Clinical trial NCT03819790: The Effect of Soliqua on Glucose Variability in Type 2 Patients Among South Asians
Official title: 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Diabetes Mellitus, Type 2
Keywords: Diabetes, type 2
GLP-1 RA
Insulin glargine
Glucose variability
Insulin Titration
South Asians
Lead sponsor: LMC Diabetes & Endocrinology Ltd.
Sponsor class: OTHER
First posted: 2019-01-29
Enrollment: 119
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention 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.
Primary purpose: TREATMENT

Brief summary: 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: 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).

Eligibility criteria: 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

Primary outcomes:
measure: Time in range at week 13
timeFrame: 7 days
measure: Time in range within 12-hours (6 AM -6 PM) at week 13
timeFrame: 7 days
Secondary outcomes:
measure: Daily glucose standard deviation (SD) at week 13
timeFrame: 7 days
measure: Overall SD of CGM glucose at week 13
timeFrame: 7 days
measure: Mean of glucose at week 13
timeFrame: 7 days
measure: Frequency of hypoglycemia at week 13
timeFrame: 7 days
measure: Time in hypoglycemia at week 13
timeFrame: 7 days
measure: Frequency of hyperglycemia at week 13
timeFrame: 7 days
measure: Time in hyperglycemia at week 13
timeFrame: 7 days
measure: Daily glucose standard deviation (SD) within 12 hours (6AM-6PM) at week 13
timeFrame: 7 days
measure: Overall SD of glucose within 12 hours (6AM-6PM) at week 13
timeFrame: 7 days
measure: Mean of glucose within 12 hours (6AM-6PM) at week 13
timeFrame: 7 days
measure: Frequency of hypoglycemia within 12 hours (6AM-6PM) at week 13
timeFrame: 7 days
measure: Time in hypoglycemia within 12 hours (6AM-6PM) at week 13
timeFrame: 7 days
measure: Frequency of hyperglycemia within 12 hours (6AM-6PM) at week 13
timeFrame: 7 days
measure: Time in hyperglycemia within 12 hours (6AM-6PM) at week 13
timeFrame: 7 days
measure: A1C mean at week 13
timeFrame: Week 13
measure: Changes A1C
timeFrame: 15 weeks
measure: Proportion of A1C <7% at week 13
timeFrame: Week 13
measure: Proportion of A1C <8% at week 13
timeFrame: Week 13
measure: Mean basal insulin dose at week 13
timeFrame: Week 13
measure: Change in weight
timeFrame: 15 weeks
measure: Change in waist circumference
timeFrame: 15 weeks
measure: Change in carbohydrate intake
timeFrame: 14 weeks
measure: Proportion of patients who have A1C ≤ 7% with no hypoglycemia and no weight gain from baseline
timeFrame: Week 13
measure: Proportion of patients who have A1C ≤ 7% with no hypoglycemia and weight gain <3% from baseline
timeFrame: Week 13
measure: Proportion of patients who have fasting blood glucose ≤ 5.5 mmol/L without nocturnal hypoglycemia
timeFrame: Week 13
measure: Change in DiabMedSat Score
timeFrame: 14 weeks
measure: Change in HFS Score
timeFrame: 14 weeks
measure: HCP treatment satisfaction score
timeFrame: Week 13
Other outcomes:
Locations:
city: Brampton
country: Canada
facility: LMC Brampton
state: Ontario
city: Etobicoke
country: Canada
facility: LMC Etobicoke
state: Ontario
city: Toronto
country: Canada
facility: LMC Scarborough
state: Ontario
Study officials:
References:
citation: Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998 Sep 12;352(9131):837-53.
citation: Lipska KJ, Yao X, Herrin J, McCoy RG, Ross JS, Steinman MA, Inzucchi SE, Gill TM, Krumholz HM, Shah ND. Trends in Drug Utilization, Glycemic Control, and Rates of Severe Hypoglycemia, 2006-2013. Diabetes Care. 2017 Apr;40(4):468-475. doi: 10.2337/dc16-0985. Epub 2016 Sep 22.
citation: Tobias DK, Pan A, Jackson CL, O'Reilly EJ, Ding EL, Willett WC, Manson JE, Hu FB. Body-mass index and mortality among adults with incident type 2 diabetes. N Engl J Med. 2014 Jan 16;370(3):233-44. doi: 10.1056/NEJMoa1304501.
citation: Scheen AJ, Van Gaal LF. Combating the dual burden: therapeutic targeting of common pathways in obesity and type 2 diabetes. Lancet Diabetes Endocrinol. 2014 Nov;2(11):911-22. doi: 10.1016/S2213-8587(14)70004-X. Epub 2014 Feb 19.
citation: Degn KB, Brock B, Juhl CB, Djurhuus CB, Grubert J, Kim D, Han J, Taylor K, Fineman M, Schmitz O. Effect of intravenous infusion of exenatide (synthetic exendin-4) on glucose-dependent insulin secretion and counterregulation during hypoglycemia. Diabetes. 2004 Sep;53(9):2397-403. doi: 10.2337/diabetes.53.9.2397.
citation: Degn KB, Juhl CB, Sturis J, Jakobsen G, Brock B, Chandramouli V, Rungby J, Landau BR, Schmitz O. One week's treatment with the long-acting glucagon-like peptide 1 derivative liraglutide (NN2211) markedly improves 24-h glycemia and alpha- and beta-cell function and reduces endogenous glucose release in patients with type 2 diabetes. Diabetes. 2004 May;53(5):1187-94. doi: 10.2337/diabetes.53.5.1187.
citation: Flint A, Raben A, Astrup A, Holst JJ. Glucagon-like peptide 1 promotes satiety and suppresses energy intake in humans. J Clin Invest. 1998 Feb 1;101(3):515-20. doi: 10.1172/JCI990.
citation: Leiter LA, Nauck MA. Efficacy and Safety of GLP-1 Receptor Agonists Across the Spectrum of Type 2 Diabetes Mellitus. Exp Clin Endocrinol Diabetes. 2017 Jul;125(7):419-435. doi: 10.1055/s-0043-103969. Epub 2017 Jul 19. German.
citation: Zaccardi F, Htike ZZ, Webb DR, Khunti K, Davies MJ. Benefits and Harms of Once-Weekly Glucagon-like Peptide-1 Receptor Agonist Treatments: A Systematic Review and Network Meta-analysis. Ann Intern Med. 2016 Jan 19;164(2):102-13. doi: 10.7326/M15-1432. Epub 2015 Dec 8.
citation: Rosenstock J, Fonseca VA, Gross JL, Ratner RE, Ahren B, Chow FC, Yang F, Miller D, Johnson SL, Stewart MW, Leiter LA; Harmony 6 Study Group. Advancing basal insulin replacement in type 2 diabetes inadequately controlled with insulin glargine plus oral agents: a comparison of adding albiglutide, a weekly GLP-1 receptor agonist, versus thrice-daily prandial insulin lispro. Diabetes Care. 2014 Aug;37(8):2317-25. doi: 10.2337/dc14-0001. Epub 2014 Jun 4.
citation: Diamant M, Nauck MA, Shaginian R, Malone JK, Cleall S, Reaney M, de Vries D, Hoogwerf BJ, MacConell L, Wolffenbuttel BH; 4B Study Group. Glucagon-like peptide 1 receptor agonist or bolus insulin with optimized basal insulin in type 2 diabetes. Diabetes Care. 2014 Oct;37(10):2763-73. doi: 10.2337/dc14-0876. Epub 2014 Jul 10.
citation: Writing Group for the DCCT/EDIC Research Group; Orchard TJ, Nathan DM, Zinman B, Cleary P, Brillon D, Backlund JY, Lachin JM. Association between 7 years of intensive treatment of type 1 diabetes and long-term mortality. JAMA. 2015 Jan 6;313(1):45-53. doi: 10.1001/jama.2014.16107.
citation: Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008 Oct 9;359(15):1577-89. doi: 10.1056/NEJMoa0806470. Epub 2008 Sep 10.
citation: Lind M, Svensson AM, Kosiborod M, Gudbjornsdottir S, Pivodic A, Wedel H, Dahlqvist S, Clements M, Rosengren A. Glycemic control and excess mortality in type 1 diabetes. N Engl J Med. 2014 Nov 20;371(21):1972-82. doi: 10.1056/NEJMoa1408214.
citation: Esposito K, Giugliano D, Nappo F, Marfella R; Campanian Postprandial Hyperglycemia Study Group. Regression of carotid atherosclerosis by control of postprandial hyperglycemia in type 2 diabetes mellitus. Circulation. 2004 Jul 13;110(2):214-9. doi: 10.1161/01.CIR.0000134501.57864.66. Epub 2004 Jun 14.
citation: Kilpatrick ES, Rigby AS, Atkin SL. A1C variability and the risk of microvascular complications in type 1 diabetes: data from the Diabetes Control and Complications Trial. Diabetes Care. 2008 Nov;31(11):2198-202. doi: 10.2337/dc08-0864. Epub 2008 Jul 23.
citation: Bajaj HS, Venn K, Ye C, Patrick A, Kalra S, Khandwala H, Aslam N, Twum-Barima D, Aronson R. Lowest Glucose Variability and Hypoglycemia Are Observed With the Combination of a GLP-1 Receptor Agonist and Basal Insulin (VARIATION Study). Diabetes Care. 2017 Feb;40(2):194-200. doi: 10.2337/dc16-1582. Epub 2016 Dec 2.
citation: Chiu M, Austin PC, Manuel DG, Tu JV. Comparison of cardiovascular risk profiles among ethnic groups using population health surveys between 1996 and 2007. CMAJ. 2010 May 18;182(8):E301-10. doi: 10.1503/cmaj.091676. Epub 2010 Apr 19.
citation: Chiu M, Maclagan LC, Tu JV, Shah BR. Temporal trends in cardiovascular disease risk factors among white, South Asian, Chinese and black groups in Ontario, Canada, 2001 to 2012: a population-based study. BMJ Open. 2015 Aug 10;5(8):e007232. doi: 10.1136/bmjopen-2014-007232.
citation: Gujral UP, Pradeepa R, Weber MB, Narayan KM, Mohan V. Type 2 diabetes in South Asians: similarities and differences with white Caucasian and other populations. Ann N Y Acad Sci. 2013 Apr;1281(1):51-63. doi: 10.1111/j.1749-6632.2012.06838.x. Epub 2013 Jan 14.
citation: Yale JF, Berard L, Groleau M, Javadi P, Stewart J, Harris SB. TITRATION: A Randomized Study to Assess 2 Treatment Algorithms with New Insulin Glargine 300 units/mL. Can J Diabetes. 2017 Oct;41(5):478-484. doi: 10.1016/j.jcjd.2017.06.007. Epub 2017 Aug 10.
citation: Bajaj HS, Chu L, Bansal N, Brown RE, Dhillon G, Gupta R, Bhela JS, Padda JK, Khandwala H, Venn K, Aronson R. Randomized Comparison of Initiating the Fixed-Ratio Combination of iGlarLixi or Biosimilar Insulin Glargine Together With Gliclazide in Participants of South Asian Origin With Type 2 Diabetes: VARIATION 2 SA Trial. Can J Diabetes. 2022 Jul;46(5):495-502. doi: 10.1016/j.jcjd.2022.02.003. Epub 2022 Feb 11.