Milrinone in Congenital Diaphragmatic Hernia

• Register: ClinicalTrials.gov
• Last refreshed on: 11 March 2024
• Main ID: NCT02951130
• Date of registration: 14/10/2016
• Prospective Registration: Yes
• Primary sponsor: NICHD Neonatal Research Network
• Public title: Milrinone in Congenital Diaphragmatic Hernia
• Scientific title: Milrinone in Congenital Diaphragmatic Hernia
• Date of first enrolment: August 22, 2017
• Target sample size: 66
• Recruitment status: Recruiting
• URL: https://clinicaltrials.gov/ct2/show/NCT02951130
• Study type: Interventional
• Study design: Allocation: Randomized. Intervention model: Parallel Assignment. Primary purpose: Treatment. Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor).
• Phase: Phase 2

Countries of recruitment

United States

Contacts

• Name: Satyan Lakshminrusimha, M.D.

• Name: Satyan Lakshminrusimha, M.D.
• Affiliation: University of California, Davis

Key inclusion & exclusion criteria

Eligibility criteria:

Infants are eligible if they meet all of the following criteria:

- = 36 0/7 weeks PMA by best obstetric estimate AND birth weight of = 2000g

- postnatal age =7 days (168 hours of age)

- invasive mechanical ventilation (defined as ventilation with an endotracheal tube) and

- one arterial blood gas with an OI = 10 (after tracheal tube obstruction and other
easily resolvable mechanical causes for increased OI are ruled out) on the most recent
arterial blood gas within 12 hours prior to the time of randomization.

- if an arterial blood gas is not available at the time of randomization, a preductal
OSI of = 5 can be used as an inclusion criterion instead of OI = 10; (the OSI should
be based on the most recent preductal pulse oximetry recording and must be within 12
hours of randomization)

- postnatal blood gas with PCO2 = 80 mmHg (arterial, capillary or venous blood gas) on
the most recent blood gas sample obtained within 12 hours prior to randomization Note:
Criteria (iv) to (vi) must be met at the most recent analysis within 12 hours prior to
randomization.

Exclusion Criteria:

Infants are ineligible if they meet any of the following criteria:

- known hypertrophic cardiomyopathy

- Note 1: infants of diabetic mothers with asymmetric septal hypertrophy can be
included as long as there is no evidence of obstruction to left ventricular
outflow tract on echocardiogram,

- Note 2: infants with other acyanotic congenital heart disease (CHD) and CDH may
be included in the study and will be a predetermined subgroup for analysis)

- cyanotic CHD - transposition of great arteries (TGA), total anomalous pulmonary venous
return (TAPVR), partial anomalous pulmonary venous return (PAPVR), truncus arteriosus
(TA), tetralogy of Fallot (TOF), single ventricle physiology - hypoplastic left heart
syndrome (HLHS), tricuspid atresia, critical pulmonic stenosis or atresia etc.,

- enrolled in conflicting clinical trials (such as a randomized controlled blinded trial
of another pulmonary vasodilator therapy); Note: mothers enrolled in fetal tracheal
occlusion studies such as FETO may be enrolled if permitted by investigators of the
fetal tracheal occlusion study; [FETO refers to fetoscopic endoluminal tracheal
occlusion and involves occlusion of fetal trachea with a balloon device at
mid-gestation and subsequent removal in later gestation]

- infants with bilateral CDH

o Note 3: infants with anterior and central defects are included in the study

- associated abnormalities of the trachea or esophagus (trachea-esophageal fistula,
esophageal atresia, laryngeal web, tracheal agenesis)

- renal dysfunction (with serum creatinine > 2 mg/dL not due to maternal factors) or
severe oligohydramnios associated with renal dysfunction at randomization; renal
dysfunction may be secondary to renal anomalies or medical conditions such as acute
tubular necrosis

- severe systemic hypotension (mean blood pressure < 35 mm Hg for at least 2 h with a
vasoactive inotrope score of > 30)

- decision is made to provide comfort/ palliative care and not full treatment

- Intracranial bleed (including the following findings on the cranial ultrasound)

- Cerebral parenchymal hemorrhage

- Blood/echodensity in the ventricle with distension of the ventricle

- Periventricular hemorrhagic infarction

- Posterior fossa hemorrhage

- Cerebellar hemorrhage

- persistent thrombocytopenia (platelet count < 80,000/mm3) despite blood product
administration on the most recent blood draw prior to randomization

- coagulopathy (PT INR > 1.7) despite blood product administration on the most recent
blood draw (if checked - there is no reason to check PT for the purpose of this study)

- aneuploidy associated with short life span (such as trisomy 13 or 18) will not be
included in the study (infants with trisomy 21 can be included in the study)

- elevated arterial, venous or capillary PCO2 > 80 mmHg in spite of maximal ventilator
support (including high frequency ventilation) on the most recent blood gas obtained
within 12 hours prior to randomization

- use of milrinone infusion prior to randomization (the use of other inhaled pulmonary
vasodilators such as iNO, inhaled epoprosternol, inhaled PGE1 and oral such as
endothelin receptor antagonists is permitted - Note: it is unlikely to be on oral
pulmonary vasodilators early in the course of CDH)

- ongoing therapy with parenteral (intravenous or subcutaneous) pulmonary vasodilators
such as IV/SQ prostacyclin analogs (Epoprostenol - Flolan or Treprostinil - Remodulin
or PGE1 - Alprostadil) or IV phosphodiesterase 5 inhibitors (sildenafil - Revatio) at
the time of randomization. In addition, initiation of therapy with these two classes
of parenteral medications during the first 24 hours of study drug initiation is not
permitted and will be considered a protocol deviation. The risk of systemic
hypotension is high during the first 24 hours of study-drug (milrinone) infusion and
hence parenteral administration of other pulmonary vasodilators is avoided to minimize
risk of hypotension.

- Subjects already on ECMO or patients who are being actively considered for ECMO by the
neonatal or surgical team

- attending (neonatal, critical care or surgical) refusal for participation in the trial
(including concern about presence of hemodynamic instability)



Age minimum: 0 Hours
Age maximum: 168 Hours
Gender: All

Health Condition(s) or Problem(s) studied

Pulmonary Hypoplasia

Hypoxemic Respiratory Failure

Persistent Pulmonary Hypertension of the Newborn

Congenital Diaphragmatic Hernia

Intervention(s)

Drug: Milrinone

Drug: Placebo (5% Dextrose)

Primary Outcome(s)

Oxygenation Response [Time Frame: 24 h after initiation of study drug]

Secondary Outcome(s)

Adjusted Oxygen Response [Time Frame: 24 h after initiation of study drug]

Supplemental Continuous Oxygen [Time Frame: 28 days and 56 days postnatal age (or discharge whichever comes first)]

Vasoactive Inotrope Score and Systemic Blood Pressure [Time Frame: 72 hours after initiation of study drug]

Feasibility to perform a definitive trial (incidence of systemic hypotension) [Time Frame: From initial recruitment: 16 patients enrolled per month to complete the trial in 4 years]

Survival to discharge without ECMO [Time Frame: Measured by no ECMO at time of hospital discharge or at the time the infant reaches 120 days of life and remains in the hospital, whichever comes earlier]

Changes in estimated systolic pulmonary arterial pressure on echocardiogram [Time Frame: Prior to initiation of study drug to between 24 and 72 hours after initiation of study drug]

Feasibility and sample size calculation to Perform a Definitive Trial (primary outcome - improvement in survival without ECMO [Time Frame: From initial recruitment: 16 patients enrolled per month to complete the trial in 4 years]

Feasibility to perform a definitive trial (incidence of intracranial bleeding) [Time Frame: From initial recruitment: 16 patients enrolled per month to complete the trial in 4 years]

Feasibility to perform a definitive trial (incidence of arrhythmias) [Time Frame: From initial recruitment: 16 patients enrolled per month to complete the trial in 4 years]

Oxygenation Response to Additional Inotropes or Pulmonary Vasodilators [Time Frame: Through 24 h post study drug initiation]

Oxygenation Response at 48 and 72 h [Time Frame: 48 and 72 h after initiation of study drug]

Area Under the Curve for Inspired Oxygen [Time Frame: After initiation of the study drug at 4 time points per day - every 6 hours x 72 hours or discontinuation of study drug (whichever comes first)]

Clinical status (Pulmonary and Nutritional) [Time Frame: All clinical status measures (as defined by protocol) will be obtained just prior to the infants discharge from the hospital and again at 12 months of age.]

Secondary ID(s)

UG1HD027904

UG1HD027880

U10HD036790

UG1HD053089

UG1HD027851

UG1HD087229

UG1HD034216

UG1HD053109

UG1HD040689

UG1HD021364

UG1HD027853

UG1HD068263

UG1HD068278

UG1HD087226

NICHD-NRN-0057

UG1HD040492

UG1HD068244

Source(s) of Monetary Support

Please refer to primary and secondary sponsors

Secondary Sponsor(s)

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)