Researchers have designed a Phase 2 clinical trial to test the safety and preliminary effectiveness of Revatio (sildenafil) in preventing pulmonary hypertension (PH) in premature infants with severe bronchopulmonary dysplasia (BPD).
An overview of the study, “Safety of sildenafil in premature infants with severe bronchopulmonary dysplasia (SILDI-SAFE): a multicenter, randomized, placebo-controlled, sequential dose-escalating, double-masked, safety study,” was published in the journal BMC Pediatrics.
BPD is a disorder affecting the function and development of the lungs in infants, which is commonly complicated by PH. Premature infants are at particularly high risk for BPD, and PH is associated with more severe BPD and higher mortality. There are currently no available therapies indicated for the prevention of PH in premature infants with BPD.
Revatio, marketed by Pfizer, is a pulmonary vasodilator, a medication that opens the lung blood vessels, which are restricted in PH causing high blood pressure. The therapy is approved by the U.S. Food and Drug Administration to treat PH in adults, but the agency provides no recommendation for use in the treatment of infants.
However, despite a lack of data on the safety and efficacy of Revatio in infants, physicians are increasingly using the therapy to treat premature infants with BPD and/or PH. Data from case studies suggest that Revatio can help improve the development of alveoli (lung air sacs) and blood vessels in the lungs of these infants.
The Phase 2 trial, known as SILDI-SAFE (NCT04447989), will assess Revatio’s safety, preliminary efficacy, and pharmacokinetics — the movement of a compound into, through, and out of the body — in premature infants with severe BPD who are at risk for PH.
“This clinical trial will be essential to better understand the safety of this already commonly used medication in critically ill infants with severe BPD,” the researchers wrote.
In the double-blind study, in which neither the patients nor the researchers know who receives the therapy and who receives the placebo, 120 premature infants will be randomly assigned to receive either Revatio or a placebo. The patients will be divided into three groups of 40, with 30 in each receiving escalating treatment doses.
To be eligible for the study, which is not yet recruiting, infants must have been born before 29 weeks of pregnancy (gestational age), with an adjusted age (chronological age post-birth plus gestational age) of 32–40 weeks, and be receiving respiratory support. The study will be conducted at approximately 30 sites where patients will be recruited from the neonatal intensive care unit.
Revatio’s safety will be determined by measuring the incidence of low blood pressure that requires clinical intervention from the start of treatment through 28 days after the last day of treatment. Revatio’s pharmacokinetics will also be assessed through a blood sample analysis seven days into treatment.
The preliminary effectiveness of Revatio will be assessed based on PH incidence. Pharmacokinetics data and PH diagnosis will be used to develop a model to simulate the impact of varying doses of Revatio on PH development in the study population.
“The strategies utilized in this study are innovative to the field of infant clinical research, and create value for both patients and the community,” the researchers wrote.
Dose escalation will occur during the study for as long as the patient requires respiratory support and markers for liver damage remain low. Doses will be increased until the goal dose is reached, at which point the therapy will be administered at that dose for 28 days.
Group 1 will receive escalating doses up to 0.5 mg/kg intravenously (IV) or 1 mg/kg enterally (through the gastrointestinal tract); Group 2 will receive doses up to 1 mg/kg IV or 2 mg/kg enterally; and Group 3 will receive doses up to 2 mg/kg IV or 4 mg/kg enterally. Groups 2 and 3 will be weaned off treatment after the last study day. All doses will be administered every eight hours for up to 34 days.
Participants will be monitored for up to 28 days for adverse effects. Respiratory function will be assessed daily during treatment, weaning, and follow-up. Blood pressure will be checked prior to the first dose and first escalation dose and before, during, and after each treatment with the lowest reading being recorded. Overall patient global outcomes and non-treatment-related health conditions will also be assessed.
Researchers will use the results from the Phase 2 trial to design a pivotal Phase 3 efficacy trial.
“This clinical trial will make significant strides in understanding the use of sildenafil in premature infants with PH, and provide a foundation for further exploration of utilization of sildenafil as a treatment modality for this condition,” the team concluded.
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