VMGMProtocol: Glycaemic & Cardiovascular Treatment Outcomes of Voglibose Vs Glibenclamide Added to Metformin in T2DM Patients

Sponsor

University of Zambia (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05688332

Collaborator

University Teaching Hospital, Lusaka, Zambia (Other)

118

Enrollment

Arms

5.9

Anticipated Duration (Months)

Study Details

Study Description

Brief Summary

The goal of this clinical trial is to compare blood-sugar and blood circulatory system risk-position in type 2 diabetes patients on voglibose versus those on glybenclamide when the two drugs are added to metformin because metformin alone is not controlling the blood-sugar well. The results of this trial will help in improving the health and treatment results of the type 2 diabetic patients.

The main question the trial aims to answer is whether there is a difference in blood-sugar and blood circulatory system treatment results between voglibose + metformin and glibenclamide + metformin treatment combinations.

Participants that agree to participate in the trial will be asked to provide a sample of blood so that the following measurable laboratory factors will be used to compare any differences in treatment results between the two treatment groups from the beginning to the end of the trial:

Total Cholesterol (TC),
Low Density Lipoproteins (LDL-c),
High Density Lipoproteins (HDL-c),
Fasting Triglycerides (FTG),
Fasting blood sugar (FBS),
Post prandial blood sugar (PPBG),
Glycated hemoglobin (HbA1c) correlated to hemoglobin level,
creatinine,
blood urea and
electrolytes (K+, Na+, Cl-).

Condition or Disease	Intervention/Treatment	Phase
Diabetes Mellitus Type 2 Without Complication	Drug: Voglibose + Metformin Drug: Glibenclamide + Metformin	Phase 3

Detailed Description

BACKGROUND: Diabetes is an increasingly important risk factor for CVD, and individuals with diabetes as compared to those without diabetes continue to have an increased risk of both all-cause and cardiovascular mortality. It can be classified as type 1 diabetes mellitus (T1DM), type 2 diabetes mellitus (T2DM), gestational diabetes mellitus (GDM) and others. Metformin is a T2DM first line Oral Hypoglycaemic Agent (OHA). It usually requires a second line add-on drug if blood glucose control is not on target. The add-on drug can either be insulin, an injectable incretin mimetic, or an OHA. The choice of the OHA should be considered with regard to improving the glycaemic control as well as reducing the cardiovascular disease risk.

Glibenclamide, a Sulphonylurea, is a commonly used OHA in Zambia. Sulphonylureas are associated with hypoglycaemia and arrhythmias. On the other hand Voglibose, an alpha glucosidase inhibitor (AGI), is not associated with hypoglycaemia or with negative cardiovascular events. The alpha-glucosidase inhibitors (AGIs), (acarbose, voglibose and miglitol) reduce postprandial hyperglycaemia by reducing the absorption of glucose in the gastrointestinal tract after a carbohydrate meal. AGIs are more effective at lowering postprandial insulin levels than Sulphonylureas. Reduced postpradial glycaemia prevents macrovascular complications. Since maize (a carbohydrate) is a staple food in Zambia, there is need to investigate the glycaemic control in patients with T2DM using voglibose which is as affordable as glibenclamide.

The main aim of this study will be to investigate the extent of glycaemic control and cardiovascular risk parameter effects of voglibose versus glibenclamide add-on therapies in Zambian patients with T2DM as we do not have published studies on these parameters in our patients.

METHODOLOGY: This study will be a 12 weeks dual-center prospective interventional open-label randomised controlled trial to comparatively evaluate the glycaemic and cardiovascular treatment outcomes of voglibose versus glibenclamide add-on therapies in native Zambian patients with type 2 diabetes inadequately controlled on 2g/day of metformin monotherapy. In this study, glycaemic and cardiovascular parameters will be quantified and classified in the laboratory to determine extent of glycaemic control and cardiovascular risk reduction as patients report for their scheduled visits at the adult diabetes OPD clinics at University Teaching Hospital and Matero General Hospital.

Participants to be included will be male and female native Zambian patients aged 22 to 59 years on metformin monotherapy for at least 12 weeks with HbA1c> 7.0%. They will be randomly allocated to two treatment arms i.e the voglibose-metformin or the glibenclamide-metformin regimen in a 1:1 computer generated randomisation. The participants will then be followed up to the 6th and 12th week for data collection. A comparative analysis of the expected outcome of interest which is the change in the extent of glycaemic control and cardiovascular risk reduction in the two groups will be done at the 12th week.

This study is significant as it will help to determine the glycaemic and cardiovascular risk status of patients with type 2 diabetes mellitus on voglibose and glibenclamide, thereby ascertain improvement in their healthcare and treatment outcomes.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

118 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Comparison of Glycaemic and Cardiovascular Treatment Outcomes of Voglibose Versus Glibenclamide Added to Metformin in T2DM Patients in Zambia: An Open-label Randomised Clinical Trial

Anticipated Study Start Date :

Jan 1, 2023

Anticipated Primary Completion Date :

Apr 1, 2023

Anticipated Study Completion Date :

Jul 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Voglibose + Metformin (Group B) in treatment group B, 59 participants will randomly assigned to the voglibose 0.2 or 0.3mg + metformin 500 or 850mg treatment combination to be taken 3 times daily, during or after meals. After 6 to 12 days the dose will be individually titrated on the basis of blood glucose measurements. A slow increase of dose may improve gastrointestinal tolerability. In this study, 0.9mg voglibose and 2500 mg metformin will not be exceeded daily.	Drug: Voglibose + Metformin In treatment group B, 59 participants will also be randomly assigned to the voglibose 0.2/0.3mg + metformin 500mg treatment combination to be taken orally 3 times daily (TDS), during or after meals with dose titration at day 6 and 12 if the average fasting blood glucose (FBG) level is ≥7 mmol/L (126 mg/dL) and then dosage will be maintained for the remainder of the treatment period Participants in the intervention group initially receiving voglibose 0.2mg + metformin 500mg TDS will be dose-titrated to voglibose 0.3mg +metformin 850mg TDS. The duration of therapy for each participant will be 12 weeks, which is the minimum period for evaluating the primary endpoint.
Active Comparator: Glibenclamide + Metformin (Group A) In treatment group A, 59 participants will be randomly allocated to the glibenclamide 5mg O.D + metformin 500mg TDS regimen. In this study, 15mg glibenclamide and 2500 mg metformin will not be exceeded daily.	Drug: Glibenclamide + Metformin The drugs (glibenclamide + metformin), in the control or comparator group will also be taken orally, glibenclamide once a day (OD) before meals, and metformin three times a day (TDS) also before meals. These drugs will also be taken with a dose-titration at days 6 and 12 if the average is FBG level will be ≥ 7 mmol/L and the dose will be maintained for the remainder of the study period. The duration of therapy for each participant will be 12 weeks, which is the minimum period for evaluating the primary endpoint. In this group, participants will initially receive glibenclamide 5mg once daily (OD) + metformin 500mg TDS then will be dose-titrated to glibenclamide 10mg OD + metformin 850 TDS.

Arm

Intervention/Treatment

Experimental: Voglibose + Metformin (Group B)

in treatment group B, 59 participants will randomly assigned to the voglibose 0.2 or 0.3mg + metformin 500 or 850mg treatment combination to be taken 3 times daily, during or after meals. After 6 to 12 days the dose will be individually titrated on the basis of blood glucose measurements. A slow increase of dose may improve gastrointestinal tolerability. In this study, 0.9mg voglibose and 2500 mg metformin will not be exceeded daily.

Drug: Voglibose + Metformin

In treatment group B, 59 participants will also be randomly assigned to the voglibose 0.2/0.3mg + metformin 500mg treatment combination to be taken orally 3 times daily (TDS), during or after meals with dose titration at day 6 and 12 if the average fasting blood glucose (FBG) level is ≥7 mmol/L (126 mg/dL) and then dosage will be maintained for the remainder of the treatment period Participants in the intervention group initially receiving voglibose 0.2mg + metformin 500mg TDS will be dose-titrated to voglibose 0.3mg +metformin 850mg TDS. The duration of therapy for each participant will be 12 weeks, which is the minimum period for evaluating the primary endpoint.

Active Comparator: Glibenclamide + Metformin (Group A)

In treatment group A, 59 participants will be randomly allocated to the glibenclamide 5mg O.D + metformin 500mg TDS regimen. In this study, 15mg glibenclamide and 2500 mg metformin will not be exceeded daily.

Drug: Glibenclamide + Metformin

The drugs (glibenclamide + metformin), in the control or comparator group will also be taken orally, glibenclamide once a day (OD) before meals, and metformin three times a day (TDS) also before meals. These drugs will also be taken with a dose-titration at days 6 and 12 if the average is FBG level will be ≥ 7 mmol/L and the dose will be maintained for the remainder of the study period. The duration of therapy for each participant will be 12 weeks, which is the minimum period for evaluating the primary endpoint. In this group, participants will initially receive glibenclamide 5mg once daily (OD) + metformin 500mg TDS then will be dose-titrated to glibenclamide 10mg OD + metformin 850 TDS.

Outcome Measures

Primary Outcome Measures

Change in mean Glycated Hemoglobin (HbA1c) levels [Baseline & Week 6]
The null hypothesis is that there is no significant difference between the voglibose and glibenclamide treatment groups in the change in mean HbA1c levels after 6 weeks of add-on therapy to metformin in the T2DM patients (i.e. H0: µ1 = µ2 where µ1 is the mean HbA1c change in the glibenclamide group and µ2 is the mean HbA1c change in the voglibose group). The alternative hypothesis is that there is a significant difference between the voglibose and glibenclamide groups in the change in mean HbA1c levels after 6 weeks of add-on therapy to metformin in the T2DM patients (i.e. H1: µ1 ≠ µ2).
Change in mean Glycated Hemoglobin (HbA1c) levels [Baseline & Week 12]
The null hypothesis is that there is no significant difference between the voglibose and glibenclamide treatment groups in the change in mean HbA1c levels after 12 weeks of add-on therapy to metformin in the T2DM patients (i.e. H0: µ1 = µ2 where µ1 is the mean HbA1c change in the glibenclamide group and µ2 is the mean HbA1c change in the voglibose group). The alternative hypothesis is that there is a significant difference between the voglibose and glibenclamide groups in the change in mean HbA1c levels after 12 weeks of add-on therapy to metformin in the T2DM patients (i.e. H1: µ1 ≠ µ2).

Secondary Outcome Measures

Change in Glycemic control with regard to Fasting Plasma Glucose (FPG) [Baseline & week 6]
Differences in change in glycemic control with regard to FPG: The null hypothesis is that there is no significant difference between the voglibose and glibenclamide treatment groups in the mean FPG change (i.e. H0: µ1 = µ2 where µ1 and µ2 represent the mean FPG change in the glibenclamide and voglibose groups respectively). The alternative hypothesis is that there is a difference between the voglibose and glibenclamide groups in the mean changes of FPG (i.e. H1: µ1 ≠ µ2).
Change in glycemic control with regard to Fasting Plasma Glucose (FPG) [Baseline & week 12]
Differences in change in glycemic control with regard to FPG: The null hypothesis is that there is no significant difference between the voglibose and glibenclamide treatment groups in the mean FPG change (i.e. H0: µ1 = µ2 where µ1 and µ2 represent the mean FPG change in the glibenclamide and voglibose groups respectively). The alternative hypothesis is that there is a difference between the voglibose and glibenclamide groups in the mean changes of FPG (i.e. H1: µ1 ≠ µ2).
Change in glycemic control with regard to Post Prandial Blood Glucose (PPBG) [Baseline & week 6]
Differences in Change in glycemic control with regard to PPBG: The null hypothesis is that there is no significant difference between the voglibose and glibenclamide treatment groups in the mean PPBG change (i.e. H0: µ1 = µ2 where µ1 and µ2 represent the mean PPBG change in the glibenclamide and voglibose groups respectively). The alternative hypothesis is that there is a difference between the voglibose and glibenclamide groups in the mean changes of PPBG (i.e. H1: µ1 ≠ µ2).
Change in glycemic control with regard to Post Prandial Blood Glucose (PPBG) [Baseline & week 12]
Differences in change in glycemic control with regard to PPBG: The null hypothesis is that there is no significant difference between the voglibose and glibenclamide treatment groups in the mean PPBG change (i.e. H0: µ1 = µ2 where µ1 and µ2 represent the mean PPBG change in the glibenclamide and voglibose groups respectively). The alternative hypothesis is that there is a difference between the voglibose and glibenclamide groups in the mean changes of PPBG (i.e. H1: µ1 ≠ µ2).
Lipid profile (LDL-c, HDL-c, TC, TG) comparison [Baseline & Week 6]
Lipid profile (LDL-c, HDL-c, TC, TG) comparison: The null hypothesis is that there is no difference between the voglibose and glibenclamide groups in the mean changes in lipid profile (i.e. H0: µ1 = µ2 where µ1 and µ2 represent the mean changes in lipid profile in the glibenclamide and voglibose groups respectively). The alternative hypothesis is that there is a difference between voglibose and glibenclamide groups in the mean changes in lipid profile (i.e. H1: µ1 ≠ µ2).
Lipid profile (LDL-c, HDL-c, TC, TG) comparison [Baseline & Week 12]
Lipid profile (LDL-c, HDL-c, TC, TG) comparison: The null hypothesis is that there is no difference between the voglibose and glibenclamide groups in the mean changes in lipid profile (i.e. H0: µ1 = µ2 where µ1 and µ2 represent the mean changes in lipid profile in the glibenclamide and voglibose groups respectively). The alternative hypothesis is that there is a difference between voglibose and glibenclamide groups in the mean changes in lipid profile (i.e. H1: µ1 ≠ µ2).
Anthropometric parameter changes in BMI [Baseline & Week 6]
Anthropometric parameter changes in BMI: The null hypothesis is that there is no difference between the voglibose and glibenclamide groups in the mean anthropometric parameter changes (i.e. H0: µ1 = µ2 where µ1 and µ2 represent the mean anthropometric parameter changes in the glibenclamide and voglibose groups respectively). The alternative hypothesis is that there is a difference between voglibose and glibenclamide groups in the mean anthropometric parameter changes (i.e. H1: µ1 ≠ µ2).
Anthropometric parameter changes in BMI [Baseline & Week 12]
Anthropometric parameter changes in BMI: The null hypothesis is that there is no difference between the voglibose and glibenclamide groups in the mean anthropometric parameter changes (i.e. H0: µ1 = µ2 where µ1 and µ2 represent the mean anthropometric parameter changes in the glibenclamide and voglibose groups respectively). The alternative hypothesis is that there is a difference between voglibose and glibenclamide groups in the mean anthropometric parameter changes (i.e. H1: µ1 ≠ µ2).
Anthropometric parameter changes in Waist Circumference (WC) [Baseline & Week 6]
Anthropometric parameter changes in WC: The null hypothesis is that there is no difference between the voglibose and glibenclamide groups in the mean anthropometric parameter changes (i.e. H0: µ1 = µ2 where µ1 and µ2 represent the mean anthropometric parameter changes in the glibenclamide and voglibose groups respectively). The alternative hypothesis is that there is a difference between voglibose and glibenclamide groups in the mean anthropometric parameter changes (i.e. H1: µ1 ≠ µ2).
Anthropometric parameter changes in Waist Circumference (WC) [Baseline & Week 12]
Anthropometric parameter changes in WC: The null hypothesis is that there is no difference between the voglibose and glibenclamide groups in the mean anthropometric parameter changes (i.e. H0: µ1 = µ2 where µ1 and µ2 represent the mean anthropometric parameter changes in the glibenclamide and voglibose groups respectively). The alternative hypothesis is that there is a difference between voglibose and glibenclamide groups in the mean anthropometric parameter changes (i.e. H1: µ1 ≠ µ2).
Drug related AEs [Baseline & Week 6]
Drug related AEs: The null hypothesis is that there is no difference between the proportion of participants experiencing drug related AEs in the voglibose and glibenclamide groups (i.e. H0: p1 = p2 where p1 and p2 represent the proportion of participants experiencing a drug related AE in the glibenclamide and voglibose groups, respectively). The alternative hypothesis is that there is a difference between the proportion of participants experiencing drug related AEs in the voglibose and glibenclamide groups (i.e. H1: p1 ≠ p2).
Drug related AEs [Baseline & Week 12]
Drug related AEs: The null hypothesis is that there is no difference between the proportion of participants experiencing drug related AEs in the voglibose and glibenclamide groups (i.e. H0: p1 = p2 where p1 and p2 represent the proportion of participants experiencing a drug related AE in the glibenclamide and voglibose groups, respectively). The alternative hypothesis is that there is a difference between the proportion of participants experiencing drug related AEs in the voglibose and glibenclamide groups (i.e. H1: p1 ≠ p2).

Eligibility Criteria

Criteria

Ages Eligible for Study:

22 Years to 59 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

In order to be eligible to participate in this study, an individual must meet all of the following criteria:
Provision of signed and dated informed consent form.
Stated willingness to comply with all study1 procedures and availability for the durtion of the study.
Male or female, aged 22-59 years.
In good general health as evidenced by medical history, diagnosed with T2DM and on tolerated dose of at least 2g/day of metformin monotherapy.
Ability to take oral medication and be willing to adhere to the medication regimen through out the study period.
For females of reproductive potential use of highly effective contraception.
Native-Zambian participants
Must be on metformin monotherapy for 12 weeks or longer.
Glycated haemoglobin (HbA1c) must be >7.0% within 12 weeks before screening.

Exclusion Criteria:

An individual who meets any of the following criteria will be excluded from participation in this study:
Hypersensitivity or contraindication to AGIs
Hypersensitivity or contraindication to SUs
Type 2 diabetes patients with pregnancy or lactation
Patients with acute complications like diabetic ketoacidosis, or hyperosmolar hyperglycaemic state at the time of screening
Patients with established cardiovascular disease, e.g.; HF, coronary artery disease
Patients with altered haemoglobin levels, e.g.; in conditions like anaemias and haemoglobimopathies such as thalassemia
Patients on concomitant corticosteroid therapy.