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

Phase 3

Completed

Conditions: Pulmonary Hypertension, Familial Persistent, of the Newborn

Interventions: Drug: placebo
Drug: iv sildenafil

Registration Number: NCT01720524

Lead Sponsor: Pfizer's Upjohn has merged with Mylan to form Viatris Inc.

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 available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 59

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
placebo	placebo	iv placebo of normal saline or 10% dextrose
sildenafil	iv sildenafil	Active study drug

Primary Outcome Measures

Name	Time	Method
Time on Inhaled Nitric Oxide (iNO) Treatment After Initiation of Intravenous (IV) Study Drug For Participants Without Treatment Failure	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	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.

Secondary Outcome Measures

Name	Time	Method
Percentage of Participants With Individual Components of Treatment Failure	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 Differential Saturation at Hours 6, 12 and 24 Post-Infusion	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.
Time From Initiation of Intravenous (IV) Study Drug to First Treatment Failure	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.
Change From Baseline in Oxygenation Index (OI) at Hours 6, 12 and 24 Post-Infusion	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.
Total Plasma Clearance (CL) of Sildenafil and Its Metabolite	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	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.
Time From Initiation of Intravenous (IV) Study Drug to Final Weaning of Mechanical Ventilation	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 participants with mechanical ventilation beyond 336 hours (14 days) from initiation of IV study drug, data was censored at 14 days.
Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)	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.
Part B: Visual Acuity of Verbal Participants as Assessed by Ophthalmological Assessment	Month 12 and 24 after end of study treatment in Part A (Day 1 to 14)	Standard age-appropriate ophthalmological examinations were used to assess visual acuity (performed differently for children able of verbal interaction) through visual acuity chart (VAC) quantitative, counting finger (CF), hand motion (HM), light perception (LP), no light perception (NLP) and missing at month 12 and 24. In this outcome measure, data have been reported for right and left eye separately. Rows according to visual acuity categories at specified time points are reported in this outcome measure, only when there was a non-zero data for at least 1 reporting arm.
Number of Participants With Laboratory Abnormalities	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: Composite Scores of Social-Emotional and Adaptive Behavior Questionnaire as Assessed by Bayley Scales of Infant and Toddler Development Third Edition (Bayley-III)	Month 24 after end of study treatment in Part A (Day 1 to 14)	The Bayley-III assesses infant and toddler development across five domains: cognitive, language, motor, social-emotional (SE), and adaptive behavior (AB). Assessments of the cognitive, language, and motor domains conducted using items administered to the child; assessments of the SE and AB domains conducted using the primary caregiver's responses to a questionnaire. The questionnaire comprises the SE scale (35 items) and the AB scale (241 items). Raw scores of SE and AB were converted to composite scores. Composite scores for SE and AB scale ranged from 40 to 160, where higher scores indicated better social-emotional skills and adaptive behavior in child. In this outcome measure composite scores for parent/caregiver were reported at month 24.
Part B: Number of Participants With Eye Movement Disorders as Assessed by Eye Examination	Month 12 and 24 after end of study treatment in Part A (Day 1 to 14)	Standard age-appropriate ophthalmological examinations were used to assess eye movement disorders (presence of amblyopia, strabismus, and nystagmus) at month 12 and 24. In this outcome measure, data have been reported for right and left eye separately. Rows according to eye movement disorder categories at specified time points are reported in this outcome measure, only when there was a non-zero data for at least 1 reporting arm.
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	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.
Part B: Composite Scores of Cognitive, Language, and Motor Developmental Progress of Participants as Assessed by Bayley Scales of Infant and Toddler Development Third Edition (Bayley-III)	Month 12 and 24 after end of study treatment in Part A (Day 1 to 14)	Bayley-III assesses infant and toddler development across five domains: cognitive, language, motor, social-emotional (SE), and adaptive behavior (AB). Assessments of the cognitive, language, and motor domains conducted using items administered to the child; assessments of the SE and AB domains conducted using the primary caregiver's responses to a questionnaire. Score ranges: cognitive scale 0-91, language scale 0-97 and motor scale 0-132, where higher scores indicated better cognitive function, communication and motor skills respectively. Raw scores of cognitive, language and motor domains were converted to composite scores. Composite scores of cognitive, language and motor developmental scales ranged from a scale of 40 to 160, where higher score indicated stronger skills and abilities. In this outcome measure composite scores for infants and toddlers were reported at month 12 and 24.
Part B: Visual Acuity of Verbal Participants as Assessed by LogMAR Through Visual Acuity Chart	Month 12 and 24 after end of study treatment in Part A (Day 1 to 14)	Standard age-appropriate ophthalmological examinations were used to assess visual acuity (performed differently for children able of verbal interaction) at month 12 and 24. Visual acuity (VA) of verbal children was assessed for each eye using the Snellen method, where logarithm of minimum angle of resolution (logMAR) units were derived from the Snellen ratios. Participants had to read letters from the chart at a distance of 20 feet/6 meter or 4 meter. VA (Snellen ratio) = distance between the chart and participant, divided by distance at which participant was able to see/read chart without impairment; expressed as decimal, logMAR = log10 (1/decimal VA). In this outcome measure, data have been reported for right and left eye separately.
Part B: Audiological Status of Participants as Assessed by Behavior Hearing Assessment Through Pure Tone Audiometry Test	Month 12 and 24 after end of study treatment in Part A (Day 1 to 14)	Audiological evaluations of participants were recorded and reported using behavior hearing assessment through pure tone audiometry test which includes participants with normal, abnormal, incomplete/inconclusive behavior at month 12 and 24.
Part B: Audiological Status of Participants as Assessed by Air Conduction Via Soundfield Through Pure Tone Audiometry Test	Month 12 and 24 after end of study treatment in Part A (Day 1 to 14)	Audiological evaluations of participants were recorded and reported by air conduction via soundfield through pure tone audiometry test which included participants with hearing loss ranged from \<=20 DB HL, 21-40 DB HL, 41-70 DB HL, 71-90 DB HL, \>90 DB HL or no response, and missing at frequencies ranged from 500 Hz to 4000 Hz at month 12 and 24. Rows according to air conduction categories at specified time points are reported in this outcome measure, only when there was a non-zero data for at least 1 reporting arm.
Maximum Plasma Concentration (Cmax) of Sildenafil and Its Metabolite	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.
Part B: Audiological Status of Participants as Assessed by Tympanometry Assessment (Peak Pressure) Through Immittance Audiometry Test	Month 12 and 24 after end of study treatment in Part A (Day 1 to 14)	Audiological evaluations of participants were recorded and reported by tympanometry assessment through immittance audiometry test which included participants with peak pressure signs (+) and (-) at month 12 and 24. In this outcome measure, data have been reported for right and left ear separately.
Number of Treatment-Emergent Adverse Events (AEs) According to Severity	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.
Part B: Visual Acuity of Non-Verbal Participants as Assessed by Ophthalmological Assessment	Month 12 and 24 after end of study treatment in Part A (Day 1 to 14)	Standard age-appropriate ophthalmological examinations were used to assess visual acuity (performed differently for children unable of verbal interaction) through fixates and follows (included central, steady and maintained), light perception (wince to light), no light perception, and missing at month 12 and 24. In this outcome measure, data have been reported for right and left eye separately. Rows according to visual acuity categories at specified time points are reported in this outcome measure, only when there was a non-zero data for at least 1 reporting arm.
Part B: Audiological Status of Participants as Assessed by Bone Conduction Through Pure Tone Audiometry Test	Month 12 and 24 after end of study treatment in Part A (Day 1 to 14)	Audiological evaluations of participants were recorded and reported by bone conduction assessment through pure tone audiometry test which included participants with sensorineural hearing loss, conductive hearing loss, mixed hearing loss, neural, and unspecified at month 12 and 24. Rows according to bone conduction categories at specified time points are reported in this outcome measure, only when there was a non-zero data for at least 1 reporting arm.
Part B: Audiological Status of Participants as Assessed by Transient Evoked Emission Through Otoacoustic Emissions Assessment	Month 12 and 24 after end of study treatment in Part A (Day 1 to 14)	Audiological evaluations of participants were recorded and reported by transient evoked emission through otoacoustic emissions assessment which included participants with presence of transient evoked emissions from frequencies 1000 Hz to 4000 Hz at month 12 and 24. In this outcome measure, data have been reported for right and left ear separately.
Part B: Visual Status of Participants With Abnormality as Assessed by Eye Examination of the Anterior and Posterior Segments	Month 12 and 24 after end of study treatment in Part A (Day 1 to 14)	Standard age-appropriate ophthalmological examinations were used to assess examination of anterior and posterior chamber for abnormality in lids, conjunctiva, cornea, anterior chamber, lens, iris, pupil, extraocular muscle movement and eye movements at month 12 and 24. In this outcome measure, data have been reported for right and left eye separately. Rows according to visual status categories at specified time points are reported in this outcome measure, only when there was a non-zero data for at least 1 reporting arm.
Part B: Audiological Status of Participants as Assessed by Tympanometry Assessment (Static Acoustic Admittance) Through Immittance Audiometry Test	Month 12 and 24 after end of study treatment in Part A (Day 1 to 14)	Audiological evaluations of participants were recorded and reported by tympanometry assessment through immittance audiometry test which included participants with static acoustic admittance at month 12 and 24. In this outcome measure, data have been reported for right and left ear separately.
Part B: Audiological Status of Participants as Assessed by Air Conduction Via Phones/Headphones Through Pure Tone Audiometry Test	Month 12 and 24 after end of study treatment in Part A (Day 1 to 14)	Audiological evaluations of participants were recorded and reported by air conduction via phones/headphones through pure tone audiometry test which included participants with hearing loss ranged from less than or equal to (\<=) 20 decibel hearing loss (DB HL), 21-40 DB HL, 41-70 DB HL, 71-90 DB HL, greater than (\>) 90 DB HL or no response, and missing at frequencies ranged from 500 Hertz (Hz) to 8000 Hz at month 12 and 24. In this outcome measure, data have been reported for right and left ear separately. Rows according to air conduction categories at specified time points are reported in this outcome measure, only when there was a non-zero data for at least 1 reporting arm.
Part B: Audiological Status of Participants as Assessed by Ipsilateral Stapedial Reflex Through Immittance Audiometry Test	Month 12 and 24 after end of study treatment in Part A (Day 1 to 14)	Audiological evaluations of participants were recorded and reported by ipsilateral stapedial reflex through immittance audiometry test which included participants with presence of ipsilateral stapedial reflex at frequencies ranged from 500 Hz to 2000 Hz at month 12 and 24. Ipsilateral stapedial reflex measures are used to assess the neural pathway surrounding the stapedial reflex, which occurs in response to a loud sound (70 to 90 decibel above threshold). In this outcome measure, data have been reported for right and left ear separately.
Part B: Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), and Deaths	up to 24 months after end of study treatment in Part A (maximum up to 26 months)	An AE was any untoward medical occurrence in a participant who received study medication without regard to possibility of causal relationship to it. 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. AEs included both serious and all non-serious AEs.
Part B: Audiological Status of Participants as Assessed by Distort Product Through Otoacoustic Emissions Assessment	Month 12 and 24 after end of study treatment in Part A (Day 1 to 14)	Audiological evaluations of participants were recorded and reported by distort product through otoacoustic emissions assessment which included participants with presence of distort product at frequencies ranged from 2000 Hz to 8000 Hz at month 12 and 24. Distortion-product otoacoustic emissions (DPOAEs) are generated in the cochlea in response to two tones of a given frequency and sound pressure level presented in the ear canal. Distort product otoacoustic emissions are an objective indicator of normally functioning cochlea outer hair cells. In this outcome measure, data have been reported for right and left ear separately.
Part B: Neurological Progress of Participants as Assessed by the Neurology Optimality Score	Month 12 and 24 after end of study treatment in Part A (Day 1 to 14)	The Hammersmith Infant Neurological Examination (HINE) was a standard scoring examination to assess development of cranial nerve; posture; movement; tone; and reflexes and reaction. HINE exam global score is a sum of subset (cranial nerve, posture, movement, tone, reflexes and reactions) scores, ranged from 0 to 78, where higher score represents better outcome. Here, the HINE global scores were reported at month 12 and 24.

Trial Locations

Locations (41): Sydney and Lois Eskenazi Hospital
🇺🇸
Indianapolis, Indiana, United States
The University of Oklahoma Health Sciences Center
🇺🇸
Oklahoma City, Oklahoma, United States
Fairview Hospital
🇺🇸
Cleveland, Ohio, United States
Duke University Medical Center (DUMC)
🇺🇸
Durham, North Carolina, United States
Centre Hospitalier et Regional de Lille - Hopital Jeanne de Flandre
🇫🇷
Lille, France
Leicester Royal Infirmary
🇬🇧
Leicester, United Kingdom
Seattle Children's Research Institute
🇺🇸
Seattle, Washington, United States
Henry Zarrow Neonatal Intensive Care Unit, Children's Hospital at Saint Francis
🇺🇸
Tulsa, Oklahoma, United States
CHUL du CHU de Quebec
🇨🇦
Quebec, Canada
University of California Davis Medical Center
🇺🇸
Sacramento, California, United States
Cleveland Clinic
🇺🇸
Cleveland, Ohio, United States
Seattle Childrens Hospital
🇺🇸
Seattle, Washington, United States
University of California Davis
🇺🇸
Sacramento, California, United States
Children's Mercy Hospitals & Clinics
🇺🇸
Kansas City, Missouri, United States
Hospital General Universitario Gregorio Marañon
🇪🇸
Madrid, Spain
Great Ormond Street Hospital NHS Foundation Trust
🇬🇧
London, United Kingdom
Warren Cancer Research Foundation
🇺🇸
Tulsa, Oklahoma, United States
Hospital Sant Joan de Deu
🇪🇸
Esplugues de Llobregat, Barcelona / Spain, Spain
OU Follow-Up Program, PREMIEr Clinic, Children's Hospital
🇺🇸
Oklahoma City, Oklahoma, United States
Riley Hospital for Children at IU Health
🇺🇸
Indianapolis, Indiana, United States
CHU Robert Debré
🇫🇷
Paris, France
Radboud University Nijmegen Medical Centre
🇳🇱
Nijmegen, Netherlands
Hôpital de la Conception Assistance Publique-Hôpitaux de Marseille
🇫🇷
Marseille, France
Glenfield Hospital, University Hospitals of Leicester NHS Trust
🇬🇧
Leicester, United Kingdom
University Hospital of Leipzig
🇩🇪
Leipzig, Germany
Aarhus Universitetshospital, Skejby
🇩🇰
Aarhus N, Denmark
Karolinska University Hospital
🇸🇪
Stockholm, Sweden
Centre Hospitalier et Régional de Lille,
🇫🇷
Lille, France
Hopital NECKER - Enfants Malades
🇫🇷
Paris, France
St. Michael's Hospital
🇬🇧
Bristol, United Kingdom
Indiana University Health Methodist Hospital
🇺🇸
Indianapolis, Indiana, United States
OU Neonatal Intensive Care Unit at Children's Hospital
🇺🇸
Oklahoma City, Oklahoma, United States
Neonatalklinikken Rigshospitalet, 5024
🇩🇰
Copenhagen Ø, Denmark
Neonatologia Fondazione IRCCS Policlinico San Matteo
🇮🇹
Pavia, Italy
Haukeland University Hospital
🇳🇴
Bergen, Haukeland, Norway
Arkansas Children's Hospital
🇺🇸
Little Rock, Arkansas, United States
UZ Gent
🇧🇪
Gent, Belgium
Children´s National Medical Center
🇺🇸
Washington, District of Columbia, United States
Vanderbilt Children's Hospital
🇺🇸
Nashville, Tennessee, United States
Universitair Ziekenhuis Antwerpen
🇧🇪
Edegem, Belgium
Erasmus MC, Sophia Children's hospital
🇳🇱
Rotterdam, Netherlands