Type

Range

Units

Status

Start Date

End Date

Financing

Study Design

Brief description/objective

Primary objectives:
To establish the efficacy of 3.0 mg liraglutide compared to liraglutide placebo in inducing and maintaining weight loss over 56 weeks in obese subjects and overweight subjects with comorbidities. To investigate the long term efficacy of 3.0 mg liraglutide versus liraglutide placebo in delaying the onset of type 2 diabetes in obese subjects and overweight subjects with co-morbidities diagnosed with pre-diabetes.
Secondary objective:
To investigate the long term efficacy of 3.0 mg liraglutide versus liraglutide placebo on
cardiovascular risk markers such as blood pressure, lipids, glucose parameters as well as effects on quality of life.
Safety objective:
To evaluate the safety and tolerability of liraglutide.
Trial design:
This is a randomised, double-blind, placebo controlled, parallel group, multi-centre, multinational trial in non-diabetic obese subjects and overweight subjects with co-morbidities. Subjects will be randomised in a 2:1 manner to receive either 3.0 mg liraglutide or liraglutide placebo, and based on body mass index (BMI [kg/m2]) and pre-diabetes status at randomisation subjects will be stratified to either 56 or 160 weeks of treatment (160 week treatment will only applicable to subjects with pre-diabetes at screening). Treatment will be stratified by body mass index (BMI [kg/m2]) (BMI ≥ 30 kg/m2, or BMI < 30 kg/m2) and pre-diabetes status at baseline (Yes/No, see below for definition of pre-diabetes). Treatment allocation for subjects with pre-diabetes will be double-blind for the first 56 weeks (Novo Nordisk, Investigator, and subject blinded), after which time point sponsor is un-blinded (Investigator and subject remain blinded to treatment allocation).
A subject will be classified as having pre-diabetes if falling within the following categories of increased risk for diabetes: Fasting plasma glucose 100 mg/dL ( 5.6 mmol/L) to 125 mg/dL (6.9 mmol/L) (IFG), 2-hour post-challenge (OGTT) glucose 140 mg/dL (7.8 mmol/L) to 199 mg/dL (11.0 mmol/L) (IGT), or HbA1c 5.7-6.4% both inclusive.
The maximum overall duration of the main part of the trial from screening to follow-up will be 72 weeks including the 12 week re-randomised treatment period. For subjects enrolled in the delayedonset- of-type-2-diabetes part of the trial the maximum total duration of the trial will be 164 weeks.
Trial population:
4800 subjects are expected to be screened in order to meet the randomisation target of minimum 3600 subjects in total, including a minimum of 1000 randomised subjects with pre-diabetes. If the number of subjects with pre-diabetes equals at least 1000 after randomisation of 3600 subjects, no further randomisation will be done. The screening and randomisation of subjects with pre-diabetes will be monitored closely throughout the recruitment period. If the number of subjects with prediabetes is lower than expected (approximately 30% of screened population), screening will continue with the purpose of identifying and enrolling the minimum number of subjects with prediabetes. If 3600 subjects have been randomised without reaching the minimum number of subjects with pre-diabetes (N = 1000), only subjects with pre-diabetes will be randomised. At week 56 all subjects who did not have pre-diabetes at baseline will continue in a blinded 12 week re-randomised treatment period followed by a 2 week off-treatment period for assessment of liraglutide antibody development. Subjects who have received treatment with liraglutide during the previous 56 weeks will be re-randomised 1:1 to either continue on liraglutide treatment or be switched to liraglutide placebo (for a blinded off active treatment evaluation). Subjects who had been randomised to liraglutide placebo will continue on liraglutide placebo during the 12 week rerandomised treatment period.
Key inclusion criteria:
• Informed consent obtained
• Body Mass Index (BMI) ≥ 30.0 kg/m2 or ≥ 27 kg/m2 in the presence of co-morbidities (treated or untreated hypertension or dyslipidaemia)
• Stable body weight
• Preceding failed dietary effort
Key exclusion criteria:
• Known type 1 or type 2 diabetes
• HbA1c ≥ 6.5 % (Screening visit 1) or FPG ≥ 126 mg/dL (7 mmol/L) (Screening visit 2) or 2 hr post-challenge (OGTT) plasma glucose ≥200 mg/dL (11.1 mmol/L) (Screening visit 2)
• Screening calcitonin ≥ 50 ng/L
• Family or personal history of multiple endocrine neoplasia type 2 (MEN2) or familial medullary thyroid carcinoma (FMTC)
• Personal history of non-familial medullary thyroid carcinoma
• History of acute or chronic pancreatitis
• Obesity induced by drug treatment
• Use of approved weight lowering pharmacotherapy
• Previous surgical treatment of obesity
• History of major depressive disorder or suicide attempt
• Uncontrolled hypertension (systolic blood pressure ≥ 160 mmHg and/or diastolic blood pressure ≥ 100 mmHg)
Assessments:
Endpoints to support the primary efficacy objectives include change from baseline in body weight at 56 weeks as well as the proportion of subjects losing at least 5% or more than 10% of baseline body weight at 56 weeks. Moreover, the proportion of subjects who have converted to overt diabetes at 160 weeks is included as a co-primary endpoint for subjects who had pre-diabetes at baseline.
The secondary efficacy endpoints include change from baseline in body weight at 160 weeks of treatment in subjects with pre-diabetes, the proportion of subjects losing at least 5% or ore than 10% of baseline bodyweight at week 160 and change from baseline in waist circumference, glucose control parameters (HbA1c, FPG, fasting insulin, C-peptide, OGTT-derived parameters, pre-diabetes status), blood pressure, cardiovascular biomarkers, lipids, urinary albumin-to-creatinine ratio (UACR) and Patient Reported Outcome (PRO) at 56 weeks.
Key assessments of safety include physical examination, ECG, pulse, adverse events, haematology, biochemistry (including amylase, lipase and calcitonin), liraglutide antibodies and ratings based on mental health questionnaires.
Trial product(s):
Novo Nordisk A/S will supply the following trial products:
• Liraglutide 6.0 mg/mL, 3 mL FlexPen® for subcutaneous injection