Author s response to reviews

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1 Author s response to reviews Title: Multipoint Pacing versus conventional ICD in Patients with a Narrow QRS complex (MPP Narrow QRS trial): study protocol for a pilot randomized controlled trial Authors: Maurizio Gasparini (maurizio.gasparini@humanitas.it) Paola Galimberti (paola.galimberti@humanitas.it) Renato Bragato (renato.bragato@humanitas.it) Stefano Ghio (S.Ghio@smatteo.pv.it) Claudia Raineri (C.Raineri@smatteo.pv.it) Maurizio Landolina (maurizio.landolina02@gmail.com) Enrico Chieffo (Enrico.chieffo@asst-crema.it) Maurizio Lunati (maurizio.lunati@ospedaleniguarda.it) Ederina Mulargia (ederina.mulargia@ospedaleniguarda.it) Alessandro Proclemer (proclemer.alessandro@aoud.sanita.fvg.it) Domenico Facchin (facchin.domenico@aoud.sanita.fvg.it) Roberto Rordorf (r.rordorf@smatteo.pv.it) Alessandro Vicentini (alessandro.vicentini@libero.it) Lina Marcantoni (lina.marcantoni@gmail.com) Francesco Zanon (franc.zanon@iol.it) Catherine Klersy (klersy@smatteo.pv.it) Version: 1 Date: 09 Nov 2016 Author s response to reviews: We sincerely thank the referees for their reviews, and feel that their observations have enabled us to improve the quality of our manuscript.

2 All the issues raised have been addressed and the text has been modified accordingly. We hope that our replies and the modifications we have made will be deemed appropriate by the reviewers. A point-by-point list of modifications is enclosed. In addition, please note the following: 1. All authors of this manuscript were involved in the following activities: - Study design and data analysis - Drafting and revising of the manuscript - Final manuscript approval. 2. This manuscript is not being considered for publication elsewhere. 3. None of the manuscript contents have been published elsewhere. 4. All authors have read and approved this manuscript. Once again, thank you for considering our manuscript. Sincerely, Maurizio Gasparini Reviewer #1: Gasparini and colleagues submitted a study protocol for a feasibility randomized controlled trial (pilot study) to compare a novel method of cardiac resynchronization therapy (CRT) based on multipoint pacing (MPP) with standard ICD, in patients with heart failure and indication for ICD and 100 ms < QRS < 130 ms, in promoting reverse left ventricular remodeling at 12 months. The study is interesting and relevant, and based on appropriate methods. The protocol is overall well written and clear. However some revisions should be made, concerning the study rationale and question, missing information about methods, and correctness and clarity of some statements. #1 Study rationale and question

3 As it is designed, the study implies a research question embedding in fact 2 questions: i) whether a CRT might work also in the case of narrow QRS, and ii) whether MPP might work in case of narrow QRS. As a consequence if the study fails to show any effect of MPP-based CRT compared with standard ICD with no CRT, this might be due either to the fact that a CRT does not work in the case of narrow QRS or that MPP does not work but a CRT differently implemented could still work. The reviewer would suggest: a. that authors comment on this study implication in the Discussion b. that authors help the reader to better understand the rationale for their study, in particular the rationale for testing a MPP-based CRT instead of a standard biventricular stimulation. It would help if evidence on the effect of biventricular stimulation in patients with narrow QRS (i.e. QRS prolongation) currently mentioned in Discussion (page 8, lines , "Aranda et al. ( ) with a narrow QRS[5]) was in fact moved to the Introduction section. Answer: We thank the reviewer for this comment. This is the crucial point. In patients with narrow QRS, CRT is not currently indicated as standard practice. Moreover, patients with a QRS between 100 and 130 are in a grey zone. In the light of the Echo-CRT study results, the new guidelines do not suggest implanting a CRT device in this category of patients. However, Multipoint-pacing has recently become available and has proved to be a novel CRT technology based on a different kind of pacing (from two cathodes at different delays). Literature on MPP is now also available and this suggests that the new modality is promising in patients who do not respond to CRT. We have inserted these points into the article: -page 9 line 234 Moreover, the Echo CRT study, which enrolled patients with systolic heart failure and a QRS duration < 130 ms, found that CRT did not reduce the rate of death or hospitalization [8]. Since the publication of this study, the CRT on the system guidelines have been changed -page 9, line 244 The first studies on this new technology seem to underline [11,12,13,14] an increase in responders and a reduction in QRS duration in MPP patients. Molhoek et al. [33] demonstrated that Baseline QRS was not predictive of response; however, responders showed a significant reduction in QRS duration directly after initiation of CRT, and this was maintained during follow-up. - As you suggested, we have moved the sentences "Aranda et al. ( ) with a narrow QRS[5] from page 8, lines , to the Introduction section. #2 Inclusion criteria. The reviewer could not find in the manuscript any explicit descriptions of which are the "standard indications to ICD". It should be included.

4 Answer: Thank you for underlining this missing explanation. For greater clarity, we have inserted the indication on page 5 line : All the enrolled patients must be indicated for ICD implantation in accordance with the current guidelines.[3] (An ICD is recommended in order to reduce the risk of sudden death and all-cause mortality in patients with symptomatic HF (NYHA Class II III) and an LVEF 35% despite 3 months of optimal medical therapy, provided they are expected to survive substantially longer than one year with good functional status). #3 Randomization and Blindness. The manuscript is currently lacking for important information concerning the randomization procedure (what method will be used? will be centralized or local?) and concerning blindness (who will be blinded to allocation? patients, investigators, outcome assessors, statisticians, etc.?). Answer: we have reported this information in Study Population and Randomization : randomization will be centralized by means of an online tool and a database created for this study. The allocation process will be blinded to the investigators and carried out by an external assessor (CRO). The investigators will not be blinded to the treatment groups after randomization. Importantly, the Echo data will be analyzed by a central echo core lab, which will be blinded to allocation. #4 Outcomes. All primary and secondary outcomes are in fact surrogate/intermediate outcomes. Why not to choose patient-important outcomes (e.g. measures of patient's performance, arrhythmias, hospitalization, mortality)? Would them be included in the final larger trial? This choice would deserve a comment. Answer: We thank the reviewer for this comment. We chose to use echo parameters, as in the previous studies on multipoint pacing [Optimization of left ventricular pacing site plus multipoint pacing improves remodeling and clinical response to cardiac resynchronization therapy at 1 year, Zanon, HR 2016]. Moreover, Yu CM et al. demonstrated that CRT responders who displayed LV reverse remodeling (defined as a reduction in LV end-systolic volume by >15%) showed an improvement in clinical status, cardiac function and systolic synchronicity [Predictors of left ventricular reverse remodeling after cardiac resynchronization therapy for heart failure secondary to idiopathic dilated or ischemic cardiomyopathy, Yu CM]. In another study Yu CM et al. demonstrated that a reduction in LVESV of 10% is a strong predictor of lower long-term mortality and heart failure events. [Left ventricular reverse remodeling but not clinical improvement predicts long-term survival after cardiac resynchronization therapy. Yu CM, Circulation 2005] In the study database we will collect information on hospitalization, arrhythmias and mortality. These data are not included as endpoints because this is a pilot feasibility study with a small simple size. However, these data are very important, and it is indispensable to point out that these outcomes will be the key to evaluating patient responsiveness in a future larger trial. While MPP efficacy cannot be evaluated as a hard endpoint in a pilot study, it could be evaluated in a large trial with an adequate sample size.

5 #5 Sample size calculation. The authors calculate their pilot's size adopting the approach proposed by Cock et al (J Clin Epidemiol 2013). This is a very interesting and rigorous approach, however: a. It is not clear why the authors chose 23% as a "clinically significant" effect size; where did it come from? please, clarify. b. In following and quoting the paper by Cock et al., there are sentences that sound incorrect: I. Page 7, lines 156-7: "( ) interested in whether the hypothesized treatment estimate of 23% is larger than, or equal to, the upper limit of the 90% CI computed under the null hypothesis". Should this in fact be "interested in whether the hypothesized treatment estimate is larger or equal/smaller than 0"? a. Page 7, lines 158-9: "( ) and the upper limit of the one-sided 90% confidence interval excludes the clinically relevant effect size of 23%". Should this in fact be "( ) and the upper limit of the one-sided 90% confidence interval excludes the clinically relevant effect size of 23% under the null hypothesis". Answer: A 20% difference in the proportion of success is generally considered of clinical interest in heart failure trials; a 15% reduction is the change in LVESV accepted as indicating LV remodeling. Also, an unpublished analysis of the group of patients enrolled in the CERTIFY REGISTRY (Cardiac Resynchronization Therapy in Patients With Atrial Fibrillation and The CERTIFY Study (Cardiac Resynchronization Therapy in Atrial Fibrillation Patients Multinational Registry); Gasparini et al, JACC HF-2013) presenting a QRS duration ms showed that CRT may determine LV reverse remodeling in 23% of these cases. b. We completely agree with the referee s correction; this was an error that has now been corrected in the manuscript. Thank you for pointing it out. #6 Table 1 should be reformatted with the "Inclusion criteria (A)" placed before the "Exclusion criteria (B)". Answer: the table has been reformatted Rev.2 I read with pleasure the MPP Narrow QRS manuscript of this randomized trial protocol. As it has been externally reviewed and the recruitment already started, I minimize my suggestions. In order to agree with Trials policy and to facilitate further readings, please, provide the SPIRIT table specifying where is reported any item.

6 Answer: Thank you for the suggestion to add the Spirit table. We report the Table in a separate sheet and we have inserted clearer information in the article. Background: we have expanded the introduction section. Trial Design: we have added the Study Population and Randomization chapter. Please, add that final report will follow CONSORT as well as their extensions for nonpharmacological interventions and pilot trials. Please, note that the former requires additional items not stated in SPIRIT; and that it provides important considerations about blinding. You are proposing an adaptive design. Answer: Thank you for the suggestion, we have modified the report to follow CONSORT for non-pharmacological interventions and pilot trials. About the blinding and randomization process, we will include some statements in the article. Please, state if it has been approved by a regulatory agency. Answer: the study has been approved by Ethics Committee Please, provide either the rationale or the evidence to guarantee that alpha risk is maintained at some desired level. Answer: The method takes into consideration the upper confidence limit of the clinical gain reached with 90% probability (then the alpha error accepted is 10% that is typical in pilot studies) In L148 you anticipate some attrition. It seems to me too high for patients with implantable devices -even with a long follow up. Please, consider to distinguish between deaths and losses. Answer: We consider 10% of attrition, as in a previous CRT device study design [Muto et al., Narrow QRS Study]. In this study, the final results showed a 13% drop out rate (in both groups): 10% of deaths and 3% of losses to follow-up. In the Madit CRT study, an annual death rate of approximately 3% in each study group (ICD vs CRTD) was reported [Arthur J. Moss et al. Cardiac-Resynchronization Therapy for the Prevention of Heart-Failure Events- NEJM 2009]