Effects ofMyo-inositol on Type 1 Retinopathy of Prematurity Among Preterm Infants <28 Weeks’ Gestational Age

Abstract

IMPORTANCE Previous studies of myo-inositol in preterm infants with respiratory distress found reduced severity of retinopathy of prematurity (ROP) and less frequent ROP, death, and intraventricular hemorrhage. However, no large trials have tested its efficacy or safety.OBJECTIVE To test the adverse events and efficacy of myo-inositol to reduce type 1 ROP among infants younger than 28 weeks' gestational age. DESIGN, SETTING, AND PARTICIPANTS Randomized clinical trial included 638 infants younger than 28 weeks' gestational age enrolled from 18 neonatal intensive care centers throughout the United States from April 17, 2014, to September 4, 2015 final date of follow-up was February 12, 2016. The planned enrollment of 1760 participants would permit detection of an absolute reduction in death or type 1 ROP of 7% with 90% power. The trial was terminated early due to a statistically significantly higher mortality rate in the myo-inositol group.INTERVENTIONS A 40-mg/kg dose of myo-inositol was given every 12 hours (initially intravenously, then enterally when feeding; n = 317) or placebo (n = 321) for up to 10 weeks. MAIN OUTCOMES AND MEASURES Type 1 ROP or death before determination of ROP outcome was designated as unfavorable. The designated favorable outcome was survival without type 1 ROP. RESULTS Among 638 infants (mean, 26 weeks' gestational age; 50% male), 632 (99%) received the trial drug or placebo and 589 (92%) had a study outcome. Death or type 1 ROP occurred more often in the myo-inositol group vs the placebo group (29% vs 21%, respectively; adjusted risk difference, 7% [95% CI, 0%-13%]; adjusted relative risk, 1.41 [95% CI, 1.08-1.83], P = .01). All-cause death before 55 weeks' postmenstrual age occurred in 18% of the myo-inositol group and in 11% of the placebo group (adjusted risk difference, 6% [95% CI, 0%-11%]; adjusted relative risk, 1.66 [95% CI, 1.14-2.43], P = .007). The most common serious adverse events up to 7 days of receiving the ending dose were necrotizing enterocolitis (6% for myo-inositol vs 4% for placebo), poor perfusion or hypotension (7% vs 4%, respectively), intraventricular hemorrhage (10% vs 9%), systemic infection (16% vs 11%), and respiratory distress (15% vs 13%).CONCLUSIONS AND RELEVANCE Among premature infants younger than 28 weeks' gestational age, treatment with myo-inositol for up to 10 weeks did not reduce the risk of type 1 ROP or death vs placebo. These findings do not support the use of myo-inositol among premature infants; however, the early termination of the trial limits definitive conclusions.

The efficacy and safety of inositol supplementation in preterm infants to prevent retinopathy of prematurity: a systematic review and meta-analysis

“…1). We finally enrolled 6 randomized clinical trials [15, 16, 19, 22–26] for meta-analysis.

Fig. 1Flow of Study Selection.

…”

“…All premature infants were assigned to the inositol group or placebo group. Three RCTs [15, 19, 26] supplied inositol or placebo to infants by intravenous injection firstly and then oral feeding with repeat dose (duration from 5 days to 10 weeks). Phelps 2013 [25] injected inositol or placebo intravenously with a single dose in 20 min.…”

“…Besides that, another meta-analysis also drew the similar conclusion [18]. However, the results of a recently published large multicenter randomized clinical trial (RCT) didn’t support the previous conclusion, which concluded treatment with inositol did not reduce the risk of type 1 ROP or death vs placebo [19]. Given the early termination, the trial was also not formally powered to make a conclusive assessment.…”

Unanticipated Deaths in Randomized Controlled Trials of Very Premature Infants

“…After contemporary evaluations of the pharmacokinetics of inositol in preterm infants, a recent RCT was suspended at 36% enrollment because of a manufacturing problem with the drug. 21,22 Of note, inositol is a nutritional supplement that can be used without oversight by the US Food and Drug Administration, although a parenteral form of the sugar is not available. On review by the DSMC, death was increased from 11% with the placebo to 18% with inositol supplementation (P = .007), severe retinopathy was qualitatively but not statistically increased, and there was no effect on BPD.…”

“…Of note, inositol was given within the first 2 hours of life and for 5 days in the 1992 trial, and the recent trial started therapy at 72 hours of life and continued for 10 weeks. 20,22 The caution is that a therapy that is biologically plausible and previously demonstrated to be effective may actually cause harm in very preterm infants. In contemporary practice, DSMC oversight is essential to limit harm.…”