The Effect of Soliqua on Glucose Variability in Type 2 Patients Among South Asians

Study Overview
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Brief Summary
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The overall objective of this study is to compare the effects of Soliqua, a titratable combination of insulin and GLP-1 receptor agonist in a single pen versus Glargine U100 insulin (Basaglar or Lantus) and gliclazide MR, both added to metformin, on measures of glucose variability using masked CGM data among people of South Asian origin living in Canada with type 2 diabetes (T2DM).

Detailed Description
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The VARIATION 2 SA study is a prospective, open-label, randomized controlled, multi-centre trial to compare the efficacy of two insulin initiation approaches (Soliqua vs Glargine U100 insulin (Basaglar or Lantus) + gliclazide MR) added to maximum tolerated metformin on glucose variability (using masked CGM) in South Asians with T2DM who will initiate insulin therapy with HbA1c of 7.1-11% (inclusive). After giving informed consent and being assessed by eligibility, the patient will stop other oral hypoglycemic agents except metformin (SGLT2 inhibitor may be continued if the patient has cardiovascular diseases history) and enter a 1-week run-in phase with Basaglar or Lantus insulin. During this week (considered as baseline), the patient will: 1) be administered Basaglar or Lantus insulin at an initial dose of 10 units in the morning and increase 1 U/day if fasting glucose >5.5 mmol/L; 2) complete 2 questionnaires to assess the patient-reported outcomes (PROs); 3) wear a masked continuous glucose monitor (CGM) to assess glucose variability; 4) record carbohydrate intake for at least 3 consecutive days. If a patient demonstrates good adherence to Basaglar or Lantus insulin therapy, proper CGM wearing and proper record of carbohydrate intake, and is willing to adhere to insulin treatment will be randomly assigned (1:1) to receive either Soliqua or Glargine U100 insulin (Basaglar or Lantus) + gliclazide MR treatment. The patients will initiate insulin Soliqua or Basaglar/Lantus at their end-of run-in phase insulin dose (minimum dose of 15 units in both arms) every morning (before first meal of day) and titrate by 1 U/day until fasting glucose reaches 4-5.5 mmol/L. In the next 12 weeks, the patients will be optimized their insulin doses via clinic visits or phone calls. They will also be instructed to record their daily fasting glucose, insulin dose, hypoglycemic episodes and any adverse events in a logbook. The primary outcome is to compare the difference of average percentage of Time in Range (4.0-10.0 mmol/L) within 24 hours over the CGM period between two treatments at week 13 after randomization. The co-primary is to compare the difference average percentage of Time in Range (4.0-10.0 mmol/L) within 12 hours (6 AM- 6 PM) over the CGM period between two treatments at week 13 after randomization. The secondary outcomes include the differences on other measurements of glucose variability and patient-reported outcomes (PROs).

Official Title
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Variability of Glucose Assessed in a Randomized Trial Comparing the Initiation of A Treatment Approach With Biosimilar Basal Insulin Analog Or a Titratable iGlarLixi combinatioN in Type 2 Diabetes Among South Asian Subjects (VARIATION 2 SA Trial)

Conditions
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Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: Basal insulin glargine and lixisenatide
* Drug: Basal insulin Basaglar/Lantus + gliclazide MR
* Drug: Metformin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female adults with clinical diagnosis of T2DM diagnosed at least 1 year before screening and in stable health as assessed by investigator Age between 18 and 80 years (inclusive) Body mass index (BMI) between 20-40 kg/m2 (inclusive) South Asian origin including Afghanistani, Bangladeshi, Indian, Nepali, Pakistani and Sri Lankan. This includes those patients who identify themselves as South Asian origin because their ancestors moved from South Asian to another country (e.g. Caribbean islands, Fiji, etc.) A1C in range of 7.1-11% (inclusive) Fasting glucose on self-monitoring of blood glucose (SMBG) or laboratory testing < 15 mmol/L within the last 30 days Insulin naïve, uncontrolled on oral hypoglycemic medications Kidney function assessment with eGFR >30 mL/min/1.73 m2 Written informed consent obtained Exclusion Criteria: History of insulin use (except emergency short-term use defined as less than 12 weeks for acute illness, hospitalization, pregnancy or with steroid use) Use of GLP-1 receptor agonist in the past 3 months Previous discontinuation of a GLP-1 receptor agonist due to safety, tolerability or lack of efficacy Pregnant or anticipating pregnancy Current use of steroid Currently on any supervised, intensive, weight-loss dietary or exercise program History of gastroparesis with moderate or higher severity History of pancreatitis Amylase and /or lipase more than three times the upper limit of normal or calcitonin ≥ 20 pg/mL (5.9 pmol/L) Personal or family history of medullary thyroid cancer or multiple endocrine neoplasia (MEN) syndrome Allergic reaction to insulin secretagogues History of weight loss surgery (bariatric bypass surgery or gastric banding) Inability to check SMBG or wear CGM History of severe liver disease or alcohol abuse Severe hypoglycemic reaction (defined as third-party or ambulance assistance or emergency department visit) within the last 3 months before screening visit Night-shift workers Patients who are recommended to achieve relaxed targets of A1C up to 8.5% by Diabetes Canada 2018 clinical practice guidelines Current enrollment in another intervention study Patients who miss ≥1 injections of Basaglar/Lantus or discontinue the CGM device or can not record carbohydrate intake correctly during the run-in phase

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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
Interventional Model Description: Patients will be randomized into either of two arms by an interactive system in a 1:1 ratio. Randomization will be stratified based on the use of sodium-glucose co-transporter-2 (SGLT2) inhibitors.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Insulin Glargine + GLP-1 RA<br>Insulin Soliqua (a titratable combination of insulin Glargine + GLP-1 RA) will be administered at the subject's end-of run-in phase insulin dose (minimum dose of 15 units in both arms) every morning (before first meal of day) and titrate by one unit per day until fasting glucose level of 4-5.5 mmol/L is obtained, with or without metformin. | Drug: Basal insulin glargine and lixisenatide<br>* Soliqua (insulin glargine and lixisenatide): a titratable combination of long-acting basal insulin glargine and lixisenatide (Glucagon-like peptide-1 receptor agonist)<br>Drug: Metformin<br>* Patients can be administered with most tolerant dose of metformin<br>|
| Active Comparator: Basaglar/Lantus + gliclazide MR<br>Basal insulin Basaglar/Lantus will be administered at the subject's end-of run-in phase insulin dose (minimum dose of 15 units in both arms) every morning (before first meal of day) and titrate by one unit per day until fasting glucose level of 4-5.5 mmol/L is obtained, with gliclazide MR 60 mg OD, with or without metformin. | Drug: Basal insulin Basaglar/Lantus + gliclazide MR<br>* basal long-acting insulin Basaglar/Lantus with gliclazide MR 60 mg OD<br>Drug: Metformin<br>* Patients can be administered with most tolerant dose of metformin<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time in range at week 13 | Time with CGM glucose between 4.0 - 10.0 mmol/L within 24 hours over the 7-day CGM period at week 13 after randomization | 7 days | 
| Time in range within 12-hours (6 AM -6 PM) at week 13 | Time with CGM glucose between 4.0 - 10.0 mmol/L within 12-hours (6 AM -6 PM) over the 7-day CGM period at week 13 after randomization | 7 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Daily glucose standard deviation (SD) at week 13 | Daily SD of CGM glucose over the 7-day CGM period at week 13 after randomization | 7 days | 
| Overall SD of CGM glucose at week 13 | Overall SD of CGM glucose over the 7-day CGM period at week 13 after randomization | 7 days | 
| Mean of glucose at week 13 | Mean of CGM glucose over the 7-day CGM period at week 13 after randomization | 7 days | 
| Frequency of hypoglycemia at week 13 | Number of hypoglycemic event which is defined as CGM glucose <4.0 mmol/L for at least 15 mins (3 consecutive CGM readings) over the 7-day CGM period at week 13 after randomization | 7 days | 
| Time in hypoglycemia at week 13 | Time with CGM glucose < 4.0 mmol/L over the 7-day CGM period at week 13 after randomization | 7 days | 
| Frequency of hyperglycemia at week 13 | Number of hyperglycemic event which is defined as CGM glucose >10.0 mmol/L at least 15 mins (3 consecutive CGM readings) over the 7-day CGM period at week 13 after randomization | 7 days | 
| Time in hyperglycemia at week 13 | Time with CGM glucose >10.0 mmol/L over the 7-day CGM period at week 13 after randomization | 7 days | 
| Daily glucose standard deviation (SD) within 12 hours (6AM-6PM) at week 13 | Daily SD of CGM glucose within 12 hours (6AM-6PM) over the 7-day CGM period at week 13 after randomization | 7 days | 
| Overall SD of glucose within 12 hours (6AM-6PM) at week 13 | Overall SD of CGM glucose within 12 hours (6AM-6PM) over the 7-day CGM period at week 13 after randomization | 7 days | 
| Mean of glucose within 12 hours (6AM-6PM) at week 13 | Mean of CGM glucose within 12 hours (6AM-6PM) over the 7-day CGM period at week 13 after randomization | 7 days | 
| Frequency of hypoglycemia within 12 hours (6AM-6PM) at week 13 | Number of hypoglycemic event which is defined as CGM glucose <4.0 mmol/L for at least 15 mins (3 consecutive CGM readings) within 12 hours (6AM-6PM) over the 7-day CGM period at week 13 after randomization | 7 days | 
| Time in hypoglycemia within 12 hours (6AM-6PM) at week 13 | Time with CGM glucose <4.0 mmol/L within 12 hours (6AM-6PM) over the 7-day CGM period at week 13 after randomization | 7 days | 
| Frequency of hyperglycemia within 12 hours (6AM-6PM) at week 13 | Number of hypoglycemic event which is defined as CGM glucose >10.0 mmol/L for at least 15 mins (3 consecutive CGM readings) within 12 hours (6AM-6PM) over the 7-day CGM period at week 13 after randomization | 7 days | 
| Time in hyperglycemia within 12 hours (6AM-6PM) at week 13 | Time with CGM glucose >10.0 mmol/L within 12 hours (6AM-6PM) over the 7-day CGM period at week 13 after randomization | 7 days | 
| A1C mean at week 13 | Average of A1C at week 13 after randomization | Week 13 | 
| Changes A1C | A1C value at Visit10 at 13 weeks after randomization minus A1C value at Visit 1 at week -2 (2 weeks before randomization) | 15 weeks | 
| Proportion of A1C <7% at week 13 | the number of patients who have A1C <7% divided by the total number of patients who have A1C measurement at week 13 after randomization | Week 13 | 
| Proportion of A1C <8% at week 13 | the number of patients who have A1C <8% divided by the total number of patients who have A1C measurement at week 13 after randomization | Week 13 | 
| Mean basal insulin dose at week 13 | Average of basal insulin dose from patients' diary at week 13 after randomization | Week 13 | 
| Change in weight | Weight difference between week 13 after randomization and baseline at week -2 (2 weeks before randomization) = weight at Visit 10 at week 13 - weight at Visit 1 at week -2. | 15 weeks | 
| Change in waist circumference | Waist circumference change between week 13 after randomization and baseline at week -2 (2 week before randomization)= waist circumference at Visit 10 at week 13- waist circumference at Visit 1 at week -2 | 15 weeks | 
| Change in carbohydrate intake | Carbohydrate intake change between week 13 after randomization and baseline at week -1 = carbohydrate intake at Visit 10 at week 13 - carbohydrate intake at Visit 2 at week -1 (1 week before randomization) | 14 weeks | 
| Proportion of patients who have A1C ≤ 7% with no hypoglycemia and no weight gain from baseline | the number of patients who have A1C ≤ 7% with no hypoglycemia and no weight gain from baseline divided by the total number of patients at Week 13 after randomization | Week 13 | 
| Proportion of patients who have A1C ≤ 7% with no hypoglycemia and weight gain <3% from baseline | the number of patients who have A1C ≤ 7% with no hypoglycemia and weight gain <3% from baseline divided by the total number of patients at Week 13 after randomization | Week 13 | 
| Proportion of patients who have fasting blood glucose ≤ 5.5 mmol/L without nocturnal hypoglycemia | the number of patients who have fasting blood glucose ≤ 5.5 mmol/L without nocturnal hypoglycemia divided by the total number of patients at Week 13 after randomization | Week 13 | 
| Change in DiabMedSat Score | DiabMedSat Score will be generated using Diabetes Medication Satisfaction (DiabMedSat) questionnaire. It measures the levels of the subjects' satisfaction with their diabetes medication(s). The range of the score is 0 to 100. The higher the score, the greater the satisfaction. The changes in the score will measure the score difference between Visit 10 at week 13 after randomization and Visit 2 at week -1 (1 week before randomization) | 14 weeks | 
| Change in HFS Score | HFS Score will be measured by the Hypoglycemia Fear Survey which assesses the subject's behaviors to avoid hypoglycemia and to measure the subjects' worries about hypoglycemia and its consequences in the past 3 months. The range of the score will be 0 to 132. The higher the score, the greater the fear. The changes will be the score difference between Visit 10 at week 13 after randomization and Visit 2 at week -1 (1 week before randomization). | 14 weeks | 
| HCP treatment satisfaction score | HCP treatment satisfaction score will be generated from Healthcare Provider treatment satisfaction questionnaire. It measures the levels of satisfaction of physicians in this study when prescribing this medication at Visit 10 at week 13 after randomization. The range is 0 to 15. The higher the score, the greater the satisfaction. | Week 13 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Diabetes, type 2, GLP-1 RA, Insulin glargine, Glucose variability, Insulin Titration, South Asians