Efficacy in Controlling Glycaemia With Victoza® (Liraglutide) as add-on to Metformin vs. OADs as add-on to Metformin After up to 104 Weeks of Treatment in Subjects With Type 2 Diabetes

Efficacy in Controlling Glycaemia With Victoza® (Liraglutide) as add-on to Metformin vs. OADs as add-on to Metformin After up to 104 Weeks of Treatment in Subjects With Type 2 Diabetes Inadequately Controlled With Metformin Monotherapy and Treated in a Primary Care Setting

Status

Completed

Phases

Phase 4

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02730377

Acronym

LIRA-PRIME

Enrollment

1991

Registered

2016-04-06

Start date

2016-03-28

Completion date

2019-08-12

Last updated

2020-07-07

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Diabetes, Diabetes Mellitus, Type 2

Brief summary

This trial is conducted globally. The aim of the trial is to investigate efficacy in controlling glycaemia with Victoza® (liraglutide) as add-on to metformin background treatment vs. OADs as add-on to metformin background treatment for 104 weeks of treatment in subjects with type 2 diabetes.

Interventions

DRUGliraglutide

Trial product will be prescribed by the investigator and dispensed by pharmacy or similar.

DRUGalpha-glucosidase inhibitors

Trial product will be prescribed by the investigator and dispensed by pharmacy or similar.

DRUGDPP-4 inhibitors

Trial product will be prescribed by the investigator and dispensed by pharmacy or similar.

DRUGmeglitinides

Trial product will be prescribed by the investigator and dispensed by pharmacy or similar.

DRUGSGLT-2 inhibitors

Trial product will be prescribed by the investigator and dispensed by pharmacy or similar.

DRUGsulphonylurea

Trial product will be prescribed by the investigator and dispensed by pharmacy or similar.

DRUGthiazolidinediones

Trial product will be prescribed by the investigator and dispensed by pharmacy or similar.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

- Male or female at least 18 years of age at the time of signing informed consent - Subjects diagnosed (clinically) with type 2 diabetes equal to or above 90 days prior to the screening visit - Stable daily dose of metformin as monotherapy equal to or above 1500 mg or maximum tolerated dose within 60 days prior to the screening visit - HbA1c 7.5-9.0% (59-75 mmol/mol) (both inclusive) and measured within the last 90 days prior to the screening visit

Exclusion criteria

- Female who is pregnant, breast-feeding or intends to become pregnant or is of childbearing potential and not using adequate contraceptive methods (adequate contraceptive measures as required by local regulation or practice) - Treatment with any medication for the indication of diabetes other than metformin in a period of 60 days before the screening visit. An exception is short-term treatment (below or equal to 7 days in total) with insulin in connection with intercurrent illness - Receipt of any investigational medicinal product within 30 days before the screening visit - Any disorder, which in the investigator's opinion might jeopardise subject's safety or compliance with the protocol

Design outcomes

Primary

Measure	Time frame	Description
Time to Inadequate Glycaemic Control	Weeks 26-104	Inadequate glycaemic control was defined as glycosylated haemoglobin (HbA1c) of 7.0% (53 mmol/mol) or greater at two consecutive visits after the first 26 weeks of treatment and up to 104 weeks. 25%, median (50%) and 75% percentiles for the cumulative distribution function, are obtained from the Kaplan-Meier survival function. HbA1c was recorded at weeks 38, 52, 65, 78, 91 and 104.

Secondary

Measure	Time frame	Description
Participants Who Achieve HbA1c ≤6.5% (Yes/No)	Week 104/Premature treatment discontinuation	Participants who achieved HbA1c ≤6.5% (yes/no) is presented.
Participants Who Achieve HbA1c ≤7.0% Without Weight Gain	Week 104/Premature treatment discontinuation	Participants who achieved HbA1c ≤7.0% without weight gain (yes/no) is presented.
Time to Premature Treatment Discontinuation (for Any Reason Including Inadequate Glycaemic Control)	Weeks 0-104	The time to premature treatment discontinuation (for any reason including inadequate glycaemic control) was analysed and presented using the generalised log rank test. 25%, median (50%) and 75% percentiles for the cumulative distribution function, are obtained from the Kaplan-Meier survival function.
Participants Who Achieve HbA1c ≤7.0% Without Treatment Emergent Severe Hypoglycaemic Episodes or BG Confirmed Symptomatic Hypoglycaemic Episodes	Week 104/Premature treatment discontinuation	Severe or blood glucose (BG) confirmed symptomatic hypoglycaemic episodes were defined as episodes that were severe according to the American Diabetes Association (ADA) classification (required assistance of another person to actively administer carbohydrate, glucagon, or take other corrective actions) or BG confirmed by a plasma glucose value \<3.1 millimoles per liter (mmol/L) with symptoms consistent with hypoglycaemia. Hypoglycaemic episodes were defined as treatment-emergent if the onset of the episode occurred on or after the first day of trial product administration, and no later than the day after the last day on trial product. Participants who achieved HbA1c ≤7.0% without treatment emergent severe hypoglycaemic episodes or BG confirmed symptomatic hypoglycaemic episodes (yes/no) is presented.
Participants Who Achieve HbA1c ≤7.0% Without Weight Gain and no Treatment Emergent Severe Hypoglycaemic Episodes or Blood Glucose Confirmed Symptomatic Hypoglycaemic Episodes	Week 104/Premature treatment discontinuation	Severe or BG confirmed symptomatic hypoglycaemic episodes were defined as episodes that were severe according to the ADA classification (required assistance of another person to actively administer carbohydrate, glucagon, or take other corrective actions) or BG confirmed by a plasma glucose value \<3.1 mmol/L with symptoms consistent with hypoglycaemia. Hypoglycaemic episodes were defined as treatment-emergent if the onset of the episode occurred on or after the first day of trial product administration, and no later than the day after the last day on trial product. Participants who achieved HbA1c ≤7.0% without weight gain and no treatment emergent severe hypoglycaemic episodes or BG confirmed symptomatic hypoglycaemic episodes (yes/no) is presented.
Change in Fasting Plasma Glucose (FPG)	Week 0, week 104/premature treatment discontinuation	Change from baseline (week 0) in FPG at week 104 or at premature treatment discontinuation is presented.
Change in Body Weight	Week 0, week 104/premature treatment discontinuation	Change from baseline (week 0) in body weight at week 104 or at premature treatment discontinuation is presented.
Change in Body Mass Index (BMI)	Week 0, week 104/premature treatment discontinuation	Change from baseline (week 0) in BMI at week 104 or at premature treatment discontinuation is presented.
Change in Blood Pressure (Systolic and Diastolic Blood Pressure)	Week 0, week 104/premature treatment discontinuation	Change from baseline (week 0) in systolic and diastolic blood pressure at week 104 or at premature treatment discontinuation is presented.
Number of Severe Hypoglycaemic Episodes	Weeks 0-104	Severe hypoglycaemic episodes were defined as episodes that required assistance of another person to actively administer carbohydrate, glucagon, or take other corrective actions. Number of severe hypoglycaemic episodes that occured during weeks 0-104 are presented.
Change in HbA1c	Week 0, week 104/premature treatment discontinuation	Change from baseline (week 0) in HbA1c at week 104 or at premature treatment discontinuation is presented.
Number of Documented Symptomatic Hypoglycaemic Episodes (ADA)	Weeks 0-104	Documented symptomatic hypoglycaemic were defined as episodes with typical symptoms of hypoglycaemia accompanied by measure plasma glucose concentration \<= 3.9 mmol/L. Number of documented symptomatic hypoglycaemic episodes that occured during the weeks 0-104 are presented.
Number of Serious Adverse Events (SAEs)	Weeks 0-105	A serious adverse event (SAE) was defined as any event that resulted in any of the following: death, life-threatening experience, in-patient hospitalisation or prolongation of existing hospitalisation, persistent or significant disability or incapacity, congenital anomaly or birth defect or suspicion of transmission of infectious agents via the trial product. An SAE was considered as treatment emergent if it had an onset or increase in severity on or after the time of first trial product administration and no later than 7 days after the time of last trial product administration. Number of treatment emergent serious adverse events are presented.
Number of AEs Leading to Permanent Discontinuation of Trial Product	Weeks 0-105	An adverse event (AE) was any untoward medical occurrence in a participant who administered a product, and which did not necessarily had a causal relationship with this treatment. An AE was considered as treatment emergent if it had an onset or increase in severity on or after the time of first trial product administration and no later than 7 days after the time of last trial product administration. Number of treatment emergent AEs that led to permanent discontinuation of trial product are presented.
Change in Lipids: HDL Cholesterol, LDL-cholesterol, Total Cholesterol, Triglycerides	Week 0, week 104/premature treatment discontinuation	Change from baseline (week 0) in high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, total cholesterol (TC) and triglycerides (TG) at week 104 or at premature treatment discontinuation is presented.
Change in Biochemistry- Alanine Aminotransferase (ALAT), Amylase, Aspartate Aminotransferase (ASAT), Lipase	Week 0, week 104/premature treatment discontinuation	Change from baseline (week 0) in alanine aminotransferase (ALAT), amylase, aspartate aminotransferase (ASAT) and lipase at week 104 or at premature treatment discontinuation is presented.
Change in Biochemistry- Creatinine, Total Bilirubin	Week 0, week 104/premature treatment discontinuation	Change from baseline (week 0) in creatinine and total bilirubin (TB) at week 104 or at premature treatment discontinuation is presented.
Change in Biochemistry- Estimated Glomerular Filtration Rate (eGFR) Serum	Week 0, week 104/premature treatment discontinuation	The estimated GFR was derived from serum creatinine using the MDRD (Modification of diet in renal disease) formula. eGFR was measured as milliliter per min per specific surface area (mL/min/SSA).
Change in Potassium	Week 0, week 104/premature treatment discontinuation	Change from baseline (week 0) in potassium at week 104 or at premature treatment discontinuation is presented.
Change in Haemoglobin	Week 0, week 104/premature treatment discontinuation	Change from baseline (week 0) in haemoglobin at week 104 or at premature treatment discontinuation is presented.
Change in Pulse	Week 0, week 104/premature treatment discontinuation	Change from baseline (week 0) in pulse at week 104 or at premature treatment discontinuation is presented.
Number of Severe or BG Confirmed Symptomatic Hypoglycaemic Episodes	Weeks 0-104	Severe or BG confirmed symptomatic hypoglycaemic episodes were defined as episodes that were severe according to the ADA classification (required assistance of another person to actively administer carbohydrate, glucagon, or take other corrective actions) or BG confirmed by a plasma glucose value \<3.1 mmol/L with symptoms consistent with hypoglycaemia. Number of severe or BG confirmed symptomatic hypoglycaemic episodes that occured during weeks 0-104 are presented.

Countries

Canada, Colombia, India, Latvia, Lebanon, Puerto Rico, Russia, Serbia, Turkey (Türkiye), United States

Participant flow

Recruitment details

The trial was conducted at 219 sites in Canada (11), Colombia (3), India (16), Latvia (2), Lebanon (4), Russian Federation (5), Serbia (6), Turkey (4) and the United States (168).

Pre-assignment details

Participants were randomised in a 1:1 manner to receive either liraglutide or an oral antidiabetic drug (OAD) both as add-on to background therapy with metformin.

Participants by arm

Arm	Count
Liraglutide 1.8 mg Participants were to receive a subcutaneous injection of liraglutide once daily. Participants received 0.6 milligrams (mg) liraglutide during the first week. The dose was escalated in weekly increments of 0.6 mg until the dose of 1.8 mg was reached. The treatment period was 104 weeks.	996
Oral Antidiabetic Drug Participants were to receive one selected OAD. The following OADs were allowed: alpha-glucosidase inhibitors, dipeptidyl peptidase-4 (DPP-4) inhibitors, meglitinides, sodium-glucose co-transporter-2 (SGLT-2) inhibitors, sulfonylureas or thiazolidinediones. The treatment period was 104 weeks.	995
Total	1,991

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Adverse Event	79	41
Overall Study	Death	1	8
Overall Study	Inadequate glycaemic control	368	473
Overall Study	Lack of Efficacy	4	13
Overall Study	Lost to Follow-up	25	21
Overall Study	Other	5	4
Overall Study	Pregnancy	0	1
Overall Study	Protocol Violation	23	30
Overall Study	Withdrawal by Subject	45	42

Baseline characteristics

Characteristic	Total	Oral Antidiabetic Drug	Liraglutide 1.8 mg
Age, Continuous	57.4 Years STANDARD_DEVIATION 10.8	57.1 Years STANDARD_DEVIATION 10.7	57.6 Years STANDARD_DEVIATION 11
Ethnicity (NIH/OMB) Hispanic or Latino	365 Participants	189 Participants	176 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	1626 Participants	806 Participants	820 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	9 Participants	6 Participants	3 Participants
Race/Ethnicity, Customized Asian	290 Participants	141 Participants	149 Participants
Race/Ethnicity, Customized Black or African American	207 Participants	106 Participants	101 Participants
Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander	5 Participants	2 Participants	3 Participants
Race/Ethnicity, Customized Other	42 Participants	26 Participants	16 Participants
Race/Ethnicity, Customized White	1438 Participants	714 Participants	724 Participants
Sex: Female, Male Female	947 Participants	471 Participants	476 Participants
Sex: Female, Male Male	1044 Participants	524 Participants	520 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	1 / 980	8 / 984
other Total, other adverse events	65 / 980	15 / 984
serious Total, serious adverse events	92 / 980	81 / 984

Outcome results

Primary

Time to Inadequate Glycaemic Control

Inadequate glycaemic control was defined as glycosylated haemoglobin (HbA1c) of 7.0% (53 mmol/mol) or greater at two consecutive visits after the first 26 weeks of treatment and up to 104 weeks. 25%, median (50%) and 75% percentiles for the cumulative distribution function, are obtained from the Kaplan-Meier survival function. HbA1c was recorded at weeks 38, 52, 65, 78, 91 and 104.

Time frame: Weeks 26-104

Population: FAS included all randomised participants. Overall number of participants analyzed=participants with available data.

Arm	Measure	Value (MEDIAN)
Liraglutide 1.8 mg	Time to Inadequate Glycaemic Control	108.9 Weeks
Oral Antidiabetic Drug	Time to Inadequate Glycaemic Control	64.9 Weeks

Comparison: Test for no treatment difference is based on using a generalised log-rank test for interval censored failure time data.p-value: <0.0001Log Rank

Secondary

Change in Biochemistry- Alanine Aminotransferase (ALAT), Amylase, Aspartate Aminotransferase (ASAT), Lipase

Change from baseline (week 0) in alanine aminotransferase (ALAT), amylase, aspartate aminotransferase (ASAT) and lipase at week 104 or at premature treatment discontinuation is presented.