PONE-D-22-25611

Phase II, double blind, placebo controlled, multi-site study to evaluate the safety, feasibility and desirability of conducting a phase III study of anamorelin for anorexia in people with small cell lung cancer: a study protocol (LUANA trial)

PLOS ONE

Dear Dr. Currow,

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The reviewers feel that your manuscript does not sufficiently describe the plan for statistical analyses. As such, they recommend that you clearly detail all statistical methods that will be used to analyze the data. In addition, they feel that the manuscript requires additional information regarding the chosen exclusion criteria. Furthermore, they suggest that you should clarify the distinction between your study design and another ongoing clinical trial mentioned in your review (https://clinicaltrials.gov/ct2/show/NCT03743051). 

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PLOS ONE

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“This study is sponsored by the University of Technology Sydney and funded by the Helsinn Group including the provision of study medication and matching placebo. Helsinn will not dictate design, conduct, analysis, interpretation nor dissemination of the study’s findings. Helsinn was consulted on study design and will review the manuscript of the primary paper before final submission.  “

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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: No

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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: Yes

Reviewer #2: No

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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: No

Reviewer #2: No

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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: Mariana S. Sousa et al. Presented a Study Protocol LUANA trial, a randomized phase 2 trial with anamorelin for anorexia in people with small cell lung cancer.

My main concern is about the novelty of this trial. I would like to mentioned the fact that a previous trial using the design and the same drug is alrealdy ongoing in NSCLC: “NCT03743064 A Phase 3, randomized, double-blind, placebo-controlled, multicenter study to evaluate the efficacy and safety of anamorelin HCl for the treatment of malignancy associated weight loss and anorexia in adult patients with advanced non-small cell lung cancer (NSCLC).” So, the evaluation of the the safety, feasibility and desirability in LUANA trial sounds futile to me. The drugs used in SCLC with platinum-based chemotherapy associated with immunotherapy is also the backbone of NSCLC treatment . Therefore, ANAM 17-21 trail in NSCLC does already address LUANA phase II design presented in this work.

I am also concern about the fact the list of exclusion criteria:” Pleural effusion requiring thoracentesis. Pericardial effusion requiring drainage. Oedema requiring regular diuretics. Ascites requiring drainage. Oesophagitis, gastritis, Cognitive impairment….” Will exclude most of patient treated in daily routine with advanced SCLC which is a symptomatic disease related to high proportion of metastasis. Only “super Fit” patient with SLCLC and cachexia will be enrolled in the trial. I am quite sure that this kind of patient are highly selected population, consequently the accrual in the trial as well as the clinical application in daily routine practice is questionable.

Futhermore, this kind of trial should be a pantumor trial, unless if there is strong rational to support a specific tumor histology subtype or specific oncogenic driver.

Reviewer #2: In this study protocol, a multi-site, randomized-controlled phase II clinical trial aims to assess safety and feasibility, adherence, and completion of study tools to inform the design of a robust Phase III effectiveness trial.

Major revisions:

1- Overall, the current statistical analysis plan is too vague. List and describe all the statistical methods that will be used to analyze the data.

2- Line 355: Provide more details for the following statement. “Comparison between the intervention and control groups will occur using appropriate statistical approaches, depending on the nature of the data.”

3- Lines 359-362: A repeated measures approach would be superior to repeatedly applying paired t-tests.

Minor revisions:

1- Identify the software that will be used to capture the data as well as the software that will be used for the statistical analysis.

2- Line 355: Replace “analysed” with “summarized” and summarize using both frequencies and percentages.

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Reviewer #1: No

Reviewer #2: No

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Attachments

Attachment

Submitted filename: Mariana S et al. PLOSONE.pdf

Phase II, double blind, placebo controlled, multi-site study to evaluate the safety, feasibility and desirability of conducting a phase III study of anamorelin for anorexia in people with small cell lung cancer: a study protocol (LUANA trial)

PONE-D-22-25611R1

Dear Dr. Currow,

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,

Junichi Matsubara

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 #1: Partly

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 #1: No

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

**********

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: No

**********

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

**********

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 do believe that The primary outcome measure in LUANA trial: mean change in body weight and mean change in the 5-IASS are the good readouts in the context of cachexia/anorexia in cancer. The design used here to demonstrate the superiority of anamorelin versus placebo on anorexia symptoms and the ability to complete therapy on time and on dose is less strong than weight gain or change in the 5-IASS.

Futhermore, Olanzapine improves chemo-related anorexia and has become un standard of care to prevent nausea. Therefore control arm without olanzapine is questionable.

Regarding exclusion criteria: first of all the NCT03743064 Phase 3 trial has been targeted NSCLC. We know that SCLC is the most agressive lung cancer commonly associted with pleural , pericardial effusion. Additionaly , gastritis and oesophagitis is a quite comme disease whith impact in oral, food intake in only severe cases. So i do strongly believe that these exclusions do represent the majority of SCLC patients. The exclusions criteria should fit those from the trial below.

Randomized Double-Blind Placebo-Controlled Study of Olanzapine for Chemotherapy-Related Anorexia in Patients With Locally Advanced or Metastatic Gastric, Hepato-pancreatico-biliary, and Lung Cancer.

Sandhya L. et al.

J Clin Oncol . 2023 Mar 28;JCO2201997. doi: 10.1200/JCO.22.01997. Online ahead of print

Reviewer #2: All comments have been adequately addressed.

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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 #1: Yes: Frank Aboubakar

Reviewer #2: No

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