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

Diabetes Mellitus, Type 2 Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02964247
• Other study ID #: NN2211-4315
• Secondary ID: U1111-1184-8086
• Status: Completed
• Phase: Phase 3
• Start date: March 3, 2017
• Est. completion date: May 8, 2018

Study information

• Verified date: October 2020
• Source: Novo Nordisk A/S
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 303
• Est. completion date: May 8, 2018
• Est. primary completion date: May 4, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Diabetes
• Diabetes Mellitus
• Diabetes Mellitus, Type 2

Intervention

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
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

Locations

Country	Name	City	State
Brazil	Novo Nordisk Investigational Site	Curitiba	Parana
Brazil	Novo Nordisk Investigational Site	Porto Alegre	Rio Grande Do Sul
Brazil	Novo Nordisk Investigational Site	São Paulo	Sao Paulo
India	Novo Nordisk Investigational Site	Ahmedabad	Gujarat
India	Novo Nordisk Investigational Site	Bangalore	Karnataka
India	Novo Nordisk Investigational Site	Coimbatore	Tamil Nadu
India	Novo Nordisk Investigational Site	Hyderabad	Telengana
India	Novo Nordisk Investigational Site	Indore	Madhya Pradesh
India	Novo Nordisk Investigational Site	Jaipur	Rajasthan
India	Novo Nordisk Investigational Site	Kolkata	West Bengal
India	Novo Nordisk Investigational Site	New Delhi
India	Novo Nordisk Investigational Site	Pune	Maharashtra
Israel	Novo Nordisk Investigational Site	Haifa
Israel	Novo Nordisk Investigational Site	Kfar Saba
Israel	Novo Nordisk Investigational Site	Tel Hashomer
Israel	Novo Nordisk Investigational Site	Tel-Aviv
Puerto Rico	Novo Nordisk Investigational Site	Ponce
Russian Federation	Novo Nordisk Investigational Site	Saint-Petersburg
Russian Federation	Novo Nordisk Investigational Site	Saint-Petersburg
Russian Federation	Novo Nordisk Investigational Site	Saint-Petersburg
Russian Federation	Novo Nordisk Investigational Site	Saint-Petersburg
Russian Federation	Novo Nordisk Investigational Site	St. Petersburg
United Arab Emirates	Novo Nordisk Investigational Site	Al Ain
United Arab Emirates	Novo Nordisk Investigational Site	Dubai
United Arab Emirates	Novo Nordisk Investigational Site	Umm Al Quwain
United Arab Emirates	Novo Nordisk Investigational Site	Umm Al Quwain
United States	Novo Nordisk Investigational Site	Albany	New York
United States	Novo Nordisk Investigational Site	Billings	Montana
United States	Novo Nordisk Investigational Site	Birmingham	Alabama
United States	Novo Nordisk Investigational Site	Blackfoot	Idaho
United States	Novo Nordisk Investigational Site	Charlotte	North Carolina
United States	Novo Nordisk Investigational Site	Charlotte	North Carolina
United States	Novo Nordisk Investigational Site	Charlotte	North Carolina
United States	Novo Nordisk Investigational Site	Cincinnati	Ohio
United States	Novo Nordisk Investigational Site	Columbus	Ohio
United States	Novo Nordisk Investigational Site	Dallas	Texas
United States	Novo Nordisk Investigational Site	Edinburg	Texas
United States	Novo Nordisk Investigational Site	Evansville	Indiana
United States	Novo Nordisk Investigational Site	Gainesville	Florida
United States	Novo Nordisk Investigational Site	Henderson	Nevada
United States	Novo Nordisk Investigational Site	Hollywood	Florida
United States	Novo Nordisk Investigational Site	Houston	Texas
United States	Novo Nordisk Investigational Site	Houston	Texas
United States	Novo Nordisk Investigational Site	Humble	Texas
United States	Novo Nordisk Investigational Site	Jacksonville	Florida
United States	Novo Nordisk Investigational Site	Jacksonville	Florida
United States	Novo Nordisk Investigational Site	Jacksonville	Florida
United States	Novo Nordisk Investigational Site	Kalamazoo	Michigan
United States	Novo Nordisk Investigational Site	Kinston	North Carolina
United States	Novo Nordisk Investigational Site	Lancaster	California
United States	Novo Nordisk Investigational Site	Lawrenceville	Georgia
United States	Novo Nordisk Investigational Site	Lexington	Kentucky
United States	Novo Nordisk Investigational Site	Maitland	Florida
United States	Novo Nordisk Investigational Site	McMurray	Pennsylvania
United States	Novo Nordisk Investigational Site	Memphis	Tennessee
United States	Novo Nordisk Investigational Site	Miami	Florida
United States	Novo Nordisk Investigational Site	Miami	Florida
United States	Novo Nordisk Investigational Site	Miami Lakes	Florida
United States	Novo Nordisk Investigational Site	Moncks Corner	South Carolina
United States	Novo Nordisk Investigational Site	Montgomery	Alabama
United States	Novo Nordisk Investigational Site	Mount Pleasant	South Carolina
United States	Novo Nordisk Investigational Site	Myrtle Beach	South Carolina
United States	Novo Nordisk Investigational Site	Nashville	Tennessee
United States	Novo Nordisk Investigational Site	New Orleans	Louisiana
United States	Novo Nordisk Investigational Site	Northridge	California
United States	Novo Nordisk Investigational Site	Pittsburgh	Pennsylvania
United States	Novo Nordisk Investigational Site	Rochester	Michigan
United States	Novo Nordisk Investigational Site	Roswell	Georgia
United States	Novo Nordisk Investigational Site	Round Rock	Texas
United States	Novo Nordisk Investigational Site	Sacramento	California
United States	Novo Nordisk Investigational Site	San Diego	California
United States	Novo Nordisk Investigational Site	San Ramon	California
United States	Novo Nordisk Investigational Site	Schertz	Texas
United States	Novo Nordisk Investigational Site	Spartanburg	South Carolina
United States	Novo Nordisk Investigational Site	Spokane	Washington
United States	Novo Nordisk Investigational Site	Statesboro	Georgia
United States	Novo Nordisk Investigational Site	Tampa	Florida
United States	Novo Nordisk Investigational Site	Topeka	Kansas
United States	Novo Nordisk Investigational Site	Tucson	Arizona
United States	Novo Nordisk Investigational Site	Vista	California
United States	Novo Nordisk Investigational Site	West Seneca	New York
United States	Novo Nordisk Investigational Site	Wilmington	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
Novo Nordisk A/S

Countries where clinical trial is conducted

United States,  Brazil,  India,  Israel,  Puerto Rico,  Russian Federation,  United Arab Emirates, 

References & Publications (1)

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-ADD2SGLT — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Change in Waist Circumference	Change from baseline (week 0) to week 26 in waist circumference ('in-trial' observation period).	Week 0, Week 26
Secondary	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
Secondary	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
Secondary	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