Study design
The study is a clinical trial, randomized, single-center trial, and superiority trial with two parallel arms, blinded to outcome assessors and data analysts. The intervention consists of 12 weeks of a remotely supervised home-based exercise program in which cardiometabolic, functional, and psychosocial outcomes are analyzed in individuals with T2D. This clinical trial was designed according to the guidelines for randomized clinical trials: Recommendations for interventional trials (SPIRIT) guidelines [25]. This trial is being conducted at the Physical Education School of the Federal University of Pelotas (Brazil). The RED study protocol was prospectively registered at ClinicalTrials.gov (NCT05362071).
Participants
The study participants comprise male and female patients with T2D from Pelotas, Brazil. Volunteers included in the sample are selected by recruitment advertisements on social media and basic health units.
Eligibility criteria
Inclusion and exclusion criteria for participants are defined as follows:
Inclusion criteria
1. Being under medical treatment using oral hypoglycemic agents;
2. Female and male patients with type 2 diabetes;
3. Aged ≥ 45 years old;
4. Not involved with physical exercises for at least three months (the regular practice of exercise was defined as performing any modality of physical training for at least 20 minutes on two or more days of the week);
5. Being semi-literate due to self-completion questionnaires.
Exclusion criteria
1. Make use of insulin;
2. History of cardiovascular disease (except drug-controlled high blood pressure);
3. Presence of severe autonomic neuropathy, severe peripheral neuropathy or history of foot injuries, proliferative diabetic retinopathy, severe non-proliferative diabetic retinopathy;
4. Muscle or joint impairment that precludes performing physical exercises safely;
5. Lack of internet access.
Randomization and allocation concealment
Once included in the study, the participant receives an internal number to be de-identified. The randomization sequence is stratified by sex and disease duration (< 5 years or ≥ 5 years) in blocks of different sizes with a 1:1 ratio in the Excel random function. The entire process of randomization and allocation into groups is carried out by an independent researcher not involved with the evaluations and intervention.
Sample Size
The sample calculation was performed using the GPower version 3.9.1.4 program, adopting a significance level of α = 0.05 and 80% power. Data for sample size calculation were extracted from the study results by Akinci et al. (2018) for the primary outcome of HbA1c (effect size 0.24), resulting in a total n of 38 subjects. Additionally, twelve individuals (≈30%) will be included in the study due to the possibility of sample losses, totaling 50 participants randomized into the two groups.
Intervention and control procedure
Participants are randomly allocated to the intervention group (IG), which performs a remotely supervised home-based exercise program lasting a total of 12 weeks, or to the control group (CG). The CG receives general recommendations for physical activity. A detailed description of the intervention and control procedure is provided below:
Remotely supervised exercise program
The remotely supervised home-based exercise program consists of 12 weeks. Sessions are held via video calls via WhatsApp, with a maximum of 5 participants per video call. The intervention has a weekly frequency of two sessions per week on non-consecutive days during the first six weeks and three sessions per week on non-consecutive days for the remaining six weeks. The exercise intervention consists of four 3-week mesocycles. The session structure consists of 5 min of warm-up, 37-57 min of the main part, in which a combined training program is carried out, and a final 5 min of stretching. Blocks 1 and 2 will consist of three strength exercises with body weight and alternative materials (500ml plastic bottles filled with sand) and an aerobic exercise. Between blocks 1 and 2, and later in block 3, participants take a free walk with displacement in their homes’ available space. The aerobic training intensity is based on the Borg 6-20 Perception of Effort (RPE) Scale [26], while the resistance exercises are performed at the usual/fast speed of execution. The training progression is based on the increase in the number of sets, duration of effort, total duration of the session, intensity, frequency, and complexity of exercises. An additional file presents the full periodization of the study in more detail [see Additional File 1]. Participants were instructed not to engage in any other type of activity involving exercise during the study period.
Control group
Participants allocated to the CG receive recommendations for the practice of physical activity based on information from chapters of the Physical Activity Guide for the Brazilian Population (2021) [27]. When going through all the assessments carried out at baseline, the CG participants will receive through WhatsApp the information that is available in chapters 1, 4, and 5, which address the following topics: “Understanding Physical Activity”, “Physical Activity for Adults”, and “Physical Activity for the Elderly”. When not possible to send via WhatsApp, the print booklet is delivered to the participant. At the end of the 12 weeks, the same booklet is made available to the IG participants.
Criteria for discontinuing study participation
Participants may be discontinued from the study due to withdrawal of participant consent, lack of interest, or willingness to continue. For participants allocated to the IG, participation is interrupted for safety reasons, such as medical advice or disease complication. In addition, muscle or joint injuries or a severe health event during the study precludes participation in intervention sessions.
Strategies for trial retention
Participants allocated to the IG receive text messages to reinforce the date and time of interventions. We use WhatsApp messages to ask about adverse events if an IG participant misses a session. Sending messages is stopped for participants who declare their withdrawal from the study.
Outcomes
Study results are assessed at baseline (week 0) and post-intervention (week 13). Outcomes are measured for all randomized participants, regardless of frequency or completion status. Participants who withdraw from the study at any time after randomization are invited to complete the final study assessments (12 weeks after the start of the intervention) for inclusion in the intention-to-treat analysis. Additionally, only the IG participants perform acute capillary blood glucose measurements before and immediately after an exercise session in the initial period of mesocycles 1, 2, and 4.
Primary outcome
The primary outcome is the change in the HbA1c, evaluated through blood analysis. HbA1c was chosen as the primary outcome because of its importance in disease management. HbA1c is considered the gold standard in monitoring T2D, as it is a chronic measure and reflects the average blood glucose level over the previous 8 to 12 weeks [28]. Additionally, glycemic control, assessed by HbA1c levels, effectively reduces the risk of micro and macrovascular complications [29].
Secondary outcomes
Clinically relevant secondary outcomes for individuals with T2D were established, including capillary blood glucose, systolic blood pressure (SBP), diastolic blood pressure (DBP), functional tests performance, depressive symptoms, diabetes-related emotional stress, sleep quality, and quality of life (QOL).
Capillary blood glucose is measured from blood samples collected from the participant's fingertips. SBP and DBP are determined from office measurements. Capacity will be evaluated with the following tests: Arm Curl, 30s-Chair Stand, Time Up and Go, 2 Minute Step Test, and Sit and Reach Flexibility Test. Depressive symptoms and diabetes-related emotional stress are measured using the Patient health questionnaire (PHQ-9) and the Brazilian version of the Problem Areas in Diabetes Scale (B-PAID). QOL and sleep quality will be measured using the Eurohis-QOL 8-Item and Pittsburgh Sleep Quality Index Self-Report Questionnaire (PSQI).
Other Measures
Complementary measures of physical activity level, anthropometric data, eating habits, and subjective perception of well-being were assessed.
Recruitment
The recruitment period started in May 2022 and is expected to occur until March 2023. Recruitment takes place through disseminating posters in Basic Health Units in the city and notes shared on social networks and the local newspaper. Then, patients are contacted by telephone, and complete information about the purpose of the study and a survey on the presence of conditions related to the inclusion criteria are provided. If the participant meets these criteria, he or she is invited to participate in the study.
Blinding
Blinding is applied to outcome assessors and data analysts of primary and secondary outcomes listed in this protocol. Due to the nature of the interventions, the team conducting the exercise sessions and the participants are not blinded. Participants are asked to withhold their assigned group and not talk about their interventions during outcome evaluations to ensure evaluator masking. In the event of unintentional uncovering for any reason, the researchers involved must notify the coordinator.
Data collection
A single investigator carries out the home assessments pre and post-intervention. During the assessments, he or she has a manual of standard operating procedures available. Two other researchers apply the online questionnaires. For this purpose, calls are made before to explain the procedures and immediately after the application to clarify doubts. In addition, the responsible investigator remains available to assist if any doubts arise during the completion of the questionnaire. All variables are assessed at baseline and after the intervention. Additionally, acute capillary blood glucose measurements are performed in the initial period of mesocycles 1, 2, and 4, and the subjective perception of well-being in week 13, both for the IG participants. An additional file presents the study schedule in more detail [see Additional File 2].
Measurement of the primary outcome
Glycated hemoglobin.Blood samples (are collected in a specialized laboratory for the HbA1c levels analysis of each participant). Whole blood samples (2 mL) are collected from the antecubital vein of participants after 8 hours of fasting. HbA1c levels are determined using a high-performance liquid chromatography method by a private laboratory.
Measurements of secondary outcomes
Capillary blood glucose. Initially, participants will rest for 5 min, sitting in a chair with both feet on the floor and the back resting on the back of a chair. Capillary blood glucose will be measured from blood samples (0.6 μL of blood) collected from the fingertips, using disposable lancets and reagent strips (Accu-Check Guide, São Paulo). After collection, blood samples will be immediately analyzed by a portable glucometer (Accu-Check Guide, Roche, São Paulo, Brazil).
Blood pressure. Office SBP and DBP measurements are obtained using an oscillometric BP monitor (HEM-7320, OMRON, China). The participant is kept at rest for 5 min, then a measurement is performed on each arm, and then two more measurements are obtained on the arm with the highest value, always with a 1-min interval between measurements.
Functional tests.
The 30-s Chair-Stand test measures the strength of the lower limbs. Participants are instructed to sit and stand up from a chair 42 cm high from the seat, without the aid of the upper limbs, as many times as possible for 30 s [30].
The arm Curl test is performed to check upper body strength. The test is performed holding a dumbbell in the dominant hand, with a load corresponding to 2 kg for women and 4 kg for men. Participants are instructed to perform the maximum number of elbow flexion repetitions in the full range of motion for 30 s [30].
The Time up and Go (TUG) is used to measure agility and dynamic balance. The test starts with the participant sitting in a chair with a cone positioned 3 m away in front of them. Each participant is instructed to get up from their chair, walk as quickly as possible without running, go around the cone and return to the starting position. The shortest time of two attempts is the test result. In addition, the test is also performed at the usual walking speed [31].
The 2-min step test is carried out to estimate the aerobic capacity. The test measures the maximum number of knee raises the individual can perform in 2 min. At the indicative signal, the participant starts stationary gait (without running), completing the maximum knee raises within 2 min. The minimum knee height is a midpoint between the patella and the anterior superior iliac spine. The evaluator counts the number of right knee raises [30].
Sit and Reach Flexibility Test is applied using the Wells bench, which measures the lower limbs’ flexibility. Participants must be barefoot, sit facing the base of the box with their legs extended and together, place one of their hands on top of the other and then raise their arms vertically. When the evaluator gives the signal, the participant bends the body forward and reaches with the fingertips as much as possible on the graduated ruler without bending the knees or using rocking movements (insistence). Two trials are performed, and the lowest value is recorded [32].
Quality of life. QOL is measured using the EUROHIS-QOL 8-ITEM, an instrument validated for the Brazilian population [33]. The questionnaire consists of 8 items (general QOL, general health, energy, activity of daily living, self-esteem, social relationships, finances, and home). Each item is answered individually, using a Likert-type scale, from 1 to 5 points, ranging from “very bad to very good” (rating scale), “very dissatisfied to very satisfied” (satisfaction scale), and “not at all to extremely” (intensity scale). The total score ranges from 8 to 40 and indicates that the higher the score, the better the individual's perception of their QOL.
Depressive symptoms. Depressive symptoms are measured using the PHQ-9, an instrument validated for the Brazilian population [34]. It is a tool that aims to verify the presence of depressive symptoms in the last two weeks through a Likert-type scale from 0 to 3 points. It consists of nine questions with four response options ranging from “no, not one day” (0 points) to “almost every day” (3 points). The questionnaire also has the tenth question, referring to the interference of symptoms in daily life. In total, it is possible to have a score from 0 to 27, which indicates that the lower the score, the lower the depressive symptoms.
Sleep quality. To measure sleep quality, the PSQI is used, an instrument validated for the Brazilian population [35]. The questionnaire includes 19 questions about the individual’s perception and five questions regarding the perception that the roommates of these individuals have about their sleep. If the participant does not have a roommate, the questions are not answered; therefore, they are not scored. These questions are grouped into seven components, with scores ranging from zero to three, where higher scores indicate worse sleep quality.
Emotional stress related to diabetes. The B-PAID is used to analyze the emotional stress related to diabetes and the impact of diabetes and treatment on the lives of study participants. A 5-point Likert scale is used, ranging from: “No problem=0”, “Small problem=1”, “Moderate problem=2”, “Almost a serious problem=3”, and “Serious problem=4”. The B-PAID produces a total score that ranges from 0-100, where a high score indicates a high level of emotional distress. This total score is achieved by summing the 0-4 responses given on the 20 B-PAID items and multiplying this sum by 1.25 [36].
Control Variables
Anthropometric assessment. Body mass and height measurements are performed using a digital scale (HN-289, OMRON, China) and a compact stadiometer (MD, Brazil). From these data, the body mass index (BMI) will be calculated through the equation: BMI = body mass (kg)/height² (m). Subsequently, the waist circumference is measured at the midpoint between the iliac crest and the last rib to verify the waist circumference/height ratio from these data.
Physical activity levels. To measure the level of physical activity, the IPAQ-C is used in its short version, validated in its Brazilian version [37]. The IPAQ-C includes eight self-completion questions in different domains, such as work, leisure, domestic activities, and physical exercise. Data are expressed in minutes, and the metabolic equivalent is calculated (1 MET: 3.5 ml/kg/min). Like the other questionnaires, it is applied in electronic format, as already done in a previous study [38].
Eating habits. The Food Frequency Questionnaire (FFQ) is used to control eating habits, as used in a previous study [39]. The questionnaire consists of a list of 16 foods prepared from previous studies [40, 41]. According to the Brazilian Food Guide Guidelines, these foods will be classified into two groups: in natura/minimally processed foods and processed or ultra-processed foods. Scores will be generated for these two food groups based on the frequency of consumption reported by the participants. The scores may vary from 0 to 32 points, in which higher scores represent better eating habits. A general healthy eating score will also be generated from the sum of all evaluated foods, which may vary from 0 to 64 points, where higher scores represent better eating habits.
Adherence assessments. For the IG participants, adherence measures are considered attendance and compliance in the intervention. Attendance is monitored through the online session’s frequency recording and treated as the percent of intervention sessions experienced by each participant, given the total number of applied sessions (thirty sessions). Compliance is treated as the percentage of intervention sessions performed without protocol deviations.
Data management
Data collected in online forms are identified by subject identification and contain instructions for standard operating procedures. A specific lead researcher performs the check for missing or inaccurate data.
Statistical analyses
Descriptive statistics (mean ± standard deviation) will be used to describe the sample or data set characteristics. Independent T-tests or Fisher's exact test will be used to compare the sample characterization data. If they do not present a normal distribution (Shapiro-Wilk test) and homogeneous (Levene test), the corresponding non-parametric tests will be applied. Generalized Estimating Equations (GEE) and the post hoc Bonferroni test will be used to compare moments and groups for primary and secondary outcomes. The analyses will be performed by per-protocol (PP), including participants who obtain a frequency higher than 70%, and by intention to treat (ITT), aiming to include all randomized participants. Acute capillary blood glucose will also be evaluated pre- and post-session throughout the intervention for the IG, using GEE (2x3; session and time factors). All data will be analyzed using SPSS version 22 at an alpha level of 0.05.
Data monitoring
We will not have a specific data monitoring committee because it is optional in the RED study. The remotely supervised home-based exercise program is conducted by a skilled and trained instructor who is not interested in the intervention’s specific outcome.
Harms
The patients are informed that participation in the study involves a minimal probability of risks and discomforts, especially by the professional prescription and conduction of the exercise sessions. The common discomforts in exercise, such as fatigue during and post-exercise, are also explained to patients, which may require reducing the intensity or stopping the exercise. The Research team is available to solve any adverse events. If adverse events are reported, they are collected and classified according to severity (i.e., mild, moderate, or severe), predictability (i.e., expected or unexpected), and potential relationship to study procedures (i.e., definitely related, possibly related, or unrelated).
Ethics and Dissemination
Research ethics approval
Study procedures were approved by the Human Research Ethics Committee of the Physical Education School of Federal University of Pelotas (Brazil) (CAAE: 55791622.8.0000.5313). Recruited participants are informed about all study steps, including possible risks and benefits, and sign an informed consent form if they accept to participate in the study. The identity of the participants is preserved and identified by the identification number (ID).
Protocol amendments
If necessary, amendments to the study protocol will be communicated to the Human Research Ethics Committee of the Physical Education School of the Federal University of Pelotas (Brazil). At the same time, our research team will also update the protocol of the clinical trial registry.
Access to data
The data will be available from the corresponding author upon reasonable request.
Ancillary and post-trial care
After the RED study completion, the blood test results (weeks 0 and 13) will be delivered to the participants, in addition to an easy-to-understand report on the study results. In addition, timely information from tests performed can be provided to participants for treatment issues if requested.
Dissemination policy
Upon completion of the study, our dissemination plan aims to disseminate the results found to as many interested parties as possible. First, participants will receive their reports with their measurements and interpretations in language adapted to the f the lay public’s understanding. All participants will also receive general guidance on type 2 diabetes, general health care, and physical activity. In addition, the results will be published in the press with the main findings on the topic aimed at the general public. Academic-scientific dissemination will be done through scientific articles submitted in journals and presentations at events.
Trial status
This manuscript is based on the trial protocol dated December 2022. At the time of submission, patient recruitment has begun. Patient recruitment started on May 2022 and is estimated to be completed in March 2023.