LIRA-ADD2SGLT2i - Liraglutide Versus Placebo as add-on to SGLT2 Inhibitors.

LIRA-ADD2SGLT2i - Liraglutide Versus Placebo as add-on to SGLT2 Inhibitors

The trial is conducted in Asia, Europe, North America and South America. The aim of the study is to compare the effect of liraglutide 1.8 mg/day versus placebo as add-on to an SGLT2 inhibitor with or without metformin on glycaemic control in subjects with type 2 diabetes mellitus.

Study Overview

• Status: Completed
• Conditions: Diabetes Mellitus, Type 2; Diabetes
• Intervention / Treatment: Drug: liraglutide; Drug: placebo

• Study Type: Interventional
• Enrollment (Actual): 303
• Phase: Phase 3

Contacts and Locations

Study Locations

• Brazil
  • Parana
    • Curitiba, Parana, Brazil, 80030-110
      • Novo Nordisk Investigational Site
  • Rio Grande Do Sul
    • Porto Alegre, Rio Grande Do Sul, Brazil, 90035-170
      • Novo Nordisk Investigational Site
  • Sao Paulo
    • São Paulo, Sao Paulo, Brazil, 01228-000
      • Novo Nordisk Investigational Site
• India
  • New Delhi, India, 110001
    • Novo Nordisk Investigational Site
  • Gujarat
    • Ahmedabad, Gujarat, India, 380008
      • Novo Nordisk Investigational Site
  • Karnataka
    • Bangalore, Karnataka, India, 560 017
      • Novo Nordisk Investigational Site
  • Madhya Pradesh
    • Indore, Madhya Pradesh, India, 452010
      • Novo Nordisk Investigational Site
  • Maharashtra
    • Pune, Maharashtra, India, 411004
      • Novo Nordisk Investigational Site
  • Rajasthan
    • Jaipur, Rajasthan, India, 302006
      • Novo Nordisk Investigational Site
  • Tamil Nadu
    • Coimbatore, Tamil Nadu, India, 641009
      • Novo Nordisk Investigational Site
  • Telengana
    • Hyderabad, Telengana, India, 500003
      • Novo Nordisk Investigational Site
  • West Bengal
    • Kolkata, West Bengal, India, 700080
      • Novo Nordisk Investigational Site
• Israel
  • Haifa, Israel, 35152
    • Novo Nordisk Investigational Site
  • Kfar Saba, Israel, 44281
    • Novo Nordisk Investigational Site
  • Tel Hashomer, Israel, 52621
    • Novo Nordisk Investigational Site
  • Tel-Aviv, Israel, 62038
    • Novo Nordisk Investigational Site
• Puerto Rico
  • Ponce, Puerto Rico, 00716
    • Novo Nordisk Investigational Site
• Russian Federation
  • Saint-Petersburg, Russian Federation, 190068
    • Novo Nordisk Investigational Site
  • Saint-Petersburg, Russian Federation, 199226
    • Novo Nordisk Investigational Site
  • Saint-Petersburg, Russian Federation, 190013
    • Novo Nordisk Investigational Site
  • Saint-Petersburg, Russian Federation, 195197
    • Novo Nordisk Investigational Site
  • St. Petersburg, Russian Federation, 194354
    • Novo Nordisk Investigational Site
• United Arab Emirates
  • Al Ain, United Arab Emirates, 1006
    • Novo Nordisk Investigational Site
  • Dubai, United Arab Emirates, 7272
    • Novo Nordisk Investigational Site
  • Umm Al Quwain, United Arab Emirates, 24
    • Novo Nordisk Investigational Site
  • Umm Al Quwain, United Arab Emirates, 499
    • Novo Nordisk Investigational Site
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • Novo Nordisk Investigational Site
    • Montgomery, Alabama, United States, 36109
      • Novo Nordisk Investigational Site
  • Arizona
    • Tucson, Arizona, United States, 85741
      • Novo Nordisk Investigational Site
  • California
    • Lancaster, California, United States, 93534
      • Novo Nordisk Investigational Site
    • Northridge, California, United States, 91325
      • Novo Nordisk Investigational Site
    • Sacramento, California, United States, 95821
      • Novo Nordisk Investigational Site
    • San Diego, California, United States, 92111
      • Novo Nordisk Investigational Site
    • San Ramon, California, United States, 94583
      • Novo Nordisk Investigational Site
    • Vista, California, United States, 92083
      • Novo Nordisk Investigational Site
  • Florida
    • Gainesville, Florida, United States, 32653
      • Novo Nordisk Investigational Site
    • Hollywood, Florida, United States, 33024
      • Novo Nordisk Investigational Site
    • Jacksonville, Florida, United States, 32216
      • Novo Nordisk Investigational Site
    • Jacksonville, Florida, United States, 32258
      • Novo Nordisk Investigational Site
    • Jacksonville, Florida, United States, 32256
      • Novo Nordisk Investigational Site
    • Maitland, Florida, United States, 32751
      • Novo Nordisk Investigational Site
    • Miami, Florida, United States, 33165
      • Novo Nordisk Investigational Site
    • Miami, Florida, United States, 33176
      • Novo Nordisk Investigational Site
    • Miami Lakes, Florida, United States, 33016
      • Novo Nordisk Investigational Site
    • Tampa, Florida, United States, 33606
      • Novo Nordisk Investigational Site
  • Georgia
    • Lawrenceville, Georgia, United States, 30046
      • Novo Nordisk Investigational Site
    • Roswell, Georgia, United States, 30076
      • Novo Nordisk Investigational Site
    • Statesboro, Georgia, United States, 30461
      • Novo Nordisk Investigational Site
  • Idaho
    • Blackfoot, Idaho, United States, 83221
      • Novo Nordisk Investigational Site
  • Indiana
    • Evansville, Indiana, United States, 47714
      • Novo Nordisk Investigational Site
  • Kansas
    • Topeka, Kansas, United States, 66606
      • Novo Nordisk Investigational Site
  • Kentucky
    • Lexington, Kentucky, United States, 40503
      • Novo Nordisk Investigational Site
  • Louisiana
    • New Orleans, Louisiana, United States, 70115
      • Novo Nordisk Investigational Site
  • Michigan
    • Kalamazoo, Michigan, United States, 49009
      • Novo Nordisk Investigational Site
    • Rochester, Michigan, United States, 48307
      • Novo Nordisk Investigational Site
  • Montana
    • Billings, Montana, United States, 59101
      • Novo Nordisk Investigational Site
  • Nevada
    • Henderson, Nevada, United States, 89052-2649
      • Novo Nordisk Investigational Site
  • New York
    • Albany, New York, United States, 12203
      • Novo Nordisk Investigational Site
    • West Seneca, New York, United States, 14224
      • Novo Nordisk Investigational Site
  • North Carolina
    • Charlotte, North Carolina, United States, 28277
      • Novo Nordisk Investigational Site
    • Charlotte, North Carolina, United States, 28210
      • Novo Nordisk Investigational Site
    • Charlotte, North Carolina, United States, 28226
      • Novo Nordisk Investigational Site
    • Kinston, North Carolina, United States, 28501
      • Novo Nordisk Investigational Site
    • Wilmington, North Carolina, United States, 28401
      • Novo Nordisk Investigational Site
  • Ohio
    • Cincinnati, Ohio, United States, 45245
      • Novo Nordisk Investigational Site
    • Columbus, Ohio, United States, 43212
      • Novo Nordisk Investigational Site
  • Pennsylvania
    • McMurray, Pennsylvania, United States, 15317
      • Novo Nordisk Investigational Site
    • Pittsburgh, Pennsylvania, United States, 15243
      • Novo Nordisk Investigational Site
  • South Carolina
    • Moncks Corner, South Carolina, United States, 29461
      • Novo Nordisk Investigational Site
    • Mount Pleasant, South Carolina, United States, 29464
      • Novo Nordisk Investigational Site
    • Myrtle Beach, South Carolina, United States, 29572
      • Novo Nordisk Investigational Site
    • Spartanburg, South Carolina, United States, 29303
      • Novo Nordisk Investigational Site
  • Tennessee
    • Memphis, Tennessee, United States, 38119
      • Novo Nordisk Investigational Site
    • Nashville, Tennessee, United States, 37203
      • Novo Nordisk Investigational Site
  • Texas
    • Dallas, Texas, United States, 75231
      • Novo Nordisk Investigational Site
    • Edinburg, Texas, United States, 78539
      • Novo Nordisk Investigational Site
    • Houston, Texas, United States, 77024
      • Novo Nordisk Investigational Site
    • Houston, Texas, United States, 77030
      • Novo Nordisk Investigational Site
    • Humble, Texas, United States, 77338
      • Novo Nordisk Investigational Site
    • Round Rock, Texas, United States, 78681
      • Novo Nordisk Investigational Site
    • Schertz, Texas, United States, 78154
      • Novo Nordisk Investigational Site
  • Washington
    • Spokane, Washington, United States, 99201
      • Novo Nordisk Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Informed consent obtained before any trial-related activities. Trial-related activities are any procedures that are carried out as part of the trial, including activities to determine suitability for the trial.
• Male or female, age 18 years or older at the time of signing informed consent.
• Diagnosed with type 2 diabetes mellitus.
• HbA1c of 7.0-9.5% (53-80 mmol/mol) (both inclusive).
• Stable dose of an SGLT-2 inhibitor as monotherapy or in combination (including fixed-dose drug combination) with a stable dose of metformin (1500 mg or more, or maximum tolerated dose) for at least 90 days prior to the day of screening. All medications in compliance with current local label.
• Body mass index of 20 kg/m^2 or above.

Exclusion Criteria:

• Female who is pregnant, breast-feeding or intends to become pregnant or is of child-bearing potential and not using an adequate contraceptive method (adequate contraceptive measure as required by local regulation or practice).
• History of diabetic ketoacidosis while being treated with SGLT2 inhibitors.
• Renal impairment measured as estimated Glomerular Filtration Rate (eGFR) value of less than 60 mL/min/1.73m^2 as defined by Kidney Disease Improving Global Outcomes (KDIGO) classification using isotope dilution mass spectrometry (IDMS) for serum creatinine measured at screening.
• Treatment with any medication for the indication of diabetes or obesity other than stated in the inclusion criteria within the past 90 days prior to the day of screening. However, short term insulin treatment for a maximum of 14 days during the 90 days prior to screening is allowed.
• Family or personal history of multiple endocrine neoplasia type 2 or medullary thyroid carcinoma. Family is defined as a first degree relative.
• History or presence of pancreatitis (acute or chronic).
• Impaired liver function, defined as ALT 2.5 or more times upper normal limit at screening.
• Subjects presently classified as being in New York Heart Association (NYHA) Class IV.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: liraglutide + SGLT2i ± metformin	Drug: liraglutide; Liraglutide given s.c. once daily, gradually titrated to 1.8 mg/day as an add-on to the subject's stable pre-trial SGLT2 inhibitor ± metformin for 26 weeks
PLACEBO_COMPARATOR: liraglutide placebo + SGLT2i ± metformin	Drug: placebo; Liraglutide placebo given s.c. once daily, gradually titrated to 1.8 mg/day as an add-on to the subject's stable pre-trial SGLT2 inhibitor ± metformin for 26 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in HbA1c	Change from baseline (week 0) to week 26 in glycosylated haemoglobin was evaluated for 2 different observation period 'in-trial' observation period and 'on-treatment without rescue medication" observation period. The 'in-trial' observation period represents the time-period where subjects were considered to be in the trial, regardless of whether or not the subjects had initiated rescue medication or prematurely discontinued trial product. The 'on-treatment' observation period is the part of the in-trial observation period during which subjects were treated with the trial product, that is the time from the first dose to the last dose of trial product. The 'on-treatment without rescue medication' observation period is a part of 'on-treatment' observation period during which subjects were considered treated with trial product and had not initiated any rescue medications.	Week 0, Week 26

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Body Weight	Change from baseline (week 0) to week 26 in body weight was evaluated for 2 different observation period 'in-trial' observation period and 'on-treatment without rescue medication" observation period. The 'in-trial' observation period represents the time-period where subjects were considered to be in the trial, regardless of whether or not the subjects had initiated rescue medication or prematurely discontinued trial product. The 'on-treatment' observation period is the part of the in-trial observation period during which subjects were treated with the trial product, that is the time from the first dose to the last dose of trial product. The 'on-treatment without rescue medication' observation period is a part of 'on-treatment' observation period during which subjects were considered treated with trial product and had not initiated any rescue medications.	Week 0, Week 26
Change in Fasting Plasma Glucose	Change from baseline (week 0) to week 26 in fasting plasma glucose ('in-trial' observation period)	Week 0, Week 26
Subjects Who Achieve HbA1c Below 7.0% (53 mmol/Mol), American Diabetes Association Target	Percentage of subjects who achieve HbA1c below 7.0% (53 mmol/mol), American Diabetes Association target, after 26 weeks ('in-trial' observation period)	Week 26
Subjects Who Achieve HbA1c Below or Equal to 6.5% (48 mmol/Mol), American Association of Clinical Endocrinologists Target	Percentage of subjects who achieve HbA1c below or equal to 6.5% (48 mmol/mol), American Association of Clinical Endocrinologists target, after 26 weeks ('in-trial' observation period)	Week 26
Subjects Who Achieve HbA1c Below 7.0% (53 mmol/Mol) Without Severe or Blood Glucose Confirmed Symptomatic Hypoglycaemia Episodes and no Weight Gain.	Percentage of subjects who achieve HbA1c below 7.0% (53 mmol/mol) without severe or blood glucose confirmed symptomatic hypoglycaemia episodes and no weight gain, after 26 weeks ('in-trial' observation period)	Week 26
Subjects Who Achieve HbA1c Reduction Above or Equal to 1% (11mmol/Mol) and Weight Loss Above or Equal to 3%.	Percentage of subjects who achieve HbA1c reduction above or equal to 1% (11mmol/mol) and weight loss above or equal to 3%, after 26 weeks ('in-trial' observation period)	Week 26
Change in Self-measured Plasma Glucose 7-point Profile - Mean 7-point Profile	Change in self-measured plasma glucose 7-point profile - mean 7-point profile after 26 weeks. Subjects were instructed to measure their plasma glucose at following 7 timepoints: before breakfast, 90 minutes after start of breakfast, before lunch, 90 minutes after start of lunch, before dinner, 90 minutes after start of dinner, at bedtime. Mean of the 7-point profile was calculated ('in-trial' observation period).	Week 0, Week 26
Change in Self-measured Plasma Glucose 7-point Profile - Mean Post Prandial Increments (Over All Meals)	Subjects were instructed to measure their plasma glucose at following 7 timepoints: before breakfast, 90 minutes after start of breakfast, before lunch, 90 minutes after start of lunch, before dinner, 90 minutes after start of dinner, at bedtime. The mean increment over all meals was derived as the mean of all available meal increments ('in-trial' observation period)	Week 0, Week 26
Change in Body Mass Index (BMI)	Observed mean change from baseline (week 0) to week 26 in body mass index (BMI). BMI was calculated based on body weight and height ('in-trial' observation period)	Week 0, Week 26
Subjects Who Achieve HbA1c Below 7.0% (53 mmol/Mol) and no Weight Gain	Percentage of subjects who achieve HbA1c below 7.0% (53 mmol/mol) and no weight gain, after 26 week ('in-trial' observation period).	Week 26
Subjects Who Achieve HbA1c Below 7.0% (53 mmol/Mol), no Weight Gain and Systolic Blood Pressure Below 140 mmHg.	Percentage of subjects who achieve HbA1c below 7.0% (53 mmol/mol), no weight gain and systolic blood pressure below 140 mmHg, after 26 weeks ('in-trial' observation period)	Week 26
Subjects Who Achieve HbA1c Reduction Above or Equal to 1% (11mmol/Mol)	Percentage of subjects who achieve HbA1c reduction above or equal to 1% (11mmol/mol), after 26 weeks ('in-trial' observation period)	Week 26
Subjects Who Achieve HbA1c Reduction Above or Equal to 1% (11mmol/Mol) and no Weight Gain	Percentage of subjects who achieve HbA1c reduction above or equal to 1% (11mmol/mol) and no weight gain, after 26 weeks.	Week 26
Number of Treatment Emergent Adverse Events	The on-treatment summary of adverse events includes treatment-emergent events with onset on or after the first day of exposure to randomised treatment and no later than the minimum of the date of the follow-up visit or the last day of randomised treatment + 7 days or the date of last subject-investigator contact.	Week 0 - 26 + 7 days
Number of Treatment Emergent Severe or Blood Glucose Confirmed Symptomatic Hypoglycaemia Episodes	Treatment emergent hypoglycaemic episode is defined episode with onset on or after the first day of exposure to randomised treatment and no later than the minimum of the date of the follow-up visit or the last day of randomised treatment + 1 days or the date of last subject-investigator contact. Severe or BG confirmed symptomatic hypoglycaemic episodes were defined as episodes that were severe according to American Diabetes Association's (ADA) classification or blood glucose confirmed by a plasma glucose value < 3.1 mmol/L (56 mg/dL) with symptoms consistent with hypoglycaemia. Severe hypoglycaemia according to the ADA definition: an episode requiring assistance of another person to actively administer carbohydrate, glucagon, or take other corrective actions.	Week 0 - 26
Change in Fasting Blood Lipids - Total Cholesterol	Fasting total cholesterol measured in mg/dL. Observed mean change in fasting total cholesterol from baseline (week 0) to week 26 is presented as ratio to baseline value.	Week 0, Week 26
Change in Fasting Blood Lipids - Low Density Lipoprotein (LDL) Cholesterol	Low density lipoprotein (LDL) cholesterol measured in mg/dL. Observed mean change in fasting low density lipoprotein cholesterol from baseline (week 0) to week 26 is presented as ratio to baseline value.	Week 0, Week 26
Change in Fasting Blood Lipids - High Density Lipoprotein (HDL) Cholesterol	High density lipoprotein (HDL) cholesterol measured in mg/dL. Observed mean change in fasting high density lipoprotein cholesterol from baseline (week 0) to week 26 is presented as ratio to baseline value.	Week 0, Week 26
Change in Fasting Blood Lipids - Very Low Density Lipoprotein (VLDL) Cholesterol	Very low density lipoprotein (VLDL) cholesterol measured in mg/dL. Observed mean change in fasting very low density lipoprotein cholesterol from baseline (week 0) to week 26 is presented as ratio to baseline value.	Week 0, Week 26
Change in Fasting Blood Lipids-triglycerides	Fasting triglycerides measured in mg/dL. Observed mean change in fasting triglycerides from baseline (week 0) to week 26 is presented as ratio to baseline value.	Week 0, Week 26
Change in Fasting Blood Lipids- Free Fatty Acids (FFA)	Free fatty acids measured in mg/dL. Observed mean change in fasting free fatty acids from baseline (week 0) to week 26 is presented as ratio to baseline value.	Week 0, Week 26
Change in Waist Circumference	Change from baseline (week 0) to week 26 in waist circumference ('in-trial' observation period).	Week 0, Week 26
Change in Systolic Blood Pressure	Change from baseline (week 0) in systolic blood pressure after 26 weeks ('in-trial' observation period).	Week 0, Week 26
Change in Diastolic Blood Pressure	Change from baseline (week 0) in diastolic blood pressure after 26 weeks ('in-trial' observation period).	Week 0, Week 26
Subjects Who Achieve Weight Loss by 3% or More	Percentage of subjects who achieve HbA1c reduction above or equal to 1% (11mmol/mol) and weight loss above or equal to 3%, after 26 weeks ('in-trial' observation period).	Week 26

Collaborators and Investigators

• Sponsor: Novo Nordisk A/S

Publications and helpful links

General Publications

• Blonde L, Belousova L, Fainberg U, Garcia-Hernandez PA, Jain SM, Kaltoft MS, Mosenzon O, Nafach J, Palle MS, Rea R. Liraglutide as add-on to sodium-glucose co-transporter-2 inhibitors in patients with inadequately controlled type 2 diabetes: LIRA-ADD2SGLT2i, a 26-week, randomized, double-blind, placebo-controlled trial. Diabetes Obes Metab. 2020 Jun;22(6):929-937. doi: 10.1111/dom.13978. Epub 2020 Feb 14.
• Blonde L, Fainberg U, Kaltoft MS, Mosenzon O, Ramesh C, Rea R. Efficacy of liraglutide added to sodium-glucose cotransporter-2 inhibitors in type 2 diabetes, stratified by baseline characteristics: Post-hoc analysis of LIRA-ADD2SGLT2i. Diabetes Obes Metab. 2021 Oct;23(10):2234-2241. doi: 10.1111/dom.14464. Epub 2021 Jul 8.

Study record dates

Study Major Dates

• Study Start (ACTUAL): March 3, 2017
• Primary Completion (ACTUAL): May 4, 2018
• Study Completion (ACTUAL): May 8, 2018

Study Registration Dates

• First Submitted: November 11, 2016
• First Submitted That Met QC Criteria: November 11, 2016
• First Posted (ESTIMATE): November 16, 2016

Study Record Updates

• Last Update Posted (ACTUAL): November 17, 2020
• Last Update Submitted That Met QC Criteria: October 26, 2020
• Last Verified: October 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Incretins; Liraglutide
• Other Study ID Numbers: NN2211-4315; U1111-1184-8086 (OTHER: WHO)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: According to the Novo Nordisk disclosure commitment on novonordisk-trials.com

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No