Comparison of Effect of Two-Only-Meals and Exercise against Conventional Multi-Meal Diet Pattern and Exercise on Glycosylated Hemoglobin Levels among Type 2 Diabetic Subjects: An Open Label Parallel Design Randomized Control Trial at Tertiary Care Institute Telangana

Worldwide there were 529 million people of all ages living with diabetes, yielding a global age-standardized prevalence of 6·1%.(1) Type2 Diabetes (T2D) is the rapidly growing NCD in India, with preponement of age of commencement and early organ damage.(2) The world needs ways to prevent T2D epidemic and rollback of the disease. However, the rising prevalence of T2D and Insulin Dependent Diabetes (IDD) is evidence that both lifestyle and clinical management are facing challenges. (3)

Conventional management of T2DM banks on small frequent meals, moderate exercise, and anti-diabetic medication (ADM). As per previous evidence, increased feeding frequency leads to a reduction in the total secretion of insulin, an improvement in insulin resistance and a better blood glucose control, as well as an improvement in the blood lipid profile.(4)Lifestyle modification involves two main aspects: dietary and physical activity, causing overweight, but also stress, smoking etc.(5,6)However there is weak evidence of the effectivity of lifestyle modification both on prevention or amelioration of T2DM.(7,6,8) Dietary modification further involves three aspects: meal frequency, intakes, and Time restricted feeding (TRF). Of these three aspects various modifications have been studied in an excellent systematic review concluding that fewer meals generally help control T2D glycemia profiles as compared to more meals. (9) Even then advising lifestyle modification has a due place in T2DM management.(5,10) Physical activity and meal management for glycaemic control in T2DM are separately and jointly tried.

A systemic review of meal frequency and timings has been recently published and reports favourable changes by reducing meal frequency.(9) The present study focusses on reduced meal frequency with moderate PA and there are several favourable reports that there is positive evidence to support this works.(11,12,13)

Many patients are now following a 2-meals a day frequency and modest exercise (2-OMEX) also known as Dr. Dixit lifestyle intervention with medication adjustments, this is due to a popular campaign in Maharashtra, with a reported decline in HbA1c and even remission of T2DM.(11,13) This is based on the fact that reduction in eating frequency reduces the insulin levels in blood there by helping in reduction in weight as well as reducing the risk of T2D. This Lifestyle has strong potential as a preventive and promotive strategy for obesity and T2D. Currently, various lifestyles are popular including vegan diets, small diets for calorie restriction, intermittent fasting, and all with modest daily/weekly 5 days workouts.

It is noteworthy that standard guidelines for clinical management like WHO, ADA and RSSDI now endorse fair trial for lifestyle correction to ensure physical activity, stress management, and moderate weight loss rather than committing new T2DM patients straight for anti-diabetic medication.(5)  We are therefore justified in giving a fair trial to this culturally acceptable meal frequency restriction in Indian settings in comparison with ≥ three meal frequency.

If the 2-OMEX lifestyle reducesHbA1clevels, is it because of calories reduction or sheerly by frequency reduction irrespective of intakes? In an earlier study stating reduction of 0.7gm% in HbA1c (0.94 gm% by log-normal method), participants had already experienced a reported mild reduction of about 20% or about 300 Kcal (Males297-Females334), but not severely reduced intakes like 800 Kcal in DiREct study.(14) To unravel this energy intake as a confounding factor, we plan to undertake a causal pathway mediator analysis for the role of energy intake through a structured model equation using direct and indirect pathways.

The present study aims to test this hypothesis of T2DM control and remission in two-meals- a day with exercise (2-OMEX) and conventional management arm more than two meals a day with exercise, the main difference being frequency of meals (2 only or more than 2 meals as daily routine,), while modest exercise of 30minutes (minimum of 2.5 km walk) per day for 5 days a week or 150 min of moderate exercise like walking per week, which may be spread over the week, which is being common to both arms. We want to do this as an open label parallel design randomized control trial in a tertiary care institute in uncomplicated T2DM subjects detected recently in last two years with HbA1c in between 7 to 8.5 gm% and or on oral anti-diabetic medication.

Novelty/ Innovation

There are very few studies compared the effect two meals a day and exercise against conventional meals and exercise on HbA1c and AD medication in recently diagnosed T2D patients in India. The outcome of this study will useful in determining whether 2-OMEX intervention/lifestyle can effectively reduce HbA1c and AD medication needs as compared to the conventional management of small frequent meals. This may be basis for conducting large scale studies with larger sample size all over India and further this type of dietary pattern can be incorporated in management protocol for control of T2DM and its remission. The findings of this study will be used to guide policy makers and program designers to develop future policies and interventions for the effective prevention and management  of type 2 diabetes.

Objectives of the study:

Primary objective:

a)     To compare the effect of 2-only meals and moderate exercise (2-OMEX) lifestyle intervention against conventional management of with more than 2 meals and moderate  exercise on HbA1c in recently detected T2DM subjects over a period of 180 days.

Secondary Objective

b)     Compare change in body weight, waist size, lipid profile and antidiabetic medication between the two arms over a period of 180 days.

Research Question: Does the "Two-Only-Meals and Exercise" (2-OMEX) lifestyle intervention lead to a greater reduction in fasting blood sugar levels, glycosylated hemoglobin (HbA1c) levels and antidiabetic medication use as compared to a conventional ≥3 meals diet pattern and exercise intervention among recently diagnosed T2DM subjects at the end of 180 days?

Null Hypothesis (H0): There is no difference in the improvement of fasting blood sugar levels, glycosylated hemoglobin (HbA1c) levels and antidiabetic medication use between the "Two-Only-Meals and Exercise" (2-OMEX) intervention and the conventional ≥3 meals diet pattern and exercise intervention among recently diagnosed T2DM subjects at the end 180 days.

**Alternative Hypothesis (H1):**We hypothesized that "Two-Only-Meals and Exercise" (2-OMEX) lifestyle intervention results in a greater reduction in fasting glucose levels, glycosylated hemoglobin (HbA1c) levels and antidiabetic medications use as compared to the conventional ≥3 meals diet pattern and exercise intervention among recently diagnosed Type 2 diabetic subjects at the end 180 days.  Type of study: Open label parallel design randomized control trial

METHODOLOGY

Sample size/ number of participants: calculated adequate total sample size for this RCT is 160.

PICO:

Participants

T2DM subjects, detected in last two years, not on Insulin, willing to try lifestyle change of moderate physical activity for 3-6 months for weight loss, without cardiac, renal, visual morbidity, BMI ≥ 23

|Intervention

Daily meal frequency

|Comparison

2meals/day in arm1, versus ≥3meals in arm2

|Outcomes (primary)

Baseline to endline change in HbA1c gm%

|Outcomes (secondary)

Sugar levels, lipid profile, Weight, waist, BMI, energy intakes

 Study Design and Participants:

This will be an open label parallel design hospital based randomized trial designed to evaluate the effectiveness of the 2-OMEX lifestyle intervention. The study will be conducted in the outpatient department of AIIMS Hospital, Bibinagar, Telangana. It is a nodal tertiary care referral centre in Telangana that offers comprehensive medical services. Under the supervision of investigators, doctors or clinical officers, qualified public health specialists, and data enumerators (public health professionals) will assess the eligibility criteria of people with type 2 diabetes visiting the outpatient department of the hospital. The study will be conducted as per Consolidated Standards of Reporting Trials (CONSORT) 2010 updated guidelines for reporting for randomised controlled trials, Intervention Description and Replication (TIDieR) guidelines, and local regulations. The ethical approval is obtained from the institutional Ethical Committee (attached ). Written informed consent will be obtained from each participant before enrolment in the study.

2-OMEX lifestyle intervention Arm: (a) follows only 2-OMEX-no snacking or energy drinks in between meals for 150 days out of 180 days, with no week having >2day break of 2- OMEX lifestyle intervention AND (b) weekly minimum 150 min of modest exercise (walking for 30 min/day) spread over period of 5 days a week.

Conventional ≥ 3 meals Diet pattern & moderate exercise control Arm: All factors same as the intervention arm, except meal frequency  3 meals per day.

Anti-diabetic medications by oral hypoglycaemic agent is not having any risk of hypoglycaemia (i.e. METFORMIN with dosage range from 500 to 2000 mg) will be used as per physician’s advice in both groups in similar way & doses will be adjusted as per their requirement. Metformin is a very safest antidiabetic drug which doesn’t have any hypoglycaemic complications.

Energy Distribution:

2-OMEX Lifestyle Intervention Group:

·       The 2-OMEX intervention involves consuming two main meals per day (e.g., breakfast and lunch) without additional snacking. Therefore, the total daily caloric intake is distributed primarily across these two meals.

·       Each meal in the 2-OMEX group is designed to provide a balanced mix of macronutrients (carbohydrates, proteins, fats) to meet the participant’s energy needs for the day.

 Â·       The distribution of calories between the two meals is adjusted to ensure adequate energy supply and nutrient intake, considering individual requirements and metabolic demands.

Conventional ≥ 3 meals Diet pattern & Exercise control Group:

·       The conventional multi-meal diet pattern includes three main meals (breakfast, lunch, and dinner) with the addition of snacks between meals.

·       Calories are distributed more evenly throughout the day among multiple meals and snacks.

·       Each meal and snack in the conventional group is carefully planned to provide similar caloric content per eating occasion as the 2-OMEX meals.

Meal Composition and Nutrient Distribution:

2-OMEX Lifestyle Intervention Group:

·       Meals in the 2-OMEX group are nutritionally dense, focusing on whole foods rich in fiber, lean proteins, healthy fats, and complex carbohydrates.

·       Nutrient distribution is optimized to support glycemic control, satiety, and energy levels throughout the day.

·       Emphasis is placed on nutrient-dense foods to minimize nutrient deficiencies despite reduced meal frequency.

Conventional ≥ 3 meals Diet pattern & Exercise control Group:

·       Meals and snacks in the conventional group adhere to standard dietary recommendations for diabetes management, emphasizing balanced macronutrient distribution.

·       The composition includes a variety of food sources, both plant-based and animal-based, to meet nutrient requirements and provide sustained energy.

• Definition of dropout/noncompliance: If >6 days are missed in any month (equivalent to 20% missed days) for 2-OMEX lifestyle intervention arm separately, the subject will be treated as non-compliant and deleted from study. If a subject is not answering call and not reporting to the clinic for >30 days. He/she will be reported as a drop out.

Consent: All subjects will be explained about the project, interventions, and fully informed consent will be taken

Study procedures

The study will be carried out at AIIMS Bibinagar Hospital. As per medicine department OPD census at present daily around eight to ten patients of T2DM are reporting at medicine OPD among these three to four are recently diagnosed patients.  A total of 160eligible recently diagnosed T2DM will be recruited in three months in the trial and will be followed for 24 weeks. After baseline examination, participants will be followedat 12 weeks and 24 weeks.

Screening:

Purpose: The screening process aims to identify eligible participants for the study based on predefined inclusion and exclusion criteria.

Steps:

• Potential participants will be screened based on their medical records and recent diagnosis of Type 2 diabetes at the tertiary care institute.
• Screening assessments will include demographic information, medical history, diabetes diagnosis date, and current medication use.
• Individuals meeting initial criteria will undergo further assessments to confirm eligibility, including laboratory tests (e.g., HbA1c levels, FBS etc.), physical examinations, and assessment of diabetes stability.

Prospective study participants, who will give a written informed consent, will be assessed for eligibility to participate in the study during a two-week period prior to intervention. A list of eligible T2DM subjects for this study will be prepared based on the inclusion and exclusion criteria. These T2DM subjects will be contacted through phone calls by investigator. The eligible T2DM subjects will be explained regarding the objectives of the study. An information sheet with details of the study approved by IEC/IRB will be provided and discussed with the subjects. If eligible T2DM subjects will give consent for participating in the study, an appointment will be set up at the study site where the study physician/investigators/ project staff will counsel eligible T2DM subjects. Consent in writing will be obtained, followed by detailed history and physical examination. Information to be collected and procedures to be conducted during screening include:

·        Demographic data: This will include Personal data, anthropometry etc.

• Medical History: This will include Medication use history, Family History, Risk factors, Present and Past Medical History, Addiction History, History of participation in any nutrition intervention trial, History of any major illness and other medical problems as per inclusion and exclusion criteria will be assessed**.**
• Physical Examination: Physical examination will include vital signs (blood pressure, heart rateand respiratory rate etc.), measurement of weight and height, and systemic examination. Subjects who failed screening will be recorded on a screen failure log showing reason for failure. The list of the eligible T2DM subjects found following the screening will be prepared.Nutrition and Physical Exercise**:**History will be collected as per mentioned criteria in the protocol.

Randomization:

Purpose: Randomization ensures that participants are assigned to intervention groups in a random and unbiased manner, minimizing selection bias and confounding variables.

Steps:

·        Eligible participants will be randomized using computer-generated randomization sequences prepared by an investigator not involved in participant recruitment or assessment.

·        Randomization will be stratified based on key factors such as age, gender, and baseline HbA1c levels to ensure balanced distribution of participant characteristics between intervention groups.

·        Allocation concealment will be maintained to ensure that study staff and participants remain unaware of the group assignment until after eligibility is confirmed.

·        Randomization will be carried out by using random numbers generated online. Random numbers will be generated by investigator and will remain concealed.

Allocation Concealment:

Purpose: Allocation concealment prevents selection bias and ensures that participants and study staff remain blinded to group assignment during the screening and randomization processes.

Steps:

·        Randomization codes will be stored securely by an investigator

·        Group allocation will be revealed to participants only after eligibility is confirmed and baseline assessments are completed.

·        Investigator involved in participant recruitment, assessments, and interventions will be blinded to group assignment to minimize bias during the study.

Allocationwill be done by investigator after subject selection as per eligibility criteria. After completion of allocation investigator will release the next random number. Reasons for non-inclusion will be noted. We will generate random numbers (RN) for two groups with concealment. Will apply the RN to the listed T2DM subjects, detected recently, in the OPD.

Follow-up

Weekly Phone Calls:

·        Participants will receive weekly phone calls from investigator to inquire about their adherence to the assigned diet, medication use and exercise regimen. During these calls, participants will be asked to provide details on their daily meals, meal frequency, ADM use, exercise activities and any adverse events for the past week.

Biweekly Clinic Visits for first 3months:

·       Participants will visit the clinic every two weeks for face-to-face follow-up assessments for initial 3 months. During these visits, the following assessments will be conducted:

·       Review of completed diary cards (if applicable).

·       Anthropometric Measurement, ADM use, blood pressure recording, and adverse events.

·       Blood sample collection for laboratory tests, including glycosylated hemoglobin (HbA1c) levels at the end of 3 months after intervention.

·       Health education and counselling for strict adherence to recommended diet, exercise, glucometer use and self-monitoring of blood sugar levels if there will be any hypoglycemia attacks.

·       Discussion with T2DM subjects regarding diet, exercise, ADM use any challenges or concerns related to the interventions and adverse events.

Monthly visits for 3rd month onwards:

·       Participants will have monthly consultations with a Physician/public health specialist to review their diary, dietary intake, exercise record, ADM use, adverse events, provide guidance on meal planning, and address any nutritional concerns or questions.

·       Blood sample collection for laboratory tests, including glycosylated hemoglobin (HbA1c) levels at the end of 6 months after intervention.

·       Health education and counselling for strict adherence to recommended diet, exercise, glucometer use and self-monitoring of blood sugar levels if there will be any hypoglycemia attacks.

Physical Activity Monitoring:

·       Continuous monitoring of physical activity using activity trackers “Google fit” or self-reported exercise logs.

Follow-Up Reminders

Frequency:

·       Participants in both groups will receive follow-up reminders at the same frequency. Reminders will be sent weekly for the first month, bi-weekly for the next two months, and monthly thereafter until the end of the study period.

Methods:

• SMS/Email: Weekly text messages or emails will be sent to remind participants about upcoming follow-up appointments, adherence to their respective diet and exercise regimens, and to complete any required diaries or logs.
• Phone Calls: Monthly phone calls will be made by study coordinators to check on participants’ well-being, encourage adherence, and address any concerns or questions they might have.

Content:

• Reminders will include motivational messages, the importance of adherence to the study protocol, and instructions for completing any required activities (e.g., logging meals, recording physical activity).

Monitoring Physical Activity Dropouts

Tracking Adherence:

• Activity Logs: Participants will be provided with physical activity logs to record their daily exercise routines. These logs will be reviewed during follow-up visits.
• Free online Phone App: â€œGoogle Fit” A mobile app will be used for participants to log their physical activities, which will be monitored by the investigator.

**Follow-Up Visits:**Follow-up visits will be scheduled at first 3 months biweekly, and from 3rd month onwards every month. During these visits, physical activity logs and data from google fit app will be reviewed.

• Consistency: The same procedures and criteria for reviewing and recording physical activity adherence will be applied to both the control and test groups.

Addressing Dropouts:

• Identification: Dropouts will be identified based on missed follow-up appointments, failure to return activity logs, or insufficient data from Google fit app.
• **Follow-Up Actions:**Investigator will contact subjects who miss follow-up appointments or show signs of non-adherence. They will attempt to re-engage these subjects through motivational interviewing and problem-solving strategies to address barriers to adherence.
• Documentation: All contact attempts and participant responses will be documented systematically.

Intervention Adjustments:

• Reinforcement: For participants showing signs of dropout or non-adherence, additional reinforcement and support strategies will be provided, such as more frequent follow-up calls or personalized motivational messages.
• Problem-Solving: The investigator will work with participants to identify and address specific barriers to maintaining their physical activity and diet regimen.

Additional Follow-Up:

·        Participants will be encouraged to contact the investigator if they experience any adverse events, changes in medication, or other relevant issues during the study period.

Research Team Contact Information:

1. Participants will have access to contact information for the principal investigator/Co-Investigators for any study-related queries or emergencies.

Anthropometry:

All the measurements will be recorded by trained research staff using standardized and calibrated equipment. Two readings of all anthropometric measurements will be taken and recorded.

·        Height – will be measured using a stadiometer, while standing straight and head set in Frankfurt plane and without shoes

·        Weight – will be measured using an electronic digital weighing scale while wearing light clothes without shoes, value would be recorded up to 2 decimal points

·        Waist and Hip circumference- will be recorded by non-stretchable tailors’ tape as per standard WHO protocol.

Alcohol intake and smoking status (categorized as never smoked, ex-smoker or current smoker) will be assessed by self-report via questionnaire.

Blood pressure will be recorded and calculated as the mean of three measurements using digital sphygmomanometer. (JNC VII and VIII guidelines)

Clinical and biochemical measures will be carried out by trained staff following standardized protocols.

Apparatus: digital weight machine, stadiometer, Transasia XL 1000 fully automated biochemistry analyzer, Arkray ADAMs-8180T HPLC based automate analyzer (in house)

Case record sheet will be pretested and used for both arms. (Enclosed).

Assessment of weight, waist circumference, fasting and postprandial BSL, and medication adjustment will be done under advice of physician/Investigator.   FPG, PPBS, Lipid profile and HbA1c on venous sample as per schedule will be assessed -at inclusion (baseline), after 90 days and after 180 days. We will follow them as per above mentioned follow-up protocol. Dietary intervention, antidiabetic medications and requisite exercise will be monitored by in similar way in both armsby using simple daily diary card (using tick mark) and also confirmed by using Google fit online free walking monitoring app, exercise logs, and food pics will be uploaded in Google drive/Google form

Intervention:

Patient safety will be assessed each week on phone call, and advice about AD medication adjustment for 2-meals frequency arm will be done to avoid hypoglycaemia. Subjects will be explained and counselled to report hypoglycaemia and urine output, tingling, vision complaints. A Principal Investigator/co-investigators will call each patient at least once every week. All patients will have cell-phone numbers of PI/CO-PIs for anytime access.

Data protection and safety (of subjects) monitoring plan

All data sheets will be kept confidential, with access only to investigators.

Withdrawal criteria (Circumstances that could lead to a decision to withdraw the participant from the study)

·       Intolerance to meal frequency lasting after >10 days,

·       If >6 days are missed in any month (equivalent to 20% missed days) for 2-OMEX separately, the subject will be treated as non-compliant and deleted from study.

·       If a subject is not answering call and not reporting to the clinic for >30 days.

·       He/she will be reported as a drop out

Rescue criteria (Measures that will be taken in case of expected adverse outcomes)

Hypoglycaemia is important but we have designed protocol in such a way no one should suffer from this complication. By chance if any enrolled subject will develop this complication to monitor this complication, we are going to provide them glucometer to record this complication and report it immediately to investigator. For this we have prepared safety protocol mentioned below.

Limitations: The study is limited to short period of six months while T2DM is chronic disease of years of life. We cannot test sustenance or effectivity of the intervention though we can test efficiency of the same.

4.2 Data analysis plan

The data will be recorded on case-record sheets, annexed herewith (annexure). P<0.05 will be taken as a level of significance for all tests.  Data management will be done in epi-data software by trained data manager and analysed on JAMOVI or SPSS.  Following variables and co-variates will be studied.

1. Descriptive Statistics:

• Summary statistics (mean, standard deviation, median, range) will be calculated for demographic characteristics (e.g., age, gender, BMI) and baseline measurements (e.g., HbA1c levels) of participants in each intervention arm and conventional management arm.

2. Primary Outcome Analysis:

• The primary outcome is the change in glycosylated hemoglobin (HbA1c) levels from baseline to the end of the study period.
• Analysis will be conducted using an intention-to-treat (ITT) approach, including all randomized participants.
• The difference in mean change in HbA1c levels between the 2-OMEX intervention arm and the conventional management arm will be assessed using analysis of covariance (ANCOVA), adjusting for baseline HbA1c levels and other relevant covariates.

3. Secondary Outcome Analysis:

• Changes in secondary outcomes (e.g., sugar levels, body weight, BMI, lipid profiles, blood pressure) will be analyzed similarly using ANCOVA or appropriate statistical methods, adjusting for baseline values and covariates.
• Subgroup analyses may be conducted based on factors such as age, gender, or baseline disease severity, to explore potential effect modifiers.

4. Adherence and Sensitivity Analyses:

• Adherence to the assigned interventions (2-OMEX arm vs. conventional arm) will be assessed and analyzed as a potential modifier of treatment effects.
• Sensitivity analyses will be performed to evaluate the robustness of the primary results by exploring different statistical models or handling missing data (e.g., multiple imputation).

 Safety Protocol for Hypoglycemia Prevention &Management In 2-OMEX Lifestyle Intervention Trial for T2DM Participants

1. Introduction

Hypoglycaemia is a common risk in individuals with Type 2 diabetes, especially when undergoing dietary and exercise interventions. This protocol outlines the procedures for identifying, managing, and preventing hypoglycemia in participants enrolled in the study.

2. Definition of Hypoglycaemia

Hypoglycaemia is defined as a blood glucose level < 70 mg/dL. Symptoms may include being: nervous or anxious, sweating, chills & clamminess, irritability or impatient, confusion, fast heartbeat, feeling light headed or dizzy, hunger, nausea, color draining in the skin, feeling sleepy, feeling week or having no energy, blurred/impaired vision, tingling numbness in the lips, tongue, or cheeks, headaches, coordination problem, clumsiness, night mares or crying out during sleep, seizures

3. Identification and Monitoring

• Participant Education:
• At the start of the study, we will educate participants on the symptoms of hypoglycemia and the importance of regular monitoring of blood glucose levels. We will continue and refresh them every month or as and when required.
• All participants will be trained how to use glucometer. We will conduct health education and training sessions at baseline, every month refreshment training for how to use glucometer as well as for detection, prevention and control of hypoglycemia.

Target blood glucose levels at every time it is tested will be

Target FBS: 80-125, PPBS: 120-180, Hypoglycemia <70**(Ref.**https://main.icmr.nic.in/sites/default/files/guidelines/ICMR_GuidelinesType2diabetes2018_0.pdf)

• Self-Monitoring: Participants will be provided with glucometers and instructed to measure their blood glucose levels:

Whenever symptoms of hypoglycemia are experienced.

·       Before each meal.

·       At bedtime.

• Regular Check-ins: Participants will report their blood glucose levels and any hypoglycemic events during their follow-up visits and through weekly telephone check-ins. This will be also recorded in their daily diary.

4. Immediate Management of Hypoglycemia

Mild Hypoglycemia (Blood glucose (BG) = 54-69 mg/dL):

·       We will instruct participants to consume immediately 15-20 grams of fast-acting carbohydrates (e.g., Sugar, glucose tablets, fruit juice, regular soda etc.). We will ask them to keep ready with them glucose tablets or above-mentioned things at bed side to prevent hypoglycemia in the night.

·       We will ask them to recheck blood glucose after 15 minutes.

·       If blood glucose remains < 70 mg/dL, repeat the treatment.

·       Once blood glucose is > 70 mg/dL, participants should eat a snack or meal to prevent recurrence.

Severe Hypoglycemia (BG < 54 mg/dL or unable to self-treat):

They will be advised to take immediate help:  Call emergency services immediately

If the patient is unable or unwilling (because of neuroglycopenia) to take carbohydrates orally, parenteral therapy is necessary. Patient will be hospitalized under medicine department at AIIMS Bibinagar hospital or nearby hospital. IV administration of glucose (25 g) will be followed by a glucose infusion guided by serial plasma glucose measurements. (Ref.Harrsion 24th edition, Chapter 406: Page 3134)

We will ask them to recheck blood glucose after 15 minutes and follow the same steps

as for mild hypoglycemia until levels stabilize.

5. Follow-Up After Hypoglycemic Events

• Documentation: All hypoglycemic events will be documented, including the time of occurrence, blood glucose levels, treatment administered, and participant symptoms.
• Medical Review: Participants experiencing hypoglycemia will be provided medication and intervention plans and this will be reviewed by the study medical team to assess the need for adjustments.
• Reassessment of Intervention: Treating physician/public health specialist will evaluate the appropriateness of the medicine, dietary and exercise regimen for the affected participant and make necessary modifications. If patients develop hypoglycemic attacks more than twice a week immediately participant will be called for physician’s check-ups at AIIMS hospital.  After complete physician’s check-ups, he will take decision to reduce the dose to prevent and control hypoglycemia. Then participants will be followed as per regular follow-ups schedule. The same will be recorded in the patient diary and updated in patient case record form.
• Patients will not be removed from the intervention arm but followed up till the completion of study. They will be included in the analysis as per protocol.

6. Prevention Strategies

• Dietary Adjustments: we will ensure all participants in the 2-OMEX group receive adequate caloric intake during their two meals. We will instruct them to drink green tea or thin butter milk or coconut water in between major meals if necessary.
• Exercise Precautions:  we will advise all participants to monitor blood glucose levels before and after exercise. Encourage them to carry fast-acting carbohydrates i.e., Sugar or glucose tablets or fruit juice or regular soda during physical activity.
• Medication Review: we will regularly review participants’ diabetes medications to ensure dosages are appropriate and adjust them as needed to reduce the risk of hypoglycemia.
• Education: Every time we will educate participants about the importance of adhering to meal timings, recognizing early signs of hypoglycemia& to keep ready sugar or glucose tablets or fruit juice at bedside in the bed room during night to prevent hypoglycemia in the night. We will ask them to eat or drink above mentioned things immediately and report the incidence and to check blood sugar levels with glucometer.

7. Emergency Contacts

• Study Coordinator: We will provide to all participants with contact information for the PI/study coordinator and medical team for immediate assistance during hypoglycemic events. (Cell no.1.Physician: Dr Shakthivadivel – 9962528811, 2. PI- 9985397984)
• Emergency Services: we will advise participants to contact local emergency services if severe hypoglycemia occurs and if they are unable to manage it at home.

8. Reporting and Compliance

• Incident Reporting: All hypoglycemic events will be reported to the Institutional Ethical committee (IEC)/IRC as per the study’s reporting guidelines.
• Compliance Monitoring: We will monitor participants’ adherence to the safety protocol and provide additional support or training if non-compliance will be identified.