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A Randomized, Controlled Study to Assess Growth and Safety of the Exclusive Human Milk Diet (EHMD) in Very Low Birth Weight (VLBW) Infants (<1,500 g)

A Randomized, Controlled Study to Assess Growth and Safety of the Exclusive Human Milk Diet (EHMD) in Very Low Birth Weight (VLBW) Infants (<1,500 g)
JASMINE - JApanese Study of an Exclusive Human MIlk Diet in Premature Neonates

147

Of the 147 subjects randomized, when groups were compared with statistical procedures that may have required Monte Carlo procedures to determine the p-value, no significant differences were seen in the mean birth weight, mean GA, or mean head circumference. Differences in length at birth were also not significant. There were slightly more males than females in the EHMD group, 44 (57.1%) and 33 (42.9%), respectively, in contrast to the Standard Diet group, 33 (47.1%) vs 37 (52.9%), respectively; the sex differences in each group were not statistically significant. There were no meaningful differences in demographic and baseline variables between the ITT population and PPS. Of the 129 subjects in the Japanese Race subset, no significant differences were seen in the mean birth weight, mean GA, mean head circumference, or mean length at birth between the feeding groups. As in the ITT population, there were slightly more males than females in the EHMD group, which was the reverse in the Standard Diet group. The sex distributions were not statistically significant.

There were 147 subjects who were randomized (ITT population). All 147 subjects were included in the Safety population, and 135 subjects were included in the PPS.

Exposure The mean intake of MOM was substantially higher in the EHMD group (3572.46 mL) compared to the Standard Diet group (576.08 mL), with a similar trend for DM intake (EHMD 707.16 mL vs. Standard Diet 94.36 mL). For the EHMD group only, there was variability of exposure to the 3 HM-derived products evaluated on study. By volume, the highest exposure was to PBCLN-008 (mean 1215.81 mL, range: 0 to 4608.8 mL), followed by PBCLN-007 (mean 905.550 mL, range: 29.50 to 2942.60 mL), and PBCLN-009 (mean 303.894 mL, range: 0 to 781.70 mL). Adverse Events The analysis of treatment-emergent adverse events (TEAEs) in the clinical study revealed slight differences between the EHMD and Standard Diet groups, and consistency between the Safety Population and the Japanese Race Subset. In terms of TEAEs, the EHMD group showed slightly higher rates of TEAEs overall, as well as TEAEs assessed as moderate and severe TEAEs compared to the Standard Diet group in both the Safety Population and the Japanese Race Subset. The types of TEAEs observed varied between the 2 feeding groups. In the EHMD group, GI disorders, Infections, and Metabolism and Nutritional disorders were more common, with events such as gastroesophageal reflux disease, pneumonia, and feeding intolerance. The EHMD group had 4 severe TEAEs including death, sepsis, septic shock, and gastrointestinal issues, the majority of which were not treatment related, compared to 2 in the Standard Diet group. In summary, the EHMD group exhibited a slightly higher incidence of TEAEs, compared to the Standard Diet group. Of those TEAEs determined to be severe, only 1 was assessed as treatment related (1 infant with abdominal distension and diarrhea). Overall, the incidence rates and types of TEAEs observed in both groups within this study align with those documented for the VLBW NICU population in Japan. This suggests that the TEAEs observed in this study are reflective of broader trends within the VLBW NICU population in Japan, underlining the relevance and applicability of the findings within this specific context. Morbidity and Mortality Index The assessment of the Morbidity and Mortality Index revealed a higher incidence of predefined clinical outcomes, including BPD and ROP, in the EHMD group compared to the Standard Diet group, but these differences were not statistically significant. Chemistry Parameters The analysis of chemistry parameters revealed few statistically or clinically significant differences between neonatal subjects receiving EHMD and those on the Standard Diet, offering insights into the potential effects of dietary composition on biochemical markers. Nearly all observed differences between treatment groups were sporadic and occurred at different points throughout the treatment period, indicating a metabolic equivalence in the micronutrient content of the two diets. Furthermore, most reported values fell within the expected ranges for premature infants during the initial weeks of life, affirming the nutritional micronutrient adequacy of both dietary approaches. One exception was blood urea nitrogen levels, which were consistently higher in the EHMD group compared to the Standard Diet group from Week 2 through Week 11, indicating potential improvement in protein metabolism or nitrogen balance between the two dietary regimens. Nutritional Laboratory Parameters An analysis of nutritional laboratory markers, prealbumin and IGF-1, between EHMD and Standard Diet groups was limited by a small sample size, particularly for IGF-1, where statistical tests were not feasible for most timepoints.

Primary Endpoints The primary outcome for this study was weight velocity (measured as g/kg/day) in the ITT population. The first planned analysis was a noninferiority analysis, followed by a preplanned subsequent superiority analysis. The mean weight velocity was 13.44+-3.914 g/kg/day in the EHMD group versus 11.96+-3.061 g/kg/day in the Standard Diet control group. The 97.5% lower bound of the one-sided CI for differences in group means was 0.3214 and noninferiority was demonstrated based on the NIM of -1.45 g/kg/day; the subsequent superiority analyses for the ITT population was statistically significantly in favor of the EHMD fed group (p=0.0063). Regression analyses (adjustment model) accounting for GA agreed with the primary superiority analyses between groups. Secondary Endpoints The secondary outcome of weight z-score change was significant (p < 0.0001) between the 2 feeding groups either unadjusted or adjusted (using GA), p < 0.0001, with the EHMD group exhibiting the superior outcome. Growth was also evaluated in terms of length and head circumference (length being a better predictor of lean body mass than weight, and head circumference predictive of better long-term neurodevelopmental outcomes). As z-scores follow a growth of infant trajectory compared to normal growth curves, the less change in z-score is more favorable. Infants who gain weight without good length and head circumference growth are at risk for long term metabolic syndrome (e.g., type 2 diabetes, insulin resistance, obesity). This was not the case for the EHMD group, which showed statistically superior length growth (p = 0.0022, adjusted for gestational age) and near statistically significantly superior head growth (p = 0.0786, adjusted for gestational age) in this regard. Time to full feed, or full feed reached within 2 weeks from birth in both populations was confounded by the fact that most infants were fluid restricted and never reached 160 mL/kg/day (which was defined as full feed) as shown in overall exposure by volume for the study. There were more days on PN initially for the EHMD group, which was significant in the ITT population. There were significantly more ventilator days in the EHMD group, which could have been confounded by the health status of the infant at birth. However, degree of illness or SNAP (Score for Neonatal Acute Physiology) score variables were not collected and specific conclusions regarding degree of critical illness in each population cannot be drawn. Indeed, the GA and birthweights were lower numerically, but not statistically significantly so, in the EHMD group compared to the standard feeding group, which might have led to increased ventilator use. Subjects in the EHMD group had significantly fewer days on antibiotics after 72 hours of age in the EHMD group after adjustment for GA. Less antibiotic usage is often indicative of clinical stability and possibly better outcomes for these infants and may highlight a key benefit with EHMD. Body mass was only measured in a handful of babies in one center. Fat mass was similar between the feeding groups, but with a trend to greater fat-free mass in the EHMD group. While there were too few data to draw conclusions, this trend has been seen with EHMD in other trials and fat-free mass has been linked to better long-term metabolic outcomes. Finally, length of hospital stay and incidence of feeding intolerance events were similar between the study groups in both populations (ITT, PPS) including in and for feeding intolerance in the Japanese race subpopulation for feeding intolerance (hospital length of stay was not evaluated in this sub population).

Significantly improved weight velocity in EHMD-fed infants was demonstrated, with both noninferiority and superiority analyses confirming its effectiveness. The safety evaluation confirmed that the safety profile of EHMD is aligned with expectations for the neonatal Japanese population, showing similar outcomes to the Standard Diet. These results suggest that EHMD is a viable nutritional management strategy for Japanese VLBW infants, facilitating better growth outcomes without heightened safety risks.

June. 30, 2026

Yes

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https://jrct.mhlw.go.jp/latest-detail/jRCT2031210384

Kato Yoshio

DOT WORLD Co., Ltd.

4F NBF COMODIO Shiodome , 2-14-1 Higashi-Shimbashi, Minato-ku, Tokyo

kato.yoshio@crodot.jp

Kato Yoshio

DOT WORLD Co., Ltd.

4F NBF COMODIO Shiodome , 2-14-1 Higashi-Shimbashi, Minato-ku, Tokyo

+81-3-3433-6060

kato.yoshio@crodot.jp

Complete

Oct. 22, 2021

Interventional

randomized controlled trial

open(masking not used)

active control

parallel assignment

treatment purpose

1.VLBW infants (<1,500 g) born before 31 weeks 0 days gestational age
2.Within the first 10 days of life (day 0-10)
3.Diet consisted of 100% exclusive HM (MOM or DM) or NPO prior to study enrollment
4.Willing to follow the study diet and adhere to study procedures per the legal guardian
5.Written informed consent from the legal guardian of the infant
6.Informed consent obtained prior to reaching 50 ml/kg/day because this is when fortification begins

1.Lethal or otherwise significant congenital abnormalities known at the time of inclusion 2.Chromosomal anomalies known at the time of inclusion 3.Known gastrointestinal malformation at the time of inclusion 4.Participation in another intervention trial aiming at having an effect on growth, nutrition, feeding intolerance, or severe complications such as NEC and sepsis in VLBW infants,
however it is permissible to participate in the interventional clinical trial of DM that is currently being run in Japan in parallel with this trial. 5.The subject is unable to start enteral feeding within the first 3 days of life and parenteral feeding within the first 2 days of life 6.Infants who, for medical reasons, cannot receive a feeding volume of at least 130 ml/kg/day 7.In the opinion of the investigator, the subject is incapable of receiving IMP and standard nutritional management. This may be due to very intensive respiratory support, medication needed to assist blood pressure, or need for multiple episodes of cardiopulmonary resuscitation on Days 1-2 of life, among others. 8. Those who have a history of hypersensitivity to the components of this drug. 9. Infant who develops NEC or sepsis prior to randomization must be excluded from the study.

Both

VLBW infants (< 1,500 g), enrolled before day 10 of life.See (5) Additional information throughout.

Subjects will receive either the investigational drug or the standard diet for a maximum of 34 weeks 0 days of gestation. For the investigational drug group at 34 weeks day 1 a subject should take at least 3 days to transition to standard nutrition, and the nutrition transfer completion date is the evaluation end date. At the discretion of the investigator, infants who require continuous standard nutritional support may continue on the study until the time of hospital discharge.

The rate of growth [velocity of weight gain (g/kg/day)] (calculated by Patel's exponential method) during the period from birth to 34 weeks and 0 days of gestation will be evaluated to determine whether the rate of growth of subjects in the EHMD group is inferior to that of subjects in the standard nutrition group, with a non-inferiority margin of -1.45 g/kg/day.

+81-3-5213-0028

Sept. 22, 2021

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