Clinical Trial Results:
An Open-Label Extension Study of APD811-003 in Patients with Pulmonary Arterial Hypertension
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Summary
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EudraCT number |
2014-003042-27 |
Trial protocol |
CZ HU ES PL RO SK |
Global end of trial date |
29 Mar 2021
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Results information
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Results version number |
v1(current) |
This version publication date |
05 Sep 2024
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First version publication date |
05 Sep 2024
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Other versions |
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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 |
APD811-007
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02279745 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
United Therapeutics Corp.
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Sponsor organisation address |
55 TW Alexander Drive, Durham, United States, 27709
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Public contact |
Global Medical Information, United Therapeutics Corp., +1 9194858350, clinicaltrials@unither.com
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Scientific contact |
Global Medical Information, United Therapeutics Corp., +1 9194858350, clinicaltrials@unither.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 |
21 Jun 2021
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
29 Mar 2021
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Global end of trial reached? |
Yes
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Global end of trial date |
29 Mar 2021
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
Primary:
To evaluate the long-term safety and tolerability of ralinepag in patients with World Health Organization (WHO) Group 1 pulmonary arterial hypertension (PAH) who completed Study APD811-003.
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Protection of trial subjects |
In accordance with federal/national regulations and ICH GCP guidelines, Clinical Monitors for UTC or its designee periodically contacted the sites and conducted on-site visits. During these visits, the Monitor, at a minimum, confirmed ethical treatment of subjects, assessed study progress, reviewed data collected, conducted source document verification, verified drug accountability periodically, and identified any issues requiring resolution. The Investigator was required to allow the Monitor direct access to all relevant documents and allocate his/her time and his/her staff to discuss any findings or any relevant issues. In addition, Auditors for UTC or its designee periodically contacted the sites and conducted on-site visits.
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Background therapy |
Concomitant medications and concomitant nondrug treatments were recorded. Subjects were permitted PAH-specific oral therapy consisting of an endothelin receptor antagonist (ERA) and/or a phosphodiesterase type 5 inhibitor (PDE5-I) or a soluble guanylate cyclase (sGC) stimulator. If on a single therapy at Baseline, the on-study addition of an ERA or PDE5-I or a sGC stimulator was permitted. In addition to ralinepag, subjects could be prescribed no more than 1 agent from the ERA class and 1 agent from the PDE5-I/sGC stimulator class at any given time. Substitution and dose adjustment within each of these classes was permitted. Subjects were evaluated for the presence of clinical worsening if additional therapy or dose adjustments/substitutions of current therapies was required. In addition, the following therapies, which may have affected PAH, were permitted and adjusted in dose as needed: • Vasodilators (including calcium channel blockers) • Digoxin • Spironolactone • L-Arginine supplementation. Diuretics were dosed as clinically indicated throughout the study. Subjects who required treatment with a prostacyclin/prostacyclin analogue (IV, subcutaneous, oral, or inhaled), except for acute vasodilator testing during cardiac catheterization, were discontinued from the study. | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
08 Jul 2015
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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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 |
Poland: 2
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Country: Number of subjects enrolled |
Romania: 5
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Country: Number of subjects enrolled |
Spain: 6
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Country: Number of subjects enrolled |
Bulgaria: 1
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Country: Number of subjects enrolled |
Czechia: 4
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Country: Number of subjects enrolled |
Hungary: 2
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Country: Number of subjects enrolled |
United States: 7
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Country: Number of subjects enrolled |
Australia: 9
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Country: Number of subjects enrolled |
Serbia: 9
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Worldwide total number of subjects |
45
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EEA total number of subjects |
20
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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) |
39
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From 65 to 84 years |
6
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85 years and over |
0
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Recruitment
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Recruitment details |
The study was conducted by 23 investigators at 23 study centers in the US, Europe, and Australia. No formal sample size calculation was conducted. All eligible subjects from Study APD811-003 could be enrolled into Study APD811-007. | ||||||||||||||||||||||||||||||
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Pre-assignment
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Screening details |
Each subject must have met all of the inclusion criteria and none of the exclusion criteria to be eligible for enrollment in the study. Eligible subjects completed the Phase 2 study, APD811-003, or were assigned to receive placebo and were discontinued due to clinical worsening. | ||||||||||||||||||||||||||||||
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Period 1
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Period 1 title |
Baseline
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||||||||||||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Received Placebo in APD811-003 | ||||||||||||||||||||||||||||||
Arm description |
- | ||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||
Investigational medicinal product name |
Ralinepag
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Investigational medicinal product code |
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Other name |
APD811
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Pharmaceutical forms |
Capsule, Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Ralinepag was provided for oral administration as 10, 20, 30, 40, and 100 mcg immediate-release capsule dose strengths, and later was provided as 50, 250, and 400 mcg (0.05, 0.25, and 0.4 mg) extended-release tablet dose strengths.
Subjects who received ralinepag in Study APD811-003 remained on their current dose. Subjects in the placebo treatment group of Study APD811-003 underwent a ralinepag Dose Titration Period (up to 9 weeks) until a stable maximum tolerated dose (MTD) was reached. The maximum total daily dose (TDD) was 600 mcg which could be increased at the discretion of the Investigator. Incremental dose increases were allowed after the Dose Titration Period (ie, during the Treatment Period) at the discretion of the Investigator (as clinically indicated) and according to the stepwise titration scheme. If a dose was not tolerated by the subject, it could have been adjusted as directed by the Investigator.
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Arm title
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Received Ralinepag in APD811-003 | ||||||||||||||||||||||||||||||
Arm description |
- | ||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||
Investigational medicinal product name |
Ralinepag
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Investigational medicinal product code |
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Other name |
APD811
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Pharmaceutical forms |
Capsule, Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Ralinepag was provided for oral administration as 10, 20, 30, 40, and 100 mcg immediate-release capsule dose strengths, and later was provided as 50, 250, and 400 mcg (0.05, 0.25, and 0.4 mg) extended-release tablet dose strengths.
Subjects who received ralinepag in Study APD811-003 remained on their current dose. Subjects in the placebo treatment group of Study APD811-003 underwent a ralinepag Dose Titration Period (up to 9 weeks) until a stable MTD was reached. The maximum TDD was 600 mcg which could be increased at the discretion of the Investigator. The dose achieved for each subject at the end of the Dose Titration Period could have been maintained throughout the Treatment Period; however, incremental dose increases were allowed during the Treatment Period at the discretion of the Investigator (as clinically indicated) and according to the stepwise titration scheme. If a dose was not tolerated
by the subject, it could have been adjusted as directed by the Investigator.
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Period 2
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Period 2 title |
Treatment Period
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Is this the baseline period? |
No | ||||||||||||||||||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||||||||||||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Received Placebo in APD811-003 | ||||||||||||||||||||||||||||||
Arm description |
- | ||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||
Investigational medicinal product name |
Ralinepag
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Investigational medicinal product code |
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Other name |
APD811
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Pharmaceutical forms |
Capsule, Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Ralinepag was provided for oral administration as 10, 20, 30, 40, and 100 mcg immediate-release capsule dose strengths, and later was provided as 50, 250, and 400 mcg (0.05, 0.25, and 0.4 mg) extended-release tablet dose strengths.
Subjects who received ralinepag in Study APD811-003 remained on their current dose. Subjects in the placebo treatment group of Study APD811-003 underwent a ralinepag Dose Titration Period (up to 9 weeks) until a stable MTD was reached. The maximum TDD was 600 mcg which could be increased at the discretion of the Investigator. The dose achieved for each subject at the end of the Dose Titration Period could have been maintained throughout the Treatment Period; however, incremental dose increases were allowed during the Treatment Period at the discretion of the Investigator (as clinically indicated) and according to the stepwise titration scheme. If a dose was not tolerated
by the subject, it could have been adjusted as directed by the Investigator.
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Arm title
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Received Ralinepag in APD811-003 | ||||||||||||||||||||||||||||||
Arm description |
- | ||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||
Investigational medicinal product name |
Ralinepag
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Investigational medicinal product code |
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Other name |
APD811
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Pharmaceutical forms |
Capsule, Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Ralinepag was provided for oral administration as 10, 20, 30, 40, and 100 mcg immediate-release capsule dose strengths, and later was provided as 50, 250, and 400 mcg (0.05, 0.25, and 0.4 mg) extended-release tablet dose strengths.
Subjects who received ralinepag in Study APD811-003 remained on their current dose. Subjects in the placebo treatment group of Study APD811-003 underwent a ralinepag Dose Titration Period (up to 9 weeks) until a stable MTD was reached. The maximum TDD was 600 mcg which could be increased at the discretion of the Investigator. The dose achieved for each subject at the end of the Dose Titration Period could have been maintained throughout the Treatment Period; however, incremental dose increases were allowed during the Treatment Period at the discretion of the Investigator (as clinically indicated) and according to the stepwise titration scheme. If a dose was not tolerated
by the subject, it could have been adjusted as directed by the Investigator.
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Baseline characteristics reporting groups
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Reporting group title |
Baseline
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Reporting group description |
- | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Received Placebo in APD811-003
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Reporting group description |
- | ||
Reporting group title |
Received Ralinepag in APD811-003
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Reporting group description |
- | ||
Reporting group title |
Received Placebo in APD811-003
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Reporting group description |
- | ||
Reporting group title |
Received Ralinepag in APD811-003
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Reporting group description |
- | ||
Subject analysis set title |
Safety Population
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
The Safety Population included any subject who received ralinepag at any time during the course
of Study APD811-007. All analyses were based on the Safety Population.
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End point title |
Change from Baseline in Pulmonary Vascular Resistance [1] | ||||||||
End point description |
The hemodynamic parameters of pulmonary vascular resistance, cardiac output, cardiac index, and mean pulmonary artery pressure were collected by right heart catheterization (RHC).
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End point type |
Primary
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End point timeframe |
At 1 or 2 years after the subject enrolled in the study, pending their last RHC prior to Protocol Amendment 2.
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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: This was an open-label extension study, and all participants in the Safety Population received ralinepag. The presented results show the overall change from baseline in pulmonary vascular resistance for the Safety Population. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Change from Baseline in Cardiac Output [2] | ||||||||
End point description |
The hemodynamic parameters of pulmonary vascular resistance, cardiac output, cardiac index, and mean pulmonary artery pressure were collected by RHC.
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End point type |
Primary
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End point timeframe |
At 1 or 2 years after the subject enrolled in the study, pending their last RHC prior to Protocol Amendment 2.
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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: This was an open-label extension study, and all participants in the Safety Population received ralinepag. The presented results show the overall change from baseline in cardiac output for the Safety Population. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Change from Baseline in Cardiac Index [3] | ||||||||
End point description |
The hemodynamic parameters of pulmonary vascular resistance, cardiac output, cardiac index, and mean pulmonary artery pressure were collected by RHC.
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End point type |
Primary
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End point timeframe |
At 1 or 2 years after the subject enrolled in the study, pending their last RHC prior to Protocol Amendment 2.
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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: This was an open-label extension study, and all participants in the Safety Population received ralinepag. The presented results show the overall change from baseline in cardiac index for the Safety Population. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Change from Baseline in Mean Pulmonary Artery Pressure [4] | ||||||||
End point description |
The hemodynamic parameters of pulmonary vascular resistance, cardiac output, cardiac index, and mean pulmonary artery pressure were collected by RHC.
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End point type |
Primary
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End point timeframe |
At 1 or 2 years after the subject enrolled in the study, pending their last RHC prior to Protocol Amendment 2.
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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: This was an open-label extension study, and all participants in the Safety Population received ralinepag. The presented results show the overall change from baseline in mean pulmonary artery pressure for the Safety Population. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Change From Baseline in 6MWD [5] | ||||||||||||||||||||||||||||||||||||||||||||
End point description |
6-Minute Walk Distance (6MWD) was measured at Baseline (prior to starting study drug) and every 3 months thereafter including the End of Study Visit.
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End point type |
Primary
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End point timeframe |
From Baseline to discontinuation of study drug, up to 235 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: This was an open-label extension study, and all participants in the Safety Population received ralinepag. The presented results show the overall change from baseline in 6MWD for the Safety Population. |
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| Notes [6] - The number of subjects varied from month to month based on total study population at each visit. |
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||
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End point title |
Change From Baseline in WHO/NYHA FC [7] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
WHO/New York Heart Association (NYHA) Functional Class (FC) was measured at Baseline (prior to starting study drug) and every 3 months thereafter including at the End of Study and 28-Day Follow-up Visits.
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End point type |
Primary
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End point timeframe |
From Baseline to 28 days following discontinuation of study drug, up to 235 weeks.
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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: This was an open-label extension study, and all participants in the Safety Population received ralinepag. The presented results show the overall change from baseline in WHO/NYHA FC for the Safety Population. |
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| Notes [8] - The number of subjects varied from month to month based on total study population at each visit. |
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End point title |
Time From Randomization to the First Protocol-defined Clinical Worsening Event | ||||||||
End point description |
Clinical worsening events were defined as death, or onset of a treatment-emergent AE with a fatal outcome occurring ≤14 days after treatment discontinuation; hospitalization for worsening PAH, heart-lung or lung transplant, or atrial septostomy; necessity of addition (or dose change) of any prostacyclin/prostacyclin analogue, PDE5-I or sGC stimulator, or ERA; and the combined occurrence of a decrease in 6MWD by at least 20% from Baseline, confirmed on two 6-Minute Walk Tests (6MWTs) on different days; worsening in WHO/NYHA FC from baseline; and appearance of or worsening of signs/symptoms of right heart failure that did not respond to optimized oral diuretic therapy.
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End point type |
Secondary
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End point timeframe |
From Baseline to 28 days following discontinuation of study drug, up to 235 weeks.
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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 |
AEs were recorded for each subject throughout the course of the study from Baseline to 28 days following discontinuation of study drug (up to 235 weeks).
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Adverse event reporting additional description |
Monitoring of AEs was continued up to 30 days after cessation of study drug administration. If an AE was not resolved or stabilized within 30 days, the Sponsor in consultation with the Investigator decided whether to continue to monitor the AE or close out the event in the database. SAEs were monitored until resolution or stabilization.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
23.1
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Reporting groups
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Reporting group title |
Safety Population
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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15 Aug 2014 |
The main changes implemented with this amendment were:
• Added ECG assessments to all dose-titration visits (Weeks 1 to 9), to be completed pre-dose and 2 hours post-dose.
• Moved clinical laboratory assessments from Weeks 4 and 8 to Weeks 5 and 9 and moved serum pregnancy test from Week 4 to Week 5.
• Moved assessment of clinical worsening and WHO/NYHA FC to pre-dose procedures. |
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09 Oct 2017 |
The main changes implemented with this amendment were:
• Secondary objectives: modified text explaining criteria for clinical worsening and added hemodynamics as an efficacy endpoint.
• Changed treatment time from 6 months to indefinite. Information that incremental dose increases are allowed during the Treatment Period was added.
• Added RHC to efficacy assessments. |
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04 Jun 2018 |
The main changes implemented with this amendment were:
• Added plan to transition subjects from IR drug formulation to XR drug formulation.
• Removed placebo capsule information and instruction, added XR tablet information and instruction.
• Added dosing guidance to transition from IR to XR formulation. |
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15 May 2019 |
The main changes implemented with this amendment were:
• Subjects who remain on ralinepag at study termination and meet all eligibility requirements are able to enroll in the Phase 3 open-label extension study (ROR-PH-303).
• Removed stipulation that uptitration of ralinepag should not occur within 6 weeks of an efficacy assessment.
• Removed treatment with inotropes for right ventricular failure as a prohibited medication.
• Changed requirement for assessing subject mortality status from yearly contact following subject discontinuation from the study to contact of all subjects at the time of study termination.
• Changed storage of XR tablet blister cards to 15ºC to 30ºC (59ºF to 86ºF).
• Removed 250 and 400 mcg tablets for oral administration. |
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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. | |||
| None reported | |||
Online references |
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| http://www.ncbi.nlm.nih.gov/pubmed/38198043 |
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