Lifestyle Modification and Liraglutide
Condition: Obesity
Intervention: CMS-recommended lifestyle counseling; Liraglutide 3.0mg; Portion-Controlled Diet; Placebo Oral Tablet; Phentermine 15 MG; Extension Study CMS-recommended lifestyle counseling
Intervention description: 21 brief (15 minute) lifestyle counseling visits provided by a physician, nurse practitioner, or registered dietitian.; Liraglutide is a once-daily self-administered, subcutaneous (beneath the skin) injection.; A 1000-1200 kcal/day portion-controlled diet prescribed for 12 weeks.; 4 brief (15 minute) lifestyle counseling visits provided by a physician, nurse practitioner, or registered dietitian.
Intervention MeSH terms: Liraglutide; Phentermine
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Masking description: In the 12 week extension study, participants who are eligible will continue to take liraglutide 3.0 mg in an open fashion. Participants will be randomly assigned in a double-blind fashion to placebo or phentermine.
Enrollment: 150.0
Sex: All
Minimum age: 21 Years
Maximum age: 70 Years
Healthy volunteers: No

Summary:

      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.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Participants must have a BMI ≥ 30 and ≤ 55 kg/m²

          2. Age ≥ 21 years and ≤ 70 years

          3. 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

          4. Ability to provide informed consent before any trial-related activities

          5. 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:

          1. Pregnant or nursing, or plans to become pregnant in the next 18 months, or not using
             adequate contraceptive measures

          2. Personal or family history of medullary thyroid cancer or multiple endocrine neoplasia
             syndrome type 2

          3. Uncontrolled hypertension (systolic blood pressure ≥ 160 mm Hg or diastolic blood
             pressure ≥ 100 mm Hg)

          4. Type 1 diabetes

          5. Type 2 diabetes

          6. A fasting glucose ≥ 126 mg/dl (on second assessment after first elevated value)

          7. 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

          8. Clinically significant hepatic or renal disease

          9. Thyroid disease, not controlled

         10. History of malignancy (except for non-melanoma skin cancer) in past 5 years

         11. Current major depressive episode, active suicidal ideation, or history of suicide
             attempts

         12. Psychiatric hospitalization within the past 6 months

         13. Self-reported alcohol or substance abuse within the past 12 months, including at-risk
             drinking (current consumption of ≥ 14 alcoholic drinks per week)

         14. 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)

         15. Loss of ≥ 10 lb of body weight within the past 3 months

         16. History of (or plans for) bariatric surgery

         17. Inability to walk 5 blocks comfortably or engage in some other form of aerobic
             activity (e.g., swimming)

         18. Known or suspected allergy to trial medication(s), excipients, or related products

         19. Hypersensitivity to liraglutide or any product components

         20. The receipt of any investigational drug within 6 months prior to this trial

         21. Previous participation in this trial (e.g., randomized and failed to participate)

         22. History of pancreatitis

         23. 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:

          1. Use of monoamine oxidase inhibitors in the past 2 weeks

          2. Glaucoma

          3. Presence or history of marked agitation

          4. History of drug abuse

          5. Known hypersensitivity to sympathomimetic amines

          6. Current use of selective serotonin re-uptake inhibitors (e.g., fluoxetine, sertraline,
             etc)

          7. Current use of any other weight loss medications (besides liraglutide 3.0 mg/d)

          8. History of coronary artery disease