Title: Safety and efficacy of ninjin’yoeito along with iron supplementation therapy for
preoperative anemia, fatigue, and anxiety in patients with gynecological disease: an open-label,
single-center, randomized phase-II trial
Version: 2 Date: 28 Mar 2022
Reviewer:  Naruto Taira
Reviewer's report:
This study is a randomized controlled trial of the efficacy and safety of administration
of Ninjin'yoeito (NYT) in addition to iron supplementation in preoperative patients with
gynecological diseases with anemia. Although the sample size is small and the results should be
interpreted with caution, additional administration of NYT showed a significant improvement
in fatigue, as assessed based on CFS. This is one of the few trials showing that NYT may be
effective, and thus, the results are meaningful. However, there are many inconsistencies in the
text and there seems to be insufficient confirmation of the findings. My comments are below.
1. Abstract
# Is the statement "the difference in the elevations in Hb between both groups was statistically
insignificant (P = 0.72)." in the Results section correct? The p-value has not reached a
significance level.
#There was no significant difference in the change in the outcome index for anemia between the
two groups. Therefore, the statement that "NYT administration along with iron supplementation
safely and efficiently improved the preoperative anemia, fatigue and anxiety." in the Conclusion
section is not accurate.
2. Methods
# There are two time points for observation of the outcome index: at registration and at
admission. Could this study design cause a difference in the duration of intervention between the
two groups; that is, an observation bias? A full explanation of the potential bias in the observation
period is required.
#Please describe the basis for setting the sample size.
# In the description of the statistical analysis, it is insufficient to just describe the test method.
Please also include the variables used for each outcome and how the comparison between the
groups was performed.
3. Results
# At the beginning of the Results, there is a statement that "3 patients were excluded because their
NYT administration period was <10 days", but in the study consort shown in Fig. 1, these 3 cases
are included in the iron supplementation group. Please explain or correct this inconsistency.
# ITT analysis seems to be the principle method used for comparison in randomized controlled
trials. For example, cases with a NYT administration period <10 days were excluded from the
analysis, but it is extremely arbitrary to exclude these cases if they are in compliance with NYT
adverse events. There is a need for a detailed description of the justification for exclusion of
subjects based on an administration period of <10 days, as well as why the three excluded cases
had low dosing compliance.
# As mentioned above regarding the observation bias, the intervention period did not differ
significantly between the groups, but the data in Table 1 indicate that this period has a wide
SD range. Therefore, in addition to showing the SD for the intervention period, please include
information on the shortest and longest intervention periods.