You have already added 0 works in your ORCID record related to the merged Research product.
Inhaled PGE1 in neonates with hypoxemic respiratory failure: two pilot feasibility randomized clinical trials
Copyright policy )Background Inhaled nitric oxide (INO), a selective pulmonary vasodilator, has revolutionized the treatment of neonatal hypoxemic respiratory failure (NHRF). However, there is lack of sustained improvement in 30 to 46% of infants. Aerosolized prostaglandins I2 (PGI2) and E1 (PGE1) have been reported to be effective selective pulmonary vasodilators. The objective of this study was to evaluate the feasibility of a randomized controlled trial (RCT) of inhaled PGE1 (IPGE1) in NHRF. Methods Two pilot multicenter phase II RCTs are included in this report. In the first pilot, late preterm and term neonates with NHRF, who had an oxygenation index (OI) of ≥15 and <25 on two arterial blood gases and had not previously received INO, were randomly assigned to receive two doses of IPGE1 (300 and 150 ng/kg/min) or placebo. The primary outcome was the enrollment of 50 infants in six to nine months at 10 sites. The first pilot was halted after four months for failure to enroll a single infant. The most common cause for non-enrollment was prior initiation of INO. In a re-designed second pilot, co-administration of IPGE1 and INO was permitted. Infants with suboptimal response to INO received either aerosolized saline or IPGE1 at a low (150 ng/kg/min) or high dose (300 ng/kg/min) for a maximum duration of 72 hours. The primary outcome was the recruitment of an adequate number of patients (n = 50) in a nine-month-period, with fewer than 20% protocol violations. Results No infants were enrolled in the first pilot. Seven patients were enrolled in the second pilot; three in the control, two in the low-dose IPGE1, and two in the high-dose IPGE1 groups. The study was halted for recruitment futility after approximately six months as enrollment targets were not met. No serious adverse events, one minor protocol deviation and one pharmacy protocol violation were reported. Conclusions These two pilot RCTs failed to recruit adequate eligible newborns with NHRF. Complex management RCTs of novel therapies for persistent pulmonary hypertension of the newborn (PPHN) may require novel study designs and a longer period of time from study approval to commencement of enrollment. Trial registration: ClinicalTrials.gov Pilot one: NCT number: 00598429 registered on 10 January 2008. Last updated: 3 February 2011. Pilot two: NCT number: 01467076 17 October 2011. Last updated: 13 February 2013. Electronic supplementary material The online version of this article (doi:10.1186/1745-6215-15-486) contains supplementary material, which is available to authorized users.
Microsoft Academic Graph classification: Clinical trial Pulmonary hypertension medicine.disease medicine Saline medicine.medical_treatment Arterial blood Pediatrics medicine.medical_specialty Clinical study design Adverse effect Randomized controlled trial law.invention law Placebo business.industry business
Pharmacology (medical), Medicine (miscellaneous), Research, Hypoxemic respiratory failure, Neonatal, Pulmonary hypertension, Aerosols, Nebulizers, Prostaglandins, Clinical trial, Administration, Inhalation, Alprostadil, Early Termination of Clinical Trials, Feasibility Studies, Humans, Hypoxia, Infant, Newborn, Patient Selection, Persistent Fetal Circulation Syndrome, Pilot Projects, Respiratory Insufficiency, Sample Size, Time Factors, Treatment Outcome, United States, Vasodilator Agents
Pharmacology (medical), Medicine (miscellaneous), Research, Hypoxemic respiratory failure, Neonatal, Pulmonary hypertension, Aerosols, Nebulizers, Prostaglandins, Clinical trial, Administration, Inhalation, Alprostadil, Early Termination of Clinical Trials, Feasibility Studies, Humans, Hypoxia, Infant, Newborn, Patient Selection, Persistent Fetal Circulation Syndrome, Pilot Projects, Respiratory Insufficiency, Sample Size, Time Factors, Treatment Outcome, United States, Vasodilator Agents
Microsoft Academic Graph classification: Clinical trial Pulmonary hypertension medicine.disease medicine Saline medicine.medical_treatment Arterial blood Pediatrics medicine.medical_specialty Clinical study design Adverse effect Randomized controlled trial law.invention law Placebo business.industry business
- Duke University
- Stanford University United States
- Department of Pediatrics University of California San Diego United States
- State University of New York at Potsdam United States
- National Institutes of Health United States
4915
Roberts, JD, Fineman, JR, Morin, FC, Shaul, PW, Rimar, S, Schreiber, MD, Polin, RA, Zwass, MS, Zayek, MM, Gross, I, Heymann, MA, Zapol, WM. Inhaled nitric oxide and persistent pulmonary hypertension of the newborn: the inhaled nitric oxide study group. N Engl J Med. 1997; 336: 605-610 [OpenAIRE] [PubMed] [DOI]
Clark, RH, Kueser, TJ, Walker, MW, Southgate, WM, Huckaby, JL, Perez, JA, Roy, BJ, Keszler, M, Kinsella, JP. Low-dose nitric oxide therapy for persistent pulmonary hypertension of the newborn: clinical inhaled nitric oxide research group. N Engl J Med. 2000; 342: 469-474 [OpenAIRE] [PubMed] [DOI]
Truog, WE, Castor, CA, Sheffield, MJ. Neonatal nitric oxide use: predictors of response and financial implications. J Perinatol. 2003; 23: 128-132 [OpenAIRE] [PubMed] [DOI]
Inhaled nitric oxide in full-term and nearly full-term infants with hypoxic respiratory failure: the neonatal inhaled nitric oxide study group. N Engl J Med. 1997; 336: 597-604 [OpenAIRE] [PubMed] [DOI]
Krieg, P, Wahlers, T, Giess, W, Rohde, R, Hartrumpf, M, Bund, M, Haverich, A. Inhaled nitric oxide and inhaled prostaglandin E1: effect on left ventricular contractility when used for treatment of experimental pulmonary hypertension. Eur J Cardiothorac Surg. 1998; 14: 494-502 [OpenAIRE] [PubMed] [DOI]
Walmrath, D, Schermuly, R, Pilch, J, Grimminger, F, Seeger, W. Effects of inhaled versus intravenous vasodilators in experimental pulmonary hypertension. Eur Respir J. 1997; 10: 1084-1092 [OpenAIRE] [PubMed] [DOI]
Kumar, VH, Swartz, DD, Rashid, N, Lakshminrusimha, S, Ma, C, Ryan, RM, Morin, FC. Prostacyclin and milrinone by aerosolization improve pulmonary hemodynamics in newborn lambs with experimental pulmonary hypertension. J Appl Physiol. 2010; 109: 677-684 [OpenAIRE] [PubMed] [DOI]
Putensen, C, Hormann, C, Kleinsasser, A, Putensen-Himmer, G. Cardiopulmonary effects of aerosolized prostaglandin E1 and nitric oxide inhalation in patients with acute respiratory distress syndrome. Am J Respir Crit Care Med. 1998; 157: 1743-1747 [OpenAIRE] [PubMed] [DOI]
Olschewski, H, Simonneau, G, Galie, N, Higenbottam, T, Naeije, R, Rubin, LJ, Nikkho, S, Speich, R, Hoeper, MM, Behr, J, Winkler, J, Sitbon, O, Popov, W, Ghofrani, HA, Manes, A, Kiely, DG, Ewert, R, Meyer, A, Corris, PA, Delcroix, M, Gomez-Sanchez, M, Siedentop, H, Seeger, W. Inhaled iloprost for severe pulmonary hypertension. N Engl J Med. 2002; 347: 322-329 [OpenAIRE] [PubMed] [DOI]
Meyer, J, Theilmeier, G, Van Aken, H, Bone, HG, Busse, H, Waurick, R, Hinder, F, Booke, M. Inhaled prostaglandin E1 for treatment of acute lung injury in severe multiple organ failure. Anesth Analg. 1998; 86: 753-758 [OpenAIRE] [PubMed]
- National Institutes of Health (NIH)
- 5U10HD021385-20
- EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH &HUMAN DEVELOPMENT
- National Institutes of Health (NIH)
- 5U10HD053089-03
- EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH &HUMAN DEVELOPMENT
- National Institutes of Health (NIH)
- 5U10HD027880-24
- EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT
- National Institutes of Health (NIH)
- 5U10HD068278-05
- EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT
- Duke University
- Stanford University United States
- Department of Pediatrics University of California San Diego United States
- State University of New York at Potsdam United States
- National Institutes of Health United States
- National Institute of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development United States
- National Institute of Health (NIH/NICHD) United States
- University of New Mexico Health Sciences Center United States
- The University of Texas Southwestern Medical Center United States
- RTI International United States
- Children's Hospital of Michigan United States
- University of California Los Angeles
- University of New Mexico Health Sciences Center United States
- WOMEN AND INFANTS HOSPITAL-RHODE ISLAND
- NATIONAL INSTITUTE OF HEALTH United States
- University of Iowa
- National Institute of Child Health and Human Development United States
- University of New Mexico
- University of California System United States
- Duke University United States
- University of Iowa United States
- Brown University United States
- UNIVERSITY OF ALABAMA AT BIRMINGHAM
- National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development United States
- National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Development United States
Background Inhaled nitric oxide (INO), a selective pulmonary vasodilator, has revolutionized the treatment of neonatal hypoxemic respiratory failure (NHRF). However, there is lack of sustained improvement in 30 to 46% of infants. Aerosolized prostaglandins I2 (PGI2) and E1 (PGE1) have been reported to be effective selective pulmonary vasodilators. The objective of this study was to evaluate the feasibility of a randomized controlled trial (RCT) of inhaled PGE1 (IPGE1) in NHRF. Methods Two pilot multicenter phase II RCTs are included in this report. In the first pilot, late preterm and term neonates with NHRF, who had an oxygenation index (OI) of ≥15 and <25 on two arterial blood gases and had not previously received INO, were randomly assigned to receive two doses of IPGE1 (300 and 150 ng/kg/min) or placebo. The primary outcome was the enrollment of 50 infants in six to nine months at 10 sites. The first pilot was halted after four months for failure to enroll a single infant. The most common cause for non-enrollment was prior initiation of INO. In a re-designed second pilot, co-administration of IPGE1 and INO was permitted. Infants with suboptimal response to INO received either aerosolized saline or IPGE1 at a low (150 ng/kg/min) or high dose (300 ng/kg/min) for a maximum duration of 72 hours. The primary outcome was the recruitment of an adequate number of patients (n = 50) in a nine-month-period, with fewer than 20% protocol violations. Results No infants were enrolled in the first pilot. Seven patients were enrolled in the second pilot; three in the control, two in the low-dose IPGE1, and two in the high-dose IPGE1 groups. The study was halted for recruitment futility after approximately six months as enrollment targets were not met. No serious adverse events, one minor protocol deviation and one pharmacy protocol violation were reported. Conclusions These two pilot RCTs failed to recruit adequate eligible newborns with NHRF. Complex management RCTs of novel therapies for persistent pulmonary hypertension of the newborn (PPHN) may require novel study designs and a longer period of time from study approval to commencement of enrollment. Trial registration: ClinicalTrials.gov Pilot one: NCT number: 00598429 registered on 10 January 2008. Last updated: 3 February 2011. Pilot two: NCT number: 01467076 17 October 2011. Last updated: 13 February 2013. Electronic supplementary material The online version of this article (doi:10.1186/1745-6215-15-486) contains supplementary material, which is available to authorized users.