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A Study To Evaluate Safety And Efficacy Of IV Sildenafil In The Treatment Of Neonates With Persistent Pulmonary Hypertension Of The Newborn

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ClinicalTrials.gov Identifier: NCT01720524
Recruitment Status : Completed
First Posted : November 2, 2012
Results First Posted : March 25, 2020
Last Update Posted : November 27, 2020
Sponsor:
Information provided by (Responsible Party):
Pfizer

Tracking Information
First Submitted Date  ICMJE September 17, 2012
First Posted Date  ICMJE November 2, 2012
Results First Submitted Date  ICMJE October 16, 2019
Results First Posted Date  ICMJE March 25, 2020
Last Update Posted Date November 27, 2020
Actual Study Start Date  ICMJE August 5, 2013
Actual Primary Completion Date October 17, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 24, 2020)
  • Time on Inhaled Nitric Oxide (iNO) Treatment After Initiation of Intravenous (IV) Study Drug For Participants Without Treatment Failure [ Time Frame: 14 days from the initiation of IV study drug or hospital discharge, whichever occurs first (maximum of 14 days) ]
    Time in days, on iNO treatment, for participants without iNO treatment failure, was calculated 14 days from the initiation of IV study drug or hospital discharge, whichever occurred first. iNO treatment failure was defined as need for additional treatment targeting PPHN, need for extra corporeal membrane oxygenation (ECMO), or death during the study.
  • Treatment Failure Rate [ Time Frame: 14 days from the initiation of IV study drug or hospital discharge, whichever occurs first (maximum of 14 days) ]
    Treatment failure rate was defined as percentage of participants who needed additional treatment targeting PPHN, needed ECMO, or died during the study.
Original Primary Outcome Measures  ICMJE
 (submitted: October 31, 2012)
  • Time on inhaled nitric oxide treatment after initiation of iv study drug [ Time Frame: Day 14 or hospital discharge ]
  • Treatment failure rate, defined as need for additional treatment targeting persistent pulmonary hypertension of the newborn. [ Time Frame: day 14 or hospital discharge ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: March 24, 2020)
  • Time From Initiation of Intravenous (IV) Study Drug to Final Weaning of Mechanical Ventilation [ Time Frame: 14 days from the initiation of IV study drug or hospital discharge, whichever occurs first (maximum of 14 days) ]
    Time in days, from initiation of IV study drug to final weaning of mechanical ventilation among participants achieving final weaning of mechanical ventilation for PPHN was evaluated. Kaplan-Meier method was used for estimation. For subjects with mechanical ventilation beyond 336 hours (14 days) from initiation of IV study drug, data was censored at 14 days.
  • Time From Initiation of Intravenous (IV) Study Drug to First Treatment Failure [ Time Frame: 14 days from the initiation of IV study drug or hospital discharge, whichever occurs first (maximum of 14 days) ]
    Time in days, from initiation of IV study drug to first treatment failure (defined as need for additional treatment targeting PPHN, need for ECMO, or death) for participants with treatment failure was evaluated. Kaplan-Meier method was used for estimation. For participants without treatment failure by the endpoint assessment date, data was censored at the endpoint assessment date.
  • Percentage of Participants With Individual Components of Treatment Failure [ Time Frame: 14 days from the initiation of IV study drug or hospital discharge, whichever occurs first (maximum of 14 days) ]
    Percentage of participants with individual components of treatment failure (need to start additional treatment targeting PPHN, need to start ECMO, or death) were evaluated. Some participants could have had multiple qualifying events for treatment failure.
  • Change From Baseline in Oxygenation Index (OI) at Hours 6, 12 and 24 Post-Infusion [ Time Frame: Baseline, Hours 6, 12 and 24 after start of infusion ]
    Oxygenation index was calculated as the product of fraction of inspired oxygen (FiO2) and mean airway pressure divided by partial pressure of oxygen dissolved in arterial blood (PaO2) [(FiO2*mean airway pressure)/PaO2] measured in centimeter of water per millimeter of mercury (cmH2O/mmHg). FiO2 is the measure of oxygen concentration that is breathed. Mean airway pressure is defined as an average of the airway pressure throughout the respiratory cycle. PaO2 is the measure of oxygen level dissolved in the arterial blood.
  • Change From Baseline in Differential Saturation at Hours 6, 12 and 24 Post-Infusion [ Time Frame: Baseline, Hours 6, 12 and 24 after start of infusion ]
    Differential oxygenation saturation is a simple way to detect the right-to left shunting at ductus arteriosus using 2 pulse oximeters. It is the difference between pre-ductal and post-ductal sites pulse oxygen saturation (SpO2). Where, pre-duct refers to right upper extremity and post-duct refers to lower limb. Oxygenation saturation is measured as percentage of hemoglobin binding sites occupied by oxygen in the blood.
  • Change From Baseline in Ratio of Partial Pressure of Oxygen in Arterial Blood to Fraction of Inspired Oxygen (P/F) at Hours 6, 12 and 24 [ Time Frame: Baseline, Hours 6, 12 and 24 after start of infusion ]
    The ratio of partial pressure of arterial oxygen to fraction of inspired oxygen is a ratio between the oxygen level in the arterial blood and the oxygen concentration that is breathed. It helps to determine the degree of any problems with how the lungs transfer oxygen to the blood.
  • Maximum Plasma Concentration (Cmax) of Sildenafil and Its Metabolite [ Time Frame: Loading dose, Day 1: prior to the start of infusion, 5, 30 minutes after end of loading infusion; Maintenance dose: 48 to 72, 96 to 120 hours during infusion and immediately prior to end of maintenance infusion (up to maximum on Day 14) ]
    Cmax was obtained for Sildenafil and its major metabolite UK-103,320.
  • Total Plasma Clearance (CL) of Sildenafil and Its Metabolite [ Time Frame: Loading dose: prior to the start of infusion, 5, 30 minutes after end of loading infusion on Day 1; Maintenance dose: between 48 to 72, 96 to 120 hours during infusion and immediately prior to end of infusion on Day 1 ]
    CL is volume of the body fluid/ plasma from which the drug or the metabolite is completely removed per unit time. CL was obtained for Sildenafil and its major metabolite UK-103,320.
  • Central Volume of Distribution (Vc) of Sildenafil and Its Metabolite [ Time Frame: Loading dose: prior to the start of infusion, 5, 30 minutes after end of loading infusion on Day 1; Maintenance dose: between 48 to 72, 96 to 120 hours during infusion and immediately prior to end of infusion on Day 1 ]
    Vc is the hypothetical volume into which a drug or a metabolite initially distributes upon administration. It was determined by using a population-based analysis, non-linear mixed-effects modeling (NONMEM), version 7.4.0. Vc was calculated for Sildenafil and its major metabolite, UK-103,320.
  • Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Baseline up to 31 days after end of study drug infusion (up to 45 days) ]
    An AE was any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. A SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly; medically important events. Treatment-emergent are events between first infusion of study drug and up to 31 days after end of study drug infusion (up to 45 days) that were absent before treatment or that worsened relative to pretreatment state. AEs included both SAEs and non-SAEs.
  • Number of Treatment-Emergent Adverse Events (AEs) According to Severity [ Time Frame: Baseline up to 31 days after end of study drug infusion (up to 45 days) ]
    AE: untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. SAE: AE resulting in any of the following outcomes: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly; medically important events. Treatment-emergent are events between first infusion of study drug and up to 31 days after end of study drug infusion (up to 45 days) that were absent before treatment or that worsened relative to pretreatment state. AEs included both SAEs and non-SAEs. Severity criteria: mild=did not interfere with subject's usual function; moderate=interfered to some extent with participant's usual function and severe=interfered significantly with participant's usual function. Missing baseline severities were imputed as mild.
  • Number of Participants With Laboratory Abnormalities [ Time Frame: Up to 14 days from initiation of study drug infusion ]
    Criteria for laboratory values: Hematology: hemoglobin, hematocrit, red blood cell count <0.8*lower limit of normal (LLN), platelets<0.5*LLN, >1.75*upper limit of normal (ULN), white blood cells count <0.6*LLN, >1.5*ULN; Liver function: total and direct bilirubin >1.5*ULN, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase >3.0*ULN, total protein <0.8*LLN, >1.2*ULN; Renal function: blood urea nitrogen, creatinine >1.3*ULN; Electrolytes: sodium <0.95*LLN, >1.05*ULN, potassium, chloride, calcium, bicarbonate (venous) <0.9*LLN, >1.1*ULN.
  • Part B: Developmental Progress of Participants as Assessed by Bayley Scales of Infant Development and Behavior Questionnaire [ Time Frame: Months 12 and 24 after end of study treatment Part A ]
    The results for this outcome measure shall be reported when all participants have completed or discontinued from the 2-year follow-up visit (at the end of 2020).
  • Part B: Visual Status of Participants as Assessed by Eye Examinations of the Anterior and Posterior Segments [ Time Frame: Months 12 and 24 after end of study treatment Part A ]
    The results for this outcome measure shall be reported when all participants have completed or discontinued from the 2-year follow-up visit (at the end of 2020).
  • Part B: Audiological Status of Participants as Assessed by Physiological and Behavioral Tests [ Time Frame: Months 12 and 24 after end of study treatment Part A ]
    The results for this outcome measure shall be reported when all participants have completed or discontinued from the 2-year follow-up visit (at the end of 2020).
  • Part B: Safety Assessed by Adverse Events and Survival [ Time Frame: Months 12 and 24 after end of study treatment Part A ]
    The results for this outcome measure shall be reported when all participants have completed or discontinued from the 2-year follow-up visit (at the end of 2020).
  • Part B: Neurological Progress of Participants as Assessed by the Neurology Optimality Score [ Time Frame: Months 12 and 24 after end of study treatment Part A ]
    The results for this outcome measure shall be reported when all participants have completed or discontinued from the 2-year follow-up visit (at the end of 2020).
Original Secondary Outcome Measures  ICMJE
 (submitted: October 31, 2012)
  • Time to final weaning of mechanical ventilation for persistent pulmonary hypertension of the newborn [ Time Frame: Day 14 or hospital discharge ]
  • Time from initiation of study drug to treatment failure [ Time Frame: Day 14 or hospital discharge ]
  • Change in oxygenation parameters at 6, 12, and 24 hours from baseline [ Time Frame: Day 14 or hospital discharge ]
  • Sildenafil plasma concentrations and corresponding PK parameters [ Time Frame: Day 14 or hospital discharge ]
  • Safety parameters: incidence and severity of adverse events and abnormal laboratory parameters [ Time Frame: Day 14 or hospital discharge ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Study To Evaluate Safety And Efficacy Of IV Sildenafil In The Treatment Of Neonates With Persistent Pulmonary Hypertension Of The Newborn
Official Title  ICMJE A MULTI-CENTRE, RANDOMIZED, PLACEBO-CONTROLLED, DOUBLE-BLIND, TWO-ARMED, PARALLEL GROUP STUDY TO EVALUATE EFFICACY AND SAFETY OF IV SILDENAFIL IN THE TREATMENT OF NEONATES WITH PERSISTENT PULMONARY HYPERTENSION OF THE NEWBORN (PPHN) OR HYPOXIC RESPIRATORY FAILURE AND AT RISK FOR PPHN, WITH A LONG TERM FOLLOW-UP INVESTIGATION OF DEVELOPMENTAL PROGRESS 12 AND 24 MONTHS AFTER COMPLETION OF STUDY TREATMENT
Brief Summary This study will evaluate whether IV sildenafil can reduce the time on inhaled nitric oxide treatment and reduce the failure rate of available treatments for persistent pulmonary hypertension of the newborn.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Pulmonary Hypertension, Familial Persistent, of the Newborn
Intervention  ICMJE
  • Drug: placebo
    IV placebo or 0.9% sodium chloride or 10% dextrose. Infusion rate based on weight.
  • Drug: iv sildenafil
    loading dose of 0.1 mg/kg over 30 minutes followed by maintenance dose of 0.03 mg/kg/h. To infuse minimum 48 hours and maximum of 14 days.
    Other Name: revatio
Study Arms  ICMJE
  • Placebo Comparator: placebo
    iv placebo of normal saline or 10% dextrose
    Intervention: Drug: placebo
  • Experimental: sildenafil
    Active study drug
    Intervention: Drug: iv sildenafil
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: February 22, 2019)
59
Original Estimated Enrollment  ICMJE
 (submitted: October 31, 2012)
64
Actual Study Completion Date  ICMJE September 28, 2020
Actual Primary Completion Date October 17, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Neonates with persistent pulmonary hypertension of the newborn
  • Age <=96 hours and >=34 weeks gestational age
  • Oxygenation Index >15 and <60
  • Concurrent treatment with inhaled nitric oxide and >=50% oxygen

Exclusion Criteria:

  • Prior or immediate need for extracorporeal membrane oxygenation or cardiopulmonary resuscitation
  • Expected duration of mechanical ventilation <48 hours
  • Profound hypoxemia
  • Life-threatening or lethal congenital anomaly
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE up to 4 Days   (Child)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Belgium,   Canada,   Denmark,   France,   Germany,   Italy,   Netherlands,   Norway,   Spain,   Sweden,   United Kingdom,   United States
Removed Location Countries Austria
 
Administrative Information
NCT Number  ICMJE NCT01720524
Other Study ID Numbers  ICMJE A1481316
2012-002619-24 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.
URL: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests
Responsible Party Pfizer
Study Sponsor  ICMJE Pfizer
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Pfizer CT.gov Call Center Pfizer
PRS Account Pfizer
Verification Date November 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP