PONE-D-22-22897A randomized stepped wedge trial of an intensive combination approach to roll back the HIV epidemic in Nigerian Adolescents: iCARE Nigeria treatment support protocolPLOS ONE

Dear Dr. Kuhns,

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Joel Msafiri Francis, MD, MS, PhD

Academic Editor

PLOS ONE

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This publication was supported by funding from the Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health under Award Number UH3HD096920. 

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This publication was supported by funding from the Eunice Kennedy Shriver National Institute of Child Health & Human Development (https://www.nichd.nih.gov) of the National Institutes of Health under Award Number UH3HD096920. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health under award number UH3HD096920 to BT and RG. The funding source has no role in the original design of this study, analysis and interpretation of data, or decision to submit results.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions?

The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field.

Reviewer #1: Partly

Reviewer #2: Yes

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2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses?

The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory.

Reviewer #1: Partly

Reviewer #2: Yes

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3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable?

Descriptions of methods and materials in the protocol should be reported in sufficient detail for another researcher to reproduce all experiments and analyses. The protocol should describe the appropriate controls, sample size calculations, and replication needed to ensure that the data are robust and reproducible.

Reviewer #1: No

Reviewer #2: Yes

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4. Have the authors described where all data underlying the findings will be made available when the study is complete?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception, at the time of publication. The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

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5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

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6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics.

You may also provide optional suggestions and comments to authors that they might find helpful in planning their study.

(Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: I have read with interest this submission whose intention seems to publish the protocol of a future cluster randomized trial based on a previous smaller pilot study investigating the same intervention.

Although this type of submission should be encouraged it also represents a stage at which the trial design might be questioned by external reviewers. I have the following requests of clarifications:

Major points

1. The timing is unclear. When is time 0 likely to be for the earliest cluster to enter the study and over which time-span is the RCT planned to occur?

2. Primary endpoint. A HIV-1 COBAS® assay (Roche Molecular Systems, Inc.) with a lower detection limit of 20 copies/mL is going to be used to measure viral load. Unclear why a threshold d of 200 copies is used to establish viral suppression instead. Also unclear from Table 1 whether blood will be drawn after control periods and follow-up periods. These viral loads are crucial for the comparison with the values measured after intervention.

3. Unclear why the statistical unit in the trial are the 3 clusters and not the clinical site. If I understood well ultimately Cluster 2 will be equivalent to sequence 2 and Cluster 3 to sequence 3. It would make more sense to me that each site (apart from site #1 for which I appreciate the rationale for being allocated deterministically to sequence 1) have equal chance to be allocated either to sequence 2 or sequence 3. In general, there the need to clarify the advantages of such a cluster trial randomisation as opposed to individual participants randomisation.

4. It is not uncommon that at least one statistician in the trial team is not blind to the randomisation. The justification given (the complexity of the analysis) is however unusual. I assume that the authors mean that one statistician will remain un-blind to be able to produce interim analysis reports by clusters and sequence. Please clarify.

5. More details are needed to describe the creation of randomisation schedules. What kind of randomisation will be employed? The number of clusters available is limited and therefore simple forms of randomization may not achieve balance between intervention and control arms at either the cluster- or participant-level.

6. Unclear why such a small OR of 1.5 was used to calculate statistical power. The pilot study indicates that the magnitude of the effect is likely to be a lot larger and up to 14-fold difference. Also unclear how the individual correlation (r=0.5) and cluster-correlation (r?? <0.5) estimates are coming from.

7. Statistical analysis section is quite short and has little details/clarity. Because of the use of GEE methods my understanding is that the strategy will be compared only within clusters (so that each participant act as his/her own control). Will be any comparison between sequences? If so, what is going to be the approach to analysis? Clusters can be considered independent and therefore GEE should not be needed.

8. The trial is going to be costly. I am not an expert in the field but is there a plan to evaluate whether the possible benefit in terms of increased number of youths with a suppressed viral load as a consequence of the intervention is going to be cost-effective? There is only a hint to this possible analysis in the last paragraph of the Discussion.

9. One of the possible advantages of publishing a trial protocol is aiming to pre-register the study with a journal prior to data collection/collation, to avoid publication bias and limit researcher degrees of freedom. Authors should clarify whether this is an intent as it would strengthen the submission.

Minor points

1. Wording is fairly confusing with some of the sentences phrased in the future ‘it is anticipated that…’ ‘participants will be….’ ‘quality checks will be conducted’ ‘data will be analysed’ etc. vs. others which are placed in the past (like the trial has actually already occurred) e.g. ‘Cluster 1 was not randomised’ ‘participants were recruited’ etc. Suggest phrasing is standardised throughout.

2. Lines 90-96. Form the way the paragraph is structured, it is not obvious at first reading that these are the results of a separate pilot study and not those produced by preliminary data of the current protocol.

3. Line 95. Please indicate exact p-value instead of <0.05.

Reviewer #2: The authors present a description of the methods for a cluster randomized stepped wedge trial of an intervention to increase viral suppression on HIV-1 antiretroviral treatment targeted towards youth. The protocol is clear and well written and is presented in a manner that others could replicate. I have no substantive edits for the authors. Thanks for following the SPIRIT guidelines.

Minor comment:

Based on the results of the pilot, it would appear the trial is overpowered if the target is 1.5 times the odds of viral suppression comparing pre to post implementation. The authors might want to consider what is a clinically important increase in viral load suppression (although anything up from the baseline in the 30's would be better) rather than the 1.5 which would not result viral suppression levels that are beneficial at a the target population level.

It appears the population for the intervention is all youth regardless of mode of acquisition of HIV infection. Do the authors anticipate any difference in response to the intervention by youth who were perinatally infected versus infected as adolescents or young adults?

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Reviewer #1: No

Reviewer #2: No

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A randomized stepped wedge trial of an intensive combination approach to roll back the HIV epidemic in Nigerian Adolescents: iCARE Nigeria treatment support protocol

PONE-D-22-22897R1

Dear Dr. Kuhns,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Joel Msafiri Francis, MD, MS, PhD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions?

The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field.

Reviewer #2: Yes

**********

2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses?

The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory.

Reviewer #2: Yes

**********

3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable?

Descriptions of methods and materials in the protocol should be reported in sufficient detail for another researcher to reproduce all experiments and analyses. The protocol should describe the appropriate controls, sample size calculations, and replication needed to ensure that the data are robust and reproducible.

Reviewer #2: Yes

**********

4. Have the authors described where all data underlying the findings will be made available when the study is complete?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception, at the time of publication. The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics.

You may also provide optional suggestions and comments to authors that they might find helpful in planning their study.

(Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #2: The authors have addressed my comments. I think the effect size used in the sample size calculation is still too conservative given the use of an odds ratio as the measure of effect but the authors have adequately addressed my question.

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7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #2: No

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