Evaluation of Liraglutide 3.0mg in Patients With Poor Weight-loss and a Suboptimal Glucagon-like Peptide-1 Response

Study Overview
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Brief Summary
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A double-blinded, randomised, placebo-controlled trial of liraglutide 3.0 mg in patients with poor weight-loss and a suboptimal glucagon-like peptide-1 response following bariatric surgery

Detailed Description
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Subjects with poor weight loss response (<20% of their total weight) following 1 year or more primary gastric bypass or primary sleeve gastrectomy, will be identified from the trial site (University College London Hospital) and participant identification centre (Whittington Hospital) and invited to attend a screening visit. The screening assessment will be undertaken only upon patients providing informed consent to undergo such procedure. Information regarding medical history and concomitant medications will be gathered. In addition, full physical examination, blood test and a meal test will be performed. All female participants of childbearing potential will be tested for pregnancy. Once all data related to the screening visit has been acquired, the investigator will review the participants' eligibility for BARI-OPTIMISE trial. Patients with suboptimal GLP-1 response and fulfilling the inclusion and exclusion criteria will be invited to take part in the trial and asked to sign a second consent form. Assurance of adequate use of contraceptive throughout the trial period will be obtained before a written informed consent is sought. Consented participants will then be asked to attend a baseline visit. During the baseline visit, data such as body weight, body composition, physical function, physical activity level and health-related quality of life will be collected. Adverse events will be reviewed and a meal test will be repeated. Upon completion of all the baseline procedures, participants will be randomised to receive either subcutaneous injection of liraglutide 3.0 mg or identical placebo for 24 weeks. Participants will be counselled for a calorie-reduced diet and to increase their level of physical activity. Participants will also be taught how to self-administer the treatment (by subcutaneous injection). For safety purpose, subject visits will be carried out at weeks 2, 4, 8, 17 and 24 of the treatment initiation. At all these visits, targeted physical examination will be performed and adverse events will be assessed. End-of-study visit will be over the phone 4 weeks after the end of treatment (i.e. week 28).

Official Title
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BARI-OPTIMISE: a Double-blinded, Randomised, Placebo-controlled Trial of Liraglutide 3.0 mg in Patients With Poor Weight-loss and a Suboptimal Glucagon-like Peptide-1 Response Following Bariatric Surgery

Conditions
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Obesity

Intervention / Treatment
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* Drug: Liraglutide Pen Injector [Saxenda]
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients, 1 year or more after primary RYGB or primary SG, with poor weight-loss (<20% WL) that is not caused by either a surgical or psychological problem. Adults, 18-64 years inclusive. Suboptimal nutrient-stimulated GLP-1 response assessed by a meal test. Suboptimal active GLP-1 response is defined as a ≤2-fold increase in active GLP-1 circulating levels between time 0 and time 30 minutes. Females of childbearing potential and males must be willing to use an effective method of contraception (hormonal or barrier method of birth control, abstinence) from the time consent is signed until 6 weeks after treatment discontinuation. Females of childbearing potential must have a negative pregnancy test within 7 days prior to being registered for trial treatment. NOTE: Subjects are considered not of child bearing potential if they are surgically sterile (i.e. they have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are postmenopausal. ≤5 % variation in body weight over preceding 3 months. Fluent in English and able to understand and complete questionnaires. Willing and able to provide written informed consent and comply with the trial protocol. Exclusion Criteria: Had a surgical procedure other than gastric bypass and sleeve gastrectomy. Pregnant or lactating mothers. Participation in other clinical intervention trial. Lifetime history of suicidal behaviour or severe depression assessed by direct questioning. Clinically significant medical abnormalities (e.g., unstable hypertension, clinically significant ECG abnormalities, liver cirrhosis, AST or ALT > 3x the upper normal limit). Heart rate ≥ 100 beats/minute at screening on two separate measurements. Uncontrolled hypertension (systolic blood pressure ≥ 160 mmHg or diastolic blood pressure ≥ 100 mmHg). Renal impairment (estimated glomerular infiltration rate (eGFR <30 ml/min 1.73 m2) Known or suspected hypersensitivity to liraglutide 3.0 mg and placebo or any of the excipients involved in their formulation. Personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2. Personal history of pancreatitis. Uncontrolled hypothyroidism or hyperthyroidism. History of stroke, unstable angina, acute coronary syndrome, congestive heart failure New York Heart Association class III-IV within the preceding 12 months. History of arrhythmias. Inflammatory bowel disease. Diabetic gastroparesis. Concomitant GLP-1 receptor agonist usage. Concomitant usage of medications that cause weight gain or weight loss. Concomitant usage of DPPIV-inhibitors. Insulin usage.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 64 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This study is a double-blind, randomised, placebo-controlled, two-arm, parallel group, single-site trial
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment<br>Daily subcutaneous injection of liraglutide 3.0 mg Study dosing of liraglutide: Week 1: 0.6 mg once daily Week 2: 1.2 mg once daily Week 3: 1.8 mg once daily Week 4: 2.4 mg once daily Week 5-24: 3.0 mg once daily In addition to the daily injection of liraglutide/placebo, participants in both groups will be advised to cut down approximately 500 calories from their usual food intake and to achieve a minimum of 150 minutes per week of physical activity. | Drug: Liraglutide Pen Injector [Saxenda]<br>* Daily injection of GLP-1 agonist (liraglutide 3.0 mg) for obese patients presenting poor weight loss (<20%) after bariatric surgery and suboptimal GLP-1 levels.<br>* Other names: Saxenda;|
| Placebo Comparator: Control<br>Daily subcutaneous injection of placebo; the same dosage regimen as treatment to be followed. In addition to the daily injection of liraglutide/placebo, participants in both groups will be advised to cut down approximately 500 calories from their usual food intake and to achieve a minimum of 150 minutes per week of physical activity. | Drug: Placebo<br>* Daily subcutaneous injection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| %WL | The primary objective of this trial is to compare the efficacy of 24-weeks of subcutaneous liraglutide 3.0 mg versus placebo administration, as an adjunct to diet and exercise, on %WL in participants with poor weight-loss and a sub-optimal active GLP-1 response following primary RYGB or SG at the end of the 24-week treatment period. | 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| %fat | To compare the effect of 24-weeks of subcutaneous liraglutide 3.0 mg versus placebo administration as an adjunct to diet and exercise at the end of the 24-week treatment period on % body fat assessed using DXA scanning | 24 weeks | 
| Skeletal muscle mass | To compare the effect of 24-weeks of subcutaneous liraglutide 3.0 mg versus placebo administration as an adjunct to diet and exercise at the end of the 24-week treatment period on skeletal muscle mass assessed using DXA scanning | 24 weeks | 
| Bone mineral density | To compare the effect of 24-weeks of subcutaneous liraglutide 3.0 mg versus placebo administration as an adjunct to diet and exercise at the end of the 24-week treatment period on bone mineral density assessed using DXA scanning | 24 weeks | 
| Glucose level | To compare the effect of 24-weeks of subcutaneous liraglutide 3.0 mg versus placebo administration as an adjunct to diet and exercise at the end of the 24-week treatment period on fasted and meal-stimulated levels of glucose assessed using blood test | 24 weeks | 
| Insulin | To compare the effect of 24-weeks of subcutaneous liraglutide 3.0 mg versus placebo administration as an adjunct to diet and exercise at the end of the 24-week treatment period on fasted and meal-stimulated levels of insulin assessed using blood test | 24 weeks | 
| HbA1c | To compare the effect of 24-weeks of subcutaneous liraglutide 3.0 mg versus placebo administration as an adjunct to diet and exercise at the end of the 24-week treatment period on fasted and meal-stimulated levels of HbA1c assessed using blood test | 24 weeks | 
| Leptin | To compare the effect of 24-weeks of subcutaneous liraglutide 3.0 mg versus placebo administration as an adjunct to diet and exercise at the end of the 24-week treatment period on fasted and meal-stimulated levels of leptin assessed using blood test | 24 weeks | 
| Gut Hormones | To compare the effect of 24-weeks of subcutaneous liraglutide 3.0 mg versus placebo administration as an adjunct to diet and exercise at the end of the 24-week treatment period on fasted and meal-stimulated levels of gut hormones assessed using blood test | 24 weeks | 
| Adipokines | To compare the effect of 24-weeks of subcutaneous liraglutide 3.0 mg versus placebo administration as an adjunct to diet and exercise at the end of the 24-week treatment period on fasted and meal-stimulated levels of adipokines assessed using blood test | 24 weeks | 
| physical functional assessment | To compare the effect of 24-weeks of subcutaneous liraglutide 3.0 mg versus placebo administration as an adjunct to diet and exercise at the end of the 24-week treatment period on physical functioning assessed using the 6-minute walk test (6-MWT) | 24 weeks | 
| physical function assessment | To compare the effect of 24-weeks of subcutaneous liraglutide 3.0 mg versus placebo administration as an adjunct to diet and exercise at the end of the 24-week treatment period on physical functioning assessed using the sit-to-stand test (STS Test) | 24 weeks | 
| physical function assessment | To compare the effect of 24-weeks of subcutaneous liraglutide 3.0 mg versus placebo administration as an adjunct to diet and exercise at the end of the 24-week treatment period on physical functioning assessed using hand-grip strength | 24 weeks | 
| physical function assessment | To compare the effect of 24-weeks of subcutaneous liraglutide 3.0 mg versus placebo administration as an adjunct to diet and exercise at the end of the 24-week treatment period on physical functioning assessed using the Paffenbarger Physical Activity Questionnaire (PPAQ) | 24 weeks | 
| HRQoL | To compare the effect of 24-weeks of subcutaneous liraglutide 3.0 mg versus placebo administration as an adjunct to diet and exercise at the end of the 24-week treatment period on health related quality of life assessed using an adapted Client Service Receipt Inventory (CSRI) | 24 weeks | 
| HRQoL | To compare the effect of 24-weeks of subcutaneous liraglutide 3.0 mg versus placebo administration as an adjunct to diet and exercise at the end of the 24-week treatment period on health related quality of life assessed using EuroQol-5D (ED5DEQ-5D) | 24 weeks | 
| HRQoL | To compare the effect of 24-weeks of subcutaneous liraglutide 3.0 mg versus placebo administration as an adjunct to diet and exercise at the end of the 24-week treatment period on health related quality of life assessed using Impact of weight on quality of life-lite (IWQOL-Lite) | 24 weeks | 
| HRQoL | To compare the effect of 24-weeks of subcutaneous liraglutide 3.0 mg versus placebo administration as an adjunct to diet and exercise at the end of the 24-week treatment period on health related quality of life assessed using Beck depression inventory (BDI) | 24 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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obesity, GLP-1, liraglutide, diabetes, bariatric surgery