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Date: 10/25/2022 To: "Faith D Ottery"
From: "The Green Journal" [email protected] Subject: Your Submission ONG-22-1689
RE: Manuscript Number ONG-22-1689
Phase 3, Randomized, 52-Week Safety Study of Fezolinetant for Vasomotor Symptoms Associated With Menopause Dear Dr. Ottery:
Thank you for sending us your work for consideration for publication in Obstetrics & Gynecology. Your manuscript has been reviewed by the Editorial Board and by special expert referees. The Editors would like to invite you to submit a revised version for further consideration.
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EDITOR COMMENTS:
Please note the following:
* Thank you for your submission. Please verify if there is a separate manuscript on 52-week efficacy data under evaluation. Concern was raised that if there is another manuscript there may be significant overlap.
* Help us reduce the number of queries we add to your manuscript after it is revised by reading the Revision Checklist at https://journals.lww.com/greenjournal/Documents/RevisionChecklist_Authors.pdf and making the applicable edits to your manuscript.
* Figures 1-3 may be resubmitted as-is unless changes have been requested by the Statistical Editor.
REVIEWER COMMENTS:
Reviewer #1: The authors present data from a phase 3 trial to evaluate the safety of two doses of fezolinetant for treatment of menopausal VMS. This was a randomized, double-blind, 52-week safety study versus placebo. Specific endpoints were treatment-emergent adverse events, endometrial hyperplasia/malignancy, BMD and liver enzyme changes.
1. Methods, line 71: Why the limitations on BMI?
2. Methods, lines 112-113: Was there an assessment of compliance with medication usage? If so, were study outcomes analyzed based upon this versus just the first dose of study intervention?
3. Results, lines 153-161 and Table 3: The results presented in the manuscript body are different than those presented in Table 3. The body of the document reports 1 endometrial hyperplasia in the fezolinetant 45mg group and 1 endometrial
malignancy in the fezolinetant 30mg group. However, table 3 reports more cases. Please explain the discrepancy.
4. Discussion, lines 217-221: Is there any theoretical reason why fezolinetant would impact the risk of endometrial hyperplasia?
5. Discussion, line 222: I did not see data presented on any other malignancies. This data should be presented, particularly with the concerns regarding breast cancer with hormone therapies.
6. Table 3: What is meant by "preferred term".
Reviewer #2: This very well written and relatively complete manuscript on the safety of fezolinetant for VMS is informative and reassuring about safety issues for NK3R antagonists raised following data published for pavinetant in 2019. Questions and comments for the authors follow:
1) Please include in the abstract that participants were not blinded for 40 of the 52 weeks of data collection (if this is correct), discuss how this might affect your findings in the discussion section, and revise figure 1 to show the period of time that individuals were not blinded to study arm.
2) The details of safety by fezolinetant dosage is informative, i.e. is there a dose response (please comment on this), but lacking is an overall report of safety by placebo vs active drug which is of merit due to your small numbers for an outcome such as endometrial proliferation. Please include this information and provide statistical analyses, comparing placebo vs study drug (both doses) for endometrial safety and hepatic biomarkers. Given the multiple comparisons, comment on chance of finding significance of any findings (if there are any) in your discussion.
3) Results (lines 177-178): "No signal of increased risk was identified in this in-depth investigation based on various considerations, such as short latency, apparent pre-existing neoplasm at study entry, alternative etiology, past medical history, and known risk factors." Provide the reader with details to support this statement, along with a summary statistic on placebo vs intervention on those with increase ET, EH, and EC. Either provide these endometrial safety results in a separate table including only the 599 women in these analyses or incorporate this information into an existing table. As is, the message is confusing as the data are included with the other 1231 study participants without endometrial safety data with inappropriate "n"s at the tops of the columns. Or if you do keep this information in Table 3, do as a subset showing new ns at the tops of your columns or by presenting numerators and denominators as you did in table 4. Because you are not powered on endometrial safety, readers are looking for any signal that suggests that eventually through time (over 5-10 years), fezolinetant might result in endometrial proliferation and endometrioid carcinoma. Include details either in a supplemental table or in text on age, AUB and BM of those with EH and EC. Any personal history of breast or colon cancer?
Family history of endometrial, breast, colon cancer? When during the study was the biopsy abnormal - you stated embx was done if AUB. If that embx was normal, did the ptcpt continue? If so was the 52 week embx also normal? Provide background rate for EH and EC over one year for people in your study age group in your discussion that would support this sentence, lines 177-178 in your results section. Also relevant here is the FSH data that is not fully presented. Did FSH really drop?
4) One of the cases reported by the investigator was deemed to be AEH. How was this decided? Through the study arbitration process - which I believe included reading of all biopsies by 3 different pathologists from 3 different companies (i.e. >1198 biopsies, at least 2 for 599 women)? Were they all gyn pathologists? Why was the worse diagnosis chosen as the final rather than a discussion and consensus and how did that affect your findings? And was that diagnosis confirmed at hysterectomy? Provide greater details please. Give EH classification system used by the 3 pathologists.
5) One individual had AEH. What other EH diagnoses were there?
6) Abstract - "Minimal changes in FSH concentrations occurred." Provide this information (mean change from baseline) between placebo and active groups.
7) Methods: add that women with NAFLD and nonalcoholic steathorrheic hepatiis were included (as stated in the discussion). If there were many of these women, perhaps consider adding to characteristics in table 1.
8) Methods (line 79): please define "other clinically significant findings".
9) Why was change in FSH BL to 52 weeks exploratory? Your data showed that FSH decreased rather than increased over the year on study. Please provide values in the results section, BL mean and 52-week follow-up mean, in addition to change values, and why you think this occurred in the discussion section.
10) Sentence 115-119 is a bit confusing - you define "acceptable" in the text - but what do you mean by "satisfactory endometrial biopsy result" on 118 day 326 or later? Earlier in the sentence you state "satisfactory tissue." Do you mean sufficient tissue for a diagnosis? It is not uncommon to obtain an embx stating "scant tissue, unable to evaluate, clinical
correlation suggested" or something to that effect. Would such a finding be "satisfactory" in your study? What did you do with scant tissue, unable to determine if EH or EC present?
11) Was DPE associated with uterine bleeding?
12) Were any of hepatic changes in the individuals with NAFLD and nonalcoholic steathorrheic hepatiis at BL or did this occur in otherwise healthy individuals?
13) Discussion (line 224-226): Although a limited number of [do you mean endometrial?] malignancies were diagnosed during the treatment or follow-up periods, no evidence of increased risk was identified and only one (fezolinetant 45 mg group) was reported by the investigator as treatment-related." This sentence is in contradistinction from the abstract, stating no increased risk for endometrial EH or malignancy. Why did the investigator feel it was definitely related to fezolinetant?
14) Line 247, provide n for those with ET< 4 mm.
15) Table 2, clarify use of term "drug-related" I think you mean "study related"? or "possibly drug- related"? How could someone in the placebo arm have a "drug-related" event, unless there is something in the placebo the investigator had concerns about? TEAEs are identified, then if they are severe, unblinding occurs. In this circumstance, I believe most TEAEs were unblinded. Did the study clinician really feel that the TEAEs in table 2 were due to fezolinetant or were a reaction to the placebo or possibly or probably related?
16) Table 2 shows one death. Yet this is not shown in figure 2. Please clarify. Thank you.
Reviewer #3:
Summary of the study
This is a phase 3, randomized double blinded clinical trial of fezolinetant and placebo to evaluate the safety and tolerability over 52 weeks. A total of 1830 study participants were randomized to placebo, 30mg or 45 mg fezolinetant and were evaluated for the treatment-emergent adverse events (TEAEs). Among these, 599 participants were evaluated for endometrial safety of the treatment. As the incidence of TEAEs and endometrial hyperplasia/malignancy were similar across treatment groups, the study concluded the safety and tolerability of fezolinetant at 52-week treatment.
Overall comments
The study was well designed, and the manuscript is well written compliant with the CONSORT guideline. The evaluation of safety and tolerability of fezolinetant supports the development of this novel non-hormonal treatment for vasomotor symptoms among menopausal women. Despite a non-hormonal nature of fezolinetant, the FDA requires the data on endometrial safety for treatment intervention for menopausal symptoms. With limited sample size to evaluate endometrial safety, the analysis may not have enough power to ensure the insignificant different across treatment groups.
Introduction
The background and rationale are clearly stated.
Methods
The study design and measurement of each outcome are generally thoroughly mentioned.
Line 110: The sample size calculation was based on the total TEAEs. As the study also focuses on the endometrial safety, the sample size and/or power calculation should be described on the endometrial outcome.
Line 113: "Any participant erroneously receiving a treatment that was different from the randomized treatment was assigned to the treatment group that the patient received as first dose." The author should provide the data on how many of participants received error doses and clarify why using the first treatment, not the most received treatment.
Results
Line 135: As the withdrawal rate of placebo was higher than fezolinetant, the additional report of TEAEs based on participants with completed follow up would provide more comparable results across groups.
Line 162: In addition to the least square mean used in the statistical comparison, the raw data on baseline and follow up endometrial thickness may be more meaningful for the clinicians. Especially as the prevalence of uterine bleeding was higher in placebo, the correlation between endometrial thickness and bleeding is interesting to know.
Discussion
The authors concluded each aspect of the results and pointed out to the FDA safety regulations and clinical relevancy.
Line 242: Although the paper described multifactorial limitation on small sample size for endometrial evaluation, however,
the paper should point out on the possible consequence of limited sample size especially when the outcome was rare and may not allow adequate power for comparison.
STATISTICAL EDITOR COMMENTS:
General: The stated goal was to assess safety and efficacy over 52 weeks, but only ~ 1300 (~ 70%) had follow-up data at 52 weeks. Need to clarify this in Abstract. Were those who completed 52 weeks similar in clinical/demographic profile to those who did not complete? Need to show comparison. Tables 1, 2 and 3 therefore show events that occurred after the initiation and by 52 weeks, with variable follow-up times. This does not guarantee that missing was at random.
Table 3, 4: Each of these adverse events occurred at low frequency, but that confers poor stats power to discern any differences. Should report point estimates with 95% CIs, esp for placebo vs combined fezolinetant doses. Should also include upper bound of CIs when the point estimate = 0. To illustrate the low power, using the data from ALT or AST >3x ULN for placebo vs 45 mg dose, the discernable rate for the treatment group would have to exceed 5.3%, rather than the 2.0% found. Put another way, in order to detect a 2x increase compared to the placebo group, based on 80% power, the sample sizes would have to be ~ 2400 per cohort, not ~ 600. So, one can conclude that the rates of adverse outcomes are low, state the upper bounds based on these data, but cannot conclude that there is no increased risk compared to placebo, but rather the ALT risk given as an example could not exceed 5x that of the placebo group.
For the biopsy related outcomes in Table 3, the math re: power to detect is even less favorable, in part because the incidence rates are so low over a short time span. Also, the endometrial health set was comprised of N = 599 of 1830 (lines 242-243), yet Table 3 gives the results with column headings for all 1830 patients and the rates are computed using those denominators. Need to provide the actual denominators, show that this subset was representative of the entire cohort and compute the rates based on the actual denominators.
-- Sincerely,
Jason D. Wright, MD Editor-in-Chief
The Editors of Obstetrics & Gynecology
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