Table 4.

Proposed study design: Long-term metabolic and neurodevelopmental outcomes following early hyperglycemia treatment in preterm infants receiving standardized nutrition

Study population	Very low birth weight (VLBW) infants (<32 weeks or <1500 grams)
Study design	Multi-center prospective international cohort and randomized control trial
Study groups	(1) Normoglycemia (2) Hyperglycemia
Treatment Randomization	Reduction of GIR to basal metabolic caloric needs followed by insulin versus no nutritional modification with insulin
Hyperglycemia	Blood glucose over 150 mg/dL (>8.3 mmol/L) ≥4 hours during the first two weeks of life
Treatment threshold	Blood glucose over 180 mg/dL (>10 mmol/L) ≥4 hours during the first two weeks of life
Assessment (glucose)	Continuous glucose monitoring
Nutrition	Standardized parenteral and enteral nutrition and vitamin supplementation during the first 2 weeks of life
Estimated sample size	N=750 (normoglycemia=250, hyperglycemia=500; 250 randomized to GIR reduction with or without insulin, 250 randomized to insulin) calculated by assumption of a 65% follow-up rate to detect a 15% difference in primary outcome between groups at 80% power at an alpha level of 0.05.
Assessment (time)	12-months PMA, 24-months PMA, 5-years of age, 15-years of age
Primary outcome	Survival without significant metabolic or neurodevelopmental impairment at 5-years of age*.
Secondary outcomes	Individual components of primary outcome, anthropometrics, BSID-III, need for glasses, body composition, glucose metabolism, quality of life measurements
Modifying variables	Insulin treatment, sex, duration/severity of hyperglycemia
Confounding variables	Maternal characteristics, demographic characteristics, infant characteristics, morbidities associated with preterm birth, food consumption, social determinants of health, hypoglycemia

^*Any of the following: BMI≥85 percentile, fasting glucose≥100 mg/dL, HbA1c≥5.7%, sBP or dBP>95 percentile, cerebral palsy, Movement Assessment Battery for Children-2 (MABC-2) total score ≤ 5^th percentile, hearing impairment requiring hearing aids, visual acuity of 6/60, full scale IQ standard score > 1 standard deviation below the mean, visual acuity of 6/60 or worse in best eye, ADHD/Mental health diagnosis requiring behavior/psychological therapy, early intervention, or medication.