To assess the efficacy of bosentan in neonates with persistent pulmonary hypertension of the newborn (PPHN) who are in need of continued inhaled nitric oxide (iNO) after at least 4 hours of continuous iNO treatment and to evaluate the…
ID
Source
Brief title
Condition
- Cardiac and vascular disorders congenital
- Pulmonary vascular disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Exploratory efficacy endpoints:
* Proportion of patients with treatment failure:
- Need for extra corporeal membrane oxygenation (ECMO) or
- Initiation of alternative pulmonary vasodilator
* Time to complete weaning from iNO
* Time to weaning from mechanical ventilation
* Proportion of patients requiring re-initiation of iNO therapy
* Change from baseline to 3, 5, 12, and 24 hours following the first drug
administration and thereafter daily until end of study treatment for:
- Oxygenation index
- Arterial blood gas values (pH, SaO2, PaO2, PaCO2)
- Pulse oximetry (SpO2)
* Pulmonary hypertension (assessed by echocardiography)
Change from baseline to 24 hours and end of study treatment in:
* Extra-pulmonary shunting of blood at the PFO or PDA (if present)
* Estimated RVSP/systemic arterial pressure ratio by TRJV or by gradient across
PDA or across septal defects (if present)
* RV dilation and interventricular septal movement pattern
In order to interpret the exploratory efficacy data, the following information
at 3, 5, 12, and 24 hours following the first drug administration, then daily
until EOS will be collected:
- If on mechanical ventilation: mean airway pressure, PEEP (positive
end-expiratory pressure), PIP (peak inspiratory pressure), rate, and tidal
volume or,
- If on high frequency oscillatory ventilation: mean airway pressure,
frequency, and amplitude
Secondary outcome
TOLERABILITY / SAFETY ENDPOINTS:
Treatment-emergent adverse events (AEs) and SAEs
* AEs leading to premature discontinuation of study drug
* Change from baseline in vital signs during the treatment period
* Treatment-emergent electrocardiogram (ECG) abnormalities reported as AE
* Treatment-emergent laboratory abnormalities
* Incidence of treatment-emergent ALT or AST > 3 × ULN
* Incidence of treatment-emergent severe intracranial hemorrhage (grade III or
IV), periventricular leukomalacia, and ventriculomegaly
*Treatment emergent* AEs and SAEs are those for which onset occurs from 1st
dosing with double-blind treatment and up to 7 days after last double-blind
treatment administration.
PHARMACOKINETIC ENDPOINTS:
All PK endpoints will be evaluated based on concentrations measured in dried
blood spot samples.
The following endpoints will be derived by non-compartmental analysis of
concentration-time profiles obtained on Day 1 and on Day 5 of bosentan
treatment, if applicable.
o Cmax and tmax (Days 1 and 5), AUC0-12h (Day 1), AUC0-* (Day 5), and AUC0-24h
(Days 1 and 5) for bosentan and its metabolites (Ro 48-5033, Ro 47-8634, Ro
64-1056) following administration of bosentan.
o For those subjects whose PK assessments will be performed on Days 1 and 5,
the accumulation index, defined as the ratio between AUC0-* (Day 5) and
AUC0-12h (Day 1) will be calculated.
Background summary
Persistent pulmonary hypertension of the newborn (PPHN) is an uncommon and
life-threatening disease that occurs in 2 out of 1,000 live births and that
causes severe breathing difficulties. Before birth, infants get his/her oxygen
from the mother. After birth, changes occur that will allow blood to reach the
baby's lungs where it gets a fresh supply of oxygen. Because these changes fail
in babies with PPHN, the blood carries less oxygen and the baby suffers from
breathing difficulties that can lead to suffocation and death.
The standard treatment for PPHN is to improve oxygenation using breathing
assistance (mechanical ventilation) and increasing the proportion of oxygen in
the inhaled air. A gas called nitric oxide (NO) is also added to the air
inhaled by the baby. This gas is the only treatment currently approved by
health authorities to treat babies suffering from PPHN. It helps by dilating
the small blood vessels in the lungs which results in better oxygenation of
blood within a few hours of treatment. However, a significant number of babies
do not respond well to this treatment or remain dependent on it and this
appears to be the case for the baby.
Tracleer (bosentan) is a drug that reduces the unwanted effects of a hormone (a
chemical messenger in the body) called endothelin. There is an increased amount
of endothelin in the blood of patients with pulmonary arterial hypertension
(PAH) which contributes to the narrowing of the small blood vessels in the
lungs. Taking bosentan blocks the effect of endothelin and improves the flow of
blood in the lungs and the rest of the body. This helps to make patients
breathing easier.
Tracleer (bosentan) is approved in over 30 countries for the treatment of
moderate to severe PAH.
To date, the potential effects of bosentan in babies with PPHN have not been
studied. As in PAH patients, there is an increased amount of endothelin in the
blood of babies with PPHN which contributes to the narrowing of small blood
vessels in the lungs. Some of the mechanisms involved in PPHN are the same as
in PAH. Bosentan could help to make breathing easier in babies with PPHN. Few
cases of babies with PPHN have been reported to be successfully treated with
bosentan; nevertheless this still needs to be confirmed in a controlled
clinical trial.
The main purpose of this study is to evaluate the efficacy and safety of
bosentan in babies with PPHN and for whom standard treatment with inhaled NO
(iNO) is not satisfactory.
Study objective
To assess the efficacy of bosentan in neonates with persistent pulmonary
hypertension of the newborn (PPHN) who are in need of continued inhaled nitric
oxide (iNO) after at least 4 hours of continuous iNO treatment and to evaluate
the pharmacokinetics (PK), tolerability, and safety of bosentan in this patient
population.
Study design
Exploratory, multicenter, double-blind, randomized, placebo-controlled,
parallel-group, phase 3 study.
An interim pharmacokinetic (PK) and safety analysis will be performed on the
first six PK evaluable patients in order to amend the dose if necessary.
Intervention
Formulation: dispersible and quadrisectible 32 mg tablet of bosentan or
matching placebo.
Route: nasogastric or orogastric tube, according to site standard practice.
Dose 2 mg/kg of weight at birth twice daily (b.i.d.) Dose could be changed
depending on the results of the interim PK and safety analysis.
Randomization 2:1. 20 patients receive bosentan, 10 placebo
Study burden and risks
RISKS
The study medication and procedures have risks and discomforts: as in any
clinical research study there is a possibility of experiencing side effects to
the study medication or procedures. Bosentan can have side effects even when
used as directed.
Bosentan has never been used in newborns in a controlled trial and therefore
very limited information is available regarding safety of bosentan in newborns.
In animals, a preclinical study in rat newborns has recently evaluated bosentan
effects on development (growth and organ maturation), behavior (hearing,
movement capacity, learning, and memory), fertility, and histology (microscopic
analysis of organs). This study established that bosentan had no observable
side effects at daily doses that are close to 4 times higher than the dose used
in this study.
In humans, few cases of bosentan use in newborns with PPHN have been published,
three of them reported no side effect, and one had mild systemic hypotension
(slightly low blood pressure) shortly after bosentan administration which has
been quickly corrected without treatment interruption. Over 9 years of
post-marketing experience, Actelion's safety department has been informed of 1
case of side effect reported to be related to bosentan use in newborns. The
newborn was reported to have mild abnormal liver function which resolved 2 days
after bosentan discontinuation.
The side effects collected from 20 placebo-controlled studies in teenagers and
adults treated with bosentan are described in the table below. They are ranked
according to their frequency using the following convention: very common
(affects more than 1 patient in 10); common (affects 1-10 patients in 100);
uncommon (affects 1-10 patients in 1,000); rare (affects 1-10 patients in
10,000).
Very common Headache
Very common Abnormal liver function blood test
Very common Oedema, fluid retention (swelling of the legs and ankles)
Common Anemia*, hemoglobin decrease
Common Allergic reactions (including skin inflammation, itching and rash)
Common Syncope (fainting)
Common Palpitations
Common Flushing
Common Low blood pressure
Common Diarrhea
Common Skin redness
Uncommon Thrombocytopenia (low number of blood platelets)
Uncommon Neutropenia, leukopenia (low number of white blood cells)
Uncommon Aminotransferase elevations associated with hepatitis and/or jaundice
(yellowing of the skin or the whites of the eyes)
Rare Anaphylaxis (generally allergic reaction) and/or angioedema (swelling,
most commonly around the eyes, lips, tongue or throat)
Rare Liver cirrhosis (scarring of the liver), liver failure (serious
disturbance of liver function)
* Sometimes requiring transfusion
The study will be conducted during the baby's stay in the hospital intensive
care unit where the investigators and other medical staff will pay the greatest
attention to any unusual effects throughout the treatment period.
It is possible that complications and side effects of study drug, which are
still unknown at this time, may occur. The ethics committees and health
authorities will be informed about any new findings on bosentan.
FERTILITY IN MALES
Compounds of the same class as bosentan have been linked to the development of
testicular injury and sterility in rats when used at very high doses for a long
period of time. A recent study with bosentan administered for 70 days to rat
newborns did not show any testicular injury at daily doses close to 4 times the
dose that is used in this study. In this study, very high doses of bosentan (>
10 times and > 33 times the study dose) have been associated with a decrease in
testis weight and sperm number but without microscopic alterations of testis
and sperm quality.
It is not known whether testicular injury can occur with bosentan in humans
when the dose and length of exposure is much less than the test doses used in
rats. To date, there was no confirmed report of fertility impairment in men who
received bosentan, but this does not rule out the possibility of a risk of a
testicular injury.
BENEFITS
There is no guarantee that the patient population will benefit directly from
this research. Information obtained during the course of this clinical research
study may contribute to a better understanding of the disease and may be useful
in selecting medicines for future treatment for PPHN. Regardless of any
individual benefit, the knowledge gained from this study may contribute to
information that would allow the use of this drug or similar drugs in other
newborns with PPHN.
Gewerbestrasse 16
4123 Allschwil
Switzerland
Gewerbestrasse 16
4123 Allschwil
Switzerland
Listed location countries
Age
Inclusion criteria
1. Signed informed consent by the parent(s) or the legal representative(s).
2. Term and near-term newborns (gestational age > 34 weeks).
3. Post natal age * 12 hours and < 7 days.
4. Weight at birth * 2,500 g.
5. Idiopathic PPHN or PPHN due to parenchymal lung disease (e.g., respiratory distress syndrome, meconium aspiration syndrome, pneumonia, sepsis without multi-organ failure).
6. Pulmonary hypertension (PH) confirmed by echocardiography:
a) Predominant extrapulmonary right-to-left or bidirectional shunting of blood at a patent foramen ovale (PFO) or patent ductus arteriosus (PDA) or
b) Estimated right ventricular systolic pressure (RVSP) > 2/3 of systemic arterial pressure by tricuspid regurgitant jet velocity (TRJV) or by gradient across septal defect (if present) or
c) Marked right ventricular (RV) dilation and paradoxical shift of interventricular septum.
7. Need for continued iNO at a dose > 10 ppm after at least 4h of continuous iNO treatment.
8. Last two consecutive oxygenation index (OI) values prior to randomization * 15.
9. Mechanical ventilation with fraction of inspired oxygen (FiO2) * 50%.
Exclusion criteria
1. Pulmonary Hypertension associated with conditions other than PPHN.
2. Immediate need for cardiac resuscitation or extracorporeal membrane oxygenation (ECMO) (profound hypoxemia [PaO2] < 30 mm Hg; OI > 40).
3. Lethal congenital anomalies.
4. Congenital diaphragmatic hernia.
5. Significant congenital heart disease or significant left to right shunt.
6. Pneumothorax.
7. Active seizures.
8. Expected duration of mechanical ventilation of less than 48 hours.
9. Mean systemic blood pressure < 35 mmHg despite therapy with volume infusions and cardiotonic support.
10. Hepatic failure or all conditions with aspartate aminotransferase (AST) or alanine aminotransferase (ALT) values > 2 × upper limit of normal (ULN).
11. Renal function impairment such as serum creatinine > 3 × ULN or anuria.
12. Known intracranial hemorrhage grade III or IV.
13. Hemoglobin or hematocrit level < 75% of the lower limit of normal (LLN).
14. Thrombocytopenia (platelet count < 50,000 cells /*L).
15. Leukopenia (white blood cells [WBC] < 2,500 cells/ *L).
16. Any condition precluding the use of a nasogastric/orogastric tube.
17. Administration of prohibited medication prior to randomization.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2011-000203-41-NL |
| CCMO | NL37236.078.11 |