Conditions: Obesity
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 150
Healthy volunteers: no

Brief 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.

Arms:
arm 1: Lifestyle counseling, as currently recommended by the CMS. arm 2: CMS lifestyle counselling plus liraglutide. arm 3: CMS-Liraglutide plus a 1000-1200 kcal/day portion-controlled diet prescribed for 12 weeks. arm 4: 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. arm 5: 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.

Interventions: intervention 1: CMS-recommended lifestyle counseling intervention 2: Liraglutide 3.0mg intervention 3: Portion-Controlled Diet intervention 4: Placebo Oral Tablet intervention 5: Phentermine 15 MG intervention 6: Extension Study CMS-recommended lifestyle counseling
Intervention descriptions: intervention 1: 21 brief (15 minute) lifestyle counseling visits provided by a physician, nurse practitioner, or registered dietitian. intervention 2: Liraglutide is a once-daily self-administered, subcutaneous (beneath the skin) injection. intervention 3: A 1000-1200 kcal/day portion-controlled diet prescribed for 12 weeks. intervention 4: None intervention 5: None intervention 6: 4 brief (15 minute) lifestyle counseling visits provided by a physician, nurse practitioner, or registered dietitian.

Protocol document:
Prot_SAP_000.pdf: 
   Version 3.3  September 25, 2018 
Page 1 
 
 
Protocol: Combining Lifestyle Modification and Liraglutide to 
Improve Weight Loss and Health Outcomes. Addendum to the 
Protocol in order to Study the Efficacy of Liraglutiude 3.0 
mg/d Combined with Phentermine 15 mg/d to Increase Weight 
Loss in a 12-Week Placebo-Controlled Trial, Following 
Completion of the Original 1-Year Study 
 
 
September 25, 2018 
 
 
NCT02911818 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Combining Lifestyle Modification and Liraglutide to 
Improve Weight Loss and Health Outcomes 
 
Addendum to the Protocol in order to Study the 
Efficacy of Liraglutiude 3.0 mg/d Combined with 
Phentermine 15 mg/d to Increase Weight Loss in a 12-
Week Placebo-Controlled Trial, Following Completion 
of the Original 1-Year Study   
 
 
 
 
 
INVESTIGATOR-INITIATED STUDY PROTOCOL 
 
UTN: U1111-1171-6243 
 
 
 
 
 
Department of Psychiatry 
Perelman School of Medicine, University of Pennsylvania 
3535 Market St # 3029 
Philadelphia, PA 19104 
 
 
 
Correspondence to: 
 
Thomas A. Wadden, Ph.D. 
 
Director, Center for Weight and Eating Disorders 
Perelman School of Medicine, 
University of Pennsylvania 
3535 Market Street, Suite 3029 
Philadelphia, PA 19104 
Phone: 215-898-7314 
Fax: 215-898- 2878 
wadden@mail.med.upenn.edu 
 


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Table of Contents 
BACKGROUND AND SIGNIFICANCE: ...................................................................... 5 
SPECIFIC OBJECTIVES: .............................................................................................. 6 
PRIMARY OBJECTIVE ....................................................................................................... 6 
SECONDARY OBJECTIVES ................................................................................................. 6 
RESEARCH DESIGN AND METHODS:...................................................................... 7 
STUDY HYPOTHESES: ....................................................................................................... 7 
ENDPOINTS: ..................................................................................................................... 8 
STUDY TYPE: .................................................................................................................... 8 
RATIONALE FOR STUDY DESIGN ...................................................................................... 9 
STUDY POPULATION: ................................................................................................ 10 
RATIONALE FOR STUDY POPULATION ............................................................................. 10 
INCLUSION CRITERIA ..................................................................................................... 10 
EXCLUSION CRITERIA .................................................................................................... 11 
WITHDRAWAL CRITERIA ................................................................................................ 12 
SUBJECT REPLACEMENT ................................................................................................ 13 
VISIT PROCEDURES ................................................................................................... 13 
FIGURE 1. STUDY FLOW DIAGRAM ................................................................................ 13 
SCREENING PROCEDURES .............................................................................................. 13 
SCREENING VISIT ........................................................................................................... 14 
RANDOMIZATION VISIT .................................................................................................. 14 
TABLE 1. SCHEDULE OF STUDY ASSESSMENTS AND LIFESTYLE INTERVENTION 
COUNSELING VISITS ...................................................................................................... 16 
LIFESTYLE COUNSELING VISITS – ALL GROUPS ............................................................ 17 
LIFESTYLE COUNSELING VISITS: THE THREE TREATMENT GROUPS .............................. 18 
FIGURE 2. DOSING SCHEDULE FOR LIRAGLUTIDE .......................................................... 19 
MEDICAL MONITORING VISITS ...................................................................................... 19 
ASSESSMENTS FOR EFFICACY ............................................................................... 20 
PRIMARY EFFICACY MEASURE ...................................................................................... 20 
SECONDARY EFFICACY MEASURES ................................................................................ 20 
ASSESSMENTS FOR SAFETY .................................................................................... 21 
SUBJECT COMPLIANCE ............................................................................................ 22 
STATISTICAL CONSIDERATIONS: ......................................................................... 22 
SAMPLE SIZE CALCULATION .......................................................................................... 22 
STATISTICAL METHODS ................................................................................................. 22 
DATA HANDLING AND RECORD KEEPING: ....................................................... 24 
ETHICS: .......................................................................................................................... 25 
STUDY SCHEDULE: ..................................................................................................... 25 
STUDY DRUGS AND MATERIALS: .......................................................................... 26 


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STUDY MEDICATION ...................................................................................................... 26 
PACKAGING AND LABELLING OF STUDY MEDICATION .................................................. 26 
STORAGE AND DRUG ACCOUNTABILITY OF STUDY MEDICATION .................................. 26 
RANDOMIZATION AND BLINDING ........................................................................ 27 
BREAKING OF BLINDED CODES ...................................................................................... 27 
CONCOMITANT ILLNESSES AND MEDICATIONS: ........................................... 27 
ADVERSE EVENTS: ..................................................................................................... 27 
LIABILITY AND SUBJECT INSURANCE: ............................................................... 30 
EVALUABILITY OF SUBJECTS:............................................................................... 30 
PREMATURE TERMINATION OF STUDY: ............................................................ 30 
PUBLICATION PLAN: ................................................................................................. 30 
REFERENCES: .............................................................................................................. 30 
DESCRIPTION OF THE PROPOSED EXTENSIONSTUDY……………………...34
 
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BACKGROUND AND SIGNIFICANCE: 
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A 5–10% reduction in body weight in obese individuals improves several risk factors for 
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cardiovascular disease (CVD) including elevated blood glucose, blood pressure, and 
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plasma triglyceride concentrations.1 Losses of this magnitude can be induced by a high 
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intensity program of lifestyle modification (i.e., diet, physical activity, and behavior 
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therapy) provided in 14 or more counseling sessions in 6 months. This is the frequency of 
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group or individual counseling recommended by a recent NIH expert panel.1 It also is the 
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frequency of brief (10-15 minute), individual counseling prescribed and reimbursed by 
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the Centers for Medicare and Medicaid Services (CMS).2 Remarkably, the efficacy of the 
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specific CMS model of counseling has not been evaluated. 
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A loss of 5-10% of initial weight also may be achieved with the use of pharmacologic 
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agents,3 including liraglutide 3.0,4 lorcaserin,5 combination naltrexone plus bupropion,6 
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and combination phentermine plus topirimate.7 Liraglutide 3.0 (Saxenda®) belongs to a 
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class of medications called glucagon-like peptide-1 (GLP-1) receptor agonists. 
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Liraglutide is a once-daily self-administered, subcutaneous (beneath the skin) injection 
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that may reduce appetite and help overweight or obese adults lose weight and it off. 
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Liraglutide is approved by the U.S. Food and Drug Administration (FDA) for chronic 
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weight management, when combined with a reduced-calorie diet and increased physical 
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activity. 
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Weight loss medications typically are used with a less intensive program of lifestyle 
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modification (e.g., monthly visits), consistent with the limitations of busy primary care 
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practices.3 Adding weight loss medication to high intensity lifestyle modification 
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typically results in a mean weight loss equal to the sum of the two separate interventions.8 
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This finding was demonstrated with sibutramine in studies of both obese adults8,9 and 
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adolescents.10 Wadden et al found that sibutramine alone (10-15 mg/d) reduced initial 
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weight by 5% at 1 year in adults, compared with 7% achieved with high intensity lifestyle 
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modification alone, and 12% resulting from the combination of the two therapies.8 
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Berkowitz et al found that lifestyle modification alone produced a 4% reduction in initial 
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weight in adolescents at 6 months, which increased to 8% with the addition of 
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sibutramine.10 
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Larger weight losses of 10-15% of initial weight are associated with greater 
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improvements in risk factors11 and are more consistent with obese individuals’ desired 
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weight loss goals.12, 13 Portion-controlled diets that provide 1000-1200 kcal/day (in the 
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form of liquid shakes, meal bars, and prepared entrees) reliably induce mean weight 
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losses that are 3 to 5 kg (and 3 to 5 percentage points) greater than losses achieved with 
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an equivalent calorie diet comprised of conventional foods.14, 15 This is because portion-
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controlled diets help patients come closer to meeting their prescribed calorie targets. 
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Numerous studies have reported losses of 10-12% of initial weight in subjects who (for 
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12-16 weeks) consumed a 1000-1200 kcal/d diet in combination with intensive lifestyle 
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modification.16, 17 
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The proposed 52-week randomized controlled trial will compare three treatment groups: 
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1) CMS lifestyle counselling (CMS-Alone); 2) CMS lifestyle counselling plus liraglutide 
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(i.e., CMS-Liraglutide), and 3) CMS-Liraglutide plus a 1000-1200 kcal/day portion-
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controlled diet (i.e., Multi-Component Intervention). This is the first evaluation of the 
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CMS-recommended schedule of lifestyle counselling (14 sessions in 26 weeks, followed 
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by monthly sessions in weeks 27-52) and the first assessment of the benefits of adding 
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liraglutide 3.0 to the CMS counselling program. The study will also assess the benefits of 
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adding a portion-controlled diet to the combination of CMS lifestyle counselling and 
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liraglutide, with a goal of achieving a mean weight loss of 14% or more of initial weight, 
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similar to losses our research team produced with the triple combination of high intensity 
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lifestyle modification, sibutramine, and a portion-controlled diet.9 
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Three factors suggest that the results of this study will significantly improve the 
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management of obesity in primary care practice. First, this is the first trial to assess the 
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efficacy of the CMS-recommended program of lifestyle modification for obesity, which 
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includes 14 brief (15-minute) individual counseling sessions in 26 weeks, delivered by a 
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physician, nurse practitioner, physician assistant, or registered dietitian (the latter 
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working incident to the former practitioners).2  Six additional monthly sessions are 
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provided in weeks 27-52. The demonstration of the efficacy of this intervention, as 
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indicated by the loss of approximately 5% of initial weight in 6 months, would facilitate 
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the fuller adoption of this treatment model in primary care practice. Our research team 
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also would facilitate this adoption by posting on a web site the lifestyle intervention that 
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we will use, which is based on the Diabetes Prevention Program.18 (CMS currently 
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provides practitioners no recommendations for a lifestyle intervention protocol.) Second, 
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the trial will demonstrate that practitioners can increase weight loss by 5% by combining 
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CMS counseling with liraglutide 3.0 (i.e., Saxenda) and increase it further with the 
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combination of liraglutide 3.0 plus a 1000-1200 portion-controlled diet (i.e., Multi-
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Component Intervention).  Increased weight loss will be associated with a third benefit – 
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greater improvements in CVD risk factors, mood, eating behavior, appetite, quality of 
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life, sleep, and satisfaction with weight loss. Subjects who receive adjunctive therapy also 
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will report greater satisfaction with their weight loss compared to individuals who receive 
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CMS lifestyle counseling alone.  Obese individuals would like to lose 25-35% of their 
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initial body weight but report being generally satisfied after achieving losses of 
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approximately 10% of baseline weight.12, 13 
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SPECIFIC OBJECTIVES: 
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Primary Objective 
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To compare the 52-week mean percentage reduction in initial weight achieved with 
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CMS-Alone to that achieved with both CMS-Liraglutide and the Multi-Component 
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Intervention.  
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Secondary Objectives 
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To compare the three interventions at week 52 in the proportion of subjects who lose 
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>5%, >10%, and >15% of initial weight, as well as the % reduction in weight at week 24 
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and the proportion of subjects who meet the categorical weight losses at this time.  
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To compare the three groups at week 52 on changes in cardiovascular disease (CVD) risk 
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factors (i.e, blood pressure, triglycerides, LDL and HDL cholesterol, C reactive protein, 
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and waist circumference), glycemic control (i.e., fasting blood sugar, HbA1c, insulin, and 
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HOMA), mood (PHQ-9), quality of life (i.e, SF-36 and IWQOL-Lite), eating behavior 
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(i.e., Eating Inventory, Eating Disorder Examination-Questionnaire, and Yale Food 
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Addiction Scale), appetite (i.e., visual analogue scales), sleep (i.e., Pittsburgh Sleep 
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Quality Index), and weight loss satisfaction.  
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RESEARCH DESIGN AND METHODS: 
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Study Hypotheses: 
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Primary aim 1: To compare the 52-week mean percentage reduction in initial weight 
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achieved with CMS-Alone to that achieved with both CMS-Liraglutide and the Multi-
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Component Intervention.  
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H1: CMS lifestyle counseling combined with liraglutide will produce significantly greater 
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mean weight loss at 52 weeks than will CMS-Alone (with expected mean losses of 9.5% 
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and 5.0%, respectively). The Multi-Component Intervention (i.e., CMS counseling + 
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liraglutide + portion-controlled diet) similarly will produce significantly greater mean 
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weight loss at 52 weeks than will CMS-Alone (with expected mean losses of 14.0% and 
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5.0%, respectively).  
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The trial has the following secondary aims and hypotheses. 
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Aim 2: To compare the 52-week mean percentage reduction in initial weight achieved 
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with the Multi-Component Intervention to that achieved with CMS-Liraglutide. 
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H2: The Multi-Component Intervention will produce significantly greater mean weight 
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loss at 52 weeks than will CMS-Liraglutide (with expected mean losses of 14.0% and 
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9.5%, respectively). 
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Aim 3: To compare the three treatment groups in the proportion of subjects who lose 
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>5%, >10% and >15% of initial body weight at week 52. 
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H3: A significantly greater proportion of subjects in the Multi-Component Intervention 
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will meet the three categorical weight loss criteria (i.e., >5%, >10% and >15% loss) than 
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will subjects assigned to CMS-Liraglutide which, in turn, will be superior to CMS-Alone.  
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Aim 4: To compare differences among the three treatment groups in the mean percentage 
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reduction in initial weight at week 24, as well as the proportion of subjects who meet the 
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three categorical weight loss criteria.    
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H4: Subjects assigned to the Multi-Component Intervention will lose significantly more 
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weight at 6 months than those assigned to CMS-Liraglutide which, in turn, will be 
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superior to CMS-Alone. Achievement of categorical weight loss criteria will follow the 
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same pattern. 
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Aim 5: To compare the three treatment groups on changes, as measured from 
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randomization to week 52, in cardiovascular disease (CVD) risk factors (i.e, blood 
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pressure, triglycerides, LDL and HDL cholesterol, C reactive protein, and waist 
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circumference), glycemic control (i.e., fasting blood sugar, HbA1c, insulin, and HOMA), 
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mood (PHQ-9), quality of life (i.e, SF-36 and IWQOL-Lite), eating behavior (i.e., Eating 
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Inventory, Eating Disorder Examination-Questionnaire, and Yale Food Addiction Scale), 
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appetite (i.e., visual analogue scales), sleep (i.e., Pittsburgh Sleep Quality Index), and 
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weight loss satisfaction. 
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H5: Subjects in the Multi-Component Intervention will achieve greater improvements on 
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these secondary outcomes than will those assigned to CMS-Liraglutide which, in turn, 
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will be superior to CMS-Alone. (We note that these latter comparisons are considered 
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exploratory. The study is not powered to determine significant differences among groups 
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on these outcomes.) 
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Endpoints: 
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Primary 
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The primary endpoint is change in body weight (i.e., % reduction in initial weight), as 
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measured from randomization to week 52. 
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Secondary 
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Secondary endpoints include mean percentage reduction in initial weight as measured 
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from randomization to week 24; the proportion of subjects who lose >5%, >10% and >15% 
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of initial body weight as measured from randomization to week 52 and to week 24; and 
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changes from randomization to week 52 in cardiovascular disease (CVD) risk factors (i.e, 
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blood pressure, triglycerides, LDL and HDL cholesterol, C reactive protein, and waist 
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circumference), glycemic control (i.e., fasting blood sugar, HbA1c, insulin, and HOMA), 
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mood (PHQ-9), quality of life (i.e, SF-36 and IWQOL-Lite), eating behavior (i.e., Eating 
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Inventory, Eating Disorder Examination-Questionnaire, and Yale Food Addiction Scale), 
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appetite (i.e., visual analogue scales), sleep (i.e., Pittsburgh Sleep Quality Index), and 
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weight loss satisfaction. (Please see Table 1 for study timeline and endpoint assessments.) 
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Study type: 
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This is a 52 week, single center, open-labeled, randomized controlled, parallel group 
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design trial. Neither subjects nor investigators will be masked to treatment assignment. 
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A total of 150 subjects with obesity, who are free of types 1 and 2 diabetes, as well as 
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contraindications to weight loss (described later), will be randomly assigned to one of 
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three treatment groups: 1) CMS lifestyle counseling (CMS-Alone; N = 50); 2) CMS 
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lifestyle counseling plus liraglutide (i.e., CMS-Liraglutide; N = 50); or 3) CMS-
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Liraglutide plus a portion-controlled diet (i.e., Multi-Component Intervention; N = 50).  
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Subjects in all three groups will have 14 brief (15 minute) lifestyle counseling visits the 
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first 24 weeks, followed by monthly visits in weeks 25-52. This is the schedule and 
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duration of counseling visits recommended by CMS.2 Counseling sessions will be 
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delivered by a nurse practitioner or registered dietitian (RD). (RDs are eligible to provide 
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lifestyle counseling under CMS rules, when supervised by a primary care provider. In 
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addition, in the U.S., the Affordable Care Act is likely to cover weight loss counseling as 
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provided by RDs and a range of other trained interventionists.)  Subjects in all three 
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groups also will have brief physician visits at weeks 1, 4, 8, 16, 24, 36, and 52 (total of 7 
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visits). These visits are needed for subjects in both liraglutide groups to monitor their 
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response to the medication. These visits are included for subjects in CMS-Alone to match 
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the intensity of medical care provided the two other groups.   
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This is an open-label trial, the rationale for which is discussed in the next section (i.e., 
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Rationale for Study Design). 
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The trial incorporates an additive treatment design, which will test the benefit of 
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intensifying CMS counseling with the addition of liraglutide 3.0, as well as liraglutide 3.0 
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combined with a 1000-1200 kcal/day portion-controlled diet.  
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Individual subjects will receive lifestyle counseling for 52 weeks. The total study 
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duration from time of first subject recruitment to data analysis and presentation of the 
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first abstract will be 2.5 years. (Please see Table 2 for study timeline.) 
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Rationale for Study Design 
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The study design does not include the use of a placebo in comparing CMS-Alone to 
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CMS-Liraglutide. This decision is based on multiple prior demonstration that liraglutide 
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is superior to placebo (i.e., the medication’s efficacy is not in question).19  We plan to use 
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liraglutide in the manner recommended by the U.S. Food and Drug Administration 
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(FDA), by adding it to a program of diet and exercise counseling. We have conducted 
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three previous studies in adults, which combined lifestyle modification with an FDA-
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approved weight loss medication (i.e., sibutramine). None of these studies included a 
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placebo (i.e., they were open-label studies). Two of the trials were published in the 
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New England Journal of Medicine,8, 20 and one in Archives of Internal Medicine.9 
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Our study design also does not include assignment to a Usual Care group, against which 
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to judge the efficacy of the CMS-Alone intervention (i.e., lifestyle counseling alone). We 
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have omitted a Usual Care group because of concerns that it does not meet current 
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guidelines from the U.S. Preventive Services Task Force to “offer all obese individuals 
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intensive lifestyle counseling.”21 Previous studies have shown that Usual Care induces a 
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weight loss of approximately 1 kg at 1 year,22 which potentially would present problems 
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in retaining subjects in the study (i.e., they would drop out because of dissatisfaction with 
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their weight change). The present study nonetheless will provide the first estimate (from a 
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randomized controlled trial) of the weight loss that can be expected from CMS 
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counseling. 
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The study design also does not include a treatment group that is assigned to CMS 
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counseling combined with a portion-controlled diet alone, without liraglutide. Numerous 
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prior studies have demonstrated that low-calorie, portion-controlled diets increase weight 
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loss as compared with a diet of conventional foods.14, 15, 23 We do not think there is a need 
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to replicate this finding in the present study. Instead, we wish to focus this trial on 
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inducing and maintaining large weight losses (> 10% of initial weight), as desired by 
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obese individuals.12, 13  We believe that the combination of CMS counseling plus 
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liraglutide plus a 1000-1200 kcal/d portion-controlled diet provides the best opportunity 
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for achieving and maintaining robust losses.24 
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Study Population: 
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This study is open to men and women with obesity who meet the criteria described below 
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(i.e., inclusion/exclusion). Subjects will be recruited from advertisements in local media 
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outlets (e.g., newspapers, online ads), as well as flyers posted at the University of 
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Pennsylvania. We also will advertise the study to health care providers who work in 23 
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Penn-owned primary care practices, located throughout greater Philadelphia.   
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Rationale for study population 
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The study population has been selected to be consistent with that for which the US FDA 
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approved liraglatide 3.0 (Saxenda) for the treatment of obesity. 
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Number of subjects to be randomized: 150 
290 
 
291 
Planned number of subjects to be screened: 175 in-person screenings to obtain 150 
292 
 
293 
Planned number of subjects to be treated in run-in period: No run-in period 
294 
 
295 
Planned number of subjects to be randomized to study medication(s): 100 
296 
 
297 
 
298 
Inclusion Criteria 
299 
 
300 
1. BMI ≥30 kg/m² and ≤55 kg/m²  
301 
2. Age ≥ 21 years and ≤ 70 years 
302 
3. Eligible female patients will be: 
303 


   Version 3.3   September 25, 2018 
Page 11 
 
 non-pregnant, evidenced by a negative urine dipstick pregnancy test 
304 
 non-lactating 
305 
 surgically sterile or postmenopausal, or they will agree to continue to use 
306 
an accepted method of birth control during the study 
307 
4. Ability to provide informed consent before any trial-related activities 
308 
5. Subjects must: 
309 
 have a primary care provider (PCP) who is responsible for providing 
310 
routine care 
311 
 have reliable telephone or Internet service to communicate with study staff  
312 
 understand and be willing to comply with all study-related procedures and 
313 
agree to participate in the study by giving written informed consent 
314 
 plan to remain in the Philadelphia area for the next 18 months or more 
315 
 
316 
Exclusion Criteria 
317 
 
318 
1. Pregnant or nursing, or plans to become pregnant in the next 18 months, or not 
319 
using adequate contraceptive measures 
320 
2. Personal or family history of medullary thyroid cancer or multiple endocrine 
321 
neoplasia syndrome type 2 
322 
3. Uncontrolled hypertension (systolic blood pressure ≥ 160 mm Hg or diastolic 
323 
blood pressure ≥ 100 mm Hg) 
324 
4. Type 1 diabetes 
325 
5. Type 2 diabetes 
326 
6. A fasting glucose ≥ 126 mg/dl (on second assessment after first elevated value) 
327 
7. Recent history of cardiovascular disease (e.g., myocardial infarction or stroke 
328 
within the past 6 months), congestive heart failure, or heart block greater than first 
329 
degree 
330 
8. Clinically significant hepatic or renal disease 
331 
9. Thyroid disease, not controlled 
332 
10. History of malignancy (except for non-melanoma skin cancer) in past 5 years 
333 
11. Current major depressive episode, active suicidal ideation, or history of suicide 
334 
attempts 
335 
12. Psychiatric hospitalization within the past 6 months 
336 
13. Self-reported alcohol or substance abuse within the past 12 months, including at-
337 
risk drinking (current consumption of ≥ 14 alcoholic drinks per week) 
338 
14. Use in past 3 months of medications known to induce significant weight loss (i.e., 
339 
prescription weight loss medications) or weight gain (e.g., chronic use of oral 
340 
steroids, second generation antipsychotics) 
341 
15. Loss of ≥ 10 lb of body weight within the past 3 months 
342 
16. History of (or plans for) bariatric surgery 
343 
17. Inability to walk 5 blocks comfortably or engage in some other form of aerobic 
344 
activity (e.g., swimming) 
345 
18. Known or suspected allergy to trial medication(s), excipients, or related products 
346 
19. Hypersensitivity to liraglutide or any product components  
347 
20. The receipt of any investigational drug within 6 months prior to this trial 
348 
21. Previous participation in this trial (e.g., randomized and failed to participate) 
349 


   Version 3.3   September 25, 2018 
Page 12 
 
22. History of pancreatitis 
350 
23. Subjects will be included/excluded according to the latest updated US PI. 
351 
 
352 
Withdrawal Criteria 
353 
 
354 
A subject may voluntarily withdraw from the study at any time for any reason. The 
355 
investigator or sponsor also may withdraw the subject from further participation at any 
356 
time, if it is considered in the best interest of the subject or the study, without prejudice to 
357 
the subject’s future medical care.  
358 
 
359 
The primary reason for a subject’s premature discontinuation from the study will be 
360 
selected from the following standard categories and documented in the source 
361 
documents: 
362 
 
363 
Adverse event (AE): One or more clinical or laboratory events which, in the medical 
364 
judgment of the investigator, are grounds for discontinuation, even if the event does not 
365 
appear to be related to study drug. The subject may withdraw because of an AE even if 
366 
the investigator does not feel that it is grounds for discontinuation. This category includes 
367 
subject death. 
368 
 
369 
Withdrawal of consent: The subject desires to withdraw from further participation in the 
370 
study. 
371 
 
372 
Lost to follow-up: In the case of subjects who do not return to the center for study 
373 
procedures and cannot be contacted, study personnel will make vigorous and repeated 
374 
attempts (minimum of 3) to contact the subject. These attempts will include at least 1 
375 
certified mail receipt. If all attempts to contact the subject fail, that subject will be 
376 
considered to be lost to follow-up and discontinued from the study. 
377 
 
378 
Protocol violation: The subject’s laboratory or other findings or conduct fail to meet the 
379 
protocol entry criteria or fail to adhere to the protocol requirements. 
380 
 
381 
Subject pregnancy or intention of becoming pregnant 
382 
 
383 
Subjects will be withdrawn according to risk mentioned in the latest updated US PI. 
384 
 
385 
The Stopping Criteria for individual subjects include: 
386 
 
387 
1. The Principal Investigator and/or Medical Monitor conclude it is unsafe for the 
388 
subject to continue. 
389 
2. A new diagnosis is made of a significant medical condition which could influence 
390 
the response to liraglutide (e.g., renal failure). 
391 
3. A medication is begun that could alter the subject’s responses to liraglutide. 
392 
 
393 
Subjects meeting individual stopping criteria will be withdrawn from the trial. 
394 
 
395 


   Version 3.3   September 25, 2018 
Page 13 
 
Subject Replacement 
396 
 
397 
Subjects who prematurely discontinue from the study or become ineligible will not be 
398 
replaced. 
399 
 
400 
Visit Procedures 
401 
 
402 
Figure 1 shows the flow of subjects through randomization. Table 1 presents the schedule 
403 
of study assessments and treatment visits.  
404 
 
405 
Figure 1. Study Flow Diagram 
406 
 
407 
 
408 
 
409 
Screening Procedures  
410 
 
411 
All applicants will be screened by phone to determine whether they potentially meet 
412 
eligibility criteria. We will obtain a waiver of written documentation of consent for the 
413 
telephone screen. Those who appear to meet eligibility criteria and remain interested in 
414 
the trial will be scheduled for an in-person interview. The Weight and Lifestyle Inventory 
415 
(WALI),25 a paper-and-pencil inventory that assesses general eating and lifestyle 
416 
behaviors, and the Beck Depression Inventory (BDI),26 will be forwarded to eligible 
417 
subjects following the phone screen and completed by them prior to their 
418 
screening/informed consent visit. (All patients and subjects at our Center complete the 
419 
WALI and BDI to facilitate their initial interview.) The in-person interview will be 
420 
conducted by a psychologist, who will obtain informed consent and evaluate subjects’ 
421 
behavioral eligibility (i.e., willingness and appropriateness to participate). This will 
422 


   Version 3.3   September 25, 2018 
Page 14 
 
include our assessment of the applicant’s mood (as measured by interview and the BDI) 
423 
and suicidality (including history of suicidal ideation and behavior, as assessed at 
424 
screening by interview and the Columbia-Suicide Severity Rating Scale).  
425 
 
426 
Subjects who remain interested and pass this portion of the assessment will proceed to 
427 
meet with the study physician, who will obtain a medical history and conduct a physical 
428 
examination to determine medical eligibility. Persons who continue to remain eligible 
429 
will proceed to have an electrocardiogram (EKG) and fasting blood test to determine that 
430 
final eligibility criteria are met. As detailed below, safety screening labs include a 
431 
comprehensive metabolic panel (including glucose), lipids, hemoglobin A1c, insulin, hs-
432 
CRP and a urine pregnancy test (for females of child-bearing age).  
433 
Screening Visit 
434 
 
435 
The following procedures will be completed at the screening visit as discussed above: 
436 
informed consent; behavioral evaluations; medical history; full physical exam; review of 
437 
medication; 12-lead EKG; blood draw; weight; height; and sitting blood pressure and 
438 
pulse rate. For women of childbearing potential, a urine pregnancy test also will be 
439 
performed. Results of these tests will be reviewed by the study physician to determine 
440 
whether the subject has any contraindications to weight loss or to the use of liraglutide, as 
441 
detailed in the inclusion/exclusion criteria.  
442 
 
443 
Participants also will be provided a food record and asked to complete it for 1 week 
444 
so that they can determine, prior to starting the study, whether they want to keep 
445 
daily food records for 6 months or more. Keeping such records is a component of 
446 
lifestyle counseling.Randomization Visit 
447 
 
448 
Participants who meet all eligibility criteria assessed at the screening visit will be 
449 
scheduled for a randomization screening visit at the Center within 3 weeks of their 
450 
screening. Approximately 2-3 days before the randomization visit, they will be instructed 
451 
to complete the self-reported outcomes (described later), either online (using a link e-
452 
mailed to them) or using paper-and-pencil questionnaires (for those who prefer this 
453 
method). Their questionnaires will be reviewed for completeness at the outset of the 
454 
randomization visit, with any omissions or errors corrected. The participant’s weight, 
455 
blood pressure, and pulse will then be measured, following the methods described later 
456 
(see Assessment for Efficacy). 
457 
 
458 
Participants will then be randomly assigned to the three interventions in equal numbers 
459 
(i.e., 1:1:1 ratio). This will be accomplished using a computer-generated algorithm 
460 
operated by the Center for Weight and Eating Disorders at the University of 
461 
Pennsylvania. Assignment will be made from randomly varied block sizes (3, 6, or 9).20 
462 
 
463 
Following randomization, all participants will have a medical visit with the study 
464 
physician who will instruct patients in the two medication groups in the use of liraglutide 
465 
3.0 (as described later) and provide the first months supply of medication. All 
466 


   Version 3.3   September 25, 2018 
Page 15 
 
participants also will have an individual lifestyle intervention session (as described in the 
467 
next session). 
468 


   Version 3.3   September 25, 2018 
Page 16 
 
Table 1. Schedule of Study Assessments and Lifestyle Intervention Counseling Visits 
469 
 
Weeks 
 
Screen 
R/1 
2 
3 
4 
6 
8 
10 
12 
14 
16 
18 
20 
22 
24 
28 
32 
36 
40 
44 
48 
52 
 
Visit Number 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
All subjects 
Informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Behavioral 
evaluation 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
History and 
physical 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood draw 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
Labs 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
Self-reported 
outcomes 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
Medical visit 
 
X 
 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
Lifestyle 
intervention 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
(Weight, BP, 
HR) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CMS-Liraglutide Group and Multi-Component Intervention Group Only (CMS + Liraglutide + Meal Replacements) 
Liraglutide 
provided 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Multi-Component Intervention Only (CMS + Liraglutide + Meal Replacements) 
Meal 
replacements 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
Note. R=randomization. Randomization will be followed immediately by week 1 medical visits and lifestyle intervention sessions. Columns shaded 
in grey indicate principal outcome assessment visists. 


   Version 3.3   September 25, 2018 
Page 17 
 
Lifestyle Counseling Visits – All Groups 
470 
 
471 
Subjects in all three treatment groups (i.e., CMS-Alone; CMS-Liraglutide; and Multi-
472 
Component Intervention) will receive the same program of diet, physical activity, and 
473 
behavior therapy, as currently recommended (and reimbursed) by the CMS.2 All study 
474 
subjects will be provided 14 brief (15 min), face-to-face visits during the first 6 months 
475 
and 7 visits the second 6 months (total of 21 visits). Lifestyle counseling will be delivered 
476 
by a nurse practitioner (NP) or by a registered dietitian (RD), the latter working incident 
477 
to an NP or physician, as required by CMS.28  
478 
 
479 
Visits will be scheduled weekly for the first 4 weeks (weeks 1, 2, 3, and 4) and every-
480 
other week from weeks 6-24  (weeks 6, 8, 10, 12, 14, 16, 18, 20, 22, and 24) and will be 
481 
delivered following an abbreviated version of the Diabetes Prevention Program (DPP).18 
482 
(We developed and demonstrated the efficacy of this protocol in our prior POWER-UP 
483 
study.) From weeks 25-52, subjects will have one brief (15 min) visit per month, as 
484 
provided by CMS (weeks 28, 32, 36, 40, 44, 48, and 52).  
485 
 
486 
Dietary intake will be prescribed following methods used in DPP18 and the Look 
487 
AHEAD study.29, 30 Subjects in CMS-Alone and CMS-Liraglutide who weigh <250 lb 
488 
will be prescribed a diet of 1200-1499 kcal/d, comprised of conventional foods, with 
489 
approximately 15-20% kcal from protein, 20-35% from fat, and the remainder from 
490 
carbohydrate. (Those who weigh >250 lb will be prescribed 1500-1800 kcal/d.) They will 
491 
be instructed (for the first 24 weeks) to record their food and calorie intake daily, using 
492 
paper-and-pencil diaries or on-line trackers (including MyFitnessPal or Lose-It). Subjects 
493 
will be provided meal plans (which offer breakfast, lunch, and dinner options for the 
494 
week) that were provided in the DPP18 and POWER-UP studies.20 The meal plans are 
495 
culturally tailored. (As described later, subjects in the Multi-Component Intervention will 
496 
be prescribed a 1000-1200 portion controlled diet for weeks 4-16 with 2 subsequent 
497 
weeks of re-feeding, but thereafter will consume the same diet prescribed for subjects in 
498 
the two other treatment groups.) 
499 
 
500 
The physical activity prescription will be similar to that used in Look AHEAD30 and 
501 
POWER-UP.20 All individuals will be instructed to engage in low-to-moderate intensity 
502 
physical activity (principally walking or similar aerobic activity) 5 days per week, 
503 
gradually building to ≥180 minutes per week by week 24. The goal will be increased to 
504 
>225 minutes/week from weeks 25-52, consistent with targets required for the 
505 
maintenance of lost weight.31 Subjects will be instructed to record their activity daily and 
506 
will receive a traditional pedometer (Yamax, Digi-Walker) if they do not own a smart 
507 
phone with which to track their steps.  
508 
 
509 
The 15 minute intervention visits in the three treatment groups will be conducted using 
510 
the same format, employed in the POWER-UP study.20 A subject first will be weighed, in 
511 
light clothing without shoes. Subject and provider will discuss the weight change from 
512 
the prior session and whether it meets expectations. They will then review the subject’s 
513 
food and activity records for their prior week to determine the number of days records 
514 
were kept and the total number of calories consumed and minutes of activity for the 
515 


   Version 3.3   September 25, 2018 
Page 18 
 
week. Problem solving will be used to address any difficulties encountered. (Records 
516 
from additional weeks will be reviewed as time allows.) The provider will then review a 
517 
new topic in weight management, from the treatment protocol, and discuss the subject’s 
518 
accompanying homework assignments for the next session. Subject handouts, which 
519 
summarize the key learning points and homework assignments for the next session, will 
520 
be provided for each session. The 14 sessions during the first 24 weeks will provide a full 
521 
curriculum on behavioral weight control. The 7 sessions from weeks 25-52 will address 
522 
cardinal behaviors for maintaining lost weight, including regular monitoring of body 
523 
weight, high levels of physical activity, and relapse prevention.32 Food and activity 
524 
records will be collected for the first 24 weeks. 
525 
 
526 
Subjects will be provided print materials, including handouts and food and activity 
527 
diaries, for those who wish them. However, the 21 DPP lessons20 will be posted on our 
528 
Center’s web-site, and subjects will have the option of recording their food intake using a 
529 
variety of apps. Our guiding principle is to tailor the method in which the DPP is 
530 
delivered to meet the subjects’ preferences.  
531 
 
532 
Missed visits will be rescheduled whenever possible. If the subject is unable to complete 
533 
the visit in person, a telephone call of 15 minute visits may be substituted for the face-to-
534 
face meeting. The same meeting format, including a report of the subject’s weight, will 
535 
be followed for phone-delivered sessions as face-to-face meetings. A growing body of 
536 
evidence indicates that phone-delivered lifestyle counseling is as effective as face-to-face 
537 
meetings.33, 34 
538 
 
539 
Interventionists will include RDs and NPs who are experienced in delivering lifestyle 
540 
modification. Before beginning the study, interventionists will receive a 2-hour overview 
541 
of obesity and its behavioral management, followed by ongoing monthly supervision to 
542 
deliver the DPP, following the detailed protocols developed for POWER-UP. 
543 
Interventionists will treat equal numbers of subjects in each of the three treatment groups 
544 
(to eliminate the possibility of confounding of interventionist and treatment group).  
545 
Lifestyle Counseling Visits: The Three Treatment Groups 
546 
 
547 
CMS-Alone. The intervention for subjects assigned to CMS-Alone is described above. 
548 
There are no additions are alterations to this treatment plan. 
549 
 
550 
CMS-Liraglutide. Participants in this group will receive the identical program of 
551 
lifestyle modification as those in the CMS-Alone group. The former individuals, 
552 
however, will be provided liraglutide 3.0 (Saxenda) beginning at week 1. Liraglutide 3.0,  
553 
a glucagonlike peptide-1 receptor agonist, is a once-daily self-administered, subcutaneous 
554 
injection.19 Liraglutide 3.0 will be provided as pre-filled, disposable, personal injectors. 
555 
Patients will be taught (by the study physician) how to properly perform subcutaneous 
556 
injections into their abdomen, thigh, or upper arm. In addition, patients will be given an 
557 
instruction card about how to administer the medication. To reduce the likelihood of 
558 
gastrointestinal symptoms (e.g., nausea, vomiting), the medication will be initiated at 0.6 
559 
mg daily for 1 week, and then increased by 0.6 mg/day in weekly intervals until a dose of 
560 
3 mg/day is achieved (please see below for dosing schedule). Patients will be instructed 
561 


   Version 3.3   September 25, 2018 
Page 19 
 
that if they miss a dose, to resume the once-daily regimen with the next scheduled dose 
562 
and not to give an extra dose or higher dose. If patients miss more than 3 days, they will 
563 
be instructed to call the study coordinator/physician who will initiate therapy at 0.6 
564 
mg/day to avoid gastrointestinal symptoms. Patients who do not tolerate an increased 
565 
dose during dose escalation will have a delayed dose escalation by up to 7 days. Study 
566 
medical staff will help participants develop a medication schedule, based on when and 
567 
where participants will take the medication each day and how they will remind 
568 
themselves to do so. 
569 
 
570 
Figure 2. Dosing Schedule for Liraglutide 
571 
 
572 
 
573 
 
574 
Lifestyle interventionists working with subjects in this treatment group will briefly 
575 
review the individual’s medication adherence at each visit, determining the number of 
576 
days liraglutide was used each week and identifying reasons for missed doses. The 
577 
number of doses of medication taken each week will be tracked. Lifestyle interventionists 
578 
will not query subjects about side-effects. These will be reported to the research 
579 
coordinator or the study physician (or NP) at regularly scheduled visits.   
580 
 
581 
Multi-Component Intervention. Subjects in this group will receive the same treatment 
582 
as those in CMS-Liraglutide, with one exception. Beginning at week 4 (4th brief 
583 
counseling visit), they will be instructed to consume, for 12 weeks (weeks 4-16), a 1000-
584 
1200 kcal/d diet that provides four servings daily of a liquid shake (Health Management 
585 
Resources – HMR; 160 kcal per shake) and an evening meal comprised of a frozen food 
586 
entrée (250-300 kcal), with a serving of fruit and a salad. Another serving of fruit will be 
587 
permitted after dinner, providing a diet of approximately 1000-1200 kcal/day.16, 17 All 
588 
HMR products will be provided free of charge; subjects will be responsible for 
589 
purchasing frozen food entrees and other foods.  From weeks 17-18, subjects will be 
590 
prescribed a re-feeding diet that gradually replaces the consumption of shakes with 
591 
conventional foods, so that they use of shakes will be fully terminated by week 18. 
592 
Subjects will record daily the number of meal replacements they use. (Prescription of the 
593 
portion-controlled diet is expected to increase weight loss by 3 to 5 kg in the first 24 
594 
weeks, as compared to consumption of the conventional 1200-1500 kcal/d diet.)14, 15 
595 
Medical Monitoring Visits 
596 
 
597 
Participants in all three groups also will have brief medical visits (10-15 minutes) with a 
598 
physician at weeks 1, 4, 8, 16, 24, 40, and 52 (total of 7 visits). These visits are needed 
599 
for participants in both liraglutide groups to monitor their response to the medication and 
600 
to check for possible complications of early weight loss. These visits are included for 
601 


   Version 3.3   September 25, 2018 
Page 20 
 
participants in CMS-Alone to match the intensity of medical care provided the two other 
602 
groups. Participants in CMS-Alone will be instructed in the relation of excess weight to 
603 
health and review results of their laboratory tests. At each medical visit, participant’s 
604 
weight and vital signs will be measured and their response to the medication will be 
605 
assessed. Study subjects will be asked whether there have been any changes in their 
606 
health or medications. For all non-study-related medical events, participants will be 
607 
referred to their own primary care providers. Participants also will be asked about their 
608 
mood or any thoughts of harming themselves, as assessed by the Columbia-Suicide 
609 
Severity Rating Scale (C-SSRS).27 In the event of reports of suicidal ideation or 
610 
disturbances in mood, participants will be referred to the study’s psychologist or 
611 
psychiatrist for further evaluation, as appropriate.   
612 
 
613 
Assessments for Efficacy 
614 
 
615 
Participants will attend 3 major outcome assessment visits, conducted at randomization, 
616 
week 24 and week 52 (see Table 1). All outcomes described below will be measured on 
617 
these three occasions.  
618 
Primary Efficacy Measure 
619 
 
620 
The primary outcome is % reduction in initial body weight, as measured from 
621 
randomization to week 52. Secondary outcomes include the proportion of participants 
622 
who at week 52 lose >5%, >10%, and >15% of initial weight, as well as % reduction in 
623 
weight at week 24 and the proportion of participants who meet the three categorical 
624 
weight losses at this time.  Body weight will be measured on a digital scale (to the nearest 
625 
0.1 kg) with participants dressed in light clothing, without shoes. Two measurements will 
626 
be taken on each occasion and averaged. Weight will be measured by an assessor masked 
627 
to participants’ treatment condition.  (Body weight also will be measured at each lifestyle 
628 
counseling visit but the assessor will not be masked to treatment condition on these 
629 
occasions.)  
630 
Secondary Efficacy Measures  
631 
 
632 
The secondary efficacy measures include changes in cardiovascular disease (CVD) risk 
633 
factors (i.e, blood pressure, triglycerides, LDL and HDL cholesterol, C reactive protein, 
634 
and waist circumference), glycemic control (i.e., fasting blood sugar, HbA1c, insulin, and 
635 
HOMA), mood (PHQ-9), quality of life (i.e, SF-36 and IWQOL-Lite), eating behavior 
636 
(i.e., Eating Inventory, Eating Disorder Examination-Questionnaire, and Yale Food 
637 
Addiction Scale), appetite (i.e., visual analogue scales), sleep (i.e., Pittsburgh Sleep 
638 
Quality Index), and satisfaction with weight loss.  
639 
 
640 
Cardiometabolic risk factors will be assessed at screening and weeks 24 and 52, 
641 
following methods described previously.4, 20 (Screening values will be used as the 
642 
randomization value, given that they will be obtained within 3 weeks of participants 
643 
being randomized.)   
644 
 
645 


   Version 3.3   September 25, 2018 
Page 21 
 
Fasting blood samples (i.e., following an 8-hr overnight fast) will be drawn by study 
646 
personnel on each occasion and assayed for comprehensive metabolic panel (including 
647 
glucose), lipids (e.g., triglycerides, total-, HDL-, and LDL-cholesterol), hemoglobin A1c, 
648 
insulin, and hs-CRP. Insulin sensitivity will be calculated using HOMA. (Blood samples 
649 
will be analyzed by Quest Diagnostics.)  
650 
 
651 
Blood pressure and pulse will be measured at each outcome assessment using an 
652 
automated monitor (Dinamap, model 9300).4, 20 Two readings will be taken on each 
653 
occasion (at 1-minute intervals), after participants have been seated for at least 5 minutes. 
654 
(Blood pressure and pulse also will be measured at all medical visits, as well as at 
655 
lifestyle counseling visits.)  
656 
 
657 
Waist circumference will be measured (following methods described previously) to the 
658 
nearest 0.1 cm on the same three occasions.35 Two waist measurements will be obtained 
659 
at each assessment visit and averaged. 
660 
 
661 
Mood, quality of life, eating behavior, and appetite. Mood will be assessed on the 
662 
same schedule as the primary outcome using the PHQ-9.36 Quality of life will be assessed 
663 
on the same schedule as the primary outcome using SF-36 37 and IWQOL-Lite.38 
664 
Cognitive restraint, disinhibition, and hunger will be evaluated at the same time, using the 
665 
Eating Inventory (EI)39 and visual analogue scales40, and binge eating will be assessed by 
666 
the Eating Disorder Examination-Questionnaire (EDE-Q).41 Food addiction will be 
667 
measured using the Yale Food Addiction Scale.42 Satisfaction with weight loss will be 
668 
assessed following methods used by Foster and Wadden.   
669 
 
670 
Assessments for Safety 
671 
 
672 
Safety endpoints include physical examination, adverse events (AEs), standard laboratory 
673 
tests, and mental health/suicidal behavior as assessed by the Columbia Suicide Severity 
674 
Rating Scale (C-SSRS). As detailed above, participants in all three groups also will have 
675 
brief medical visits (10-15 minutes) with a physician at weeks 1, 4, 8, 16, 24, 40, and 52 
676 
(total of 7 visits). These visits are needed for participants in both liraglutide groups to 
677 
monitor their response to the medication and to check for possible complications of early 
678 
weight loss. At each medical visit, participant’s response to the medication will be 
679 
assessed. Study subjects will be asked whether there has been any change in their health 
680 
or medications. They also will be asked about their mood or any thoughts of harming 
681 
themselves, as determined by the C-SSRS. In the event of adverse mental health events, 
682 
participants will be referred to the study’s psychologist or psychiatrist for further 
683 
evaluation, if required. For all non-study-related medical events, participants will be 
684 
referred to their own primary care provider.  
685 
 
686 
Participants will have fasting blood draws (comprehensive metabolic panel, lipids, 
687 
hemoglobin A1c, insulin, hs-CRP) at screening, and weeks 24 and 52. Vital signs (blood 
688 
pressure and pulse) and weights will be measured at screening and weeks 1, 2, 3, 4, 6, 8, 
689 
10, 12, 14, 16, 18, 20, 22, 24, 28, 32, 36, 40, 44, 48, and 52.  
690 


   Version 3.3   September 25, 2018 
Page 22 
 
 
691 
Subject Compliance 
692 
 
693 
We will measure subject’s medication adherence using injection counts from visual 
694 
inspection of the dose counter taken from subjects’ injection pens. Patients will be 
695 
instructed to bring the pen to each session, and we will record missed doses and problem 
696 
solve with patients if they are missing doses. Patients will be instructed to keep a 
697 
medication diary, as part of their food and activity monitoring. 
698 
 
699 
STATISTICAL CONSIDERATIONS: 
700 
Sample Size Calculation 
701 
 
702 
At week 52, subjects assigned to CMS-Alone are predicted to lose 5% (SD=5.0) of initial 
703 
weight, while those in CMS-Liraglutide will lose 9.5% (SD=7.0), and those assigned to 
704 
the Multi-Component Intervention will lose 14% (SD=8.0). The predicted effect for 
705 
CMS-Alone is based on the results of the Hopkins POWER study in which 15 brief (15-
706 
20 min) individual telephone calls with a trained interventionist induced a mean loss of 
707 
6.1 kg in 24 weeks (equal to 5% of initial weight). The effect for CMS-Liraglutide is 
708 
estimated at 9.5%, with the expectation that liriglutide 3.0 mg/d will increase weight loss 
709 
above placebo by 4.5% (a conservative estimate based on results of the three SCALE 
710 
studies summarized in the Saxenda PI).19 The 14% reduction in initial weight for the 
711 
Multi-Component Intervention is based on our prior results with the combination of an 
712 
intensive lifestyle intervention plus sibutramine plus a 1000-1200 kcal/d diet.9 
713 
 
714 
Using a sample size equation for longitudinal clustered samples, a randomization sample 
715 
of 50 subjects in CMS-Alone, 50 in CMS-Liraglutide, and 50 in the Multi-Component 
716 
Intervention provides >80% power to detect the two primary contrasts to be statistically 
717 
significant at the Holm’s43 adjusted alpha levels noted above. This estimate allows for 
718 
20% attrition during the 52-week trial, resulting in approximately 40 treatment 
719 
completers per group. (The 20% attrition level is conservative; it is higher than what we 
720 
observe in most of our trials conducted at Penn.) The ITT longitudinal statistical design 
721 
will further improve power by allowing the inclusion of available data for non-completers 
722 
and the adjustment of possible variance reducing baseline covariates. All secondary 
723 
analyses will be considered exploratory and evaluated at the alpha = 0.05 level. The 
724 
power analysis was conducted using PASS 11. 
725 
Statistical Methods 
726 
 
727 
Preliminary Analyses 
728 
 
729 
All data will first be assessed by the data management staff for missing data and out-of-
730 
range values with basic statistical procedures such as univariate statistics (i.e., means, 
731 
standard deviations, ranges, frequencies, proportions, percentiles) and graphs, such as 
732 
histograms, box and whisker plots, scatter plots and Q-Q plots. In addition, plots will be 
733 
produced of individual and average trajectories of all repeated measures over time 
734 
according to assigned treatment. All questions of data quality and integrity will be 
735 


   Version 3.3   September 25, 2018 
Page 23 
 
investigated before any statistical modeling is conducted.  
736 
 
737 
Next, a preliminary analysis of all outcome and baseline demographic variables will be 
738 
performed to test for differences in baseline measures between the randomized groups. 
739 
The test of the adequacy of randomization will consist of tests of differences between the 
740 
treatment conditions to see if the baseline variables are equally distributed between them. 
741 
These baseline comparisons will be based on: t-tests or Wilcoxon rank sum tests for 
742 
continuous variables, depending on the symmetry of the distributions; on Chi-square, 
743 
Fisher’s Exact or logistic regression for binary or ordinal variables; and on Poisson log-
744 
linear regression for count data. If imbalances are found at baseline, then the relevant 
745 
variables will be treated as confounders in the post study analyses. 
746 
 
747 
The primary analysis will test the hypothesis that subjects randomly assigned to CMS-
748 
Liraglutide and the Multi-Component Intervention will lose a significantly greater 
749 
percentage of initial weight at week 52 than will those assigned to CMS-Alone. A linear 
750 
mixed model will be fit using the mixed procedure in the statistical software package 
751 
SAS, version 9.3. An intention-to-treat (ITT) analysis (including all randomized subjects) 
752 
will fit an unstructured covariance matrix to adjust for the repeated measures data 
753 
clustered with the individual subject. In addition, these models will contain the following 
754 
fixed effects: main effect for change from baseline to each follow-up visit (weeks 24 and 
755 
52); group (3 treatment conditions); and the interaction between the visit and group.  
756 
 
757 
The study’s primary outcome will consist of two pairwise comparisons: 1) 52 week % 
758 
reduction in initial weight in CMS-Alone compared with CMS-Liraglutide; and 2) 52-
759 
week % reduction in initial weight in CMS-Alone compared with the Multi-Intervention. 
760 
Based on the Holm’s procedure, which adjusts for multiple comparisons, the smaller of 
761 
the two p values resulting from analyses of our two primary contrasts will be compared at 
762 
alpha equal to 0.025 and, if significant, the other contrast will be evaluated at 0.05.44  
763 
 
764 
Comparison of CMS-Liraglutide and the Multi-Component Intervention is considered a 
765 
secondary outcome and will be examined with alpha equal to 0.05. 
766 
 
767 
All randomized participants will be included in the primary intention-to-treat (ITT) 
768 
analysis. A per protocol analysis will be conducted that includes only those participants 
769 
who provide a measurement of body weight at week 52 (with a window of +4 weeks). All 
770 
randomized participants will be included in the safety analysis.  
771 
 
772 
Secondary Analyses 
773 
 
774 
Similar analytic strategies will be employed for all other continuous secondary efficacy 
775 
endpoints, as well as for binary (dichotomous outcomes; i.e., percentage of participants 
776 
who achieve different criterion weight losses). For the logistic model, differences will be 
777 
presented as odds ratios with confidence intervals; for linear model, the least squares 
778 
means and standard errors will be presented with confidence intervals. Analyses of all 
779 
secondary outcomes will be considered exploratory, with all pairwise-comparisons of the 
780 
three intervention groups examined with alpha equal to 0.05. 
781 


   Version 3.3   September 25, 2018 
Page 24 
 
Missing Data 
782 
 
783 
All analyses will be conducted using the ITT principle, in which all available data on all 
784 
randomized patients are included.  This approach minimizes bias if participants drop out 
785 
of the intervention for different reasons. Assuming adequate fit of the mixed effects 
786 
models to the data, the proposed nested random effects models are the most robust to 
787 
missing data assumptions among standard longitudinal models that analyze all subjects 
788 
regardless of how many post-randomization visits are missed.45 The following missing or 
789 
unbalanced data scenarios can be accommodated by such models: attrition (drop out), 
790 
missed interim visits, and missing covariate data where a subject is interviewed but data 
791 
are missing on covariates of interest.  All three types of missing data are handled by way 
792 
of maximum likelihood under the proposed mixed effects models and the missing at 
793 
random assumption (MAR). Therefore, we will explore the potential bias of missing data 
794 
by comparing completers and non-completers to see if they differ systematically on 
795 
values of non-missing variables. There are many ways to assess the assumption of MAR. 
796 
We will consider imputing missing endpoint data using multiple imputation techniques, 
797 
fitting selection models (e.g. MNAR), and fitting pattern mixture models. 
798 
 
799 
Weight loss data also will be analyzed using a per protocol analysis that, for liraglutide-
800 
treated participants, includes only those who were able to tolerate and adhered to the full 
801 
dose of liraglutide 3.0 mg.  
802 
 
803 
Interim Analysis 
804 
 
805 
No interim analyses are planned (in order to maintain full power for the end-of-study 
806 
comparisons). 
807 
 
808 
Explorative Statistical Analysis for Pharmacogenetics and Biomarkers 
809 
 
810 
No explorative statistical analysis for pharmacogenetics and biomarkers will be 
811 
performed. 
812 
 
813 
Data Handling and Record Keeping: 
814 
 
815 
Information about study subjects will be kept confidential and managed according to the 
816 
requirements of the Health Insurance Portability and Accountability Act of 1996 
817 
(HIPAA).  Those regulations require a signed subject authorization informing the subject 
818 
of the following:  
819 
 
820 
 Protected health information (PHI) collected from subjects in this study 
821 
 Who will have access to that information and why 
822 
 Who will use or disclose that information 
823 
 The rights of research subjects to revoke their authorization for use of their PHI 
824 
 View of PHI will be limited to individuals at the University of Pennsylvania 
825 
directly involved in the study. The company donating the study product will not 
826 
have access to PHI.  
827 


   Version 3.3   September 25, 2018 
Page 25 
 
 
828 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
829 
regulation, retains the ability to use all information collected prior to the revocation of 
830 
subject authorization. For subjects who have revoked authorization to collect or use PHI, 
831 
attempts will be made to obtain permission to collect at least vital status (i.e. that the 
832 
subject is alive) at the end of their scheduled study period. 
833 
 
834 
Ethics: 
835 
 
836 
The principal investigator (PI) will initiate and enroll subjects only after receiving IRB 
837 
approval of the protocol and the informed consent documents. All recruiting materials 
838 
used in the study will have IRB approval. Progress reports regarding the study will be 
839 
submitted to the IRB in accordance with institutional and regulatory guidelines.  
840 
The study will be performed in compliance with the FDA Code of Federal Regulations 
841 
for Good Clinical Practice (GCP). These procedures ensure the protection of the rights 
842 
and the integrity of the subjects, adequate and correct conduct of all study procedures, 
843 
adequate data collection, adequate documentation, and adequate data verification.  
844 
 
845 
Before being enrolled, subjects will be provided informed consent. The nature, scope, and 
846 
possible consequences of the study will have been explained in a form understandable to 
847 
them. A copy of the consent document will be given to the subject. The PI will retain the 
848 
original signed consent document.   
849 
 
850 
Subject confidentiality will be maintained throughout the study according to applicable 
851 
guidelines, regulations and IRB requirements. All laboratory samples, study clinical data, 
852 
and reports of results will de-identify individual subjects. Subjects will be identified by 
853 
initials, date of birth, gender and subject number only for use in data collection. 
854 
Published data will provide subject numbers only if needed for clarity of presentation 
855 
(e.g., in individual event listings).  
856 
 
857 
The study will be conducted in accordance with the Declaration of Helsinki. The study 
858 
will be conducted in accordance with the ICH GCP guidelines. The sponsor-investigator 
859 
will comply with all applicable regulatory and legal requirements, ICH GCP guidelines, 
860 
and the Declaration of Helsinki in obtaining and documenting the informed consent. 
861 
 
862 
Study Schedule:  
863 
 
864 
Table 2. Study Timeline 
865 
 
2016 
2017 
2018 
Study start  
5/1 
 
 
 
 
 
 
 
 
 
 
 
Recruitment 
 
 
 
 
 
 
 
 
 
 
 
 
First patient screening visit 
6/1 
 
 
 
 
 
 
 
 
 
 
 
Enrollment/randomization 
12-15 subjects/month 
 
 
 
 
 
 
 
 
Last patient first visit 
 
 
 
 
5/1 
 
 
 
5/1 
 
 
 
Data collection 
6/1 
 
 
 
 
 
 
 
5/1 
 
 
 
Data analysis/manuscripts 
 
 
 
 
 
 
 
 
 
10/30 
 
 
Final study reports 
 
 
 
 
 
 
 
 
 
10/30 
 
 
 
866 


   Version 3.3   September 25, 2018 
Page 26 
 
Study Drugs and Materials:  
867 
 
868 
Subjects assigned to liraglutide will need 365 doses (12 pens) of study medication. 
869 
Subjects will be provided with a 30-day supply of medication (1 pen) on 12 occasions. 
870 
We will assign 100 subjects to liraglutide and, thus, will need a total of 120 pens of 
871 
liraglutide.  
872 
Study Medication 
873 
 
874 
The study medication is liraglutide (i.e., Saxenda). It will be initiated at 0.6 mg 
875 
subcutaneously, daily for 1 week, and increase by 0.6 mg/day in weekly intervals until a 
876 
dose of 3 mg/day is achieved. The pen delivers doses of 0.6 mg, 1.2 mg, 1.8 mg, 2.4 mg, 
877 
or 3 mg (6 mg/mL, 3mL). 
878 
Packaging and Labelling of Study Medication 
879 
 
880 
The medication will be provided by Novo Nordisk as ready-to-use, pre-filled, multi-dose 
881 
pens by Novo Nordisk in a subject box.  
882 
Study drug will be shipped to the Center for Weight and Eating Disordersat the 
883 
University of Pennsylvania (attention Dr. Tom Wadden) for labeling and packaging. The 
884 
study drug supplies will be labeled appropriate to their use. The label for the study drug 
885 
will contain at a minimum: 
886 
 Protocol number 
887 
 Kit identification number from the randomization scheme 
888 
 Instructions for use 
889 
 Study drug name 
890 
  
891 
Storage and Drug Accountability of Study Medication 
892 
 
893 
The medication will be refrigerated (36-46°F) (the temperature will be checked daily.) 
894 
After first use, the subject may store the medication at room temperature (59-86°F) or 
895 
refrigerate (36-46°F). The injection pen expires 30 days after first use. The sponsor-
896 
investigator will ensure the availability of proper storage conditions and record and 
897 
evaluate the temperature. No trial medication(s) will be dispensed to any person not 
898 
enrolled in the study. Unused medication(s) will be stored separately from used trial 
899 
medication(s). Subjects will be instructed to inspect the medication visually for 
900 
particulate matter and discoloration prior to administration.  
901 
 
902 
We will maintain adequate drug inventory and security at all times. Upon receipt of the 
903 
study drug, the Center for Weight and Eating Disorders at Penn will perform an inventory 
904 
of the shipment, comparing the shipment inventory to actual study drug received, and 
905 
complete and sign an inventory log. The study investigators will immediately notify 
906 
Novo Nordisk (or its designee) or the drug distribution contractor of any damaged or 
907 
unusable study drug that the center receives, and document in the inventory log any 
908 
damaged or unusable study drug. We will request that additional study drug be shipped as 
909 
needed.  
910 
 
911 


   Version 3.3   September 25, 2018 
Page 27 
 
The drug supplies will be kept in a secured enclosure with limited access at the Center for 
912 
Weight and Eating Disorders, where it will be received and dispensed to subjects. The 
913 
investigator will take appropriate precautions to prevent theft or diversion of the study 
914 
drug. 
915 
 
916 
At the conclusion of the study, a final inventory of study drug shipped, dispensed, and 
917 
remaining at the Center for Weight and Eating Disorders will be performed by the 
918 
investigator. This reconciliation will be entered on the drug accountability log. The 
919 
investigator will return all unused drug to Novo Nordisk or its designee, unless 
920 
alternative arrangements for drug disposal are authorized. No study drug will be retained 
921 
when the study is completed; all study drugs will be returned to Novo Nordisk or its 
922 
designee for destruction.  
923 
 
924 
Randomization and Blinding 
925 
 
926 
Dr. Jena Shaw from the Center for Weight and Eating Disorders will generate the 
927 
randomization code. The randomization will be generated using a randomization scheme 
928 
of CMS-Alone to CMS-Liraglutide to Multi-Component Intervention. The first subject to 
929 
meet the treatment criteria will be assigned the first number in the sequence; each 
930 
subsequent subject to meet treatment criteria will be assigned the next number in the 
931 
sequence. This is an open-labelled randomized trial.  
932 
Breaking of Blinded Codes 
933 
 
934 
Not applicable 
935 
 
936 
Concomitant Illnesses and Medications: 
937 
 
938 
At trial entry (i.e., the screening visit), we will record details of any concomitant illness 
939 
(i.e., any illness that is present at the start of the trial) that is present and concomitant 
940 
medication (i.e., any medication other than the trial product(s) that is taken during the 
941 
trial, including the screening and run-in periods) in each patient’s record. The information 
942 
collected for each concomitant medication will include the start date, stop date or 
943 
continuing, and indication. For each concomitant illness, we will record the date of onset, 
944 
date of resolution or continuing. Any changes in concomitant medication use will be 
945 
recorded at each visit. If the change influences the subject’s eligibility to continue in the 
946 
trial, the Sponsor will be informed. 
947 
 
948 
Adverse Events: 
949 
 
950 
At each contact with subjects, study personnel will be responsive to reports of adverse 
951 
events with specific questioning and, as outlined in the procedures section, by physical 
952 
examination. The investigator will be report all adverse events including serious adverse 
953 
events (SAE), suspected unexpected serious adverse reactions (SUSARs), serious adverse 
954 
drug reactions (SADRs) (as defined below) to the Data Safety and Monitoring Board 
955 
established for the trial, and to the Penn IRB. Information on all adverse events will be 
956 
recorded immediately in the source document and reported immediately, and also in the 
957 


   Version 3.3   September 25, 2018 
Page 28 
 
appropriate adverse event module of the case report form (CRF). Information on study 
958 
name, patient identification, event (i.e., diagnosis, causality), drug, and reporter 
959 
identification (e.g., name) will be collected and recorded in the source document (as 
960 
detailed below). All serious adverse events will be reported to the IRB within 24 hours. 
961 
The investigator will report to Novo Nordisk all SAEs, SUSARs, and SADRs at the same 
962 
time such events are reported to regulatory authorities or within 15 days from the 
963 
investigator becoming aware of such adverse events, whichever comes first.  
964 
 
965 
The PI and his investigative team acknowledge the definition of adverse events (AEs), 
966 
serious adverse events (SAEs), and other untoward occurences as spelled out below. 
967 
 
968 
Adverse Event (AE): 
969 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
970 
administered/using a product and which does not necessarily have to have a causal 
971 
relationship with this treatment. An Adverse Event can therefore be any unfavourable and 
972 
unintended sign (including an abnormal laboratory finding), symptom, or disease 
973 
temporally associated with the use of a product, whether or not considered related to the 
974 
product. 
975 
 
976 
Clinical Laboratory Adverse Event: 
977 
A clinical laboratory AE is any clinical laboratory abnormality regarded as clinically 
978 
significant i.e. an abnormality that suggests a disease and/or organ toxicity and is of a 
979 
severity that requires active management, (i.e. change of dose, discontinuation of trial 
980 
product, more frequent follow-up or diagnostic investigation). 
981 
 
982 
Serious Adverse Event (SAE): 
983 
A serious AE is an experience that at any dose results in any of the following: 
984 
• Death 
985 
• A life-threatening* experience 
986 
• In-patient hospitalisation or prolongation of existing hospitalization 
987 
• A persistent or significant disability/incapacity 
988 
• A congenital anomaly/birth defect 
989 
• Suspicion of transmission of infectious agents 
990 
• Important medical events that may not result in death, be life-threatening*, or require 
991 
  hospitalisation may be considered an SAE when, based upon appropriate medical 
992 
judgement, they may jeopardise the subject and may require medical or surgical 
993 
intervention to prevent one of the outcomes listed in this definition 
994 
*The term life-threatening in the definition of SAE refers to an event in which the subject was at risk of 
995 
death at the time of the event. It does not refer to an event which hypothetically might have caused death if 
996 
it was more severe. 
997 
 
998 
Suspected Unexpected Serious Adverse Reaction (SUSAR): A SUSAR is an SAE 
999 
which is unexpected and regarding as possibly or probably related to the trial/study 
1000 
product by the investigator. 
1001 
 
1002 
Serious Adverse Drug Reaction (SADR):  
1003 


   Version 3.3   September 25, 2018 
Page 29 
 
An adverse drug reaction (ADR) is an adverse event for which a causal relationship 
1004 
(Possible/Probable relation) between the study drug and the occurrence of the event is 
1005 
suspected. The ADR should be classified as serious if it meets one or more of the 
1006 
seriousness criteria.  
1007 
 
1008 
Medical Events of Special Interest (MESI): A MESI is (1) a medication error (e.g. 
1009 
wrong drug administration or wrong route of administration) or (2) a suspected 
1010 
transmission of an infectious agent via the product 
1011 
 
1012 
Non-Serious Adverse Event: 
1013 
A non-serious AE is any AE which does not fulfil the definition of an SAE. 
1014 
 
1015 
Severity Assessment Definitions: 
1016 
• Mild: Transient symptoms, no interference with the subject’s daily activities 
1017 
• Moderate: Marked symptoms, moderate interference with the subject’s daily activities 
1018 
• Severe: Considerable interference with the subject’s daily activities, unacceptable 
1019 
 
1020 
Relationship to study medication Assessment Definitions: 
1021 
• Probable: Good reasons and sufficient documentation to assume a causal relationship 
1022 
• Possible: A causal relationship is conceivable and cannot be dismissed 
1023 
• Unlikely: The event is most likely related to an etiology other than the trial product 
1024 
 
1025 
The US PI will be used to evaluate all unexpected events and adverse reactions. 
1026 
 
1027 
Outcome Categories and Definitions: 
1028 
• Recovered: Fully recovered or by medical or surgical treatment the condition has 
1029 
returned to the level observed at the first trial related activity after the subject signed the 
1030 
informed consent 
1031 
• Recovering: The condition is improving and the subject is expected to recover from the 
1032 
event. This term should only be used when the subject has completed the trial 
1033 
• Recovered with sequelae: As a result of the AE, the subject suffered persistent and     
1034 
significant disability/incapacity (e.g. became blind, deaf, paralysed). Any AE recovered 
1035 
with sequelae should be rated as an SAE 
1036 
• Not recovered 
1037 
• Fatal 
1038 
• Unknown 
1039 
 
1040 
Collection, Recording and Reporting of Adverse Events 
1041 
All events meeting the definition of an adverse event will be collected and reported from 
1042 
the first trial related activity after the subject has signed the informed consent and until 
1043 
the end of the posttreatment follow-up period as stated in the protocol.  
1044 
 
1045 
Follow-up of Adverse Events 
1046 
During and following subjects’ participation in the study, the investigator and institution 
1047 
will provide adequate medical care to the study subject for any study-related adverse 
1048 
events, including clinically significant laboratory values related to the study. (Note: This 
1049 


   Version 3.3   September 25, 2018 
Page 30 
 
section of the protocol will be written in consultation with Penn’s IRB, Office of 
1050 
Research Services, and Office of Legal Affairs. It will be addressed pending approval of 
1051 
the scientific aspects of the study.) 
1052 
 
1053 
Pregnancy 
1054 
Study subjects will be instructed to notify the investigator immediately if they become 
1055 
pregnant. The investigator will report to Novo Nordisk any pregnancy occurring during 
1056 
the trial period. Reporting of pregnancy by the investigator will occur within the same 
1057 
timelines described above for reporting of Adverse Events. Pregnancy complications will 
1058 
be recorded as adverse event(s). If the infant has a congenital anomaly/birth defect this 
1059 
will be reported and followed up as a serious adverse event. 
1060 
 
1061 
Precautions/Over-dosage 
1062 
In case of suspected overdose, subjects will be instructed to call their healthcare provider 
1063 
immediately, as excessive intake of Saxenda may cause severe nausea and vomiting.  
1064 
 
1065 
Liability and Subject Insurance: 
1066 
Liability and subject insurance will be discussed during the second phase of the 
1067 
application, in consultation with Penn’s Office of Research Services and Legal Affairs.  
1068 
 
1069 
Evaluability of Subjects: 
1070 
Participants will be excluded from data analysis in the event of pregnancy, amputation, 
1071 
bariatric surgery, or death.  Additional criteria associated with subject censorship will be 
1072 
considered prior to initiating recruitment. 
1073 
 
1074 
Premature Termination of Study: 
1075 
We believe that it is highly unlikely that the study will be terminated prematurely, given 
1076 
the safety of the intervention and its expected effects. Termination would be considered, 
1077 
however, in view of: 
1078 
 Unacceptable safety concerns of the study medication 
1079 
 The benefits observed do not ethically permit the trial to continue 
1080 
 
1081 
Publication Plan: 
1082 
We will register the study with a publicly assessable database such as clinicaltrials.gov.  
1083 
An initial report of the findings will be presented at an annual scientific meeting (e.g., 
1084 
American Diabetes Association, The Obesity Society, The American Heart Association). 
1085 
We plan to publish the study results approximately 6 months after study completion.  
1086 
 
1087 
The report of the primary outcome will be submitted to the New England Journal of 
1088 
Medicine. Secondary papers likely will be submitted to Obesity, International Journal of 
1089 
Obesity, or primary care journals. 
1090 
 
1091 
References: 
1092 
 
1093 
1. Jensen MD, Ryan DH, Apovian CM, et al. Executive summary: Guidelines (2013) for 
1094 
the management of overweight and obesity in adults: A Report of the American 
1095 


   Version 3.3   September 25, 2018 
Page 31 
 
College of Cardiology/America Heart Association Task Force on Practice Guidelines 
1096 
and The Obesity Society Published by The Obesity Society and American College of 
1097 
Cardiology/American Heart Association Task Force on Practice Guidelines. Based on 
1098 
a systematic review from The Obesity Expert Panel, 2013. Obesity  2014; 22:S5-39. 
1099 
2. Centers for Medicare and Medicaid Services. Decision memo for intensive behavioral 
1100 
therapy for obesity (CAG-00423N).  (Accessed June 24, 2015, at 
1101 
http://www.cms.gov/medicare-coverage-database/details/nca-
1102 
decisionmemo.aspx?&NcaName=Intensive%20Behavioral 
1103 
%20Therapy%20for%20Obesity&bc=ACAAAAAAIAAA&NCAId=253.) 
1104 
3. Yanovski SZ, Yanovski, JA. Long-term drug treatment for obesity: a systematic and 
1105 
clinical review. J of Amer Med Assoc 2014;311:74-86. 
1106 
 
1107 
4. Wadden TA, Hollander P, Klein S, et al. Weight maintenance and additional weight 
1108 
loss with liraglutide after low-calorie-diet-induced weight loss: the SCALE 
1109 
maintenance randomized study. Int J Obes (Lond) 2013;37:1443-51. 
1110 
5. Smith SR, Weissman NJ, Anderson CM, et al. Multicenter, placebo-controlled trial of 
1111 
lorcaserin for weight management. N Engl J of Med 2010;363:245-56. 
1112 
6. Greenway FL, Fujioka K, Plodowski RA, et al. Effect of naltrexone plus buproprion 
1113 
on weight loss in overweight and obese adults (COR-I): a multi-centre, randomised, 
1114 
double-blind, placebo-controlled, phase 3 trial [abstract]. Lancet 2010; 376:595-605. 
1115 
7. Gadde KM, Allison DB, Ryan DH, et al. Effects of low-dose, controlled-release, 
1116 
phentermine plus topiramate combination on weight and associated comorbidities in 
1117 
overweight and obese adults (CONQUER): a randomised, placebo-controlled, phase 
1118 
3 trial. Lancet 2011;377:1341-52. 
1119 
8. Wadden TA, Berkowitz RI, Womble LG, et al. Randomized trial of lifestyle 
1120 
modification and pharmacotherapy for obesity. N Engl J Med. 2005;353:2111-20.  
1121 
9. Wadden TA, Berkowitz RI, Sarwer DB, Prus-Wisniewski R, Steinberg C. Benefits of 
1122 
lifestyle modification in the pharmacologic treatment of obesity: a randomized trial. 
1123 
Arch Int Med 2001;161:218-27. 
1124 
10. Berkowitz RI, Wadden, TA, Tershakovec AM, Cronquist JL. Behavior therapy and 
1125 
sibutramine for the treatment of adolescent obesity: a randomized controlled trial. J 
1126 
Amer Med Assoc 2003;289:1805-12. 
1127 
11. Wing RR, Lang W, Wadden TA, et al. Benefits of modest weight loss in improving 
1128 
cardiovascular risk factors in overweight and obese individuals with type 2 diabetes. 
1129 
Diabetes Care 2011;34:1481-6.  
1130 
12. Foster GD, Wadden TA, Vogt RA, Brewer G. What is a reasonable weight loss? 
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Patients’ expectations and evaluations of obesity treatment outcomes [abstract].  J 
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Consult Clin Psychol 1997;65:79-85. 
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13. Wadden TA, Womble LG, Sarwer DB, et al. Great expectations: "I'm losing 25% of 
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my weight no matter what you say". J Consult Clin Psychol 2003;71:1084-9. 
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14. Heymsfield SB, van Mierlo CA, van der Knaap HC, et al. Weight management using 
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a meal replacement strategy: meta and pooling analysis from six studies. Int J Obes. 
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15. Tsai AG, Wadden TA. The evolution of very-low-calorie-diets: an update and meta-
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analysis. Obesity (Silver Spring) 2006;14:1283-93. 
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16. Donnelly JE, Goetz J, Gibson C, et al. Equivalent weight loss for weight management 
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programs delivered by phone and clinic. Obesity (Silver Spring) 2013;21:1951-9.  
1146 
 
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17. Wadden TA, Foster GD, Sarwer DB, Anderson DA, Gladis M, Sanderson RS, et al. 
1148 
Dieting and the development of eating disorders in obese women: results of a 
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randomized controlled trial. Am J Clin Nutr 2004;80:560-8. 
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18. Knowler WC; Diabetes Prevention Program Research Group. Reduction in the 
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incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 
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2002;346:393-403. 
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19. Liraglutide (rDNA origin) injection [package insert]. Plainsboro, NJ: Novo Nordisk, 
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Inc.; 2014. 
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20. Wadden TA, Volger S, Sarwer DB, et al. A two-year randomized trial of obesity 
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treatment in primary care practice. N Engl J Med. 2011;365:1969-79. 
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21. Moyer VA, U.S. Preventive Services Task Force. Screening for and management of 
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obesity in adults: U.S. Preventive Services Task Force recommendation statement. 
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Ann Intern Med. 2012;157:373-8. 
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22. Wadden TA, Butryn ML, Hong PS, Tsai AG. Behavioral treatment of obesity in 
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patients encountered in primary care settings: a systematic review.  J Amer Med 
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Assoc 2014;312:1779-91. 
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23. Metz JA, Stern JS, Kris-Etherton P, et al. A randomized trial of improved weight loss 
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with a prepared meal plan in overweight and obese patients: impact on cardiovascular 
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risk reduction. Arc Int Med 2000;160:2150-8. 
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24. Apfelbaum M, Vague P, Ziegler O, Hanotin C, Thomas F, Leutenegger E. Long-term 
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maintenance of weight loss after a very-low-calorie diet: a randomized blinded trial of 
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the efficacy and tolerability of sibutramine. Am J Med 1999;106:179-84.  
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25. Wadden TA, Foster GD. Weight and Lifestyle Inventory (WALI). Surg Obes and 
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26. Beck AT, Ward CH, Mendelson M, Mock J, Erbaugh J. An inventory for measuring 
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depression. Arch Gen Psychiatry. 1961;4:561–71. 
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27. Posner K, Brent D, Lucas C, et al. Columbia-Suicide Severity Rating Scale (C-
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SSRS). New York, NY: Columbia University Medical Center; 2008 
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28. Centers for Medicare and Medicaid Services. Services and supplies incident to a 
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physician’s professional services: Conditions. 42 CFR § 410.26. (2011). (Accessed 
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July 15, 2014, at http://www.gpo.gov/fdsys/pkg/CFR-2011-title42-vol2/pdf/CFR-
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2011-title42-vol2-sec410-26.pdf.) 
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29. Look AHEAD Research Group. Cardiovascular effects of intensive lifestyle 
1191 
intervention in type 2 diabetes. N Engl J Med. 2013;369:145-54. 
1192 
 
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30. Look AHEAD Research Group, Wadden TA, West DS, et al. The Look AHEAD 
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study: a description of the lifestyle intervention and the evidence supporting it. 
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Obesity (Silver Spring) 2006;14:732-52. 
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31. Donnelly JE, Blair SN, Jakicic JM, Manore MM, Rankin JW, Smith BK, et al. 
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American College of Sports Medicine Position Stand.  Appropriate physical activity 
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intervention strategies for weight loss and prevention of weight regain for adults. Med 
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Sci Sports Exerc 2009;41:459-71. 
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32. Wing RR, Tate DF, Gorin AA, Raynor HA, Fava JL. A self-regulation program for 
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maintenance of weight loss. N Engl J Med 2006;355:1563-71. 
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33. Donnelly JE, Smith BK, Dunn L, Mayo MM, Jacobsen DJ, Stewart EE, et al. 
1205 
Comparison of a phone vs clinic approach to achieve 10% weight loss. Int J Obes 
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(2005) 2007;31:1270-6. 
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34. Perri MG, Limacher MC, Durning PE, Janicke DM, Lutes LD, Bobroff LB, et al. 
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Extended-care programs for weight management in rural communities: the treatment 
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of obesity in underserved rural settings (TOURS) randomized trial. Arch Int Med 
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2008;168:2347-54. 
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35. Clinical guidelines on the identification, evaluation, and treatment of overweight and 
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obesity in adults: executive summary. Expert Panel on the Identification, Evaluation, 
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and Treatment of Overweight in Adults. Amer J Clin Nutr 1998;68:899-917. 
1214 
 
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36. Kroenke K, Spitzer RL, Williams JB: The PHQ-9: validity of a brief depression 
1216 
severity measure. J Gen Intern Med 2001, 16:606-613. 
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37. McHorney CA, Ware JE Jr, Lu JF, Sherbourne CD. The MOS 36-item Short-Form 
1219 
Health Survey (SF-36): III. Tests of data quality, scaling assumptions, and reliability 
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across diverse patient groups. Med Care 1994;32:40–66. 
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38. Kolotkin RL, Crosby RD, Kosloski KD, Williams GR. Development of a brief 
1222 
measure to assess quality of life in obesity. Obes Res 2001;9: 102–111. 
1223 
39. Stunkard A, Messick S. Eating Inventory Manual. Psychological Corporation: San 
1224 
Antonio, TX, USA, 1988. 
1225 
40. Womble LG, Wadden TA, Chandler JM, Martin AR. Agreement between weekly vs. 
1226 
daily assessment of appetite. Appetite 2003;40:131-5. 
1227 
41. Fairburn CG, Beglin SJ, Assessment of eating disorders: interview or self-report 
1228 
questionnaire. Int J Eat Disord 1994;16:363–370. 
1229 
42. Gearhardt AN, Corbin WR, Brownell KD. Preliminary validation of the Yale Food 
1230 
Addiction Scale. Appetite 2009;52:430–436. 
1231 
43. Appel LJ, Clark JM, Yeh HC, Wang NY, Coughlin JW, Daumit D, Miller ER 3rd, et 
1232 
al. Comparative effectiveness of weight-loss interventions in clinical practice. N Engl 
1233 
J Med 2011;365:1959-68. 
1234 
44. Holm S. A simple sequentially rejective multiple test procedure. Scand J Stat 
1235 
1979;6:65-70. 
1236 
45. Diggle P, Heagerty P, Liang KY, Zeger S. Analysis of longitudinal data: Oxford U P; 
1237 
2013. 
1238 
 
1239 
 
1240 
 
1241 
 
1242 
 
1243 
 
1244 
 
1245 
 
1246 
 
1247 
 
1248 
 
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Addendum to the Protocol in Order to Study the 
1250 
Efficacy of Liraglutiude 3.0 mg/d Combined with 
1251 
Phentermine 15 mg/d to Increase Weight Loss in a 12-
1252 
Week Placebo-Controlled Trial, Following Completion 
1253 
of the Original 1-Year Study   
1254 
 
1255 
Table of Contents 
1256 
SUMMARY OF THE PROPOSED PROTOCOL ADDENDUM……………...……36 
1257 
BACKGROUND AND SIGNIFICANCE…………………………………………..…38 
1258 
SPECIFIC OBJECTIVES………………………………………………………….….39 
1259 
   PRIMARY OBJECTIVES…….…………………………………………….…….…..39 
1260 
   CO-PRIMARY OBJECTIVE……………………………………………….…………39 
1261 
   SECONDARY OBJECTIVE……………………………………………….……..…..39 
1262 
RESEARCH DESISN AND METHODS………………………………………….….40 
1263 
   STUDY HYPOTHESES………………………………………………………….……40 
1264 
   STUDY ENDPOINTS…………………………………………………………..……..40 
1265 
   STUDY TYPE…………………………………………………………...….…………41 
1266 
   RATIONALE FOR STUDY DESIGN………………………………………………...41 
1267 
   STUDY POPULATION…………………………………………………………….....42 
1268 
   RATIONALE FOR STUDY POPULATION………………….………………………42 
1269 
   INCLUSION CRITERIA………………………………………………………………43 
1270 
   EXCLUSION CRITERIA………………………………………………..…...............43 
1271 
VISIT PROCEDURES…………………………………..............................................43 
1272 
    FIGURE 3. EXTENSION STUDY FLOW DIAGRAM……………………………….44 
1273 
   TABLE 3. SCHEDULE OF EXTENSION STUDY VISITS…………………………..45 
1274 
   SCREENING PROCEDURES…………………………..............................................46 
1275 
   SCREENING VISIT……………………………………………………………………46 
1276 
   RANDOMIZATION VISIT………………………………………..….……................46 
1277 
   LIFESTYLE COUNSELING VISITS…………………………..………….................47 
1278 
   MEDICAL MONITORING VISITS…………………….……………………………..48 
1279 
ASSESSMENTS FOR EFFICACY……………………………………..……………..48 
1280 
   PRIMARY EFFICACY MEASURE…………………….…………………….……….48 
1281 
   SECONDARY EFFICACY MEASURE……………………………………...............48 
1282 
ASSESSMENTS FOR SAFETY…………………………..…….…………................49 
1283 
SUBJECT COMPLICANCE………………………………………………….……….49 
1284 
STATISTICAL CONSIDERATIONS………………….………………..……..……..49 
1285 
   SAMPLE SIZE CALCULATION…………………………..………………..…..…….49 
1286 
   STATISTICAL METHODS………………………………….……………..,…..……..50 
1287 
DATA HANDLING AND RECORD KEEPING……………….…………………….50 
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   Version 3.3   September 25, 2018 
Page 36 
 
ETHICS…………………………….………………………….……….…….………..50 
1289 
STUDY SCHEDULE……………….…………………………….…….…….…….....51 
1290 
STUDY DRUGS AND MATERIA.LS…………………………….……..……….….51 
1291 
   STUDY MEDICATION…………………………….…….……………………..…...51 
1292 
   PACKAGING AND LABELLING OF STUDY MEDICATIONS……………..……51 
1293 
STORAGE AND DRUG ACCOUNTABILITY………………………………….…52 
1294 
RANDOMIZATION AND BLINDING………………………………………..…....52 
1295 
   BREAKING OF BLINDED CODES………………………….….………………..…52 
1296 
CONCOMITANT ILLNESSES AND MEDICATIONS……………….……..…....52 
1297 
ADVERSE EVENTS………………………….……………..………………………..52 
1298 
LIABILITY AND SUBJECT INSURANCE……………….….…………………….55 
1299 
EVALUABILITY OF SUBJECTS……………………………….………..…………55 
1300 
PREMATURE TERMINATION OF STUDY………………….………..…..………55 
1301 
PUBLICATION PLAN…………………………………..……….…………..……….55 
1302 
REFERENCES……………………………….……….………….……………………55 
1303 
 
1304 
 
1305 
 
1306 
 
1307 
 
1308 
 
1309 
 
1310 
 
1311 
 
1312 
 
1313 
 
1314 
 
1315 
 
1316 
 
1317 
 
1318 
 
1319 
 
1320 
 
1321 


   Version 3.3   September 25, 2018 
Page 37 
 
SUMMARY OF THE PROPOSED PROTOCOL ADDENDUM 
1322 
The above protocol describes a 52-week, open-label, three arm trial titled "Combining 
1323 
lifestyle modification and liraglutide to improve weight loss and health outcomes." The 
1324 
study, with a total sample of 150 participants, compares changes in weight and other 
1325 
health outcomes in individuals randomly assigned to: 1) brief lifestyle counseling alone, 
1326 
as recommended by the Centers for Medicare and Medicaid Services (CMS-Alone); 2) 
1327 
CMS counseling plus liraglutide 3.0 mg/d (CMS-Liraglutide); or 3) the combination of 
1328 
CMS counseling, liraglutide 3.0 mg/d, and the provision of a 1000-12000 meal 
1329 
replacement diet for the first 12 weeks (i.e., Multi-Component Intervention).   
1330 
 
1331 
The study’s primary hypothesis is that participants assigned to the Multi-Component 
1332 
Intervention will lose significantly more weight at 1 year than those assigned to CMS-
1333 
Liraglutide (14.0%  vs 9.5%), who, in turn, will lose significantly more than those 
1334 
assigned to CMS-Alone (9.5% vs 5.0%).  
1335 
 
1336 
The Addendum described below requests no changes to the present 1-year protocol.  
1337 
 
1338 
Instead, it proposes a 20-week extension of the present 1-year trial for participants 
1339 
assigned to the CMS-Liraglutide and the Multi-Component Intervention groups. 
1340 
During the first 12 weeks of the extension, we will test, in a randomized, placebo-
1341 
controlled trial, the hypothesis that the addition of phentermine 15 mg/d to liraglutide 3.0 
1342 
mg/d will produce significantly greater weight loss at week 12 than will the combination 
1343 
of placebo plus liraglutide 3.0 mg/d. We hypothesize that the difference between groups 
1344 
will be approximately 3.5% of initial weight, as measured from randomization. Patients 
1345 
and their practitioners would welcome this additional weight loss, if the medications 
1346 
together were shown to have an acceptable safety profile, which we believe they will. 
1347 
 
1348 
At the end of week 12 (post-randomization), phentermine and placebo will be terminated, 
1349 
but both groups will remain on liraglutide 3.0 mg/d until week 20. We wish to observe, 
1350 
from weeks 12 to 20, the change in body weight that occurs with the termination of 
1351 
phentermine 15 mg/d. At week 20, liraglutide also will be terminated in both groups of 
1352 
participants. At week 24 (post-randomization), all participants will have a final 
1353 
assessment with a physician or nurse practitioner to determine participants’ health status.  
1354 
 
1355 
All participants from the CMS-Liraglutide and Multi-Component Intervention groups 
1356 
who complete the original 1-year randomized trial – and who have remained on 
1357 
liraglutide 3.0 mg/d - will be invited to enroll in the 20-week extension study, 
1358 
immediately upon completing the prior 1-year trial. (Participants in the CMS-Alone 
1359 
group will not be eligible to receive medication but they will be offered continued brief-
1360 
monthly lifestyle counseling sessions, similar to those provided in the original 1-year 
1361 
trial.) Participants eligible for the 20-week medication-extension study will sign a new, 
1362 
separate consent form, apprising them of the potential risks and benefits of treatment with 
1363 
liraglutide plus phentermine (or placebo). They all will complete a brief history and 
1364 
physical examination, including an EKG, prior to randomization and will be determined 
1365 
to have acceptable blood pressure and pulse rate. (Participants in the CMS-Alone group 
1366 
who wish to continue in the 6-month extension study will sign a separate consent form 
1367 


   Version 3.3   September 25, 2018 
Page 38 
 
and will not be required to undergo additional safety assessment/monitoring, beyond the 
1368 
assessment conducted at the end of the original 1-year trial. 
1369 
 
1370 
All study participants from the original CMS-Liraglutide and Multi-Component 
1371 
Intervention groups will be prescribed liraglutide 3.0 mg/d for an additional 20 weeks. In 
1372 
addition, they will be stratified into two groups, based on whether they have lost >10% of 
1373 
initial weight at the end of the 1-year. They will be randomly assigned from these blocks 
1374 
to liraglutide 3.0 mg/d plus phentermine 15 mg/d or liraglutide 3.0 plus placebo.  
1375 
Phentermine will be purchased by the principal investigator (using discretionary funds, 
1376 
not provided by Novo Nordisk) and will be prepared in matching drug and placebo 
1377 
capsules by Dr. Ken Rockwell, director of Penn’s Investigational Drug Service. Dr. 
1378 
Rockwell will be responsible for distributing phentermine and placebo and for 
1379 
randomizing participants to treatment. Phentermine will be provided as 8.0mg/d during 
1380 
the first 2 weeks of the extension study and increased to 15 mg/d at week 3. Phentermine 
1381 
(or placebo) will be down-titrated (back to 8.0 mg/d) or terminated in patients who report 
1382 
that they cannot tolerate the medication after a prolonged effort to do so.  Down-titration 
1383 
will be managed in a blinded manner by Dr. Rockwell, in response to notification from 
1384 
the principal investigator (or study co-investigators) of patients’ complaints of symptoms. 
1385 
(With Dr. Rockwell, we successfully used this titration method in a prior randomized 
1386 
placebo-controlled trial of sibutramine for weight loss.46) Participants in whom 
1387 
phentermine (or placebo) is terminated will continue to receive liraglutide 3.0 mg, in an 
1388 
open-label manner, as they have for the prior 1-year trial.    
1389 
 
1390 
All participants in the randomized, 12-week extension study will meet with a physician or 
1391 
nurse practitioner at randomization (week 0) and at weeks 2, 4, 8 and 12. On each 
1392 
occasion they will review patients’ blood pressure and pulse, assess suicidal ideation, and 
1393 
record and respond to reports of changes in physical health. As during the 1-year prior 
1394 
trial, brief lifestyle counseling (15 min) will provided at each visit (except week 2) by the 
1395 
physician or nurse practitioner or by a registered dietitian or behavioral psychologist,  
1396 
working incident to the two first providers.   
1397 
 
1398 
At the conclusion of the 12-week randomized extension, all participants will stop taking 
1399 
phentermine 15 mg/d (or placebo). They will continue to receive liraglutide 3.0 mg/d for 
1400 
an additional 8 weeks (week 20). They will meet at weeks 16 and 20 with a physician or 
1401 
nurse practitioner who will review their blood pressure and pulse, assess suicidal 
1402 
ideation, and record and respond to reports of changes in physical health. Brief lifestyle 
1403 
counseling visits (15 min) will be provided at each visit as described previously. At week 
1404 
20, liraglutide 3.0 mg/d will be terminated in all patients, who will have a final 
1405 
assessment with a physician or nurse practitioner at week 24 to determine  
1406 
 
1407 
We anticipate that 35 (of 50) participants from the original CMS-Liraglutide group and 
1408 
35 (of 50) from the Multi-Component Intervention will be eligible to participate in the 
1409 
extension study and will elect to do so. We anticipate that 32 participants in each group 
1410 
will complete the 12-week randomized, extension trial and that those who receive 
1411 
liraglutide 3.0 mg/d plus phentermine 15.0 mg/d will lose, from randomization to week 
1412 
12, 3.5±3.5% (of randomization weight), compared with 0.0±0.5% for those assigned to 
1413 


   Version 3.3   September 25, 2018 
Page 39 
 
liraglutide plus placebo. With the expected sample size, we will have 80% power to 
1414 
detect this difference, using a two-tailed p value of p = 0.05. (We also will examine total 
1415 
weight loss in the two groups, as measured from the original randomization weight [from 
1416 
the preceding 1-year trial], but this is not a primary outcome of the study.) 
1417 
 
1418 
The finding that phentermine 15.0 mg/d produces additional weight loss when added to 
1419 
liraglutide after 1 year’s use of the latter medication would be welcomed news to patients 
1420 
and their practitioner.  Patients wish to lose more weight than current treatments induce, 
1421 
and they particularly seek methods to resume weight loss after hitting a prolonged 
1422 
plateau. The proposed pilot study provides a highly efficient method for both the 
1423 
investigative team to determine whether the combination of liraglutide 3.0 mg/d plus 
1424 
phentermine 15.0 mg/d provides such benefit, or at least a signal of such benefit. The 8-
1425 
week observational follow-up period, from weeks 12-20, in which all participants will 
1426 
continue to receive liraglutide 3.0 mg/d, but not phentermine (or placebo), will provide 
1427 
preliminary evidence concerning the maintenance of weight loss (or possible weight 
1428 
regain) following termination of phentermine 15.0 mg/d.   
1429 
 
1430 
The sections that follow parallel the original sections of the protocol for the 1-year trial 
1431 
described above. Additional information is added to each section, as required, to describe 
1432 
the 12-week extension study and any modifications to the original methods needed for 
1433 
the 12-week trial (e.g., change in eligibility criteria). With each section, in the absence of 
1434 
the need for additional material to explain the extension study, the reader is referred back 
1435 
to the original sections presented for the 1-year trial. 
1436 
 
1437 
BACKGROUND AND SIGNIFICANCE 
1438 
 
1439 
The perils of obesity and benefits of weight loss are well documented, including in the 
1440 
original Background and Significance section of this protocol. Liraglutide 3.0 mg/d, a 
1441 
glucagon-like peptide-1 (GLP-1) agonist, has been shown to induce clinically significant, 
1442 
long-term weight loss of approximately 8.0% of initial body weight, when combined with 
1443 
a moderate-intensity program of lifestyle modification. Larger weight losses, as desired 
1444 
by patients, potentially may be obtained by combining liraglude 3.0 with a low-calorie 
1445 
meal replacement diet (i.e., 1000-1200 kcal/d), delivered during a preliminary run-in 
1446 
period.47 Larger weight losses also may be obtained by combining the medication with 
1447 
intensive behavior therapy (IBT), providing 14 or more brief, individual counseling 
1448 
sessions in 6 months, as currently being tested in two randomized clinical trials supported 
1449 
by Novo Nordisk. A third option to increase weight loss with liraglutide 3.0 mg/d is to 
1450 
combine it with another weight loss medication. Phentermine hydrochloride (15.0 mg/d) 
1451 
is one such option. 
1452 
 
1453 
Phentermine, as monotherapy, is the most widely used weight loss medication in the U.S. 
1454 
It was approved by the Food and Drug Administration (FDA) in 1959 for “short-term” 
1455 
use, commonly interpreted as 12 or fewer weeks.48 Phentermine is a sympathomimetic 
1456 
amine that is thought to reduce food intake by increasing norepinephrine and possibly 
1457 
serotonin levels in the hypothalamus. When provided as 8.0 or 15.0 mg/d, the medication 
1458 
induces weight loss of approximately 4.0 kg (or 4.0%) greater than placebo at 12 to 28 
1459 


   Version 3.3   September 25, 2018 
Page 40 
 
weeks.48 Phentermine also increases weight loss when combined with other medications 
1460 
known to affect body weight. The FDA-approved combination of phentermine and 
1461 
topirimate, prescribed at 15.0 mg/d and 92 mg/d, respectively, produced a mean loss of 
1462 
11.6% of initial weight at 28 weeks, compared with 7.4% for phentermine alone and 
1463 
8.8% for topirimate alone (using the same doses for monotherapy.  Placebo produced a 
1464 
loss of 2.3%.49 
1465 
 
1466 
A recent 12-week pilot study showed that the addition of 15 mg/d of phentermine to 
1467 
lorcaserin (10 mg/BID) increased weight loss from 3.3+3.4% to 6.7+5.4%. The addition 
1468 
of 30 mg/d of phentermine (to lorcaserin) increased the loss to only 7.2+4.6%, but 
1469 
substantially increased adverse events as compared with the 15 mg dose of phentermine. 
1470 
This combination therapy had a relatively favorable side-effect profile, particularly with 
1471 
the 15 mg dose of phentermine. Systolic and diastolic pressure fell by 3.3 and 1.4 mm 
1472 
Hg, respectively, with lorcaserin/phentermine 15 mg/d, compared with reductions of 5.5 
1473 
and 2.5, respectively, in the lorcaserin-alone group. Pusle rate increased by 1.1 beats per 
1474 
minute (BPM) in the combination group, compared with a fall of 1.9 BPM in the 
1475 
lorcaserin group. Aronne et al observed similar, generally favorable changes in blood 
1476 
pressure and pulse at 28 weeks with phentermine 15.0 mg.49 
1477 
 
1478 
OBJECTIVES 
1479 
 
1480 
Primary Objective 
1481 
 
1482 
To compare the 12-week mean percentage reduction in weight in participants, who 
1483 
following completion of the original 1-year trial, are randomly assigned to receive 
1484 
liraglutide 3.0 mg/d combined with phentermine 15 mg/d versus liraglutide 3.0 mg/d 
1485 
combined with placebo.   
1486 
 
1487 
Co-Primary Objective  
1488 
 
1489 
To assess the safety of liraglutide 3.0 mg/d combined with phentermine 15 mg/d, as well 
1490 
as liraglutide 3.0 alone, as determined by assessment of standard blood chemistries 
1491 
(measured throughtout the 1-year trial), measurement of blood pressure and pulse, and 
1492 
recording of adverse events (AEs) reported by participants. AEs of special interest, 
1493 
previously reported with phentermine 15 mg/d, include dry mouth, constipation, nausea, 
1494 
and insomnia. 
1495 
     
1496 
Secondary Objective 
1497 
 
1498 
To compare the two medication regimens in the proportion of participants who lose 5% 
1499 
or more or 10% or more of initial weight from randomization to week 12.  
1500 
 
1501 
To compare differences between the two groups in 12-week changes in secondary 
1502 
endpoints, described in the next section. 
1503 
 
1504 


   Version 3.3   September 25, 2018 
Page 41 
 
To compare the total mean weight loss achieved by participants in the two medication 
1505 
regimens, as determined from their original randomization weight at the start of the 
1506 
original 1-year trial. 
1507 
 
1508 
To examine the change in body weight (in the two groups) from weeks 12 to 20 when 
1509 
participants will have terminated phentermine (or placebo) but remained on liraglutide 
1510 
3.0 mg/d. This is an observational, exploratory outcome. 
1511 
 
1512 
RESEARCH DESIGN AND METHODS: 
1513 
 
1514 
Study Hypotheses: 
1515 
 
1516 
Primary aim 1: To compare the 12-week mean percentage reduction in weight in 
1517 
participants, who following completion of the original 1-year trial, are randomly assigned 
1518 
to receive liraglutide 3.0 mg/d combined with phentermine 15 mg/d versus liraglutide 3.0 
1519 
mg/d combined with placebo.   
1520 
 
1521 
H1: The combination of liraglutide 3.0 mg and phentermine 15 mg/d will produce 
1522 
significantly greater mean weight loss at 12 weeks post-randomiization than will 
1523 
liraglutide 3.0 mg combined with placebo (with expected mean losses of 3.5% and 0.0%, 
1524 
respectively).  
1525 
 
1526 
Co-primary aim 1: To assess the safety of liraglutide 3.0 mg combined with 
1527 
phentermine 15 mg/d, as well as that of liraglutide 3.0 mg combined with placebo, 
1528 
during the 12 week placebo-controlled trial. Standard assessments of safety will be 
1529 
conducted, as described in the original protocol for the 1-year trial.  
1530 
 
1531 
Endpoints: 
1532 
 
1533 
Primary 
1534 
 
1535 
The primary endpoint is change in body weight (i.e., % reduction in randomization  
1536 
weight), as measured from randomization (week 0) to week 12. 
1537 
 
1538 
Secondary 
1539 
 
1540 
Secondary endpoints include the proportion of subjects who lose > 5% or > 10% of initial 
1541 
weight from randomization to week 12, as well as changes from randomization to week 
1542 
12 in cardiovascular disease (CVD) risk factors (i.e, blood pressure, triglycerides, LDL 
1543 
and HDL cholesterol, and waist circumference), glycemic control (i.e., fasting blood 
1544 
sugar), mood (PHQ-9), quality of life (i.e, SF-36 and IWQOL-Lite), eating behavior (i.e., 
1545 
Eating Inventory, Eating Disorder Examination-Questionnaire, and Yale Food Addiction 
1546 
Scale), appetite (i.e., visual analogue scales), sleep (i.e., Pittsburgh Sleep Quality Index), 
1547 
and weight loss satisfaction. (All of these measures were administered in the original 1-
1548 
year trial.)  
1549 
 
1550 


   Version 3.3   September 25, 2018 
Page 42 
 
A secondary analysis will examine differences between the two randomized groups in 
1551 
changes in weight and other outcomes as measured from participants’ original 
1552 
randomization values, when starting the original 1-year trial. 
1553 
 
1554 
Study type: 
1555 
 
1556 
This is a 12-week, single center, randomized placebo-controlled, parallel group design 
1557 
trial. Participants and investigators will be masked to participants’ assignment to 
1558 
phentermine 15 mg/d versus placebo. Participants in both groups will receive liraglutide 
1559 
in an open-label manner.  
1560 
   
1561 
We anticipate that 35 (of 50) participants from the original CMS-Liraglutide group and 
1562 
35 (of 50) from the Multi-Component Intervention will be eligible to participate in the 
1563 
extension study and will elect to do so. We anticipate that 32 participants in each group 
1564 
will complete the 12-week extension study and that those who receive liraglutide 3.0 mg 
1565 
plus phentermine 15.0 mg/d will lose, from randomization to week 12, 3.5+3.5% of 
1566 
initial weight, compared with 0.0+0.5% for those assigned to liraglutide plus placebo. 
1567 
 
1568 
All participants in the extension study will meet with a physician or nurse practitioner at 
1569 
randomization (week 0) and at weeks 2, 4, 8 and 12. On each occasion they will review 
1570 
patients’ blood pressure and pulse, assess suicidal ideation, and record and respond 
1571 
appropriately to reports of changes in physical health. As during the 1-year prior trial, 
1572 
brief lifestyle counseling (15 min) will provided at monthly visits (excluding week 2) by 
1573 
the physician or nurse practitioner or by a registered dietitian or behavioral psychologist, 
1574 
working under their supervision. The lifestyle intervention will be the same as that 
1575 
provided during the last 6 months of both the CMS-Liraglutide and Multi-Component 
1576 
interventions.   
1577 
 
1578 
Following the 12-week randomized trial, phentermine (or placebo) will be terminated, 
1579 
and all participants will continue to receive liraglutide 3.0 mg/d for an additional 8 weeks 
1580 
(i.e., weeks 12-20) and have lifestyle counseling and medical assessments at weeks 16 
1581 
and 20. Liraglutide 3.0 mg/d will be terminated at week 20, and participants will have a 
1582 
final safety assessment at week 24. 
1583 
 
1584 
Rationale for Study Design 
1585 
 
1586 
The proposed study will provide only 12 weeks of treatment with the combination of 
1587 
liraglutide 3.0 mg/d and phentermine 15 mg/d. The limited duration is based on 
1588 
phentermine’s only being approved by the FDA for short-term use, commonly interpreted 
1589 
as 12 weeks. Our adherence to this duration of use should limit participants’ exposure to 
1590 
any unknown (and unexpected) risks. We believe, however, that the 12-week duration 
1591 
will be sufficiently long to detect a signal that the combination is effective in increasing 
1592 
weight loss and that it is generally safe. The trial will provide valuable pilot data that 
1593 
could form the basis of larger study, capable of fully assessing the long-term safety and 
1594 
efficacy of the combination 
1595 
 
1596 


   Version 3.3   September 25, 2018 
Page 43 
 
Our study does not include a comparison of liraglutide 3.0 mg alone to phentermine 15 
1597 
mg alone, because we are using liraglutide as a background treatment for all participants 
1598 
to determine whether the addition of phentermine 15 mg/d increases weight loss, as 
1599 
compared to the use of liraglutide alone. In this regard, the study contains no comparative 
1600 
assessments of the benefits of liraglutide 3.0 mg vs phentermine 15 mg alone, in the same 
1601 
manner that the recent lorcaserin plus phentermine study did not directly compare the 
1602 
efficacy of the two medications.50 
1603 
   
1604 
Study Population: 
1605 
 
1606 
All participants from the original CMS-Liraglutide and Multi-Component Intervention 
1607 
groups who complete the 1-year trial – and have remained on liraglutide 3.0 mg/d - will 
1608 
be potentially eligible to enroll in the 12-week extension study, immediately upon 
1609 
completing the prior 1-year trial. (Participants in the CMS-Alone group will not be 
1610 
eligible to participate in the randomized trial. However, they will be offered 6 additional, 
1611 
monthly brief lifestyle counseling visits, through week 20 of the extension study.) 
1612 
Participants eligible for the extension study will sign a new consent form, apprising them 
1613 
of the potential risks and benefits of treatment with liraglutide plus phentermine (or 
1614 
placebo). Prior to randomization, they all will complete a brief history and physical 
1615 
examination, including an EKG, and will be determined to have acceptable blood 
1616 
pressure and pulse, using the same criteria employed in the original study. (Participants in 
1617 
the CMS-Alone group also will complete a new consent form but will not be required to 
1618 
undergo additional safety assessments or monitoring, past the assessment conducted at 
1619 
the 1-year visit in the original study.) 
1620 
 
1621 
This study is open to men and women with obesity who meet the criteria described in the 
1622 
original protocol (i.e., inclusion/exclusion).  
1623 
 
1624 
Rationale for study population 
1625 
 
1626 
The study population has been selected to be consistent with those for which the US FDA 
1627 
approved liraglatide 3.0 mg/d and approved phentermine 15.0 mg/d. 
1628 
 
1629 
Number of subjects to be randomized: 70 (from the 1-year randomized trial that all 
1630 
participants will have completed) 
1631 
 
1632 
Planned number of subjects to be screened: approximately 85-90 (i.e., all participants in 
1633 
the two liraglutide treated conditions who complete the 1-year trial – and remain on 
1634 
liraglutide 3.0 - will be invited to participate in the 12-week extension study).  
1635 
 
1636 
Planned number of subjects to be treated in run-in period: No run-in period 
1637 
 
1638 
Planned number of subjects to be randomized to study medication(s): 35 randomized to 
1639 
liraglutide plus phentermine and 35 to liraglutide plus placebo. 
1640 
 
1641 


   Version 3.3   September 25, 2018 
Page 44 
 
Inclusion Criteria 
1642 
 
1643 
 Inclusion criteria are those described for the original 1-year trial (enumerated above). 
1644 
The principal exception from these criteria is that participants will only be required to 
1645 
have a BMI > 27 kg/m2, with or without co-morbidities, to be eligible to participate in the 
1646 
extension study. All participants will have met BMI inclusion criteria when they initiated 
1647 
the use of liraglutide and now will use it, potentially with phentermine 15 mg/d, to 
1648 
facilitate to the maintenance of lost weight. (Liraglutide is approved for chronic weight 
1649 
management, including following successful weight loss.) We do not wish to enroll 
1650 
participants with a BMI < 27 kg/m2 because of the possibility that they could reduce 
1651 
substantially below a BMI of 24.9 kg/m2, the upper limit of “normal” weight. 
1652 
 
1653 
Exclusion Criteria 
1654 
 
1655 
Exclusion criteria will include those listed in the original protocol, including those 
1656 
specific to the use of liraglutide 3.0 mg/d (e.g., family history of medullary thyroid 
1657 
cancer). 
1658 
 
1659 
Additional exclusion criteria added to the 12-week extension study are specific to the use 
1660 
of phentermine 15 mg/d. They include: 
1661 
 
1662 
1. Use of monoamine oxidase inhibitors in the past 2 weeks  
1663 
2. Glaucoma 
1664 
3. Presence or history of marked agitation 
1665 
4. History of drug abuse 
1666 
5. Known hypersensitivity to sympathomimetic amines 
1667 
6. Current use of selective serotonin re-uptake inhibitors (e.g., fluoxetine, sertraline, 
1668 
etc) 
1669 
7. Current use of any other weight loss medications (besides liraglutide 3.0 mg/d) 
1670 
8. History of coronary artery disease 
1671 
 
1672 
Withdrawal Criteria 
1673 
 
1674 
Please refer to the original protocol for all information required in this section.   
1675 
 
1676 
Visit Procedures 
1677 
 
1678 
Figure 3 shows the flow of subjects through the 12-week extension trial (and the 
1679 
subsequent 8-week observational period on liraglutide 3.0 mg/d). Table 3 presents the 
1680 
schedule of study assessments and treatment visits. 
1681 


   Version 3.3   September 25, 2018 
Page 45 
 
Figure 3. Extension Study Flow Diagram 
1682 
 
1683 
 
1684 


   Version 3.3   September 25, 2018 
Page 46 
 
Table 3. Schedule of Extension Study Assessments and Lifestyle Intervention Counseling Visit
1685 
Original 52 Week Study 
Extension Study 
  
Weeks 
 
Weeks 
  
Screen 
R/1 
2 
3 
4 
6 
8 
10 12 14 16 18 20 22 24 28 32 36 40 44 48 
52 
 
Screen 
R/0 
2 
4 
8 
12 
16 
20 
24 
  
Visit Number 
 
Visit Number   
  
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 11 12 13 14 15 16 17 18 19 20 21 
22 
 
 23 
24 
25 
26 
27 
28 
29 
30 
31 
All subjects 
Informed 
consent 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
X 
  
  
  
  
  
  
  
  
Behavioral 
evaluation 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
  
  
  
  
  
  
  
  
History and 
physical 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
X 
  
  
  
  
  
  
  
  
ECG 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
X 
  
  
  
  
  
  
  
  
Blood draw 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
  
  
  
  
  
  
X 
 
  
 
  
  
  
X 
  
  
  
  
Labs 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
  
  
  
  
  
  
X 
 
  
 
  
  
  
  
X 
  
  
  
  
Self-reported 
outcomes 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
X 
  
  
  
  
  
  
X 
 
  
X 
  
  
  
X 
  
  
  
Medical 
Assessment 
  
X 
  
  
X 
  
X 
  
  
  
X 
  
  
  
X 
  
  
  
X 
  
  
X 
 
  
X 
X 
X 
X 
X 
X 
X 
X 
Lifestyle 
intervention 
  
X 
X X X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
  
X 
X 
X 
X 
X 
X 
  
Vital signs 
(Weight, BP, 
HR) 
X 
X 
X X X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse 
events 
X 
X 
X X X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
  
CMS-Liraglutide Group and Multi-Component Intervention Group Only (CMS + Liraglutide + Meal Replacements) 
Extension Study Participants 
Liraglutide 
provided 
  
X 
  
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
X 
X 
X 
X 
X 
X 
  
Liraglutide + 
phentermine 
(or placebo) 
provided 
 
X 
  
X 
X 
  
  
  
  
Multi-Component Intervention Only (CMS + Liraglutide + Meal Replacements) 
Meal 
replacements 
  
  
  
  
X X X 
X 
X 
X 
X 
X 
  
  
  
  
  
  
  
  
  
  Liraglutide 
only 
 
 
 
 
 
X 
 X 
 
 
Note. R=randomization. Randomization will be followed immediately by week 1 medical visits and lifestyle intervention sessions. Columns shaded in grey indicate principal 
outcome assessment visits. 
 


   Version 3.3   September 25, 2018 
Page 47 
 
Screening Procedures  
 
All participants in the CMS-Liraglutide and Multi-Component interventions will be 
informed of the 12-week extension study at the time of their 48-week visit for the original 
1-year trial (i.e., 1 month before the trial’s conclusion). They will be apprised of the study 
extension by their lifestyle coach (who include physicians, nurse practitioners, and 
registered dietitians). The coach will explain the extension study and answer any 
questions concerning it. Participants interested in participating in the study will meet, 
immediately following their coaching visit, with the principal investigator or one of his 
designees who will assess the participants’ likely appropriateness for the study and  
obtain written informed consent from the participant. (Participants in the CMS-Alone 
group will be informed of the extension, randomized controlled trial and told that it is 
only open to participants in the two medication groups. They also will be informed of the 
opportunity to receive 5 additional monthly counseling visits [weeks 4-20] and provide 
informed consent if they wish to continue to participate.) 
Screening Visit 
 
Participants who wish to participate in the extension randomized controlled trial (RCT) 
will meet at week 52 (of the original trial) with a study physician or nurse practitioner for 
the final medical visit of the 1-year trial (see Table 1 from the original 1-year protocol). 
The practitioner will further assess the participants’ eligibility for the extension study, 
and an EKG will be conducted to ensure that the participant has no cardiac abnormalities. 
Blood pressure and pulse will be checked to ensure that they are within the upper limit of 
normal (< 160/100 mm Hg, with a resting pulse no greater than 85 beats per minute 
(BPM), given the possible effects of both liraglutide and phentermine in increasing heart 
rate). All participants also will have a blood draw at week 52 to examine cardiometabolic 
risk factors (described in the original protocol), as well as standard blood chemistries 
(e.g., liver function tests).  
 
Randomization Visit 
 
Participants who appear to meet all eligibility criteria (to be confirmed by the results of 
blood tests) will be scheduled the following week for a randomization visit for the 
extension study. They will be instructed to continue to take liraglutide 3.0 mg/d for the 
week between the screening visit and the randomization visit. 
 
Participants’ eligibility status, as well as completion of all questionnaires from the week 
52 visit (from the original 1-year trial), will be examined a final time at the beginning of 
the randomization visit. Participants who remain fully eligible will be randomly assigned 
to the two medication interventions in equal numbers (i.e., 1:1 ratio). The randomization 
will be conducted by Dr. Ken Rockwell, director of the Investigational Drug Service at 
Penn. The randomization will be from stratified blocks, based on whether participants 
lost >10 of initial weight during the 1-year trial. This will control for any influence that 
prior treatment arm had on patients’ end-of-treatment weight loss and ensure that the two 
groups are balanced (on prior weight loss) at the outset of the extension study. 
 


   Version 3.3   September 25, 2018 
Page 48 
 
Following randomization, all participants will have a medical visit with the study 
physician or nurse practitioner who will instruct patients in the two treatment groups in 
the continued use of liraglutide 3.0 and in the addition of the second medication, which 
will be presented in capsule form. Participants will be encouraged to take both 
medications in the morning upon awakening. 
 
Phentermine will be provided as 8.0mg/d for the first 2 weeks to facilitate its acceptance 
to participants. The dose will be increased at week 4 to 15 mg/d (or further placebo) in all 
participants. Phentermine (or placebo) will be down-titrated (back to 8.0mg/d) or 
terminated in patients who report that they cannot tolerate the medication after a 
prolonged effort to do so.  Down-titration will be managed in a blinded manner by Dr. 
Rockwell, in response to notification from the principal investigator (or study co-
investigators) of patients’ complaints of symptoms. (With Dr. Rockwell, we successfully 
used this titration method in a prior randomized placebo-controlled trial of sibutramine 
for weight loss.46) Participants in whom phentermine (or placebo) is terminated will 
continue to receive liraglutide 3.0 mg/d in an open-label manner, as they have for the 
prior year.   
 
Following randomization, all participants also will have an individual lifestyle 
intervention session with their provider to review their diet and physical activity goals 
Lifestyle Counseling Visits – All Groups  
 
Participants in both medication groups in the extension study (i.e.,liragltide + 
phentermine vs liraglutide + placebo) will receive the same program of diet, physical 
activity, and behavior therapy, as provided during the last 6 months of the original 1-year 
trial. All participants will be provided 4 brief (15 min), face-to-face visits during the 12 
weeks, with visit scheduled at weeks 0 (randomization), 4, 8, and 12. Lifestyle counseling 
will be delivered by a physician, nurse practitioner (NP) or a registered dietitian (RD) or 
behavioral psychologist, the latter working incident to an NP or physician. (Participants 
in the CMS-Alone group will be eligible for this same schedule of lifestyle counseling 
visits.) 
 
Participants who weigh <250 lb will be prescribed a diet of 1200-1499 kcal/d, comprised 
of conventional foods, with approximately 15-20% kcal from protein, 20-35% from fat, 
and the remainder from carbohydrate. (Those who weigh >250 lb will be prescribed 
1500-1800 kcal/d.) They will be instructed to continue to record their food and calorie 
intake daily, using paper-and-pencil diaries or on-line trackers (including MyFitnessPal 
or Lose-It).  
 
All individuals will be instructed to continue to engage in low-to-moderate intensity 
physical activity (principally walking or similar aerobic activity) 5 days per week, for at 
least 180 minutes per week and preferably >225 minutes/week.  Subjects will be 
instructed to record their activity daily and will receive a traditional pedometer (Yamax, 
Digi-Walker) if they do not own a smart phone, Fitbit, or other device with which to track 
their steps.  
 


   Version 3.3   September 25, 2018 
Page 49 
 
Missed visits will be rescheduled whenever possible. If the subject is unable to complete 
the visit in person, a telephone call of 15 minutes may be substituted for the face-to-face 
meeting. The same meeting format, including a report of the subject’s weight, will be 
followed for phone-delivered sessions as for face-to-face meetings. A growing body of 
evidence indicates that phone-delivered lifestyle counseling is as effective as face-to-face 
meetings. 
Medical Monitoring Visits 
 
Following randomization, all participants in both medication groups will have brief 
medical assessments (5-10 minutes) with a physician or nurse practitioner at weeks 2, 4, 
8, and 12. At each medical assessment, participant’s weight and vital signs will be 
measured and their response to the medication will be assessed. Study subjects will be 
asked whether there have been any changes in their health or medications. For all non-
study-related medical events, participants will be referred to their own primary care 
providers. Participants also will be asked about their mood or any thoughts of harming 
themselves, as assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS).27 In 
the event of reports of suicidal ideation or disturbances in mood, participants will be 
referred to the study’s psychologist or psychiatrist for further evaluation, as appropriate.   
 
Liraglutide 3.0 mg Continuation Study from Weeks 12 to 20 
 
At the end of week 12 (post-randomization), phentermine and placebo will be terminated, 
but both groups will remain on liraglutide 3.0 mg/d until week 20. Participants will 
continue to have both lifestyle counseling and medical visits at weeks 16 and 20 (and 
those in CMS Alone will be offered counseling visits on the same schedule). We wish to 
observe, from weeks 12 to 20, the change in body weight that occurs with the termination 
of phentermine 15 mg/d. At week 20, liraglutide also will be terminated in all 
participants. At week 24 (post-randomization), all participants will have a final 
assessment with a physician or nurse practitioner to determine participants’ health status.  
 
Assessments for Efficacy 
 
Participants will attend 2 major outcome assessment visits, conducted at randomization 
(the week 52 visit of the 1-year trial) and week 12.   
Primary Efficacy Measure 
 
The primary outcome is % reduction in initial body weight, as measured from 
randomization to week 12. Secondary outcomes include the proportion of participants 
who at week 12 lose >5% or >10% of randomization weight. Body weight will be 
measured on a digital scale (to the nearest 0.1 kg) with participants dressed in light 
clothing, without shoes. Two measurements will be taken on each occasion and averaged. 
Weight will be measured by an assessor masked to participants’ treatment conditions. 
Secondary Efficacy Measures  
 


   Version 3.3   September 25, 2018 
Page 50 
 
The secondary efficacy measures, to be assessed at week 12 of the extension study, 
include changes 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 satisfaction with weight loss. All of these measures are described in 
the original protocol.   
 
A secondary analysis will examine differences between the two randomized groups in 
changes in weight and other outcomes as measured from participants’ original 
randomization values, when starting the original 1-year trial. 
 
Changes in weight from week 12 to week 20, when participants receive liraglutide alone, 
will be examined using descriptive statistics. 
 
Assessments for Safety 
 
Safety endpoints include physical examination, adverse events (AEs), standard laboratory 
tests, and mental health/suicidal behavior as assessed by the Columbia Suicide Severity 
Rating Scale (C-SSRS). As detailed above, participants in all three groups also will have 
brief medical visits (5-10 minutes) with a physician or nurse practitioner at weeks 2, 4, 8, 
12, 16, and 20 (total of 6 visits). At each medical visit, participant’s response to the 
medication will be assessed. Study subjects will be asked whether there has been any 
change in their health or medications. They also will be asked about their mood or any 
thoughts of harming themselves, as determined by the C-SSRS. In the event of adverse 
mental health events, participants will be referred to the study’s psychologist or 
psychiatrist for further evaluation, if required. For all non-study-related medical events, 
participants will be referred to their own primary care provider.  
 
Participants will have fasting blood draws (comprehensive metabolic panel, lipids, etc) at 
screening and week 12 of the extension study. Vital signs (blood pressure and pulse) and 
weights will be measured at weeks 0 (randomization) and 2, 4, 8, 12, 16, and 20.  
 
Subject Compliance 
 
We will measure subject’s medication adherence to liraglutide using injection counts 
from visual inspection of the dose counter taken from subjects’ injection pens. Patients 
will be instructed to bring the pen to each session, and we will record missed doses and 
problem solve with patients if they are missing doses. We will track adherence to 
phentermine/placebo by counting the number of unused capsules at each visit. Patients 
will be instructed to keep a medication diary, as part of their food and activity monitoring. 
 
STATISTICAL CONSIDERATIONS: 
Sample Size Calculation 
 


   Version 3.3   September 25, 2018 
Page 51 
 
At week 12 of the extension study, subjects assigned to liraglutide-phentermine are 
predicted to lose 3.5% (SD=3.5) of randomization weight, while those assigned to 
liraglutide-placebo are expected to lose 0.0% (SD=0.5). (Both values will be measured as 
change from randomization to week 12 and do not reflect weight lost in the prior 1-year 
trial.) These estimates are based on the results previously described by Aronne et al in a 
study of phentermine plus topirimate and a study of Smith et al in a study of phentermine 
combined with loracserin.49,50 Using a sample size equation for longitudinal clustered 
samples, a randomization sample of 35 subjects in liraglutide-phentermine and 35 
subjects in liraglutide-placebo provides >80% power to detect a statistically significant 
difference (p < 0.05, two tailed test) between the two groups. This estimate allows for 
10% attrition during the 12-week trial, resulting in approximately 32 treatment 
completers per group. (The 10% attrition level is conservative; all participants will have 
demonstrated that they are highly adherent as a result of completing the prior 1-year trial.  
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. All secondary analyses will be considered exploratory and 
evaluated at the alpha = 0.05 level. The power analysis was conducted using PASS 11. 
Statistical Methods 
 
Preliminary Analyses 
 
All data analyses will proceed using the same principles and methods described in the 
Statistical Methods section of the original protocol.  
 
Interim Analysis 
 
No interim analyses are planned (in order to maintain full power for the end-of-study 
comparisons). 
 
Explorative Statistical Analysis for Pharmacogenetics and Biomarkers 
 
No explorative statistical analysis for pharmacogenetics and biomarkers will be 
performed. 
 
Data Handling and Record Keeping: 
 
The same procedures will be used to address these issues as used in the original trial.  
 
Ethics: 
 
The same procedures will be used to address these issues as used in the original trial.  
 
 
 
 


   Version 3.3   September 25, 2018 
Page 52 
 
Study Schedule:  
 
Table 4. Extension Study Timeline 
 
2017 
2018 
2019 
First patient screening  
 
 
9/20 
 
 
 
 
 
 
 
Last patient randomization 
 
 
 
 
 
5/28 
 
 
 
 
Last patient last visit 
 
 
 
 
 
 
8/20 
 
 
 
Data collection 
 
 
 
 
 
 
 
 
 
 
Data analysis/manuscripts 
 
 
 
 
 
 
 
 
2/28 
 
Final study reports 
 
 
 
 
 
 
 
 
2/28 
 
 
 
 
Study Drugs and Materials:  
 
For the randomized extension trial, participants assigned to liraglutide-phentermine, as 
well as phentermine-placebo, will need 91 doses (13 weeks  x 7 doses per week) of 
liraglutide. (This includes 1 week of liraglutide to be used between the screening visit [at 
week 52] and the randomization visit [at week 0]). Subjects will be provided with a 30-
day supply of medication (5 pens) at randomization and weeks 4 and 8. Liraglutide will 
be provided in an open-label manner, as it was throughout the 1-year prior trial. 
 
At the randomization visit (week 0), participants in both medication groups will be 
provided 15 identical capsules containing either phentermine 8.0 mg/d or placebo 
(depending upon their treatment assignment). Upon returning at week 2, they will be 
provided 15 additional capsules containing either phentermine 15.0 mg or placebo. At 
week 4, and again at week 8, all participants will be provided 30 capsules containing 
phentermine 15.0 mg or placebo.    
 
Following completion of the 12-week extension trial, all participants will discontinue 
phentermine (or placebo) but will remain on liraglutide 3.0 mg/d for an additional 8 
weeks. Participants will require an additional 56 doses (8 weeks x 7 doses per week) of 
liraglutide from weeks 12 to 20. Participants will be provided a 30-day supply (5 pens) at 
both weeks 12 and 16.  
Study Medications 
 
The study medications are liraglutide 3.0 mg/d and phentermine 15.0 mg/d (or placebo).   
Packaging and Labelling of Study Medications 
 
Liraglutide will be packaged, labelled, and distributed to patients, as it was during the 1-
year trial. The medication will be provided by Novo Nordisk as ready-to-use, pre-filled, 
multi-dose pens by Novo Nordisk in a subject box.  
Study drug will be shipped to the Center for Weight and Eating Disorders at the 
University of Pennsylvania (attention Dr. Tom Wadden) for labeling and packaging. The 
study drug supplies will be labeled appropriate to their use. The label for the study drug 
will contain at a minimum: 


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 Protocol number 
 Kit identification number from the randomization scheme 
 Instructions for use 
 Study drug name 
 
Phentermine (and placebo) will be purchased and then packaged in blinded capsules by 
Dr. Ken Rockwell, director of the Investigational Drug Service at Penn. Dr. Rockwell has 
prepared medications before for our Center in this manner. Dr. Rockwell will store all 
phentermine-placebo at the hospital, to be picked up on a weekly basis by study 
coordinators and distributed to study patients.   
  
Storage and Drug Accountability of Study Medication 
 
The same procedures will be used to address these issues as used in the original trial.  
 
Randomization and Blinding 
 
Dr. Ken Rockwell from Penn’s Investigational Drug Service will generate the 
randomization code. The first subject to meet the treatment criteria will be assigned the 
first number in the sequence; each subsequent subject to meet treatment criteria will be 
assigned the next number in the sequence. This study combines the open-label provision 
of liraglutide with blinded assignment to phentermine or placebo.  
Breaking of Blinded Codes 
 
Dr. Rockwell will be prepared to break the blinded code in the event of patient 
emergency. 
 
Concomitant Illnesses and Medications: 
 
At trial entry (i.e., the screening visit), we will record details of any concomitant illness 
(i.e., any illness that is present at the start of the trial) that is present and concomitant 
medication (i.e., any medication other than the trial product(s) that is taken during the 
trial, including the screening and run-in periods) in each patient’s record. The information 
collected for each concomitant medication will include the start date, stop date or 
continuing, and indication. For each concomitant illness, we will record the date of onset, 
date of resolution or continuing. Any changes in concomitant medication use will be 
recorded at each visit. If the change influences the subject’s eligibility to continue in the 
trial, the Sponsor will be informed. 
 
 
Adverse Events: 
 
At each contact with subjects, study personnel will be responsive to reports of adverse 
events with specific questioning and, as outlined in the procedures section, by physical 
examination. The investigator will be report all adverse events including serious adverse 


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events (SAE), suspected unexpected serious adverse reactions (SUSARs), serious adverse 
drug reactions (SADRs) (as defined below) to the Data Safety and Monitoring Board 
established for the trial, and to the Penn IRB. Information on all adverse events will be 
recorded immediately in the source document and reported immediately, and also in the 
appropriate adverse event module of the case report form (CRF). Information on study 
name, patient identification, event (i.e., diagnosis, causality), drug, and reporter 
identification (e.g., name) will be collected and recorded in the source document (as 
detailed below). All serious adverse events will be reported to the IRB within 24 hours. 
The investigator will report to Novo Nordisk all SAEs, SUSARs, and SADRs at the same 
time such events are reported to regulatory authorities or within 15 days from the 
investigator becoming aware of such adverse events, whichever comes first.  
 
The PI and his investigative team acknowledge the definition of adverse events (AEs), 
serious adverse events (SAEs), and other untoward occurrences as spelled out below. 
 
Adverse Event (AE): 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered/using a product and which does not necessarily have to have a causal 
relationship with this treatment. An Adverse Event can therefore be any unfavourable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a product, whether or not considered related to the 
product. 
 
Clinical Laboratory Adverse Event: 
A clinical laboratory AE is any clinical laboratory abnormality regarded as clinically 
significant i.e. an abnormality that suggests a disease and/or organ toxicity and is of a 
severity that requires active management, (i.e. change of dose, discontinuation of trial 
product, more frequent follow-up or diagnostic investigation). 
 
Serious Adverse Event (SAE): 
A serious AE is an experience that at any dose results in any of the following: 
• Death 
• A life-threatening* experience 
• In-patient hospitalisation or prolongation of existing hospitalization 
• A persistent or significant disability/incapacity 
• A congenital anomaly/birth defect 
• Suspicion of transmission of infectious agents 
• Important medical events that may not result in death, be life-threatening*, or require 
  hospitalisation may be considered an SAE when, based upon appropriate medical 
judgement, they may jeopardise the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition 
*The term life-threatening in the definition of SAE refers to an event in which the subject was at risk of 
death at the time of the event. It does not refer to an event which hypothetically might have caused death if 
it was more severe. 
 


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Suspected Unexpected Serious Adverse Reaction (SUSAR): A SUSAR is an SAE 
which is unexpected and regarding as possibly or probably related to the trial/study 
product by the investigator. 
 
Serious Adverse Drug Reaction (SADR):  
An adverse drug reaction (ADR) is an adverse event for which a causal relationship 
(Possible/Probable relation) between the study drug and the occurrence of the event is 
suspected. The ADR should be classified as serious if it meets one or more of the 
seriousness criteria.  
 
Medical Events of Special Interest (MESI): A MESI is (1) a medication error (e.g. 
wrong drug administration or wrong route of administration) or (2) a suspected 
transmission of an infectious agent via the product 
 
Non-Serious Adverse Event: 
A non-serious AE is any AE which does not fulfil the definition of an SAE. 
 
Severity Assessment Definitions: 
• Mild: Transient symptoms, no interference with the subject’s daily activities 
• Moderate: Marked symptoms, moderate interference with the subject’s daily activities 
• Severe: Considerable interference with the subject’s daily activities, unacceptable 
 
Relationship to study medication Assessment Definitions: 
• Probable: Good reasons and sufficient documentation to assume a causal relationship 
• Possible: A causal relationship is conceivable and cannot be dismissed 
• Unlikely: The event is most likely related to an etiology other than the trial product 
 
The US PI will be used to evaluate all unexpected events and adverse reactions. 
 
Outcome Categories and Definitions: 
• Recovered: Fully recovered or by medical or surgical treatment the condition has 
returned to the level observed at the first trial related activity after the subject signed the 
informed consent 
• Recovering: The condition is improving and the subject is expected to recover from the 
event. This term should only be used when the subject has completed the trial 
• Recovered with sequelae: As a result of the AE, the subject suffered persistent and     
significant disability/incapacity (e.g. became blind, deaf, paralysed). Any AE recovered 
with sequelae should be rated as an SAE 
• Not recovered 
• Fatal 
• Unknown 
 
 
Collection, Recording and Reporting of Adverse Events 


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All events meeting the definition of an adverse event will be collected and reported from 
the first trial related activity after the subject has signed the informed consent and until 
the end of the posttreatment follow-up period as stated in the protocol.  
 
Follow-up of Adverse Events 
During and following subjects’ participation in the study, the investigator and institution 
will provide adequate medical care to the study subject for any study-related adverse 
events, including clinically significant laboratory values related to the study. (Note: This 
section of the protocol will be written in consultation with Penn’s IRB, Office of 
Research Services, and Office of Legal Affairs. It will be addressed pending approval of 
the scientific aspects of the study.) 
 
Pregnancy 
Study subjects will be instructed to notify the investigator immediately if they become 
pregnant. The investigator will report to Novo Nordisk any pregnancy occurring during 
the trial period. Reporting of pregnancy by the investigator will occur within the same 
timelines described above for reporting of Adverse Events. Pregnancy complications will 
be recorded as adverse event(s). If the infant has a congenital anomaly/birth defect this 
will be reported and followed up as a serious adverse event. 
 
Precautions/Over-dosage 
In case of suspected overdose, subjects will be instructed to call their healthcare provider 
immediately, as excessive intake of Saxenda may cause severe nausea and vomiting.  
 
Liability and Subject Insurance: 
Liability and subject insurance have been addressed in the contract that governed the 
original 1-year trial. These conditions will continue in the 12-week extension study.  
 
Evaluability of Subjects: 
Participants will be excluded from data analysis in the event of pregnancy, amputation, 
bariatric surgery, or death.  Additional criteria associated with subject censorship will be 
considered prior to initiating recruitment. 
 
Premature Termination of Study: 
We believe that it is highly unlikely that the study will be terminated prematurely, given 
the safety of the intervention and its expected effects. Termination would be considered, 
however, in view of: 
 Unacceptable safety concerns of the study medication 
 The benefits observed do not ethically permit the trial to continue 
 
Publication Plan: 
We will register the study with a publicly assessable database such as clinicaltrials.gov.  
An initial report of the findings will be presented at an annual scientific meeting (e.g., 
American Diabetes Association, The Obesity Society, The American Heart Association). 
We plan to publish the study results approximately 6 months after study completion.  
 


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The report of the primary outcome likely will be submitted to the International Journal of 
Obesity or the journal Obesity. The study’s short duration and small sample size make 
these journals the most appropriate outlets for publication. 
 
 
 
References: 
 
46. 
Berkowitz RI, Wadden TA, Tershakovec AM, et al. Behavior therapy and 
sibutramine for the treatment of adolescent obesity: a randomized controlled trial. 
JAMA 2003;289:1805-12. 
 
47. 
Wadden TA, Hollander P, Klein S, et al. Weight maintenance and additional 
weight loss with liraglutide after low-calorie-diet-induced weight loss: the 
SCALE maintenance randomized study. Int J Obes (Lond) 2013;37:1443-51. 
 
48. 
Apovian CM, Aronne LJ, Bessesen DH, et al. Pharmacological management of 
obesity: an endocrine Society clinical practice guideline. J Clin Endocrinol Metab 
2015;100(2):342–62 
 
49. 
Aronne LJ, Wadden TA, Peterson C, Winslow D, Odeh S, Gadde KM. Evaluation 
of phentermine and topiramate versus phentermine/topiramate extended-release in 
obese adults. Obesity (Silver Spring) 2013;21(11):2163–71. 
 
50. 
Smith SR, Garvey WT, Greenway FL, et al. Coadministration of lorcaserin and 
phentermine for weight management: A 12-week, randomized, pilot safety study. 
Obesity (Silver Spring) 2017;25(5):857–65.