Background: Breastmilk is the most appropriate food for infants and exclusive breastfeeding is highly recommended for the first six months of life to promote adequate growth and development and lower infant morbidity and mortality. Among the best-documented benefits of breastfeeding is the reduced risk of disease and infections such as pneumonia, diarrhea and acute otitis media. Nonetheless, there are situations in which the infant cannot be breastfed; therefore, it is essential to use an appropriately designed infant formula. As current infant formulas incorporate novel ingredients to partly mimic the composition of human milk, the safety and suitability of each specific infant formula should be tested by clinical evaluation in the target population. Here, we report the results of a multicenter, randomized, blinded, controlled clinical trial that aimed to evaluate a novel starting formula on weight gain and body composition of infants up to 6 and 12 months (INNOVA 2020 study), as well as safety and tolerability. The complete protocol of this study has been previously issued. Study design: 210 infants (70/group) were enrolled in the study, and completed the intervention until 12 months of age. For the intervention period, infants were divided into three groups: group 1 received the formula 1 (Nutriben Innova1 or INN), with a lower amount of protein, and enriched in alpha-lactalbumin protein, and with a double amount of docosahexaenoic acid (DHA)/ arachidonic acid (ARA) than the standard formula; it also contained a thermally inactivated postbiotic (Bifidobacterium animalis subsp. lactis, BPL1TM HT). Group 2 received the standard formula or formula 2 (Nutriben Natal or STD) and the third group was exclusively breastfed for exploratory analysis and used as a reference (BFD group). During the study, visits were made at 21 days, 2, 4, 6, and 12 months of age, with 3 days for the visit at 21 days of age, 1 week for the visit at 2 months, and 2 weeks for the others. During the first 6 months of the study, and until obtaining the main variable, the infants were only supplied with the starting formula or natural breastfeeding. Results: The primary outcome, weight gain, was higher in both formula groups than in the BFD group at 6 and 12 months, whereas no differences were found between STD and INN groups neither at 6 nor at 12 months. Likewise, BMI was higher in infants fed the two formulas compared with the BFD group. Regarding body composition, length, head circumference and tricipital/subscapular skinfolds were alike between groups. The INN formula was considered safe as weight gain and body composition were within the normal limits, according to WHO standards. The BFD group exhibited more liquid consistency in the stools compared to both formula groups. All groups showed similar digestive tolerance and infant behavior. However, most adverse events were reported by the STD formula group (291), followed by the INN formula (282) and the BFD groups (227). Nonetheless, most of the adverse events (95.5%) were not considered to be related to the type of feeding There were fewer respiratory, thoracic, and mediastinal disorders among BFD children. Additionally, infants receiving the INN formula experienced significantly fewer general disorders and disturbances than those receiving the STD formula Indeed, atopic dermatitis, bronchitis, and bronchiolitis were significantly more prevalent among infants who were fed the STD formula compared to those fed BFD formula or INN formula. To evaluate whether there are significant differences between formula treatments, beyond growth parameters, it would seem necessary to examine more precise health biomarkers including those based on omics sciences, such as metabolomics, proteomics and metagenomics.

The present study was funded by Alter Farmacia S. A. The funding sponsor had no role in the design of the study, the collection, analysis, or interpretation of the data, and the writing of the manuscript.

NCT05303077

https://clinicaltrials.gov/ct2/show/NCT05303077

The present study was funded by Alter Farmacia S. A. The funding sponsor had no role in the design of the study, the collection, analysis, or interpretation of the data, and the writing of the manuscript.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

This clinical trial was carried out following the recommendations of the International Conference on Harmonization Tripartite, the ethical-legal principles established in the latest revision of the Declaration of Helsinki, as well as the current regional regulations that regulate pharmacovigilance and food safety. The study protocol and any material delivered to the subject, as well as any advertising material or compensation offered to the participating subjects. Prior to the study start, the Ethics Committee approves the study for Drug Research (ECDR). This approval was documented in a letter sent to each researcher specifying the date on which the ECDR met to give its approval. The present study was approved by the CEIm-R, the Committee for Technical Investigation in Regional Medicine in the Madrid Community (CEIm-R) dated 11/05/2018 under the name INNOVA2020 version 2.0. All personal data obtained in this study are confidential. They were treated in accordance with the Spanish Organic Law 3/2018, of December 5, on the Protection of Personal Data and guarantee of digital rights. The researcher or the institution allowed direct access to the data or source documents for monitoring, auditing, and review by the ECDR. This also allowed inspection of the trial by the health authorities.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

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I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.

Yes

All data produced in the present study are available upon reasonable request to the authors