The study was designed as a prospective single-blinded parallel control trial and will follow the principles of the Consolidated Standards of Reporting Trials (CONSORT). The study protocol was written in accordance with the Standard Protocol Items. Recommendations for Interventional Trails (SPIRIT) guidelines. Figure (Fig.) 1 is a sample of high-sustained pressure and alerting screens. The flowchart of the study design is shown in Fig. 2 and a detailed schedule of enrollment, intervention and assessment is given in Fig. 3. The trial is registered in the United States Clinical-trial.gov (NCTT05074849) on 29 September 2021.
This is a sample of high-sustained pressure alerting screens from the SurroSense RX smartwatch (Orpyx Medical Technologies Inc., Calgary, Canada). This sustained pressure could be because of the presence of a foreign object inside shoes that may remain unnoticed because of loss of protective plantar sensation in people with diabetes and neuropathy. When an alert is triggered, the user receives auditory, vibratory, and visual feedback from the watch. When the user acknowledges the alert, a map of each connected insoles is shown with the area of high-pressure alert identified in red .
Study sites include Baylor College of Medicine (BCM), Michael E. DeBakey VA Medical Center (MEDVAMC) and Texas Woman’s University (TWU) respectively. Many of our adult diabetic patients are seen at our various clinics (i.e., Endocrine and Primary Care at MEDVAMC and Division of Vascular and Endovascular Therapy and Interdisciplinary Consortium on Advanced Motion Performance (iCAMP) at BCM. Michael E. DeBakey Department of Surgery and BCM are the primary sites for recruitment. BCM is a unique environment for innovation. Researchers collaborate across institutions, creating a vast biomedical research ecosystem , building on over a century of leadership in biomedical research.
The proposed study will recruit 72 patients, men and women, 18 years and above, ambulatory and have prescribed diabetic shoes seen in the clinics and centers around Houston, Texas. Individuals will be eligible for the trial if they meet the following inclusion criteria: (1) History of diabetes peripheral neuropathy (DFN) with and without history of peripheral artery disease (PAD); (2) history of foot ulcers within the last 6 months; (3) willing and able to attend follow up visits such as long distance (i.e., greater than 30 miles to recruitment sites); (4) able to read and follow directions; and (5) those going through hemodialysis. However, individuals will not be enrolled into this trial if they meet the following exclusion criteria: (1) Active Charcot Arthropathy or major foot deformity; (2) wide spread malignancy or systemically immunocompromising disease; (3) gangrene, active infection; (4) major amputation (above ankle); (5) Mini Mental Status-Examination (MMSE<20); (6) unable to keep research appointments; (7) unable to walk safely a distance of 100 feet with or without walking assistance; (8) cardiopulmonary disease (e.g., recent MI, Stroke); (9) significant lower extremity edema which may limit the participant from fitting into standard diabetic foot wear;(10) refusal to wear prescribed diabetic footwear; (11) those with alcohol and drug abuse over the last 6 months; and (12) severe orthopedic and/or neuromuscular impairments. Individuals interested in the study will undergo a telephone interview by a member of the research team. Those meeting the preliminary inclusion criteria will be invited to discuss their potential participation in details. During the screening visit, detailed information will be provided to study participants. Verbal and written information of potential benefits and risks of the study will be provided; their questions and concerns will be addressed. Written informed consent will be obtained by a trained researcher at the baseline visit. On the consent form, participants will be asked whether they agree to use their data when they withdraw from the trial and ask for permission for the research team to share their de-identify data with people from both universities taking part in the research or from the regulatory authorities.
Sample size calculation
This is a randomized control trial (RCT) study. The 63 participants will provide basic descriptive information on the various outcomes in the study (e.g., increased adherence to footwear, increased offloading, and decreased foot ulcers and improved foot self-care knowledge,). Sample size was estimated based on an initial study using a smart insole, conducted by Najafi et al. (Co- Investigator) . In their study, the researchers observed that, in the group with at least one alert every 2 hours (high-alert group), adherence to footwear was improved and became significantly higher than in the low-alert group after 3 months of daily use of the technology (adherence to the prescribed footwear: 8.0±3.7 hours in the high-alert group v. 3.6±1.8 hours in the low-alert group, p = 0.035, Cohen’s effect size d = 1.37) indicating very large effect size. A priori power analysis was conducted using Optimal Design 3.01. Based on a desired level of power set at 0.80, an alpha level of 0.05, and a more conservative large, standardized effect size of d = 0.80, a minimum sample size of 63 is required for the 3 repeated measures on the primary outcome adherence to observe a significant difference between groups over time. With consideration of 10% drop out rate and the even sample size distribution among the 3 groups, a total of 72 (24 per group) are needed at the beginning of the study.
Randomization and blinding
Participants (72 participants) meeting the inclusion and exclusion criteria will be randomized (24 per group) into 3 groups: 1) smart insoles + foot self-care education (Group 1); 2) smart insoles (Group 2); and 3) usual-care controls with no smart insoles or education (Group 3) using a software/random table. Study personnel will be instructed not to randomize until subjects have been confirmed to meet all the inclusion/exclusion criteria. An independent offsite investigator who is not involved in the enrollment or assessment of participants will be responsible for keeping the randomization schedule in sealed envelope. After the baseline assessment, the independent offsite investigator will open an opaque envelope sequentially and assign eligible participants to each group. Participants will be blinded to their allocated groups. Thus, this trial will be a single-blinded randomized control trial. Only the research team and the statistician will be aware of treatment allocation until the end of the study.
All participants will be invited to attend the baseline visit and two-three other visits by participants in groups 1 and 2 respectively. Data at every visit will be collected in case report forms (CRFs) by the trial team. Research assistants (i.e., data collectors) will enter all data into a secure database. In the current trial and further ancillary studies, there are no plan for collection, laboratory evaluation, and storage of biological specimens for genetic or molecular analysis.
When the potential participants return for the baseline visit, the research staff will use a scripted protocol to explain the study and the consent form. All questions raised by participants will be addressed, and potential participants will be invited to participate in the study. If an individual agrees, a consent form will be obtained. The following will be performed: (1) review the study with the subject and obtain written informed consent and Health Insurance Portability and Accountability Act of 1996 (HIPPA authorization); (2) assign subjects a unique screening/enrollment number; (3) review and record medical history, surgical history, and medication history to determine eligibility based on inclusion/exclusion criteria; (4) record demographics (age, race, ethnicity, gender); (5) document height, weight (Body Mass Index [BMI]), Blood glucose and Hemoglobin A1C; (6) document all current medications including medications over-the-counter and herbal medications; (7) perform foot examinations; and (8) administer screening questioners MMSE, Foot-Care Knowledge and Practice, Foot-Care Confidence Scale.
Data collection procedure
Evaluate the efficacy of smart insoles with real-time alert component +foot self-care education H1, to improve adherence to prescribed footwear and offloading in people with diabetes and at high risk for DFU. To achieve this hypothesis, Orthimeter (Germany) will tag patients’ diabetic shoes. The system has 1-year battery life and enables continuous measuring adherence to footwear by measuring temperature. Adherence to footwear will be assessed every 2 months until 6 months or incidence of ulcers. Daily Adherence to Device Wear in hours (Sensor Data and Self-Report Questionnaire): participants will gather adherence data objectively using data recorded by the sensors and compared to subjective reports. The questionnaire will ask participants to estimate their wear time per day as 0-2 hours, 2-4 hours, 4-6 hours, 8-10 hours, or 10+ hours. To determine acceptability, ease of use, and perception of benefit, we will use a Technology Acceptable Model (TAM) tailored for the study.
TAM will assess users’ perception of benefits, acceptability, and ease of use with the wearable device. Participants will provide information on how strongly they agree or disagree with statements regarding benefits, acceptability, and ease of the wearable device on a 5-point scale with the following anchor: 1) strongly disagree, 2) somewhat disagree, 3) neutral, 4) somewhat agree, and 5) strongly agree. An average of four or higher indicates successful achievement on the TAM. We will also assess for the following: Foot Self-Care Knowledge and Practice, which has 15 questions on knowledge and 15 questions for practice. Cronbach’s alpha for the knowledge scale is 0.79, and practice is 0.72.
Diabetes Foot-Care Behavior Self-Efficacy
The Foot Care Confidence Scale will be used to test foot care self-efficacy. Comprising 12 items, with Cronbach’s alpha of from 0.78 - 0.92. Our assumptions are that H1: Participants randomized to the smart insole + foot self-care education group will be more adherent (as confirmed by sensor data and self-report questionnaire) to footwear and offloading after 6 months, compared to participants randomized to the smart insoles and usual-care groups. H2: Changes in adherence will be mediated by self-efficacy and perception of benefits. Self-efficacy will be assessed baseline and 6 months with the Foot Care Confidence Scale (FCCS), while perception of benefits will be assessed 2, 4, and 6 months with TAM. While TAM will test for perception of benefits. H3: Participants randomized to the smart insole + foot self-care education group will have higher acceptability and perception (as confirmed by TAM) of the benefits of their intervention, compared to those randomized to the smart insoles only and usual-care control groups.
There will be a biweekly visits in the first month, 2, 4, and 6 months, 30-minute one-on-one follow-up phone discussion (i.e., daily foot hygiene and cleanliness, foot protection, use of insoles and smart watch, adverse effects, addressing feedback and questions regarding the intervention and prevention of foot-related complications) on participants in groups 1 and 2. Participants in groups 1 and 2 will also return for a group visit within 1-3 weeks post baseline for intervention (group 1 receiving both foot self-care foot education as well as insoles fitting on their diabetic shoes as well as the smart watch while group 2 will only receive only insoles on their diabetic shoes and smart watch). Participants in groups 1 and 2 will be followed for additional 2, 4, and 6 months to assess for daily adherence of device wear, successful response rate to alert and duration, user perception of benefits, acceptability, and ease of use of device among others. While participants in group 3 will be followed for 2, 4, and 6 months. At 6 months, all participants including those in the usual care group 3 will return for the following: (1) assess adverse effects; (2) assess for complications following treatments; (3) document current medications including over-the-counter and herbal medications; (4) perform foot examinations and document any foot ulcers or complications; (5) document height, weight (Body Mass Index [BMI]); (6) blood glucose and Hemoglobin A1C; and (7) administer screening questioners (Foot-Care Knowledge and Practice, Foot-Care Confidence Scale, TAM, Research Activity Log, Sensor Data and Self-Report and Successful Response rate to Alert and Unresponded Alert Duration).
At each visit, if participants make a withdrawal request or are not eligible to continue due to the presence of severe concomitant diseases or conditions listed in the exclusion criteria, they will be discontinued from the study. For participants who drop out, the following information including the incidence of foot ulcer; footwear and offloading adherence, plantar pressures (if possible), as well as administer study questionnaires (Foot-Care Knowledge and Practice, Foot-Care Confidence Scale) will be collected. All subjects are free to withdraw from participation at any time, for any reason, specified or unspecified, and without prejudice. Reasonable attempts will be made by the investigator to provide a reason for subject withdrawals. The reason for the subject’s withdrawal from the study will be specified in the subject’s source documents and workbook on foot-care strategies and pamphlets for self-guidance. If a subject is withdrawn due to adverse effects (such as diabetic ulcers), the subject will be followed and treated by the investigators until the abnormal parameter of symptoms has resolved or stabilized. The investigators must make every effort to contact subjects who are lost to follow-up. Attempts to contact such subjects must be documented in the subject’s records (e.g., times and dates of attempted telephone contact, receipt for sending a registered letter, etc.).
To improve participants’ retention and complete follow-up, the following measures will be adopted: participants’ contact information as well as contact information for at least two persons who would know the participants’ whereabouts and could get messages to them; assign a “coach” from the team who will develop relationships, reinforce participation, and help overcome barriers that can lead to study withdrawal; and compensate for study-related visits at $50 for each visit.
A 6-month intervention consisting of (Baseline: Weeks 1-3): 1) contacting prospective participants, 2) screening, 3) completing informed consent, and 4) randomization. Week 4: A 90-minute group session to educate patients on foot self-care strategies (daily foot hygiene and cleanliness, foot protection, use of insoles and smart watch). Participants (72 participants) will be randomized (24 per group) into 3 groups: 1) smart insoles + education (Group 1); 2) smart insoles (Group 2); and 3) usual-care controls with no smart insoles or education (Group 3).
Insoles with Smart Watches
Smart insole with an alert watch (the SurroSense RX system, Orpyx Medical Technologies, Inc., Calgary, Ca, Fig. 1) , is for cuing plantar pressure offloading during activities of daily living . Each insole consists of eight individual pressure sensors: three distributed across the metatarsal heads, two distributed along the lateral plantar surface, and one distributed at the heel, one distributed at the great toe, and one in the distribution of the lateral toes. . The insoles collect pressure information from the plantar surface of the foot and wirelessly transmit this information to the smart watch worn by participants. The device alerts the user when “safe” pressure and time thresholds are exceeded . These thresholds are based on the clinical understanding of pressure ulcer formation, which indicates that a conservative threshold would be >35-50 mmHg for >15 minutes. If > 95% of measurements taken by a single sensor over a 15-minute scanning window exceed 35-50 mmHg, an alert will be sent to the user via the smart watch to guide him/her to appropriately offload that area. A successful response to an alert is defined as a pressure offloading occurring within 20 minutes of alert onset .
Foot Self-Care Education
Contents for the foot self-care education are adapted from standard diabetes organization [2, 39-42], comprising information (i.e., risk factors of diabetes foot complications, foot self-examination, daily foot hygiene and cleanliness, foot protection, prevention of foot-related complications, and need for an annual evaluation by a healthcare professional) [2, 39-42]. A foot-care package, consisting of a pamphlet on foot self-care, a nail clipper, a water-based lotion, and a small towel will be provided to each participant.
Participation in Group Education Program and Follow-up Telephone Calls
A 90-minute group educational session will be conducted once in person in a conference room at the study centers. The educational session will cover foot-care strategies (i.e., risk factors of diabetes foot complications, foot self-examination, daily foot hygiene and cleanliness, foot protection, prevention of foot- related complications, benefits of wearing prescribed diabetic footwear, using smart insole with smart watch, and need for an annual evaluation by a healthcare professional) [2, 38-41]. A call will be conducted every 2 weeks to follow-up on participants’ progress and address concerns for groups 1 and 2. Participants will be advised to call the research staff with questions and concerns at any time.
Each participant in group 1 will receive a workbook on foot-care strategies and pamphlets for self-guidance. In addition, all participants in each group will receive a foot care package (i.e., pamphlet, nail clipper, water-based lotion, and small towel) . Participants are expected to keep the workbook, pamphlet, and foot-care package at the end of the study.
Primary outcome measures are adherent to footwear and offloading. To objectively monitor adherence to the prescribed shoes, participants’ shoes will be tagged by a miniaturized temperature + a radio-frequency identification (RFID) sensor named Orthimeter (Germany). The pressure sensing device is equipped with audio-visual alerts and offloading instructions when sustained elevated pressures are detected. The system enables continuous monitoring of the individual’s adherence to wearing the prescribed diabetic footwear.
Secondary outcome measures are incidence of diabetic foot ulcers (DFUs) measured by self-report and foot examinations by the podiatrist and study team. DFU is defined as a full-thickness wound, through the dermis, below the ankle on weight-bearing or exposed surface in an individual with diabetes . We will also monitor for improved foot self-care knowledge and Practice with Foot Self-Care Knowledge and Practice baseline and at 6 months. Foot Self-Care Knowledge and Practice has 15 questions on knowledge and 15 questions for practice. Cronbach’s alpha for the knowledge scale is 0.79, and practice is 0.72 [45, 46]. In addition, we will monitor for daily adherence to device wear in hours and off-loading at 2, 4, and 6 months with the sensor data and self-report. To enhance retention and compliance, participants will undergo a detailed orientation and cognitive evaluation (e.g., Mini Mental State Examination [MMSE]) . A score of MMSE <20 indicates mild degree of impairment and participants will not be enrolled in the study . Perception of benefit, acceptability, and ease of use measured by the TAM . Participants will provide information on how strongly they agree or disagree with statements regarding benefits, acceptability, and ease of the wearable device on a 5-point scale with the following anchor: 1) strongly disagree, 2) somewhat disagree, 3) neutral, 4) somewhat agree, and 5) strongly agree. An average of 4 or higher indicates successful achievement on the TAM . A mediation outcome self-efficacy will be assessed at baseline and 6 months by the Foot Self-Care Knowledge and Practice [46, 47] and Diabetes Foot-Care Behavior Self-Efficacy [47, 48]. Our assumptions are that H1: Participants randomized to the smart insole + foot self-care education group will be more adherent (as confirmed by sensor data and self-report questionnaire) to footwear after 6 months, compared to participants randomized to in the smart insoles and usual-care groups. H2: Changes in adherence will be mediated by self-efficacy and perception of benefit. The Foot Care Confidence Scale will assess for self-efficacy; a 12 items scale with a Cronbach’s of from 0.78 - 0.92 in those with diabetes who monitored for foot ulcer . While TAM will test for perception of benefits. H3: Participants randomized to the smart insole + foot self-care education group will have higher acceptability and perception (as confirmed by TAM) of the benefits of their intervention, compared to those randomized to the smart insoles only and usual-care control groups.
Demographics and clinical indicators
Participants’ characteristic of age, weight, body mass index, current medication issues, current medications, diabetes history, other chronic diseases such as high blood pressure, periphery artery diseases, neuropathy will be collected using electronic case report forms. Participants will be asked for number and types of medications taken, medication scheduling, and the dose used to self-manage diabetes as well as DFU symptoms at baseline and at 6 months.
All researchers including investigators, data collectors (i.e., research assistants), study coordinators, site monitors, data managers, outcome assessors, and statistician will receive special training regarding the standard procedure and data management. The Principal Investigator will be responsible to ensure the study is conducted in accordance with the protocol, Good Clinical Practice (GCP), applicable regulatory requirements, and that the data recorded is valid. To achieve this objective, the study will be continuously monitored and reviewed in a monthly basis by the study team.
Clinical site monitoring is conducted to ensure that the rights and well-being of human subjects are protected, that the reported trial data are accurate, complete, and verifiable, and that the conduct of the trial complies with the currently approved protocol/amendment(s) with GCP, and with applicable regulatory requirements(s). A Clinical Monitoring Plan will be created by the Sponsor and describe in details as well as who will conduct the monitoring, and the distribution of monitoring reports.
Data handling and record keeping
The collection of personal patient information will be limited to the amount necessary to achieve the aims on the research, so that no unneeded sensitive information is being collected. Only study personnel will collect data. Hard copy documents will be retained for the duration of the study until data entry and will be saved for at least 5 years after publication. All hard copy documents related to the research will be saved in a locked filling cabinet of GCP at MEDVAC/BCM, while electronic documents will be stored in a special computer with protected password. Data will be exported into the Excel or SAS file format (password protected), which will then be used for data analysis. Only de-identified data will be used for data analysis. Collected de-identified data will be sent to a biostatistician for statistical analysis. If readers have any questions about our published data, they could contact our corresponding author (i.e., the principal investigator) to obtain the original data.
At the end of this trial, all original data without participants’ name and the random sequences will be sent to a statistician for data analysis. Data will be downloaded from each smart watch and analyzed, using SPSS (IBM, version 25, Chicago IL) and MPlus v7.3 . To identify possible predictors of adherence rates, participants will be categorized, based on whether they responded to alert or not (HA: high-alert group) or less (LA: low-alert group) defined as one alert every 2 hours that the device is worn. Intent-to-treat procedures will be used to treat the missing data on the outcomes for Aim 1-H1. Results will be expressed as means ± standard deviation (SD). Repeated measures ANOVA will be used to compare adherences among the three groups at 2 months and 6 months. If overall significance is found, post hoc comparison using Tukey’s test will be used to examine the adherence difference between every two groups. If assumption of homogeneity of variables is violated Games-Howell post hoc test will be used instead. Pearson’s correlation analysis will be used to examine correlation between changes in adherence over 2 months to 6 months and number of alerts triggered per hour in each group. Cohen’s d effect size will be used to estimate mean- difference effect sizes between groups. Cohen’s d value of 0.2, 0.5, and 0.8 will be considered small, medium, and large effect sizes, respectively [14, 50]. Latent growth curve mediation model will be used to test the effect of the combined smart insole and foot self-care education on improving adherence to footwear at every 2 months till 6 months, in which time points will be used as repeated measures, baseline demographics and treatment will be included as first level fixed effect, participants will be as second level random effect, and perception/self-efficacy will be the third level random effect. Mixed models accommodate the longitudinal design with random effects; allow for testing differences between groups in patterns over time as well as at specific time points;, and are valid for data which are missing completely at random or at random (2). Latent growth models are particularly used in the mediation analysis to examine the individual trajectory change over 6 months of period and that a relatively large intra-individual change is anticipated. All statistical analyses will be performed using SPSS (IBM, version 25, Chicago IL) and MPlus v7.31, with a significance level of P < .05.