Clinical trial NCT02951130: Milrinone in Congenital Diaphragmatic Hernia
Official title: Milrinone in Congenital Diaphragmatic Hernia
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Congenital Diaphragmatic Hernia
Persistent Pulmonary Hypertension of the Newborn
Hypoxemic Respiratory Failure
Pulmonary Hypoplasia
Keywords: CDH
PPHN
HRF
Lead sponsor: NICHD Neonatal Research Network
Sponsor class: NETWORK
Collaborators: name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
First posted: 2016-11-01
Enrollment: 66
Sex: ALL
Minimum age (years): 0
Maximum age (years): 168
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Infants with congenital diaphragmatic hernia (CDH) usually have pulmonary hypoplasia and persistent pulmonary hypertension of the newborn (PPHN) leading to hypoxemic respiratory failure (HRF). Pulmonary hypertension associated with CDH is frequently resistant to conventional pulmonary vasodilator therapy including inhaled nitric oxide (iNO). Increased pulmonary vascular resistance (PVR) can lead to right ventricular overload and dysfunction. In patients with CDH, left ventricular dysfunction, either caused by right ventricular overload or a relative underdevelopment of the left ventricle, is associated with poor prognosis. Milrinone is an intravenous inotrope and lusitrope (enhances cardiac systolic contraction and diastolic relaxation respectively) with pulmonary vasodilator properties and has been shown anecdotally to improve oxygenation in PPHN. Milrinone is commonly used during the management of CDH although no randomized trials have been performed to test its efficacy. Thirty percent of infants with CDH in the Children's Hospital Neonatal Database (CHND) and 22% of late-preterm and term infants with CDH in the Pediatrix database received milrinone. In the recently published VICI trial, 84% of patients with CDH received a vasoactive medication. In the current pilot trial, neonates with an antenatal or postnatal diagnosis of CDH will be randomized to receive milrinone or placebo to establish safety of this medication in CDH and test its efficacy in improving oxygenation.

Detailed description: This is a pilot trial to determine if milrinone infusion in neonates ≥ 36 weeks' postmenstrual age (PMA) at birth with CDH would lead to an increase in PaO2 with a corresponding decrease in OI by itself or in conjunction with other pulmonary vasodilators such as iNO at 24 h post-infusion.

Eligibility 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)

Primary outcomes:
measure: Oxygenation Response
timeFrame: 24 h after initiation of study drug
Secondary outcomes:
measure: Oxygenation Response at 48 and 72 h
timeFrame: 48 and 72 h after initiation of study drug
measure: Changes in estimated systolic pulmonary arterial pressure on echocardiogram
timeFrame: Prior to initiation of study drug to between 24 and 72 hours after initiation of study drug
measure: Vasoactive Inotrope Score and Systemic Blood Pressure
timeFrame: 72 hours after initiation of study drug
measure: Area Under the Curve for Inspired Oxygen
timeFrame: 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)
measure: Oxygenation Response to Additional Inotropes or Pulmonary Vasodilators
timeFrame: Through 24 h post study drug initiation
measure: Supplemental Continuous Oxygen
timeFrame: 28 days and 56 days postnatal age (or discharge whichever comes first)
measure: Survival to discharge without ECMO
timeFrame: 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
measure: Clinical status (Pulmonary and Nutritional)
timeFrame: 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.
measure: Feasibility and sample size calculation to Perform a Definitive Trial (primary outcome - improvement in survival without ECMO
timeFrame: From initial recruitment: 16 patients enrolled per month to complete the trial in 4 years
measure: Feasibility to perform a definitive trial (incidence of systemic hypotension)
timeFrame: From initial recruitment: 16 patients enrolled per month to complete the trial in 4 years
measure: Feasibility to perform a definitive trial (incidence of intracranial bleeding)
timeFrame: From initial recruitment: 16 patients enrolled per month to complete the trial in 4 years
measure: Feasibility to perform a definitive trial (incidence of arrhythmias)
timeFrame: From initial recruitment: 16 patients enrolled per month to complete the trial in 4 years
measure: Adjusted Oxygen Response
timeFrame: 24 h after initiation of study drug
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Palo Alto
country: United States
facility: Stanford University
state: California
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Iowa City
country: United States
facility: University of Iowa
state: Iowa
city: Kansas City
country: United States
facility: Children's Mercy
state: Missouri
city: Albuquerque
country: United States
facility: University of New Mexico
state: New Mexico
city: New York
country: United States
facility: Columbia University
state: New York
city: Rochester
country: United States
facility: University of Rochester
state: New York
city: Durham
country: United States
facility: RTI International
state: North Carolina
city: Durham
country: United States
facility: Duke University
state: North Carolina
city: Cincinnati
country: United States
facility: Cincinnati Children's Medical Center
state: Ohio
city: Cleveland
country: United States
facility: Case Western Reserve University, Rainbow Babies and Children's Hospital
state: Ohio
city: Columbus
country: United States
facility: Research Institute at Nationwide Children's Hospital
state: Ohio
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Providence
country: United States
facility: Brown University, Women & Infants Hospital of Rhode Island
state: Rhode Island
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center at Dallas
state: Texas
city: Houston
country: United States
facility: University of Texas Health Science Center at Houston
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
city: Milwaukee
country: United States
facility: Children's Hospital of Wisconsin
state: Wisconsin
Study officials:
affiliation: University of California, Davis
name: Satyan Lakshminrusimha, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Lakshminrusimha S, Keszler M, Kirpalani H, Van Meurs K, Chess P, Ambalavanan N, Yoder B, Fraga MV, Hedrick H, Lally KP, Nelin L, Cotten M, Klein J, Guilford S, Williams A, Chaudhary A, Gantz M, Gabrio J, Chowdhury D, Zaterka-Baxter K, Das A, Higgins RD. Milrinone in congenital diaphragmatic hernia - a randomized pilot trial: study protocol, review of literature and survey of current practices. Matern Health Neonatol Perinatol. 2017 Nov 27;3:27. doi: 10.1186/s40748-017-0066-9. eCollection 2017.