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

Study Overview
=================
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.

Official Title
-----------------
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

Conditions
-----------------
Pulmonary Hypertension, Familial Persistent, of the Newborn

Intervention / Treatment
-----------------
* Drug: placebo
* Drug: iv sildenafil


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 0 Days
Maximum Age: 4 Days

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: placebo<br>iv placebo of normal saline or 10% dextrose | Drug: placebo<br>* IV placebo or 0.9% sodium chloride or 10% dextrose. Infusion rate based on weight.<br>|
| Experimental: sildenafil<br>Active study drug | Drug: iv sildenafil<br>* 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.<br>* Other names: revatio;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time on Inhaled Nitric Oxide (iNO) Treatment After Initiation of Intravenous (IV) Study Drug For Participants Without Treatment Failure | 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. | 14 days from the initiation of IV study drug or hospital discharge, whichever occurs first (maximum of 14 days) | 
| Treatment Failure Rate | Treatment failure rate was defined as percentage of participants who needed additional treatment targeting PPHN, needed ECMO, or died during the study. | 14 days from the initiation of IV study drug or hospital discharge, whichever occurs first (maximum of 14 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time From Initiation of Intravenous (IV) Study Drug to Final Weaning of Mechanical Ventilation | 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. | 14 days from the initiation of IV study drug or hospital discharge, whichever occurs first (maximum of 14 days) | 
| Time From Initiation of Intravenous (IV) Study Drug to First Treatment Failure | 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. | 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 | 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. | 14 days from the initiation of IV study drug or hospital discharge, whichever occurs first (maximum of 14 days) | 
| Change From Baseline in Oxygenation Index (OI) at Hours 6, 12 and 24 Post-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. | Baseline, Hours 6, 12 and 24 after start of infusion | 
| Change From Baseline in Differential Saturation at Hours 6, 12 and 24 Post-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. | Baseline, Hours 6, 12 and 24 after start of infusion | 
| 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 | 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. | Baseline, Hours 6, 12 and 24 after start of infusion | 
| Maximum Plasma Concentration (Cmax) of Sildenafil and Its Metabolite | Cmax was obtained for Sildenafil and its major metabolite UK-103,320. | 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) | 
| Total Plasma Clearance (CL) of Sildenafil and Its Metabolite | 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. | 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 | 
| Central Volume of Distribution (Vc) of Sildenafil and Its Metabolite | 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. | 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 | 
| Part B: Neurological Progress of Participants as Assessed by the Neurology Optimality Score | 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. | Month 12 and 24 after end of study treatment in Part A (Day 1 to 14) | 
| Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | 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. | Baseline up to 31 days after end of study drug infusion (up to 45 days) | 
| Number of Treatment-Emergent Adverse Events (AEs) According to Severity | 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. | Baseline up to 31 days after end of study drug infusion (up to 45 days) | 
| Number of Participants With Laboratory Abnormalities | 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. | Up to 14 days from initiation of study drug infusion | 
| 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) | 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. | Month 12 and 24 after end of study treatment in Part A (Day 1 to 14) | 
| 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) | 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. | Month 24 after end of study treatment in Part A (Day 1 to 14) | 
| Part B: Number of Participants With Eye Movement Disorders as Assessed by Eye Examination | 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. | Month 12 and 24 after end of study treatment in Part A (Day 1 to 14) | 
| Part B: Visual Acuity of Verbal Participants as Assessed by Ophthalmological Assessment | 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. | Month 12 and 24 after end of study treatment in Part A (Day 1 to 14) | 
| Part B: Visual Acuity of Non-Verbal Participants as Assessed by Ophthalmological Assessment | 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. | Month 12 and 24 after end of study treatment in Part A (Day 1 to 14) | 
| Part B: Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), and Deaths | 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. | up to 24 months after end of study treatment in Part A (maximum up to 26 months) | 
| Part B: Visual Acuity of Verbal Participants as Assessed by LogMAR Through Visual Acuity Chart | 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. | Month 12 and 24 after end of study treatment in Part A (Day 1 to 14) | 
| Part B: Visual Status of Participants With Abnormality as Assessed by Eye Examination of the Anterior and Posterior Segments | 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. | Month 12 and 24 after end of study treatment in Part A (Day 1 to 14) | 
| Part B: Audiological Status of Participants as Assessed by Behavior Hearing Assessment Through Pure Tone Audiometry Test | 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. | Month 12 and 24 after end of study treatment in Part A (Day 1 to 14) | 
| Part B: Audiological Status of Participants as Assessed by Bone Conduction Through Pure Tone Audiometry Test | 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. | Month 12 and 24 after end of study treatment in Part A (Day 1 to 14) | 
| Part B: Audiological Status of Participants as Assessed by Air Conduction Via Phones/Headphones Through Pure Tone Audiometry Test | 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. | Month 12 and 24 after end of study treatment in Part A (Day 1 to 14) | 
| Part B: Audiological Status of Participants as Assessed by Air Conduction Via Soundfield Through Pure Tone Audiometry Test | 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. | Month 12 and 24 after end of study treatment in Part A (Day 1 to 14) | 
| Part B: Audiological Status of Participants as Assessed by Tympanometry Assessment (Peak Pressure) Through Immittance Audiometry Test | 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. | Month 12 and 24 after end of study treatment in Part A (Day 1 to 14) | 
| Part B: Audiological Status of Participants as Assessed by Tympanometry Assessment (Static Acoustic Admittance) Through Immittance Audiometry Test | 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. | Month 12 and 24 after end of study treatment in Part A (Day 1 to 14) | 
| Part B: Audiological Status of Participants as Assessed by Ipsilateral Stapedial Reflex Through Immittance Audiometry Test | 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. | Month 12 and 24 after end of study treatment in Part A (Day 1 to 14) | 
| Part B: Audiological Status of Participants as Assessed by Transient Evoked Emission Through Otoacoustic Emissions Assessment | 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. | Month 12 and 24 after end of study treatment in Part A (Day 1 to 14) | 
| Part B: Audiological Status of Participants as Assessed by Distort Product Through Otoacoustic Emissions Assessment | 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. | Month 12 and 24 after end of study treatment in Part A (Day 1 to 14) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
persistent pulmonary hypertension, newborn, neonates, iv sildenafil, hypoxic respiratory failure and at risk of persistent pulmonary hypertension of the newborn