Post-healing follow-up study of patients in remission for diabetic foot ulcers Pied-REM study.

The rate of recurrence for diabetic foot ulcer (DFU) is 50% at 2 years Armstrong DG, 2017. International recommendations call for regular monitoring to prevent DFU recurrence. We aim to investigate the relation between post-healing follow-up and recurrence rates. The study will begin in November 2021 and end in April 2022; final study results are scheduled for December 2022. The purpose of the study is to evaluate the benefit of the multidisciplinary follow-up of healed DFU patients at the rate of two annual consultations and its impact on foot wound recurrence.

1. Introduction

Diabetic foot ulcers (DFU) are a major health problem throughout the world. The rate of DFU recurrence is 40% in the first year after healing, 50% at 2 years, and 65% at 5 years [1]. The mortality of patients with a history of DFU is 2.5 times greater than those without this history [2]. The main causes of DFU recurrence are inadequate footwear, lack of pedicure care, and lack of selfcare [3]. The International Working Group on the Diabetic Foot (IWGDF) recommends specific podiatric management to prevent the risk of recurrence of trophic disorders; this management must be reassessed or repeated every 1 to 3 months if necessary [4]. At the Centre Hospitalier Sud Francilien, France, the diabetic foot outpatient unit created a specific consultation for healed DFU patients in 2016. Consultations for the management of diabetic foot in remission assess the recommended items in any patient at the rate of two visits per year. In the literature, there is no evidence for preventing the recurrence of foot wounds. Nevertheless, we believe that post-wound follow-up reduces the risk of recurrence.

The study was approved by Centre hospitalier Sud Francilien hospital etichal committee on May 18, 2021 with apouval number _ 26.07.15.38991

2. Material and methods

The study protocol was approved by ethics committee of the Centre Hospitalier Sud Francilien and registered in the protocol registration system as NCT04892771

2.1. Description of study protocol

Pied-REM is a retrospective observational study. Comprehensive information about the study was provided to each patient in a document printed for this purpose. Since 2016, the Diabetology Unit in the Centre Hospitalier Sud Francilien has offered a specialized bi-annual consultation to all patients in remission for DFU. This study will assess the relevance of this human and material investment in the context of a multidisciplinary follow-up approach (a team made up of a podiatrist, podo-orthositis, orthoprotesitis, a nurse specializing in the management of diabetic foot and a diabetologist)The 2-year follow-up period will allow for a sufficient number of patients to be included: the first patients will be monitored from 2017 to 2019 and the last ones from 2019 to 2021Two groups of patients will be defined according to the number of consultations held over a 2-year period. Patients who complete at least two annual visits for 2 years or two sessions over 2 years will be included in the experimental group. Patients who do not attend this minimum number of visits will be included in the control group.

2.2. Study objectives

The main objective of the study was to evaluate the impact of the multidisciplinary follow-up of healed DFU patients on wound recurrence. Our secondary objectives were to evaluate the requirements for hospitalization due to recurrence, the pedicure follow-up of patients, and their use of suitable footwear.

2.3. Participants

The inclusion criteria are patients aged 18 years and over with type 1 or 2 diabetes who receive follow-up care at the Centre Hospitalier Sud-Francilien for healed DFU. Patients must freely give informed consent to participate in the study. Exclusion criteria are patient refusal.

All study patients have a high podiatric risk.

2.4. Data collection

The data will be collected in patient files in the computer database of the diabetology department over a 2-year period. The collected data are the following: verification of inclusion criteria, age, sex, type and duration of diabetes, presence of arterial disease, diabetic neuropathy, history of amputation, and glycosylated hemoglobin.

During the 2-year observation period from the date of inclusion, we will collect the following information: number of follow-up consultations over 2 years from inclusion, recurrence of foot wounds, hospitalization for foot wounds, pedicure follow-up, and use of suitable footwear.

2.5. Statistical methods

Regarding the sample size, to demonstrate a difference of 25% to 40% between two groups, with a risk of first species of 5%, a power of 80%, and continuity correction, 158 patients are required. We estimate that 200 diabetic patients are currently being monitored at the hospital for multidisciplinary “foot remission” consultations, which should largely be able to enlist the required number of patients.

Categorical variables will be presented as numbers and percentages and compared using the exact Fisher test or chi2 test. Quantitative variables will be presented as medians and interquartile ranges or as means and standard deviations and compared using the t-test or Wilcoxon test according to their distribution. Recurrence, hospitalization, pedicure follow-up, and use of adapted footwear will be compared between the two groups using the exact Fisher test.

The time to recurrence in each group will be measured using the Kaplan-Meier estimator and compared between the two groups using a log-rank test.

All tests will be carried out bilaterally, with a risk of first species alpha set at 5%. Statistical analysis will be conducted with R software [5].

3. Discussion

The Pied-REM study begins on November 2021, with the duration of inclusion set at 1 year. Results will be published around December 2022.

The rate of recurrence of foot wounds remains very high despite improved management [1]. The recurrence of wounds has been evaluated using different approaches: preventive surgical interventions [6], insoles with integrated sensors [7], and follow-up with podiatrists [8] or nurses [9]. Temperature monitoring also helps to limit recurrence [10], as does the use of therapeutic shoes and treatment adherence [11]. In the literature, only one study incorporates all the IWGDF recommendations [4]. Another study from Lithuania showed that multidisciplinary follow-up reduces the risk of recurrence of foot wounds [12]. However, as this study is quite dated (1999) and has a relatively small population size (56 patients), the subject deserves a new evaluation.

The wound recurrence rate is the primary assessment outcome in our study, which was previously evaluated in a meta-analysis [13]. A study on the economic impact of hospitalization costs related to DFU recurrence shows that patients are less often amputated but more frequently hospitalized [14]. Podiatric monitoring recommended by IWGDF can reduce the number of recurrences [8]. Wearing suitable footwear is also part of the recommendations, as the use of customized footwear reduces recurrence rates [3]. We therefore want to show that customized and therapeutic shoes reduce recurrence. The studied population corresponds to all the patients followed for a DFU. As it has been demonstrated that an initial ulceration is highly predictive of recurrence, these patients should be closely monitored [15].

This monocentric retrospective observational study will allow us to justify our approach used for the past 5 years, in which remission foot consultations are offered to all patients with healed DFU. The two study groups include the experimental group that attends all the recommended consultations (two per year) and the control group that does not. The study will compare the rate of wound recurrence between the two groups. The expected findings of this study are a decrease in the number of recurrences in patients with optimal post-healing follow-up. If the results are verified, this will confirm our hypothesis and our approach based on the IWGDF recommendations [4].

The limitation of this study is the methodology, as a retrospective observational study has a very low level of evidence, since it is not randomized and its two groups can have heterogeneous sizes. In this type of study, randomization seems unethical, since it would result in a loss of chance for patients in the control group who would not benefit from post-healing follow-up.

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Post-healing follow-up study of patients in remission for diabetic foot ulcers Pied-REM study.

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7 Feb 2022

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Reviewer #1: Yes

Reviewer #2: Yes

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2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses?

The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory.

Reviewer #1: Partly

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: Congratulation of well done effort in your clinical practive. DFU is a complicated and frustrating issue to many patients and physicians and hopefully you will have meaningful results to help the medical community.

I do have few points:

- Correct the world “Mai” to “May” in the Introduction

- "The study protocol was approved by" was mentioned twice in same page, in the Introduction and in the Description of study protocol. Possibly to remove it from the Introduction.

- In the Study description, it was mentioned that the study is a retrospective observational and the part mentioned in Data collection about collecting patients files and reviewing their cases seems appropriate with the definition of this study. But also mentioned in the Data collection that there will be a 2-year observation period from the date of inclusion with different variables intended to be measured which seems to be a different period than the initial one described. So, will there be a prospective observational part in this study? If yes, then it needs to be mentioned clearly in the Description of study protocol.

- Mentioned in the Statistical methods that there are two groups, experimental and control based on the number of visits, this study protocol needs to be mentioned in the Description of study protocol, not in the Statistical methods.

- It seems from the Statistical method that the measured outcome is based on having or not having an intervention which is the number of visits or sessions over 2 years between the two groups (experimental and control). That has not been clearly defined in the Study objectives.

- There are study protocol description information in the discussion that needs to placed in the material and methods and better to review and place needed information in appropriate place. For example: “The 2-year follow-up period will allow for a sufficient number of patients to be included: the first patients will be monitored from 2017 to 2019 and the last ones from 2019 to 2021”, this sentence belongs to Material and methods.

Reviewer #2: In the part of the abstract, the author mentioned that ,The rate of recurrence for diabetic foot ulcer (DFU) is 50% at 2 years. For this statement need to add the reference.( what is the source of information).

In the part of Introduction, study objective part the author mention the word the multidisciplinary

follow-up of healed DFU patients, but did not explore what author mean by multidisciplinary.

In the part of Participants- the author did not mention the total number of sample size, Gender of the Participants, and average age of the participants.

The study only based on Quantitative methodology. If the authors conduct the study by mixed methodology (quantitative and qualitative) its would more efficient to explore the socio-economic reasons/ factors behind the yearly follow-up for the experimental group and explore the socio-economic reasons/ factors behind are barriers are works for the yearly follow-up for the control group.

**********

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Reviewer #1: No

Reviewer #2: No

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2 Mar 2022

Response to Reviewers

Dear editor and reviewers:

Many thanks for your comments and for the interest you have given to our manuscript please find the answers to your remarks

Reviewer #1

1 - Correct the world “Mai” to “May” in the Introduction: Done ( we are very sorry for this mistake)

2- "The study protocol was approved by" was mentioned twice in same page, in the Introduction and in the Description of study protocol. Possibly to remove it from the Introduction : modification done

3- In the Study description, it was mentioned that the study is a retrospective observational and the part mentioned in Data collection about collecting patients files and reviewing their cases seems appropriate with the definition of this study. But also mentioned in the Data collection that there will be a 2-year observation period from the date of inclusion with different variables intended to be measured which seems to be a different period than the initial one described. So, will there be a prospective observational part in this study? If yes, then it needs to be mentioned clearly in the Description of study protocol.

thank you very much for your comment, the study is completely retrospective with an observation period of 2 years post healing of a foot in a living diabetic patient, there is no prospective component

4- Mentioned in the Statistical methods that there are two groups, experimental and control based on the number of visits, this study protocol needs to be mentioned in the Description of study protocol, not in the Statistical methods.

Modification done

5- - It seems from the Statistical method that the measured outcome is based on having or not having an intervention which is the number of visits or sessions over 2 years between the two groups (experimental and control). That has not been clearly defined in the Study objectives.

Modification done

6-There are study protocol description information in the discussion that needs to placed in the material and methods and better to review and place needed information in appropriate place. For example: “The 2-year follow-up period will allow for a sufficient number of patients to be included: the first patients will be monitored from 2017 to 2019 and the last ones from 2019 to 2021”, this sentence belongs to Material and methods

Modification done

Reviewer # 2

1-In the part of the abstract, the author mentioned that ,The rate of recurrence for diabetic foot ulcer (DFU) is 50% at 2 years. For this statement need to add the reference.( what is the source of information).

Reference added

2-In the part of Introduction, study objective part the author mention the word the multidisciplinary

follow-up of healed DFU patients, but did not explore what author mean by multidisciplinary

Thank you very much for your comment, the explanation has been added

3-In the part of Participants- the author did not mention the total number of sample size, Gender of the Participants, and average age of the participants.

thank you very much for your comment, at the current state it is proposed that the study design the results of patient demographics will be proposed in the final publication, thank you for your understanding

4-The study only based on Quantitative methodology. If the authors conduct the study by mixed methodology (quantitative and qualitative) its would more efficient to explore the socio-economic reasons/ factors behind the yearly follow-up for the experimental group and explore the socio-economic reasons/ factors behind are barriers are works for the yearly follow-up for the control group.

thank you very much for this comment, we are going to make an amendment to study the socio-economic reasons associated with the recurrence of wounds

Submitted filename: Response to Reviewers plose one .docx

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26 Apr 2022

POST-HEALING FOLLOW-UP STUDY OF PATIENTS IN REMISSION FOR DIABETIC FOOT ULCERS Pied-REM study

PONE-D-21-28523R1

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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?

The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field.

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?

The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory.

Reviewer #1: Partly

Reviewer #2: Yes

**********

3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable?

Descriptions of methods and materials in the protocol should be reported in sufficient detail for another researcher to reproduce all experiments and analyses. The protocol should describe the appropriate controls, sample size calculations, and replication needed to ensure that the data are robust and reproducible.

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 requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception, at the time of publication. The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: No

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

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.

(Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: My comments were responded approximately. There are non additional comments. Best of luck to authors.

Reviewer #2: I read the manuscript overall. The authors meet all of my quires and now it seems sound good. Hopefully, the authors reviews it again and submit it.

**********

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Reviewer #1: No

Reviewer #2: Yes: S M Raduan Hossin

10 May 2022

PONE-D-21-28523R1

POST-HEALING FOLLOW-UP STUDY OF PATIENTS IN REMISSION FOR DIABETIC FOOT ULCERS Pied-REM study

Dear Dr. dardari:

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