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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02964247
Recruitment Status : Completed
First Posted : November 16, 2016
Results First Posted : July 10, 2019
Last Update Posted : November 17, 2020
Sponsor:
Information provided by (Responsible Party):
Novo Nordisk A/S

Study Description
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Brief 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.

Condition or disease Intervention/treatment Phase
Diabetes Diabetes Mellitus, Type 2 Drug: liraglutide Drug: placebo Phase 3

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 303 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: LIRA-ADD2SGLT2i - Liraglutide Versus Placebo as add-on to SGLT2 Inhibitors
Actual Study Start Date : March 3, 2017
Actual Primary Completion Date : May 4, 2018
Actual Study Completion Date : May 8, 2018

Resource links provided by the National Library of Medicine

Drug Information available for: Liraglutide

Arms and Interventions
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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


Outcome Measures
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Primary Outcome Measures :
  1. Change in HbA1c [ Time Frame: Week 0, Week 26 ]
    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.


Secondary Outcome Measures :
  1. Change in Body Weight [ Time Frame: Week 0, Week 26 ]
    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.

  2. Change in Fasting Plasma Glucose [ Time Frame: Week 0, Week 26 ]
    Change from baseline (week 0) to week 26 in fasting plasma glucose ('in-trial' observation period)

  3. Subjects Who Achieve HbA1c Below 7.0% (53 mmol/Mol), American Diabetes Association Target [ Time Frame: Week 26 ]
    Percentage of subjects who achieve HbA1c below 7.0% (53 mmol/mol), American Diabetes Association target, after 26 weeks ('in-trial' observation period)

  4. Subjects Who Achieve HbA1c Below or Equal to 6.5% (48 mmol/Mol), American Association of Clinical Endocrinologists Target [ Time Frame: Week 26 ]
    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)

  5. Subjects Who Achieve HbA1c Below 7.0% (53 mmol/Mol) Without Severe or Blood Glucose Confirmed Symptomatic Hypoglycaemia Episodes and no Weight Gain. [ Time Frame: Week 26 ]
    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)

  6. Subjects Who Achieve HbA1c Reduction Above or Equal to 1% (11mmol/Mol) and Weight Loss Above or Equal to 3%. [ Time Frame: Week 26 ]
    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)

  7. Change in Self-measured Plasma Glucose 7-point Profile - Mean 7-point Profile [ Time Frame: Week 0, Week 26 ]
    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).

  8. Change in Self-measured Plasma Glucose 7-point Profile - Mean Post Prandial Increments (Over All Meals) [ Time Frame: Week 0, Week 26 ]
    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)

  9. Change in Body Mass Index (BMI) [ Time Frame: Week 0, Week 26 ]
    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)

  10. Subjects Who Achieve HbA1c Below 7.0% (53 mmol/Mol) and no Weight Gain [ Time Frame: Week 26 ]
    Percentage of subjects who achieve HbA1c below 7.0% (53 mmol/mol) and no weight gain, after 26 week ('in-trial' observation period).

  11. Subjects Who Achieve HbA1c Below 7.0% (53 mmol/Mol), no Weight Gain and Systolic Blood Pressure Below 140 mmHg. [ Time Frame: Week 26 ]
    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)

  12. Subjects Who Achieve HbA1c Reduction Above or Equal to 1% (11mmol/Mol) [ Time Frame: Week 26 ]
    Percentage of subjects who achieve HbA1c reduction above or equal to 1% (11mmol/mol), after 26 weeks ('in-trial' observation period)

  13. Subjects Who Achieve HbA1c Reduction Above or Equal to 1% (11mmol/Mol) and no Weight Gain [ Time Frame: Week 26 ]
    Percentage of subjects who achieve HbA1c reduction above or equal to 1% (11mmol/mol) and no weight gain, after 26 weeks.

  14. Number of Treatment Emergent Adverse Events [ Time Frame: Week 0 - 26 + 7 days ]
    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.

  15. Number of Treatment Emergent Severe or Blood Glucose Confirmed Symptomatic Hypoglycaemia Episodes [ Time Frame: Week 0 - 26 ]
    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.

  16. Change in Fasting Blood Lipids - Total Cholesterol [ Time Frame: Week 0, Week 26 ]
    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.

  17. Change in Fasting Blood Lipids - Low Density Lipoprotein (LDL) Cholesterol [ Time Frame: Week 0, Week 26 ]
    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.

  18. Change in Fasting Blood Lipids - High Density Lipoprotein (HDL) Cholesterol [ Time Frame: Week 0, Week 26 ]
    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.

  19. Change in Fasting Blood Lipids - Very Low Density Lipoprotein (VLDL) Cholesterol [ Time Frame: Week 0, Week 26 ]
    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.

  20. Change in Fasting Blood Lipids-triglycerides [ Time Frame: Week 0, Week 26 ]
    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.

  21. Change in Fasting Blood Lipids- Free Fatty Acids (FFA) [ Time Frame: Week 0, Week 26 ]
    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.

  22. Change in Waist Circumference [ Time Frame: Week 0, Week 26 ]
    Change from baseline (week 0) to week 26 in waist circumference ('in-trial' observation period).

  23. Change in Systolic Blood Pressure [ Time Frame: Week 0, Week 26 ]
    Change from baseline (week 0) in systolic blood pressure after 26 weeks ('in-trial' observation period).

  24. Change in Diastolic Blood Pressure [ Time Frame: Week 0, Week 26 ]
    Change from baseline (week 0) in diastolic blood pressure after 26 weeks ('in-trial' observation period).

  25. Subjects Who Achieve Weight Loss by 3% or More [ Time Frame: Week 26 ]
    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).


Eligibility Criteria
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Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02964247


Locations
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Sponsors and Collaborators
Novo Nordisk A/S
  Study Documents (Full-Text)

Documents provided by Novo Nordisk A/S:
Study Protocol  [PDF] September 26, 2018
Statistical Analysis Plan  [PDF] September 26, 2018

More Information
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Publications of Results:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Novo Nordisk A/S
ClinicalTrials.gov Identifier: NCT02964247    
Other Study ID Numbers: NN2211-4315
U1111-1184-8086 ( Other Identifier: WHO )
First Posted: November 16, 2016    Key Record Dates
Results First Posted: July 10, 2019
Last Update Posted: November 17, 2020
Last Verified: October 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: According to the Novo Nordisk disclosure commitment on novonordisk-trials.com

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
Layout table for MeSH terms
Diabetes Mellitus
Diabetes Mellitus, Type 2
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Liraglutide
 Hypoglycemic Agents
Physiological Effects of Drugs
Incretins
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists