E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Persistent Pulmonary Hypertension of the Newborn |
Aanhoudende pulmonaire hypertensie van de pasgeborene |
|
E.1.1.1 | Medical condition in easily understood language |
High Blood Pressure in the Lungs of Newborn Babies |
Hoge bloeddruk in de longen van pasgeboren baby's
|
|
E.1.1.2 | Therapeutic area | Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 22.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10053592 |
E.1.2 | Term | Newborn persistent pulmonary hypertension |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
|
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
We hypothesize that intravenous milrinone used in conjunction with iNO results in the reduction in the time on iNO therapy and the time spent on invasive ventilation in infants ≥ 34 weeks gestation and ≥ 2000 grams with a clinical and echocardiography diagnosis of PPHN.
The aim is to compare: the incidence of the use of other inotropes; critically low LV and RV function and output measured by echocardiography and a non-invasive cardiac output monitor (NICOM); the rate of adverse effects associated with milrinone including the incidence of hypotension; and the pre-discharge outcomes in the two groups. |
|
E.2.2 | Secondary objectives of the trial |
In this pilot study, we aim to assess the practicality of instituting the protocol and contributing to a sample size calculation for a definitive multicentre study. |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
All infants with a gestation ≥ 34 weeks and a birth weight ≥ 2000 grams admitted to the neonatal intensive care unit with a clinical diagnosis of PPHN, and commenced on iNO will be deemed potentially eligible for this study. The process of iNO initiation in PPHN on clinical grounds and is standardised in the NICUs and is detailed in Appendix 2. The decision is made by the attending physician In addition; the infants must satisfy the following criteria:
1) ≤ 10 postnatal days of life and within 4 days of admission
2) Echocardiography diagnosis of PPHN (see below)
3) Absence of significant congenital heart defect excluding a small atrial septal defect or ventricular septal defect (measuring less than 3mm)
4) Oxygenation index of ≥ 10 measured obtained from an arterial blood sample and calculated using the following formula:
OI = (Mean airway pressure × FiO2 × 100) ÷ (paO2 in kilopascals)
|
|
E.4 | Principal exclusion criteria |
1) Lethal congenital anomalies or obvious syndrome
2) Bleeding diathesis (abnormal coagulation screen/platelet <100,000/ mm3)
3) The presence of Intraventricular haemorrhage.
4) Diastolic Hypotension (defined as a diastolic blood pressure less than the 3rd centile for any given gestation) unresponsive to medical treatment (≥30 mL/kg fluid bolus and ≥ 2 inotropes of at least 10 μg/ kg/min)
5) Hypoxic-ischemic encephalopathy undergoing therapeutic hypothermia
6) Evidence of renal impairment (Creatinine > 100micromol/l)
7) Severe Hypovolaemia: Heart rate > 180, capillary refill > 5 seconds, urine output < 0.5ml/kg/hour, in addition to diastolic hypotension mentioned above.
|
|
E.5 End points |
E.5.1 | Primary end point(s) |
The primary outcome of this study is the time on iNO in hours and the time on invasive ventilation. A standardised protocol for iNO weaning is detailed in the protocol. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Determined at the time of discontinuation of iNO up to day 5 post delivery. |
|
E.5.2 | Secondary end point(s) |
We will collect the following demographic characteristics and rele¬vant short-term secondary outcomes: duration of hospital stay; time to extubation; duration of oxygen therapy, and survival.
De¬tails of cardiorespiratory stability (blood pressure, heart rate, oxygen saturation), ventilation support (FiO2, mean airway pressure (MAP), oxygenation index [MAP × F FiO2/PaO2]), efficacy of oxygenation [PaO2], plasma lactate, pH, PCO2, HCO3-, Base excess; and relevant co-treatments (i.e., sedation, analgesics, muscle relaxants, inotropes, fluid administration) at the following time points:
1) Prior to treatment
2) Following the load¬ing dose
3) 12 hours after initiation of therapy
4) 24 hours after initiation of therapy
5) Two hours after discontinuation of therapy
Monitoring of blood parameters will be carried out as follows during the study period and 24 hours after drug discontinuation:
• Full blood count (including platelets): daily
• Electrolytes, Urea and Creatinine: daily
• Liver function tests (ALT, AST, GGT): daily
• Blood gas analysis: 12 hourly
Echocardiography will be performed according to the following schedule: a timing window of ± 3 hours will be applied. Scans performed outside the ± 3 hour window will constitute a protocol deviation:
1) Prior to the Commencement of Study Drug: Diagnose PPHN and rule out CHD
2) 12 hours following the administration of Study Drug
3) 24 hours following the administration of the study drug
4) 8 hours following the discontinuation of the study drug
Non-invasive Cardiac output Monitoring (NICOM) will be commenced prior to the commencement of the study drug and continued until the last echocardiogram, 8 hours after the discontinuation of the study medication.
Cranial ultrasound will performed prior to treatment commencement and after the discontinuation of the infusion. Intraventricular haemorrhage will be defined and graded with the Papile classification. Echocardiography will carried out at baseline as detailed above and at 12 hours, 24 hours, 2 hours after discontinuation of therapy, and before discharge.
|
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | No |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 3 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |