PONE-D-24-49788Cabergoline as a preventive migraine treatment

A randomized clinical pilot trialPLOS ONE

Dear Dr. Hjelholt,

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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: Partly

Reviewer #2: No

Reviewer #3: Yes

Reviewer #4: Yes

Reviewer #5: Yes

Reviewer #6: Yes

Reviewer #7: No

Reviewer #8: Yes

Reviewer #9: Yes

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

Reviewer #1: Yes

Reviewer #2: No

Reviewer #3: I Don't Know

Reviewer #4: Yes

Reviewer #5: I Don't Know

Reviewer #6: Yes

Reviewer #7: No

Reviewer #8: Yes

Reviewer #9: Yes

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3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). 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: Yes

Reviewer #3: Yes

Reviewer #4: No

Reviewer #5: Yes

Reviewer #6: Yes

Reviewer #7: Yes

Reviewer #8: Yes

Reviewer #9: Yes

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4. 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

Reviewer #3: Yes

Reviewer #4: Yes

Reviewer #5: Yes

Reviewer #6: Yes

Reviewer #7: Yes

Reviewer #8: Yes

Reviewer #9: Yes

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1:  The sample size is extremely small and so the study is not qualified as a randomized trial. The results are hardly generalizable. Also results are dominated for female subjects.

Yet from Table 3 we can see a large number of adverse events in the Cabergoline group compared to control group, even for this small study. The drug may not be safely applied.

The results are full of uncertainty. For example, the box plots in Figure 2 are very wide. The chronic migraine subjects even show smaller changes for placebo group than cabergoline group.

Reviewer #2:  This is a double-blind, placebo-controlled study that investigated the effect of cabergoline 0.5mg for migraine prevention. There are several key issues with this trial that need to be explained.

1. According to the clinicaltrial.gov online registry, this is supposed to be a study of chronic migraine, which is defined as having more of than 15 headache days per month, of which at least 8 are migrainous headaches. Therefore, the inclusion criteria clearly contradict the topic of this registration, and the current study includes both episodic and chronic migraine.

2. There is insufficient evidence to justify the use of cabergoline as a migraine preventive drug, given the potential side effects of gambling/sex/other urges, and others. The authors did not provide sufficient argument for its use in migraine other than case series of comorbid migraine and hyperprolactinemia. The potential binding affinity of cabergoline to 5-HT1B/1D receptors is not a valid argument, as studies with triptans (5-HT1B/1D agonists) do not provide evidence of prevention but may increase the risk of medication overuse headache.

3. The study cohort is small (18 cabergoline vs. 18 placebo). There is no information on the power calculation and whether the study is sufficiently powered to detect a difference between the two cohorts.

4. The primary outcome registered on the clinicaltrial.gov was the reduction in migraine days from baseline for the entire study cohort. The result was negative, showing no difference between the two cohorts. The positive result presented in the abstract, is based on the subgroup analysis targeting the episodic migraine subgroup (n=20, 11 for cabergoline vs 9 for placebo), and the result is actually borderline (p=0.04). If the main analysis remains insignificant, the subgroup analysis must be well-founded (better defined a priori) and correct for multiple comparisons, otherwise it is more like data torturing. More importantly, the selective presentation of the subgroup analysis in the abstract is misleading.

Reviewer #3:  This paper clarified that cabergoline significantly reduced monthly migraine days in episodic migraine without serious adverse effects, supporting further investigation into the use of cabergoline for migraine prevention.

This reviewer finds the paper is well written, and appropriate for publication after minor correction shown as follows.

Line 87: [13th of June] -> [13th of June 2023]

Line 168: “Forty-five” will be replaced with “Fifty-four”

Reviewer #4:  Thank you for inviting me to review this manuscript. I believe the authors have conducted a clinical study that is beneficial for migraine patients. Its quality is sufficient to be published after revisions. Below are my suggestions:

1. Further Discussion on Study Limitations

Although the discussion section mentions the small sample size as a limitation, other potential influencing factors (e.g., short follow-up duration, sample selection bias) should be explored further. Suggestions for addressing these limitations, such as conducting multicenter or larger-scale studies in the future, can also be included.

2. Clarify Titles and Annotations in Figures

The data presented in the figures are central to the manuscript, particularly Figures 2 and 3. Strengthening the descriptions in the figure titles and annotations can facilitate readers' quick understanding while highlighting the key conclusions of the study.

3. Enhance the Rigor of Background Argumentation

The background section mentions that "the relationship between dopamine and migraines remains controversial," but the cited references are not sufficiently comprehensive. Recent findings on the role of dopamine in migraine mechanisms should be incorporated to improve the relevance and credibility of the references.

4. Improve Readability of Statistical Method Descriptions

The statistical analysis mentions the use of linear regression models and non-parametric tests, but the rationale for selecting these methods is not well explained. Additional clarification on why these methods were chosen and how potential confounding factors were controlled would enhance the methodological clarity.

5. Supplement Detailed Analysis of Adverse Events

While the types and frequencies of adverse events are listed, their impact on patients has not been detailed. Adding analyses based on scales or patient feedback to quantify the impact of adverse events on quality of life could strengthen this aspect of the manuscript.

6. Enhance the Title and Abstract to Increase Appeal

The title and abstract are crucial for capturing readers' attention. The current title is straightforward but lacks appeal. It is recommended to highlight terms such as “first evidence” or “significant efficacy” in the title. The abstract should also emphasize the study's innovative contribution compared to previous research.

7. Refine Discussion of Limited Effects on Chronic Migraine

The discussion mentions that cabergoline has limited efficacy for chronic migraine, but the potential mechanism differences (e.g., varying responses to the CGRP pathway) or directions for treatment optimization are not deeply explored. Adding hypotheses or further discussion in this section would add depth. The authors could also enrich this section by citing related articles at appropriate positions in the discussion

(e.g., https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0304370).

8. Improve Data Availability and Ethics Statements

The data sharing statement mentions that sensitive data cannot be fully disclosed but does not elaborate on how other researchers can access the data. It is recommended to provide a more specific data request process in the “Data Availability” section.

Reviewer #5:  I thank the authors for testing, in an RCT, the effects of a molecule with significant metabolic effects, acting on the hypothalamic-pituitary axis.

In my opinion, the RCT yielded interesting results.

I suggest that the authors evaluate the effect of cabergoline on glucose metabolism (1, 2) as a potential mechanism underlying the reduction in MMD in episodic migraine (3, 4).

If the authors had monitored weight, BMI, and HOMA-IR at baseline and after the intervention, it would be useful to include these data in the manuscript.

The following point, in my opinion, requires correction:

You wrote: "Cabergoline significantly reduced MMD in episodic migraine and led to a significant global patient perceived improvement in both episodic and chronic migraine," but in the chapter Patient Global Impression of Change you stated: "PGIC significantly improved after cabergoline compared to placebo in the entire group, and in participants with episodic migraine. No significant difference was found in chronic migraine."

So, was there a significant improvement in PGIC in chronic migraine or not?

If my observation is correct, you should also revise the graphical abstract to reflect this aspect.

References

1. Inancli SS, Usluogullari A, Ustu Y, Caner S, Tam AA, Ersoy R, et al. Effect of cabergoline on insulin sensitivity, inflammation, and carotid intima media thickness in patients with prolactinoma. Endocrine. 2013;44:193–9.

2. dos Santos Silva CM, Barbosa FR, Lima GA, Warszawski L, Fontes R, Domingues RC, et al. BMI and metabolic profile in patients with prolactinoma before and after treatment with dopamine agonists. Obes (Silver Spring). 2011;19:800–5.

3. Gross EC, Lisicki M, Fischer D, Sándor PS, Schoenen J. The metabolic face of migraine - from pathophysiology to treatment. Nat Rev Neurol. 2019 Nov;15(11):627-643.

4. Del Moro L, Rota E, Pirovano E, Rainero I. Migraine, Brain Glucose Metabolism and the "Neuroenergetic" Hypothesis: A Scoping Review. J Pain. 2022 Aug;23(8):1294-1317.

Reviewer #6:  Thank you for the opportunity to review this manuscript. Overall this paper is clinically relevant and very well written. I have some minor points only.

Introduction: Please remove the last sentence on primary outcome (lines 81-82)

Methods:

- Please write the year when the recruitement ended.

- You excluded patients on dopamine antagonists, however some widely used antiemetics in migraine are dopamine antagonists, eg. metoclopramide and domperidone. Were these medications allowed? If yes, would you perform stratified analyses on patients who took antidopaminergic antiemetics vs those who didn't?

- I couldn’t find any comment on power analysis. On which basis did you decide to include 36 participants only? Please explain. This is important given that, although non-significant, the carbegoline group had a higher reduction of MMD. Might it be that in a bigger population the difference would become significant? I guess that the biologic analgetic effect of placebo in pain studies (which you rightly touch on in the discussion section) makes reaching the statistical significance more difficult, which requires a careful planning.

Discussion:

- When comparing absolute values of MMD reduction from your study to other studies, please be careful, as those results are likely based on populations with different baseline characteristics. I get the point and would not delete that part, but I would make the reader aware, that such comparisons should be interpreted with caution.

- In the part where you discuss the risk of valvulopathy, please clarify whether there is a lack of evidence (eg due to scarcity of experience with the carbegoline), or whether there is evidence of a low risk of valvulopathy. As it reads now, I get the impression that there is no data available, which is different to evidence of a low risk. This is obviously important, because we do not want to gather experience on valvulopathy on migraine patients treated with carbegoline, given that the majority are young females.

Reviewer #7:  I have to congratulate the authors to perform such interesting IIT in a time when everyone is talking CGRP only.

The study is in gerenal sound and the manuscript is well written. Knowing that this is a pilot study, it would still be very interesting, if the authors performed a sample size calculation.

Still, as the study has failed the primary outcome, this is a negative study. This has to been stated clearly throughout the whole manuscript and especially in the abstract. After that some secondary endpoints and subgroup findings can be discussed and presented. But this has to be somewhat more conservative. All in all the numbers - especially for the subgroups - are rahter small to draw any conclusion. What is in the end confusing is the fact, that there was a difference in eM of 3.6 MMD and 2.3 in cM, but for the whole group only 1.3 (please explain, this is small number statistics!!)

Minor:

- line 49: what is the reference here. The life-time prevalance of migraine is much higher. 15% corresponds rather to point-prevalence.

- line 168: This should maybe read "Fifty-four", otherwise the sum is not correct

- line 271: this is not fully true, in some studies also RWE effects in cM were much higher

- line 276: if you divert eM and cM in the others you also should do this for your data: 3.6 and 2.3 days (than there is less difference in cM)

Please explain/discuss:

- Line 233: why was there no change in MIDAS/HIT-6

- Line 236: why did so many guess correctly?

- It seems that Cabergoline can not be blinded? Differences in AEs, so many guess correctly, difference in PGIC?!

- Please discuss possible issues of MOH in the long-term when acting and 5HT-receptors!

Reviewer #8:  Dear Author,

I think this is a very interesting study that suggests another possibility for migraine prophylaxis, so it is worth publishing. However, I would like to point out several points where more information should be added.

Firstly, when did recruitment end? The 13th of June 2023? If so, please add "2023" to the text (line 87).

The second is about the recorded "migraine" attacks. A migraine day seems to be defined by an electronic diary recorded by the participants themselves. How did the authors confirm that these pain attacks were really migraine attacks? Especially in CM patients, attacks can have several different patterns. Were there no participants with multiple types of headaches, such as tension-type headache?

Also, in line 168-169, "Forty-five patients" should be "Fifty-four patients".

The last point concerns the discussion. Although I agree with the significant efficacy of cabergoline shown in this study, it was still unclear whether this can be generalized beyond the sex difference, as most participants were female. In addition, the authors refer to an interesting change that occurred in female mice, reported in one of the references. Therefore, I think that the suggested efficacy of the present study should be limited to female patients. I will not deny possibility of efficacy in male patients; however, it is not able to refer that in this study. This is one of the limitations of this study.

Reviewer #9:  The sample size is too small, the results are not convincing, and the reduction in MMD days alone is not convincing. More pain characteristic needs to be provided, such as pian duration, changes in VAS scores, and changes in accompanying symptoms.

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

Reviewer #4: No

Reviewer #5: Yes:  Lorenzo Del Moro

Reviewer #6: No

Reviewer #7: No

Reviewer #8: No

Reviewer #9: No

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Cabergoline as a preventive migraine treatment

A randomized clinical pilot trial

PONE-D-24-49788R1

Dear Dr. Hjelholt,

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.

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Sherief Ghozy, M.D.

Academic Editor

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Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

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2. 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

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

Reviewer #1: Yes

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4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). 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

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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

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6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: This paper can be published as a pilot study. The previous comments are minor. I don't have additional issues with this revision.

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Reviewer #1: No

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