Real World Effectiveness of Combining an Employer-based Weight Management Program With Medication for Chronic Weight Management in Employees With Obesity - a Pragmatic Randomized Trial
Phase: PHASE4
Conditions: Obesity
Sponsor: Novo Nordisk A/S

Cover Page for Protocol 
 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT03799198  
Sponsor trial ID: 
NN8022-4432 
Official title of study: 
Real world effectiveness of combining an employer-based 
weight management program with medication for chronic 
weight management in employees with obesity – a pragmatic 
randomized trial 
Document date: 
10 October 2018 
 

Novo Nordisk
Protocol No. NN8022-4432
UTN: U1111-1218-8104
 
Clinical Study Report
Confidential
Appendix 16.1.1 
Version 1.0; December 14, 2020
16.1.1 Protocol and protocol amendments
 
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Protocol No. NN8022-4432
UTN: U1111-1218-8104
 
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Real world effectiveness of combining an employer-based weight management 
program with medication for chronic weight management in employees with
obesity – a pragmatic randomized trial
Protocol No. NN8022-4432
Novo Nordisk
Novo Nordisk
October 10, 2018
Version 1.0
Trial Phase: 4
This document and its contents are the property of Novo Nordisk and are confidential.  
Unauthorized copying or use is prohibited.
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This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.

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STUDY APPROVALS
Protocol No: NN8022-4432
October 10, 2018
Sponsor Approval:
Name:
Title:  
, Clinical Development & Outcomes Research
Signature:  
Date:
Name:
Title:  
, Biostatistics
 
Signature:  
Date:
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Study Physician Agreement:
I have read the protocol “Real world effectiveness of combining an employer-based weight 
management program with medication for chronic weight management in employees with 
obesity – a pragmatic randomized trial” and agree to ensure that all staff members involved in 
the conduct of this study are informed of their obligations and that they meet the commitments of 
the protocol in accordance with Good Clinical Practice (GCP) requirements. I have familiarized 
myself with the prescribing information corresponding with the study drugs associated with this 
study. I agree to provide information regarding the risks associated with study drugs to subjects 
who are prescribed study drugs in a manner consistent with standard care.
I acknowledge that I am responsible for overall study conduct. I understand GCP requirements 
and agree to personally conduct or supervise the described pragmatic study in accordance with 
GCP.
Signature:  
Print Name: 
Date:
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TABLE OF CONTENTS
STUDY APPROVALS.................................................................................................................. 2 
STUDY PHYSICIAN AGREEMENT:....................................................................................... 3 
TABLE OF CONTENTS ............................................................................................................. 4 
SYNOPSIS..................................................................................................................................... 8 
LIST OF ABBREVIATIONS .................................................................................................... 13 
1 
INTRODUCTION............................................................................................................... 16 
2 
STUDY OBJECTIVES....................................................................................................... 17 
2.1 
Primary Objective................................................................................................................................................... 17 
2.2 
Secondary Objectives ............................................................................................................................................ 17 
3 
STUDY ENDPOINTS......................................................................................................... 18 
3.1 
Primary Endpoint ................................................................................................................................................... 18 
3.2 
Secondary Endpoints............................................................................................................................................. 18 
4 
STUDY DESIGN................................................................................................................. 19 
4.1 
Overview .................................................................................................................................................................... 19 
4.2 
Study Site and Subject Selection........................................................................................................................ 20 
4.2.1 
Study Site ................................................................................................................................................................................... 20 
4.2.2 
Subject Recruitment and Eligibility ............................................................................................................................... 20 
4.2.3 
Subject Inclusion Criteria ................................................................................................................................................... 21 
4.2.4 
Subject Exclusion Criteria .................................................................................................................................................. 21 
4.2.5 
Subject Enrollment ................................................................................................................................................................ 22 
4.2.6 
Randomization ........................................................................................................................................................................ 22 
Figure 1. Study design diagram. ........................................................................................................................................ 22 
5 
STUDY PROCEDURES .................................................................................................... 22 
5.1 
Enrollment Procedures ........................................................................................................................................ 23 
5.2 
Screening and Randomization Visit ................................................................................................................. 23 
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5.2.1 
Subject Characteristics ........................................................................................................................................................ 23 
5.2.2 
Treatments ............................................................................................................................................................................... 23 
5.2.2.1 
Weight management program ............................................................................................................................. 23 
5.2.2.2 
Obesity medication (WMP + Rx arm only) ..................................................................................................... 24 
Table 5-1. Approved medications for chronic weight management in the US available in the study. ... 25 
5.2.2.3 
Concomitant medications....................................................................................................................................... 25 
5.3 
Questionnaires ........................................................................................................................................................ 25 
5.3.1 
Patient Reported Outcomes (PROs) .............................................................................................................................. 25 
5.3.1.1 
Work Productivity and Activity Impairment Questionnaire Specific Health Problem v2.0 
(WPAI:SHP) .......................................................................................................................................................................................... 26 
5.3.1.2 
Work Limitations Questionnaire 8-Item (WLQ-8) Self-administered Short Form....................... 26 
5.4 
Study Period ............................................................................................................................................................. 26 
5.5 
End of Study (EOS) .................................................................................................................................................. 26 
5.6 
Pharmacy Data ........................................................................................................................................................ 27 
5.7 
Withdrawals ............................................................................................................................................................. 27 
5.7.1 
Study Site ................................................................................................................................................................................... 27 
5.7.2 
Subjects ...................................................................................................................................................................................... 27 
6 
STATISTICAL METHODS .............................................................................................. 27 
6.1 
Analysis Overview .................................................................................................................................................. 27 
6.1.1 
Estimands .................................................................................................................................................................................. 27 
6.1.2 
Primary Endpoint and Confirming Hypothesis ........................................................................................................ 28 
6.2 
Study Populations................................................................................................................................................... 28 
6.3 
Sample Size Determination ................................................................................................................................. 29 
6.3.1 
Power and Sample Size for Primary Objective ......................................................................................................... 29 
Table 6-1. Power calculations for selected total N, treatment effects, and standard deviations ............. 30 
6.3.2 
Interim Analysis ..................................................................................................................................................................... 30 
6.4 
Primary Estimand for the Primary Endpoint ............................................................................................... 30 
6.4.1 
Primary Estimand Missing Data Imputation ............................................................................................................. 30 
6.4.2 
Sensitivity Analysis of the Primary Estimand for the Primary Endpoint ..................................................... 31 
6.4.3 
Secondary Estimand for the Primary Endpoint ....................................................................................................... 31 
6.4.4 
Supplementary Analyses .................................................................................................................................................... 31 
6.5 
Primary Estimand for the Secondary Endpoints ........................................................................................ 32 
6.5.1 
Categorical Weight Loss...................................................................................................................................................... 32 
6.5.2 
Adherence to Weight Management Program (WMP) ............................................................................................ 32 
6.5.3 
Adherence to Obesity Medication .................................................................................................................................. 32 
6.5.4 
Patient Reported Outcome (PRO) Analysis ................................................................................................................ 33 
6.5.5 
Supplementary Patient Reported Outcome (PRO) Analysis............................................................................... 33 
6.6 
Secondary Estimand for the Secondary Endpoints .................................................................................... 33 
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6.7 
Safety Analysis ......................................................................................................................................................... 34 
7 
ADVERSE EVENT (AE) REPORTING .......................................................................... 34 
7.1 
Adverse Events (AEs) ............................................................................................................................................ 34 
7.2 
Serious Adverse Events (SAEs) .......................................................................................................................... 34 
7.2.1 
Reporting Period of Serious Adverse Events (SAEs) ............................................................................................. 34 
7.3 
Pregnancy .................................................................................................................................................................. 35 
7.3.1 
Reporting Period of Pregnancy ......................................................................................................................... 35 
7.4 
Technical Complaints ............................................................................................................................................ 35 
8 
DATA COLLECTION....................................................................................................... 35 
8.1 
Data Sources ............................................................................................................................................................. 35 
8.2 
Electronic Case Report Forms (eCRFs) ........................................................................................................... 36 
8.3 
Database Lock .......................................................................................................................................................... 36 
9 
STUDY MANAGEMENT.................................................................................................. 36 
9.1 
Regulatory and Ethical Consideration ............................................................................................................ 36 
9.1.1 
Institutional Review Board (IRB) ................................................................................................................................... 36 
9.1.2 
Informed Consent .................................................................................................................................................................. 36 
9.2 
Record Retention and Access ............................................................................................................................. 37 
10 PUBLICATION OF STUDY RESULTS.......................................................................... 37 
11 INDEMNIFICATION ........................................................................................................ 38 
12 REFERENCES.................................................................................................................... 39 
APPENDIX 1-1: TIME AND EVENTS SCHEDULE............................................................. 42 
APPENDIX 1-2: DATA COLLECTED FROM PHARMACY CARD ................................. 45 
APPENDIX 2-1: PRO INSTRUMENTS – WORK PRODUCTIVITY AND ACTIVITY 
IMPAIRMENT QUESTIONNAIRE SPECIFIC HEALTH PROBLEM V2.0 (WPAI:SHP)
....................................................................................................................................................... 46 
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APPENDIX 2-2: PRO INSTRUMENTS – WORK LIMITATIONS QUESTIONNAIRE 8-
ITEM SELF-ADMINISTERED SHORT FORM (WLQ-8)................................................... 48 
APPENDIX 3: CAUSALITY AND OUTCOME DEFINITIONS FOR SERIOUS 
ADVERSE EVENT (SAE) REPORTING................................................................................ 56 
 
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SYNOPSIS
Title: Real world effectiveness of combining an employer-based weight management program with 
medication for chronic weight management in employees with obesity – a pragmatic randomized trial 
Sponsor: Novo Nordisk
Study Treatment: Cleveland Clinic’s Integrated Medical Weight Management Program (WMP) 
with medication approved for chronic weight management in the US, i.e., “WMP + Rx”
Active Ingredient: One of following approved medications: orlistat (per os (p.o.)), lorcaserin or 
lorcaserin extended-release (p.o.), phentermine/topiramate extended-release (p.o.), 
naltrexone/bupropion extended-release (p.o.), liraglutide 3.0 mg (subcutaneous (s.c.))
Comparator Treatment: Cleveland Clinic’s Integrated Medical WMP with no medication for 
weight management, i.e., “WMP”
Protocol No.: NN8022-4432
Study Site: This is a single-center study conducted at the Cleveland Clinic’s Endocrinology and 
Metabolism Institute, Cleveland, Ohio.
Country: United States
Subjects: Eligible subjects include adults with obesity (body mass index (BMI) ≥ 30 kg/m2) enrolled 
in the Cleveland Clinic Employee Health Plan for whom treatment with medication for chronic 
weight management may be indicated.
Planned enrollment in this study is 200. Subjects will be randomized 1:1 to receive either WMP + Rx 
or WMP alone.
Study Objectives: The objectives of this study are as follows:
x
The primary objective is to demonstrate superior effect of treatment with an employer-based 
weight management program in combination with medication for chronic weight 
management compared to an employer-based weight management program alone in subjects 
with obesity on weight loss.
x
The secondary objectives are to compare the effects of treatment with an employer-based 
weight management program in combination with medication for chronic weight 
management to an employer-based weight management program alone in subjects with 
obesity with regards to:
o
Categorical weight loss
o
Adherence to the weight management program
o
Patient-reported outcomes (PROs) on work productivity and work limitations
x
Furthermore, the secondary objectives will assess adherence to medication for chronic 
weight management (only in the treatment arm randomized to an employer-based chronic 
weight management program with medication for chronic weight management).
Study Design: This is a one-year, single-center, randomized, open-label, parallel-group pragmatic 
clinical trial (PCT) comparing Cleveland Clinic’s existing Integrated Medical WMP combined with 
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medication for chronic weight management versus Cleveland Clinic’s existing Integrated Medical 
WMP with no medication for weight management in subjects with obesity. Subjects will be 
randomized 1:1 to receive either Cleveland Clinic’s Integrated Medical WMP with medication for 
chronic weight management (“WMP + Rx”) or Cleveland Clinic’s Integrated Medical WMP alone 
(“WMP”).
To preserve the real-world nature of the study, the subject experience will be as close to routine 
clinical care as possible. The weight management program provided to all study subjects will be 
similar to the Integrated Medical WMP that is currently offered by the Cleveland Clinic. Consistent 
with standard practice of the Integrated Medical WMP, subjects in both treatment groups will attend 
monthly shared medical appointments (SMAs) and will be responsible for a co-payment. In the WMP 
+ Rx arm, obesity medications approved by the Food and Drug Administration (FDA) for chronic 
weight management are allowed and selection of specific medication is at the discretion of the study 
clinician. To simulate the co-payment that would be applied if a health plan covered treatment with 
medications for chronic weight management, subjects will pay a set fee for the obesity medication.
Study visits include an individual screening and randomization visit (visit 1; informed consent must 
be obtained at visit 1 before screening), followed by twelve once-monthly visits set up in the context 
of SMAs (visit 2 to visit 13). All subjects will be referred to a nutritionist appointment between visit 
1 and visit 2. End of Study (EOS) is visit 13 (month 12 (-14 days, +28 days)). Effort will be made to 
obtain a month 12 (visit 13) weight measurement from all randomized subjects, unless they have 
withdrawn consent. There will not be a follow-up period.
Subject Selection:
Inclusion Criteria: 
Subjects must meet all of the following inclusion criteria to be eligible for the study:
1.
Informed consent obtained before any study-related activities. Study-related activities are any 
procedures that are carried out as part of the study, including activities to determine 
eligibility for the study.
2.
Male or female, age ≥ 18 years at the time of signing informed consent
3.
Body mass index (BMI) ≥ 30 kg/m2
4.
Enrolled in Cleveland Clinic Employee Health Plan, and expecting to be covered by the 
Cleveland Clinic Employee Health Plan for the duration of the study
Exclusion Criteria:
Subjects presenting with any of the following exclusion criteria will not be eligible for the study:
1.
Contraindications to all of the medications approved by the FDA for chronic weight 
management according to the label.
2.
Previous participation in this study. Participation is defined as signed informed consent. 
3.
Female who is pregnant, breast-feeding or intends to become pregnant or is of child-bearing 
potential and not using adequate contraceptive methods (adequate contraceptive measures as 
required by local regulation or practice).
4.
Participation in another clinical trial within 30 days before screening. 
5.
Treatment with any medication with the intention of weight loss within 90 days before 
screening. 
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6.
Previous or current participation in Cleveland Clinic’s Integrated Medical Weight 
Management Program. 
7.
History of (or plans during the study period for) bariatric surgery, or use of minimally-
invasive weight loss devices (i.e., intragastric balloons, lap bands) not removed within 1 year 
prior to screening. 
8.
History of type 1 or type 2 diabetes mellitus. 
9.
HbA1c ≥ 6.5% at screening or within 90 days prior to randomization. 
10. Any condition, unwillingness or inability, not covered by any of the other exclusion criteria, 
which, in the study clinician’s opinion, might jeopardize the subject’s safety or compliance 
with the protocol.
Study Procedures:
x
Potentially eligible subjects will be identified during the course of routine implementation of 
Cleveland Clinic’s Employee Wellness Program, "Healthy Choice," or referred to the study 
via the study advertisement or another health care provider.
x
Study clinicians will obtain informed written consent from subjects and if eligible, subjects 
will be randomized to either WMP + Rx or WMP.
x
Study data will be collected on electronic Case Report Forms (eCRFs) via an electronic data 
capture (EDC) system.
x
Assessments at the screening and randomization visit (visit 1/baseline (month 0)) include: 
eligibility (including urine pregnancy test (if applicable) and point of care (POC) hemoglobin 
A1c (HbA1c) measurement if an HbA1c measurement is not available within 90 days prior 
to randomization), demographic data, relevant medical history, concomitant medications, 
height, and body weight.
x
All subjects will enroll in the Integrated Medical WMP at the Cleveland Clinic’s 
Endocrinology and Metabolism Institute. In this program, as part of usual care, subjects will:
o
discuss and choose one of three diet options: protein-sparing modified fast, 
Mediterranean, or meal replacement.
o
be referred to a nutritionist appointment.
o
initiate a series of twelve monthly study visits (visits 2-13) in the context of SMAs 
covering nutrition, physical activity, appetite control, sleep issues, and 
anxiety/depression/stress.
o
be referred to an exercise physiologist for a personalized physical activity program.
o
if assessed relevant by the study clinician, be referred to a mental health specialist 
and/or sleep clinic.
x
Subjects enrolled in the WMP + Rx arm will be provided a prescription for medication 
indicated for chronic weight management (obesity medication) at the time of randomization
(visit 1).
x
Disallowed medications:                                                                                                                 
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o
Other than the medication prescribed by the study clinician for chronic weight 
management in the WMP + Rx arm, use of any medication, on- or off-label, for 
weight loss purposes is not allowed in either arm during the study.
o
The use of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-
glucose co-transporter 2 (SGLT-2) inhibitors for diabetes diagnosed during the study 
is not allowed.
x
Assessments during monthly study (i.e., SMA) visits include: weight, pregnancy and serious 
adverse events (SAEs), attendance at SMAs, and use of disallowed medications.
x
Prescription fill data for obesity medication (WMP + Rx arm) will be collected from 
randomization through EOS.
x
Questionnaires: PROs on work productivity and work limitations will be assessed by the 
Work Productivity and Activity Impairment Questionnaire Specific Health Problem v2.0 
(WPAI:SHP) and the Work Limitations Questionnaire 8-Item (WLQ-8) Self-administered 
Short Form at visit 1, visit 7, and visit 13.
Study Duration: Total study duration for the individual subjects will be approximately one year. 
Subjects will be followed and data collection will continue for the full duration of the study, unless 
the subject withdraws informed consent. The full duration of the study is defined as up to and 
including visit 13. Effort will be made to obtain a month 12 (visit 13) weight measurement from all 
randomized subjects.
Analysis: Two estimands, each targeting a unique research question, have been defined to adequately 
describe the effect of an employer-based WMP combined with obesity medication compared to an 
employer-based WMP alone.
The primary estimand for all endpoints is an “intention-to-treat” estimand. This estimand will 
quantify the average treatment effect of an employer-based WMP combined with medication for 
chronic weight management compared to the employer-based WMP alone after 12 months, in all 
randomized subjects and regardless of adherence to randomized treatment. 
The secondary estimand for body weight loss, categorical weight loss, and PROs is an “if all subjects 
had adhered” estimand. This estimand will quantify the average treatment effect of an employer-
based WMP combined with medication for chronic weight management compared to the employer-
based WMP alone after 12 months, in all randomized subjects had they adhered to their randomized 
treatment for the entire planned study duration.
The primary endpoint is percent change in body weight from baseline (month 0) to month 12 (visit 
13). The study is designed to have 80% power to confirm superiority of WMP + Rx versus WMP 
alone on % weight change from baseline (month 0) to month 12 (visit 13).
The full analysis set (FAS) comprising all randomized subjects analyzed according to the treatment 
group to which they were assigned at randomization will be the analysis population for the evaluation 
of both the primary and secondary estimands. The primary estimand will be estimated based on the 
FAS and % weight change will be modeled using linear regression (Analysis of Covariance 
(ANCOVA)) with randomized treatment as a factor and baseline body weight (kg) as a covariate. 
Prior to analysis, missing month 12 weight data will be imputed by multiple imputations. For the 
secondary estimand, the primary endpoint will be analyzed using a mixed model for repeated 
measurements (MMRM) including all subjects, but for subjects considered non-adherent to 
randomized treatment, only data prior to non-adherence will be used.
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The significance level used in all statistical analyses will be 5% (two-sided).
Supplementary Analyses: A supplementary analysis will be conducted on the subset of subjects 
with month 12 (visit 13) body weight data who adhered to randomized treatment up to and including 
visit 13.
Secondary Analyses: Secondary analyses will compare WMP + Rx versus WMP in terms of 
categorical weight loss, adherence to the WMP, and PRO measures. Additionally, adherence to 
obesity medication will be descriptively summarized for the WMP + Rx arm. The primary estimand 
will be assessed for all secondary endpoints. Additionally, the secondary estimand will be assessed 
for categorical weight loss and PRO measures.
Safety: For the purposes of this study, adverse events (AEs) will only be required to be collected if 
they meet the definition of an SAE. Study clinicians are responsible for reporting all SAEs and 
following the subject until the outcome of the event is closed out. All SAEs will be reported from 
randomization until EOS at month 12, or until the subject withdraws from the study. Study clinicians 
are also responsible for recording all pregnancies in female subjects from randomization until EOS at 
month 12 or subject study withdrawal. The subject will be followed for the duration of the pregnancy 
until one month post-delivery to report the pregnancy outcome and any AEs or SAEs observed in the 
fetus or newborn until 1 month of age. Safety will be summarized descriptively.
 
 
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LIST OF ABBREVIATIONS
 
Abbreviation
Definition 
AE
Adverse Event
ANCOVA
Analysis of Covariance
API
Active Pharmaceutical Ingredient
BMI
Body Mass Index
eCCG
Electronic Case Report Form Completion Guidelines
CFR
Code of Federal Regulations
CI
Confidence Interval
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
EMR
Electronic Medical Record
EOS
End of Study
FAS
Full Analysis Set
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendment Act
GCP
Good Clinical Practice
GLP-1 RA
Glucagon-Like Peptide-1 Receptor Agonists
HbA1c
Hemoglobin A1c
HIPAA
Health Insurance Portability and Accountability Act
ICF
Informed Consent Form
ICMJE
International Committee of Medical Journal Editors
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Abbreviation
Definition 
IRB
Institutional Review Board
LSFV
Last Subject First Visit
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
Mixed Model for Repeated Measurements
OR
Odds Ratio
PCD
Primary Completion Date
PCT
Pragmatic Clinical Trial
PDC
Proportion of Days Covered
PO
Per Os
POC
Point of Care
PRO
Patient Reported Outcome
PT
Preferred Term
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SC
Subcutaneous
SD
Standard Deviation
SGLT-2
Sodium-Glucose Co-transporter 2
SMA
Shared Medical Appointment
SOC
System Organ Class
US
United States
WLQ-8
Work Limitations Questionnaire 8-Item
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Abbreviation
Definition 
WMP
Weight Management Program
WPAI:SHP
Work Productivity and Activity Impairment Questionnaire Specific 
Health Problem
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1
INTRODUCTION 
The prevalence of obesity has been increasing globally based on pooled data from the years 1975 
to 2016. [1] In the United States (US), nearly 40% of adults have obesity, with prevalence 
ranging from 22% to 38% among the different states. [2] Obesity raises the risk of morbidity 
from a multitude of diseases, including hypertension, dyslipidemia, type 2 diabetes mellitus, 
coronary heart disease, stroke, gallbladder disease, osteoarthritis, sleep apnea, respiratory 
problems, fatty liver disease, and some cancers. [3] [4] Obesity is also associated with increased 
risk of all-cause and cardiovascular diseases mortality. [5] In recognition of the biological basis 
and seriousness of obesity, several professional associations and health organizations worldwide
[4] [6] [7] [8] now recognize obesity as a disease. 
Lifestyle intervention in the form of improving diet and increasing physical activity is 
foundational treatment for obesity and overweight [9], but the majority of people with obesity 
and overweight struggle to achieve and maintain their weight loss. [10] Medications approved 
for chronic weight management can be useful adjuncts to lifestyle change for patients who have 
been unsuccessful with diet and exercise alone. [11] Five medications have been approved by the 
US Food and Drug Administration (FDA) for chronic weight management: orlistat (per os (p.o.),
lorcaserin or lorcaserin extended-release (p.o.), phentermine/topiramate extended-release (p.o.),
naltrexone/bupropion extended-release (p.o.), liraglutide 3.0 mg (subcutaneous (s.c.)).
In the US, employers are the ultimate purchasers of health care for the majority (56%) of 
Americans. [12] Recommendations support addressing obesity in the workplace; however, real-
world evidence of best practices for chronic weight management, including impact of longer-
term pharmacological treatment, in the employer context is lacking. [13] Currently, in order for 
medications for chronic weight management to be included in the health care offered to 
employees, employers have to “opt-in” or deliberately decide to pay for these medications for 
employees, even when payers have added them to their formulary. The Cleveland Clinic 
provides a unique environment to investigate the impact of including approved medications for 
chronic weight management in the context of an employer-based weight management program. 
The Cleveland Clinic is one of the largest hospital systems in the US. The Cleveland Clinic’s 
Employee Health Plan provides health coverage for approximately 66,000 adults, including
employees and spouses. Among this population, approximately 18,000 are known to have 
obesity defined by body mass index (BMI) ≥ 30 kg/m2, making the prevalence of obesity within 
the Cleveland Clinic Employee Health Plan consistent with that observed in the general US adult 
population. [2] Cleveland Clinic’s Employee Health Plan provides employees diagnosed with
obesity support for participating in a weight management program of their choice, but does not 
currently offer coverage for medications for chronic weight management. One of the weight 
management programs offered to employees is the Cleveland Clinic’s Integrated Medical Weight 
Management Program (WMP). This program is administered through shared medical 
appointments (SMAs) which is a concept based on the chronic care model [14] that combines 
group appointments for patients with clinical intervention, consisting of encounters with a 
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nutritionist, exercise physiologist, and endocrinologist/obesity medicine specialist. [15] [16] [17]
As part of the comprehensive evaluation of a patient with obesity in which mood disorders and 
obstructive sleep apnea are common, at risk patients are also referred to a mental health provider 
and/or sleep clinic.
The use of a pragmatic clinical trial (PCT) design aims to study the effects of a weight 
management program that includes treatment with medication for chronic weight management in 
an employer-based real-world setting while employing a prospective comparison between two 
randomly assigned interventions in employees with obesity. The two interventions included in 
this study are a weight management program combined with FDA approved medication for 
chronic weight management versus a weight management program without medication for 
weight management. 
The key objective of the study is to demonstrate the impact of including medication for chronic 
weight management in a real-world employer setting of an integrated medical weight 
management program.
2
STUDY OBJECTIVES 
2.1
Primary Objective
The primary objective is to demonstrate superior effect of treatment with an employer-based 
weight management program in combination with medication for chronic weight management 
compared to an employer-based weight management program alone in subjects with obesity on 
weight loss.
2.2
Secondary Objectives
The secondary objectives are to compare the effects of treatment with an employer-based weight 
management program in combination with medication for chronic weight management to an 
employer-based weight management program alone in subjects with obesity with regards to:
x
Categorical weight loss
x
Adherence to the weight management program
x
Patient-reported outcomes (PROs) on work productivity and work limitations
Furthermore, the secondary objectives will assess adherence to medication for chronic weight 
management (only in the treatment arm randomized to an employer-based chronic weight 
management program with medication for chronic weight management).
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3
STUDY ENDPOINTS
3.1
Primary Endpoint
The primary endpoint of this study is:
x
Change from baseline (month 0) to month 12 (visit 13) in body weight (%)
3.2
Secondary Endpoints
Supportive secondary endpoints of this study include:
x
Subjects who after 12 months achieve (yes/no):
o
≥5% reduction in body weight from baseline
o
≥10% reduction in body weight from baseline
x
Adherence to Cleveland Clinic’s Integrated Medical WMP from baseline (month 0) to 
month 12 (visit 13), as:
o
Number of SMAs attended
o
Subjects attending ≥9 SMAs (yes/no)
x
Adherence to medication for chronic weight management from baseline (month 0) to 
month 12 (visit 13) in the treatment arm randomized to the WMP in combination with 
medication for chronic weight management, as:
o
Proportion of days covered (PDC) by prescription claims for medication for 
chronic weight management
o
Subjects covered by prescription claims for medication for chronic weight 
management for at least 80% of days (yes/no) 
x
Change in PROs from baseline (month 0) to month 12 (visit 13) in
o
Work limitation as measured by Work Limitations Questionnaire Self-
administered Short-Form (WLQ-8)

At-Work Productivity Loss Index (point)

Time Management (point)

Physical Tasks (point)

Mental/Interpersonal Tasks (point)

Output Tasks (point)
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o
Work productivity as measured by Work Productivity and Activity Impairment 
Questionnaire Specific Health Problem V2.0 (WPAI:SHP)

Work time missed due to excess weight (%)

Impairment while working due to excess weight (%)

Overall work impairment due to excess weight (%)

Activity impairment due to excess weight (%)
4
STUDY DESIGN
4.1
Overview
This is a one-year, single-center, randomized, open-label, parallel-group PCT comparing 
Cleveland Clinic’s existing Integrated Medical WMP combined with medication for chronic 
weight management versus Cleveland Clinic’s existing Integrated Medical WMP with no 
medication for weight management in subjects with obesity. Subjects will be randomized 1:1 to 
receive either Cleveland Clinic’s Integrated Medical WMP with medication for chronic weight 
management (“WMP + Rx”) or Cleveland Clinic’s Integrated Medical WMP alone (“WMP”). 
To ensure that the study setting is as close to real-world as possible, the weight management 
program provided to all study subjects will be similar to the Integrated Medical WMP that is 
currently offered by the Cleveland Clinic. In this program, SMAs are covered by the Cleveland 
Clinic Employee Health Plan and employees are responsible for a co-payment. 
In the WMP + Rx arm, obesity medications approved by the FDA for chronic weight 
management listed in Table 5-1 are allowed. Selection of specific medication is at the discretion 
of the study clinician. Subjects randomized to the WMP + Rx arm will pay a fee for the 
medication, simulating the co-payment that would be applied if the Health Plan covered 
treatment with medications for chronic weight management. 
Total study duration for the individual subjects will be approximately one year. Subjects will be 
followed and data collection will continue for the full duration of the study, unless the subject 
withdraws informed consent. The full duration of the study is defined as up to and including visit 
13.
Study visits include an individual screening and randomization visit (visit 1; informed consent 
must be obtained at visit 1 before screening), followed by twelve once-monthly visits set up in 
the context of SMAs (visit 2 to visit 13; further described in Section 5.2.2.1). All subjects will be 
referred to a nutritionist appointment between visit 1 and visit 2. End of Study (EOS) is visit 13 
(month 12 (-14 days, +28 days)) (section 5.5). Effort will be made to obtain a month 12 (visit 13) 
weight measurement from all randomized subjects. Subjects who potentially have stopped 
attending the SMAs prior to EOS will be encouraged to attend visit 13 for a weight measurement 
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and completion of questionnaires within the visit window, unless they have withdrawn consent. 
There will not be a follow-up period.
4.2
Study Site and Subject Selection
4.2.1
Study Site
This is a single-center study conducted at the Cleveland Clinic’s Endocrinology and Metabolism 
Institute, Cleveland, Ohio.
4.2.2
Subject Recruitment and Eligibility
Eligible subjects include adults with obesity (BMI ≥ 30 kg/m2) enrolled in the Cleveland Clinic 
Employee Health Plan for whom treatment with medication for chronic weight management may
be indicated. Subjects must also meet all of the inclusion criteria (section 4.2.3) and none of the 
exclusion criteria (section 4.2.4). Inclusion and exclusion criteria are minimally restrictive to 
ensure that a broad population of employees (and health plan member spouses) with obesity is 
captured, in order to generate data on a heterogeneous population that reflects a real-world 
population in scope for employer-based weight management programs, and support the study 
objectives of evaluating the impact of including medication for chronic weight management in a 
real-world employer-based integrated chronic weight management program.
To preserve the real-world nature of the study, potential subjects will be approached for 
enrollment into the study in a manner consistent with how health plan members are approached 
for participation in the Integrated Medical WMP as part of Healthy Choice, the wellness program 
benefit for Cleveland Clinic Employee Health Plan subscribers and their spouses. Members of 
Cleveland Clinic Employee Health Plan receive an annual end-of-year communication via e-
mail/US mail with notification of the Healthy Choice status of both the employee and spouse (if 
applicable) and enrollment instructions. If an employee or spouse has one of qualifying chronic 
diseases (asthma, diabetes, hyperlipidemia, hypertension, tobacco use, or overweight), he/she is 
eligible for the Healthy Choice program only if he/she joins the disease management program for 
that diagnosis.
The Integrated Medical WMP employed in this study is one of the weight management programs 
offered to health plan members with obesity via the Healthy Choice program. Health plan 
members identified as eligible for one of Cleveland Clinic’s employer-based weight management 
programs will be invited to attend an informational session and will be approached for potential 
enrollment into the study. If he/she decides to participate in the Integrated Medical WMP and is
interested in the study, the prospective subject will be scheduled for a screening and 
randomization visit (i.e., study visit 1) with a study clinician. If he/she chooses not to participate 
in the study, it will not have any implications for the employee, and he/she may join the 
Integrated Medical WMP or other weight management programs offered to health plan members 
with obesity via the Healthy Choice program.
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Additionally, potential study participants will be recruited through an advertisement outlining the 
details of this study posted on the Cleveland Clinic intranet, or through referral by another health 
care provider. Potential study participants identified in this manner will also be informed of the 
Integrated Medical WMP and requirements of this study prior to screening and randomization.
4.2.3
Subject Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for the study:
1. Informed consent obtained before any study-related activities. Study-related activities are 
any procedures that are carried out as part of the study, including activities to determine 
eligibility for the study.
2. Male or female, age ≥ 18 years at the time of signing informed consent
3. Body mass index (BMI) ≥ 30 kg/m2
4. Enrolled in Cleveland Clinic Employee Health Plan, and expecting to be covered by the 
Cleveland Clinic Employee Health Plan for the duration of the study
4.2.4
Subject Exclusion Criteria
Subjects presenting with any of the following exclusion criteria will not be eligible for the study:
1. Contraindications to all of the medications approved by the FDA for chronic weight 
management according to the label.
2. Previous participation in this study. Participation is defined as signed informed consent. 
3. Female who is pregnant, breast-feeding or intends to become pregnant or is of child-
bearing potential and not using adequate contraceptive methods (adequate contraceptive 
measures as required by local regulation or practice).
4. Participation in another clinical trial within 30 days before screening. 
5. Treatment with any medication with the intention of weight loss within 90 days before 
screening. 
6. Previous or current participation in Cleveland Clinic’s Integrated Medical Weight 
Management Program. 
7. History of (or plans during the study period for) bariatric surgery, or use of minimally-
invasive weight loss devices (i.e., intragastric balloons, lap bands) not removed within 1 
year prior to screening. 
8. History of type 1 or type 2 diabetes mellitus. 
9. HbA1c ≥ 6.5% at screening or within 90 days prior to randomization. 
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10. Any condition, unwillingness or inability, not covered by any of the other exclusion 
criteria, which, in the study clinician’s opinion, might jeopardize the subject’s safety or 
compliance with the protocol.
4.2.5
Subject Enrollment
Planned number of subjects to be screened: 240
Planned number of subjects to be randomized: 200
Expected number of subjects to complete (defined as end of trial on-site weight measurement) 
the trial: 150
4.2.6
Randomization
Subjects will be randomized to either WMP + Rx or WMP in a 1:1 ratio via centralized 
allocation. The study design and subject randomization is depicted in Figure 1.
 
Figure 1. Study design diagram. Subjects will be randomized in a 1:1 manner using centralized 
allocation to receive WMP + Rx or WMP.
WMP + Rx: Cleveland Clinic’s Integrated Medical Weight Management Program with 
medication for chronic weight management; WMP: Cleveland Clinic’s Integrated Medical 
Weight Management Program alone
5
STUDY PROCEDURES
The study visit schedule and data collection are summarized in Appendices 1-1 and 1-2. Study 
clinicians or site personnel will collect subject characteristics and study data at each study visit 
as outlined in the Time and Events Schedule (Appendix 1-1), either directly from the subject or 
extracted from the subject’s medical records, and enter them into the electronic Case Report 
Form (eCRF).
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5.1
Enrollment Procedures
Potentially eligible subjects will be identified during the course of routine implementation of 
Cleveland Clinic’s wellness program, Healthy Choice, through an advertisement outlining the 
details of this study posted on the Cleveland Clinic intranet, or through referral by another health 
care provider (section 4.2.2). Eligibility for the study will be assessed by the study clinician 
using the inclusion and exclusion criteria. Informed consent will be obtained prior to any study-
related activities.
5.2
Screening and Randomization Visit
Following informed consent and confirmation of eligibility, subjects will be randomized to either 
WMP + Rx or WMP. Data collection at the screening and randomization visit will include data 
on inclusion/exclusion criteria as well as the data outlined in the sections below. All subject 
information collected prior to randomization is considered medical history and will be collected 
per routine medical practice. Subjects will also complete PRO questionnaires (section 5.3.1). 
Additionally, a nutritionist appointment will be scheduled for the subject. 
5.2.1
Subject Characteristics
Baseline assessments at the screening and randomization visit will include: eligibility (including 
urine pregnancy test (if applicable) and point of care (POC) hemoglobin A1c (HbA1c)
measurement if an HbA1c measurement is not available within 90 days prior to randomization), 
demographic data, relevant medical history, concomitant medications, height, and body weight 
(as measured on a designated calibrated scale). Height and body weight will be recorded to one 
decimal place.
5.2.2
Treatments
To preserve the real-world nature of the study, the subject experience will be as close to routine 
clinical care as possible.
5.2.2.1
Weight management program
All subjects will enroll in the Integrated Medical WMP at the Cleveland Clinic’s Endocrinology 
and Metabolism Institute. After randomization, subjects will discuss and choose one of three diet 
options: protein-sparing modified fast, Mediterranean, or meal replacement. Subjects will then be 
referred to a nutritionist appointment. Consistent with real-world implementation of the WMP, 
the subject’s diet choice will be at the discretion of the subject and subjects will be free to change 
their diet choice throughout participation in the WMP.
Subjects will then initiate a series of twelve monthly study visits in the context of SMAs with up 
to approximately 10 subjects each. The SMAs will be run by a health care provider and a 
nutritionist and will be approximately 90 minutes in length. The 5 components of the WMP will 
be reviewed at every SMA and include: nutrition, physical activity, appetite control, sleep issues, 
and anxiety/depression/stress. SMA content will focus on accomplishing a healthier lifestyle, 
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including rotating topics related to nutrition (meal plan education, self-monitoring/record-
keeping, emotions related to eating such as comfort foods, “fear” foods, etc., stimulus control, 
problem-solving, eating competence skills, mindful eating, internal regulation skills relating to 
hunger/fullness/satisfaction, how to choose and prepare healthy food, trying new foods, social 
eating and eating outside of the home); information and advice regarding different exercise 
programs and compliance with exercise physiologist referral; issues related to healthy sleep 
habits; and specific topics regarding behavior modification and stress management (goal setting, 
accountability, relapse prevention). 
As part of the WMP, subjects will be referred to an exercise physiologist for a personalized 
physical activity program. Additionally, if assessed relevant by the study clinician, subjects may 
also be referred to a mental health specialist and/or sleep clinic.
Subjects in the two treatment arms will be allocated to separate SMA groups according to their 
randomized intervention (WMP + Rx versus WMP). In addition, effort will be made to keep the 
initial assigned SMA groups intact for the duration of the study for continuity of SMA 
participants (subjects and providers) month to month. All subjects will be responsible for paying 
the SMA monthly co-payment, as currently required by the Cleveland Clinic Employee Health 
Plan. Consistent with usual practice, subjects will be eligible for reimbursement of their SMA 
co-payments if they are compliant with their treatment plan according to the pre-defined 
Cleveland Clinic Health Plan criteria for weight management SMAs (attend SMAs, have a 
realistic personalized (based on BMI) weight loss goal set, demonstrate actual weight loss during 
each quarter, adhere to any medications etc.).
5.2.2.2
Obesity medication (WMP + Rx arm only)
After randomization, subjects randomized to the WMP + Rx arm will initiate treatment with 
prescription medication indicated for chronic weight management (obesity medication). The 
prescription will be provided at the time of randomization (visit 1) as agreed between the study 
clinician and the subject, and this and any monitoring, counseling or follow-up will be consistent 
with usual clinical practice and standard of care. Medication choice, dose, and dose escalation 
will be at the discretion of the study clinician among those medications indicated for chronic 
weight management (Table 5-1). Only medications approved by the FDA for chronic weight 
management are allowed; all other medications for the purpose of weight management, on- or 
off-label, are not allowed.
Subjects in the WMP + Rx arm may switch to another obesity medication (switch), temporarily 
discontinue (suspend), or permanently discontinue (discontinue) obesity medication throughout 
the study according to standard clinical practice at the discretion of the study clinician. If a 
subject chooses to suspend or discontinue his/her obesity medication, he/she will be asked to
notify the study clinician of his/her decision to ensure a safe withdrawal. In case of an obesity 
medication discontinuation, subjects will be encouraged to initiate treatment with another obesity 
medication (i.e., to switch) at the discretion of the study clinician according to routine practice. 
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Subjects who discontinue obesity medication will be encouraged to continue attending the study 
visits and assessments in their originally allocated treatment arm.
In order for the study to remain as close as possible to real-world conditions, subjects 
randomized to WMP + Rx arm will pay a nominal fee for the prescribed obesity medication 
simulating the co-payment patients would pay at a retail pharmacy if the medication was covered 
by their employer. The fee will be the same for all obesity medications utilized in the study 
regardless of market price. All prescription medications approved in the US for chronic weight 
management will be available for study subjects randomized to WMP + Rx (Table 5-1).
Table 5-1. Approved medications for chronic weight management in the US available in the 
study.
API (route of administration) 
Brand name 
Year of FDA 
approval 
Orlistat (p.o.) 
Xenical® 
1999
Lorcaserin/Lorcaserin extended-release (p.o.) 
Belviq®/Belviq XR®
2012
Phentermine/Topiramate extended-release (p.o.) Qsymia® 
2012
Naltrexone/Bupropion extended-release (p.o.) 
Contrave® 
2014
Liraglutide 3.0 mg (s.c.) 
Saxenda® 
2014
FDA: Food and Drug Administration; API: active pharmaceutical ingredient; s.c.: subcutaneous; p.o.: per os (by 
mouth)
5.2.2.3
Concomitant medications
Concomitant medications for medical conditions other than obesity are allowed in both treatment 
arms at the discretion of the study clinician, except for the use of glucagon-like peptide-1
receptor agonists (GLP-1 RAs) and sodium-glucose co-transporter 2 (SGLT-2) inhibitors for 
diabetes diagnosed during the study. Other than the medication prescribed by the study clinician 
for chronic weight management in the WMP + Rx arm (section 5.2.2.2), use of any medication, 
on- or off-label, for weight loss purposes is not allowed in either arm during the study. Through 
routine medication review during SMA study visits, use of medications that are not allowed per 
protocol (i.e., “disallowed”) will be identified and will be indicated in the eCRF. The subject will 
remain in the study.
5.3
Questionnaires
5.3.1
Patient Reported Outcomes (PROs)
Work productivity and work limitations will be assessed by the following instruments at visit 1, 
visit 7, and visit 13. Subjects will self-administer these instruments on paper. Site study 
personnel will review for completeness and enter responses into the eCRF.
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5.3.1.1
Work Productivity and Activity Impairment Questionnaire Specific Health Problem 
v2.0 (WPAI:SHP)
The WPAI:SHP questionnaire (Appendix 2-1) assesses both work productivity through 
absenteeism (i.e., work time missed), presenteeism (i.e., impairment at work or reduced on-the-
job effectiveness), and work productivity loss, as well as daily activity impairment (e.g., work 
around the house, shopping, exercising, childcare, studying) attributable to excess weight. 
WPAI:SHP outcomes are expressed as impairment percentages, with higher scores indicating 
greater impairment and less productivity, i.e., worse outcomes.
5.3.1.2
Work Limitations Questionnaire 8-Item (WLQ-8) Self-administered Short Form 
The WLQ-8 questionnaire (Appendix 2-2) assesses the degree to which subjects have difficulty 
related to time management, physical tasks, mental/interpersonal tasks, and output tasks due to 
their physical and/or emotional health. The WLQ-8 produces subscale scores as well as an index 
of overall at-work productivity loss. WLQ-8 outcomes are expressed as proportion time with 
difficulty, with higher scores indicating greater limitations, i.e., worse outcomes.
5.4
Study Period
Subjects will be followed from baseline (month 0) to EOS at month 12 (visit 13), during which 
study clinicians or trained site personnel will collect study data and record them in the eCRF 
during monthly SMA study visits, including: weight as measured on a designated calibrated 
scale, pregnancy and serious adverse events (SAEs) (section 7), attendance at SMAs, and use of 
disallowed medications (section 5.2.2.3). PRO questionnaires will be completed as described in 
section 5.3. (Appendix 1-1)
Other than withdrawal of consent, subjects will remain in the study, and effort will be made to 
obtain a month 12 (visit 13) weight measurement from all randomized subjects regardless of 
SMA attendance or obesity treatment discontinuation during the study period. If a subject stops 
attending SMAs prior to EOS, he/she will be encouraged to attend visit 13 for a weight 
measurement within the visit window. Subjects who come back for a visit 13 weight 
measurement will also be asked to complete the PRO questionnaires during the visit and to 
report SAEs or disallowed medication use.
5.5
End of Study (EOS)
EOS is defined as 12 months (-14 days, +28 days) after baseline.
If a subject does not attend visit 13, a stepwise approach to obtaining weight will be 
implemented according to the following hierarchy:
1. Subject called into office for month 12 weight measurement (-14 days, +28 days from 
scheduled month 12/visit 13).
2. Recent (-14 days, +28 days from scheduled month 12/visit 13) weight extracted from the 
electronic medical record (EMR).
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3. Recent (-14 days, +28 days from scheduled month 12/visit 13) subject-reported weight 
used.
5.6
Pharmacy Data
In addition to prospectively collected clinical data and PROs, this study will also collect 
prescription fill data for obesity medication from randomization through EOS.
5.7
Withdrawals
5.7.1
Study Site
The Sponsor and/or the Institutional Review Board (IRB) reserves the right to terminate 
participation of the study site at any time. The study site may also be terminated for cause per 
contractual agreement. In such cases, all data collection will end. After the collected data are 
received, the study clinicians will be compensated as contractually agreed.
5.7.2
Subjects
Participation in the study is voluntary, and all subjects are free to withdraw his/her consent at any 
time. A subject will only be withdrawn from the study if he/she withdraws consent. In the event 
of study withdrawal, the study clinician will record the reason for study withdrawal and continue 
to follow-up with the subject as medically indicated for any unresolved SAEs or pregnancies, if 
subject agrees. Upon subject consent withdrawal from the study, all data collection will end, but
all study data collected up to withdrawal will be included in the study database.
6
STATISTICAL METHODS
6.1
Analysis Overview
Subjects will be randomized 1:1 to WMP + Rx or WMP alone. The data analyses for this study 
will be outlined in further detail in a Statistical Analysis Plan (SAP).
The significance level used in all statistical analyses will be 5% (two-sided).
6.1.1
Estimands
Two estimands, each targeting a unique research question, have been defined to adequately 
describe the effect of an employer-based WMP combined with obesity medication compared to 
an employer-based WMP alone.
Primary estimand
The primary estimand for all endpoints is an “intention-to-treat” estimand (also known as an 
“effectiveness” or a “treatment policy” estimand). This estimand will quantify the average 
treatment effect of an employer-based WMP combined with medication for chronic weight 
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management compared to the employer-based WMP alone after 12 months, in all randomized 
subjects and regardless of adherence to randomized treatment. 
Secondary estimand 
The secondary estimand for body weight loss, categorical weight loss, and PROs is an “if all 
subjects had adhered” estimand (also known as an “efficacy” estimand). This estimand will 
quantify the average treatment effect of an employer-based WMP combined with medication for 
chronic weight management compared to the employer-based WMP alone after 12 months, in all 
randomized subjects had they adhered to their randomized treatment for the entire planned study 
duration as defined in Section 6.4.3.
6.1.2
Primary Endpoint and Confirming Hypothesis
The primary endpoint is percent change in body weight from baseline (month 0) to month 12 
(visit 13), as defined:
% weight change =
body weight at visit 13 – body weight at baseline
x 100%
body weight at baseline
where a negative value indicates a body weight loss from baseline (month 0) to month 12 (visit 
13).
One confirmatory hypothesis will be tested:
x
Superiority of WMP + Rx versus WMP alone on % weight change from baseline (month 
0) to month 12 (visit 13).
The test will be evaluated as a two-sided test of the null hypothesis that the mean weight change 
(%) in the two treatment arms is the same (H0: % weight change [WMP + Rx] = % weight 
change [WMP]). Superiority will be claimed if the two-sided p-value is less than 5% and the 
estimated difference in mean weight change favors WMP + Rx (Ha: % weight change [WMP + 
Rx] < % weight change [WMP]).
6.2
Study Populations
The following analysis sets will be defined:
Full analysis set (FAS): Includes all randomized subjects analyzed according to the treatment 
group to which they were assigned at randomization.
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6.3
Sample Size Determination
6.3.1
Power and Sample Size for Primary Objective
Assumptions for sample size calculations included:
x
Two sample two sided t-test with equal variances
x
5% significance level, but superiority is only claimed if estimated difference in mean 
weight loss favors WMP + Rx (this corresponds to a one-sided test on a 2.5% 
significance level).
x
1:1 randomization
x
50% of subjects in both arms are expected to drop out (based on input from the Cleveland 
Clinic)
o
Among subjects who drop out, 50% are expected to return for a month 12 (visit 
13) assessment (retrieved drop outs).
o
Retrieved and non-retrieved drop outs in the WMP arm are assumed to have the 
same effect as subjects who complete the WMP arm.
o
Non-retrieved drop outs in the WMP + Rx arm are assumed to have an effect 
corresponding to subjects in the WMP arm.
o
Retrieved drop outs in the WMP + Rx arm are assumed to have an effect 
corresponding to half the weight loss difference (compared to WMP) of subjects 
who complete the study in the WMP + Rx arm. 
x
The following expected distribution of prescriptions in the WMP + Rx arm (based on 
input from the Cleveland Clinic):
o
0% Orlistat (Xenical® )
o
10% Lorcaserin/Lorcaserin extended-release (Belviq®/BelviqXR)
o
30% Phentermine/Topiramate extended-release (Qsymia®) 
o
30% Naltrexone/Bupropion extended-release (Contrave®)
o
30% Liraglutide 3.0 mg (Saxenda®)
Table 6-1 presents several sample size scenarios and power calculations based on the above 
assumptions, varying expected mean differences in weight loss between treatment arms 
(treatment effect) over 1 year and standard deviations (SD) as the variation of weight loss 
between subjects within the same treatment arm. Treatment effect scenarios of 3, 3.5, 4, and 5% 
were chosen based on product labels. SD of 8, 9, 10, and 11 % were chosen based on the 
NN8022 (SCALE) program [18] [19] [20] and the TRAMOMTANA [21] study.
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Table 6-1. Power calculations for selected total N, treatment effects, and standard 
deviations
Treatment effect (%)
3
3.5
4
5
SD (%)
SD (%)
SD (%)
SD (%)
Total 
N
8
9
10
11
8
9
10
11
8
9
10
11
8
9
10
11
160 
0.65 
0.55 
0.47 
0.40 
0.79 
0.69 
0.59 
0.52 
0.88 
0.80 
0.71 
0.63 
0.98 
0.94 
0.88 
0.82 
180 
0.71 
0.60 
0.52 
0.44 
0.83 
0.74 
0.65 
0.56 
0.92 
0.84 
0.76 
0.68 
0.99 
0.96 
0.92 
0.86 
200 
0.75 
0.65 
0.56 
0.48 
0.87 
0.78 
0.69 
0.61 
0.94 
0.88 
0.80 
0.73 
0.99 
0.97 
0.94 
0.89 
240 
0.82 
0.73 
0.64 
0.56 
0.92 
0.85 
0.77 
0.69 
0.97 
0.93 
0.87 
0.80 
1.00 
0.99 
0.97 
0.94 
300 
0.90 
0.82 
0.74 
0.65 
0.97 
0.92 
0.86 
0.78 
0.99 
0.97 
0.93 
0.88 
1.00 
1.00 
0.99 
0.98 
Total N = sum of subjects in both treatment arms; treatment effect = difference in one-year weight loss of WMP + 
Rx compared to WMP alone; standard deviation (SD) =variation in weight loss between subjects within the same 
treatment arm.
Based on the above mentioned assumptions and results from the referenced studies, a 4% 
treatment effect and 10% SD is a conservative, yet realistic scenario. Therefore, a total sample 
size of 200 subjects (100 subjects per treatment arm) with 80% power for the confirmatory 
hypothesis assuming a 25% attrition rate over 12 months was chosen.
6.3.2
Interim Analysis
There is no interim analysis planned for this study.
6.4
Primary Estimand for the Primary Endpoint
The primary estimand will be estimated based on the FAS and % weight change will be modeled 
using linear regression (Analysis of Covariance (ANCOVA)) with randomized treatment as a 
factor and baseline body weight (kg) as a covariate. The treatment difference between WMP + 
Rx and WMP alone will be estimated and reported together with the associated 95% confidence 
interval (CI) and corresponding p-value.
6.4.1
Primary Estimand Missing Data Imputation
Prior to analysis, missing month 12 weight data will be imputed by multiple imputations. For the 
primary analysis, missing month 12 weight data will be imputed by sampling among all available 
assessments at visit 13 in the WMP arm (including values from retrieved drop outs). This 
approach is also known as “jump to reference” and makes the assumption that subjects instantly 
lose any effect of randomized treatment beyond what can be expected from the WMP after 
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discontinuation. Body weight measurements at visits between baseline (month 0) and month 12
(visit 13) are not used for this imputation approach. Imputation details will be further described 
in the SAP. 
6.4.2
Sensitivity Analysis of the Primary Estimand for the Primary Endpoint
A multiple imputation approach as described by McEvoy [22] will be used as sensitivity 
analysis. In this approach, month 12 measurements at visit 13 for non-retrieved drop outs will be 
imputed by sampling from values obtained from retrieved drop outs in the corresponding 
treatment arm and according to the timing of last available body weight. If this approach is not 
feasible, no sensitivity analysis will be done.
6.4.3
Secondary Estimand for the Primary Endpoint
The secondary estimand of the primary endpoint will address the efficacy of medication for 
chronic weight management if all subjects adhere to their randomized treatment (WMP + Rx or 
WMP). For the secondary estimand, the primary endpoint will be analyzed using a mixed model 
for repeated measurements (MMRM) including all subjects, but for subjects considered non-
adherent to randomized treatment, only data prior to non-adherence will be used. Month 12 (visit 
13) assessments for retrieved drop outs will not be used in this analysis. The MMRM for efficacy 
will only use assessments from subjects who are adherent to the randomized treatment until end 
of treatment, or up until the subject is considered non-adherent to the randomized treatment. 
Subjects in the WMP arm will be considered non-adherent if/when criterion 1 below is met. 
Subjects in the WMP + Rx arm will be considered non-adherent if/when criterion 1 or 2 is met: 
1. Missing 4 SMA visits. In this case, the last assessment made prior to the 4th missed SMA 
visit will be used as the last assessment. This is also the case if, e.g., 4 SMA visits in a 
row are missed. 
2. Period with no coverage of prescription claims according to PDC exceeds 20% of 
planned medication duration, or number of days from visit 1 to visit 13. For subjects that 
drop out early, the expected visit 13 date (derived from the subjects’ planned SMA group 
visit) will be used to calculate planned study duration. The last assessment made prior to 
exceeding 20% of planned study duration with no prescription claims will be used as last 
assessment.
The MMRM for efficacy will be fitted using % weight change with randomized treatment as 
factor and baseline body weight (kg) as covariate, all nested within visit. An unstructured 
covariance matrix for measurements within the same subject will be employed, assuming that 
measurements for different subjects are independent.
6.4.4
Supplementary Analyses
The analyses of % weight change will be supplemented with a completer analysis based on the 
subset of subjects with month 12 (visit 13) body weight data who were adherent to the 
randomized treatment.
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Completer analysis 
In the context of this supplementary analysis, completers will be defined as subjects with month 
12 (visit 13) body weight data who adhered to randomized treatment up to and including visit 13. 
Adherence is defined as for the secondary estimand for the primary endpoint in section 6.4.3, 
i.e., subjects in the WMP arm will be considered non-adherent if/when criterion 1 above is met 
and subjects in the WMP + Rx arm will be considered non-adherent if/when either criterion 1 or 
2 above is met. As an example, a subject in the WMP + Rx arm that misses visit 10, 11, and 12, 
but attends all other visits and is covered by prescription claims for at least 80% of the planned 
study duration, is considered a completer in this context if month 12 (visit 13) weight data are 
available.
This analysis will use the same ANCOVA model described for the primary estimand analysis of 
the primary endpoint (section 6.4).
6.5
Primary Estimand for the Secondary Endpoints
The following analyses are planned to further support the primary objective to compare weight 
loss of WMP + Rx versus WMP. They will also address the secondary objectives of this study to 
compare WMP + Rx versus WMP with respect to categorical weight loss, WMP adherence, and 
PROs, as well as adherence to obesity medication within the WMP + Rx cohort.
All secondary analyses described in this section will be the primary estimand based on the FAS. 
No sensitivity analyses are planned for the secondary endpoints.
6.5.1
Categorical Weight Loss
For the categorical weight loss endpoints (≥5% weight reduction from baseline, ≥10% weight 
reduction from baseline), the proportion of subjects achieving each endpoint will be analyzed 
using a logistic regression model with treatment as categorical effect and baseline weight (kg) as 
covariate. From the model, the estimated odds ratio (OR) (WMP + Rx / WMP) will be presented 
with the 95% CI and p-value. An OR above 1 favors WMP + Rx. Missing weight data will be 
imputed as described for the primary estimand for the primary endpoint (section 6.4.1).
6.5.2
Adherence to Weight Management Program (WMP)
WMP adherence will be assessed through SMA attendance endpoints. SMA attendance will be 
reported as the percentage planned SMAs attended, i.e., number of SMAs attended/12 planned 
SMAs. SMA attendance and the proportion of subjects achieving ≥9 SMAs will be descriptively 
summarized by treatment arm. No formal statistical testing will be conducted. 
6.5.3
Adherence to Obesity Medication
Adherence to obesity medication will be assessed through PDC (to be defined in the SAP) for the 
WMP + Rx treatment arm only. The PDC and the proportion of subjects with at least 80% PDC 
will be descriptively summarized for the WMP + Rx treatment arm. No formal statistical testing 
will be conducted.
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6.5.4
Patient Reported Outcome (PRO) Analysis
Work productivity and work limitations will be assessed by the WPAI:SHP and WLQ-8
instruments (section 5.3.1). Analysis of change from baseline (month 0) to month 12 (visit 13) in 
work productivity and work limitation endpoints defined in section 3.2 will follow the method 
described for the primary estimand for the primary endpoint: ANCOVA model with randomized 
treatment as a factor and baseline value of the endpoint variable as covariate. Estimated 
difference (WMP + Rx minus WMP) in change from baseline (month 0) to month 12 (visit 13) 
will be presented with 95% CI and corresponding p-value. If examination of the data indicate 
that it is not justifiable to model data based on assumptions of normality, e.g., many responses of 
0% or close to 0%, alternative statistical modeling will be used (e.g. logistic regression after 
definition of a responder limit).
6.5.5
Supplementary Patient Reported Outcome (PRO) Analysis
As a supplementary PRO analysis, the PRO analysis described in section 6.5.4 will be repeated 
for change from baseline (month 0) to month 6 (visit 7) in work productivity and work limitation 
endpoints.
6.6
Secondary Estimand for the Secondary Endpoints
Categorical Weight
The secondary estimand for the categorical weight endpoint of ≥ 5% reduction in body weight 
from baseline (5% responder) will be assessed using the MMRM for efficacy as described for the 
secondary estimand for the primary endpoint in section 6.4.3. Analysis will only use assessments 
from subjects who are adherent to the randomized treatment until end of treatment, or up until 
the subject is considered non-adherent to the randomized treatment. From the MMRM, 
individually predicted values for % weight change at month 12 will be used to classify each 
subject as 5% responder or not. This classification will then be analyzed using a logistic 
regression model with treatment as the only factor. From the model, the estimated OR (WMP + 
Rx / WMP) will be presented with the 95% CI and p-value.
PROs
The secondary estimand for change from baseline (month 0) to month 12 (visit 13) in work 
productivity and work limitation endpoints (section 3.2) will be assessed using the MMRM for 
efficacy as described for the secondary estimand for the primary endpoint in section 6.4.3. The
MMRM for efficacy will only use PRO assessments from subjects who are adherent to the 
randomized treatment until end of treatment, or up until the subject is considered non-adherent to 
the randomized treatment. The MMRM for efficacy will be fitted using change in PRO endpoint 
with randomized treatment as factor and baseline value of the endpoint variable as covariate, all 
nested within visit. An unstructured covariance matrix for measurements within the same subject 
will be employed, assuming that measurements for different subjects are independent.
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Supplementary PRO Analysis
As a supplementary PRO analysis, the above described PRO analysis will be repeated for change 
from baseline (month 0) to month 6 (visit 7) in work productivity and work limitation endpoints.
6.7
Safety Analysis
SAEs will be collected as described in section 7. No formal safety analyses are planned for this 
study. SAEs will be coded using Medical Dictionary for Regulatory Activities (MedDRA) and 
descriptively summarized by System Organ Class (SOC) and Preferred Term (PT).
7
ADVERSE EVENT (AE) REPORTING
7.1
Adverse Events (AEs)
An AE is defined as any untoward medical occurrence in a subject administered a 
pharmaceutical product or medical device, which does not necessarily have to have a causal 
relationship to the product or device. Worsening of existing medical conditions, if considered 
serious and related by the investigator, should be reported as AEs.
For the purposes of this study, AEs will only be required to be collected if they meet the 
definition of an SAE (section 7.2).
7.2
Serious Adverse Events (SAEs)
All AEs meeting the definition of SAE will be collected. An SAE is defined as any AE which 
results in at least one of the following outcomes:
x
Initial inpatient hospitalization or prolongation of existing inpatient hospitalization
x
A life-threatening event, i.e., an event in which the subject was at immediate risk of 
dying at the time of the event; not an event that hypothetically could have caused death 
had it been more severe
x
Persistent or significant disability or incapacity
x
Congenital anomaly or birth defect in offspring
x
Death
x
Is deemed serious for any other reason, i.e., if it is an important medical event based on 
appropriate medical judgement which may jeopardize the subject and may require 
medical or surgical intervention to prevent one of the other listed outcomes.
7.2.1
Reporting Period of Serious Adverse Events (SAEs)
SAEs will be reported from randomization until EOS at month 12, or until the subject withdraws 
from the study. Study clinicians will follow SAEs that occur in any subject during this study in a 
manner consistent with routine clinical practice.
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The study clinician is responsible for alerting Novo Nordisk or its designee to any SAE within 24 
hours of becoming aware of it via electronic data capture (EDC) entry. The subject should be 
followed until the outcome of the event is closed out. Follow-up information should be reported 
within 24 hours of it becoming available. Requests for follow-up information should be resolved 
within 14 calendar days.
The study clinician is responsible for assessment of causality and outcome of SAEs, as defined in 
Appendix 3. Causality and outcome should be provided at the time of reporting an SAE.
If an investigator becomes aware of SAEs after EOS at end of month 12, that are possibly related 
to the study product, these should be reported as spontaneous events.
7.3
Pregnancy
Any abnormal pregnancy outcome (e.g., spontaneous miscarriage, fetal death, congenital 
anomaly/birth defect, etc.) is considered an SAE. For the purposes of this study, any pregnancies 
in participating female subjects will be reported, along with pregnancy outcome and any AEs or 
SAEs observed in the fetus or newborn until 1 month of age.
7.3.1
Reporting Period of Pregnancy
Pregnancies will be reported from the time a subject is randomized until EOS at month 12 or 
until the subject withdraws from the study. Information will be recorded on the appropriate form 
and submitted to Novo Nordisk within 14 calendar days of learning of a subject's pregnancy. The 
subject will be followed to determine the outcome of the pregnancy. The study physician will 
collect follow-up information on subject and neonate, which will be forwarded to Novo Nordisk. 
Any termination of pregnancy should be reported, regardless of fetal status (presence or absence 
of anomalies) or indication for procedure. A spontaneous abortion is always considered to be an 
SAE and should be reported as such.
7.4
Technical Complaints
Technical complaints may be reported as per usual practice and local regulations. However, any 
SAEs resulting from a technical complaint must be reported via the EDC.
8
DATA COLLECTION
8.1
Data Sources
Data sources include primary data collected prospectively by study site at study visits 
(demographic and clinical data, subject-completed PRO data) and entered into the eCRF, as well 
as secondary data collection utilizing pharmacy dispensing data. In order to maintain subject 
confidentiality, each subject will be assigned a unique subject study ID number upon signing 
informed consent to use in place of subject name or any other identifying information (e.g., 
medical record number). Primary eCRF data and pharmacy derived variables will be integrated 
into one analysis dataset.
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8.2
Electronic Case Report Forms (eCRFs)
Study data prospectively collected at the study site will be entered into eCRF by trained site 
study personnel through a fully validated, 21 CFR 11 and HIPAA compliant EDC system. 
Subjects will complete PRO questionnaires on paper and the site study personnel will enter the 
completed forms into the EDC system. Site users will be provided eCRF Completion Guidelines 
(eCCGs) to assist with study data collection and entry. Study personnel will access the EDC 
system through a secure study website.
The study clinician has the ultimate responsibility for the collection and reporting of all study 
data through the eCRFs, as well as ensuring that they are accurate and complete to the extent 
possible.
8.3
Database Lock
Database lock will occur once data collection of the last subject follow up visit and data 
management activities are complete.
9
STUDY MANAGEMENT
9.1
Regulatory and Ethical Consideration
All study activities will be conducted in accordance with Good Clinical Practice (GCP) 
guidelines. Study personnel at clinician sites will be provided training on the study protocol, the 
Informed Consent Form (ICF), data collection, and data entry to ensure both the protection of
potential study subjects as well as the scientific integrity of the study. Site monitoring will be 
conducted by HealthCore staff.
9.1.1
Institutional Review Board (IRB)
The study clinician will have prospective IRB approval of the study protocol, ICF, and any 
subject information or recruiting materials prior to commencement of any study activities at 
his/her site. In the case of a protocol amendment, the study clinician must sign the revised 
protocol and submit the amendment to the IRB for review and approval prior to implementation 
of any changes specified in the protocol amendment. All changes in research activity and all 
unanticipated problems involving risk to human subjects or others must be reported to the IRB as 
required.
The study clinician will obtain continued review of the IRB study approval at intervals not to 
exceed one year or otherwise specified by the IRB.
9.1.2
Informed Consent
An ICF describing the purpose, procedures, and potential risks and benefits of the study will be 
developed and approved by the IRB prior to study initiation. Written informed consent will be 
obtained prior to initiation of any study-related procedures. Each subject will receive a copy of 
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the signed ICF. The study clinician will retain the original signed ICF for each subject. The IRB 
must prospectively approve any changes to the ICF during the course of the study before use.
If a protocol amendment increases the potential risk to the subject, the ICF must be revised and 
submitted to the IRB for review and approval prior to implementation. The revised ICF must 
then be used to obtain consent from new subjects entering the study as well as from currently 
enrolled subjects if they are affected by the amendment, per IRB guidance.
9.2
Record Retention and Access
This study may be subject to audits or inspections by regulatory authorities or Novo Nordisk (or 
its designee). To enable such inspections and/or audits, the study clinician must agree to maintain 
and allow access to required subject and study records. The study clinician agrees to keep the 
identity of all participating subjects (sufficient information to link records, e.g., hospital records), 
all original signed ICFs, source documents, detailed records of treatment disposition, and 
adequate documentation of relevant correspondence (e.g., letters, meeting minutes, telephone 
calls, reports) as specified in the Clinical Study Agreement.
10 PUBLICATION OF STUDY RESULTS
All information collected for this study is considered confidential information belonging to Novo
Nordisk. Information regarding the study will be disclosed at clinicaltrials.gov and novonordisk-
trials.com. It will also be disclosed according to other applicable requirements such as those of 
the International Committee of Medical Journal Editors (ICMJE) [23], the Food and Drug 
Administration Amendment Act (FDAAA) [24], European Commission Requirements [25] [26]
and other relevant recommendations or regulations. If a subject requests to be included in the 
trial via the Novo Nordisk e-mail contact at these web sites, Novo Nordisk may disclose the 
investigator’s contact details to the subject. As a result of increasing requirements for
transparency, some countries require public disclosure of investigator names and their 
affiliations.
The Primary Completion Date (PCD) is the last assessment of the primary endpoint, and is for 
this trial Last Subject First Visit (LSFV) + 12 months (-14 days +28) corresponding to visit 13. If 
the last subject is withdrawn early, the PCD is considered the date when the last subject would 
have completed visit 13. The PCD determines the deadline for results disclosure at 
clinicaltrials.gov according to FDAAA.
A final study report will be generated following completion of data collection and analysis. 
Results and findings will be submitted to conferences and for publication in peer-reviewed 
scientific journals. Novo Nordisk reserves the right to postpone publication and/or 
communication for up to 60 days to protect intellectual property.
Novo Nordisk commits to communicating, and otherwise making available for public disclosure, 
results of studies regardless of outcome. Public disclosure includes publication of a paper in a 
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scientific journal, abstract submission with a poster or oral presentation at a scientific meeting, or 
disclosure by other means.
The results of this study will be subject to public disclosure on external web sites according to 
international and national regulations, as reflected in the Novo Nordisk Code of Conduct for 
Clinical Trial Disclosure.
11
INDEMNIFICATION
Novo Nordisk carries product liability for its products, and liability as assumed under the special 
laws, acts and/or guidelines for conducting clinical trials in any country, unless others have 
shown negligence.
Novo Nordisk assumes no liability in the event of negligence or any other liability of the sites or 
investigators conducting the trial or by persons for whom the said site or investigator are 
responsible.
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[24]  U.S. Department of Health and Human Services, Food and Drug Administration, Food 
and Drug Administration Amendments Act of 2007 as amended by the Final Rule 
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Appendix 1-1: Time and Events Schedule
 
Study NN8022-4432
Screening and 
Randomization
Weight Management Program
Visit (V)
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
V12
V13
Timing of visit (months)
0
1
2
3
4
5
6
7
8
9
10
11
12
Visit window (days)
0
±14
±14
±14
±14
±14
±14
±14
±14
±14
±14
±14
-14, +28
SUBJECT-RELATED INFORMATION AND ASSESSMENTS
Informed consent
X
Demographya
X
Inclusion criteria
X
Exclusion criteria
X
Randomization
X
Medical history/concomitant 
illness
X
Concomitant medication
X
Disallowed medicationb
X
X
X
X
X
X
X
X
X
X
X
X

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Study NN8022-4432
Screening and 
Randomization
Weight Management Program
Visit (V)
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
V12
V13
Timing of visit (months)
0
1
2
3
4
5
6
7
8
9
10
11
12
Visit window (days)
0
±14
±14
±14
±14
±14
±14
±14
±14
±14
±14
±14
-14, +28
EFFICACY
Height
X
Body weight
X
X
X
X
X
X
X
X
X
X
X
X
Xc
WPAI-SHP
X
X
X
WLQ-8
X
X
X
SMA attendance
X
X
X
X
X
X
X
X
X
X
X
X
SAFETY
Adverse event
Xd
X
X
X
X
X
X
X
X
X
X
X
X
REMINDERS
HbA1c
Xe
Urine pregnancy test
Xf
Schedule nutritionist 
appointment
X
Refer to exercise physiologist
X
a Demography consists of date of birth, sex, ethnicity, and race.

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b Disallowed medications include GLP-1 RAs or SGLT-2 inhibitors for diabetes and any medication on- or off-label prescribed for 
weight loss other than the medication prescribed by the study clinician for chronic weight management (section 5.2.2.3). Use of these 
medications will be assessed during routine medication review at SMAs and entered into the eCRF.
c If a subject does not attend the SMA at visit 13, a stepwise approach to obtaining weight data will be applied to obtain a month 12 
weight measurement (-14 days, +28 days from scheduled month 12/visit 13): calling subject in for a month 12/visit 13 weight 
measurement, extract recent weight data from the electronic medical record, or use recent subject-reported weight.
d Screening and randomization are one visit. Serious adverse event and pregnancy collection will begin after informed consent and
randomization.
e A POC HbA1c measurement will be performed at screening if an HbA1c measurement is not available within 90 days prior to 
randomization.
f A urine pregnancy test will be performed prior to randomization in women of child bearing potential who are not using adequate 
contraception at the discretion of the study physician.
WPAI:SHP: Work Productivity and Activity Impairment Questionnaire Specific Health Problem; WLQ-8: Work Limitations 
Questionnaire Self-administered Short-Form; SMA: Shared Medical Appointment 
 
 

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Appendix 1-2: Data collected from pharmacy card
 
Study NN8022-4432
Visit 1 to visit 13
Pharmacy card dispensing data for medication for chronic 
weight management (mediation, fill date, days supply, quantity 
dispensed)
X

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Appendix 2-1: PRO Instruments – Work Productivity and Activity Impairment Questionnaire 
Specific Health Problem v2.0 (WPAI:SHP)
Work Productivity and Activity Impairment Questionnaire:
Specific Health Problem V2.0 (WPAI:SHP)
The following questions ask about the effect of your PROBLEM on your ability to work and 
perform regular activities.  Please fill in the blanks or circle a number, as indicated.
1.
Are you currently employed (working for pay)? 
_____ NO ___ YES
If NO, check “NO” and skip to question 6.
The next questions are about the past seven days, not including today.
2. During the past seven days, how many hours did you miss from work because of problems 
associated with your PROBLEM?  Include hours you missed on sick days, times you went 
in late, left early, etc., because of your PROBLEM.  Do not include time you missed to 
participate in this study.
_____ HOURS
3. During the past seven days, how many hours did you miss from work because of any other 
reason, such as vacation, holidays, time off to participate in this study?
_____HOURS
4. During the past seven days, how many hours did you actually work?
_____HOURS (If “0”, skip to question 6.)
 
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5. During the past seven days, how much did your PROBLEM affect your productivity while
you were working?  
Think about days you were limited in the amount or kind of work you could do, days you 
accomplished less than you would like, or days you could not do your work as carefully as 
usual.  If PROBLEM affected your work only a little, choose a low number.  Choose a high 
number if PROBLEM affected your work a great deal.  
Consider only how much PROBLEM affected 
productivity while you were working.
PROBLEM had 
no effect on my 
work
PROBLEM 
completely 
prevented me 
from working
0
1
2
3
4
5
6
7
8
9
10
CIRCLE A NUMBER
6. During the past seven days, how much did your PROBLEM affect your ability to do your 
regular daily activities, other than work at a job?  
By regular activities, we mean the usual activities you do, such as work around the house, 
shopping, childcare, exercising, studying, etc.  Think about times you were limited in the 
amount or kind of activities you could do and times you accomplished less than you would 
like.  If PROBLEM affected your activities only a little, choose a low number.  Choose a 
high number if PROBLEM affected your activities a great deal.  
Consider only how much PROBLEM affected your ability 
to do your regular daily activities, other than work at a job.
PROBLEM had 
no effect on my 
daily activities
PROBLEM 
completely 
prevented me 
from doing my 
daily activities
0
1
2
3
4
5
6
7
8
9
10
                          
CIRCLE A NUMBER
WPAI:SHP  V2.0 (US English)     
Reilly MC, Zbrozek AS, Dukes E: The validity and reproducibility of a work productivity and activity impairment measure.  PharmacoEconomics 1993;
4(5):353-365.
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Appendix 2-2: PRO Instruments – Work Limitations Questionnaire 8-Item Self-administered 
Short Form (WLQ-8)
 
CONFIDENTIAL
Work Limitations Questionnaire©
Self-Administered Online Short-Form
Work Limitations Questionnaire, © 1998, The Health Institute, Tufts Medical Center f/k/a New England Medical 
Center Hospitals, Inc.; Debra Lerner, Ph.D.; Benjamin Amick III, Ph.D.; and GlaxoWellcome, Inc.  All Rights 
Reserved.
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Instructions
Health problems can make it difficult for working people to perform certain parts of their 
jobs.  We are interested in learning about how your health may have affected you at 
work during the past 2 weeks.
(1) The questions will ask you to think about your physical health or emotional 
problems.  These refer to any ongoing or permanent medical conditions you may 
have and the effects of any treatments you are taking for these.  Emotional 
problems may include feeling depressed or anxious.
(2) The questions are multiple choice.  They ask you to answer by placing a mark in a 
box.  
For example:
a.  How satisfied are you with your local schools? 
                                                   (Mark one box.)
Not At All Satisfied

Moderately Satisfied

Very Satisfied

b.  How satisfied are you with your local police department? 
                                                 
(Mark one box.)
Not At All Satisfied

Moderately Satisfied

Very Satisfied

        
These marks tell us you are very satisfied with your local schools and   
moderately satisfied with your local police department.
        
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OPTIONAL PAGE
(3)
Before you begin answering any questions, we would like you to write some
information on the calendar.
x
Find today’s date.  Mark that box.
x
Count back 2 weeks and mark that box too.
This 2-week period is the subject of most of the questions.  Feel free to mark other 
important dates such as birthdays, family events, or work deadlines.  Please use the 
calendars to help you answer correctly.
Insert calendar here.
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Questions 1 through 5 ask about how your health has affected you at work during the past 
2 weeks. Please answer these questions even if you missed some workdays. 
uring
s. 
x
Mark the “Does not apply to my job” box only if the question describes something that 
is not part of your job.
x
If you have more than one job, report on your main job only.
1a.  In the past 2 weeks, how much of the time did your physical health or 
emotional problems make it difficult for you to get going easily at the beginning 
of the workday? 
                                                   (Mark one box.)
Difficult all of the time (100%)

Difficult most of the time

Difficult some of the time 
(about 50%)

Difficult a slight bit of the time

Difficult none of the time (0%)

Does not apply to my job

1b.  In the past 2 weeks, how much of the time did your physical health or 
emotional problems make it difficult for you to start on your job as soon as you 
arrived at work?
                                                   (Mark one box.)
Difficult all of the time (100%)

Difficult most of the time

Difficult some of the time 
(about 50%)

Difficult a slight bit of the time

Difficult none of the time (0%)

Does not apply to my job

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These questions ask you to rate the amount of time you were 
able to handle certain parts of your job without difficulty.
2a. In the past 2 weeks, how much of the time were you able to sit, stand, or stay 
in one position for longer than 15 minutes while working, without difficulty caused 
by physical health or emotional problems? 
                                                   (Mark one box.)
Able all of the time (100%)  

Able most of the time  

Able some of the time (about 
50%)  

Able a slight bit of the time  

Able none of the time (0%)  

Does not apply to my job  

2b.  In the past 2 weeks, how much of the time were you able to repeat the same 
motions over and over again while working, without difficulty caused by physical 
health or emotional problems?
(Mark one box.)
Able all of the time (100%)  

Able most of the time  

Able some of the time (about 
50%)  

Able a slight bit of the time  

Able none of the time (0%)  

Does not apply to my job  

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This question asks about difficulties you may have had at work.
3.   In the past 2 weeks, how much of the time did your physical health or 
emotional problems make it difficult for you to concentrate on your work?
                                                   (Mark one box.)
Difficult all of the time (100%)  

Difficult most of the time  

Difficult some of the time 
(about 50%)  

Difficult a slight bit of the time  

Difficult none of the time (0%)  

Does not apply to my job  

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The next question asks about difficulties in relation to the people you
came in contact with while working.  These may include employers,
supervisors, coworkers, clients, customers, or the public.
4. In the past 2 weeks, how much of the time did your physical health or 
emotional problems make it difficult for you to speak with people in-person, in 
meetings or on the phone?  
(Mark one box.)
Difficult all of the time (100%)  

Difficult most of the time  

Difficult some of the time 
(about 50%)  

Difficult a slight bit of the time  

Difficult none of the time (0%)  

Does not apply to my job  

v05_20_2010
 
 
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These questions ask about how things went at work overall.
5a. In the past 2 weeks, how much of the time did your physical health or 
emotional problems make it difficult for you to handle the workload?
(Mark one box.)
Difficult all of the time (100%)  

Difficult most of the time  

Difficult some of the time 
(about 50%)  

Difficult a slight bit of the time  

Difficult none of the time (0%)  

Does not apply to my job  

5b. In the past 2 weeks, how much of the time did your physical health or 
emotional problems make it difficult for you to finish work on time?
(Mark one box.)
Difficult all of the time (100%)  

Difficult most of the time  

Difficult some of the time 
(about 50%)  

Difficult a slight bit of the time  

Difficult none of the time (0%)  

Does not apply to my job  

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Appendix 3: Causality and Outcome Definitions for Serious Adverse Event (SAE) 
Reporting
 
Assessment of Causality
The investigator is obligated to assess the relationship between trial product and the occurrence
of each AE/SAE.
Relationship between an AE/SAE and the relevant trial product(s) should be assessed as:
x
Probable: Good reason and sufficient documentation to assume a causal relationship.
x
Possible: A causal relationship is conceivable and cannot be dismissed.
x
Unlikely: The event is most likely related to etiology other than the trial product.
Alternative etiology, such as underlying disease(s), concomitant medication, and other risk
factors, as well as the temporal relationship of the event to trial product administration will be
considered and investigated.
The investigator should use the individual product information for the assessment. For each 
AE/SAE, the investigator must document in the medical records that he/she has reviewed the 
AE/SAE and has provided an assessment of causality.
There may be situations in which an SAE has occurred and the investigator has minimal
information to include in the initial report. However, it is important that the investigator
always makes an assessment of causality for every event before the initial transmission of 
the SAE data.
The investigator may change his/her opinion of causality in light of follow-up information and
send a follow-up report with the updated causality assessment.
The causality assessment is one of the criteria used when determining regulatory reporting
requirements.
Final Outcome
The investigator will select the most appropriate outcome:
x
Recovered/resolved: The subject has 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.
x
Recovering/resolving: The condition is improving and the subject is expected to recover 
from the event. This term is only applicable if the subject has completed the trial or has 
died from another AE.
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x
Recovered/resolved with sequelae: The subject has recovered from the condition, but
with lasting effect due to a disease, injury, treatment or procedure. If a sequelae meets an 
SAE criterion, the AE must be reported as an SAE.
x
Not recovered/not resolved: The condition of the subject has not improved and the
symptoms are unchanged or the outcome is not known.
x
Fatal: This term is only applicable if the subject died from a condition related to the
reported AE. Outcomes of other reported AEs in a subject before he/she died should be
assessed as “recovered/resolved,” “recovering/resolving,” “recovered/resolved with
sequelae,” or “not recovered/not resolved.” An AE with a fatal outcome must be reported
as an SAE.
x
Unknown: This term is only applicable if the subject is lost to follow-up.
 
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