatment (EOT) within the analysis set was considered to be treatment-emergent. The SERENADE OL safety analysis set included all subjects who received at least 1 dose of macitentan 10 mg.
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End point type |
Primary
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End point timeframe |
Up to 30 days after study treatment discontinuation (treatment exposure ranged from 0.4 to 126 weeks)
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Notes [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No inferential statistics was planned for this primary endpoint. |
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No statistical analyses for this end point |
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End point title |
Number of Subjects with TEAEs Leading to Premature Discontinuation of Study Treatment [4] | ||||||
End point description |
An adverse event is any untoward medical event that occurs in a subject administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product. Any AE occurring at or after the study treatment start up to 30 days after EOT within the analysis set was considered to be treatment-emergent. The SERENADE OL safety analysis set included all subjects who received at least 1 dose of macitentan 10 mg.
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End point type |
Primary
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End point timeframe |
Up to 30 days after study treatment discontinuation (treatment exposure ranged from 0.4 to 126 weeks)
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Notes [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No inferential statistics was planned for this primary endpoint. |
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No statistical analyses for this end point |
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End point title |
Change from Baseline in Systolic and Diastolic Arterial Blood Pressure (BP) at Week 24 [5] | ||||||||||||
End point description |
Change from baseline in systolic and diastolic arterial BP at Week 24 was reported. The SERENADE OL safety analysis set included all subjects who received at least 1 dose of macitentan 10 mg. Here, "N" (number of subjects analysed) specifies number of subjects evaluable for this endpoint.
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End point type |
Primary
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End point timeframe |
Baseline and Week 24
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Notes [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No inferential statistics was planned for this primary endpoint. |
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No statistical analyses for this end point |
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End point title |
Change from Baseline in Systolic and Diastolic Arterial BP at Week 52 [6] | ||||||||||||
End point description |
Change from baseline in systolic and diastolic arterial BP at Week 52 was reported. The SERENADE OL safety analysis set included all subjects who received at least 1 dose of macitentan 10 mg. Here, "N" (number of subjects analysed) specifies number of subjects evaluable for this endpoint.
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End point type |
Primary
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End point timeframe |
Baseline and Week 52
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Notes [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No inferential statistics was planned for this primary endpoint. |
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No statistical analyses for this end point |
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End point title |
Change from Baseline in Pulse Rate at Week 24 [7] | ||||||||
End point description |
Change from baseline in pulse rate at Week 24 was reported. The SERENADE OL safety analysis set included all subjects who received at least 1 dose of macitentan 10 mg. Here, "N" (number of subjects analysed) specifies number of subjects evaluable for this endpoint.
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End point type |
Primary
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End point timeframe |
Baseline and Week 24
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Notes [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No inferential statistics was planned for this primary endpoint. |
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No statistical analyses for this end point |
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End point title |
Change from Baseline in Pulse Rate at Week 52 [8] | ||||||||
End point description |
Change from baseline in pulse rate at Week 52 was reported. The SERENADE OL safety analysis set included all subjects who received at least 1 dose of macitentan 10 mg. Here, "N" (number of subjects analysed) specifies number of subjects evaluable for this endpoint.
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End point type |
Primary
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End point timeframe |
Baseline and Week 52
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Notes [8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No inferential statistics was planned for this primary endpoint. |
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No statistical analyses for this end point |
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End point title |
Change from Baseline in Body Weight at Week 24 [9] | ||||||||
End point description |
Change from baseline in body weight at Week 24 was reported. The SERENADE OL safety analysis set included all subjects who received at least 1 dose of macitentan 10 mg. Here, "N" (number of subjects analysed) specifies number of subjects evaluable for this endpoint.
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End point type |
Primary
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End point timeframe |
Baseline and Week 24
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Notes [9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No inferential statistics was planned for this primary endpoint. |
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No statistical analyses for this end point |
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End point title |
Change from Baseline in Body Weight at Week 52 [10] | ||||||||
End point description |
Change from baseline in body weight at Week 52 was reported. The SERENADE OL safety analysis set included all subjects who received at least 1 dose of macitentan 10 mg. Here, "N" (number of subjects analysed) specifies number of subjects evaluable for this endpoint.
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End point type |
Primary
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End point timeframe |
Baseline and Week 52
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Notes [10] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No inferential statistics was planned for this primary endpoint. |
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No statistical analyses for this end point |
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End point title |
Number of Subjects with Treatment-emergent Marked Laboratory Abnormalities (MLAs) up to 30 Days After Study Treatment Discontinuation [11] | ||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Number of subjects with treatment-emergent MLAs (Hemoglobin [grams/Litre{L}], Hematocrit [L/L], Leukocytes [10^9cells/L], Lymphocytes [10^9cells/L], Alanine Aminotransferase [Units/L {U/L}], Aspartate Aminotransferase [U/L], Bilirubin [micromoles/L {mcmol/L}], Alkaline Phosphatase [U/L], Creatinine [mcmol/L], Urea Nitrogen [mmol/L], Urate [mcmol/L], Potassium [mmol/L], Sodium [mmol/L], Magnesium [mmol/L], Calcium [mmol/L] were reported. Abnormalities that occurred after study treatment start and up to 30 days after study treatment discontinuation, that were not present at baseline, were treatment-emergent. SERENADE OL safety analysis set included all subjects who received at least 1 dose of macitentan 10 mg. N=subjects evaluable for this endpoint; >:greater than; <:less than; ULN=upper limit of normal; L=Low, H=High, LL=low/low, HH=high/high LLL=lower/worse than LL, HHH=higher/worse than HH.
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End point type |
Primary
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End point timeframe |
Up to 30 days after study treatment discontinuation (treatment exposure ranged from 0.4 to 126 weeks)
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Notes [11] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No inferential statistics was planned for this primary endpoint. |
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No statistical analyses for this end point |
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End point title |
Change from Baseline in Hemoglobin at Week 24 [12] | ||||||||
End point description |
Change from baseline in hemoglobin at Week 24 was reported. The SERENADE OL safety analysis set included all subjects who received at least 1 dose of macitentan 10 mg. Here, "N" (number of subjects analysed) specifies number of subjects evaluable for this endpoint.
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End point type |
Primary
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End point timeframe |
Baseline and Week 24
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Notes [12] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No inferential statistics was planned for this primary endpoint. |
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No statistical analyses for this end point |
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End point title |
Change from Baseline in Hemoglobin at Week 52 [13] | ||||||||
End point description |
Change from baseline in hemoglobin at Week 52 was reported. The SERENADE OL safety analysis set included all subjects who received at least 1 dose of macitentan 10 mg. Here, "N" (number of subjects analysed) specifies number of subjects evaluable for this endpoint.
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End point type |
Primary
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End point timeframe |
Baseline and Week 52
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Notes [13] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No inferential statistics was planned for this primary endpoint. |
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No statistical analyses for this end point |
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End point title |
Change from Baseline in Leukocytes and Platelets at Week 24 [14] | ||||||||||||
End point description |
Change from baseline in leukocytes and platelets at Week 24 was reported. The SERENADE OL safety analysis set included all subjects who received at least 1 dose of macitentan 10 mg. Here, "N" (number of subjects analysed) specifies number of subjects evaluable for this endpoint.
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End point type |
Primary
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End point timeframe |
Baseline and Week 24
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Notes [14] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No inferential statistics was planned for this primary endpoint. |
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No statistical analyses for this end point |
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End point title |
Change from Baseline in Leukocytes and Platelets at Week 52 [15] | ||||||||||||
End point description |
Change from baseline in leukocytes and platelets at Week 52 was reported. The SERENADE OL safety analysis set included all subjects who received at least 1 dose of macitentan 10 mg. Here, "N" (number of subjects analysed) specifies number of subjects evaluable for this endpoint.
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End point type |
Primary
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End point timeframe |
Baseline and Week 52
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Notes [15] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No inferential statistics was planned for this primary endpoint. |
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No statistical analyses for this end point |
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End point title |
Change from Baseline in Alanine Aminotransferase and Aspartate Aminotransferase at Week 24 [16] | ||||||||||||
End point description |
Change from baseline in alanine aminotransferase and aspartate aminotransferase at Week 24 was reported. The SERENADE OL safety analysis set included all subjects who received at least 1 dose of macitentan 10 mg. Here, "N" (number of subjects analysed) specifies number of subjects evaluable for this endpoint; "n" specifies those subjects who were analysed for specified categories.
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End point type |
Primary
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End point timeframe |
Baseline and Week 24
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Notes [16] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No inferential statistics was planned for this primary endpoint. |
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No statistical analyses for this end point |
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End point title |
Change from Baseline in Alanine Aminotransferase and Aspartate Aminotransferase at Week 52 [17] | ||||||||||||
End point description |
Change from baseline in alanine aminotransferase and aspartate aminotransferase at Week 52 was reported. The SERENADE OL safety analysis set included all subjects who received at least 1 dose of macitentan 10 mg. Here, "N" (number of subjects analysed) specifies number of subjects evaluable for this endpoint.
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End point type |
Primary
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End point timeframe |
Baseline and Week 52
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Notes [17] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No inferential statistics was planned for this primary endpoint. |
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No statistical analyses for this end point |
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End point title |
Change from Baseline in Bilirubin at Week 24 [18] | ||||||||
End point description |
Change from baseline in bilirubin at Week 24 was reported. The SERENADE OL safety analysis set included all subjects who received at least 1 dose of macitentan 10 mg. Here, "N" (number of subjects analysed) specifies number of subjects evaluable for this endpoint.
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End point type |
Primary
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End point timeframe |
Baseline and Week 24
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Notes [18] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No inferential statistics was planned for this primary endpoint. |
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No statistical analyses for this end point |
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End point title |
Change from Baseline in Bilirubin at Week 52 [19] | ||||||||
End point description |
Change from baseline in bilirubin at Week 52 was reported. The SERENADE OL safety analysis set included all subjects who received at least 1 dose of macitentan 10 mg. Here, "N" (number of subjects analysed) specifies number of subjects evaluable for this endpoint.
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End point type |
Primary
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End point timeframe |
Baseline and Week 52
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Notes [19] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No inferential statistics was planned for this primary endpoint. |
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No statistical analyses for this end point |
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End point title |
Change from Baseline in Estimated Glomerular Filtration Rate (eGFR) at Week 24 [20] | ||||||||
End point description |
Change from baseline in eGFR rate at Week 24 was reported. The SERENADE OL safety analysis set included all subjects who received at least 1 dose of macitentan 10 mg. Here, "N" (number of subjects analysed) specifies number of subjects evaluable for this endpoint.
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End point type |
Primary
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End point timeframe |
Baseline and Week 24
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Notes [20] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No inferential statistics was planned for this primary endpoint. |
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No statistical analyses for this end point |
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End point title |
Change from Baseline in Estimated Glomerular Filtration Rate (eGFR) at Week 52 [21] | ||||||||
End point description |
Change from baseline in eGFR rate at Week 52 was reported. The SERENADE OL safety analysis set included all subjects who received at least 1 dose of macitentan 10 mg. Here, "N" (number of subjects analysed) specifies number of subjects evaluable for this endpoint.
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End point type |
Primary
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End point timeframe |
Baseline and Week 52
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Notes [21] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No inferential statistics was planned for this primary endpoint. |
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No statistical analyses for this end point |
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Adverse events information
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Timeframe for reporting adverse events |
Up to 30 days after study treatment discontinuation (treatment exposure ranged from 0.4 to 126 weeks)
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Adverse event reporting additional description |
The SERENADE OL safety analysis set included all subjects who received at least 1 dose of macitentan 10 milligrams (mg).
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Assessment type |
Non-systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
24.0
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Reporting groups
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Reporting group title |
Macitentan 10 mg
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Reporting group description |
Eligible subjects who remained in the main study (2016-003653-15) for at least 24 weeks after randomisation entered this open-label extension study to receive macitentan 10 milligrams (mg) tablet orally once daily until the end of the treatment (treatment exposure ranged from 0.4 to 126 weeks). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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02 Aug 2018 |
The purpose of this amendment was to correct the description of the investigational medicinal product used in the study. |
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16 May 2019 |
The purpose of this amendment was to: introduce a new efficacy endpoint, the 6-minute walk distance (6MWD), assessed by the 6-minute walk test (6MWT), as part of a substudy to assess the change from baseline in exercise capacity; include the collection of mid-regional pro-atrial natriuretic peptide (MR-proANP) and a research biomarker (optional) sample at scheduled visits and at the time of a fluid retention or worsening heart failure event to continue the analysis from the main study; include the collection of N-terminal pro-brain natriuretic peptide (NT-proBNP) at the time of fluid retention or worsening heart failure event to support the clinical event committee (CEC) review. |
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06 Feb 2020 |
The purpose of this amendment was to: align the strategy for subject enrollment into this open-label (OL) extension study due to premature termination of recruitment into the main study (AC-055G202/ SERENADE)-eligible subjects could enroll into this OL extension study after remaining in the main study for at least 24 weeks; remove evaluation of the efficacy assessments (that is, Kansas City cardiomyopathy questionnaire, accelerometry, echocardiography, and blood sample collection for NT-proBNP, MR-proANP, and biomarkers) in an effort to simplify the study and reduce assessment burden for subjects and study site personnel; stop the substudy assessments (6MWT and Borg Dyspnea Index), as number of subjects participating in the substudy was too low to allow for meaningful interpretation of results; remove CEC adjudication in line with the main study global protocol Version 6. The CEC was appointed to review and adjudicate in a blinded fashion worsening heart failure event, the reasons for hospitalization, and causes of death. The rationale was based on the reduction of the double-blind treatment period from 52 weeks to 24 weeks coupled with the low occurrence of clinical events, which did not allow meaningful conclusions to be drawn. However, the investigator assessment of worsening heart failure events was continued. Removal of the CEC did not affect safety monitoring and therefore, the decision was also endorsed by the independent data monitoring committee; created a single version of the SERENADE OL AC-055G203 protocol by incorporating voluntary harmonization procedure (VHP)-mandated changes into the global protocol version. |
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16 Jul 2020 |
The purpose of this amendment was to update the exclusion criteria and concomitant therapy sections pertaining to new information regarding a drug-drug-interaction of macitentan with moderate dual cytochrome P450 (CYP)3A4 and CYP2C9 inhibitors or co-administration of a combination of moderate CYP3A4 inhibitors and moderate CYP2C9 inhibitors. |
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26 Nov 2020 |
The purpose of this amendment was to adapt to changed internal safety language and reporting processes to align with TransCelerate template, to update information about post-treatment access program, study treatment storage conditions, forbidden medications, Actelion’s policy for study data disclosure, and to make minor editorial revisions and corrections. |
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Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
Limited number of efficacy parameters were assessed in an exploratory manner. Study was stopped prematurely as main double-blind study did not meet the primary efficacy endpoint. |