Clinical Trial Results:
A Multicenter, Single-arm, Open-label, Phase 3b Study to Assess the Effects of Switching From Flolan® to ACT-385781A in Patients with Pulmonary Arterial Hypertension
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Summary
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EudraCT number |
2010-018322-40 |
Trial protocol |
FR BE NL ES IT |
Global end of trial date |
02 Feb 2012
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Results information
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Results version number |
v1(current) |
This version publication date |
17 Jun 2017
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First version publication date |
17 Jun 2017
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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 |
AC-066A301
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01431716 | ||
WHO universal trial number (UTN) |
- | ||
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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 |
Global Scientific Information, Actelion Pharmaceuticals Ltd, medinfo@actelion.com
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Scientific contact |
Global Scientific Information, Actelion Pharmaceuticals Ltd, medinfo@actelion.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 |
26 Mar 2012
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
02 Feb 2012
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Global end of trial reached? |
Yes
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Global end of trial date |
02 Feb 2012
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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 |
To evaluate the change in cardiac hemodynamics from baseline to 3-month following switch from Flolan® to EFI in patients with pulmonary arterial hypertension (PAH).
To evaluate the safety and tolerability of switching from Flolan® to EFI in patients with PAH.
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Protection of trial subjects |
The clinical trial was designed and conducted in accordance with the ICH Harmonized Tripartite Guidelines for GCP, with applicable local regulations, including the European Directive 2001/20/EC, the US CFR Title 21, and with the ethical principles laid down in the Declaration of Helsinki.
The protocol, the amendments and any material provided to the patient (such as a patient information sheet or description of the study used to obtain informed consent) were reviewed and approved by the appropriate IEC before the study was started.
The investigator ensured that this study was conducted in full compliance with the
principles of the ‘Declaration of Helsinki’ and its amendments, and with the laws and
regulations of the country in which the clinical research was conducted. A copy of the
Declaration of Helsinki and International Conference on Harmonisation – Good Clinical
Practice (ICH-GCP) Guidelines was provided to each investigational site.
Written informed consent was obtained from each individual participating in the study
prior to any study procedure and after adequate explanation of the objectives, methods,
and potential hazards of the study.
During the 90-day treatment period, there were visits to the clinic on week 1, 4, and 12, and phone calls from the clinic to the patient on weeks 2, 3, 6, 8, 10 and 16, and on Day 91.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
15 Mar 2011
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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 |
Belgium: 5
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Country: Number of subjects enrolled |
Canada: 8
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Country: Number of subjects enrolled |
France: 20
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Country: Number of subjects enrolled |
Italy: 2
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Country: Number of subjects enrolled |
Netherlands: 4
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Country: Number of subjects enrolled |
Spain: 2
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Worldwide total number of subjects |
41
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EEA total number of subjects |
33
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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) |
38
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From 65 to 84 years |
3
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85 years and over |
0
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Recruitment
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Recruitment details |
Patients were enrolled at eight centers in the European Union and Canada. First patient, first visit was 15 March 2011 and last patient, last visit was 2 February 2012. | ||||||
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Pre-assignment
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Screening details |
Patients must have PAH and have been treated with Flolan for at least 12 months and on a stable dose for at least 3 months prior to enrollment. There was a screening period of up to 14 days. | ||||||
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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 | ||||||
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Arms
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Arm title
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Epoprostenol for injection (EFI/ACT-385781A) | ||||||
Arm description |
- | ||||||
Arm type |
Experimental | ||||||
Investigational medicinal product name |
Epoprostenol for Injection
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Investigational medicinal product code |
ACT-385781A
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Other name |
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Pharmaceutical forms |
Solution for injection/infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
continuous intravenous
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Baseline characteristics reporting groups
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Reporting group title |
Overall study
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Reporting group description |
Treatment | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
All-treated set
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Subject analysis set type |
Full analysis | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
Patients with at least one dose of study medication
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Subject analysis set title |
Per-protocol set
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Subject analysis set type |
Per protocol | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
Treated patients who had a pulmonary vascular resistance (PVR) value at baseline and at end of treatment (EOT) and who did not deviate from the protocol in a way that might have affected the evaluation of PVR. This set was used for a supportive analysis of PVR only.
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End points reporting groups
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Reporting group title |
Epoprostenol for injection (EFI/ACT-385781A)
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Reporting group description |
- | ||
Subject analysis set title |
All-treated set
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
Patients with at least one dose of study medication
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Subject analysis set title |
Per-protocol set
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
Treated patients who had a pulmonary vascular resistance (PVR) value at baseline and at end of treatment (EOT) and who did not deviate from the protocol in a way that might have affected the evaluation of PVR. This set was used for a supportive analysis of PVR only.
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End point title |
Not applicable [1] | ||||||
End point description |
No primary endpoint was defined.As it is an exploratory study, all efficacy endpoints were considered as exploratory endpoints
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End point type |
Primary
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End point timeframe |
Not applicable
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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 exploratory study. No statistical analysis has been specified. |
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| Notes [2] - Not applicable |
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| No statistical analyses for this end point | |||||||
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End point title |
Change in PVR from baseline to EOT. | ||||||||||||||||||||||||||||
End point description |
Right heart catheterization was performed for cardiac hemodynamic assessment at Screening or Day 1, prior to switch from Flolan® to EFI/ACT-385781A and at EOT.
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End point type |
Other pre-specified
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End point timeframe |
From baseline to 3 months
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||
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End point title |
Change in total pulmonary resistance from baseline to EOT. | ||||||||||||||
End point description |
Right heart catheterization was performed for cardiac hemodynamic assessment at Screening or Day 1, prior to switch from Flolan® to EFI/ACT-385781A and at EOT.
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End point type |
Other pre-specified
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End point timeframe |
Approximately 3 months
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| No statistical analyses for this end point | |||||||||||||||
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End point title |
Change in mean pulmonary arterial pressure from baseline to EOT. | ||||||||||||||
End point description |
Right heart catheterization was performed for cardiac hemodynamic assessment at Screening or Day 1, prior to switch from Flolan® to EFI/ACT-385781A and at EOT.
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End point type |
Other pre-specified
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End point timeframe |
Approximately 3 months
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| No statistical analyses for this end point | |||||||||||||||
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End point title |
Change in mean right atrial pressure from baseline to EOT. | ||||||||||||||
End point description |
Right heart catheterization was performed for cardiac hemodynamic assessment at Screening or Day 1, prior to switch from Flolan® to EFI/ACT-385781A and at EOT.
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End point type |
Other pre-specified
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End point timeframe |
Approximately 3 months
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| No statistical analyses for this end point | |||||||||||||||
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End point title |
Change in pulmonary capillary wedge pressure from baseline to EOT. | ||||||||||||||
End point description |
Right heart catheterization was performed for cardiac hemodynamic assessment at Screening or Day 1, prior to switch from Flolan® to EFI/ACT-385781A and at EOT.
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End point type |
Other pre-specified
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End point timeframe |
Approximately 3 months
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| No statistical analyses for this end point | |||||||||||||||
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End point title |
Change in mean cardiac index from baseline to EOT. | ||||||||||||||
End point description |
Right heart catheterization was performed for cardiac hemodynamic assessment at Screening or Day 1, prior to switch from Flolan® to EFI/ACT-385781A and at EOT.
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End point type |
Other pre-specified
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End point timeframe |
Approximately 3 months
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| No statistical analyses for this end point | |||||||||||||||
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End point title |
Change in 6-minute walk distance (6MWD) from baseline to EOT. | ||||||||||||||
End point description |
The 6MWD was assessed at Screening or Day 1, prior to switch from Flolan® to EFI/ACT-385781A and at EOT. The 6-minute walk test is a non-encouraged test that measures the distance walked for the duration of 6 min.
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End point type |
Other pre-specified
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End point timeframe |
Approximately 3 months
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| No statistical analyses for this end point | |||||||||||||||
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End point title |
Change in Borg dyspnea score from baseline to EOT. | ||||||||||||||
End point description |
The Borg dyspnea score was assessed at Screening or Day 1, prior to switch from Flolan® to EFI/ACT-385781A and at EOT. The Borg scale is a category-ratio scale, commonly used to evaluate the effects of exercise on dyspnea. The original and modified scales have ratio properties ranging from 0 = nothing at all to 10 = very, very severe, with descriptors from 0 to 10. Descriptors have been modified by others so that 10 has been labelled "extremely severe," or "the worst possible dyspnea imaginable."
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End point type |
Other pre-specified
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End point timeframe |
Approximately 3 months
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| No statistical analyses for this end point | |||||||||||||||
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End point title |
Number of participants with Improved, No Change, or Worsening of New York Heart Association Functional Class (NYHA FC) from baseline to EOT. | ||||||||||||
End point description |
NYHA FC was assessed at Screening or Day 1, prior to switch from Flolan® to EFI/ACT-385781A and at EOT. Disease severity was assessed by NYHA classification of pulmonary arterial hypertension criteria: Class I: no limitation of physical activity (PA). Ordinary PA: no undue dyspnea/fatigue, chest pain, near syncope. Class II: slight limitation of PA. Comfortable at rest. Ordinary PA: undue dyspnea/fatigue, chest pain, near syncope. Class III: marked limitation of PA. Comfortable at rest. Less than ordinary PA: undue dyspnea/fatigue, chest pain, near syncope. Class IV: inability to carry out PA without symptoms. Right heart failure. Dyspnea/fatigue may even have been present at rest. Discomfort increased by any PA.
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End point type |
Other pre-specified
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End point timeframe |
Approximately 3 months
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Change in N-terminal pro-B-type natriuretic peptide (NT proBNP) from baseline to EOT. | ||||||||||||||
End point description |
Blood sampling for NT proBNP was performed at Screening or Day 1, prior to switch from Flolan® to EFI/ACT-385781A and at EOT.
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End point type |
Other pre-specified
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End point timeframe |
Approximately 3 months
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| No statistical analyses for this end point | |||||||||||||||
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End point title |
Change in Effectiveness Score of the Abbreviated Treatment Satisfaction Questionnaire for Medication (TSQM-9) from Baseline to EOT. | ||||||||||||||
End point description |
Patients were required to complete the TSQM-9 questionnaire at Screening or Day 1, prior to switch from Flolan® to EFI/ACT-385781A and at EOT. The TSQM-9 is a validated instrument to assess patients' satisfaction with medication, including a three question effectiveness scale. The TSQM-9 domain scores range from 0 to 100 with higher scores representing higher satisfaction on that domain.
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End point type |
Other pre-specified
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End point timeframe |
Approximately 3 months
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| No statistical analyses for this end point | |||||||||||||||
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End point title |
Change in Convenience Score of the Abbreviated Treatment Satisfaction Questionnaire for Medication (TSQM-9) from Baseline to EOT. | ||||||||||||||
End point description |
Patients were required to complete the TSQM-9 questionnaire at Screening or Day 1, prior to switch from Flolan® to EFI/ACT-385781A and at EOT. The TSQM-9 is a validated instrument to assess patients' satisfaction with medication, including a three question convenience scale. The TSQM-9 domain scores range from 0 to 100 with higher scores representing higher satisfaction on that domain.
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End point type |
Other pre-specified
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End point timeframe |
Approximately 3 months
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| No statistical analyses for this end point | |||||||||||||||
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End point title |
Change in Global Satisfaction Score of the Abbreviated Treatment Satisfaction Questionnaire for Medication (TSQM-9) from Baseline to EOT. | ||||||||||||||
End point description |
Patients were required to complete the TSQM-9 questionnaire at Screening or Day 1, prior to switch from Flolan® to EFI/ACT-385781A and at EOT. The TSQM-9 is a validated instrument to assess patients' satisfaction with medication, including a three question global satisfaction scale. The TSQM-9 domain scores range from 0 to 100 with higher scores representing higher satisfaction on that domain.
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End point type |
Other pre-specified
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End point timeframe |
Approximately 3 months
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| No statistical analyses for this end point | |||||||||||||||
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End point title |
Number of participants with adverse events leading to discontinuation of study drug from baseline to EOT. | ||||||
End point description |
Adverse events that led to discontinuation of study drug from the start of study treatment until the end of study treatment were recorded.
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End point type |
Other pre-specified
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End point timeframe |
Approximately 3 months
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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 |
All adverse events (AEs) that occurred from the start of study treatment until 24 h after the end of study treatment were recorded. In addition, all serious AEs that occurred up to 30 days after the end of study treatment were also recorded.
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Adverse event reporting additional description |
All treated set
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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 |
14
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Reporting groups
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Reporting group title |
EFI/ACT-385781A
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Reporting group description |
EFI/ACT-385781A administered by continuous intravenous infusion via a central venous catheter using an ambulatory infusion pump. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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01 Nov 2010 |
1. A modification to the formulation of the
study drug and resulting changes to its
stability, availability and its name were
described:
– Changes in study drug excipients
were described. In contrast to the
previous formulation (EFI1), this
new formulation (EFI2) has not
been approved by FDA.
– Instructions for study drug
packaging, and preparation,
handling and storage of the study
drug solution were updated
accordingly.
– The drug name was changed to
Epoprostenol for injection (EFI).
– An additional dose strength of
0.5 mg was added.
2. The numbers of participating countries
and of patients to be enrolled were
increased from 20 to 25–35 patients.
3. Changes were made in the core patient
information and informed consent form.
4. Some editorial changes were made for
clarification and to correct typing errors.
5. The authors of the protocol and the
sponsor’s contact details and signatories
were changed. |
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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 | |||
