Pediatric Academic Societies' 2005 Annual Meeting LATE-BREAKER PLATFORM PRESENTATION. Late Breakers II: Clinical Trials in Neonatology Monday, May 16, 3:00pm-5:00pm Room 147 (Washington Convention Center)

Randomized Controlled Trial for the Prevention of Intraventricular Hemorrhage by Indomethacin in Japanese Extremely Low Birth Weight Infants. Masanori Fujimura, Shinya Hirano, Satoshi Kusuda, Hirofumi Aotani, Noriyuki Nakanishi. On behalf of the Neonatal Research Network Japan, Osaka, Japan Disclosure: The trial vials (indomethacin and placebo) were manufactured by Banyu, a subsidiary of Merck & Co. Inc., NJ, USA. The research grant from Dept. of Maternal and Child Health, Ministry of Health and Welfare, Japan. BACKGROUND: Prophylactic indomethacin(IND) has been shown to reduce the severe intraventricular hemorrhage(IVH) in extremely low birth weight infants. According to the Cochrane Systematic Review it still remains to be studied on the optimal dosage and the optimal target population.

OBJECTIVE: To study the efficacy and complications of low dose IND with six hours’ continuous infusion in the reduction of severe IVH in Japanese ELBW infants. DESIGN/METHODS: A multicenter prospective randomized double-blind placebo controlled trial was conducted in 21 Level-3 NICUs in Japan. Newborn infants with birth weight between g were randomized into IND or placebo groups. Eligibility: To fulfill all of the following; 1. Birth weight: 400g-999g 2. Gestation: 22 weeks 0 day ≤ weeks ≤ & birth weight standard deviation -2.0< 4. Initial dose starting within 6 hours of age 5. Informed consent

Randomization : Eligibility of the subject was examined and randomized within six hours of birth using the robot system on the Internet. Infants were stratified according to: Unit(1-21), one-min Apgar score(0-3/4-), gender, gestation(22-, 24-, 27-), and in/out born. Randomization was made using Pocock’s minimizing method & Zelen’s dynamic balancing of institutions. Statistical Methods: Intent-to-treat rule, Fisher’s exact test, and Logistic regression analysis using multiple regression model. Institutional Review: The study protocol was reviewed by IRB, and a written informed consent was obtained.

718 infants assessed for eligibility 50 : Excluded IVH grade3 or 4 within 6 hrs of age(16) PDA requiring intervension(12) Significant birth defects(9), Bleeding(13), Platelets<50,000/mm3(7), NEC(0), Maternal IND 48 hrs prior to birth(0) 67 : Not approached 469 infants were randomized 235 infants were assigned to the IND group 234 infants were assigned to the placebo group Nov – Aug : No consent 601 infants eligible

Intervention Starting within 6 hours of birth 3 doses of IND or placebo were given with 6 hours continuous i.v. infusion every 24 hours. IND was given at the dose of 0.1 mg/kg-wt/dose. Adding 0.5mg vitamin K, each covered vial for trial was colored to mask the faint yellow before use. This dose substitutes the routine vit. K. Primary outcome Grade 3 and 4 IVH assessed by serial ECHO within 7 days. Cranial ECHO and Echocardiographic Examination: Performed on all infants prior to the first dose, on days 1, 2, 3, 4, 6 and 2nd, 3rd week, and at discharge from the unit.

Characteristics IND (N=235) Placebo (N=234) p value Gestation(wks) 26.1± ±1.6 NS Birth weight(g) 775.2± ±139.8 NS Male / Female105 / / 129NS In-born / Out-born190 / 45190/ 44NS Apgar score at 1 min 4.4 ± ±2.3 NS Apgar score at 5 min 6.7 ± ±1.9 NS Primipara119 (50.6%)109 (46.6%)NS Singleton / Multiple189 / / 46NS Vaginal / C-section64 / / 166NS Antenatal steroids103 (43.8%)102 (43.6%)NS RESULTS: Base-Line Perinatal Characteristics Blue indicates stratified factors. Mean±1SD

Variable IND (N=235) Placebo (N=234) p value Birth weight <-1.5 SD for gestation 28 (11.9%) 30 (12.8%)NS Respiratory Distress Syndrome182 (77.4%)187 (79.9%)NS Pneumothorax 5 (2.1%) 8 (3.4%)NS Received surfactant 0-6 days190 (80.9%)197 (84.2%)NS Received phenobarbital 0-6days 114 (48.5%)122 (52.1%)NS Base-Line Characteristics of Infants

Outcome IND N/total N (%) Placebo N/total N (%) Odds Ratios Crude Adjusted (95%CI) p value IVH 3 or 4 <7 days 16 / 235 (6.8%) 32 /234 (13.7%) ( )0.007 PDA on day 6 42 / 230 (18.3%) 93 / 229 (40.6%) ( ) <0.001 RESULTS: Primary Outcomes

Outcomes IND (N=235) Placebo (N=234) Odds Ratios Crude Adjusted 95%CI p value IVH grade 3 or 4 within 28 days 17 (7.2%) 37 (15.8%) ( ) Died within 7 days 6 (2.6%) 7 (3.0%) NS Died within 28 days 13 (5.5%) 16 (6.8%) NS All death or IVH (12.8%) 47 (19.7%) ( ) RESULTS: Other Major Outcomes

Gestation (weeks) IND (N=235) Placebo (N=234) p value IVH3,4 / total N(%) 22 0 / 1 (0%) 4 / 4 (100%) / 22 (13.6%) 7 / 18 (38.9%) 24 3 / 35 (8.6%) 11 / 35 (31.4%) 25 7 / 53 (13.2%) 5 / 33 (15.2%) 26 3 / 48 (6.3%) 8 / 68 (11.8%) / 76 (1.3%) 2 / 76 (2.6%)NS IVH 3, 4 and Gestational Age Groups (<28 days)

Birth Weight IND (N=235) Placebo (N=234) p value IVH3,4 / total N 400g- 0 / 3 (0%) 4 / 8 (50.0%) < g- 3 / 19 (15.8%) 7 / 19 (36.8%) 600g- 4 / 50 (8.0%) 8 / 37 (21.6%) 700g- 5 / 54 (9.3%) 11 / 52 (21.2%) 800g- 3 / 60 (5.0%) 5 / 61 (8.2%) NS 900g- 2 / 49 (4.1%) 2 / 57 (3.5%) IVH Grade 3, 4 and Birth Weight Groups (<28 days)

IVH Grade IND (N=235) Placebo (N=234) NDiedN No IVH IVH IVH and Mortality (<28 days)

Outcome IND (N=235) Placebo (N=234) p value PDA requiring PG inhibitor 49 (20.9%)108 (46.2%)<0.001 Surgical closure of PDA 17 (7.2%) 22 (9.4%)NS Pulmonary hemorrhage 10 (4.3%) 27 (11.5%)0.004 Necrotizing enterocolitis 5 (2.1%) 9 (3.8%)NS Ventricular dilatation 28 (12.0%) 45 (19.2%)0.021 Periventricular leucomalacia 9 (3.8%) 5 (2.1%)NS Hydrocephalus requiring shunt or reservoir 3 (1.3%) 6 (2.6%)NS Secondary Outcomes

Reasons for Withholding Doses Reasons for Withholding Doses IND (N=235) Placebo (N=234) p value Deteriorating condition 8 9 NS Oliguria 0.5ml/kg/hr 3 1 NS IVH grade 3 or Platelet <50,000/mm3 3 0 NS Bleeding 0 0 Necrotizing Enterocolitis 2 0 NS Infant died 0 0 Consent withdrawn 0 0

Variable IND (N=235) Placebo (N=234) p value Adverse reactions <7 days8075NS Oliguria 0.5ml/kg/hr4447NS Abnormal electrolytes Increased BUN or creatinine1416NS Abnormal blood glucose94NS Adverse Reactions

CONCLUSIONS 1.This study confirms, in Japanese extremely low birth weight infants, the previous studies that the early prophylactic indomethacin is effective in reducing the severe form of IVH and PDA. 2.In infants less than 27 weeks (<800g) the indomethacin was effective in the prophylaxis of IVH grade 3 and 4. 3.Three doses of 0.1 mg/kg-wt indomethacin with 6 hours’ continuous i.v. infusion every 24 hours was shown effective without the increased risk of adverse events. 4.Significant reduction of severe IVH could be achieved with the use of early IND strategy.

Neurological function at 18 months and 3 years is under investigation. The authors are grateful for the collaboration given by Dr. Linda Wright, NICHD, and Dr. Sumner J. Yaffe.