Review Reports

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The study demonstrates that the newly developed ready-to-drink enteral formula was not inferior to the commercially available powdered formula with respect to short-term nutritional outcomes, including changes in PG-SGA score, tolerability, and selected anthropometric and biochemical parameters. However, I would appreciate additional discussion of several aspects that may affect the interpretation of the results.

First, although participant allocation was randomized, there appear to be notable baseline differences between the groups. In particular, the standard formula group included only one female participant and appeared to be older on average than the intervention group. The authors should comment on whether these imbalances could have influenced the observed outcomes and discuss their potential impact on the study's conclusions.

Second, the calcium content of the novel formula was substantially lower than that of the commercially available formula (approximately 25-fold lower). While no differences were observed during the one-month intervention period, the authors should discuss the potential implications of prolonged consumption of this formula, particularly in patients with head and neck cancer who may already be at increased risk of nutritional deficiencies and compromised bone health. A discussion of whether calcium supplementation or reformulation may be warranted for long-term use would strengthen the manuscript.

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

This article addresses a topic of high clinical and public health relevance, focusing on nutritional support for patients with head and neck cancer receiving enteral feeding. The study also explores the potential clinical utility of a ready-to-drink enteral formula, which may offer practical advantages in preparation, hygiene, and cultural acceptability. However, upon review, there are several aspects that require improvement to enhance the methodological rigor, completeness, interpretability, and scholarly value of the manuscript.

1. The title clearly indicates the study population, intervention, and general study design; however, it does not explicitly state that this is a non-inferiority randomized controlled trial. This distinction is important because the interpretation of the findings differs substantially from a superiority trial. In addition, the inclusion of “muscle strength” in the title may overemphasize a secondary outcome, whereas the primary endpoint is the change in PG-SGA score. The authors should consider revising the title to better reflect the main objective, such as nutritional non-inferiority or PG-SGA-based nutritional status, and reconsider whether muscle strength should remain in the title.
2. The abstract is generally well structured, but several important details are insufficiently reported. First, the abstract does not clearly state that this was a single-center study with only 30 participants and a short 4-week follow-up period, which may lead readers to overestimate the generalizability of the findings. Second, although the non-inferiority margin of 2 points is reported, its clinical justification is not sufficiently explained in the abstract. Third, the conclusion states that PSU Blen is supported as a practical ready-to-drink formula, but this statement may be too strong because preparation time, microbial contamination risk, cost-effectiveness, caregiver burden, quality of life, and patient satisfaction were not directly assessed. A more cautious conclusion would be appropriate.
3. The introduction adequately describes the burden of malnutrition in patients with head and neck cancer and the need for enteral nutrition; however, the rationale for the study could be strengthened. The authors mention limitations of powdered or blenderized formulas, such as labor-intensive preparation, inconsistent composition, and contamination risk, but they do not sufficiently explain why Blendera was selected as the comparator or how representative it is of standard clinical practice. Furthermore, the proposed advantages of PSU Blen, including convenience, reduced contamination risk, and Halal certification, are mostly theoretical in the introduction. The authors should provide stronger background evidence regarding the product’s prior safety, microbiological quality, nutritional stability, and clinical use. The justification for using PG-SGA change as the primary non-inferiority endpoint and for selecting a 4-week follow-up period should also be more clearly explained.
4. The methodology requires substantial clarification. First, the study began enrollment in April 2024, but trial registration was completed in July 2025, after enrollment had already commenced. Although the authors explain that this was due to administrative delay and state that registration occurred before data analysis, the delayed registration remains a methodological concern. The authors should clearly report the date of first participant enrollment, completion of recruitment, data lock, and statistical analysis. Second, the sample size was very small, with only 15 participants per group, and the non-inferiority margin of 2 PG-SGA points requires stronger clinical and statistical justification. Third, the trial was open-label, and although outcome assessors were blinded, PG-SGA includes subjective patient-reported components that may be influenced by knowledge of treatment allocation. Fourth, baseline age differed significantly between groups, and sex, body weight, and BMI also appeared imbalanced; therefore, adjusted analyses for clinically important baseline variables should be provided. Fifth, the exclusion of patients with diabetes because Blendera contains sugar may reduce the generalizability of the results, as metabolic comorbidities are common in clinical populations. Sixth, the authors state that participants received only the assigned formula, but adherence monitoring, actual intake, leftover volume, and achievement of prescribed energy and protein targets are not sufficiently described. Finally, the two formulas differed substantially in several micronutrients, including calcium, iron, zinc, vitamin D, and vitamin B12, and the potential implications of these compositional differences should be discussed.
5. The results are clearly presented but require more cautious interpretation. First, the authors describe baseline characteristics as generally comparable, although age differed significantly and sex, body weight, and BMI showed noticeable imbalance. This should be explicitly acknowledged and addressed through adjusted or sensitivity analyses. Second, the baseline PG-SGA scores were relatively low, suggesting that the participants had limited nutritional risk at study entry; this may have reduced the ability to detect clinically meaningful differences over only 4 weeks. Third, although the authors state that intention-to-treat and per-protocol analyses were identical, non-inferiority trials generally require both analyses to be clearly presented. Fourth, secondary outcomes were not significantly different between groups, but the authors should provide effect sizes or clinically meaningful thresholds rather than relying mainly on p-values. Fifth, the absence of any gastrointestinal intolerance in both groups seems unusually favorable for a tube-fed head and neck cancer population; the authors should clarify how adverse events were actively assessed, defined, and recorded. Sixth, serum potassium was significantly higher in the Blendera group at week 4, and although values remained within the normal range, this finding should be briefly interpreted.
6. The discussion is generally comprehensive, but some interpretations appear overstated. The authors suggest that ready-to-drink formulas may offer advantages in convenience, hygiene, preparation standardization, and reduced microbial contamination; however, these outcomes were not directly measured in the present study. Therefore, these should be framed as potential advantages rather than demonstrated findings. Similarly, the discussion of Halal certification is relevant but should be more cautious, as religious acceptability, adherence, patient preference, and cultural suitability were not evaluated. The comparison with previous studies should also more clearly address differences in study populations, cancer treatment phase, formula type, nutritional risk, and follow-up duration. In addition, the limitations section should more explicitly discuss delayed trial registration, open-label design, small sample size, baseline imbalance, potential institutional conflict of interest because PSU Blen was developed by the same university, and the relatively low baseline PG-SGA scores. The proposed future direction regarding gut microbiota is interesting but should be better linked to the current study or shortened.
7. The conclusion is consistent with the main results but should be more conservative. The current wording suggests that PSU Blen can be supported as a practical ready-to-drink enteral nutrition alternative. However, because this was a single-center, small-sample, short-term study involving clinically stable patients with relatively low baseline nutritional risk, the conclusion should not be generalized to all patients with head and neck cancer, patients undergoing active chemoradiotherapy, severely malnourished patients, or long-term home enteral nutrition populations. The conclusion should state that PSU Blen demonstrated short-term non-inferiority to Blendera under the conditions of this study and that larger, multicenter, longer-term trials are needed to confirm its clinical value, cost-effectiveness, safety, acceptability, and practical advantages.
8. The figures and tables are informative but could be improved. Table 1 shows substantial differences in micronutrient composition between the two formulas, particularly calcium, iron, zinc, vitamin D, and vitamin B12, but the manuscript does not sufficiently explain how these differences may affect interpretation. The authors should consider presenting estimated daily nutrient intake based on prescribed feeding volume rather than only values per 100 kcal. Table 2 shows significant age imbalance and possible imbalance in sex, body weight, and BMI; these should be highlighted and considered in adjusted analyses. Table 3 presents the non-inferiority analysis clearly, but the authors should explicitly show both intention-to-treat and per-protocol results and consider adding a visual non-inferiority plot with the prespecified margin. Figures 2 and 3 present medians and interquartile ranges, but given the small sample size, individual data points or participant-level trajectories would improve transparency. Table 4 should more clearly define the direction of the between-group difference in change to avoid misinterpretation. Table 5 should include normal reference ranges, especially because potassium differed significantly between groups while the authors state that values remained clinically normal.

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Reviewer 3 Report

Comments and Suggestions for Authors

I received an interesting article for review. This manuscript presents a randomized controlled non-inferiority trial comparing a ready-to-drink enteral formula (PSU Blen) with a powdered standard formula in patients with head and neck cancer. 

The topic is clinically relevant, and the manuscript is generally well written. The results suggest that the tested formula is non-inferior; however, several methodological and interpretative limitations should be addressed before publication.

Major comments

-Small sample size and limited statistical power
The study includes only 30 participants (n=15 per group), which substantially limits the robustness of the non-inferiority conclusion. Although the sample size calculation is provided, such a small cohort increases the risk of type II error and limits the detection of clinically meaningful differences.

-Short follow-up period
The intervention lasted only 4 weeks, which is insufficient to assess meaningful changes in nutritional status, muscle mass, or long-term outcomes. This limitation should be more explicitly discussed, particularly in the context of chronic nutritional support in oncology patients.

-Limited generalizability
The study population consisted of clinically stable patients in the follow-up phase after treatment. Therefore, the findings cannot be generalized to patients undergoing active chemoradiotherapy, who are at higher risk of malnutrition and metabolic complications.

-Open-label design
The lack of blinding may introduce performance bias, especially in feeding administration and caregiver-dependent outcomes. While assessor blinding is noted, the implications should be discussed.

-Restricted outcome measures
Key clinical endpoints are missing, including quality of life, patient satisfaction, caregiver burden, and cost-effectiveness.

These are particularly relevant for evaluating ready-to-use nutritional formulas and should at least be acknowledged as important limitations.
-Limited assessment of muscle function
Muscle function was assessed only by handgrip strength. Additional functional or body composition measures (e.g., bioimpedance analysis, gait speed) would strengthen the conclusions.

-Non-inferiority margin justification
The choice of a 2-point PG-SGA margin requires stronger clinical justification. It is unclear whether this threshold reflects a truly clinically acceptable difference in this population.

-Potential institutional bias
The tested product (PSU Blen) was developed by the authors’ institution. Although a conflict of interest is formally denied, this should be more transparently discussed in terms of potential bias.

My minor comments

-The authors should clarify whether adherence to prescribed caloric intake was monitored and how compliance was ensured.
-Provide more details on feeding administration (e.g., variability in caregiver involvement).

-Consider adding a CONSORT checklist as supplementary material.

-Improve clarity of Table 1 (micronutrient differences appear substantial and deserve a brief discussion).

-Expand discussion on clinical implications beyond non-inferiority (e.g., real-world use cases).

 

 

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

The authors have substantially revised the manuscript and addressed most of the previous concerns satisfactorily. The revised version now more clearly presents the study as a non-inferiority randomized controlled trial and better clarifies the primary PG-SGA endpoint. Additional methodological details have been provided, including the trial registration timeline, randomization procedure, adherence monitoring, adverse-event assessment, and the distinction between intention-to-treat and per-protocol analyses.

The Introduction has been improved by providing a clearer rationale for using Blendera as the active comparator and by better explaining the clinical relevance of PSU Blen. The Abstract and Conclusion have also been revised to present the findings in a more cautious and appropriate manner. In addition, the authors have added sensitivity analyses to address baseline imbalances and improved the reporting of secondary outcomes.

The presentation of tables and figures has also been strengthened, including clearer footnotes, the addition of individual participant data points, and normal reference ranges for laboratory parameters. Overall, the revised manuscript is clearer, more balanced, and more transparent than the previous version. I recommend minor language and editorial revision before final consideration.

Reviewer 3 Report

Comments and Suggestions for Authors

The authors have adequately addressed the major methodological concerns.   The revised manuscript provides a transparent and appropriately cautious interpretation of the findings.   Although limitations related to sample size, follow-up duration, and late trial registration remain, these are clearly acknowledged and do not invalidate the primary non-inferiority conclusion.