Lifestyle Modification and Liraglutide
Condition: Obesity
Study type: Interventional
Phase: Phase 4

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.
    

Detailed description: 
      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.
    

Intervention name(s): CMS-recommended lifestyle counseling; Liraglutide 3.0mg; Portion-Controlled Diet; Placebo Oral Tablet; Phentermine 15 MG; Extension Study CMS-recommended lifestyle counseling
Intervention type(s): Behavioral; Drug; Other; Drug; Drug; Behavioral
Intervention description(s): 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.
Other intervention name(s): Saxenda
Intervention MeSH terms: Liraglutide; Phentermine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment