VERIFY:A Study to Compare Combination Regimen With Vildagliptin & Metformin Versus Metformin in Treatment-naïve Patients With Type 2 Diabetes Mellitus

Study Overview
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Brief Summary
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The purpose of this study was to determine whether the initiation of a vildagliptin plus metformin combination regimen would result in more durable glycemic control than metformin monotherapy in treatment-naïve patients with type-2 diabetes mellitus (T2DM).

Detailed Description
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This was a multi-center, double-blind, placebo-controlled, 2-arm, parallel group study with a run-in period and up to 5 years treatment period. Following a screening visit (Visit 1) and a screening period of up to 2 weeks, treatment-naïve patients, meeting all eligibility criteria entered the run-in period at Visit 2. Run-in period: At Visit 2, in all eligible patients, metformin treatment was initiated and/or up-titrated. At the end of the 3-week run-in period, patients who were able to tolerate a total dose of at least 1000 mg and up to 2000 mg daily proceeded to randomization and started in Period 1. Period 1 (vildagliptin/metformin combination versus metformin): At Visit 3, patients were randomized 1:1 to one of the following study regimens: Metformin up to 1000 mg bid plus vildagliptin 50mg bid or Metformin up to 1000 mg bid plus matching placebo bid The duration of Period 1 could differ between patients depending on the time when the second of two HbA1c measurements taken at two consecutive visits after randomisation confirmed HbA1c ≥ 7.0%. • Period 2 (vildagliptin/metformin combination versus vildagliptin add-on to metformin): In the case of two consecutive HbA1c measurements ≥7.0% from two consecutive study visits during Period 1, patients who were randomised to the placebo arm in Period 1 received vildagliptin 50 mg bid. Patients who were randomised to the active vildagliptin 50 mg bid arm in Period 1 continued to receive vildagliptin 50 mg bid. All patients continued to take their metformin dose unchanged. Period 2 remained masked to the patient and both patients and investigators remained masked to the treatment allocation in Period 1. If, during Period 2, therapy intensification was required in accordance with the local guidelines, the patient entered Period 3. The duration of Period 2 could differ between patients. End of Period 2 was considered when insulin treatment was initiated, or alternatively when the patient was discontinued because insulin treatment was not initiated in Period 3. • Period 3 (insulin initiation): In Period 3, patients were to be initiated on open-label insulin. The study drug regimen continued unchanged and remained masked to the patient in Period 3 and both patients and investigators remained masked to the treatment allocation in Period 1.

Official Title
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A 5-year Study to Compare the Durability of Glycemic Control of a Combination Regimen With Vildagliptin & Metformin Versus Standard-of-care Monotherapy With Metformin, Initiated in Treatment-naïve Patients With Type 2 Diabetes Mellitus

Conditions
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Type 2 Diabetes Mellitus

Intervention / Treatment
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* Drug: Placebo of vildagliptin
* Drug: vildagliptin
* Drug: Metformin


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Type 2 Diabetes Mellitus (T2DM) diagnosed ≤ 24 months ago glycosylated hemoglobin (HbA1c) ≥6.5% and ≤7.5% at Visit 1 Treatment-naïve. Body mass index (BMI) ≥22 and ≤40 kg/m2 at Visit 1 Key Exclusion Criteria: Pregnant or nursing (lactating) women Fasting plasma glucose (FPG) ≥ 270 mg/dL (≥ 15.0 mmol/L) Previous or current participation in any vildagliptin clinical study. History of hypersensitivity to dipeptidyl peptidase-4 (DPP-4) inhibitors. Concurrent medical condition that may interfere with the interpretation of efficacy and safety data during the study. Donation of blood or significant blood loss equaling to at least one unit of blood within the past 2 weeks of start of study or a blood transfusion within the past 12 weeks or planned regular transfusions during the study period.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Vilda 50mg bid + metformin<br>Metformin + vildagliptin | Drug: vildagliptin<br>* One tablet (50 mg oral) of vildagliptin in the morning and one tablet in the evening with or without food.<br>* Other names: LAF237;Drug: Metformin<br>* Twice daily (bid) regimen during or after meals at the same time as vildagliptin.<br>|
| Experimental: Placebo + metformin<br>Metformin + Placebo of vildagliptin | Drug: Placebo of vildagliptin<br> <br> * Other names: Placebo;Drug: Metformin<br>* Twice daily (bid) regimen during or after meals at the same time as vildagliptin.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Initial Treatment Failure | Treatment failure was defined as two consecutive scheduled visits with HbA1c >= 7.0% (starting from 13 weeks after randomization) and the time to treatment failure was the number of days from randomization to the second of the consecutive scheduled visits. Participants who discontinued the study for any reason during Period 1 were censored at the date of discontinuation. Participants who remained under the threshold (or whose measurement above the threshold was not confirmed at next scheduled visit) were censored at the date of last study visit. | Visit 4 (Week 13) up to End of Study (Study Drug Discontinuation or Premature Subject Discontinuation) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of Loss in Glycemic Control During Period 1 | The rate of loss in glycemic control was estimated using the slope of HbA1c over time (years). HbA1c data collected from Week 26 up to and including the end of Period 1 visit was included in the analysis. Baseline HbA1c was the sample obtained on day 1, or the sample obtained at an earlier visit (scheduled or unscheduled) which was closest to Day 1, if the Day 1 measurement was missing. End of Period 1 was defined as the final post-baseline assessment obtained at any visit within Period 1 (scheduled or unscheduled), up to the last scheduled visit. | Visit 5 (Week 26) to End of Period 1 | 
| Rate of Loss in Glycemic Control in HbA1c Over Time During Period 2 | The rate of loss in glycemic control was estimated using the slope of HbA1c over time (years). HbA1c data collected from 26 weeks after the start of Period 2 to the end of Period 2 were included in the analysis, for participants who started insulin therapy in Period 3 or discontinued during Period 2 due to being unable or unwilling to initiate insulin therapy in period 3. Participants who completed the study in Period 1 or Period 2 were not be included in the analysis. | From 26 weeks after start of Period 2 to end of Period 2 | 
| Rate of Loss in Glycemic Control in Fasting Plasma Glucose (FPG) During Period 1 | Rate of loss in glycemic control was estimated using the slope of FPG over time (years). FPG (fasting plasma glucose) data from Week 26 to the end of Period 1 was included in the analysis. Baseline FPG was the sample obtained on day 1, or the sample obtained at an earlier visit (scheduled or unscheduled) which was closest to Day 1, if the Day 1 measurement is missing. Participants who completed the study in Period 1 or Period 2 were not be included in the analysis. | Visit 5 (Week 26) to End of Period 1 | 
| Rate of Loss in Glycemic Control in Fasting Plasma Glucose (FPG) Over Time During Period 2 | Rate of loss in glycemic control was estimated using the slope of FPG over time (years). FPG (fasting plasma glucose) data from 26 weeks after the start of Period 2 to then end of Period 2 was included in the analysis. Only participants who started insulin therapy in Period 3 or discontinued during Period 2 due to being unable or unwilling to initiate insulin therapy in period 3 were included. Participants who completed the study in Period 1 or Period 2 were not be included in the analysis. | From 26 weeks after start of Period 2 to end of Period 2 | 
| Rate of Loss of Beta Cell Function From Baseline to End of Study | The rate of change of beta cell function was assessed using the slope of AUC of ISR/G over time (years) where AUC of ISR/G is defined as (Area under curve of Insulin secretion rate (derived using c-peptide))/(Area under curve of Glucose), using meal-test data from 0 to 120 minutes. Baseline AUC of ISR/G was derived based on samples obtained on day 1, or samples obtained at an earlier visit (scheduled or unscheduled) which was closest to Day 1, if the Day 1 measurements were missing. Three analyses were included, using data from Week 13 to the end of Period 1, end of Period 2 and end of study, respectively. | Visit 4 (Week 13), End of Period 1, End of Period 2, End of Study (Study Drug Discontinuation or Premature Subject Discontinuation) | 
| Rate of Change in Insulin Sensitivity From Baseline to End of Study | The rate of change of insulin sensitivity is assessed using the slope of OGIS over time (years) where Oral glucose insulin sensitivity (OGIS) was calculated as a function of glucose and insulin, using meal-test data from 0 to 120 minutes. Baseline OGIS is derived based on samples obtained on day 1, or samples obtained at an earlier visit (scheduled or unscheduled) which was closest to Day 1, if the Day 1 measurements are missing. Three analyses were included, using data from Week 13 to the end of Period 1, end of Period 2 and end of study, respectively. | Visit 4 (Week 13), End of Period 1, End of Period 2, End of Study (Study Drug Discontinuation or Premature Subject Discontinuation) | 
| Percentage of Participants With Adverse Events, Serious Adverse Events and Death | Analysis of absolute and relative frequencies for treatment emergent Adverse Event (AE), Serious Adverse Event (SAE) and Deaths by primary System Organ Class (SOC) in each treatment arm to demonstrate that LAF237 is safe for the treatment of naïve patients with type 2 diabetes mellitus through the monitoring of relevant clinical and laboratory safety parameters. | From first dose of study treatment until End of Study (Study Drug Discontinuation or Premature Subject Discontinuation) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Type 2 Diabetes Mellitus, Vildagliptin, Elderly Patients