Safety Assessment of ELGN-2112 (Insulin Human) in Preterm Infants with Intestinal Malabsorption: A Double-Blind, Randomized, Placebo-Controlled Study

The primary objective of this study is to compare the **safety** of treatment with ELGN-2112 to placebo in preterm infants born less than 26 weeks gestational age (GA) and infants with intrauterine growth restriction (IUGR) below the 3rd percentile born at 26-32 weeks GA. This is clinically relevant as it aims to ensure the safety of ELGN-2112, a potential therapeutic intervention, in a vulnerable population of preterm and growth-restricted infants, who are at increased risk for complications.

Secondary objectives include:

• Assessing the efficacy of ELGN-2112 compared to placebo on **intestinal malabsorption** in preterm infants, measured by the time to full enteral feeding.
• Evaluating the effect of ELGN-2112 on the incidence and severity of **Necrotizing Enterocolitis (NEC)**, including the incidence of modified Bell’s stage grade ≥2a and the distribution of NEC severity.
• Determining the effect of ELGN-2112 on the number of days until full wean off parenteral nutrition (PN) and the time to achieve 120 ml/kg/day enteral feeding for three consecutive days.
• Examining the effect of ELGN-2112 on the percentage of enteral/parenteral feedings from total nutrition over time and the percentage of infants with culture-proven nosocomial **sepsis**.
• Assessing the percentage of infants experiencing adverse events of relevance, such as NEC, infections, and death.
• Evaluating the effect of ELGN-2112 on the number of days to discharge from the primary hospital and to discharge home.
• Investigating the effect of ELGN-2112 on **anthropometrics** and the activity score of **Retinopathy of Prematurity (ROP)** at 30-36 weeks postmenstrual age.
• Assessing the number of days until PN wean off, specifically the time to amino acids and lipids withdrawal.

The clinical trial involves a total of **55 participants**, focusing on preterm infants with **Intestinal Malabsorption**. The study population includes both male and female infants, specifically those born less than 26 weeks gestational age (GA) or Intra-Uterine Growth Restricted (IUGR) infants below the 3rd percentile, born between 26 to 32 weeks GA. Participants were selected based on specific criteria, including a birth weight of at least 450 grams, singleton or twin birth, and postnatal age up to and including Day 5. Infants must demonstrate cardiovascular stability and be able to tolerate enteral feeds, with an expectation to wean off parenteral nutrition at the primary hospital. The trial population is considered vulnerable, and informed consent was obtained from parents or legal guardians. The study does not specify any particular lifestyle considerations such as diet or physical activity, as the focus is on the health status and stability of the infants at the time of enrollment.

The clinical trial is designed as a **randomized**, **double-blind**, placebo-controlled study to evaluate the safety of ELGN-2112 in preterm infants with **intestinal malabsorption**. The trial will involve two arms: one receiving the investigational product, ELGN-2112, and the other receiving a placebo. The study will be conducted over a period of approximately 8 years, with an estimated recruitment start date in March 2025 and an estimated end date in August 2033. The trial will include preterm infants born less than 26 weeks gestational age (GA) and intrauterine growth-restricted (IUGR) infants born between 26 and 32 weeks GA.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on specific criteria, such as birth weight, gestational age, and cardiovascular stability. Following successful screening, participants will be randomized to receive either ELGN-2112 or placebo. The study will include multiple follow-up visits to monitor safety and efficacy endpoints, such as the number of days to achieve full enteral feeding and the incidence of necrotizing enterocolitis. The end-of-study visit will occur after the completion of the treatment period, which is a maximum of 42 days, to assess the primary and secondary endpoints.

The expected length of participant involvement is up to 42 days, with conditions for early termination including significant adverse events or if the infant is deemed unstable by the investigator. The primary endpoint is the safety of ELGN-2112 compared to placebo, while secondary endpoints include the time to achieve full enteral feeding and the incidence of nosocomial sepsis. The trial will adhere to rigorous ethical standards, with informed consent obtained from parents or legal guardians prior to participation.

The clinical trial involves the administration of **ELGN-2112**, an experimental medication formulated as an **oral solution**. The active substance in ELGN-2112 is **insulin human**, a protein of non-synthetic origin. The medication is specifically designed for pediatric use and is administered via an **enteral feeding tube**. The dosing regimen for ELGN-2112 is set at a maximum of 0.3 IU/kg per day, with the total dose not exceeding 0.3 IU/kg over the course of the treatment. The maximum treatment period is 42 days. The study aims to evaluate the safety of ELGN-2112 in preterm infants born less than 26 weeks gestational age and infants with intrauterine growth restriction (IUGR) below the 3rd percentile born at 26-32 weeks gestational age, as per the Fenton preterm growth chart.

The trial also includes a **placebo** group, which serves as the comparator treatment. The placebo is administered in the form of a powder for reconstitution for enteral administration. The placebo is designed to match the experimental treatment in appearance and administration route to maintain the double-blind nature of the study. The placebo does not contain any active pharmaceutical ingredients and is used to assess the safety profile of ELGN-2112 by providing a baseline for comparison.

The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint focuses on the safety of ELGN-2112 compared to placebo in preterm infants born under 26 weeks gestational age (GA) and **Intra-Uterine Growth Restricted (IUGR)** infants born between 26-32 weeks GA. Secondary endpoints include several parameters: the number of days to achieve full enteral feeding, defined as the first day the preterm infant can achieve enteral feeding of at least 150 ml/kg/day for three consecutive days; the number of days until weaning off parenteral nutrition (PN); and the incidence and severity of Necrotizing Enterocolitis (NEC), with specific attention to the incidence of modified Bell’s stage grade ≥2a of NEC and the distribution of severity according to modified Bell’s staging.

Additional secondary endpoints include the number of events of culture-proven nosocomial sepsis, the percentage of subjects experiencing adverse events of relevance such as NEC, infections, or death, and the number of days to reach 120 ml/kg/day for three consecutive days. The trial will also measure the number of days until PN wean off, the percentage of enteral/parenteral feedings from total nutrition over time, the number of days to discharge from the primary hospital, and the number of days from randomization to discharge home. Anthropometric measurements and the retinopathy of prematurity (ROP) activity score at 30-36 weeks postmenstrual age (PMA) will also be evaluated.