Author s response to reviews

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1 Author s response to reviews Title: The PATH Study - Subcutaneous immunoglobulin for maintenance treatment in chronic inflammatory demyelinating polyneuropathy: study protocol for a randomized controlled trial Authors: Ivo van Schaik (i.n.vanschaik@amc.uva.nl) Nan van Geloven (n.van_geloven@lumc.nl) Vera Bril (vera.bril@utoronto.ca) Hans-Peter Hartung (hans-peter.hartung@uni-duesseldorf.de) Richard Lewis (richard.lewis@cshs.org) Gen Sobue (sobueg@med.nagoya-u.ac.jp) John-Phillip Lawo (John-Philip.Lawo@cslbehring.com) Orell Mielke (Orell.Mielke@cslbehring.com) David Cornblath (dcornbl@jhmi.edu) Ingemar Merkies (isjmerkies@planet.nl) Version: 1 Date: 20 Jun 2016 Author s response to reviews: See also attached file for better readability Comments of the Editor Please, in order to improve readability, please consider the new version to be as concise as possible.

2 We have shortened the manuscript and hopefully improved readability. Abstract has been reduced from 345 to 322 words; background is unchanged, methods has been reduced from 5533 to 4744 words and discussion from 1121 to 849 words. Reviewer Fabio Besides, English editing is recommended to make the text more smooth. Please check all spelling in the text, figure and figure legends. Please indicate every abbreviation term as it present in the text for the first time, followed by consistent use of particular abbreviations in the text. The text has been seen by a native speaker. Furthermore, we scrutinized the text for spellingerrors and consistency in the use of abreviations. Article title Suggest very long title. I suggest reducing We reduced the title to: The PATH Study Subcutaneous immunoglobulin for maintenance treatment in chronic inflammatory demyelinating polyneuropathy: study protocol for a randomized controlled trial Abstract Key words: Insert different key words of title Keywords were already given and do cover the most important aspects of the study and the title. We did not change the keywords but are happy to provide additional ones if needed. Introduction

3 Please indicate every abbreviation term as it present in the text. Please check spelling SCIg IgPro20. We have checked the manuscript meticulously for abbreviations and spelling. Method Indicate the time of follow up this study We did add the follow-up time to the abstract and the method section. Reference I suggest if possible include trials of articles in reference We are not sure that we do understand what the reviewer want us to change in the manuscript. We did use the Cochrane database reviews as reference to summarize the available trial evidence in CIDP to keep the length of the reference-list acceptable. We did not change anything with regard to this point. Figure and table Reviewing the numbers of figures and tables with text We are not sure what the intention of the reviewer is in raising this point. We did review the whole manuscript.

4 Reviewer #1 The sample size of 174 patients seems to be rather optimistic. No "safety margin" for drop-outs or lost-to-follow was included. To show the efficacy of the low dose IgPro20 alone the study would be underpowered (using the numbers in the manuscript >400 patients would be required). Thus, the "success" of the study relies entirely on the notion that the trend assumption is correct. Furthermore, the protocol mentions an interims analysis. Both issues are not considered in the statistical analysis. Please discuss these issues critically. The assumptions for recruitment have been updated in the manuscript on page 18, 21 and in the abstract. The sample size calculation was based on the assumed relapse rate of 35% for the high dose group, 52% for low dose group and 65% for placebo group. 58 subjects in each group were calculated to be required to achieve a 90% power with a one-sided significance level of 2.5% (high dose vs placebo or low dose vs placebo to be superior). 350 subjects were anticipated to be screened in order to achieve 174 randomized subjects. Any randomized subject dropping out is regarded as a relapsed patient thus meeting his endpoint. Different sensitivity analyses will analyse which patients dropped out only because of relapse (sensitivity analysis A) vs those dropping out for safety reasons (sensitivity analysis B). As such the sample size for the number of patients to be screened to randomize 174 patients were tailored to expected drop-out rates and include a safety-margin. The primary endpoint analysis accounts for drop-outs after randomization by treating them as relapse cases so all subjects will be evaluable and contribute to the analysis. Thus no safety margin was established for this study phase. Text has been added to make this more clear. We think the trend assumptions are correct. Implications of non-linear relation between the dose groups have been investigated in response to a question of the FDA and no pronounced differences in power for the exact Cochran-Armitage trend test (CA) have been found. It was not planned to conduct a pairwise comparison of low dose versus placebo at 90% power and the study was thus not powered for comparing low dose to placebo. But this low dose versus placebo comparison will be done if the trend test is significant and the comparison of high dose versus placebo is significant as well, bot at 2.5% level.

5 The interim analysis has been described already under a separate subheading op page 21 and had the intention to evaluate for futility and safety. The interim analysis was not intended to evaluate efficacy and no formal stopping rules have been applied. Therefore, sample size adjustments were deemed not to be necessary. According to clinicaltrials.gov 91 centers recruit patients, i.e. on average 2 patients per center. As mentioned before, 91 centers on 3 continents recruit patients. Thus, most centers will never leave the "learning curve" of the study. Discuss this issue, in particular in respect of standards and training. Considering that many endpoints involve language dependent questionnaires, a stratification according to language would have been a good idea. 91 centers participated in the trial, 69 centers included patients. All investigators went through a comprehensive training plan including several steps 2 days Investigator meetings with dedicated training areas depending on the study role: study coordinators, evaluating and treating physicians. Certificates were provided after successful participation in the training sessions (quizzes). Certificates were required before entering any patient into the study One day site initiation visit covering covering protocol, IMP, central lab, IWRS, Medidata, SAE reporting and GCP elements A webbased internet training portal (Firecrest ) that included several mandatory trainings before entering subjects into the study. The trainings ended with a tests. Trainings included presentations, videos and instructions for handling drug and study equipment. Eligibility checks all patients included in the study were checked for eligibility Monitoring plan a detailed monitoring plan described all site related activities, site visits and monitor site interactions, sites were monitored soon after inclusion of first subject to avoid major protocol deviations

6 All outcome measures used are standard outcomes used in inflammatory neuropathies. Most investigators have ample experience with these outcome measures. All patient questionnaires were provided in the local language of the specific country and were validated for that languages We added to the discussion: As the study involved many centers through-out the world, special attention was given to standardization of outcome measures. Investigator meetings with dedicated training, on-site training and web-based trainings were all mandatory for investigators. Central eligibility checks, strict monitor protocol added to the standardization. All patient questionnaires were provided in the local language of the specific country and were validated for that languages. Include the main objective in the abstract Find more precise formulations of the Objectives (e.g. Does subcutaneous IgPro20 lower the relapse rate during a 24 week long maintenance treatment of patients with CIDP compared to placebo. (treatment duration and framework (superiority) should be included in the objective). We included the main obejective to the abstract Abstract: Mention the time period (24 weeks) during which relapses and withdrawals are observed. We added the time period as requested Abstract and Methods: Mention the time period of the study (March Dec 2016?) Study period has been added to both abstract and methods section

7 Randomization: Who performed the generation of the list, who has access to the allocation list. What was the block size of the block randomization. Why no stratified randomization (see above).(spirit 16a, 16c). Randomization was done by external service provider using IWRS technology. The randomization list was generated within that system and access is restricted to the designated people (no one involved in the conduct or analysis of the study) to keep the blind. As part of that the block size cannot be disclosed prior to breaking the blind for the study after DB lock [language added in manuscript on p13]. Stratification of subjects was only applied for Japanese subjects to ensure a balanced number of Japanese subjects is allocated to each treatment group. This has been added to the text. Amendments: mention dates of amendments und number of patients already enrolled at this time. " sample size was increased." Please be more specific. From which count to which count. What were the assumptions for the calculation? Are there any considerations for statistical analysis of the data sets before and after amendment 3? We added the dates of the amendments, specified the sample size adjustment, and have given the assumptions for the calculations. We don't have designated analyses by amendment. Figure 1: Please add time point of latest informed consent and time of formal study inclusion. Label the double arrowed bars at the bottom according to the protocol (IgG dependence phase, etc), replace "Randomization phase" with "allocation" (or random allocation). The arrow from "Relapse:." to "Withdrawn from study" is not ideal. Relapse is the endpoint of the study, thus patients with a relapse are not withdrawn (usually implying an incomplete dataset) but actual reached the end(point) of the study (with a complete data set). (Also the outcome of the rescue therapy is secondary objective and thus part of the study) Either omit the arrow or let it point to box like "end of study treatment" (which is actually already stated with "Rescue with IgPro10"). "Not Stable by week 10." -> "Not stable by week 10 " Figure 1 has adjusted according to the reviewer suggestions.

8 Try to shorten the manuscript by using more precise phrasing and try to avoid repetitions (e.g. first paragraph of Discussion contains mainly information already mentioned before e.g. "As such, baseline scores for the SC treatment period will be defined as the scores assessed at the end of the IVIg restabilization period" -> "Scores assessed at the end of the IVIg restabilization will be used as baseline" As mentioned above we have shortened the manuscript. The sponsor is not clearly mentioned in the manuscript (page 34 (where it should be addressed according to the SPIRIT check list) only contains investigator information. Has been added Please list the affiliations of the members of the DMC. Also list possible competing interests of the members. If affiliation or competing interest might raise doubts about the independence, please discuss. (check all points of the SPIRIT issue 21a) Has been added. Issue 19, data management is not mentioned on the indicated page 14. Perhaps an own chapter data management would be helpful to address how are data collected: paper CRF, ecrf (only quickly mentioned on page 15, masking), who maintains the data, who has access to the data, management of data entry quality. A data management and auditing section has been added. Issue 23 Auditing is insufficiently addressed. Does auditing take place. how often, by whom. Has now been addressed in the data management and auditing section.

9 Issue 26a: According to "Inclusion criteria", informed consent is obtained before randomization (more correctly allocation). However, according to the protocol Dependency period and Restabilisation period are part of the study. Thus, informed consent should be obtained before starting the Dependency period. Please clarify. We have corrected this. Informed consent is obtained before study entry i.e. at screening. Issue 27: there is little information about data confidentiality. Could be included data management chapter mentioned above Has now been addressed in the data management and auditing section. Issue 29: Access to data: not mentioning on the indicated page 34. Please add this. Has now been addressed in the data management and auditing section. Page 7, line 19: involved Protocol -> Involved protocol Has been corrected. Page 10, line 59: omit " after Amendment 3". Reader is not aware of amendment history at this point in the manuscript. Anyway, the manuscript describes the protocol version amendment 5, thus the above is redundant. We omitted after amendment 3. Page21, line 10 and Table 2: "Pairwise comparison between high and low-dose group." Please omit "pairwise" since it could be confused by paired analysis. Since the "pairs" are listed in the following, the word is redundant anyhow. Pair-wise has removed at indicated places.