Title:Stress Urinary Incontinence Physiotherapy: study protocol for a randomized controlled trial with 6-month follow-up

Transcription

1 Author's response to reviews Title:Stress Urinary Incontinence Physiotherapy: study protocol for a randomized controlled trial with 6-month follow-up Authors: Helena Luginbuehl (helena.luginbuehl@bfh.ch) Corinne Lehmann (corinne.lehmann@insel.ch) Jean-Pierre Baeyens (jean-pierre.baeyens@vub.ac.be) Annette Kuhn (annette.kuhn@insel.ch) Lorenz Radlinger (lorenz.radlinger@bfh.ch) Version:2Date:6 August 2015 Author's response to reviews: see over

2 Helena Luginbuehl Bern University of Applied Sciences, Health Murtenstrasse 10 CH-3008 Bern Switzerland Bern, To: The Editors Trials Journal Dear Sir or Madam, Thanks to the reviewers for their detailed comments to our manuscript Stress Urinary Incontinence Physiotherapy: study protocol for a randomized controlled trial with 6-month follow-up We addressed the comments in the revised manuscript and gave a point-by-point response to the concerns (See below). We will upload a bold version (so you can see the changes) and a plain version of the revised manuscript. We will also upload an additional file, which contains a detailed intervention plan, as proposed by reviewer 1. Regarding the problem of changing the study title please let us know if this is a prerequisite of your Journal that we change the title if so we will try to make this possible regardless of the answers to the reviewers. We are looking forward to hearing from you, Sincerely Helena Luginbuehl on behalf of the authors 1

3 ANSWERS TO THE REVIEWERS Editorial request: 1. Please ensure the title conforms to journal style for study protocol articles. The title should follow the format? : study protocol for a randomized controlled trial.? Please note that the title in the submission system should match that of your manuscript. Unfortunately it a problem to change the title due to registration and acceptation of the current title at the Swiss National Science Foundation, the Ethics Committee of the Canton of Bern and clincialtrials.gov. as this would lead to misunderstandings (lokks like different study). However we removed the abbreviation as suggested by reviewer 1 therefore the title will be Stress Urinary Incontinence Physiotherapy: study protocol for a randomized controlled trial with 6-month follow-up, which seems to conform with the journal style. Is this acceptable for you? I did not find regulations regarding the title in the Instructions for authors / study protocols. 2. Please include the date of registration with the trial registration number at the end of the Abstract. 3. Please include the full name of the approving ethical committee(s) with your ethics statement in the Methods section. 4. Please include a Competing Interests section after the list of abbreviations. If the authors have no competing interests, please state: "The authors declare that they have no competing interests." 5. Please state that all authors read and approved the final manuscript in the Authors' Contributions section. 6. Please state clearly whether or not you have funding in the Acknowledgements section. If there is no funding, please state this. 7. Please include a figure title and legend section after the reference list. (there is only a title / no legend) Reviewer 2) Charlie Goldsmith: Here are some suggestions to improve the manuscript. 1. P(age) 2, p(aragraph) 2, l(ine) 11. Replace [double] by [triple] since there are 3 sources listed. Also P 5, p 2, l P 3, p 1, l 5. Delete [only] as it implies un unstated expectation. 3. P 3, p 3, l 2. Replace [proving] by [shown]. 4. P 3, p 4, l 1. Include the date of registration as well as the date the first patient was randomized. 2

4 Done (even though the manuscript was submitted before the first patient was randomized. 5. P 6, p 2, l 6. Insert [kgm-2] after [30]. 6. P 7, p 1. Provide more description of the outcome measure: min, max, meaning of high numbers,etc. 7. P 7, p 1, l 4. Insert [For] before [measurement]. Also P 8, p 1, l P 7, p 3, l 7. Provide some more measurement properties and a R(eference) if it has a published validation in German. Fist point done. To our knowledge there is no publication regarding the validation in German, however the validation is confirmed on and was also confirmed and the German version sent by by Nikki Cotterill (See Contact on Website). 9. P 8, p 2, l 4. Provide a R. Unfortunately we cannot provide a reference as this electrode is widely used in clinical physical therapy (biofeedback and electrostimulation) in Germany and Switzerland, however to our knowledge there are no publications regarding this electrode. However we added the patent and CE numbers. 10. P 8, p 3, l 2. Insert a space between the numbers and the units as [11 km/h] and [20 cm]. Also P 9, p 1, l 11 and 12. Also P 9, p 2, l 1. Also P 10, p 1, l 3, 5, 7, P 9, p 1, l 14. Does the dominant leg matter? We will measure 10 step cycles of the right leg irrespective of leg dominance, As far as we know there is no valid test procedure to identify leg dominance clearly. And there is also no literature about influence on leg dominance on PFM activity characteristics. So we decided to choose the right leg. 12. P 10, p 2, l 4. What is the minimum clinically important difference (MCID) for this measure? There is no literature about MCID of ICIQ UIsf. Due to this fact, this has to be a part of our discussion when publishing study results. 13. P 11, p 1, l 7. The sample size should by 80/[(0.9)(0.9)] = 99 or 100 to accommodate dropouts (and normality?). You need to divide by the complement, not multiply by the rate. Also it is not usual to increase the sample size when the data are not normally distributed. Provide a R for this. Sample size calculation was accepted by the Swiss National Science Foundation and the local Ethic Committee of the Canton of Bern, Switzerland. Additionally it is published in the clinical trial register. Therefore we don t see a possibility to change this calculation in accordance with the legal authorities and without an extra ordinary extent of changing procedures and huge time delay of the study. 14. P 11, p 2, l 1. Provide a R for CONSORT. 3

5 15. P 11, p 3, l 3. LOCF is a poor method of imputation. Consider a better one since there is now good software to do it. See Little RJA et al New Eng J Med 2012 Oct 4 on how to handle missing data in trials. Generally we agree with your comment and are aware that there a different possible approaches (See also: Dossing A, Tarp S, Furst DE, Gluud C, Beyene J, Hansen BB, Bliddal H, Christensen R: Interpreting trial results following use of different intentionto-treat approaches for preventing attrition bias: a meta-epidemiological study protocol. BMJ Open 2014, 4(9)), however, LOCF was accepted by the Swiss National Science Foundation and the local Ethic Committee of the Canton of Bern, Switzerland. Additionally it is published in the clinical trial register. Therefore we don t see any possibility to change this calculation in accordance with the legal authorities and without an extra ordinary extent of changing procedures and huge time delay of the study. 16. P 11, p 3, l 9. The Brunner book is for factorial designs and does not apply to this study. Consider getting a better R. Our study design is a two factorial (two groups) design (ANOVA) with repeated measures (10 times ICIQ-UIsf). Consequently we would like to leave Brunner et al. as adequate R. 17. P 12, p 1, l 2 to 3. Provide a R for this source to justify 10 time points. You will find the arguments for 10 time points of measuring ICIQ-UIsf on page 12, lines P 12, p 2, l 6 and 7. Which statistical packages provide these features and do you have access to them? They should be cited. We relocated the sentence about statistical packages to the end of the chapter. 19. P 13, p 1, l 6. Insert after [... secretariat] [that can be opened one at a time for each eligible patient]. 20. P 13, p 1, l 7. Is this secretariat under the supervision of the authors? If so what is done to prevent breaking concealment of the envelope contents? This secretariat is independent of the authors, we added this in the manuscript. 21. P 15, p 2, l 4 and 5. Provide a R to an health economics book to justify this statement. As this is our interpretation (little costs / recommended first-line therapy) we adapted the sentence to [ therefore seems to be good value for money.] 22. P 15, p 1, l 11. Replace [prove] by [be shown]. 23. P 15, p 2, l 1. What is the current recruiting status? We wrote [Patient enrolment is planned to start by the end of January 2015] in the submitted manuscript as we submitted already in the end of January (!) to Trials. We now changed to [First patient randomized on March 11th 2015] in accordance to your proposal for the title page. 24. P 17 to 21. The R notation is NOT consistent with shortening page numbers. 25. P 17, R 2, l 1. BMC Trials likes to cite the first 30 authors before using [et al], so add some more authors. Also R 10 and 28. 4

6 26. P 17, R 3, l 4. Add the URL for this citation. This study was published in the meantime therefore I could complete the citation. 27. P 18, R 12, l 3. Insert [(German)] at the end. 28. P 19, R 17, l 4. Insert [(1)] after [83]. 29. P 19, R 21, l 2. Insert [(9)] after [111]. 30. P 19, R 22, l 3. Insert [(1)] after [110]. 31. P 20, R 25, l 2. Insert [NJ] after [Hillsdale]. 32. P 20, R 26, l 2. Insert [NY] after [York]. 33. P 20, R 29, l 2. Insert [Eds] after [Kampen M], insert a [g] to read [bridging] and on l 3, insert a [d] to read [and]. and then delete a [g] to read [Edinburgh]. See also R 31, P 21, l 1. Done, sorry for that! 34. P 21, R 34. Translate the title into English, [enclose it in square brackets] and insert [(German)] at the end of the citation. Reviewer 1) Jean Hay-Smith: MCR = major compulsory revisions (which the author must respond to before a decision on publication can be reached) MER = minor essential revisions (such as missing labels on figures, or the wrong use of a term, which the author can be trusted to correct) DR = discretionary revisions (which are recommendations for improvement but which the author can choose to ignore) SPIRIT Item 1: Descriptive title identifying the study design, population, interventions, and, if applicable, trial acronym To include all these items I suggest something like A single-centre, participant and researcher-blinded, 6-month, parallel group, non-inferiority randomised trial to investigate the effect of involuntary reflexive training in addition to standard pelvic floor muscle exercise in women with stress urinary incontinence (MER) Unfortunately it is a problem to change the title due to registration and acceptation of the current title at the Swiss National Science Foundation, the Ethics Committee of the Canton of Bern and clincialtrials.gov. However we removed the abbreviation as suggested. See also comment 1. to Editorial request I have not suggested the use of the acronym (SUIP) used by the study authors in the study title. I recommend this is removed (MER). Removed 5

7 Further, I recommend that physiotherapy is not used as a short-hand to describe the intervention anywhere in the paper as this is misleading (MER). Physiotherapy may include a wide range of interventions for a wide range of conditions and is not specific enough. Further, the intervention being tested in this trial is not the sole preserve of physiotherapists, and the type of training being investigated could equally be used by continence nurse specialists for example. I agree however that the authors need to make it clear that physiotherapists are the health professionals who deliver the intervention in this trial this needs to be made clear in the description of the intervention. We do not agree regarding removal of the term physiotherapy as this study concerns a physiotherapy specific intervention. We refer to the book evidence-based physical therapy for the pelvic floor, bridging science and clinical practice (edited by Kari Bo, Bary Berghmans, Siv Morkved and Marijke van Kampen), which explicitly uses the term Physical Therapy even in the title. Physical therapists are trained in movement and training science. The interventions in the current study are clearly based on those principles and according to our opinion (at least in our country) physical therapists are the specialists in this matter. SPIRIT Item 2a and b: (a) Trial identifier and registry name. If not yet registered, name of intended registry; (b) All items from the World Health Organization Trial Registration Data Set Trial registration reported. Regarding the WHO data set see the paper by Chan et al (2013) for the example. This could be added as a table (DR). Left away (reason: article length) SPIRIT Item 3: Date and version identifier The addition of this detail is a discretionary revision. The authors may, instead, prefer to refer readers to a trial website where a record of the trial protocol and updates is reported. We added the website (clinicaltrials.gov) in the chapter Trial status SPIRIT Item 4 and 5c: (4) Sources and types of financial, material, and other support; (5c): Role of study funders, if any, in study design; collection, management, analysis, and interpretation of data; writing of the report; and the decision to submit the report for publication, including whether they will have ultimate authority over any of these activities Not declared. Please add (MER). According to the suggestions of reviewer 2) we added under acknowledgements SPIRIT Item 5a and b: (a) Names, affiliations, and roles of protocol contributors; (b) Name and contact information for the trial sponsor Names etc are reported under the heading Authors contributions. The person assuming responsibility for the research is presumed to be the corresponding author, unless the authors wish to state otherwise. The corresponding author is not the responsible author: We added this matter. SPIRIT Item 5d: Composition, roles, and responsibilities of the coordinating centre, steering committee, endpoint adjudication committee, data management team, and other individuals or groups overseeing the trial, if applicable (see Item 21a for data monitoring committee) There is no indication of the process of trial governance. If none of these apply perhaps it is worth adding sentence that explains the trial governance process (DR). The study was approved by the Ethic Committee of the Canton of Bern, which is in accordance with the Declaration of Helsinki and the Swiss Human Research Act. We now mentioned this in the chapter Participants. 6

8 SPIRIT Item 6a and b: (a) Description of research question and justification for undertaking the trial, including summary of relevant studies (published and unpublished) examining benefits and harms for each intervention; (b) Explanation for choice of comparators The background covers most of the necessary concepts. An example of how involuntary fast reflexive contractions are trained is needed (MER). At the moment I am left wondering if the training requires women to do the things that provoke leakage in the hope that doing more of these activities will help. In addition, the authors need to make it clear if there is any difference between the training they propose and what is commonly termed The Knack (see Ashton-Miller, DeLancey et al). It seems likely as Table 2 refers to something called motor learning which may well be another name for The Knack (MER). Involuntary contractions will e.g. be trained by running (Luginbuehl H, Naeff R, Zahnd A, Baeyens JP, Kuhn A, Radlinger L: Pelvic floor muscle electromyography during different running speeds: an exploratory and reliability study. Arch Gynecol Obstet 2015, Jul 21. [Epub ahead of print] and leakage would be tolerated (Prolapse > grade 1 POP-Q = study exclusion criteria!). See also comment SPIRIT 11. The Knack (=voluntary PFM pre-contraction) is part of the standard physiotherapy, i.e. for both groups. SPIRIT Item 7: Specific objectives or hypotheses There are two discretionary revisions in the background it isn t clear that the comparison of interest is standard training plus reflexive training versus standard training alone (primary objective), and the phrasing of the secondary objective is difficult to understand. We clarified (See Page 5, Paragraph 1your first point. SPIRIT Item 8: Description of trial design including type of trial (eg, parallel group, crossover, factorial, single group), allocation ratio, and framework (eg, superiority, equivalence, non-inferiority, exploratory) Some further detail is needed under the heading Study design parallel group, noninferiority (MER). The allocation ratio is reported under statistical methods. added SPIRIT Item 9: Description of study settings (eg, community clinic, academic hospital) and list of countries where data will be collected. Reference to where list of study sites can be obtained Reported under the heading Patient recruitment SPIRIT Item 10: Inclusion and exclusion criteria for participants. If applicable, eligibility criteria for study centres and individuals who will perform the interventions (eg, surgeons, psychotherapists) Reported under the heading Participants. I would delete parous, multiparous, pre- or post-menopausal as inclusion criteria rather, women are included regardless of parity or menopausal status (DR). We cannot change due to registration and acceptation of the current title at the Swiss National Science Foundation, the Ethics Committee of the Canton of Bern and clincialtrials.gov. The statement about being stable on systemic or local oestrogen makes it sound as though women must be taking this rephrase is this is not true? (DR). we clarified Also, it is not clear what measurements would be contradicted by the conditions listed rather, is this the list of conditions that would contradict the intervention (i.e. women could not do the drop jumps etc that are required). Please 7

9 clarify (MER). We clarified in the text (added. or interventions, ) on P.6. It does not matter whether the contraindications concern the interventions or measurements, as the participants have to be fit for both. Ł Contraindication for eather means that no inclusion is possible. SPIRIT Items 11a to d: (a) Interventions for each group with sufficient detail to allow replication, including how and when they will be administered; (b) Criteria for discontinuing or modifying allocated interventions for a given trial participant (eg, drug dose change in response to harms, participant request, or improving/worsening disease; (c) Strategies to improve adherence to intervention protocols, and any procedures for monitoring adherence (eg, drug tablet return; laboratory tests); (d) Relevant concomitant care and interventions that are permitted or prohibited during the trial Neither the standard or experimental interventions could be reproduced based on current reporting. The full intervention protocol is needed and could be tabulated an extension of existing table 2? (MCR). We will submit/publish the intervention, i.e. the detailed therapy plan of both groups as an additional file provided that the editor agrees. It is not possible to include it in Table 2, as it is much too long (15 pages!) I also suggest the term basic therapies is changed as this is difficult to understand clinic visits, clinic appointment, therapy visits, or something similar would be preferable (DR). We did change the term to personal physiotherapy consultations No criteria are given for ceasing or modifying the treatment (MER). It is an inclusion criteria that participants are medically and physically fit for the exercises. We added a sentence at the end of chapter Participants regarding modifications. A patient-completed training diary is used to monitor home exercise adherence. It is not clear whether any concomitant care or activities are permitted or prohibited during the 6-month trial period. For example, if women in either group already take part in high impact physical activity will this be permitted, or if a participant usually inserts a tampon prior to high impact activities in an attempt to compress the urethra is this allowed? (MER) Just to clarify: The intervention lasts 16 weeks, the follow-up takes 6 month after the post-intervention measurements (See table 1). We added a sentence in chapter Interventions. SPIRIT Item 12: Primary, secondary, and other outcomes, including the specific measurement variable (eg, systolic blood pressure), analysis metric (eg, change from baseline, final value, time to event), method of aggregation (eg, median, proportion), and time point for each outcome. Explanation of the clinical relevance of chosen efficacy and harm outcomes is strongly recommended. Primary outcome measure: there is a lack of clarity about whether the primary outcome measure is incontinence specific quality of life or not. In the abstract quality of life is listed as a secondary outcome. In the paper (under the heading Primary outcome measure ) is says the instrument measure symptom impact on quality of life, and then later (under the heading Secondary and tertiary outcome measures ) there is reference to another quality of life measure as a secondary outcome. Clarify (MER). Primary outcome: ICIQ-UI Short Form, which provides a brief and robust measure to assess the impact of symptoms of incontinence on quality of life and outcome of treatment. Ł we clarified in the text, Secondary outcome: ICIQ-LUTSqol, which is a patient-completed questionnaire for evaluating quality of life (QoL) in urinary incontinent patients for use in research and clinical practice. 8

10 We clarified in the manuscript (See lines ). The electromyography (EMG) procedures are described in detail. Some justification is needed to substantiate the likely validity of these measures probe movement and cross talk are presumably substantial problems. What evidence is there that vaginal surface EMG is a valid measure of muscle performance in these test circumstances? (MER) We added the source of an article (e-pub ahead of print) published July, which uses a similar protocol in this study also the limitations of electromyography are discussed. We decided not to discuss the limitations in the current study protocol, as EMG measurements are only the secondary outcome. SPIRIT Item 13: Time schedule of enrolment, interventions (including any run-ins and washouts), assessments, and visits for participants. A schematic diagram is highly recommended. Nicely covered in text and the CONSORT flow diagram (figure 1). SPIRIT Item 14: Estimated number of participants needed to achieve study objectives and how it was determined, including clinical and statistical assumptions supporting any sample size calculations. Reported under the heading Statistical methods. It does seem likely the effect size will be small. While there is no trial making exactly this comparison, there are other trials comparing different approaches to pelvic floor muscle training (see the relevant Cochrane systematic review) and reference to this would further support the authors contention of a small effect size (DR). As you mentioned, there are no comparable trials and study outcomes available. We are not primarily interested in before - after intervention differences, but in group comparison after the intervention (which we expect to be small). In consequence our small effect size estimated and the related sample size calculated will be able to indicate statistical differences as significant when effect size will be greater than small. SPIRIT Item 15: Strategies for achieving adequate participant enrolment to reach target sample size Recruitment is described under the heading Patient recruitment. There is no detail about specific strategies that might be used to increase the likelihood of reaching the required sample size in timely fashion (DR). We would rather discuss this matter after completion of the study in case of recruitment problems (reason: article length). SPIRIT Item 16a to c: (a) Method of generating the allocation sequence (eg, computergenerated random numbers) and list of any factors for stratification. To reduce predictability of a random sequence, details of any planned restriction (eg, blocking) should be provided in a separate document that is unavailable to those who enrol participants or assign interventions; (b) Mechanism of implementing the allocation sequence (eg, central telephone; sequentially numbered, opaque, sealed envelopes), describing any steps to conceal the sequence until interventions are assigned; (c) Who will generate the allocation sequence, who will enrol participants, and who will assign participants to interventions. Generation of the allocation sequence is reported (under the heading Allocation of patients), although it is not clear if any methods are used to reduce predictability of the sequence (MER). The mechanism of implanting the sequence is reported. It is not clear who will generate the sequence, or who will enrol patients. Further, it is not clear if the physiotherapist phones the independent secretariat to enrol the patient, and then be told the allocation. These details need to be provided (MER). We clarified in the chapter Allocation of patients. SPIRIT Item 17a and b: (a) Who will be blinded after assignment to interventions (eg, 9

11 trial participants, care providers, outcome assessors, data analysts) and how; (b)if blinded, circumstances under which unblinding is permissible and procedure for revealing a participant s allocated intervention during the trial. Details of blinding are reported under the heading Blinding. I would avoid the term double-blinded used in the abstract and elsewhere as is not helpful in making it clear who is blind and who is not (MER). I applaud the attempt to blind participants which is rarely possible in rehabilitation trials exactly how will this be done/attempted? (MER). We followed the recommendation of Reviewer 2 changing double to triple. Blinding of participants: We think that only specialized pelvic floor therapists would realize, which group they are attending. SPIRIT Item 18a and b: (a) Plans for assessment and collection of outcome, baseline, and other trial data, including any related processes to promote data quality (eg, duplicate measurements, training of assessors) and a description of study instruments (eg, questionnaires, laboratory tests) along with their reliability and validity, if known. Reference to where data collection forms can be found, if not in the protocol; (b) Plans to promote participant retention and complete follow-up, including list of any outcome data to be collected for participants who discontinue or deviate from intervention protocols Addressed under the headings Outcomes and EMG procedure. The training of those collecting the Oxford score and EMG data could be addressed, especially if more than one data collector is being used (what is the inter-rater reliability of these measures?) (DR). Regarding retention and follow up, it is not clear if any steps will be taken to collect data from those who drop out (e.g. phone administration of self-reported measures if the participant agrees) (DR). Interrater-reliability of Oxford score: we did not discuss, as it is a tertiary outcome (we only mentioned that two experienced PF-therapists will undertake the measurements) (reason: article length).. EMG generally shows good reliability (Grape HH, Dedering A, Jonasson AF (2009) Retest reliability of surface electromyography on the pelvic floor muscles. Neurourol Urodyn 28: ; Luginbuehl H, Naeff R, Zahnd A, Baeyens JP, Kuhn A, Radlinger L: Pelvic floor muscle electromyography during different running speeds: an exploratory and reliability study. Arch Gynecol Obstet 2015, Jul 21. [Epub ahead of print]), however Interrater-reliability of EMG has not been studied so far but is expected to be good as an electronic measurement. Not mentioned in the current manuscript due to article length. Drop-outs (in case of not following the study protocol) Ł intention to treat analysis. SPIRIT Item 19: Plans for data entry, coding, security, and storage, including any related processes to promote data quality (eg, double data entry; range checks for data values). Reference to where details of data management procedures can be found, if not in the protocol. Not addressed (DR). Self-evident as Standard of Operation Procedure (SOP) of our university and also implicit as approved by the Ethics Committee (implicit: Declaration of Helsinki, Swiss Human Research Act). SPIRIT Item 20a to c: (a) Statistical methods for analysing primary and secondary outcomes. Reference to where other details of the statistical analysis plan can be found, if not in the protocol; (b) Methods for any additional analyses (eg, subgroup and adjusted analyses); (c) Definition of analysis population relating to protocol non-adherence (eg, as randomised analysis), and any statistical methods to handle missing data (eg, multiple imputation) The analysis plan is reported under the heading Statistical analysis. There are three things I think it would help to clarify (MER): 1. Which time point is the primary endpoint? 2. How will missing data be handled (e.g. participants with incomplete ICIQUIsf data)? 3. Citation support for last value carried forward as the most appropriate 10

12 method for an intention to treat analysis. Primary outcome = ICIQsf (see table 1). Statistical analysis: ANOVA with repeated measure to identify the expectable improvement during training period at different time points. Missing Data: Strict control of data (Case Report Form) & Intention to treat analysis. We are aware that there a different possible approaches (Dossing A, Tarp S, Furst DE, Gluud C, Beyene J, Hansen BB, Bliddal H, Christensen R: Interpreting trial results following use of different intention-to-treat approaches for preventing attrition bias: a meta-epidemiological study protocol. BMJ Open 2014, 4(9).), therefore we cannot add a reference describing LOCF is the most appropriate method of imputation. SPIRIT Item 21a and b, and 23: (a) Composition of data monitoring committee (DMC); summary of its role and reporting structure; statement of whether it is independent from the sponsor and competing interests; and reference to where further details about its charter can be found, if not in the protocol. Alternatively, an explanation of why a DMC is not needed; (b) Description of any interim analyses and stopping guidelines, including who will have access to these interim results and make the final decision to terminate the trial ; (23) Frequency and procedures for auditing trial conduct, if any, and whether the process will be independent from investigators and the sponsor See also 5d. There is no reporting about trial governance, data monitoring or interim analysis, stopping rules etc. These may not apply and if so should be stated (MER). These are SOP (implicit Ethics Committee approval); no ad interim analysis (not stated in article because it is obsolete to write everything that will NOT be done instead of those things which will be done, like we did. SPIRIT Item 22: Plans for collecting, assessing, reporting, and managing solicited and spontaneously reported adverse events and other unintended effects of trial interventions or trial conduct. Not reported. Essential (MER). We added a chapter Adverse events (lines ). SPIRIT Item 24: Plans for seeking research ethics committee/institutional review board (REC/IRB) approval Reported SPIRIT Item 25: Plans for communicating important protocol modifications (eg, changes to eligibility criteria, outcomes, analyses) to relevant parties (eg, investigators, REC/IRBs, trial participants, trial registries, journals, regulators) Not reported (DR) We published our protocol on clinicaltrials.gov (mentioned in Manuscript) which means that updates will be published there. We did not specifically mention updates in the manuscript due to article length. SPIRIT Item 26a and b: (a) Who will obtain informed consent or assent from potential trial participants or authorised surrogates, and how; (b) Additional consent provisions for collection and use of participant data and biological specimens in ancillary studies, if applicable Reported. SPIRIT Item 27: How personal information about potential and enrolled participants will be collected, shared, and maintained in order to protect confidentiality before, during, and after the trial Not reported (DR) SOP of our university / implicit as approved by the Ethics Committee (implicit: Declaration of Helsinki, Swiss Human Research Act). 11

13 SPIRIT Item 28: Financial and other competing interests for principal investigators for the overall trial and each study site No conflict of interest statement (MER) Done, See Chapter after Chapter Abbreviations (Recommendation Reviewer 2) SPIRIT Item 29: Statement of who will have access to the final trial dataset, and disclosure of contractual agreements that limit such access for investigators Not reported (DR) Not mentioned due to article length (= SOP / implicit Ethics Committee approval). SPIRIT Item 30: Provisions, if any, for ancillary and post-trial care, and for compensation to those who suffer harm from trial participation Not reported (DR) Our study is a Category A study (= low risk study meaning insurance is not necessary according to Swiss Human Research Act ( however our University has a liability insurance. Not reported due to article length. SPIRIT Item 31a to c: (a) Plans for investigators and sponsor to communicate trial results to participants, healthcare professionals, the public, and other relevant groups (eg, via publication, reporting in results databases, or other data sharing arrangements), including any publication restrictions; (b) Authorship eligibility guidelines and any intended use of professional writers; (c) Plans, if any, for granting public access to the full protocol, participant-level dataset, and statistical code. Not reported (DR) Not mentioned due to article length SPIRIT Item 32: Model consent form and other related documentation given to participants and authorised surrogates Not appended and could be made available via trial website (with URL link provided) (DR) As those documents are in German they are not relevant for most of the readers in an English language Journal SPIRIT Item 33: Plans for collection, laboratory evaluation, and storage of biological specimens for genetic or molecular analysis in the current trial and for future use in ancillary studies, if applicable Not applicable. 12