Title: Randomized study on the effectiveness of nomegestrol acetate plus 17#-estradiol oral
contraceptive vs dienogest oral pill in women with suspected endometriosis#associated chronic
pelvic pain
Version: 2 Date: 07 Mar 2022
Reviewer's report:
Dear Authors,
First, I would like to congratulate you for conducting the study. We know how difficult it is to
run clinical trials. Despite the widespread use of hormonal contraceptives in the treatment of
pain associated with endometriosis, there is a paucity of robust data in the literature comparing
different methods. One of the points that seem most attractive to me is the homogeneity of the
groups and the follow-up time. However, I have some considerations that, in my opinion, could
help to make the manuscript more robust.
## Introduction
I think the existing literature was little explored in the introduction. In my opinion, you could
insert information about previously published studies, raising the positive and negative points,
making clear the knowledge gaps that the present study intends to fill. I suggest exploring more
deeply the methodological limitations of the clinical trials registered so far, especially those
related to the characterization of the sample, sample size and long-term follow-up.
## Methods
1) Was the clinical trial previously registered? At where?
2) What does “TVT” mean in the second paragraph?
3) The authors inform that women with clinical and/or ultrasound signs of rectovaginal
endometriosis, ovarian endometrioma, or adenomyosis were excluded. Does this mean that
only women without a finding suggestive of an infiltrative lesion were included? Were women
diagnosed or suspected of having bladder or bowel injury included?
4) Have these women previously undergone any type of treatment?
5) Did they already have a confirmed diagnosis of endometriosis on any other occasion?
6) There was an approximate quarter rate of dropout due to spotting. This information is curious.
Do patients improve and feel safe with the suspension of treatment? Or does spotting have a
very relevant meaning?
7) In my opinion, repeated measures ANOVA is old-fashioned. It is not better or more accurate
than mixed models. I strongly recommend that time series analyzes be redone with this in mind.
8) The “quantification” of clinical improvement should be done using the effect size.
9) How many women are diagnosed with infertility in each group?
10) It was not clear to me how relevant it is to present the FSFI and FSDS cut-offs in this section.
11) Recently the IASP published the ACTTION Guide to Clinical Trials of Pain Treatment. I
strongly recommend that he be consulted for reporting on methods and results.
## Results
1) In figure 1: as it is a sample, I recommend inserting a scatter plot, keeping the trend line and
the confidence interval of the measurements. This would give the reader a clearer representation
of the dispersion of the data.
2) Perhaps reporting in a supplementary material the pain scores of women who dropped out of
the study gives us an idea about how this measure may have biased the analysis.
3) Are the mean and standard deviation or standard error represented in figures 2 and 3? I think
a scatter plot or even a box plot would be clearer to represent scattering.
4) Correlation charts could also be included as supplementary material.
## Discussion
1) I think the first paragraph should be replaced by a paragraph summarizing the results.
2) I don't think the most significant clinical improvement in the DNG group is clear. As
mentioned in my comments on the “methods” section, I think mixed models are more suitable
and should be used to confirm the findings.
3) If these findings are confirmed, do the authors consider the difference between 2.4 and 2.0
measured by the VAS at the end of one year to be clinically relevant? How to interpret this in
the light of current literature?
3) In the authors' opinion, what is the plausibility of having similar clinical improvement for
pain relief, but more significant improvement in other parameters?
4) In my opinion, the dropout rate needs to be discussed. Why do the authors think this dropout
rate of approximately 25% occurs? What impact would this have on the interpretation of the
results. Would these patients have had recurrence of symptoms?
5) Limitations need to be mentioned and discussed, mainly: withdrawal rates, effect size,
blinding, registration, statistical power…