Clinical Trial Results:
Prospective, Multi-center, Single-arm, Open-label Long-term Study Assessing the Safety, Tolerability, and Effectiveness of Macitentan in Fontan-palliated Adult and Adolescent Subjects
Summary
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EudraCT number |
2018-002821-45 |
Trial protocol |
FR DE GB DK PL CZ |
Global end of trial date |
18 Jan 2022
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Results information
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Results version number |
v1(current) |
This version publication date |
30 Jul 2022
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First version publication date |
30 Jul 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-055H302
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT03775421 | ||
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) |
Yes
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EMA paediatric investigation plan number(s) |
EMEA-001032-PIP03-19 | ||
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? |
Yes
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
18 Jan 2022
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
18 Jan 2022
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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 the trial was to assess the long-term safety and tolerability of macitentan in Fontan-palliated adult and adolescent subjects.
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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 |
03 May 2019
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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 |
Australia: 10
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Country: Number of subjects enrolled |
Canada: 4
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Country: Number of subjects enrolled |
China: 5
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Country: Number of subjects enrolled |
Czechia: 16
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Country: Number of subjects enrolled |
Denmark: 17
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Country: Number of subjects enrolled |
France: 7
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Country: Number of subjects enrolled |
United Kingdom: 3
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Country: Number of subjects enrolled |
New Zealand: 2
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Country: Number of subjects enrolled |
Poland: 23
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Country: Number of subjects enrolled |
Taiwan: 6
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Country: Number of subjects enrolled |
United States: 18
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Worldwide total number of subjects |
111
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EEA total number of subjects |
63
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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) |
12
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Adults (18-64 years) |
99
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
- | ||||||||||||||||||||
Pre-assignment
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Screening details |
1 subject was enrolled twice with 2 different subjects IDs but only 111 subjects were enrolled in the study. Of these 111 enrolled subjects, 1 subject 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 |
Subjects received macitentan 10 milligrams (mg) oral tablets once daily with or without food from Day 1 either until the end of the treatment (129 weeks) or when sponsor decided to stop this study. | ||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||
Investigational medicinal product name |
Macitentan
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Investigational medicinal product code |
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Other name |
ACT-064992 Opsumit JNJ-67896062
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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 with or without food from Day 1 until the end of treatment (129 weeks) or when sponsor decided to stop this study.
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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 |
Subjects received macitentan 10 milligrams (mg) oral tablets once daily with or without food from Day 1 either until the end of the treatment (129 weeks) or when sponsor decided to stop this study. | |||||||||||||||||||||||||||||||||||||||
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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 |
Subjects received macitentan 10 milligrams (mg) oral tablets once daily with or without food from Day 1 either until the end of the treatment (129 weeks) or when sponsor decided to stop this study. |
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End point title |
Number of Subjects with Treatment-emergent Adverse Events (TEAEs) [1] | ||||||
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 end of treatment (EOT) (limits included) within the analysis set was considered to be treatment-emergent. The RUBATO open-label extension set (OLES) included all subjects who were enrolled in this study and 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 133 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 Treatment-emergent Serious AEs (SAEs) [2] | ||||||
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 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 SAE occurring at or after the study treatment start up to 30 days after end of treatment (EOT) (limits included) within the analysis set was considered to be treatment-emergent. The RUBATO OLES included all subjects who were enrolled in this study and 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 133 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 TEAEs Leading to Death [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. Any AE occurring at or after the study treatment start up to 30 days after end of treatment (EOT) (limits included) within the analysis set was considered to be treatment-emergent. The RUBATO OLES included all subjects who were enrolled in this study and 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 133 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 end of treatment (EOT) (limits included) within the analysis set was considered to be treatment-emergent. The RUBATO OLES included all subjects who were enrolled in this study and 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 133 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 |
Number of Subjects with Treatment-emergent Marked Laboratory Abnormalities up to 30 Days After Study Treatment Discontinuation [5] | ||||||||||||||||||||||||||||||||||||||||
End point description |
Number of subjects with treatment-emergent marked laboratory abnormalities (Hemoglobin [gram/Litre{L}], Platelets [10^9/L], Leukocytes [10^9/L], Lymphocytes [10^9/L], Neutrophils [10^9/L], Prothrombin International Normalized Ratio [PINR; Ratio], Aspartate Aminotransferase [Units/L {U/L}], Bilirubin [micromoles/L {mcmol/L}], Alkaline Phosphatase [U/L], Glomerular Filtration Rate [millilitre/minute/1.73 metre square], Glucose [mmol/L], Potassium [mmol/L], Sodium [mmol/L], Triglycerides [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. RUBATO OLES: all subjects who were enrolled in this study and received at least 1 dose of macitentan 10mg. n=subjects who were analysed for specified categories; >=:greater than or equal to; <=:less than or equal to; ULN=upper limit of normal; L=Low, H=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 133 weeks
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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 Hemoglobin Over Time [6] | ||||||||||||||||||
End point description |
Change from baseline in hemoglobin over time was reported. The RUBATO OLES included all subjects who were enrolled in this study and 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 at specified timepoints.
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End point type |
Primary
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End point timeframe |
Baseline up to Week 130
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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 Hematocrit Over Time [7] | ||||||||||||||||||
End point description |
Change from baseline in hematocrit over time was reported. The RUBATO OLES included all subjects who were enrolled in this study and 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 at specified timepoints.
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End point type |
Primary
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End point timeframe |
Baseline up to Week 130
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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 Leukocytes, Neutrophils, Lymphocytes, and Platelets Over Time [8] | ||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Change from baseline in leukocytes, neutrophils, lymphocytes, and platelets over time were reported. The RUBATO OLES included all subjects who were enrolled in this study and 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 at specified timepoints.
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End point type |
Primary
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End point timeframe |
Baseline up to Week 130
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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 Systolic and Diastolic Arterial Blood Pressure (BP) Over Time [9] | ||||||||||||||||||||||||||||
End point description |
Change from baseline in systolic and diastolic arterial BP over time was reported. The RUBATO OLES included all subjects who were enrolled in this study and 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 at specified timepoints.
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End point type |
Primary
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End point timeframe |
Baseline up to Week 130
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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 Pulse Rate Over Time [10] | ||||||||||||||||||
End point description |
Change from baseline in pulse rate over time was reported. The RUBATO OLES included all subjects who were enrolled in this study and 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 at specified timepoints.
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End point type |
Primary
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End point timeframe |
Baseline up to Week 130
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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 |
Change from Baseline in Oxygen Saturation (SpO2) Over Time [11] | ||||||||||||||||||
End point description |
Change from baseline in SpO2 over time was reported. The RUBATO OLES included all subjects who were enrolled in this study and 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 analyzed at specified timepoints.
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End point type |
Primary
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End point timeframe |
Baseline up to Week 130
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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 Body Weight Over Time [12] | ||||||||||||||||||
End point description |
Change from baseline in body weight over time was reported. The RUBATO OLES included all subjects who were enrolled in this study and 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 at specified timepoints.
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End point type |
Primary
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End point timeframe |
Baseline up to Week 130
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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 Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Alkaline Phosphatase (AP), and Gamma Glutamyl Transferase (GGT) Over Time [13] | ||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Change from baseline in ALT, AST, AP, and GGT over time were reported. The RUBATO OLES included all subjects who were enrolled in this study and 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 at specified timepoints.
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End point type |
Primary
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End point timeframe |
Baseline up to Week 130
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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 Bilirubin, Direct Bilirubin, and Creatinine Over Time [14] | ||||||||||||||||||||||||||||||||||||||
End point description |
Change from baseline in bilirubin, direct bilirubin, and creatinine over time were reported. The RUBATO OLES included all subjects who were enrolled in this study and 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 at specified timepoints.
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End point type |
Primary
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End point timeframe |
Baseline up to Week 130
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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 Glomerular Filtration Rate (GFR) Over Time [15] | ||||||||||||||||||
End point description |
Change from baseline in GFR over time was reported. The RUBATO OLES included all subjects who were enrolled in this study and 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 at specified timepoints.
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End point type |
Primary
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End point timeframe |
Baseline up to Week 130
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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 Prothrombin Time Over Time [16] | ||||||||||||||||||
End point description |
Change from baseline in prothrombin time over time was reported. The RUBATO OLES included all subjects who were enrolled in this study and 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 at specified timepoints.
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End point type |
Primary
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End point timeframe |
Baseline up to Week 130
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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 Prothrombin International Normalized Ratio Over Time [17] | ||||||||||||||||||
End point description |
Change from baseline in prothrombin international normalized ratio over time was reported. The RUBATO OLES included all subjects who were enrolled in this study and 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 at specified timepoints.
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End point type |
Primary
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End point timeframe |
Baseline up to Week 130
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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 Peak Oxygen Uptake/Consumption (VO2) | ||||||||||||
End point description |
Change from baseline in peak VO2 was reported. The RUBATO OLES included all subjects who were enrolled in this study and 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 at specified timepoints.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 52, and Week 104
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No statistical analyses for this end point |
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End point title |
Change from Baseline in Mean Count per Minute of Daily Physical Activity Measured by Accelerometer (PA-Ac) | ||||||||||||||||
End point description |
Change from baseline in mean count per minute of daily PA-Ac was reported. The RUBATO OLES included all subjects who were enrolled in this study and 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 at specified timepoints.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 26, Week 52, Week 78, and Week 104
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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 133 weeks
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Adverse event reporting additional description |
The RUBATO open-label extension set (OLES) included all subjects who were enrolled in this study and 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 |
Subjects received macitentan 10 milligrams (mg) oral tablets once daily with or without food from Day 1 either until the end of the treatment (129 weeks) or when sponsor decided to stop this study. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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20 Feb 2019 |
The purpose of this amendment was to harmonize the RUBATO open-label (OL) protocol with the recently amended RUBATO double blind (DB) study. Changes were introduced to the RUBATO study to implement recommendations from the Fontan Advisory Board (meeting held on 19 September 2018) on ways to improve recruitment and compliance with study examinations. These measures were expected to reduce study subject burden while preserving the scientific and medical merit of the RUBATO study. Reducing the burden on subjects resulted in increased subject compliance with the evaluation and monitoring visits, hence enhanced the completeness of the efficacy and safety assessments. |
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16 Jul 2020 |
The purpose of this amendment was to update the exclusion criteria, initiation of forbidden medication and concomitant therapy sections pertaining to newly identified drug-drug interactions (DDI) between macitentan and fluconazole (a dual moderate inhibitor of cytochrome
P450 [CYP]3A4 and CYP2C9) from a preclinical study on implications of role of CYP2C9 in the metabolism of macitentan. |
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21 Jul 2020 |
The purpose of this amendment was a preclinical study newly identified DDI between macitentan and fluconazole (a dual moderate inhibitor of CYP3A4 and CYP2C9), and concluded that there were implications on the role of CYP2C9 in the metabolism of macitentan. This led to the need for an amendment for an urgent safety measure (USM). At the time of the USM, there were sites who had implemented protocol version 1 and others were already on protocol version 2. As USM updates could not be combined with other updates to the protocol, a version 1.1 had to be created for regulatory submission and approval (for those on version 1) before transitioning those sites to version 3 (which combined version 2 and the USM information) as well. |
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19 Nov 2020 |
The purpose of this amendment was to align the study protocol with updates made for the AC-055H301 RUBATO double-blind study. a. Countries that did not enroll candidates for RUBATO open-label (OL) during the RUBATO study were removed from the section on acceptable methods of contraception; b. Study treatment supply and storage information was simplified was part of the Actelion and Janssen integration; c. The study duration was adapted to help ensure treatment with macitentan was available after the expected treatment duration of 2 years per subject; d. Global safety updates were made to align the protocol with Janssen processes as part of the Janssen and Actelion integration; e. Based on recent literature on the potential prognostic value of cardiopulmonary exercise testing (CPET) in Fontan-palliated subjects, the sponsor added 2 new exploratory efficacy endpoint variables that were not collected thus far but were already part of CPET assessments evaluated by the central leading facility. One of these variables, oxygen update/consumption at ventilatory anaerobic threshold, had also been claimed to be of interest in a recently completed study with a phosphodiesterase 5 inhibitor. Finally, an appendix was added to facilitate evaluation of exclusion criterion 3.3. |
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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. | |||
The study was stopped prematurely because the main double-blind (DB) study did not meet the primary and secondary efficacy endpoints. |