PONE-D-23-17718Phase 1 studies to assess safety, pharmacokinetics, and vaginal bleeding associated with use of extended duration dapivirine and levonorgestrel vaginal ringsPLOS ONE

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"The following authors have read the journal's policy and have competing interests:  Sharon L. Achilles has received consulting fees from Mayne Pharma and Merck and has received research funding from The National Institutes of Health, the US Food and Drug Administration, the Pennsylvania Department of Health, Society of Family Planning Research Fund, Estetra SRL (an affiliate company of Mithra Pharmaceuticals), EvoFem, and Merck, all of which were managed by Magee-Womens Research Institute. Barbra A. Richardson has received payment from Gilead Sciences for DSMB membership. Brid Devlin and John Steytler were full-time salaried employees of the International Partnership for Microbicides (IPM), a non-profit company registered in the United States of America, at the time the work was performed. Craig W. Hendrix is an Inventor on patent relating to vaginal microbicides and the founder of a microbicide development company, both unrelated to this study product and both managed by Johns Hopkins University. Beatrice A. Chen has served on a Merck & Co. advisory board and has received research grants from Sebela, Mylan, and Medicines360, all of which were managed by Magee-Womens Research Institute. NIH employees (Diana L. Blithe, Jill Brown, and Jeanna M. Piper) contributed to the study design, manuscript development and the decision to publish as well as providing safety oversight during study conduct but had no role in data collection and analysis.

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Additional Editor Comments:

This is a well written, clear manuscript with important findings form 2 well conducted studies. Apologies in the delay in return as it was extremely hard to get reviewers for this and I think this may be a widespread problem that may be in part due to the pandemic. Please see below for additional minor comments

Abstract

Lines 47, 48-it is not clear which of the 2 groups being compared have the Cmax and AUC measurements that are listed on each of these lines. Are these the values for both groups in each comparison. Please clarify.

Background

Line 59-As written, implies that unintended pregnancy is a health risk. Is this the intention of this statement. Is unintended pregnancy an unintended consequence?

Line 91-will reader know what is intended with the term “single action”?

Line 92-Increased accessibility to what?

Study Design

Line 134-was the exclusion of sexually transmitted infection requiring treatment any infection? Past? Current? Chronic?

Results

Line 298- the text states that for MTN-044/IPM 053/CCN019, the median tmax was 21 days and 28 days for the 2 arms. As this is prior to removal of the it seems that 7 day difference in time to tmax is long. Is this unusual? If so what could account for this?

Line 302, 321, 345, 363-Nadir is a noun. Does it have a past tense form of nadired? Please check and if this is not a correct term, please reword.

Line 351, 360-what do the asterisks in 79.8ng*d/mL and 0.37µg*d/mL indicate?

Line 364-return should be returned

Line 376-stated that there was no difference in bleeding and both continuous and cyclic users, 89% experienced no bleeding to light bleeding. Was there a difference in when the bleeding occurred in these groups. For the cyclic group was bleeding related to when the ring was removed?

Line 411-It is stated that DPV rings used in past trials contained 25m of drug whereas the rings used in these studies contained 200mg. Presumably this is because the rings are designed to be used for longer periods of time. It might be helpful to specifically state this in the manuscript somewhere to help the reader understand why the amount of DPV in the rings is different.

Line 487-stated “genital tract DPV concentrations were not sustained following ring removal and may be fundamental to HIV prevention”. It might be helpful to remind the reader that in the 2 DPV ring studies that showed efficacy, the monthly rings were used continuously without a break between the removal of one ring and reinsertion of a new ring.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: No

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Reviewer #1: Yes

Reviewer #2: No

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Reviewer #1: Yes

Reviewer #2: Yes

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5. Review Comments to the Author

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Reviewer #1: ABSTRACT: MTN030/IPM 041 compared DPV/LNG to DPV for 14 days of use. MTN-044/IPM 053/CCN019 compared continuous or cyclic use of DPV/LNG over 90 days. Higher Cmax of DPV with DPV LNG IVR compared to DPV IVR, despite having the same concentration of DPV in each IVR. Would add that the LNG plasma concentrations are comparable with other efficacious SYSTEMICALLY delivered LNG-based contraceptives.

BACKGROUND: I think lines 85 – 88 can be removed from the introduction as this is more PD related.

METHODS: For the MTN-030/IPM 041 study – Lines 144 – 145, please clarify if the IP was inserted at a particular time in the menstrual cycle as this would potentially impact vaginal bleeding endpoint.

For the MTN-044/IPM 053/CCN 019 study, lines 158 – 159, I’m assuming that the IP was inserted at the end of menses, but please clarify if the IP insertion was timed to the menstrual cycle. Line 166 – I’m assuming these are ectocervical tissue biopsies, but please clarify.

RESULTS: Minor detail line 227 – it says 25 participants enrolled IN Pittsburgh. Should this be at Pittsburgh site? Table 2 and Table 3 are well presented. I understand from the methods how vaginal bleeding was recorded in the 90 day study (daily diary entry), would you also include how vaginal bleeding was captured in the 14 day study, since the results do go in to the incidence of vaginal bleeding in the 14-day study. I’m assuming that this was just by participant report at visits, but would you clarify. That is really great that 89% of women had no bleeding to light bleeding in the 90-day study – I would point to Table 4 in lines 376 – 377 where that result is presented.

DISCUSSION: DPV PK data is well summarized. I’m assuming that because the DPV plasma concentrations are higher with the 90 day IVRs, the assumption is that they would have comparable efficacy to the ASPIRE study DPV 28-day IVR. I’m familiar with the Cherala LNG paper (ref 46), but what is the reference for the statement on lines 418 – 419 that the threshold of 225 pg/mL using MASS SPECTROMETRY- based methods? The Cherala paper talks about the Norplant, RIA thresholds for LNG. I disagree with lines 421 – 423 – the “threshold” concentrations for LNG are for systemically delivered LNG, so the median serum concentrations of 240 pg/mL and 210 pg/mL at days 30 and 60 respectively are likely near the minimal threshold for contraceptive efficacy for systemically delivered LNG, but the “threshold” for vaginally delivered LNG is not known. I would include this caveat, because lines 421 – 423, as written may make some readers think that cyclic use would result in contraceptive failure, and this is clearly not known. I think you can work in the next paragraph (lines 424 – 430) to clarify this. I’m not really understanding how lines 428 – 430 fit in to the argument. I think you should potentially add to the discussion – why do you think the DPV Cmax was higher with the DPV/LNG IVR? Is this just statistically significant but perhaps not clinically significant.

Overall these two studies are very important data to add to the MPT literature!

Reviewer #2: Two phase 1 randomized clinical trials were conducted which aimed to evaluate safety, pharmacokinetics, and vaginal bleeding associated with the use of vaginal rings. One trial compared 14-day DPV to 14-day DPV/LNG while the other compared 90-day DPV/LNG continuous to 90-day DPV/LNG cyclic. No statistical difference was observed in the proportion of participants with grade 2 or higher genitourinary AEs in the DPV/LNG ring arm compared to the DPV ring arm. No statistically significant differences were observed in the proportion of participants with grade ≥2 genitourinary AEs in the continuous use compared with the cyclic use arm, and no statistically significant differences were observed in the proportion of participants with grade ≥3 AEs in the continuous use compared with the cyclic use.

Major revision:

Provide a comprehensive statistical analysis section, listing and describing the use of all statistical methods from which p-values were estimated.

Minor revisions:

1- Line 207: Provide a reference and note the software for calculating AUC using the trapezoidal method.

2- Indicate the date range subjects were enrolled in the studies.

3- Cite the statistical software used for the analysis.

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Reviewer #1: Yes: Andrea Thurman MD

Reviewer #2: No

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Phase 1 randomized trials to assess safety, pharmacokinetics, and vaginal bleeding associated with use of extended duration dapivirine and levonorgestrel vaginal rings

PONE-D-23-17718R1

Dear Dr. Achilles,

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Renee Ridzon

Academic Editor

PLOS ONE

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