Clinical Trial Results:
A 7-Day, Open-Label, Multicenter, Pharmacokinetic (PK) Study (Part 1) Followed by A 7-Day, Randomized, Multicenter, Double-Blind, Placebo-Controlled, Dose-Ranging, Parallel Group Study (Part 2) of Intravenous (IV) Sildenafil in the Treatment of Neonates With Persistent Pulmonary Hypertension of the Newborn (PPHN) or Hypoxic Respiratory Failure and at Risk for PPHH
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Summary
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EudraCT number |
2014-004166-23 |
Trial protocol |
Outside EU/EEA |
Global end of trial date |
16 May 2005
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Results information
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Results version number |
v1(current) |
This version publication date |
25 May 2016
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First version publication date |
05 Aug 2015
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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 |
A1481157
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Pfizer Inc.
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Sponsor organisation address |
235 E 42nd Street, New York, United States, NY 10017
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Public contact |
Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc. , 001 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com
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Scientific contact |
Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc. , 001 8007181021, ClinicalTrials.gov_Inquiries@pfizer.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-000671-PIP01-09 | ||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
Yes
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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 |
28 Apr 2006
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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 |
16 May 2005
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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 |
1. To evaluate the pharmacokinetics (PK) of intravenous (IV) sildenafil in near-term and term newborns with Persistent Pulmonary Hypertension of the Newborn (PPHN) or with hypoxic respiratory failure and at risk for PPHN to determine doses for Part 2 of the study (Part1).
2. To determine the efficacy of IV sildenafil in near-term and term newborns with PPHN or with hypoxic respiratory failure and at risk for PPHN (Part 2 ).
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Protection of trial subjects |
The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
02 Nov 2003
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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 |
France: 4
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Country: Number of subjects enrolled |
United Kingdom: 9
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Country: Number of subjects enrolled |
United States: 23
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Worldwide total number of subjects |
36
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EEA total number of subjects |
13
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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) |
36
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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) |
0
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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 |
- | ||||||||||||||
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Pre-assignment
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Screening details |
The study was initiated on 02 November 2003 and ended on 16 May 2005 in France, United Kingdom and United States. | ||||||||||||||
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Period 1
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Period 1 title |
Sildenafil (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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Sildenafil | ||||||||||||||
Arm description |
Subjects received loading dose of sildenafil infusion intravenously over 5 min (minutes) (treatment group 1), over 30 min (treatment groups 2-6), and over 180 min (treatment group 8) on Day 1, followed by a maintenance dose infused continuously at reduced rate for up to and no more than 7 days. Treatment group 7 did not receive a loading dose, the sildenafil infusion was begun at the reduced rate of the maintenance dose. Doses were escalated for each of the subsequent treatment group based on PK data from the previous treatment group. The rate of infusion was weight dependent. | ||||||||||||||
Arm type |
Experimental | ||||||||||||||
Investigational medicinal product name |
Sildenafil
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Subjects received loading dose of sildenafil infusion intravenously on Day 1 as 0.008±0.005 milligram per kilogram (mg/kg) over 5 min (treatment group 1), 0.011±0.0005 mg/kg to 0.243±0.03 mg/kg over 30 min (treatment groups 2-6), 0.427±0.046 mg/kg over 180 min (treatment group 8) followed by maintenance dose infused continuously at reduced rate for up to and no more than 7 days as 0.07 mg/kg/day (treatment group 1), 0.08 ±0.003 mg/kg/day to 1.59±0.302 mg/kg/day (treatment groups 2-6), 1.64±0.17 mg/kg/day (treatment group 8). Treatment group 7 did not receive a loading dose, the sildenafil infusion was begun at the reduced rate of the maintenance dose of 1.64±0.17 mg/kg/day. Doses were escalated for each of the subsequent treatment group based on PK data from the previous treatment group. The rate of infusion was weight dependent.
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Baseline characteristics reporting groups
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Reporting group title |
Sildenafil
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Reporting group description |
Subjects received loading dose of sildenafil infusion intravenously on Day 1 as 0.008±0.005 mg/kg over 5 min (treatment group 1), 0.011±0.0005 mg/kg to 0.243±0.03 mg/kg over 30 min (treatment groups 2-6), 0.427±0.046 mg/kg over 180 min (treatment group 8) followed by maintenance dose infused continuously at reduced rate for up to and no more than 7 days as 0.07 mg/kg/day (treatment group 1), 0.08±0.003 mg/kg/day to 1.59±0.302 mg/kg/day (treatment groups 2-6), 1.64±0.17 mg/kg/day (treatment group 8). Treatment group 7 did not receive a loading dose, the sildenafil infusion was begun at the reduced rate of the maintenance dose of 1.64±0.17 mg/kg/day. Doses were escalated for each of the subsequent treatment group based on PK data from the previous treatment group. The rate of infusion was weight dependent. | |||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Sildenafil
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Reporting group description |
Subjects received loading dose of sildenafil infusion intravenously over 5 min (minutes) (treatment group 1), over 30 min (treatment groups 2-6), and over 180 min (treatment group 8) on Day 1, followed by a maintenance dose infused continuously at reduced rate for up to and no more than 7 days. Treatment group 7 did not receive a loading dose, the sildenafil infusion was begun at the reduced rate of the maintenance dose. Doses were escalated for each of the subsequent treatment group based on PK data from the previous treatment group. The rate of infusion was weight dependent. | ||
Subject analysis set title |
UK-103320
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
UK-103320 is the metabolite of sildenafil produced via biotransformation.
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Subject analysis set title |
iNO or ECMO
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
Subjects received standard therapy (inhaled nitrogen oxide [iNO] or extracorporeal membrane oxygen [ECMO]) as a concomitant medication during the study.
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Subject analysis set title |
Standard Therapy (iNO)
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
Subjects received standard therapy (iNo) as a concomitant medication during the study.
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End point title |
Plasma Concentration of Sildenafil (Part 1) [1] | ||||||||
End point description |
Thirty Five subjects of safety population included those subjects who have received study medication during the Part 1 of the study. Results of plasma concentration of sildenafil were not summarized. Hence it has been reported as a graphical presentation attached as Plasma concentration of Sildenafil.pdf.
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End point type |
Primary
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End point timeframe |
5, 30 minutes post-infusion; every 24 hours from start of infusion; before end of infusion; at 1, 4, 8, 12, 24, 48, 72 hours post-infusion in Part 1
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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 statistical analysis was planned to be analyzed for this outcome. |
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Attachments |
Untitled (Filename: Plasma concentration of Sildenafi.pdf) |
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| Notes [2] - Data for this outcome was presented graphically as data was not summarized. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Plasma Concentration of UK-103320 (Part 1) [3] | ||||||||
End point description |
Thirty Five subjects of safety population included those subjects who have received study medication during the Part 1 of the study. Results of plasma concentration of UK-103320 were not summarized. Hence it has been reported as a graphical presentation attached as plasma concentration of UK-103320.pdf.
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End point type |
Primary
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End point timeframe |
5, 30 minutes post-infusion; every 24 hours from start of infusion; before end of infusion; at 1, 4, 8, 12, 24, 48, 72 hours post-infusion in Part 1
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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 statistical analysis was planned to be analyzed for this outcome. |
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Attachments |
Untitled (Filename: Plasma Concentration of UK-103320.pdf) |
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| Notes [4] - Data for this outcome was presented graphically as data was not summarized. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Population Pharmacokinetics of Sildenafil and UK-103320 (Part 1): Clearance (Cl) [5] | ||||||||||||
End point description |
Cl is a quantitative measure of the rate at which a drug substance is removed from the body. 1 and 2 compartmental PK models were used to evaluate Cl as population PK. The safety population for Part 1 included all subjects who had received study medication.
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End point type |
Primary
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End point timeframe |
5, 30 minutes post-infusion; every 24 hours from start of infusion; before end of infusion; at 1, 4, 8, 12, 24, 48, 72 hours post-infusion in Part 1
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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 statistical analysis was planned to be analyzed for this outcome. |
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| Notes [6] - Number of subjects analyzed signifies those subjects who were evaluable for this measure. [7] - Number of subjects analyzed signifies those subjects who were evaluable for this measure. |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Population Pharmacokinetics of Sildenafil and UK-103320 (Part 1): Central Volume of Distribution (V1) [8] | ||||||||||||
End point description |
V1 is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug. 1 and 2 compartmental PK models were used to evaluate V1 as population PK. The safety population for Part 1 included all subjects who had received study medication.
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End point type |
Primary
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End point timeframe |
5, 30 minutes post-infusion; every 24 hours from start of infusion; before end of infusion; at 1, 4, 8, 12, 24, 48, 72 hours post-infusion in Part 1
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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 statistical analysis was planned to be analyzed for this outcome. |
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| Notes [9] - Number of subjects analyzed signifies those subjects who were evaluable for this measure. [10] - Number of subjects analyzed signifies those subjects who were evaluable for this measure. |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Population Pharmacokinetics of Sildenafil and UK-103320 (Part 1): Peripheral Volume of Distribution(V2) [11] | ||||||||||||
End point description |
V2 is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug. 1 and 2 compartmental PK models were to evaluate V2 as population PK. The safety population for Part 1 included all subjects who had received study medication.
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End point type |
Primary
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End point timeframe |
5, 30 minutes post-infusion; every 24 hours from start of infusion; before end of infusion; at 1, 4, 8, 12, 24, 48, 72 hours post-infusion in Part 1
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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 statistical analysis was planned to be analyzed for this outcome. |
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| Notes [12] - Number of subjects analyzed signifies those subjects who were evaluable for this measure. [13] - Number of subjects analyzed signifies those subjects who were evaluable for this measure. |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Population Pharmacokinetics of Sildenafil and UK-103320 (Part 1): Inter-Compartmental Clearance (Q) [14] | ||||||||||||
End point description |
Q is a quantitative measure of the rate at which a drug substance is removed from the body. 1 and 2 compartmental PK models were used to evaluate Q as population PK. The safety population for Part 1 included all subjects who had received study medication.
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End point type |
Primary
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End point timeframe |
5, 30 minutes post-infusion; every 24 hours from start of infusion; before end of infusion; at 1, 4, 8, 12, 24, 48, 72 hours post-infusion in Part 1
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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 statistical analysis was planned to be analyzed for this outcome. |
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| Notes [15] - Number of subjects analyzed signifies those subjects who were evaluable for this measure. [16] - Number of subjects analyzed signifies those subjects who were evaluable for this measure. |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Number of Subjects who Received Standard Therapy (Inhaled Nitrogen Oxide [iNO] or Extracorporeal Membrane Oxygen [ECMO]): Part 2 [17] | ||||||
End point description |
Results for this outcome have not been reported since Part 2 of the study was not conducted due to premature termination of the study.
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End point type |
Primary
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End point timeframe |
Baseline up to 7 days in Part 2
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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 statistical analysis was planned to be analyzed for this outcome. |
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| Notes [18] - Data for this outcome was not reported since the study (Part 2) was terminated prematuraley. |
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| No statistical analyses for this end point | |||||||
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End point title |
Total Duration of Standard Therapy (inhaled nitrogen oxide [iNO]) Therapy: Part 2 | ||||||||
End point description |
Results for this measure have not been reported since Part 2 was not conducted due to premature termination of the study.
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End point type |
Secondary
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End point timeframe |
Baseline up to 7 days in Part 2
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| Notes [19] - Data for this outcome was not reported since the study (Part 2) was terminated prematurely. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Time From Initiation of Study Drug to Receipt of Standard Therapy (inhaled nitrogen oxide [iNO] or extracorporeal membrane oxygen [ECMO]): Part 2 | ||||||||
End point description |
Results for this measure have not been reported since Part 2 was not conducted due to premature termination of the study.
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End point type |
Secondary
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End point timeframe |
Baseline up to 7 days in Part 2
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| Notes [20] - Data for this outcome was not reported since the study (Part 2) was terminated prematurely. |
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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 |
Baseline up to 7 days (end of study treatment) in Part 1
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Adverse event reporting additional description |
The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
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Assessment type |
Non-systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
17.1
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Reporting groups
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Reporting group title |
Sildenafil
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Reporting group description |
Subjects received loading dose of sildenafil infusion intravenously on Day 1 as 0.008±0.005 mg/kg over 5 min (treatment group 1), 0.011±0.0005 mg/kg to 0.243±0.03 mg/kg over 30 min (treatment groups 2-6), 0.427±0.046 mg/kg over 180 min (treatment group 8) followed by maintenance dose infused continuously at reduced rate for up to and no more than 7 days as 0.07 mg/kg/day (treatment group 1), 0.08±0.003 mg/kg/day to 1.59±0.302 mg/kg/day (treatment groups 2-6), 1.64±0.17 mg/kg/day (treatment group 8). Treatment group 7 did not receive a loading dose, the sildenafil infusion was begun at the reduced rate of the maintenance dose of 1.64±0.17 mg/kg/day. Doses were escalated for each of the subsequent treatment group based on PK data from the previous treatment group. The rate of infusion was weight dependent. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 0% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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16 Dec 2003 |
Changed the loading dose duration from a 5 minute to a 30 minute infusion. |
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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. | |||
| Study part 2 was not performed. Use of inhaled NO to treat persistent pulmonary hypertension of newborn suggested that indication for sildenafil monotherapy may not be possible. A primary endpoint to support labelled indication has yet to be defined. | |||
