Pain alleviation in diabetic neuropathy using hybrid closed loop insulin pumps (PAINLESS) – A randomised crossover trial protocol

Simon Alexander Berry; Ahmed Iqbal; Jackie Elliott; Rajiv Gandhi; Abdul Paracha; Vaios Koutroukas; Mohummad Shaan Goonoo; Mahnoor Fatima Haq; Andrew Gerges; Gordon Sloan; Solomon Tesfaye; Pratik Choudhary; Dinesh Selvarajah

doi:10.1371/journal.pone.0357573

Peer Review History

Original SubmissionJune 12, 2026
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J.E. has received educational / speaker fees from Abbott, Boehringer, Dexcom, Glooko, Insulet, Lilly, Medtronic, Novo Nordisk, Roche, Sanofi, and Ypsomed, and research support from Dexcom. V.K. has received a travel grant from KelCon GmbH, and has received charity-funded travel grants funded by Lilly. G.S has received honoraria from Procter and Gamble, Viatris, and Eli-Lilly. P.C. has received personal fees from Abbott Diabetes Care, Insulet, Dexcom, Novo Nordisk, AstraZeneca, Medtronic, Roche Diabetes Care, and Sanofi Diabetes, and research funding support from Abbott Diabetes Care, Medtronic, and Novo Nordisk. D.S. has received lecture honoraria from Wörwag Pharma and Grünenthal, unrestricted investigator led grant funding from Withings inc., Abbott Laboratories, Tandem Diabetes and Procter and Gamble, and is an executive committee member of the Novo Nordisk UK Research Foundation. A.P., A.G., R.G., S.M.G. and M.H. have no relevant disclosures to declare.” We note that one or more of the authors are employed by a commercial company: “Abbott, Eli Lilly, Dexcom, Novo Nordisk, Sanofi, Boehringer Ingelheim, Ypsomed, Diiachi Sankyo, KelCon GmbH, Procter and Gamble, Viatris, Abbott Diabetes Care, Insulet, AstraZeneca, Medtronic, Roche Diabetes Care, and Sanofi Diabetes, Wörwag Pharma and Grünenthal, Withings inc., Abbott Laboratories, Tandem Diabetes Novo Nordisk UK Research Foundation” 1. Please provide an amended Funding Statement declaring this commercial affiliation, as well as a statement regarding the Role of Funders in your study. 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Additional Editor Comments: We have invited multiple reviewers and 2 reviewers have responded with minor revision. Please see and resubmit if you are able to address the comments [Note: HTML markup is below. Please do not edit.] Reviewer's Responses to Questions Comments to the Author 1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions? Reviewer #1: Yes Reviewer #2: Yes ******** 2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses??> Reviewer #1: Yes Reviewer #2: Yes ****** 3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable??> Reviewer #1: Yes Reviewer #2: Yes ****** 4. Have the authors described where all data underlying the findings will be made available when the study is complete??> The PLOS Data policy Reviewer #1: Yes Reviewer #2: Yes ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English??> Reviewer #1: Yes Reviewer #2: Yes ****** Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics. You may also provide optional suggestions and comments to authors that they might find helpful in planning their study. Reviewer #1: This is a protocol of a crossover study. It is well-written and I have only some minor statistical comments: 1. Analysis will be conducted by a statistician blinded to treatment allocation. I'm not sure how a statistician can do an analysis of a treatment effect without including the treatment allocation in the analysis! 2. Minimization is a broad term that could include Taves's non-randomized procedure or Pocock-Simon's randomized procedure. You do not specify or provide a reference. See Rosenberger and Lachin (2016, Randomization in Clinical Trials, Chapter 9). 3. The general inference philosophy following minimization-type procedures is that the minimized variables should be included in the model to achieve valid inference (this is mentioned in the same chapter in the reference above). You do not seem to be doing this. 4. Random effects models are used with no description of the covariance structure, what diagnostics will be used to verify model assumptions, or what the underlying distribution of the outcome variable (NRS) is. 5. 49 seems an "odd" number for a 2 arm 1:1 clinical trial. I guess you can split one of the patients in half. Reviewer #2: In the protocol, use of a hybrid closed loop (HCL) system is compared with "standard care", which is the diabetes management used by the participant on entering the study. The eligibility and exclusion criteria do not exclude somebody from the study if they are already using a HCL system. Given the protocol is designed using the assumption that glycaemic variability will be less using an HCL system v standard care, why is this not excluded? Glycaemic variability will be compared between the groups using the measurement of percentage coefficient of variation (%CV), a standard continuous glucose monitoring (CGM) reporting measure. Why is the comparison of this measure between standard care and HCL use not more prominent in the analysis plan? It would seem that this should be carried out prior to other analyses, as if there is no difference in glycaemic variability between the conditions then the stated hypothesis cannot be tested. There may be other reasons that HCL treatment improves symptoms, and therefore the experiment remains valid even if this specific hypothesis is not tested directly, but that should be made clear. People with type 2 diabetes are excluded from this study. This should be justified directly, as there is evidence that HCL can improve gllycaemia in type 2 diabetes as well. I suspect the reason is that HCL treatment is currently funded in England under NICE TA 943 for eligible adults with type 1 diabetes and therefore there is the potential for participants to continue with the treatment after completion of the study, which would not currently be the case for type 2 diabetes. However, this should be made explicit. Note that the image of a CGM device included in the PIS is of a Dexcom G6 sensor - this should be replaced with an image of the correct sensor. Minro comment - introduction paragraph 2 line 68, the abbreviation pwT1D is used without explanation - this should be explained before abbreviation. ****** what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy Reviewer #1: No Reviewer #2: No ******** [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] To ensure your figures meet our technical requirements, please review our figure guidelines: https://journals.plos.org/plosone/s/figures You may also use PLOS’s free figure tool, NAAS, to help you prepare publication quality figures: https://journals.plos.org/plosone/s/figures#loc-tools-for-figure-preparation. NAAS will assess whether your figures meet our technical requirements by comparing each figure against our figure specifications. https://doi.org/10.1371/journal.pone.0357573.r001
Revision 1
24 Jul 2026 Author Response Reviewer #1: This is a protocol of a crossover study. It is well-written and I have only some minor statistical comments: 1. Analysis will be conducted by a statistician blinded to treatment allocation. I'm not sure how a statistician can do an analysis of a treatment effect without including the treatment allocation in the analysis! Many thanks for your constructive review. I will now address each comment point-by-point. The statistician will be blinded to the treatment allocation as each intervention will be given a code e.g. treatment A or treatment B. We have added this to the text lines 353 “Analyses will be conducted by a statistician blinded to treatment sequence (the treatment sequence will be coded)”. 2. Minimization is a broad term that could include Taves's non-randomized procedure or Pocock-Simon's randomized procedure. You do not specify or provide a reference. See Rosenberger and Lachin (2016, Randomization in Clinical Trials, Chapter 9). Thank you for pointing this out. The randomization procedure uses Pocock-Simon’s randomized procedure. On lines 259-260, the sentence now reads “The randomisation will use the Pocock-Simon minimisation algorithm to ensure balance in the treatment allocation taking into account centre, age (18-39, 40-59, 60+) and gender at birth [28]”. 3. The general inference philosophy following minimization-type procedures is that the minimized variables should be included in the model to achieve valid inference (this is mentioned in the same chapter in the reference above). You do not seem to be doing this. Thank you for this comment. We agree that variables used in the minimisation procedure should be included in the analysis model. We have clarified in the Methods that the primary analysis will be adjusted for centre, age group and gender at birth on lines 366-367 “The model will include treatment arm, period, sequence, gender at birth, centre and age group as fixed effects and participant as a random effect to account for the repeated measures design.” 4. Random effects models are used with no description of the covariance structure, what diagnostics will be used to verify model assumptions, or what the underlying distribution of the outcome variable (NRS) is. Thank you for this comment. We have expanded the statistical analysis section to describe the mixed-effects model in greater detail, including the covariance structure, the planned model diagnostic assessment and the rationale for treating the NRS score as a continuous outcome (lines 368-371). “Model assumptions will be assessed using residual versus fitted plots and Q-Q plots of residuals. The NRS pain score (0-10) will be analysed as a continuous outcome, consistent with established practice in chronic pain trials. If model assumptions are violated, sensitivity analyses using alternative modelling approaches will be considered.” 5. 49 seems an "odd" number for a 2 arm 1:1 clinical trial. I guess you can split one of the patients in half. Thank you for this comment. We have updated the description to explain that 49 is an approximate number for enrolment to achieve 40 randomised participants, accounting for dropout during the screening period (lines 127-128) “To account for anticipated dropout and screen failure rate, the PAINLESS study will enrol approximately 49 participants in the screening period to achieve a randomised sample size of 40 participants in total across two research sites in the United Kingdom – Sheffield Teaching Hospitals National Health Service (NHS) Foundation Trust and University Hospitals of Leicester NHS Trust.” Reviewer #2 In the protocol, use of a hybrid closed loop (HCL) system is compared with "standard care", which is the diabetes management used by the participant on entering the study. The eligibility and exclusion criteria do not exclude somebody from the study if they are already using a HCL system. Given the protocol is designed using the assumption that glycaemic variability will be less using an HCL system v standard care, why is this not excluded? Thank you for this comment and for pointing this out. To this date, no people already using HCL have enrolled in the study. However, we will incorporate a change in the exclusion criteria into an upcoming ethics amendment to exclude those already using HCL systems, only including those on multiple daily injections or open loop insulin pump systems. Glycaemic variability will be compared between the groups using the measurement of percentage coefficient of variation (%CV), a standard continuous glucose monitoring (CGM) reporting measure. Why is the comparison of this measure between standard care and HCL use not more prominent in the analysis plan? It would seem that this should be carried out prior to other analyses, as if there is no difference in glycaemic variability between the conditions then the stated hypothesis cannot be tested. There may be other reasons that HCL treatment improves symptoms, and therefore the experiment remains valid even if this specific hypothesis is not tested directly, but that should be made clear. Thank you for the comment. We agree that it is important to establish whether a change in glucose variability has been achieved. We will continue to analyse the results regardless of whether a change in glycaemic variability has been identified, in order to determine whether HCL treatment improves pain. To address this point in the manuscript, we have added the following to the description of the statistical analysis plan lines 360-364 “As a preliminary step prior to the primary analysis, the change in the coefficient of variation (CV) between the control intervention period and HCL intervention period will be evaluated to assess intervention effect on glycaemic variability. The primary analysis will proceed regardless of whether a statistically significant difference in glucose CV is observed.” People with type 2 diabetes are excluded from this study. This should be justified directly, as there is evidence that HCL can improve glycaemia in type 2 diabetes as well. I suspect the reason is that HCL treatment is currently funded in England under NICE TA 943 for eligible adults with type 1 diabetes and therefore there is the potential for participants to continue with the treatment after completion of the study, which would not currently be the case for type 2 diabetes. However, this should be made explicit. Thank you for the comment. The decision to focus on individuals with type 1 diabetes had two main reasons. One was a pragmatic decision based on licensing. At the time of planning this study, the tandem t:slim X2 was not licensed for people with type 2 diabetes in the United Kingdom (it was only approved in mid-2026). Secondly, the pathophysiology of painful peripheral neuropathy differs between those with type 1 and type 2 diabetes, with metabolic syndrome playing a more prominent role in type 2 diabetes and glucose excursions a more prominent role in type 1 diabetes. Therefore, people with type 1 diabetes hypothetically may benefit more when reducing glycaemic variability. As a result of the differing pathophysiology, we have chosen to keep a homogenous type 1 diabetes population rather than incorporating both type 1 and 2 in one study. We definitely agree that future research should also address this question in people with type 2 diabetes. For the readers, we have explicitly stated on lines 114-116 that people with type 2 diabetes are excluded “People with type 2 diabetes are not included as the pathophysiology of PDN differs, with greater influence of metabolic syndrome and dyslipidaemia [20].” Note that the image of a CGM device included in the PIS is of a Dexcom G6 sensor - this should be replaced with an image of the correct sensor. Thank you for pointing this out. The image has been updated and we will update the PIS in an ethics amendment. Minor comment - introduction paragraph 2 line 68, the abbreviation pwT1D is used without explanation - this should be explained before abbreviation. Thank you for raising this. The abbreviation has now been explained. Attachments Attachment Submitted filename: Response to reviewers.docx https://doi.org/10.1371/journal.pone.0357573.r002
19 Aug 2026 Decision Letter - Yee Gary Ang, Editor Pain Alleviation In diabetic Neuropathy using hybrid cLosEd Loop inSulin pumpS (PAINLESS) – A randomised crossover trial protocol PONE-D-26-29075R1 Dear Dr. Berry, 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. Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication. An invoice will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager® and clicking the ‘Update My Information' link at the top of the page. For questions related to billing, please contact billing support. If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. Kind regards, Yee Gary Ang, MBBS MPH Academic Editor PLOS One Additional Editor Comments (optional): Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions? Reviewer #1: Yes Reviewer #2: Yes ******** 2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses??> Reviewer #1: Yes Reviewer #2: Yes ****** 3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable??> Reviewer #1: Yes Reviewer #2: Yes ****** 4. Have the authors described where all data underlying the findings will be made available when the study is complete??> The PLOS Data policy Reviewer #1: Yes Reviewer #2: Yes ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English??> Reviewer #1: Yes Reviewer #2: Yes ****** Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics. You may also provide optional suggestions and comments to authors that they might find helpful in planning their study. Reviewer #1: All comments have been addressed, although I still don't understand why the study statistician needs to be blinded to treatment assignment. Won't he/she write the results section of your papers? How do you do that if you don't know which treatment is which? Overkill. Statisticians do not participate in patient recruitment and are bound by a code of ethics to not divulge anything during the trial. Reviewer #2: Many thanks for the opportunity to review the revised manuscript. My previous comments have been fully addressed. I just have a coupe of very minor comments on the revised draft. P5 line 75 – people with diabetes prefer us to avoid the term “glycaemic control” – please consider an alternative such a “glucose levels” or “glycaemia” P8 line 144 – Dexcom G7 is indicated for use on the abdomen as well as the upper arm in the UK ****** what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy Reviewer #1: No Reviewer #2: No ******** https://doi.org/10.1371/journal.pone.0357573.r003
Formally Accepted
Acceptance Letter - Yee Gary Ang, Editor PONE-D-26-29075R1 PLOS One Dear Dr. Berry, I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS One. Congratulations! Your manuscript is now being handed over to our production team. At this stage, our production department will prepare your paper for publication. This includes ensuring the following: * All references, tables, and figures are properly cited * All relevant supporting information is included in the manuscript submission, * There are no issues that prevent the paper from being properly typeset You will receive further instructions from the production team, including instructions on how to review your proof when it is ready. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few days to review your paper and let you know the next and final steps. Lastly, if your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. You will receive an invoice from PLOS for your publication fee after your manuscript has reached the completed accept phase. If you receive an email requesting payment before acceptance or for any other service, this may be a phishing scheme. Learn how to identify phishing emails and protect your accounts at https://explore.plos.org/phishing. If we can help with anything else, please email us at customercare@plos.org. Thank you for submitting your work to PLOS One and supporting open access. Kind regards, PLOS One Editorial Office Staff on behalf of Dr. Yee Gary Ang Academic Editor PLOS One https://doi.org/10.1371/journal.pone.0357573.r004

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