BMJ - Decision on Manuscript ID BMJ

Transcription

1 BMJ - Decision on Manuscript ID BMJ

2 Body: 9th October 2018 Dear Ms. Valsdottir Manuscript ID BMJ entitled "Parachute use to prevent death and major trauma when jumping from aircraft: a randomised placebo-controlled trial" Thank you for sending us your paper. We enjoyed reading this interesting paper and sent it for external peer review and discussed it at our Christmas manuscript committee meeting. We recognise its potential importance and relevance to general medical readers, but I am afraid that we have not yet been able to reach a final decision on it because several important aspects of the work still need clarifying. We would very much like to see a revised version of this paper once you have had a chance to address the issues raised by the reviewers and editors. As this is intended for the Christmas edition, the timeline is tight and I will need to ask you to work to a tight deadline and return the revision to me within two weeks so that we can ensure enough time for the paper to pass through our processes if it makes it to the next stage. Please do let me know if you think this will be a problem for you and your co authors. Please remember that the author list and order were finalised upon initial submission, and reviewers and editors judged the paper in light of this information, particularly regarding any competing interests. If authors are later added to a paper this process is subverted. In that case, we reserve the right to rescind any previous decision or return the paper to the review process. Please also remember that we reserve the right to require formation of an authorship group when there are a large number of authors. If you have any queries, please do feel free to get in touch, otherwise I look forward to seeing your revised paper in due course. Best wishes Dr Sophie Cook UK research editor scook@bmj.com *** PLEASE NOTE: This is a two-step process. After clicking on the link, you will be directed to a webpage to confirm. *** ef19 **Report from The BMJ s manuscript committee meeting** These comments are an attempt to summarise the discussions at the manuscript meeting. They are not an exact transcript. Chair: Elizabeth Loder Statistician: Tim Cole Attendees: Sophie Cook, Wim Weber, Jose Merino, Tiago Villanueva, John Fletcher

3 Decision: Put points Detailed comments from the meeting: First, please revise your paper to respond to all of the comments by the reviewers. Their reports are available at the end of this letter, below. The editors' comments are listed below. In your response please provide, point by point, your replies to the comments made by the reviewers and the editors, explaining how you have dealt with them in the paper. Comments from the editors: *The editors enjoyed reading your well written paper. *Regarding the use of digits please use whole % (e.g. 0 rather than 0.0). Whole time (sec) and velocity (km/hr). It s interesting that you chose to use one decimal place for distance m, when one or two significant digits are appropriate. Also, one significant digit for P, so 1.0 becomes >0.9. *We think the information on trial registry that was shared with the editors via should be incorporated into the discussion section for transparency. *We feel that the description surrounding participant recruitment was very opaque and more information is required to help readers appreciate how participants were recruited. *While this trial illustrates many important points about participant screening and recruitment in RCTs along with the need for equipoise, we feel it is important to emphasise that this is not intended to undermine the use of RCTs, but to illustrate some of the issues that may arise. *We felt another important message from this paper is that if you make a decision based on abstract alone, this may lead you to an incorrect assumption, so this trial illustrates very well the importance of reading the whole paper. Comments from Reviewers Reviewer: 1 Recommendation: Comments: This is an admirable attempt to poke the collective eyes of skeptics of evidence-based medicine, and I congratulate the authors for their efforts. As randomized, controlled trials go, it is well-described. From a methodological perspective I have two major qualms that should be addressed. The first regards the use of the term "placebo". As it was clearly an unblinded, open-label trial (ie there was no sham parachute), the use of the term placebo-controlled in the title and multiple instances of the use of the term placebo is inaccurate. I suggest instead simply "randomized controlled trial" and in other instances either "control" or "backpack control". On a related note, the control backpack is less-well described in the methods compared to the parachute. The figure showing the differences is helpful, but more detail (ie manufacturer, whether it did or did not contain an airbag or hidden jet motor) in the text is necessary when describing an RCT. Additional justification for the choice of a plain commercial backpack instead of a sham parachute should be in the methods in addition to the discussion in the limitations paragraph.

4 While registration attempts with the Sri Lanka Clinical Trials Registry is admirable, it is unclear to me why a US-based trial would not have attempted registration with clinicaltrials.gov. If this is an attempt at humor because of the target publication (BMJ Christmas issue) it falls flat, and undermines the importance of clinical trial registration. Attempted ClinicalTrials.gov registration would be just as funny. Finally, from a 30,000-foot perspective, the discussion--while raising important issues around design and critical appraisal of clinical trials needs to be more concise--particularly if the Christmas Issue is targeted. Minor edits: Methods: P7L15--the authors note stratification by site, but this is otherwise written as a single-center study. Were there multiple sites (which would need to be described), or were blocks perhaps stratified by aircraft (the figure makes it look like the same biplane or helicopter was used in all successful enrolments)? Additional Questions: Please enter your name: Andrew McRae Job Title: Assistant Professor, Department of Emergency Medicine Institution: University of Calgary Reimbursement for attending a symposium?: No A fee for speaking?: No A fee for organising education?: No Funds for research?: No Funds for a member of staff?: No Fees for consulting?: No Have you in the past five years been employed by an organisation that may in any way gain or lose financially from the publication of this paper?: No Do you hold any stocks or shares in an organisation that may in any way gain or lose financially from the publication of this paper?: No If you have any competing interests <A HREF=' lists/declaration-competing-interests'target='_new'> (please see BMJ policy) </a>please declare them here: Reviewer: 2 Recommendation: Comments: Editor: I think this article would be suitable for the Christmas Edition. It is quirky but there are two important messages in the manuscript - that the study population needs to be comprised of individuals likely to benefit from the intervention (this was not the case here, 0 altitude & velocity) and that trials should be done early, while there is clinical equipoise. Note, in my comments I have made some assumptions

5 about the statistical tests used by the authors, they should revise this if they used different tests (e.g. Welch's two-sample t-test, Yates chi-square test). The investigators attempted to conduct a randomized, controlled trial with two objectives: 1) to determine the efficacy of parachutes to prevent death and major injury and, 2) to determine whether pre-existing beliefs about the efficacy of parachutes would impair the enrollment of subjects into the trial. For the most part the article is well-written, although some reorganization to increase clarity and coherence is required. The authors need to provide some additional information to better meet the CONSORT Statement guidelines for the reporting of randomized trials. In many places in the manuscript the authors use the term "placebo" and in other places they use the term "control". As we typically think of a placebo in a randomized trial as an identical-looking substance I suggest the authors use the term control [group] throughout including the title, which would change to:...a randomised, controlled trial. The article needs to be reorganized so that all information relating to methods appears in the Methods section and in a coherent order. P5 lines 46 to 57 are a partial description of the methods and should be removed from the Introduction. This passage could be modified to: "In order to address these important gaps in evidence we conducted the first randomized clinical trial of the efficacy of parachutes in reducing death and major injury.". Page 6: More information about the methods of recruitment should be provided, currently some information, i.e. passengers seated next to study investigators during commercial flights, appears in the Discussion but just how potential participants were recruited needs to be more clearly described. Also, the abstract states that this is a multi-centre trial but the participating centres are not described. P6L13 to P7L17: To improve coherence and readability I suggest reordering this information as follows: Study Protocol, Study Population, Interventions, Randomization, Data Collection. All the information relating to data collection (individual and circumstance) should be in the Data Collection section. Please revise P6L27 to: "...and still meeting the inclusion criteria..." or "...continuing to meet the inclusion criteria..." as it appears that the individuals had to meet the inclusion criteria at the time of screening and then later at the time of the randomization. Please revise P6L29 to: "... randomised (1:1) to the intervention or control group". Please review Items 8 to 11 of the CONSORT Statement to ensure all information relating to the random sequence generation and implementation are provided. P7L13: Please indicate how the randomization sequence was created and by whom. P7L15: "site" was a stratification variable but is not defined anywhere. P7L17: "Subjects were then instructed to jump from the aircraft." It is unclear what aircraft the subjects were on at this time. The subjects were screened for enrolment between September 2017 and August 2018 but randomized in August 2018 so

6 presumably some individuals were on one aircraft at the time of screening and a different aircraft at the time of the "jump". Please clarify. P8L47to48: Delete "at the significance level of 0.05 (two-sided)". It appears that 0.05 (two-sided) is the significance level for all tests not just the test of the primary hypothesis; a general statement "P 0.05 was considered statistically significant" should be added near the end of this section. P9L6: Revise to "...total sample size of 20...". P9L17: As written one could erroneously conclude that statistical tests were performed on the baseline characteristics of the two trial arms; this doesn't appear to be done (Table 1) and, of course, would be a grave mistake. I suggest reordering this paragraph as follows: Continuous variables were summarized by mean (standard deviation) and categorical variables by frequency and percentage. We tabulated baseline characteristics of the two arms to examine for potential imbalance in variables. We tested for differences between the outcomes of the two trial arms using Student's two-sample t-test (continuous variables) and Pearson's chi-square test or Fisher's exact test (categorical variables) if ADD RULE USED TO DECIDE BETWEEN TESTS. To better understand what drove the willingness to participate in the trial, we also compared characteristics of individuals who were screened but chose not to enroll with those who enrolled. P10L43to55 and Table 3: Confidence intervals for between-group differences should be provided (CONSORT Statement Item 17a). P11L25to27: Delete "contradicting widely held beliefs that parachute use reduces catastrophic bodily damage in this setting"; the study as conducted does not support this statement. Additional Questions: Please enter your name: Penelope Brasher Job Title: Senior Scientist Institution: Centre for Clinical Epidemiology & Evaluation, Vancouver Coastal Health Research Institute Reimbursement for attending a symposium?: No A fee for speaking?: No A fee for organising education?: No Funds for research?: No Funds for a member of staff?: No Fees for consulting?: No Have you in the past five years been employed by an organisation that may in any way gain or lose financially from the publication of this paper?: No Do you hold any stocks or shares in an organisation that may in any way gain or lose financially from the publication of this paper?: No

7 If you have any competing interests <A HREF=' lists/declaration-competing-interests'target='_new'> (please see BMJ policy) </a>please declare them here: Reviewer: 3 Recommendation: Comments: This is overall a sound study, suited to the Christmas issue, and it illustrates some important issues to do with evidence-based practice. I have a few suggestions for revision: Page 5 l36: I think equipoise is by definition a perception, so I think 'perceived lack of equipoise' is something of a pleonasm. Also on page 13. Page 5 l43: I think BMJ uses UK English, so the spelling of enroll, enrollment etc will need to be adjusted throughout. Page 8 l43: This sentence states a directional research hypothesis (which is fine) but then concludes by indicating a two-tailed test, such that the statistical alternative hypothesis is clearly non-directional (which is also fine). However, having both of these elements in the one sentence is potentially confusing. I would either state the statistical hypothesis in this sentence, or present the research and statistical hypotheses separately. Page 9 l10: I am unclear why a formal test of interaction was performed when the study was clearly not powered for this - in the event, of course, this was hardly an issue, but it might be better to explore or estimate an interaction, rather than test it, in these circumstances. Alternatively, acknowledge the lack of power. Page 9 20: statistical between-group tests of baseline variables are essentially meaningless. I would omit any reference to them in relation to the arms of the trial (particularly as their results are not reported), and relate them solely to the comparison of those recruited and those not. Page 10 l10: 'with regard to', not 'with regards to'. Page 10 l50: I think it is strictly inappropriate to report a p value of 1.00 (just as it is to report one of zero), as it seems to say that this (lack of) effect is inevitable if the null hypothesis were true. I would suggest '>.999'. Applies elsewhere. Page 11 l34: to what extent was this really a placebo-controlled trial, given that participants were not blind to the interventions? Page 12 l55: I'm not sure that this would be a reductio ad absurdum in relation to evidence-based medicine per se. It might be in respect of a specific claim within EBP that 'no treatment should ever be used until it has been subjected to a randomized trial'. Perhaps rephrase slightly. Page 13 l31: I think it might be clearer if you referred to 'the treatment under test' rather than just to 'treatment.'

8 Page 17, l39: The sentence 'Finally... away' is presumably a reference to the Sri Lankan CT Registry, but I am not sure that all readers will necessarily make the connection. Perhaps reword or omit. Page 20: inconsistent capitalization in the titles of journal articles. I think BMJ uses abbreviated journal titles. Page 27: just a suggestion: the irony of the caption might be subtler if 'remarkably' were replaced by 'it is noteworthy that'. Julius Sim Additional Questions: Please enter your name: Julius Sim Job Title: Professor of Health Care Research Institution: Keele University Reimbursement for attending a symposium?: No A fee for speaking?: No A fee for organising education?: No Funds for research?: No Funds for a member of staff?: No Fees for consulting?: No Have you in the past five years been employed by an organisation that may in any way gain or lose financially from the publication of this paper?: No Do you hold any stocks or shares in an organisation that may in any way gain or lose financially from the publication of this paper?: No If you have any competing interests <A HREF=' lists/declaration-competing-interests'target='_new'> (please see BMJ policy) </a>please declare them here: