Lifestyle Modification and Liraglutide

Study Overview
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Brief Summary
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This is a 52 week, single center, open-labeled, randomized controlled trial. A total of 150 subjects with obesity, who are free of types 1 and 2 diabetes, as well as contraindications to weight loss, will be randomly assigned to one of three treatment groups: 1) lifestyle counseling, as currently recommended by the Centers for Medicare and Medicaid Services (CMS) (i.e., CMS-Alone); 2) CMS lifestyle counseling plus liraglutide (i.e., CMS-Liraglutide); or 3) CMS-Liraglutide plus a portion-controlled diet (i.e., Multi-Component Intervention). Subjects in all three groups will have 14 brief (15 minute) lifestyle counseling visits the first 24 weeks, followed by monthly visits in weeks 25-52. This is the schedule and duration of counseling visits recommended by CMS. Counseling sessions will be delivered by a physician, nurse practitioner or registered dietitian (RD) working in consultation with the former providers. Subjects in all three groups also will have brief physician visits at weeks 1, 4, 8, 16, 24, 36, and 52 (total of 7 visits). These visits are needed for subjects in both liraglutide groups to monitor their response to the medication. These visits are included for subjects in CMS-Alone to match the intensity of medical care provided the two other groups. The primary outcome is % reduction in initial body weight, as measured from randomization to week 52. Secondary outcomes include the proportion of participants who at week 52 lose >5%, >10%, and >15% of initial weight, as well as % reduction in weight at week 24 and the proportion of participants who meet the three categorical weight losses at this time. The secondary efficacy measures include changes (from randomization to week 52) in cardiovascular disease (CVD) risk factors, glycemic control, mood, quality of life, eating behavior, appetite, sleep, and satisfaction with weight loss. Safety endpoints will include physical examination, adverse events (AEs), standard laboratory tests, and mental health assessed by the Columbia Suicidality Severity Rating Scale (C-SSRS) and Patient Health Questionnaire (PHQ-9). Statistical Analysis. Using a sample size equation for longitudinal clustered samples, a randomization sample of 50 subjects in CMS-Alone, 50 in CMS-Liraglutide, and 50 in the Multi-Component Intervention provides >80% power to detect the two primary contrasts to be statistically significant. This estimate allows for 20% attrition during the 52-week trial, resulting in approximately 40 treatment completers per group. The ITT longitudinal statistical design will further improve power by allowing the inclusion of available data for non-completers and the adjustment of possible variance reducing baseline covariates.

Detailed Description
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The addendum to the original 52-week trial, is a 12-week, single center, randomized placebo-controlled, parallel group designed trial. This 12-week extension study is separate from the original 52-week trial and will not affect the outcome or analysis of the 52-week, 3-arm trial. Participants and investigators will be masked to participants' assignment to phentermine 15 mg/d versus placebo. Participants in both groups will receive liraglutide in an open-label manner. We anticipate that 23 (of 50) participants from the original CMS-Liraglutide group and 23 (of 50) from the Multi-Component Intervention will be eligible to participate in the extension study and will elect to do so. We anticipate that 20 participants in each group will complete the 12-week extension study and that those who receive liraglutide 3.0 mg plus phentermine 15.0 mg/d will lose, from randomization to week 12, 3.5+3.5% of initial weight, compared with 0.0+0.5% for those assigned to liraglutide plus placebo. All participants in the extension study will meet with a physician or nurse practitioner at randomization (week 0) and at weeks 2, 4, 8 and 12. On each occasion they will review patients' blood pressure and pulse, assess suicidal ideation, and record and respond appropriately to reports of changes in physical health. As during the 1-year prior trial, brief lifestyle counseling (15 min) will provided at monthly visits (excluding week 2) by the physician or nurse practitioner or by a registered dietitian or behavioral psychologist, working under their supervision. The lifestyle intervention will be the same as that provided during the last 6 months of both the CMS-Liraglutide and Multi-Component interventions. Following the 12-week randomized trial, phentermine (or placebo) will be terminated, and all participants will continue to receive liraglutide 3.0 mg/d for an additional 8 weeks (i.e., weeks 12-20) and have lifestyle counseling and medical assessments at weeks 16 and 20. Liraglutide 3.0 mg/d will be terminated at week 20, and participants will have a final safety assessment at week 24. The primary endpoint of the 12-week extension trial is change in body weight (i.e., % reduction in randomization weight), as measured from randomization (week 0) to week 12. Secondary endpoints include the proportion of subjects who lose > 5% or > 10% of initial weight from randomization to week 12, as well as changes from randomization to week 12 in cardiovascular disease (CVD) risk factors (i.e, blood pressure, triglycerides, LDL and HDL cholesterol, and waist circumference), glycemic control (i.e., fasting blood sugar), mood (PHQ-9), quality of life (i.e, SF-36 and IWQOL-Lite), eating behavior (i.e., Eating Inventory, Eating Disorder Examination-Questionnaire, and Yale Food Addiction Scale), appetite (i.e., visual analogue scales), sleep (i.e., Pittsburgh Sleep Quality Index), and weight loss satisfaction. (All of these measures were administered in the original 1-year trial.) Safety endpoints will include physical examination, adverse events (AEs), standard laboratory tests, and mental health assessed by the Columbia Suicidality Severity Rating Scale (C-SSRS) and Patient Health Questionnaire (PHQ-9). All data analyses will proceed using the same principles and methods used in the original protocol.

Official Title
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Combining Lifestyle Modification and Liraglutide to Improve Weight Loss and Health Outcomes

Conditions
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Obesity

Intervention / Treatment
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* Behavioral: CMS-recommended lifestyle counseling
* Drug: Liraglutide 3.0mg
* Other: Portion-Controlled Diet
* Drug: Placebo Oral Tablet
* Drug: Phentermine 15 MG
* Behavioral: Extension Study CMS-recommended lifestyle counseling


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants must have a BMI ≥ 30 and ≤ 55 kg/m² Age ≥ 21 years and ≤ 70 years Eligible female patients will be: non-pregnant, evidenced by a negative urine dipstick pregnancy test non-lactating surgically sterile or postmenopausal, or they will agree to continue to use an accepted method of birth control during the study Ability to provide informed consent before any trial-related activities Participants must: have a primary care provider (PCP) who is responsible for providing routine care have a reliable telephone service with which to communicate with study staff understand and be willing to comply with all study-related procedures and agree to participate in the study by giving written informed consent plan to remain in the Philadelphia area for the next 18 months Exclusion Criteria: Pregnant or nursing, or plans to become pregnant in the next 18 months, or not using adequate contraceptive measures Personal or family history of medullary thyroid cancer or multiple endocrine neoplasia syndrome type 2 Uncontrolled hypertension (systolic blood pressure ≥ 160 mm Hg or diastolic blood pressure ≥ 100 mm Hg) Type 1 diabetes Type 2 diabetes A fasting glucose ≥ 126 mg/dl (on second assessment after first elevated value) Recent history of cardiovascular disease (e.g., myocardial infarction or stroke within the past 6 months), congestive heart failure, or heart block greater than first degree Clinically significant hepatic or renal disease Thyroid disease, not controlled History of malignancy (except for non-melanoma skin cancer) in past 5 years Current major depressive episode, active suicidal ideation, or history of suicide attempts Psychiatric hospitalization within the past 6 months Self-reported alcohol or substance abuse within the past 12 months, including at-risk drinking (current consumption of ≥ 14 alcoholic drinks per week) Use in past 3 months of medications known to induce significant weight loss (i.e., prescription weight loss medications) or weight gain (e.g., chronic use of oral steroids, second generation antipsychotics) Loss of ≥ 10 lb of body weight within the past 3 months History of (or plans for) bariatric surgery Inability to walk 5 blocks comfortably or engage in some other form of aerobic activity (e.g., swimming) Known or suspected allergy to trial medication(s), excipients, or related products Hypersensitivity to liraglutide or any product components The receipt of any investigational drug within 6 months prior to this trial Previous participation in this trial (e.g., randomized and failed to participate) History of pancreatitis Subjects will be included/excluded according to the latest updated US PI. 12-Week Extension Trial: Inclusion Criteria Inclusion criteria are those described for the original 1-year trial (enumerated above). The principal exception from these criteria is that participants will only be required to have a BMI > 27 kg/m2, with or without co-morbidities, to be eligible to participate in the extension study. All participants will have met BMI inclusion criteria when they initiated the use of liraglutide and now will use it, potentially with phentermine 15 mg/d, to facilitate to the maintenance of lost weight. (Liraglutide is approved for chronic weight management, including following successful weight loss.) We do not wish to enroll participants with a BMI < 27 kg/m2 because of the possibility that they could reduce substantially below a BMI of 24.9 kg/m2, the upper limit of normal weight. Exclusion Criteria: Exclusion criteria will include those listed in the original protocol, including those specific to the use of liraglutide 3.0 mg/d (e.g., family history of medullary thyroid cancer). Additional exclusion criteria added to the 12-week extension study are specific to the use of phentermine 15 mg/d. They include: Use of monoamine oxidase inhibitors in the past 2 weeks Glaucoma Presence or history of marked agitation History of drug abuse Known hypersensitivity to sympathomimetic amines Current use of selective serotonin re-uptake inhibitors (e.g., fluoxetine, sertraline, etc) Current use of any other weight loss medications (besides liraglutide 3.0 mg/d) History of coronary artery disease

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 70 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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: CMS-Alone<br>Lifestyle counseling, as currently recommended by the CMS. | Behavioral: CMS-recommended lifestyle counseling<br>* 21 brief (15 minute) lifestyle counseling visits provided by a physician, nurse practitioner, or registered dietitian.<br>|
| Active Comparator: CMS-Liraglutide<br>CMS lifestyle counselling plus liraglutide. | Behavioral: CMS-recommended lifestyle counseling<br>* 21 brief (15 minute) lifestyle counseling visits provided by a physician, nurse practitioner, or registered dietitian.<br>Drug: Liraglutide 3.0mg<br>* Liraglutide is a once-daily self-administered, subcutaneous (beneath the skin) injection.<br>* Other names: Saxenda;|
| Active Comparator: Multi-Component Intervention<br>CMS-Liraglutide plus a 1000-1200 kcal/day portion-controlled diet prescribed for 12 weeks. | Behavioral: CMS-recommended lifestyle counseling<br>* 21 brief (15 minute) lifestyle counseling visits provided by a physician, nurse practitioner, or registered dietitian.<br>Drug: Liraglutide 3.0mg<br>* Liraglutide is a once-daily self-administered, subcutaneous (beneath the skin) injection.<br>* Other names: Saxenda;Other: Portion-Controlled Diet<br>* A 1000-1200 kcal/day portion-controlled diet prescribed for 12 weeks.<br>|
| Active Comparator: 12-Week Extension Study: Phentermine Group<br>After the 1-year trial, half the participants who join the extension study will be randomized to phentermine 15.0 mg/d in a double-blind fashion, while continuing to take liraglutide. They will also continue to receive monthly lifestyle counseling. To be eligible for the extension study, participants must have been assigned to one of two medication groups in the original study. | Drug: Liraglutide 3.0mg<br>* Liraglutide is a once-daily self-administered, subcutaneous (beneath the skin) injection.<br>* Other names: Saxenda;Drug: Phentermine 15 MG<br> <br> Behavioral: Extension Study CMS-recommended lifestyle counseling<br>* 4 brief (15 minute) lifestyle counseling visits provided by a physician, nurse practitioner, or registered dietitian.<br>|
| Active Comparator: 12-Week Extension Study: Placebo Group<br>After the 1-year trial, half the participants who join the extension study will be randomized to placebo in a double-blind fashion, while continuing to take liraglutide. They will also continue to receive monthly lifestyle counseling. To be eligible for the extension study, participants must have been assigned to one of two medication groups in the original study. | Drug: Liraglutide 3.0mg<br>* Liraglutide is a once-daily self-administered, subcutaneous (beneath the skin) injection.<br>* Other names: Saxenda;Drug: Placebo Oral Tablet<br> <br> Behavioral: Extension Study CMS-recommended lifestyle counseling<br>* 4 brief (15 minute) lifestyle counseling visits provided by a physician, nurse practitioner, or registered dietitian.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change in Baseline Weight |  | Randomization and 52 weeks | 
| Extension Study Primary Outcome: Percent Change in Re-randomization Weight |  | Re-randomization and 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Systolic Blood Pressure |  | Randomization and 52 weeks | 
| Change in Diastolic Blood Pressure |  | Randomization and 52 weeks | 
| Change in Heart Rate |  | Randomization and 52 weeks | 
| Change in Waist Circumference |  | Randomization and 52 weeks | 
| Change in Total Cholesterol |  | Randomization and 52 weeks | 
| Change in LDL Cholesterol |  | Randomization and 52 weeks | 
| Change in HDL Cholesterol |  | Randomization and 52 weeks | 
| Change in Triglycerides |  | Randomization and 52 weeks | 
| Change in C Reactive Protein |  | Randomization and 52 weeks | 
| Change in Fasting Glucose |  | Randomization and 52 weeks | 
| Change in HbA1c |  | Randomization and 52 weeks | 
| Change in Fasting Insulin |  | Randomization and 52 weeks | 
| Change in HOMA-IR | HOMA-IR is a measurement for insulin resistance and is calculated from: fasting insulin (U/L) x fasting glucose (mg/dL)/405. A decrease from baseline to the end of treatment, a negative value, indicates an improvement | Randomization and 52 weeks | 
| Change in 36-Item Short Form Survey (SF-36) - Physical Component Summary | All sub scales are scored from 0 - 100, with higher scores indicating better health. Each component summary is a normed score with a mean of 50 and standard deviation of 10 in the US general population. Higher scores indicate better health. Z-scores are computed for each subscale, which are then converted into a component summary z-score using a weighted formula. The component summary z-score is then converted to a t-distribution with a mean of 50 and standard deviation of 10. Scores are scaled to a T-score with a mean of 50 and standard deviation of 10. Scores above 50 indicate better health. | Randomization and 52 weeks | 
| Change 36-Item Short Form Survey (SF-36) - Mental Component Summary | All sub scales are scored from 0 - 100, with higher scores indicating better health. Each component summary is a normed score with a mean of 50 and standard deviation of 10 in the US general population. Higher scores indicate better health. Z-scores are computed for each subscale, which are then converted into a component summary z-score using a weighted formula. The component summary z-score is then converted to a t-distribution with a mean of 50 and standard deviation of 10. Scores are scaled to a T-score with a mean of 50 and standard deviation of 10. Scores above 50 indicate better health. | Randomization and 52 weeks | 
| Change in Patient Health Questionnaire (PHQ-9) | PHQ-9 is scored based on a 0-27 scale in which higher scores indicate more severe depression. Values are summed to compute the total score. | Randomization and 52 weeks | 
| Extension Study Secondary Outcome: Change in Systolic Blood Pressure |  | Re-randomization and 12 weeks | 
| Extension Study Secondary Outcome: Change in Diastolic Blood Pressure |  | Re-randomization and 12 weeks | 
| Extension Study Secondary Outcome: Change in Heart Rate |  | Re-randomization and 12 weeks | 
| Extension Study Secondary Outcome: Change in Waist Circumference |  | Re-randomization and 12 weeks | 
| Extension Study Secondary Outcome: Change in Total Cholesterol |  | Re-randomization and 12 weeks | 
| Extension Study Secondary Outcome: Change in LDL Cholesterol |  | Re-randomization and 12 weeks | 
| Extension Study Secondary Outcome: Change in HDL Cholesterol |  | Re-randomization and 12 weeks | 
| Extension Study Secondary Outcome: Change in Triglycerides |  | Re-randomization and 12 weeks | 
| Extension Study Secondary Outcome: Change in c-Reactive Protein |  | Re-randomization and 12 weeks | 
| Extension Study Secondary Outcome: Change in Fasting Glucose |  | Re-randomization and 12 weeks | 
| Extension Study Secondary Outcome: Change in HbA1c |  | Re-randomization and 12 weeks | 
| Extension Study Secondary Outcome: Change in Fasting Insulin |  | Re-randomization and 12 weeks | 
| Extension Study Secondary Outcome: Change in HOMA-IR | HOMA-IR is a measurement for insulin resistance and is calculated from: fasting insulin (U/L) x fasting glucose (mg/dL)/405. A decrease from baseline to the end of treatment, a negative value, indicates an improvement | Re-randomization and 12 weeks | 
| Extension Study Secondary Outcome: SF-36 - Physical Health Component | All sub scales are scored from 0 - 100, with higher scores indicating better health. Each component summary is a normed score with a mean of 50 and standard deviation of 10 in the US general population. Higher scores indicate better health. Z-scores are computed for each subscale, which are then converted into a component summary z-score using a weighted formula. The component summary z-score is then converted to a t-distribution with a mean of 50 and standard deviation of 10. Scores are scaled to a T-score with a mean of 50 and standard deviation of 10. Scores above 50 indicate better health. | Re-randomization and 12 weeks | 
| Extension Study Secondary Outcome: SF-36 - Mental Health Component | All sub scales are scored from 0 - 100, with higher scores indicating better health. Each component summary is a normed score with a mean of 50 and standard deviation of 10 in the US general population. Higher scores indicate better health. Z-scores are computed for each subscale, which are then converted into a component summary z-score using a weighted formula. The component summary z-score is then converted to a t-distribution with a mean of 50 and standard deviation of 10. Scores are scaled to a T-score with a mean of 50 and standard deviation of 10. Scores above 50 indicate better health. | Re-randomization and 12 weeks | 
| Extension Study Secondary Outcome: Patient Health Questionnaire (PHQ-9) | PHQ-9 is scored based on a 0-27 scale in which higher scores indicate more severe depression. Values are summed to compute the total score. | Re-randomization and 12 weeks |