Clinical trial NCT03596450
Conditions: Diabetes Mellitus, Type 2
Sponsor: Novo Nordisk A/S
Start date: 2018-07-13; Completion date: 2023-06-09
Enrollment: 1278 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The main purpose of this study is to compare the effects of semaglutide (Ozempic®) with the effects of other treatments for type 2 diabetes in a normal practice setting. The participant will be assigned by chance (like flipping a coin) to one of the following treatment groups: Group 1: semaglutide (Ozempic®) (by injection into skin) Group 2: standard of care antidiabetic medication (oral or injectable). The participant has an equal chance of being in either of the treatment groups. Neither the participant nor the study doctor or study staff will be able to pick which group the participant is in, but the participant will know which study drug the participant has been assigned to. The study doctor will provide the participant with a prescription for the study diabetes medication based on the treatment group the participant is assigned. The participation will last about 2 years.

Detailed description:

Arms: arm 1: Participants will receive semaglutide subcutaneously (s.c.) in addition to metformin monotherapy as treatment intensification in the course of routine clinical practice. Participants will be followed for 2 years, regardless of changes in antidiabetic treatment over the course of the study. arm 2: Participants will receive standard of care in addition to metformin monotherapy as treatment intensification in the course of routine clinical practice. Participants will be followed for 2 years, regardless of changes in antidiabetic treatment over the course of the study.
Interventions: intervention 1: Semaglutide intervention 2: Standard of care
Intervention descriptions: intervention 1: Participants will be prescribed commercially available semaglutide s.c. and will be instructed to initiate treatment with semaglutide s.c. according to the approved label. The study doctor will determine the intended maintenance dose of semaglutide, as well as changes to the maintenance dose thereafter. intervention 2: Participants will receive standard of care, defined as commercially available oral or injectable antidiabetic medication other than semaglutide. Participants will be prescribed and instructed to initiate commercially available antidiabetic medication according to the approved label and, if relevant for the specific antidiabetic medication, adjusted at the discretion of the study doctor.

Protocol documents:
Prot_002.pdf: 
Cover Page for Protocol 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT03596450 
Sponsor trial ID: 
NN9535-4416 
Official title of study: 
Long Term Comparative Effectiveness of Once Weekly 
Semaglutide Versus Standard of Care in a Real World Adult 
US Population With Type 2 Diabetes - a Randomized 
Pragmatic Trial 
Document date: 
05 December 2019 
*Document date refers to the date on which the document was most recently updated.
Note: The date in the footer of Page 2 is the date of compilation of the documents and not of an update to content.


16.1.1 Protocol and protocol amendments 
16.1.1.1 Protocol 
Confidential  
Appendix 16.1.1
Clinical Study Report   
Version 1.0; April 4, 2024
Novo Nordisk  
Protocol No. NN953-4416
UTN: U1111-1207-6474
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Redacted protocol 
Includes redaction of personal identifiable information only. 
. 


PROTOCOL No. NN9535-4416 – Novo Nordisk Semaglutide Study 
UTN: U1111-1207-6474 
Long term comparative effectiveness of once weekly 
semaglutide versus standard of care in a real world adult US 
population with type 2 diabetes - a randomized pragmatic 
clinical trial 
Trial ID NN9535-4416 
Novo Nordisk 
March 13, 2018 
Version 1.0 
Trial Phase: 4 
Investigational Substance: Semaglutide 
 
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STUDY APPROVALS 
Protocol No:  NN9535-4416 
13-MAR-2018 
Sponsor Approval: 
Name:  
 
Title:  
 
 
Novo Nordisk 
Signature: 
Date: 
Name:  
 
Title:  
 
Novo Nordisk 
Signature: 
Date: 
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Principal Study Physician Agreement: 
I have read the protocol “Long term comparative effectiveness of once weekly semaglutide 
versus standard of care in a real world adult US population with type 2 diabetes - a randomized 
pragmatic clinical 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 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 
PRINCIPAL STUDY PHYSICIAN AGREEMENT ................................................................. 3 
TABLE OF CONTENTS ............................................................................................................. 4 
SYNOPSIS ..................................................................................................................................... 7 
LIST OF ABBREVIATIONS .................................................................................................... 11 
LIST OF DEFINITIONS ........................................................................................................... 14 
1 
INTRODUCTION............................................................................................................... 16 
1.1 
Background and Rationale .............................................................................................................................. 16 
2 
STUDY OBJECTIVES ....................................................................................................... 17 
2.1 
Primary Objective ............................................................................................................................................... 17 
2.2 
Secondary Objectives ........................................................................................................................................ 17 
3 
STUDY ENDPOINTS ......................................................................................................... 17 
3.1 
Baseline .................................................................................................................................................................. 17 
3.2 
Primary Endpoint ............................................................................................................................................... 17 
3.3 
Secondary Endpoints ......................................................................................................................................... 18 
3.3.1 
Confirmatory Secondary Endpoints .............................................................................................................................. 18 
3.3.2 
Supportive Secondary Endpoints ................................................................................................................................... 18 
3.3.3 
Exploratory Endpoints ........................................................................................................................................................ 20 
4 
STUDY DESIGN ................................................................................................................. 20 
4.1 
Overview ................................................................................................................................................................ 20 
4.2 
Practice and Patient Selection ........................................................................................................................ 21 
4.2.1 
Physician Practice Eligibility ............................................................................................................................................ 21 
4.2.2 
Patient Recruitment and Eligibility ............................................................................................................................... 22 
4.2.3 
Patient Inclusion Criteria ................................................................................................................................................... 22 
4.2.4 
Patient Exclusion Criteria .................................................................................................................................................. 22 
4.2.5 
Patient Enrollment ................................................................................................................................................................ 22 
4.2.6 
Patient Randomization ........................................................................................................................................................ 23 
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5 
STUDY PROCEDURES .................................................................................................... 23 
5.1 
Enrollment Procedures..................................................................................................................................... 23 
5.2 
Randomization Visit .......................................................................................................................................... 24 
5.2.1 
Patient Characteristics ........................................................................................................................................................ 24 
5.2.2 
Treatments ............................................................................................................................................................................... 24 
5.3 
Patient Reported Outcomes, Clinician Reported Outcomes, and Diabetes Treatment 
Satisfaction ........................................................................................................................................................................... 27 
5.3.1 
PRO and Treatment Satisfaction questionnaires ..................................................................................................... 27 
5.3.1.1 
Diabetes Treatment Satisfaction Questionnaire (DTSQ) [8] [9] [10] [11] ....................................... 27 
5.3.1.2 
Short Form 12‐Item version 2 (SF‐12 v2) Health Survey [12] .............................................................. 27 
5.3.1.3 
Work Productivity and Activity Impairment: General Health (WPAI‐GH) Questionnaire [13]
27 
5.3.1.4 
Patient Global Impression of Disease Severity (PGI‐S) and Patient Global Impression of 
Change (PGI‐C) ................................................................................................................................................................................... 27 
5.3.2 
Clinician Global Impression of Disease Severity (CGI‐S) and Clinician Global Impression of Change 
(CGI‐C) 28 
5.4 
Study Period ......................................................................................................................................................... 28 
5.5 
Administrative Claims Data – HIRDSM .......................................................................................................... 28 
5.6 
Withdrawals ......................................................................................................................................................... 29 
5.6.1 
Physician Practices ............................................................................................................................................................... 29 
5.6.2 
Patients ....................................................................................................................................................................................... 29 
6 
STATISTICAL METHODS .............................................................................................. 29 
6.1 
Introduction ......................................................................................................................................................... 29 
6.1.1 
Estimands .................................................................................................................................................................................. 29 
6.1.2 
Confirmatory Endpoints and Hypotheses .................................................................................................................. 30 
6.1.3 
Study Populations .................................................................................................................................................................. 30 
6.2 
Sample Size Determination ............................................................................................................................. 31 
6.2.1 
Power and Sample Size for Primary Objective ......................................................................................................... 31 
6.3 
Statistical Analysis for the Primary Estimand ........................................................................................... 31 
6.4 
Statistical Analysis for the Secondary Estimand ...................................................................................... 32 
6.5 
Supplementary Analyses .................................................................................................................................. 33 
6.6 
PRO Analysis ........................................................................................................................................................ 33 
6.7 
Safety Analysis ..................................................................................................................................................... 33 
6.8 
Other Analyses ..................................................................................................................................................... 33 
6.8.1 
Supportive Analyses of Glycemic Control ................................................................................................................... 34 
6.8.2 
Weight Loss .............................................................................................................................................................................. 34 
6.8.3 
Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) ............................................................... 34 
6.8.4 
Hypoglycemia .......................................................................................................................................................................... 34 
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6.8.5 
Healthcare Resource Utilization (HCRU) .................................................................................................................... 34 
6.8.6 
Adherence and Persistence to Treatment .................................................................................................................. 35 
6.8.7 
Antidiabetic Treatment Patterns .................................................................................................................................... 35 
6.8.8 
Exploratory Predictive Analysis ...................................................................................................................................... 35 
6.8.9 
Evaluation of the Study Population ............................................................................................................................... 35 
7 
ADVERSE EVENT COLLECTION................................................................................. 36 
7.1 
Adverse Events .................................................................................................................................................... 36 
7.2 
Serious Adverse Events ..................................................................................................................................... 36 
7.2.1 
Collection Period of Serious Adverse Events ............................................................................................................ 37 
7.3 
Pregnancy .............................................................................................................................................................. 37 
7.3.1 
Reporting Period of Pregnancy ....................................................................................................................................... 37 
7.4 
Technical Complaints ........................................................................................................................................ 37 
8 
DATA COLLECTION ....................................................................................................... 37 
8.1 
Data Sources ......................................................................................................................................................... 37 
8.2 
Electronic Case Report Forms (eCRFs) ........................................................................................................ 38 
8.3 
Year One Database Lock ................................................................................................................................... 38 
9 
STUDY MANAGEMENT .................................................................................................. 38 
9.1 
Regulatory and Ethical Consideration ......................................................................................................... 38 
9.1.1 
Institutional Review Board (IRB) ................................................................................................................................... 39 
9.1.2 
Informed Consent .................................................................................................................................................................. 39 
9.2 
Record Retention and Access .......................................................................................................................... 39 
10  PUBLICATION OF STUDY RESULTS .......................................................................... 39 
11  INDEMNIFICATION ........................................................................................................ 40 
REFERENCES ............................................................................................................................ 41 
APPENDIX 1: TIME AND EVENTS SCHEDULE ................................................................ 42 
APPENDIX 2: ADDITIONAL DERIVED OUTCOME VARIABLES FOR SUPPORTIVE 
ANALYSES ................................................................................................................................. 45 
APPENDIX 3: PATIENT REPORTED OUTCOME ADDITIONAL INFORMATION .... 47 
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SYNOPSIS 
 
Title: Long term comparative effectiveness of once weekly semaglutide versus standard of care in a 
real world US adult population with type 2 diabetes – a randomized pragmatic clinical trial 
Sponsor: Novo Nordisk 
Study Treatment: Semaglutide in a prefilled pen (Ozempic®) 
Active Ingredient: Semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1 RA) 
Comparator Treatment: Standard of Care (SOC) (excluding semaglutide) 
Trial ID:  NN9535-4416 
Study Physician Sites: Participation of approximately 285 physician sites, including both primary 
care practitioners and endocrinologists, that have a population of patients with the target indication, 
type 2 diabetes mellitus (T2DM), actively enrolled in an 
 affiliated commercial health plan. 
Country: United States (US) 
Patients: Eligible patients include adult T2DM patients on metformin monotherapy whose physician 
deems that they have inadequate glycemic control and need treatment intensification with an additional 
antidiabetic oral or injectable medication. 
Planned enrollment in this study is 2250. Patients will be randomized 1:1 to receive either semaglutide 
or SOC.  
Study Objectives: The objectives of this study are as follows: 
1.) The primary objective is to demonstrate superior long term effects of treatment with 
semaglutide compared to SOC both added to metformin on glycemic control when used as 
intensification in routine clinical practice in adult patients with T2DM. 
2.) The secondary objectives are to compare the long term effect of semaglutide versus SOC both 
added to metformin and used as intensification in routine clinical practice in adult patients with 
T2DM with regards to: 
a. Weight loss 
b. Patient reported outcomes (PROs) and clinician reported outcomes (ClinROs) 
c. Hypoglycemia  
d. Healthcare Resource Utilization (HCRU) 
e. Adherence and persistence to treatment 
Study Design: This is a 2-year, multi-center, randomized, open label, parallel group, active comparator 
pragmatic clinical trial (PCT) comparing semaglutide versus SOC when added to metformin 
monotherapy as treatment intensification among adult T2DM patients in the course of routine clinical 
practice. Patients will be randomized 1:1 to receive either semaglutide or SOC. The decision that 
further antidiabetic treatment intensification with oral or injectable antidiabetic medication is indicated 
is at the discretion of the study physician and will be made prior to and independent of enrollment in 
this study. The study physician will have determined the patient’s suitability for treatment with 
semaglutide prior to signing informed consent, but the determination to initiate semaglutide versus 
SOC will be made by randomization. 
In keeping with the study objectives and pragmatic design to evaluate semaglutide versus SOC in real 
world, routine clinical practice, inclusion and exclusion criteria are minimally restrictive and there are 
few study-specific evaluations. Study physicians will follow and treat patients according to their 
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routine clinical practice and judgement. All oral and injectable antidiabetic medications are allowed at 
the study physicians' discretion, with the exception of semaglutide in the SOC group. Patients will be 
followed for 2 years, regardless of changes in antidiabetic treatment over the course of the study. 
It is anticipated that patients will undergo medical evaluation at regular intervals over the course of the 
study duration as per standard of care, but the only dedicated study visits are at randomization, at year 
1, and at year 2. The study will also capture clinical data collected at the sites during routine care visits, 
i.e., office visits and other patient contacts that occur as part of routine clinical practice. Assessments
will be conducted according to the study physician’s routine clinical practice, with a few study-specific
assessments as outlined in Study Procedures. Additionally, medical and pharmacy claims data will be
captured utilizing the HealthCore Integrated Research Database (HIRDSM) for the 2 year study period.
HIRD data for the 12 months prior to randomization will also be collected if available.
Participant Selection: 
Inclusion Criteria:   
Patients 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. 
2.) Male or female, age ≥ 18 years at the time of signing informed consent. 
3.) Type 2 diabetes mellitus diagnosis. 
4.) Treatment with metformin as antidiabetic monotherapy 
5.) Current member of an 
 affiliated commercial health plan. 
6.) Recorded glycosylated hemoglobin A1c (HbAlc) value within the last 90 days prior to 
randomization. 
7.) Further intensification with an additional antidiabetic oral or injectable medication is indicated 
to achieve glycemic target at the discretion of the study physician according to approved 
labelling. 
Exclusion Criteria: 
Patients presenting with any of the following exclusion criteria will not be eligible for the study: 
1.) Previous randomization in this study. 
2.) Treatment with any medication for the indication of diabetes other than metformin in a period 
of 30 days before the day of eligibility assessment. Temporary/emergency use of any type of 
insulin is allowed, as is prior insulin treatment for gestational diabetes.  
3.) Contraindications to semaglutide according to the FDA approved label. 
4.) Female who is pregnant, breastfeeding or intends to become pregnant. 
5.) Participation in another clinical trial. 
Study Procedures: 

Study physicians will identify eligible patients for participation.

Study physicians will obtain written informed consent from patients and if eligible, patients
will be randomized to either semaglutide or SOC.

Study data will be collected on electronic Case Report Forms (eCRFs) via an electronic data
capture (EDC) system.

Study physicians or site personnel will collect demographic, clinical (i.e., height, weight,
systolic blood pressure (SBP), diastolic blood pressure (DBP)), medical and T2DM specific
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history, antidiabetic medications, and pre-specified concomitant medications related to 
cardiovascular risk data prior to or at randomization. Individualized HbA1c target will be set 
prior to randomization. 
 
Baseline HbA1c will be collected from physician sites during eligibility assessment and will 
be the value closest to the date of randomization, within 90 days. All post-randomization 
HbA1c values will be recorded as available per routine clinical practice during the 2 year study 
period. Post-randomization HbA1c values are required for the year 1 and year 2 dedicated 
study visits. 
 
PROs and ClinROs will be completed at randomization, year 1, and year 2. 
 
Study physicians will collect patient data (HbA1c, study and antidiabetic medication changes, 
pre-specified concomitant medications related to cardiovascular risk, weight, SBP, DBP, 
hypoglycemic events leading to inpatient admission or emergency room (ER) encounter, 
adverse events (AEs) leading to study drug discontinuation, serious adverse events (SAEs), 
and pregnancies at the dedicated year 1 and year 2 study visits, as well as at any routine care 
visits during the 2 year study period. 
 
Administrative medical claims, pharmacy claims and health plan eligibility data will be 
captured from the HIRD for the duration of the 2 year study period. HIRD data for the 12 
months prior to study randomization will also be collected if available. This data will be used 
for HCRU measures, as well as adherence and persistence to treatment.  
Study Duration: Planned patient time on study will be 2 years. Administrative claims data will also 
be captured during this time period. Patients will be followed for the full 2 year study period regardless 
of changes in or discontinuation of antidiabetic treatment, other than withdrawal of consent. 
Questionnaires: Diabetes treatment satisfaction, generic health-related quality of life (HRQoL), work 
productivity, and patient and clinician global assessments will be measured at the randomization, year 
1, and year 2 dedicated study visits. 
Statistical Analysis: Two estimands, each targeting a unique research question, have been defined to 
adequately describe the effect of semaglutide as compared to SOC (excluding semaglutide).  
The primary estimand for all objectives will be the “intention-to-treat” estimand evaluating the 
effectiveness of randomized treatment intervention, irrespective of adherence to this randomized 
intervention or changes to other antidiabetic medication. 
The secondary estimand for all objectives, with the exception of the adherence and persistence to 
treatment objective, is the “if all patients had adhered” estimand. This estimand evaluates the effect of 
randomized treatment intervention for all randomized patients if all patients had adhered to randomized 
treatment, regardless of changes to other antidiabetic medication. 
Baseline is defined as ≤ 90 days prior to randomization visit (week 0) for HbA1c. For secondary 
endpoint assessments, baseline is defined as ≤ 4 weeks prior to the randomization visit (week 0). 
Primary completion date (PCD) is the date the last patient completes the year 1 dedicated study visit. 
The primary endpoint is binary, with success represented by an HbA1c <7.0% (53 mmol/mol) at year 
1 (yes/no). Confirmatory secondary endpoints include:  
 
Change in HbA1c (%-point) from baseline to year 1 
 
HbA1c <7.0% (53 mmol/mol) at year 2 (yes/no) 
 
Change in HbA1c (%-point) from baseline to year 2 
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This study is designed to have 90% power to jointly confirm superiority of the primary endpoint and 
the above three confirmatory secondary endpoints based on an analysis of the primary estimand for 
each of the endpoints.    
The confirmatory endpoints will all be tested under multiplicity control via a hierarchical testing 
scheme according to the order given in the above bullet list. 
The estimand informs choices about data foundation and statistical analysis including possible 
imputation of missing data, hereby ensuring that randomization is preserved as a sound basis for 
statistical inference; i.e., estimation of effect size, associated uncertainty, and statistical testing.  
The full analysis set (FAS) comprising all randomized patients will be the analysis population for 
evaluation of both the primary and secondary estimands. For both estimands, the primary endpoint, 
HbA1c <7.0%, will be analyzed using a logistic regression model with a logit link function and will 
include treatment and baseline HbA1c as independent variables. Continuous endpoints will be analyzed 
using analysis of covariance (ANCOVA) and will include the same independent variables. Prior to 
analysis, missing data will be imputed by multiple imputation on the continuous HbA1c scale and 
subsequently dichotomized for the primary endpoint. 
Supplementary Analyses: Two complete case analyses will complement the analyses for the primary 
and secondary estimands. The supplementary complete case analyses will be based on the subset of 
patients without missing endpoint data, i.e., patients that do not have their endpoint imputed in the two 
analyses used for the primary estimand and the secondary estimand, respectively.    
Secondary Analyses: Secondary analyses will compare semaglutide versus SOC treatment groups in 
terms of change in body weight, SBP, DBP, and PRO and ClinRO measures, based on the similar 
analysis methods as for the primary and secondary estimands. Similarly, binary endpoints and other 
secondary endpoints will be compared statistically between treatment groups, including HCRU and 
adherence/persistence to treatment measures, hypoglycemic events leading to inpatient admission or 
ER encounter, as well as composite measures of HbA1c, weight loss, and hypoglycemia. 
Safety: The principal study physician is responsible for monitoring the safety of participating patients. 
For the purposes of this study, AEs that do not meet the definition of an SAE will only be 
collected/recorded in the EDC if they lead to study drug discontinuation. Study physicians are 
responsible for reporting all SAEs and following the patient until the outcome of the SAE is closed 
out. All SAEs will be reported from randomization until end of study (EOS) at year 2 or patient study 
withdrawal. Study physicians are also responsible for recording all pregnancies in female patients from 
randomization until EOS at year 2 or patient study withdrawal. The patient 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  
ADA 
American Diabetes Association 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
eCCGs 
Electronic Case Report Form Completion Guidelines 
CFR 
Code of Federal Regulations 
CGI-C 
Clinical Global Impression of Change 
CGI-S 
Clinician Global Impression of Disease Severity 
CI 
Confidence Interval 
ClinRO 
Clinician Reported Outcome 
eCRF 
Electronic Case Report Form 
DBP 
Diastolic Blood Pressure 
DPP-4 
Dipeptidyl peptidase 4 
DTSQ 
Diabetes Treatment Satisfaction Questionnaire 
DTSQc 
Diabetes Treatment Satisfaction Questionnaire, change version 
DTSQs 
Diabetes Treatment Satisfaction Questionnaire, status version 
EASD 
European Association for the Study of Diabetes 
EDC 
Electronic Data Capture 
EOS 
End of Study 
ER 
Emergency Room 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FDC 
Fixed Dose Combination 
GCP 
Good Clinical Practice 
GLP-1 RA 
Glucagon-Like Peptide-1 Receptor Agonists 
HbA1c 
Glycosylated Hemoglobin A1c 
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HCRU 
Healthcare Resource Utilization 
HEDIS 
Healthcare Effectiveness Data and Information Set 
HIRDSM 
HealthCore Integrated Research Database 
HIPAA 
Health Insurance Portability and Accountability Act 
HRQoL 
Health-Related Quality of Life 
ICF 
Informed Consent Form 
ICMJE 
International Committee of Medical Journal Editors 
ID 
Identifier 
IRB 
Institutional Review Board 
ITT 
Intent to Treat 
LPLV 
Last Patient Last Visit 
MedDRA 
Medical Dictionary for Regulatory Activities 
MCS-12 
Mental Summary Component (of the Short Form 12-Item version 2) 
MPR 
Medication Possession Ratio 
OR 
Odds Ratio 
PCD 
Primary Completion Date 
PCS-12 
Physical Summary Component (of the Short Form 12-Item version 2) 
PCT 
Pragmatic Clinical Trial 
PDC 
Proportion Days Covered 
PGI-C 
Patient Global Impression of Change 
PGI-S 
Patient Global Impression of Disease Severity 
PRO 
Patient Reported Outcome 
PT 
Preferred Term 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
SD 
Standard Deviation 
SF-12v2 
Short Form 12-Item version 2 
SGLT-2 
Sodium-Glucose Co-transporter 2 
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SM 
Service Mark 
SOC 
Standard of Care 
SUSTAIN 
Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes 
T2DM 
Type 2 Diabetes Mellitus 
TD 
Treatment Difference 
US 
United States 
WPAI-GH 
Work Productivity and Activity Impairment, General Health 
 
 
 
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LIST OF DEFINITIONS 
 
Term 
Definition  
Administrative Claims 
Data 
Medical, pharmacy, and health plan eligibility data created in the 
processing of medical and pharmacy claims. The claims data utilized in 
this study are obtained from the HealthCore Integrated Research 
Database (HIRD). 
Baseline 
Baseline refers to assessments conducted and patient data collected at 
or prior to randomization. Baseline HbAlc may be ≤ 90 days prior to 
randomization. Baseline for secondary endpoint assessments may be ≤ 
4 weeks prior to randomization. 
Baseline Endpoint 
For continuous endpoints and endpoints derived from continuous 
sources, the baseline value is defined as the last assessment taken prior 
to or at the randomization visit and before first use of study drug. 
Comparator Treatment 
Standard of Care (SOC) (excluding semaglutide); Commercially 
available oral or injectable antidiabetic medication, excluding 
semaglutide, prescribed at the discretion of the study physician for 
antidiabetic treatment intensification following randomization. 
Complete the Study 
Complete the study at 52 weeks: Patient has year 1 HbA1c data 
Complete the study at 104 weeks: Patient has year 2 HbA1c data 
Dedicated Study Visit 
One of three required study visits: randomization, year 1, and year 2. 
Enrollment 
Randomization 
Estimand 
The estimate targeted to address the research question posed by the 
study objective, i.e., “what is to be estimated.” [1] The estimand 
translates the study objective into a precise definition of the effect of 
treatment. 
Healthcare Resource 
Utilization (HCRU) 
Broad term encompassing use of healthcare services, including 
inpatient admissions, ER encounters, outpatient encounters including 
office visits, and pharmacy prescription fills. 
Index Date 
The date corresponding to an event of interest. In this study, index date 
is the date corresponding to a claims-based proxy for antidiabetic 
treatment intensification for 2 comparator populations, thus mimicking 
randomization date in the study population. 
Principal Study 
Physician 
Physician at study site who is responsible for the overall conduct and 
oversight of the study at their site, including: supervision of study 
personnel, monitoring the safety of all participating patients, ensuring 
the accurate and complete collection and reporting of study data, 
continued review of the IRB study approval, and maintenance of study 
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records. This term is analogous to “Investigator” in Good Clinical 
Practice (GCP) requirements.  
Randomization 
The point at which a patient is assigned by chance to either semaglutide 
or standard of care (SOC). 
Routine Care Visit 
An office visit or other patient contact during the study period that 
occurs outside of the dedicated study visits (randomization, year 1, and 
year 2) according to routine clinical practice. 
Study Physician 
Physician at study site who participates in the conduct of the study. 
Study/Trial 
For the purposes of this protocol, study and trial are considered 
synonyms. Study is used throughout the body of the text as it reflects 
the post-regulatory approval setting and real world design. Trial is used 
in the title and in referring to the PCT acronym to maintain consistency 
with the industry standard Pragmatic Clinical Trial or PCT.  
Study Drug 
Study drug is the first antidiabetic oral or injectable medication 
prescribed for treatment intensification following randomization. A 
patient can start and stop study drug throughout the study. At any time 
during the duration of the study, if a patient is taking study drug as 
defined, they will be considered “on study drug” regardless of prior 
study drug discontinuations. 
For the semaglutide treatment group, study drug is defined as
semaglutide.
For the SOC treatment group, study drug is defined as the drug class
of the first antidiabetic oral or injectable medication prescribed for
treatment intensification following randomization. If a fixed dose
combination (FDC) product is prescribed, one of the drugs will be
chosen by the study physician to be the study drug. A patient
randomized to the SOC treatment group will still be considered “on
study drug” if they are taking a drug in the same drug class as their
first study drug, even if it is not the same individual drug. This also
applies to treatment intensification with a FDC product if one of the
drugs is in the same drug class as the first study drug.
Study Drug 
Discontinuations 
Study drug discontinuation is termination of the study drug. A patient 
can start and stop study drug throughout the study; therefore a patient’s 
study drug discontinuation status can change throughout the duration of 
the study. At any time during the duration of the study, if a patient is 
not taking study drug as defined, they will be considered “off study 
drug.” 
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1 
INTRODUCTION 
1.1 
Background and Rationale 
The American Diabetes Association (ADA) and European Association for the Study of Diabetes 
(EASD) position statement recommends a patient-centric approach to the selection of 
pharmacological treatment for type 2 diabetes mellitus (T2DM), including considerations on 
effectiveness, hypoglycemia risk, impact on body weight, side effects, costs, and patient 
preferences. [2] Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are recommended for 
the management of hyperglycemia in T2DM, primarily in combination with other antidiabetic 
medications. [2] [3] 
Semaglutide, a human GLP-1 analogue for once-weekly subcutaneous administration, has been 
shown to improve glycemic control in adults with T2DM as monotherapy when the use of 
metformin is considered inappropriate, or as add-on to other glucose lowering therapies 
including insulin. In the Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes 
(SUSTAIN) clinical development program, semaglutide demonstrated clinically relevant and 
superior glycemic control, as well as weight loss versus placebo and active comparators, both 
when used as mono- and combination therapy in inadequately controlled patients with T2DM. In 
addition, a significant reduction in cardiovascular risk was demonstrated for semaglutide versus 
placebo in patients with T2DM at high risk of cardiovascular events. The overall safety profile of 
semaglutide was consistent with the well-established GLP-1 RA safety profile. [4] 
Pragmatic clinical trials (PCTs) are designed and conducted to reflect patient outcomes and to 
investigate how a product is used and performs in routine clinical practice. This type of study 
compares two or more medical interventions that are directly relevant to clinical care and strives 
to assess those interventions’ effectiveness in real world practice. They use broad eligibility 
criteria and recruit patients from a variety of practice settings to ensure the inclusion of the type 
of patients whose care will be influenced by the study´s results. Such studies are increasingly 
important to generate evidence regarding real world treatment outcomes to inform and support 
appropriate market access. [5] 
The current local US study serves the purpose of evaluating the long term comparative 
effectiveness of semaglutide with existing commercially available antidiabetic medications in a 
real world population and in a variety of practice settings, thereby maximizing external validity 
while balancing the internal validity of a randomized controlled trial. This will generate data to 
complement the findings from the SUSTAIN clinical development program. Taken together, 
these findings may provide important evidence for decision making by clinicians, payers, and 
policy makers in routine clinical practice. 
This local US study will enroll adult patients with T2DM who have inadequate glycemic control 
on metformin as their only antidiabetic medication, as defined by the need for treatment 
intensification with an additional antidiabetic oral or injectable medication per the study 
physician´s discretion. The current study targets patients at this particular treatment point 
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because they represent the population inadequately controlled on the current ADA recommended 
first lines of treatment of T2DM. The addition of a GLP-1 RA as second-line treatment is in line 
with the ADA guidance from 2017. [6] In keeping with the ADA and EASD position statement 
recommending a patient-centric approach to treatment selection for T2DM patients, in addition 
to comparative effectiveness, this study will also evaluate hypoglycemia risk, body weight, 
healthcare resource utilization (HCRU), patient reported outcomes (PROs), and clinician 
reported outcomes (ClinROs). Adverse events (AEs) leading to study drug discontinuation will 
also be collected. [2] 
  
2 
STUDY OBJECTIVES  
2.1 
Primary Objective 
The primary objective is to demonstrate superior long term effects of treatment with semaglutide 
compared to standard of care (SOC) both added to metformin on glycemic control when used as 
intensification in routine clinical practice in adult patients with T2DM.  
2.2 
Secondary Objectives 
The secondary objectives are to compare the long term effect of semaglutide versus SOC both 
added to metformin and used as intensification in routine clinical practice in adult patients with 
T2DM with regards to: 
 Weight loss 
 Patient reported outcomes (PROs) and clinician reported outcomes (ClinROs) 
 Hypoglycemia  
 Healthcare Resource Utilization (HCRU) 
 Adherence and persistence to treatment 
  
3 
STUDY ENDPOINTS 
3.1 
Baseline 
Baseline is defined as ≤ 90 days prior to randomization visit (week 0) for glycosylated 
hemoglobin A1c (HbA1c). For secondary endpoint assessments, baseline is defined as ≤ 4 weeks 
prior to the randomization visit (week 0). 
3.2 
Primary Endpoint 
Primary completion date (PCD) is the date the last patient completes the year 1 dedicated study 
visit. 
The primary endpoint of this study is: 
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
HbA1c <7.0% (53 mmol/mol) at year 1 (yes/no)
3.3 
Secondary Endpoints 
3.3.1 Confirmatory Secondary Endpoints 
Confirmatory secondary endpoints of this study include: 

Change in HbA1c (%-point) from baseline to year 1

HbA1c <7.0% (53 mmol/mol) at year 2 (yes/no)

Change in HbA1c (%-point) from baseline to year 2
3.3.2 Supportive Secondary Endpoints
Supportive secondary endpoints of this study include: 

Individualized HbA1c target attained at year 1 (yes/no)

HbA1c <7.0% (53mmol/mol) or at least 1% point improvement in HbA1c compared to
baseline at year 1 (yes/no)

HbA1c target attainment per Healthcare Effectiveness Data and Information Set (HEDIS)
criteria (<8.0% if age ≥65 years or with defined comorbidities, otherwise <7.0%) at year
1 (yes/no)

Change in body weight (lb) from baseline to year 1

Change in body weight (%) from baseline to year 1

Change in systolic blood pressure (SBP; mm Hg) from baseline to year 1

Change in diastolic blood pressure (DBP; mm Hg) from baseline to year 1

Time to first study drug discontinuation during 2 years (day)

Time to first treatment intensification (add-on) or change (switch) after randomization
during 2 years (day)

Study drug medication adherence for the first year of the study, as measured by
medication possession ratio (MPR) (%)

Number of hypoglycemic episodes leading to an inpatient admission or emergency room
(ER) encounter from baseline to year 2

Diabetes Treatment Satisfaction Questionnaire, change version (DTSQc), Total treatment
satisfaction score measured at year 1

DTSQc, Total treatment satisfaction score measured at year 2

Change from baseline in Short Form 12-Item Version 2 Survey (SF-12 v2), Physical
summary component (PCS-12) score at year 1
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
Change from baseline in SF-12 v2, PCS-12 score at year 2

Change from baseline in SF-12 v2, Mental summary component (MCS-12) score at year
1

Change from baseline in SF-12 v2, MCS-12 score at year 2

Change from baseline in Work Productivity and Activity Impairment, General Health
questionnaire (WPAI-GH) Absenteeism (work time missed) score at year 1

Change from baseline in WPAI-GH Absenteeism (work time missed) score at year 2

Change from baseline in WPAI-GH Presenteeism (impairment at work / reduced on-the-
job effectiveness) score at year 1

Change from baseline in WPAI-GH Presenteeism (impairment at work / reduced on-the-
job effectiveness) score at year 2

Change from baseline in WPAI-GH Work productivity loss (overall work impairment /
absenteeism plus presenteeism) score at year 1

Change from baseline in WPAI-GH Work productivity loss (overall work impairment /
absenteeism plus presenteeism) score at year 2

Change from baseline in WPAI-GH Activity Impairment score at year 1

Change from baseline in WPAI-GH Activity Impairment score at year 2
All cause healthcare resource utilization (HCRU) from baseline to year 2: 

Number of inpatient admissions

Cumulative length of stay for inpatient admissions (days)

Number of ER encounters

Number of outpatient encounters

Number of medications

Occurrence of inpatient admission (yes/no)

Occurrence of ER encounter (yes/no)

Occurrence of outpatient encounter (yes/no)
Diabetes related HCRU from baseline to year 2: 

Number of diabetes related inpatient admissions

Cumulative length of stay for diabetes related inpatient admissions (days)

Number of diabetes related ER encounters
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 Number of diabetes related outpatient encounters 
 Number of diabetes related medications 
 Occurrence of diabetes related inpatient admission (yes/no) 
 Occurrence of diabetes related ER encounter (yes/no) 
 Occurrence of diabetes related outpatient encounter (yes/no) 
3.3.3 Exploratory Endpoints 
Not applicable. 
  
4 
STUDY DESIGN 
4.1 
Overview 
This is a 2-year, multi-center, randomized, open label, parallel group, active comparator PCT 
comparing semaglutide versus SOC when added to metformin monotherapy as treatment 
intensification among adult T2DM patients in the course of routine clinical practice. Patients will 
be randomized 1:1 to receive either semaglutide or SOC. 
The decision that further antidiabetic treatment intensification with an additional oral or 
injectable antidiabetic medication is indicated is at the discretion of the study physician and will 
be made prior to and independent of enrollment in this study. The study physician will have 
determined the patient’s suitability for treatment with semaglutide prior to inviting them to 
participate in the study. However, the determination to initiate semaglutide versus SOC will be 
made by randomization.  
Patients will be followed for 2 years, regardless of changes in antidiabetic treatment over the 
course of the study. Data collection will continue for the full 2 year study period unless a patient 
withdraws informed consent. Patients who enroll in the study agree to the release of health 
information, and to answer questions about their health during the course of the study. 
Additionally, medical and pharmacy claims data will be extracted for the 2 year study period, as 
well as up to 12 months prior to randomization as available. 
In keeping with the study objectives and pragmatic design to evaluate semaglutide versus SOC in 
real world, routine clinical practice, inclusion and exclusion criteria are minimally restrictive and 
there are few study-specific evaluations. Study physicians will follow and treat patients 
according to their routine clinical practice and judgement. All oral and injectable antidiabetic 
medications are allowed at the study physicians' discretion, with the exception of semaglutide in 
the SOC group. It is anticipated that patients will undergo medical evaluation at regular intervals 
over the course of the study duration as per standard of care, but the only dedicated study visits 
are at randomization, at year 1, and at year 2. The study will also capture clinical data collected 
at the sites during routine care visits, i.e., office visits and other patient contacts that occur as part 
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of routine clinical practice. Assessments will be conducted according to the study physician’s 
routine clinical practice, with a few study-specific assessments as described in section 5. The 
data available may differ from site to site and patient to patient. To ensure flexibility, the 
dedicated year 1 and year 2 study visits have a window of ±6 weeks. 
4.2 
Practice and Patient Selection 
The target population for this study consists of adult, commercially-insured, T2DM patients on 
metformin mono-therapy who are in need of treatment intensification with an additional 
antidiabetic oral or injectable medication. Physician practice and participant eligibility criteria 
were guided by feasibility data from the HealthCore Integrated Research Database (HIRDSM) 
prior to protocol development. 
Physician sites recruited for the study will be those who provide care for members of 
 
health plans, one of the largest healthcare insurance providers in the US. 
 provides 
medical coverage for roughly 1 in 8 Americans, and although this is mostly concentrated in the 
employer-supported, commercially-insured market, the data in the HIRD are overall 
representative of the entire US population. [7] Study site recruitment will target both primary 
care practitioners and specialized endocrinologists to reflect diverse treatment settings and 
patient populations. Potential sites will be evaluated regarding feasibility of their participation in 
the study, including having a T2DM population of 
 members to meet enrollment goals, 
based on the initial data analysis from the HIRD. Potential sites will be tiered based on their 
estimated number of eligible study patients, and outreach will begin with all sites that meet a pre-
determined minimum number of potentially eligible patients. Outreach and follow-up will be 
performed until the requisite number of physician sites is enrolled. Study-specific assessments 
have been kept to a minimum, thereby decreasing burden on study sites and increasing 
participation to a wide range of sites. 
 health plans serve a large population of T2DM patients. In feasibility data from the 
HIRD, the number of patients with T2DM, at least one claim for metformin in the most recent 6 
months, and without prior use of other antidiabetic drug classes (per study exclusion criterion 
#2), amounts to circa 300,000 potential eligible patients distributed across 61,803 unique 
providers. 
4.2.1 Physician Practice Eligibility 
Participation of approximately 285 physician sites in the US, including both general practitioners 
and endocrinologists that have a T2DM population, is anticipated. Physician sites will be limited 
to those that participate in the care of patients who are actively enrolled in an 
 
 
 health plan (hence forth referred to as 
 health plans). 
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4.2.2 Patient Recruitment and Eligibility 
Eligible patients include adult T2DM patients whose physicians determine that they have 
inadequate glycemic control on metformin antidiabetic monotherapy. Inadequate glycemic 
control is defined by the need for T2DM treatment intensification with an additional antidiabetic 
oral or injectable medication, as determined by the study physician. Patients 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 a broad population of adult 
T2DM patients to generate data in a population that reflects the heterogeneity of a real world 
population treated in general practice, and support the study objectives to evaluate semaglutide 
versus SOC in real world, routine clinical practice. 
4.2.3 Patient Inclusion Criteria 
Patients 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.
2. Male or female, age ≥ 18 years at the time of signing informed consent.
3. Type 2 diabetes mellitus diagnosis.
4. Treatment with metformin as antidiabetic monotherapy.
5. Current member of an 
 affiliated commercial health plan.
6. Recorded HbAlc value within last 90 days prior to randomization.
7. Further intensification with an additional antidiabetic oral or injectable medication is
indicated to achieve glycemic target at the discretion of the study physician according to
approved labelling.
4.2.4 Patient Exclusion Criteria 
Patients presenting with any of the following exclusion criteria will not be eligible for the study: 
1. Previous randomization in this study.
2. Treatment with any medication for the indication of diabetes other than metformin in a
period of 30 days before the day of eligibility assessment. Temporary/emergency use of
any type of insulin is allowed, as is prior insulin treatment for gestational diabetes.
3. Contraindications to semaglutide according to the FDA approved label.
4. Female who is pregnant, breastfeeding or intends to become pregnant.
5. Participation in another clinical trial.
4.2.5 Patient Enrollment
Planned number of patients to be randomized: 2250 
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Expected number of patients to complete the study after 52 weeks: 1687 
Expected number of patients to complete the study after 104 weeks: 1260 
4.2.6 Patient Randomization 
Study patients will be randomized to either semaglutide or SOC in a 1:1 ratio. The study design 
and patient randomization is depicted in Figure 1. 
Figure 1 Study design diagram. Patients will be randomized in a 1:1 manner using centralized 
allocation to receive semaglutide or SOC as add-on to metformin.  
5 
STUDY PROCEDURES 
The study visit schedule is summarized in Appendix 1. 
5.1 
Enrollment Procedures 
The determination that a patient has inadequate glycemic control on metformin antidiabetic 
monotherapy, and the subsequent decision to intensify antidiabetic treatment with an additional 
oral or injectable antidiabetic medication, will be made by the study physician during the course 
of routine clinical practice. Following the decision to initiate treatment intensification, the study 
physician will determine the patient’s suitability for the study. Suitability for the study will be 
assessed using the current inclusion and exclusion criteria, including the approved label for 
semaglutide. Only patients who are eligible for treatment intensification and have been found 
suitable for treatment with semaglutide, as determined by the study physician, are in scope for 
randomization. Prior to being randomized, patients must be willing to intensify with an 
antidiabetic medication, including GLP-1 receptor agonists. Study physicians will set and 
document an individualized HbA1c target for patients prior to randomization based on their 
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clinical judgement and knowledge of the patient. To preserve the real-world nature of the study, 
patients will be approached for potential enrollment into the study when they present to their 
physician as part of their standard care. 
Informed consent will be obtained prior to any study related activities. The most recent HbA1c 
completed in the course of routine care up to 90 days prior to and including the date of 
randomization will be considered a baseline assessment and does not need to be repeated. 
Study physicians or site personnel will collect patient characteristics and study data at each study 
visit as outlined in the Time and Events Schedule (Appendix 1), either directly from the patient 
or abstracted from the patient’s medical records, and enter them into the electronic Case Report 
Form (eCRF). 
5.2 
Randomization Visit 
Following informed consent and confirmation of inclusion/exclusion criteria, patients will be 
randomized to either semaglutide or SOC. Data collection at the randomization visit will include 
inclusion/exclusion criteria as well as the data outlined in the sections below. PRO and ClinRO 
questionnaires will also be administered (section 5.3). 
5.2.1 Patient Characteristics 
Baseline assessments at the randomization visit will include: demographic data, medical history, 
diabetes history including antidiabetic medications and diabetes complications, pre-specified 
concomitant medications related to cardiovascular risk, and clinical data (weight, height, HbA1c, 
SBP, DBP). Individualized HbA1c target will be set prior to randomization. The baseline HbA1c 
will be the patient’s most recent HbA1c within 90 days of randomization. 
5.2.2 Treatments 
To preserve the real-world nature of the study, the patient experience will be as close to routine 
care as possible. The study physician will be one of the patient’s own treating physicians, who 
may make treatment adjustments according to their clinical judgement. The study physician can 
make repeat prescriptions of the study drug as usual, which are collected by patients from the 
pharmacy of their choice. Patients will be randomized to either semaglutide or SOC. Treatment 
details will be recorded in the eCRF. 
Semaglutide Group 
Patients randomized to the semaglutide group will be prescribed commercially available 
semaglutide in a prefilled pen injector and will be instructed to initiate treatment with 
semaglutide according to the approved label. The study physician will determine the intended 
maintenance dose of semaglutide, as well as changes to the maintenance dose thereafter. Add-on, 
discontinuation or dose modification of antidiabetic medication, including semaglutide, during 
the study is allowed at the discretion of the study physician. 
Semaglutide Study Drug: For patients randomized to the semaglutide group, study drug is 
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defined as semaglutide. 
SOC Group 
SOC is defined as commercially available oral or injectable antidiabetic medication (see current 
representative list below) other than semaglutide. Patients randomized to SOC will be prescribed 
and instructed to initiate commercially available antidiabetic medication according to the 
approved label and, if relevant for the specific antidiabetic medication, adjusted at the discretion 
of the study physician. Patients randomized to SOC may discontinue SOC, add-on to the SOC or 
switch to another antidiabetic medication during the study, with the exception of semaglutide 
which is not allowed in the SOC group for the duration of the study. 
SOC Study Drug: For patients randomized to the SOC group, study drug is defined as the 
drug class of the first antidiabetic oral or injectable medication prescribed for treatment 
intensification following randomization. If a fixed dose combination (FDC) product is 
prescribed, one of the drugs will be chosen by the study physician to be the study drug. A 
patient randomized to the SOC treatment group will still be considered “on study drug” if 
they are taking a drug in the same class as their first study drug, even if it is not the same 
individual drug. This also applies to treatment intensification with a FDC product if one 
of the drugs is in the same class as the first study drug. 
Study Drug: Start/Stop, Discontinuations 
Study drug discontinuation is termination of the study drug. A patient can stop or start study drug 
throughout the study; therefore a patient’s study drug discontinuation status can change 
throughout the duration of the study. At any time during the duration of the study, if a patient is 
not taking study drug as defined, they will be considered “off study drug.” Conversely, at any 
time during the duration of the study, if a patient is taking study drug as defined, they will be 
considered “on study drug,” regardless of prior study drug discontinuations.  
If a participating patient becomes pregnant, the study physician will review the patient’s 
antidiabetic treatment regimen and make any changes necessary according to standard care of 
patients with T2DM during pregnancy. Semaglutide will be discontinued and will not be 
restarted unless the patient is no longer pregnant or breast-feeding. All study drug copay 
assistance will end.  
Copay assistance 
The study products will be handled and dispensed by the patients’ pharmacy(s) per their 
preference and health plan benefits. In order to minimize the impact of any differential in out-of-
pocket costs between the treatment groups, an out-of-pocket maximum will be provided by Novo 
Nordisk as part of the study. In both treatment groups, the patient’s copay will be up to the 
specified maximum for the study drug (as defined above) and ancillary needles (if required to 
administer the study drug). Copay assistance will only apply to the study drug as defined above 
(i.e., not to any subsequent add-on treatment or treatment changes outside the study drug 
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definition). Because patients can start and stop study drug throughout the study, copay assistance 
may also start and stop throughout the study. For the duration of the study, any time a patient is 
“on study drug” they will receive copay assistance, and any time a patient is “off study drug” 
they will not receive copay assistance. The only exceptions are if a patient initiates prescription 
coverage through Medicare or Medicaid, at which point all copay assistance will end. 
Products 
A current representative list of the products used in this study is below. All treatments will be 
used in accordance with local clinical practice and guidelines. Products with more than one 
active substance i.e., FDC products, can be used in this study. 
Semaglutide: Semaglutide in a prefilled pen (Ozempic®) 
Oral antidiabetic drugs: The oral antidiabetic drug classes included in this study are the 
commercially available options (listed in alphabetic order): 
 Alpha-glucosidase inhibitors 
 Dipeptidyl peptidase 4 (DPP-4) inhibitors 
 Meglitinides 
 Sodium-glucose co-transporter 2 (SGLT-2) inhibitors 
 Sulfonylureas 
 Thiazolidinediones 
 Other 
o Bromocriptine 
o Colesevelam 
Injectable antidiabetic drugs: The injectable antidiabetic drug classes included in this study 
are the commercially available options (listed in alphabetic order): 
 GLP-1 RAs 
 Basal Insulin 
o Long acting insulin 
o Intermediate acting insulin including premix 
 Prandial Insulin 
o Short acting insulin 
o Rapid acting insulin 
 Other 
o Pramlintide 
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Background medication: The following treatment is considered background medication: 
metformin. Patients may discontinue metformin at any time during the study. Patients may 
change the pre-study dose and frequency of metformin at any time during the study. Background 
medication will not be provided nor reimbursed by Novo Nordisk.   
5.3 
Patient Reported Outcomes, Clinician Reported Outcomes, and Diabetes 
Treatment Satisfaction 
Diabetes treatment satisfaction, generic health-related quality of life (HRQoL), work 
productivity, and patient and clinician global assessments will be assessed by the following 
instruments at randomization, year 1, and year 2. Patients will self-administer these instruments 
on paper. Site study personnel will review for completeness and enter responses into the eCRF. 
5.3.1 PRO and Treatment Satisfaction questionnaires 
5.3.1.1 Diabetes Treatment Satisfaction Questionnaire (DTSQ) [8] [9] [10] [11] 
The Diabetes Treatment Satisfaction Questionnaire (DTSQ) evaluates patient satisfaction with 
treatment. The DTSQ status version (DTSQs) will be completed at the randomization visit and 
the DTSQ change version (DTSQc) will be completed at the year 1 and year 2 dedicated study 
visits. 
5.3.1.2 Short Form 12-Item version 2 (SF-12 v2) Health Survey [12] 
The SF-12 v2 is a generic HRQoL questionnaire that assesses physical and mental functioning 
and overall HRQoL. The SF-12v2 standard 4-week recall period questionnaire will be completed 
at the randomization, year 1, and year 2 dedicated study visits. 
5.3.1.3 Work Productivity and Activity Impairment: General Health (WPAI-GH) 
Questionnaire [13] 
The WPAI-GH questionnaire assesses both absenteeism (i.e., work time missed) and 
presenteeism (i.e., impairment at work or reduced on-the-job effectiveness) as well as daily 
activity impairment (e.g., work around the house, shopping, exercising, childcare, studying) 
attributable to general health. The WPAI-GH will be administered at the randomization, year 1, 
and year 2 dedicated study visits. 
5.3.1.4 Patient Global Impression of Disease Severity (PGI-S) and Patient Global Impression 
of Change (PGI-C) 
The PGI-S is a 1-item measure that assesses the patient’s impression of disease severity based on 
their present diabetes symptoms, i.e., normal, mild, moderate, or severe, whereas the PGI-C 
assesses the patient’s impression of changes in diabetes symptoms, based on their diabetes 
symptoms now, compared with how they were before they began taking the study drug, i.e., very 
much better, much better, a little better, no change, a little worse, much worse, or very much 
worse. The PGI-S will be administered at the randomization visit and the PGI-C will be 
administered at the year 1 and year 2 dedicated study visits. 
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5.3.2 Clinician Global Impression of Disease Severity (CGI-S) and Clinician Global 
Impression of Change (CGI-C) 
The CGI-S is a 1-item measure that assesses the clinician’s impression of the patient’s disease 
severity, based on the patient’s present diabetes symptoms, i.e., normal, mild, moderate, or 
severe, whereas the CGI-C assesses the clinician’s impression of change in the patient’s diabetes 
symptoms, based on the patient’s diabetes symptoms now, compared with how they were before 
they began taking the study drug, i.e., very much better, much better, a little better, no change, a 
little worse, much worse, or very much worse. The study physician will complete the CGI-S at 
the randomization visit and the CGI-C at the year 1 and year 2 dedicated study visits. 
5.4 
Study Period 
Patients will be followed from randomization to end of study (EOS) at 2 years, during which 
study physicians or trained site personnel will collect study data and record it in the eCRF at 
dedicated study visits (randomization, year 1, year 2) and routine care visits. Patients will be 
followed for the full 2 year study period regardless of treatment changes or discontinuation 
during the study period, other than withdrawal of consent. If a patient leaves the 
 health 
plan network during the 2 year study period, administrative claims data will be collected from 
randomization through the date they leave the health plan. In this scenario, site-based study data 
collection will continue without change. 
On-study data collection at dedicated study visits and routine care visits (if available per local 
clinical practice) will include: clinical data (weight, HbA1c, SBP, DBP), treatment details (study 
drug, other antidiabetic medication, pre-specified concomitant medications related to 
cardiovascular risk, reasons for treatment discontinuation as applicable), hypoglycemia leading 
to inpatient admission or ER encounter, AEs leading to study drug discontinuation, pregnancy, 
and serious adverse events (SAEs). Additionally, PRO and ClinRO instruments will be 
completed at randomization, year 1, and year 2.  
EOS visit is 2 years (±6 weeks) after randomization. 
5.5 
Administrative Claims Data – HIRDSM
In addition to prospectively collected clinical data and PROs, this study will also utilize claims 
data from the HIRD for all study patients. Data collected will include integrated medical claims, 
pharmacy claims, and health plan eligibility files for the 2 years after the respective patient’s 
study randomization. Extraction of this data will take place approximately 3 months after the last 
patient’s last visit (LPLV) to allow for data lags in the claims. Administrative claims data will 
also be collected for up to 12 months prior to study randomization, if available. The 
prospectively collected eCRF study data and claims data will be merged into one dataset via a 
study-specific patient identifier (ID) for analysis. 
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5.6 
Withdrawals 
5.6.1 Physician Practices 
Novo Nordisk and/or the Institutional Review Board (IRB) reserve the right to terminate the 
study any time. In this event, all data collection will end. After the collected data is received, 
study physicians will be compensated as contractually agreed. 
The IRB reserves the right to terminate participation of individual study sites at any time. 
Individual study sites may also be terminated for cause by Novo Nordisk per contractual 
agreement. In such cases, all data collection at terminated study sites will end. After the collected 
data is received, the study physicians will be compensated as contractually agreed. 
5.6.2 Patients 
Participation in the study is voluntary, and all patients are free to terminate their participation at 
any time. A patient will only be withdrawn from the study if they withdraw consent. In the event 
of study withdrawal, the study physician will record the reason for study withdrawal and 
continue to follow-up with the patient for any unresolved SAEs or pregnancies, if patient agrees. 
Upon patient 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 
Introduction 
Patients are randomized 1:1 to semaglutide or SOC. The data analyses for this study will be 
outlined in further detail in a Statistical Analysis Plan (SAP) developed prior to database lock at 
year 1. 
For continuous endpoints and categorical endpoints derived from continuous sources, the 
baseline value is defined as the last assessment taken prior to or at the randomization visit and 
before first use of study drug. 
If endpoint data is missing then any routine care data that are collected within ±10 weeks of the 
dedicated study visit will be used. 
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 semaglutide as compared to SOC (excluding semaglutide).  
The primary estimand for all objectives will be the “intention-to-treat” (ITT) estimand evaluating 
the effectiveness of randomized treatment intervention irrespective of adherence to this 
randomized intervention or changes to other antidiabetic medication during follow-up. The 
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purpose of this estimand is to quantify the expected effect size in the commercially-insured 
health plan population upon adoption of semaglutide as compared SOC (excluding semaglutide), 
and is as such relevant to inform and support appropriate market access and population based 
treatment guidance. 
The secondary estimand for all objectives with the exception of the adherence and persistence to 
treatment objective, is the “if all patients had adhered” estimand. This estimand evaluates the 
effect of randomized treatment intervention for all randomized patients if all patients had 
adhered to randomized treatment, regardless of changes to other (i.e., non-study drug) 
antidiabetic medication. The purpose of this estimand lies in quantifying the expected effect size 
for an individual patient in the commercially-insured health plan population who is prescribed, 
initiates, and continues treatment with semaglutide as compared to SOC (excluding 
semaglutide). The relevance of this effect measure is to inform decision making for individual 
patients and prescribing physicians. 
6.1.2 Confirmatory Endpoints and Hypotheses 
The primary endpoint is HbA1c <7.0% (53 mmol/mol) at year 1 (yes/no). This is a binary 
endpoint. Confirmatory secondary endpoints include:  
 Change in HbA1c (%-point) from baseline to year 1 
 HbA1c <7.0% (53 mmol/mol) at year 2 (yes/no) 
 Change in HbA1c (%-point) from baseline to year 2 
The primary and confirmatory endpoints will all be tested for superiority under multiplicity 
control via a hierarchical testing scheme according to the order given in the above bullet list. 
Confirmatory testing will only be performed for the primary estimand with the secondary 
estimand being supportive. The testing procedure will be stopped the first time an analysis fails 
to confirm superiority of the endpoint in question using a two-sided significance level of 5%. 
Superiority on HbA1c <7.0% will be evaluated with respect to the odds ratio (OR) (odds 
semaglutide / odds SOC): 
H0: OR≤1 against Ha: OR>1 
Superiority on change in HbA1c (year 1 – baseline; year 2 – baseline) will be evaluated with 
respect to the mean treatment difference (TD) (semaglutide – SOC):  
H0: TD≥0 against Ha: TD<0 
6.1.3 Study Populations 
The following analysis set will be defined: 
Full analysis set (FAS): Includes all randomized patients analyzed according to the treatment 
group to which they were assigned at randomization. 
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6.2 
Sample Size Determination  
6.2.1 Power and Sample Size for Primary Objective 
Assumptions for the sample size were based on input from the HIRD claims/laboratory results 
database. In line with the primary ITT estimand, the assumptions for the proportion of patients 
with HbA1c < 7.0% at year 1 and year 2, and for the change from baseline in HbA1c, were based 
on the claims/laboratory results data within the 
 population for all patients initiating 
treatment intensification, regardless of whether patients adhered to this treatment. Specifically, 
for semaglutide, assumptions were based on data for liraglutide and dulaglutide. For SOC, 
assumptions were based on all intensifications in the claims database. The study sample size of 
2,250 was calculated based on the following assumptions, informed from HIRD data: 10% 
difference in proportion patients with HbA1c < 7.0% at year 1 and year 2 (60% semaglutide 
versus 50% SOC), absolute difference in change from baseline HbA1c of 0.5%-point (SD=2.3%) 
between treatment groups, 90% power, and an overall alpha leve1 of 5%. Sample size 
calculations, including different sample size scenarios and a summary of the data from the 
HIRD, will be documented in the SAP. 
The proportion of missing data for the confirmatory endpoints was estimated to be 25% after one 
year and 44% after two years. In the sample size calculation, it was assumed that only non-
missing data at year 1 and year 2 would be used for the respective analyses. This is considered 
conservative, since the use of imputed data in the actual primary analysis (see 6.3) will increase 
the power. When accounting for missing data, randomizing 2250 patients will contribute 1687 
patients for the year 1 analyses and 1260 patients for the year 2 analyses, achieving a total power 
of 90% for confirming all 4 confirmatory hypotheses. The corresponding marginal powers for 
presence of HbA1c < 7.0% at year 1, change in HbA1c to 1 year, presence of HbA1c < 7.0% at 
year 2, and change in HbA1c to 2 years are 99%, 99%, 95%, and 97% respectively. 
6.3 
Statistical Analysis for the Primary Estimand 
The primary estimand will be estimated based on the FAS using data from all patients with 
observations at the dedicated study visit (year 1 for the primary endpoint), with the exception of 
patients who, in violation of the protocol, have initiated semaglutide in the SOC treatment group. 
The data collected following initiation of semaglutide from these patients will be censored and 
imputed together with missing data. The primary endpoint, HbA1c < 7.0%, will be analyzed with 
a logistic regression model with a logit link function, treatment as a categorical effect, and 
baseline HbA1c as covariate. From the model, the estimated OR (semaglutide versus SOC) will 
be presented. The underlying continuous endpoint of change in HbA1c will be analyzed using 
analysis of covariance (ANCOVA) that will include the same independent variables. From the 
model, the estimated mean difference in change from baseline to dedicated study visit 
(semaglutide versus SOC) will be presented. The estimated treatment effect from each of these 
analyses will be complemented with associated 95% confidence interval (CI) and two-sided p-
value for testing the null-hypothesis of no difference.  
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Prior to analysis, missing data will be imputed by multiple imputation on the continuous HbA1c 
scale and subsequently dichotomized for the primary endpoint. 500 complete data sets will be 
generated to adequately account for the uncertainty due to missing data. Missing endpoint data 
will be imputed separately by treatment group and based on patients who remained in the study 
according to study drug treatment status, i.e., according to whether these patients are on or off 
study drug at the dedicated study visit. Data will be imputed based on the assumption that, within 
treatment groups, patients with missing endpoint data will behave like patients with the same 
study drug treatment status at endpoint as the missing patients’ last registered treatment status 
prior to the missing endpoint. For example, for patients withdrawing from the study with an “off 
study drug” treatment status, data will be imputed based on the assumption that the withdrawn 
patients will behave like patients who remain in the study but are not receiving study drug at the 
dedicated study visit. Technically, the imputation model will be an ANCOVA for the endpoint 
data. The ANCOVA will include baseline HbA1c, diabetes duration, age, and sex as independent 
variables. After this model has been used to predict missing values, each of the now 500 
complete data sets will be analyzed as described above. Finally, the multiple analysis results will 
be combined using Rubin’s rule. [14] For the OR the results will be combined on the logarithm 
scale.   
Superiority for the primary endpoint, HbA1c <7.0% at year 1, will be considered established if 
the OR 95% CI is greater than 1, or similarly if the two-sided p-value is significant on a 5% level 
and the treatment OR is in favor of semaglutide. 
If the hierarchical testing scheme allows, superiority for change from baseline to dedicated study 
visit in HbA1c will be considered established if the 95% CI for the estimated treatment 
difference is smaller than 0, or similarly if the two-sided p-value is significant on a 5% level and 
the treatment difference is in favor of semaglutide. 
6.4 
Statistical Analysis for the Secondary Estimand 
The secondary estimand will be estimated based on the FAS. The analysis is similar to the 
primary analysis for the primary endpoint, but varies with regards to the data used and the 
imputation of missing data. Specifically, data will only be used from the subset of patients who 
are receiving study drug at the dedicated study visit (year 1 for the primary endpoint), in order to 
estimate the treatment effect if all patients had continued treatment. Patients who no longer are 
receiving study drug will be censored and imputed together with missing data. The same will 
apply to patients who, in violation of the protocol, have initiated semaglutide in the SOC group. 
Collectively, missing and censored data will be imputed separately by treatment group based on 
all patients who are on study drug at the dedicated study visit. Data will be imputed based on the 
assumption that withdrawn or censored patients behave like patients that remain in the study and 
continue on study drug. 
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The technical aspects of missing data imputation based on multiple imputation, the statistical 
analysis of the multiple complete data sets, and combination of the multiple results will be the 
same as that described for the primary estimand. 
6.5 
Supplementary Analyses 
The HbA1c analyses described for the two estimands above will be complemented with two 
complete case analyses based on the subset of patients without missing endpoint data, i.e., 
patients that do not have their endpoint imputed in the two analyses used for the primary and 
secondary estimand.  
Complete case analysis 
This analysis will be based only on patients with available measurements at the dedicated study 
visit including measurements irrespective of whether patients discontinued study drug or not. 
The analysis will use the same analysis model as described under the primary estimand. 
Complete case on-study drug analysis 
The analysis will be based only on patients with available measurements at the dedicated study 
visit including only measurements for patients still on study drug. The analysis will use the same 
analysis model as described under the primary estimand. 
6.6 
PRO Analysis 
PRO and physician assessments will be measured with the instruments described in Section 5.3. 
Analysis of these measures will address the secondary objective of this study to compare 
semaglutide versus SOC in the study’s patient population as is relates to PRO, i.e., treatment 
satisfaction, generic health outcomes, work productivity, and patient and physician global 
assessment measures, over one and two year observation periods. PRO analysis will 
descriptively summarize these measures at baseline, year 1, and year 2, as well as compare 
semaglutide versus SOC for change from baseline to year 1 and year 2. The continuous change 
from baseline endpoints will be analyzed using the same analysis approach as described under 
the primary estimand, secondary estimand, and supplementary analysis section. Details will be 
fully described in the SAP. 
6.7 
Safety Analysis 
SAEs and AEs will be collected as described in Section 7. No formal safety analyses are planned 
for this study. SAEs, AEs leading to study drug discontinuation, and pregnancies will be coded 
using Medical Dictionary for Regulatory Activities (MedDRA) and descriptively summarized by 
System Organ Class and Preferred Term (PT). 
6.8 
Other Analyses 
The following analyses are planned to further support the primary objective to compare 
semaglutide versus SOC in glycemic control. They will also address the secondary objectives of 
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this study to compare semaglutide versus SOC in the study’s patient population over one and two 
year observation periods as is relates to body weight loss, hypoglycemia, HCRU, and adherence 
and persistence to treatment. The binary and continuous endpoints will be analyzed using the 
same analysis approach as described under the primary estimand, secondary estimand, and 
supplementary analysis sections. Further details of these analyses and details for analyses of 
other endpoint types will be fully described in the SAP. 
6.8.1 Supportive Analyses of Glycemic Control 
The proportion of patients achieving the secondary endpoints related to glycemic control at year 
1 as defined in section 3.3.2 (individualized HbA1c target, HbA1c <7.0% (53mmol/mol) or at 
least 1% point improvement in HbA1c from baseline, HbA1c target attainment per HEDIS 
criteria) will be compared between semaglutide and SOC treatment groups using the same 
analysis approach as described under the primary estimand, secondary estimand, and 
supplementary analysis sections. 
Additionally, derived outcome variables for supportive measures of glycemic control (Appendix 
2) will be utilized to support these analyses.
6.8.2 Weight Loss 
Change in patient weight from baseline to year one will be calculated in pounds and percentage 
as defined in section 3.3.2. Mean change in weight will be compared between semaglutide and 
SOC treatment groups using the same analysis approach as described under the primary 
estimand, secondary estimand, and supplementary analysis sections. 
Additionally, derived outcome variables for supportive measures of body weight loss (Appendix 
2) will be utilized to support these analyses.
6.8.3 Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) 
Change in patient SBP and DBP from baseline to year 1 and baseline to year 2 will be calculated 
as defined in section 3.3.2 and Appendix 2. Mean change in SBP and DBP will be compared 
between semaglutide and SOC treatment groups using the same analysis approach as described 
under the primary estimand, secondary estimand, and supplementary analysis sections. 
6.8.4 Hypoglycemia 
The number of hypoglycemic episodes leading to an inpatient admission or ER encounter will be 
reported by patients and compared by semaglutide and SOC treatment groups utilizing a negative 
binomial model. 
Additionally, derived outcome variables for supportive measures of hypoglycemia (Appendix 2) 
will be utilized to support these analyses. 
6.8.5 Healthcare Resource Utilization (HCRU) 
HCRU analyses will compare all-cause and diabetes-related HCRU (inpatient admissions, ER 
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encounters, outpatient encounters, and pharmacy utilization) as defined in section 3.3.2 from the 
HIRD by semaglutide and SOC treatment group from baseline to year 2.   
The details of claims data definitions and calculations will be fully described in the SAP. 
6.8.6 Adherence and Persistence to Treatment 
Adherence and persistence to the study drug will be calculated and compared between 
semaglutide and SOC treatment groups. 
Medication adherence refers to a patient’s conformance to the provider’s recommendation with 
respect to timing, dosage, and frequency of medication taken during the prescribed length of 
time. In claims, adherence is typically measured using either medication possession ratio (MPR) 
or proportion of days covered (PDC). 
Medication persistence refers to whether a patient stays on therapy or the time from initiation to 
discontinuation of therapy. In claims, persistence is typically defined as the duration of time from 
initiation of the therapy to discontinuation or switching, whichever comes first. 
Adherence and persistence will be further defined in the SAP.  
6.8.7 Antidiabetic Treatment Patterns 
Antidiabetic treatment patterns will be assessed and compared between semaglutide and SOC 
treatment groups. This analysis will summarize the number and classification type of antidiabetic 
medications taken during the study period.  
6.8.8 Exploratory Predictive Analysis 
An exploratory predictive analysis will be performed within and between the semaglutide and 
SOC treatment groups to identify predictors of treatment adherence and persistence and glycemic 
control. The objectives of the exploratory predictive analyses are to identify within and between 
treatment groups: 1) patients less likely to discontinue treatment and 2) patients more likely to 
reach clinical target.  
6.8.9 Evaluation of the Study Population 
To evaluate the generalizability of the study results, an analysis of the study population will be 
performed. The primary objective of this analysis is to evaluate the external validity of the study 
and to understand how the study population fits into the larger T2DM populations within study 
sites and 
 as a whole. Two claims-based T2DM patient populations will be described and 
compared to the study population: (1) commercially-insured 
 T2DM patients treated with 
metformin who undergo an antidiabetic treatment intensification, and (2) within the study sites, 
commercially-insured 
 T2DM patients treated with metformin who are not enrolled in 
the study, but who undergo an antidiabetic treatment intensification. The analysis will compare 
the demographics, HCRU, and HbA1c between the study population and the two comparator 
populations during the 12 month period prior to randomization (for study population) or prior to 
a claims-based proxy for antidiabetic treatment intensification index date (for comparators). 
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Additionally, treatment patterns of non-enrolled T2DM patients within the practices from which 
the study patients are recruited will be evaluated to identify any relevant patterns of care 
suggesting channeling of certain types to patients away from the study. These analyses will help 
to contextualize study results within the T2DM population broadly. 
The details of this analysis will be fully described in the SAP. 
  
7 
Adverse Event Collection 
The principal study physician is responsible for monitoring the safety of participating patients. 
All SAEs reported by the patients during the study observational period are required to be 
documented on the appropriate SAE reporting form. For the purposes of this study, AEs that do 
not meet the definition of SAE will only be collected if they lead to study drug discontinuation. 
7.1 
Adverse Events 
An AE is defined as any untoward medical occurrence in a patient administered a pharmaceutical 
product or medical device, which does not necessarily have to have a causal relationship to the 
product of device. Study physicians will follow AEs that occur in any patient during this study in 
a manner consistent with routine clinical practice. For the purposes of this study, AEs that do not 
meet the definition of an SAE (section 7.2) will only be collected in the eCRF if they lead to 
study drug discontinuation. 
7.2 
Serious Adverse Events 
All AEs meeting the definition of SAE will be collected in the eCRF. SAEs will be reported 
from the time a patient is randomized until EOS at year 2, or until the patient withdraws from the 
study. An SAE is defined as any AE which results in at least one of the following outcomes: 
 Initial inpatient admission or prolongation of existing inpatient admission 
 A life-threatening event, i.e., an event in which the patient 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 
 Persistent or significant disability or incapacity 
 Congenital anomaly or birth defect in offspring 
 Death 
 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 patient and may require 
medical or surgical intervention to prevent one of the other listed outcomes. 
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7.2.1 Collection Period of Serious Adverse Events 
SAEs will be reported from the time a patient is randomized until EOS at year 2, or until the 
patient withdraws from the study. The principal study physician 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 patient 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. 
At each visit (both routine care visits and dedicated study visits), patients will be asked about 
AEs including hypoglycemic events, e.g. “Have you experienced any problems since the last 
contact?” 
If an investigator becomes aware of SAEs after EOS at year 2 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 patients 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 patient is randomized until EOS at year 2 or until 
the patient withdraws from the study. The principal study physician is responsible for alerting 
Novo Nordisk or its designee to any drug exposure during pregnancy within 14 days of the first 
knowledge of the pregnancy via the pregnancy reporting form. The study physician will follow 
the patient for the duration of the pregnancy. 
7.4 
Technical Complaints 
Technical complaints may be reported as per usual practice. However, any SAEs resulting from a 
technical complaint must be reported via EDC. 
8 
DATA COLLECTION 
8.1 
Data Sources 
Data sources include primary data collected prospectively by study sites at study visits 
(demographic and clinical data, patient-completed PRO data, and physician reported global 
assessments) as well as secondary data collection utilizing administrative claims data from the 
HIRD.  In order to maintain patient confidentiality, each patient will be assigned a unique patient 
study ID number upon signing informed consent to use in place of patient name or any other 
identifying information (e.g., medical record number). Clinical study data, PROs/ClinROs and 
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claims-derived variables will be integrated into one analysis dataset via this confidential patient 
ID. 
8.2 
Electronic Case Report Forms (eCRFs) 
All clinical study data will be collected at the physician office and entered into eCRF by trained 
site study personnel through a fully validated, 21 CFR 11 and HIPAA compliant EDC system.  
Patients 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.  
Some clinical assessments utilized in this study may be completed in the course of routine 
clinical practice by site personnel not affiliated with study (e.g., blood pressure), however any 
activities completed solely for the study (e.g., data entry, PRO administration) must be done by 
trained site study personnel. For example, a nurse not affiliated with the study may measure 
blood pressure as part of routine care. The data from this assessment may be used for this study, 
but must be extracted from the patient’s medical record and entered into the eCRF by trained site 
study personnel.  
The principal study physician has the ultimate responsibility for the collection and reporting of 
all clinical and patient data through the eCRFs, as well as ensuring that they are accurate and 
complete to the extent possible. 
8.3 
Year One Database Lock 
The primary analysis for this study is a year 1 analysis. Once data collection for year 1 has 
completed, a database lock and year 1 analysis will be performed. The year 1 analysis will not be 
integrated with HCRU and will be limited to year 1 endpoints derived from eCRF data, including 
PRO data. To maintain study integrity for the remaining study period, data from year 1 will be 
used for limited and confidential communications while complying with public disclosure 
requirements. All other analyses will be conducted following a second database lock once data 
collection for the entire study is 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 physician 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 patients as well as the scientific integrity of the study. Site monitoring will be 
conducted by 
staff.  
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9.1.1 Institutional Review Board (IRB) 
The principal study physician will have prospective IRB approval of the study protocol, ICF, and 
any patient information or recruiting materials prior to commencement of any study activities at 
their site. In the case of a protocol amendment, the study physician 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 patients or others must be reported to the IRB as 
required. 
The principal study physician 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. The principal study physician must 
ensure that each study patient is informed of the study and authorizes release of health 
information prior to study-related activities. The study physician, or study personnel designated 
by the study physician, will obtain written informed consent from each patient prior to initiation 
of any study-related procedures. Each patient will be given a copy of the signed ICF. The 
principal study physician will retain the original signed ICF for each patient. 
The IRB must prospectively approve the ICF and any changes to the ICF during the course of the 
study before use. If a protocol amendment increases the potential risk to the patient, 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 patients entering the study as well as 
from currently enrolled patients 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 principal study physician must agree 
to maintain and allow access to required patient and study records. The principal study physician 
agrees to keep the identity of all participating patients (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). The principal study physician should retain records according 
to local regulations, or as specified in the Clinical Study Agreement, whichever is longer. 
 
10 
PUBLICATION OF STUDY RESULTS 
All information related to this study is considered confidential information belonging to Novo 
Nordisk and 
 as consistent with contractual agreement. A final study report will be 
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generated following completion of data collection and analysis. Results and findings will be 
submitted to conferences and for publication in peer-reviewed scientific journals with authorship 
following the International Committee of Medical Journal Editors (ICMJE) guidelines. 
Information regarding the study will be disclosed at clinicaltrials.gov and novonordisk-
trials.com. 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 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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REFERENCES 
[1] International Council for Harmonisation of Technical Requirements for Pharmaceuticals
for Human Use, "ICH Harmonised Draft Guidline: Estimands and Sensitivity Analysis in
Clinical Trials E9(R1)," 2017.
[2] S. Izzucchi, R. Bergentstal, J. Buse and e. al., "Management of hyperglyacaemia in type 2
diabetes, 2015: a patient-centred approach. Update to a position statement of the American
Diabetes Association and the European Association for the Study of Diabetes,"
Diabetologia, vol. 58, no. 3, pp. 429-442, 2015.
[3] American Diabetes Association, "Diabetes advocacy. Sec. 15 In Standards of Medical Care
in Diabetes - 2016," Diabetes Care, vol. 40, no. Suppl. 1, pp. S128-S129, 2016.
[4] Investigator's Brochure for s.c. Semaglutide (NN9535), Edition 12 or any updates hereof.
2017.
[5] Health AwpfI: Why pharma needs to work differently with payers and INDs on RWE:
Learnings from recent survey and symposium..
[6] "Standards of Medical Care in Diabetes-2017: Summary of Revisions," Diabetes Care, vol.
40, no. Suppl 1, pp. S4-S5, 2017.
[7] T. Wasser, J. Ycas and O. Tunceli, "Applying Weighting Methodologies to a Commercial
Database to Project US Census Demographic Data," The American Journal of Accountable
Care, 2015.
[8] C. Bradley, "The Diabetes Treatment Satisfaction Questionnaire: DTSQ," in Handbook of
Psychology and Diabetes: a guide to psychological measurement in diabetes research and
practice, C. Bradley, Ed., Abingdon, Routledge, 1994, pp. 111-132.
[9] C. Bradley, "The Diabetes Treatment Satisfaction Questionnaire (DTSQ): change version
for use alongside status version provides appropriate solution where ceiling effects occur,"
Diabetes Care, vol. 22, no. 3, pp. 530-532, 1999.
[10] C. Bradley, "Patient perceptions of diabetes and diabetes therapy: assessming quality of
life," Diabetes Metabolism Research and Reviews, vol. 18, pp. S64-S69, 2002.
[11] C. Bradley, R. Plowright, J. Stewart, J. Valentine and E. Witthaus, "The Diabetes
Treatment Satisfaction Questionnaire change version (DTSQc) evaluated in insulin
glargine trials shows greater responsiveness to improvements than the original DTSQ,"
Health and Quality of Life Outcomes, vol. 5, no. 5, p. 57, 2007.
[12] J. Ware, M. Kosinski and S. Keller, "A 12-item short-form health survey: construction of
scales and preliminary tests of reliability and validity," Med Care, vol. 34, no. 3, pp. 220-
233, 1996.
[13] M. Reilly, A. Zbrozek and E. Dukes, "The validity and reproducibility of a work
productivity and activity impairment instrument," PharmacoEconomics, vol. 4, no. 5, pp.
353-365, 1993.
[14] R. Little and D. Rubin, Statistical analysis with missing data., J. Wiley, Ed., New York:
John Wiley and Sons, 1987.
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Appendix 1: Time and Events Schedule  
Study NN9535‐4416 
Dedicated Study visit, 
Randomization 
Routine Care  visits, 
Year 1 
Dedicated Study visit, 
Year 1 
Routine Care visits, 
Year 2 
Dedicated Study visit, 
Year 2 
Time of visit (Weeks)a
0* 
0‐52** 
52±6 
52‐104** 
104±6 
PATIENT AND TREATMENT RELATED ASSESSMENTSb 
Informed consentc
X
Inclusion/Exclusion criteria 
X
Demographics (date of birth, gender, race, 
ethnicity) 
X
Selected medical history 
X
Diabetes history and diabetes 
complications 
X
Individualized HbA1c targetd 
X
Type of glucose‐lowering medication 
including semaglutide 
X 
X 
X 
X 
X 
Concomitant cardiovascular medication
X 
X 
X 
X 
X 
Reason for discontinuation of any glucose 
lowering medication 
X 
X 
X 
X 
EFFECTIVENESS AND SAFETY RELATED ASSESSMENTS 
Body weight 
X 
X 
X
X 
X 
Height 
X
SBP / DBP 
X 
X 
X
X 
X 
HbA1c
Xe 
X 
X
X 
X
SAEs, pregnancies, and AEs leading to 
study drug discontinuation 
X 
X 
X 
X 
Healthcare resource utilizationf
X 
X 
X 
X 
Hypoglycemia leading to inpatient 
admission or ER encounter
X 
X 
X 
X 
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Study NN9535‐4416 
Dedicated Study visit, 
Randomization 
Routine Care  visits, 
Year 1 
Dedicated Study visit, 
Year 1 
Routine Care visits, 
Year 2 
Dedicated Study visit, 
Year 2 
PROs and Physician Completed Assessments 
DTSQs 
X
DTSQc
X
X 
SF‐12v2 
X
X
X 
WPAI‐GH 
X
X
X 
PGI‐S
X
PGI‐C
X
X 
CGI‐S 
X
CGI‐C
X
X 
END OF STUDY 
End of study
 
X 
* Eligibility assessment may take place up to 4 weeks prior to the randomization visit. If eligibility assessment
occurs prior to the randomization visit, any changes in collected medical history, diabetes history, diabetes
complications, glucose lowering medications and concomitant cardiovascular mediations will be collected at the
randomization visit.
** The year 1 and year 2 routine care visit windows are determined by the date of the patient’s dedicated year 1
study visit. The year 1 routine care visit window will end immediately prior to the dedicated year 1 study visit. The
year 2 routine care visit window will begin immediately following the dedicated year 1 study visit.
Note: In this study, data will be collected from two different data sources: 
1)
Data entered into the eCRF will be collected at dedicated study visits and routine care visits (if available
per local clinical practice) and will include: demographics, selected medical history, diabetes medical
history and diabetes complications, individualized HbA1c target, type of glucose-lowing medication,
concomitant cardiovascular medication, reason for discontinuation of any glucose lowering medication,
body weight, height, SBP, DBP, HbA1c, AEs leading to study drug discontinuation, SAEs, pregnancies and
hypoglycemia leading to inpatient admission or ER encounter. Additionally, PRO and ClinRO data will be
collected at the dedicated study visits and entered into the eCRF.
2)
Healthcare resource utilization and pharmacy prescription data will be extracted from the HIRD and will
not be entered into the eCRF.
a Routine care visits will follow standard of care frequency and any available data will be entered in the eCRF. 
b Assessments at dedicated study visits will be collected in eCRF. Assessments at routine care visits will be collected 
as available/according to local clinical practice in eCRF.  
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c Informed consent must be obtained before any study related activities. 
d Individualized HbA1c target must be set and documented prior to randomization. 
e The HbA1c value is based on historical data collected from the study physician and is the value closest to the date 
of randomization, within the last 90 days. 
f Data from the HIRD. Data will be extracted from the HIRD at the end of the study, but will include data from 
patient randomization through EOS or withdrawal. 
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Appendix 2: Additional Derived Outcome Variables for Supportive Analyses 
Supportive Measures of Glycemic Control 

Individualized HbA1c target attained at year 2 (yes/no)

HbA1c <7.0% (53 mmol/mol) or at least 1% point improvement in HbA1c compared to
baseline at year 2 (yes/no)

HbA1c <8.0% (64 mmol/mol) at year 1 (yes/no)

HbA1c <8.0% (64 mmol/mol) at year 2 (yes/no)

HbA1c <7.0% (53 mmol/mol) and no further antidiabetic medication intensification after
randomization at year 1 (yes/no)

HbA1c <7.0% (53 mmol/mol) and no further antidiabetic medication intensification after
randomization at year 2 (yes/no)

HbA1c target attainment per HEDIS criteria (<8.0% if age ≥65 years or with defined
comorbidities, otherwise <7.0%) at year 2 (yes/no)

HbA1c <7.0% (53 mmol/mol) at year 1 in patients with HbA1c >9.0% at baseline
(yes/no)

HbA1c <7.0% (53 mmol/mol) at year 2 in patients with HbA1c >9.0% at baseline
(yes/no)

HbA1c <8.0% (64 mmol/mol) at year 1 in patients with HbA1c >9.0% at baseline
(yes/no)

HbA1c <8.0% (64 mmol/mol) at year 2 in patients with HbA1c >9.0% at baseline
(yes/no)
Body Weight Loss 

Change in body weight (%) from baseline to year 2

Change in body weight (lb) from baseline to year 2
Blood Pressure 

Change in SBP (mm Hg) from baseline to year 2

Change in DPB (mm Hg) from baseline to year 2
Hypoglycemia 

Reported hypoglycemia leading to inpatient admission or ER encounter during year 1
(yes/no)
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
Reported hypoglycemia leading to inpatient admission or ER encounter during year 2
(yes/no)
Composite Variables 

HbA1c <7.0% (53 mmol/mol) without experiencing hypoglycemia leading to inpatient
admission or ER encounter and body weight loss of  ≥5% vs baseline at year 1 (yes/no)

Absolute HbA1c reduction of ≥0.5% without experiencing hypoglycemia leading to
inpatient admission or ER encounter and a body weight loss of  ≥5% vs baseline at year 1
(yes/no)

HbA1c <7.0% (53 mmol/mol) without experiencing hypoglycemia leading to inpatient
admission or ER encounter and body weight loss of  ≥5% vs baseline at year 2 (yes/no)

Absolute HbA1c reduction of ≥0.5% without experiencing hypoglycemia leading to
inpatient admission or ER encounter and a body weight loss of  ≥5% vs baseline at year 2
(yes/no)

HbA1c <7.0% (53 mmol/mol) without experiencing hypoglycemia leading to inpatient
admission or ER encounter and no body weight gain vs baseline at year 1 (yes/no)

HbA1c <7.0% (53 mmol/mol) without experiencing hypoglycemia leading to inpatient
admission or ER encounter and no body weight gain vs baseline at year 2 (yes/no)
Adherence to Treatment 

Study drug medication adherence for the two years of the study, as measured by the
medication possession ratio (MPR)
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Appendix 3: Patient Reported Outcome Additional Information 
DTSQc 
The DTSQc provides a measure of how satisfied patients are with their current diabetes 
treatment compared with previous treatment. It consists of 8 questions, which are to be answered 
on a Likert scale from -3 to +3 (-3 = much less satisfied now to +3 = much more satisfied now), 
with 0 (midpoint), representing no change. Six questions are summed to produce a Total 
treatment satisfaction score. The remaining two questions concern perceived frequency of 
hyperglycemia and perceived frequency of hypoglycemia, respectively. The DTSQc Total 
treatment satisfaction score ranges from -18 to +18, with higher scores associated with greater 
treatment satisfaction. 
SF-12 v2 
The SF-12v2 is a 12-item generic health-related quality of life measure that assesses physical and 
mental functioning. The items will be scored using the scoring software that will be provided 
with the license. The following two summary scores are used as endpoints: Physical Component 
Summary (PCS) Score and Mental Component Summary (MCS) Score. The scores are norm-
scored such that the scores range from 0-100 with a mean of 50 and standard deviation of 10.  A 
higher score is associated with better quality of life and a lower score, poorer quality of life.  
WPAI-GH 
The WPAI-GH yields four types of scores: Absenteeism (work time missed), Presenteesism 
(impairment at work / reduced on-the-job effectiveness), Work productivity loss (overall work 
impairment / absenteeism plus presenteeism), and Activity Impairment. WPAI outcomes are 
expressed as percentages, with higher numbers indicating greater impairment and less 
productivity, i.e., worse outcomes (percent work time missed due to health, percent impairment 
while working due to health, percent overall work impairment due to health, percent activity 
impairment due to health). 
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16.1.1.2 Protocol Amendments 
Novo Nordisk          
 
 
 
 
 
 
 
Protocol No. NN953-4416
          
 
 
 
 
 
 
 
 
 
UTN: U1111-1207-6474
Clinical Study Report       
 
 
Confidential       
 
 
Appendix 16.1.1
Version 1.0; March 31, 2023
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PROTOCOL No. NN9535-4416 – Novo Nordisk Semaglutide Study 
UTN: U1111-1207-6474 
Long term comparative effectiveness of once weekly 
semaglutide versus standard of care in a real world adult US 
population with type 2 diabetes - a randomized pragmatic 
clinical trial 
Trial ID NN9535-4416 
Novo Nordisk 
March 27, 2019 
Version 2.0 
Trial Phase: 4 
Investigational Substance: Semaglutide 
 
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Principal Study Physician Agreement: 
I have read the protocol “Long term comparative effectiveness of once weekly semaglutide 
versus standard of care in a real world adult US population with type 2 diabetes - a randomized 
pragmatic clinical 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 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 
PRINCIPAL STUDY PHYSICIAN AGREEMENT ................................................................. 3 
TABLE OF CONTENTS ............................................................................................................. 4 
SYNOPSIS ..................................................................................................................................... 7 
LIST OF ABBREVIATIONS .................................................................................................... 11 
LIST OF DEFINITIONS ........................................................................................................... 14 
1 
INTRODUCTION............................................................................................................... 16 
1.1 
Background and Rationale .............................................................................................................................. 16 
2 
STUDY OBJECTIVES ....................................................................................................... 17 
2.1 
Primary Objective ............................................................................................................................................... 17 
2.2 
Secondary Objectives ........................................................................................................................................ 17 
3 
STUDY ENDPOINTS ......................................................................................................... 17 
3.1 
Baseline .................................................................................................................................................................. 17 
3.2 
Primary Endpoint ............................................................................................................................................... 17 
3.3 
Secondary Endpoints ......................................................................................................................................... 18 
3.3.1 
Confirmatory Secondary Endpoints .............................................................................................................................. 18 
3.3.2 
Supportive Secondary Endpoints ................................................................................................................................... 18 
3.3.3 
Exploratory Endpoints ........................................................................................................................................................ 20 
4 
STUDY DESIGN ................................................................................................................. 20 
4.1 
Overview ................................................................................................................................................................ 20 
4.2 
Practice and Patient Selection ........................................................................................................................ 21 
4.2.1 
Physician Practice Eligibility ............................................................................................................................................ 21 
4.2.2 
Patient Recruitment and Eligibility ............................................................................................................................... 21 
4.2.3 
Patient Inclusion Criteria ................................................................................................................................................... 22 
4.2.4 
Patient Exclusion Criteria .................................................................................................................................................. 22 
4.2.5 
Patient Enrollment ................................................................................................................................................................ 22 
4.2.6 
Patient Randomization ........................................................................................................................................................ 22 
5 
STUDY PROCEDURES .................................................................................................... 23 
5.1 
Enrollment Procedures..................................................................................................................................... 23 
5.2 
Randomization Visit .......................................................................................................................................... 24 
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5.2.1 
Patient Characteristics ........................................................................................................................................................ 24 
5.2.2 
Treatments ............................................................................................................................................................................... 24 
5.3 
Patient Reported Outcomes, Clinician Reported Outcomes, and Diabetes Treatment 
Satisfaction ........................................................................................................................................................................... 27 
5.3.1 
PRO and Treatment Satisfaction questionnaires ..................................................................................................... 27 
5.3.1.1 
Diabetes Treatment Satisfaction Questionnaire (DTSQ) [8] [9] [10] [11] ....................................... 27 
5.3.1.2 
Short Form 12-Item version 2 (SF-12 v2) Health Survey [12] .............................................................. 27 
5.3.1.3 
Work Productivity and Activity Impairment: General Health (WPAI-GH) Questionnaire [13]
27 
5.3.1.4 
Patient Global Impression of Disease Severity (PGI-S) and Patient Global Impression of 
Change (PGI-C) ................................................................................................................................................................................... 27 
5.3.2 
Clinician Global Impression of Disease Severity (CGI-S) and Clinician Global Impression of Change 
(CGI-C) 28 
5.4 
Study Period ......................................................................................................................................................... 28 
5.5 
Administrative Claims Data – HIRDSM .......................................................................................................... 28 
5.6 
Withdrawals ......................................................................................................................................................... 29 
5.6.1 
Physician Practices ............................................................................................................................................................... 29 
5.6.2 
Patients ....................................................................................................................................................................................... 29 
6 
STATISTICAL METHODS .............................................................................................. 29 
6.1 
Introduction ......................................................................................................................................................... 29 
6.1.1 
Estimands .................................................................................................................................................................................. 29 
6.1.2 
Confirmatory Endpoints and Hypotheses .................................................................................................................. 30 
6.1.3 
Study Populations .................................................................................................................................................................. 30 
6.2 
Sample Size Determination ............................................................................................................................. 31 
6.2.1 
Power and Sample Size for Primary Objective ......................................................................................................... 31 
6.3 
Statistical Analysis for the Primary Estimand ........................................................................................... 31 
6.4 
Statistical Analysis for the Secondary Estimand ...................................................................................... 32 
6.5 
Supplementary Analyses .................................................................................................................................. 33 
6.6 
PRO Analysis ........................................................................................................................................................ 33 
6.7 
Safety Analysis ..................................................................................................................................................... 33 
6.8 
Other Analyses ..................................................................................................................................................... 33 
6.8.1 
Supportive Analyses of Glycemic Control ................................................................................................................... 34 
6.8.2 
Weight Loss .............................................................................................................................................................................. 34 
6.8.3 
Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) ............................................................... 34 
6.8.4 
Hypoglycemia .......................................................................................................................................................................... 34 
6.8.5 
Healthcare Resource Utilization (HCRU) .................................................................................................................... 35 
6.8.6 
Adherence and Persistence to Treatment .................................................................................................................. 35 
6.8.7 
Antidiabetic Treatment Patterns .................................................................................................................................... 35 
6.8.8 
Exploratory Predictive Analysis ...................................................................................................................................... 35 
6.8.9 
Evaluation of the Study Population ............................................................................................................................... 35 
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7 
ADVERSE EVENT COLLECTION................................................................................. 36 
7.1 
Adverse Events .................................................................................................................................................... 36 
7.2 
Serious Adverse Events ..................................................................................................................................... 36 
7.2.1 
Collection Period of Serious Adverse Events ............................................................................................................ 37 
7.3 
Pregnancy .............................................................................................................................................................. 37 
7.3.1 
Reporting Period of Pregnancy ....................................................................................................................................... 37 
7.4 
Technical Complaints ........................................................................................................................................ 37 
8 
DATA COLLECTION ....................................................................................................... 37 
8.1 
Data Sources ......................................................................................................................................................... 37 
8.2 
Electronic Case Report Forms (eCRFs) ........................................................................................................ 38 
8.3 
Year One Database Lock ................................................................................................................................... 38 
9 
STUDY MANAGEMENT .................................................................................................. 38 
9.1 
Regulatory and Ethical Consideration ......................................................................................................... 38 
9.1.1 
Institutional Review Board (IRB) ................................................................................................................................... 39 
9.1.2 
Informed Consent .................................................................................................................................................................. 39 
9.2 
Record Retention and Access .......................................................................................................................... 39 
10  PUBLICATION OF STUDY RESULTS .......................................................................... 40 
11  INDEMNIFICATION ........................................................................................................ 40 
REFERENCES ............................................................................................................................ 41 
APPENDIX 1: TIME AND EVENTS SCHEDULE ................................................................ 42 
APPENDIX 2: ADDITIONAL DERIVED OUTCOME VARIABLES FOR SUPPORTIVE 
ANALYSES ................................................................................................................................. 45 
APPENDIX 3: PATIENT REPORTED OUTCOME ADDITIONAL INFORMATION .... 47 
SUMMARY OF AMENDMENTS AND UPDATES ............................................................... 48 
 
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SYNOPSIS 
 
Title: Long term comparative effectiveness of once weekly semaglutide versus standard of care in a 
real world US adult population with type 2 diabetes – a randomized pragmatic clinical trial 
Sponsor: Novo Nordisk 
Study Treatment: Semaglutide in a prefilled pen (Ozempic®) 
Active Ingredient: Semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1 RA) 
Comparator Treatment: Standard of Care (SOC) (excluding semaglutide) 
Trial ID:  NN9535-4416 
Study Physician Sites: Participation of approximately 285 physician sites, including both primary 
care practitioners and endocrinologists, that have a population of patients with the target indication, 
type 2 diabetes mellitus (T2DM), actively enrolled in an 
 affiliated commercial health plan. 
Country: United States (US) 
Patients: Eligible patients include adult T2DM patients on up to 2 oral antidiabetic medications whose 
physician deems that they have inadequate glycemic control and need treatment intensification with an 
additional antidiabetic oral or injectable medication. 
Planned enrollment in this study is 2250. Patients will be randomized 1:1 to receive either semaglutide 
or SOC.  
Study Objectives: The objectives of this study are as follows: 
1.) The primary objective is to demonstrate superior long term effects of treatment with 
semaglutide compared to SOC both added to up to 2 oral antidiabetic medications on glycemic 
control when used as intensification in routine clinical practice in adult patients with T2DM. 
2.) The secondary objectives are to compare the long term effect of semaglutide versus SOC both 
added to up to 2 oral antidiabetic medications and used as intensification in routine clinical 
practice in adult patients with T2DM with regards to: 
a. Weight loss 
b. Patient reported outcomes (PROs) and clinician reported outcomes (ClinROs) 
c. Hypoglycemia  
d. Healthcare Resource Utilization (HCRU) 
e. Adherence and persistence to treatment 
Study Design: This is a 2-year, multi-center, randomized, open label, parallel group, active comparator 
pragmatic clinical trial (PCT) comparing semaglutide versus SOC when added to up to 2 oral 
antidiabetic medications as treatment intensification among adult T2DM patients in the course of 
routine clinical practice. Patients will be randomized 1:1 to receive either semaglutide or SOC. The 
decision that further antidiabetic treatment intensification with oral or injectable antidiabetic 
medication is indicated is at the discretion of the study physician and will be made prior to and 
independent of enrollment in this study. The study physician will have determined the patient’s 
suitability for treatment with semaglutide prior to signing informed consent, but the determination to 
initiate semaglutide versus SOC will be made by randomization. 
In keeping with the study objectives and pragmatic design to evaluate semaglutide versus SOC in real 
world, routine clinical practice, inclusion and exclusion criteria are minimally restrictive and there are 
few study-specific evaluations. Study physicians will follow and treat patients according to their 
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routine clinical practice and judgement. All oral and injectable antidiabetic medications are allowed at 
the study physicians' discretion, with the exception of semaglutide in the SOC group. Patients will be 
followed for 2 years, regardless of changes in antidiabetic treatment over the course of the study. 
It is anticipated that patients will undergo medical evaluation at regular intervals over the course of the 
study duration as per standard of care, but the only dedicated study visits are at randomization, at year 
1, and at year 2. The study will also capture clinical data collected at the sites during routine care visits, 
i.e., office visits and other patient contacts that occur as part of routine clinical practice. Assessments 
will be conducted according to the study physician’s routine clinical practice, with a few study-specific 
assessments as outlined in Study Procedures. Additionally, medical and pharmacy claims data will be 
captured utilizing the HealthCore Integrated Research Database (HIRDSM) for the 2 year study period. 
HIRD data for the 12 months prior to randomization will also be collected if available. 
Participant Selection: 
Inclusion Criteria:   
Patients 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. 
2.) Male or female, age ≥ 18 years at the time of signing informed consent. 
3.) Type 2 diabetes mellitus diagnosis. 
4.) Treatment with either 1 or 2 oral antidiabetic medications. 
5.) Current member of an 
 affiliated commercial health plan with pharmacy benefits. 
6.) Recorded glycosylated hemoglobin A1c (HbAlc) value within the last 90 days prior to 
randomization. 
7.) Further intensification with an additional antidiabetic oral or injectable medication is indicated 
to achieve glycemic target at the discretion of the study physician according to approved 
labelling. 
Exclusion Criteria: 
Patients presenting with any of the following exclusion criteria will not be eligible for the study: 
1.) Previous randomization in this study. 
2.) Treatment with more than 2 oral antidiabetic medications or any injectable medication in a 
period of 30 days before the day of eligibility assessment. Temporary/emergency use of any 
type of insulin is allowed, as is prior insulin treatment for gestational diabetes.  
3.) Contraindications to semaglutide according to the FDA approved label. 
4.) Female who is pregnant, breastfeeding or intends to become pregnant. 
5.) Participation in another clinical trial. 
Study Procedures: 
 
Study physicians will identify eligible patients for participation. 
 
Study physicians will obtain written informed consent from patients and if eligible, patients 
will be randomized to either semaglutide or SOC. 
 
Study data will be collected on electronic Case Report Forms (eCRFs) via an electronic data 
capture (EDC) system. 
 
Study physicians or site personnel will collect demographic, clinical (i.e., height, weight, 
systolic blood pressure (SBP), diastolic blood pressure (DBP)), medical and T2DM specific 
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history, antidiabetic medications, and pre-specified concomitant medications related to 
cardiovascular risk data prior to or at randomization. Individualized HbA1c target will be set 
prior to randomization. 
 
Baseline HbA1c will be collected from physician sites during eligibility assessment and will 
be the value closest to the date of randomization, within 90 days. All post-randomization 
HbA1c values will be recorded as available per routine clinical practice during the 2 year study 
period. Post-randomization HbA1c values are required for the year 1 and year 2 dedicated 
study visits. 
 
PROs and ClinROs will be completed at randomization, year 1, and year 2. 
 
Study physicians will collect patient data (HbA1c, study and antidiabetic medication changes, 
pre-specified concomitant medications related to cardiovascular risk, weight, SBP, DBP, 
hypoglycemic events leading to inpatient admission or emergency room (ER) encounter, 
adverse events (AEs) leading to study drug discontinuation, serious adverse events (SAEs), 
and pregnancies at the dedicated year 1 and year 2 study visits, as well as at any routine care 
visits during the 2 year study period. 
 
Administrative medical claims, pharmacy claims and health plan eligibility data will be 
captured from the HIRD for the duration of the 2 year study period. HIRD data for the 12 
months prior to study randomization will also be collected if available. This data will be used 
for HCRU measures, as well as adherence and persistence to treatment.  
Study Duration: Planned patient time on study will be 2 years. Administrative claims data will also 
be captured during this time period. Patients will be followed for the full 2 year study period regardless 
of changes in or discontinuation of antidiabetic treatment, other than withdrawal of consent. 
Questionnaires: Diabetes treatment satisfaction, generic health-related quality of life (HRQoL), work 
productivity, and patient and clinician global assessments will be measured at the randomization, year 
1, and year 2 dedicated study visits. 
Statistical Analysis: Two estimands, each targeting a unique research question, have been defined to 
adequately describe the effect of semaglutide as compared to SOC (excluding semaglutide).  
The primary estimand for all objectives will be the “intention-to-treat” estimand evaluating the 
effectiveness of randomized treatment intervention, irrespective of adherence to this randomized 
intervention or changes to other antidiabetic medication. 
The secondary estimand for all objectives, with the exception of the adherence and persistence to 
treatment objective, is the “if all patients had adhered” estimand. This estimand evaluates the effect of 
randomized treatment intervention for all randomized patients if all patients had adhered to randomized 
treatment, regardless of changes to other antidiabetic medication. 
Baseline is defined as ≤ 90 days prior to randomization visit (week 0) for HbA1c. For secondary 
endpoint assessments, baseline is defined as ≤ 4 weeks prior to the randomization visit (week 0). 
Primary completion date (PCD) is the date the last patient completes the year 1 dedicated study visit. 
The primary endpoint is binary, with success represented by an HbA1c <7.0% (53 mmol/mol) at year 
1 (yes/no). Confirmatory secondary endpoints include:  
 
Change in HbA1c (%-point) from baseline to year 1 
 
HbA1c <7.0% (53 mmol/mol) at year 2 (yes/no) 
 
Change in HbA1c (%-point) from baseline to year 2 
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This study is designed to have 90% power to jointly confirm superiority of the primary endpoint and 
the above three confirmatory secondary endpoints based on an analysis of the primary estimand for 
each of the endpoints.    
The confirmatory endpoints will all be tested under multiplicity control via a hierarchical testing 
scheme according to the order given in the above bullet list. 
The estimand informs choices about data foundation and statistical analysis including possible 
imputation of missing data, hereby ensuring that randomization is preserved as a sound basis for 
statistical inference; i.e., estimation of effect size, associated uncertainty, and statistical testing.  
The full analysis set (FAS) comprising all randomized patients will be the analysis population for 
evaluation of both the primary and secondary estimands. For both estimands, the primary endpoint, 
HbA1c <7.0%, will be analyzed using a logistic regression model with a logit link function and will 
include treatment and baseline HbA1c as independent variables. Continuous endpoints will be analyzed 
using analysis of covariance (ANCOVA) and will include the same independent variables. Prior to 
analysis, missing data will be imputed by multiple imputation on the continuous HbA1c scale and 
subsequently dichotomized for the primary endpoint. 
Supplementary Analyses: Two complete case analyses will complement the analyses for the primary 
and secondary estimands. The supplementary complete case analyses will be based on the subset of 
patients without missing endpoint data, i.e., patients that do not have their endpoint imputed in the two 
analyses used for the primary estimand and the secondary estimand, respectively.    
Secondary Analyses: Secondary analyses will compare semaglutide versus SOC treatment groups in 
terms of change in body weight, SBP, DBP, and PRO and ClinRO measures, based on the similar 
analysis methods as for the primary and secondary estimands. Similarly, binary endpoints and other 
secondary endpoints will be compared statistically between treatment groups, including HCRU and 
adherence/persistence to treatment measures, hypoglycemic events leading to inpatient admission or 
ER encounter, as well as composite measures of HbA1c, weight loss, and hypoglycemia. 
Safety: The principal study physician is responsible for monitoring the safety of participating patients. 
For the purposes of this study, AEs that do not meet the definition of an SAE will only be 
collected/recorded in the EDC if they lead to study drug discontinuation. Study physicians are 
responsible for reporting all SAEs and following the patient until the outcome of the SAE is closed 
out. All SAEs will be reported from randomization until end of study (EOS) at year 2 or patient study 
withdrawal. Study physicians are also responsible for recording all pregnancies in female patients from 
randomization until EOS at year 2 or patient study withdrawal. The patient 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  
ADA 
American Diabetes Association 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
eCCGs 
Electronic Case Report Form Completion Guidelines 
CFR 
Code of Federal Regulations 
CGI-C 
Clinical Global Impression of Change 
CGI-S 
Clinician Global Impression of Disease Severity 
CI 
Confidence Interval 
ClinRO 
Clinician Reported Outcome 
eCRF 
Electronic Case Report Form 
DBP 
Diastolic Blood Pressure 
DPP-4 
Dipeptidyl peptidase 4 
DTSQ 
Diabetes Treatment Satisfaction Questionnaire 
DTSQc 
Diabetes Treatment Satisfaction Questionnaire, change version 
DTSQs 
Diabetes Treatment Satisfaction Questionnaire, status version 
EASD 
European Association for the Study of Diabetes 
EDC 
Electronic Data Capture 
EOS 
End of Study 
ER 
Emergency Room 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FDC 
Fixed Dose Combination 
GCP 
Good Clinical Practice 
GLP-1 RA 
Glucagon-Like Peptide-1 Receptor Agonists 
HbA1c 
Glycosylated Hemoglobin A1c 
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HCRU 
Healthcare Resource Utilization 
HEDIS 
Healthcare Effectiveness Data and Information Set 
HIRDSM 
HealthCore Integrated Research Database 
HIPAA 
Health Insurance Portability and Accountability Act 
HRQoL 
Health-Related Quality of Life 
ICF 
Informed Consent Form 
ICMJE 
International Committee of Medical Journal Editors 
ID 
Identifier 
IRB 
Institutional Review Board 
ITT 
Intent to Treat 
LPLV 
Last Patient Last Visit 
MedDRA 
Medical Dictionary for Regulatory Activities 
MCS-12 
Mental Summary Component (of the Short Form 12-Item version 2) 
MPR 
Medication Possession Ratio 
OR 
Odds Ratio 
PCD 
Primary Completion Date 
PCS-12 
Physical Summary Component (of the Short Form 12-Item version 2) 
PCT 
Pragmatic Clinical Trial 
PDC 
Proportion Days Covered 
PGI-C 
Patient Global Impression of Change 
PGI-S 
Patient Global Impression of Disease Severity 
PRO 
Patient Reported Outcome 
PT 
Preferred Term 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
SD 
Standard Deviation 
SF-12v2 
Short Form 12-Item version 2 
SGLT-2 
Sodium-Glucose Co-transporter 2 
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SM 
Service Mark 
SOC 
Standard of Care 
SUSTAIN 
Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes 
T2DM 
Type 2 Diabetes Mellitus 
TD 
Treatment Difference 
US 
United States 
WPAI-GH 
Work Productivity and Activity Impairment, General Health 
 
 
 
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LIST OF DEFINITIONS 
 
Term 
Definition  
Administrative Claims 
Data 
Medical, pharmacy, and health plan eligibility data created in the 
processing of medical and pharmacy claims. The claims data utilized in 
this study are obtained from the HealthCore Integrated Research 
Database (HIRD). 
Baseline 
Baseline refers to assessments conducted and patient data collected at 
or prior to randomization. Baseline HbAlc may be ≤ 90 days prior to 
randomization. Baseline for secondary endpoint assessments may be ≤ 
4 weeks prior to randomization. 
Baseline Endpoint 
For continuous endpoints and endpoints derived from continuous 
sources, the baseline value is defined as the last assessment taken prior 
to or at the randomization visit and before first use of study drug. 
Comparator Treatment 
Standard of Care (SOC) (excluding semaglutide); Commercially 
available oral or injectable antidiabetic medication, excluding 
semaglutide, prescribed at the discretion of the study physician for 
antidiabetic treatment intensification following randomization. 
Complete the Study 
Complete the study at 52 weeks: Patient has year 1 HbA1c data 
Complete the study at 104 weeks: Patient has year 2 HbA1c data 
Dedicated Study Visit 
One of three required study visits: randomization, year 1, and year 2. 
Enrollment 
Randomization 
Estimand 
The estimate targeted to address the research question posed by the 
study objective, i.e., “what is to be estimated.” [1] The estimand 
translates the study objective into a precise definition of the effect of 
treatment. 
Healthcare Resource 
Utilization (HCRU) 
Broad term encompassing use of healthcare services, including 
inpatient admissions, ER encounters, outpatient encounters including 
office visits, and pharmacy prescription fills. 
Index Date 
The date corresponding to an event of interest. In this study, index date 
is the date corresponding to a claims-based proxy for antidiabetic 
treatment intensification for 2 comparator populations, thus mimicking 
randomization date in the study population. 
Principal Study 
Physician 
Physician at study site who is responsible for the overall conduct and 
oversight of the study at their site, including: supervision of study 
personnel, monitoring the safety of all participating patients, ensuring 
the accurate and complete collection and reporting of study data, 
continued review of the IRB study approval, and maintenance of study 
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records. This term is analogous to “Investigator” in Good Clinical 
Practice (GCP) requirements.  
Randomization 
The point at which a patient is assigned by chance to either semaglutide 
or standard of care (SOC). 
Routine Care Visit 
An office visit or other patient contact during the study period that 
occurs outside of the dedicated study visits (randomization, year 1, and 
year 2) according to routine clinical practice. 
Study Physician 
Physician at study site who participates in the conduct of the study. 
Study/Trial 
For the purposes of this protocol, study and trial are considered 
synonyms. Study is used throughout the body of the text as it reflects 
the post-regulatory approval setting and real world design. Trial is used 
in the title and in referring to the PCT acronym to maintain consistency 
with the industry standard Pragmatic Clinical Trial or PCT.  
Study Drug 
Study drug is the first antidiabetic oral or injectable medication 
prescribed for treatment intensification following randomization. A 
patient can start and stop study drug throughout the study. At any time 
during the duration of the study, if a patient is taking study drug as 
defined, they will be considered “on study drug” regardless of prior 
study drug discontinuations. 
 For the semaglutide treatment group, study drug is defined as 
semaglutide. 
 For the SOC treatment group, study drug is defined as the drug class 
of the first antidiabetic oral or injectable medication prescribed for 
treatment intensification following randomization. If a fixed dose 
combination (FDC) product is prescribed, one of the drugs will be 
chosen by the study physician to be the study drug. A patient 
randomized to the SOC treatment group will still be considered “on 
study drug” if they are taking a drug in the same drug class as their 
first study drug, even if it is not the same individual drug. This also 
applies to treatment intensification with a FDC product if one of the 
drugs is in the same drug class as the first study drug. 
Study Drug 
Discontinuations 
Study drug discontinuation is termination of the study drug. A patient 
can start and stop study drug throughout the study; therefore a patient’s 
study drug discontinuation status can change throughout the duration of 
the study. At any time during the duration of the study, if a patient is 
not taking study drug as defined, they will be considered “off study 
drug.” 
 
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1 
INTRODUCTION 
1.1 
Background and Rationale 
The American Diabetes Association (ADA) and European Association for the Study of Diabetes 
(EASD) position statement recommends a patient-centric approach to the selection of 
pharmacological treatment for type 2 diabetes mellitus (T2DM), including considerations on 
effectiveness, hypoglycemia risk, impact on body weight, side effects, costs, and patient 
preferences. [2] Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are recommended for 
the management of hyperglycemia in T2DM, primarily in combination with other antidiabetic 
medications. [2] [3] 
Semaglutide, a human GLP-1 analogue for once-weekly subcutaneous administration, has been 
shown to improve glycemic control in adults with T2DM as monotherapy when the use of 
metformin is considered inappropriate, or as add-on to other glucose lowering therapies 
including insulin. In the Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes 
(SUSTAIN) clinical development program, semaglutide demonstrated clinically relevant and 
superior glycemic control, as well as weight loss versus placebo and active comparators, both 
when used as mono- and combination therapy in inadequately controlled patients with T2DM. In 
addition, a significant reduction in cardiovascular risk was demonstrated for semaglutide versus 
placebo in patients with T2DM at high risk of cardiovascular events. The overall safety profile of 
semaglutide was consistent with the well-established GLP-1 RA safety profile. [4] 
Pragmatic clinical trials (PCTs) are designed and conducted to reflect patient outcomes and to 
investigate how a product is used and performs in routine clinical practice. This type of study 
compares two or more medical interventions that are directly relevant to clinical care and strives 
to assess those interventions’ effectiveness in real world practice. They use broad eligibility 
criteria and recruit patients from a variety of practice settings to ensure the inclusion of the type 
of patients whose care will be influenced by the study´s results. Such studies are increasingly 
important to generate evidence regarding real world treatment outcomes to inform and support 
appropriate market access. [5] 
The current local US study serves the purpose of evaluating the long term comparative 
effectiveness of semaglutide with existing commercially available antidiabetic medications in a 
real world population and in a variety of practice settings, thereby maximizing external validity 
while balancing the internal validity of a randomized controlled trial. This will generate data to 
complement the findings from the SUSTAIN clinical development program. Taken together, 
these findings may provide important evidence for decision making by clinicians, payers, and 
policy makers in routine clinical practice. 
This local US study will enroll adult patients with T2DM who have inadequate glycemic control 
on up to 2 oral antidiabetic medications, as defined by the need for treatment intensification with 
an additional antidiabetic oral or injectable medication per the study physician´s discretion. The 
current study targets patients at this particular treatment point because they represent the 
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population inadequately controlled on the current ADA recommended first lines of treatment of 
T2DM. The addition of a GLP-1 RA as second-line treatment is in line with the ADA guidance 
from 2017. [6] In keeping with the ADA and EASD position statement recommending a patient-
centric approach to treatment selection for T2DM patients, in addition to comparative 
effectiveness, this study will also evaluate hypoglycemia risk, body weight, healthcare resource 
utilization (HCRU), patient reported outcomes (PROs), and clinician reported outcomes 
(ClinROs). Adverse events (AEs) leading to study drug discontinuation will also be collected. [2] 
  
2 
STUDY OBJECTIVES  
2.1 
Primary Objective 
The primary objective is to demonstrate superior long term effects of treatment with semaglutide 
compared to standard of care (SOC) both added to up to 2 oral antidiabetic medications on 
glycemic control when used as intensification in routine clinical practice in adult patients with 
T2DM.  
2.2 
Secondary Objectives 
The secondary objectives are to compare the long term effect of semaglutide versus SOC both 
added to up to 2 oral antidiabetic medications and used as intensification in routine clinical 
practice in adult patients with T2DM with regards to: 
 Weight loss 
 Patient reported outcomes (PROs) and clinician reported outcomes (ClinROs) 
 Hypoglycemia  
 Healthcare Resource Utilization (HCRU) 
 Adherence and persistence to treatment 
  
3 
STUDY ENDPOINTS 
3.1 
Baseline 
Baseline is defined as ≤ 90 days prior to randomization visit (week 0) for glycosylated 
hemoglobin A1c (HbA1c). For secondary endpoint assessments, baseline is defined as ≤ 4 weeks 
prior to the randomization visit (week 0). 
3.2 
Primary Endpoint 
Primary completion date (PCD) is the date the last patient completes the year 1 dedicated study 
visit. 
The primary endpoint of this study is: 
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 HbA1c <7.0% (53 mmol/mol) at year 1 (yes/no) 
3.3 
Secondary Endpoints 
3.3.1 Confirmatory Secondary Endpoints 
Confirmatory secondary endpoints of this study include: 
 Change in HbA1c (%-point) from baseline to year 1 
 HbA1c <7.0% (53 mmol/mol) at year 2 (yes/no)  
 Change in HbA1c (%-point) from baseline to year 2 
3.3.2 Supportive Secondary Endpoints 
Supportive secondary endpoints of this study include: 
 Individualized HbA1c target attained at year 1 (yes/no) 
 HbA1c <7.0% (53mmol/mol) or at least 1% point improvement in HbA1c compared to 
baseline at year 1 (yes/no) 
 HbA1c target attainment per Healthcare Effectiveness Data and Information Set (HEDIS) 
criteria (<8.0% if age ≥65 years or with defined comorbidities, otherwise <7.0%) at year 
1 (yes/no) 
 Change in body weight (lb) from baseline to year 1 
 Change in body weight (%) from baseline to year 1 
 Change in systolic blood pressure (SBP; mm Hg) from baseline to year 1 
 Change in diastolic blood pressure (DBP; mm Hg) from baseline to year 1 
 Time to first study drug discontinuation during 2 years (day) 
 Time to first treatment intensification (add-on) or change (switch) after randomization 
during 2 years (day) 
 Study drug medication adherence for the first year of the study, as measured by 
medication possession ratio (MPR) (%) 
 Number of hypoglycemic episodes leading to an inpatient admission or emergency room 
(ER) encounter from baseline to year 2 
 Diabetes Treatment Satisfaction Questionnaire, change version (DTSQc), Total treatment 
satisfaction score measured at year 1 
 DTSQc, Total treatment satisfaction score measured at year 2 
 Change from baseline in Short Form 12-Item Version 2 Survey (SF-12 v2), Physical 
summary component (PCS-12) score at year 1 
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 Change from baseline in SF-12 v2, PCS-12 score at year 2 
 Change from baseline in SF-12 v2, Mental summary component (MCS-12) score at year 
1 
 Change from baseline in SF-12 v2, MCS-12 score at year 2 
 Change from baseline in Work Productivity and Activity Impairment, General Health 
questionnaire (WPAI-GH) Absenteeism (work time missed) score at year 1 
 Change from baseline in WPAI-GH Absenteeism (work time missed) score at year 2 
 Change from baseline in WPAI-GH Presenteeism (impairment at work / reduced on-the-
job effectiveness) score at year 1 
 Change from baseline in WPAI-GH Presenteeism (impairment at work / reduced on-the-
job effectiveness) score at year 2 
 Change from baseline in WPAI-GH Work productivity loss (overall work impairment / 
absenteeism plus presenteeism) score at year 1 
 Change from baseline in WPAI-GH Work productivity loss (overall work impairment / 
absenteeism plus presenteeism) score at year 2 
 Change from baseline in WPAI-GH Activity Impairment score at year 1 
 Change from baseline in WPAI-GH Activity Impairment score at year 2 
All cause healthcare resource utilization (HCRU) from baseline to year 2: 
 Number of inpatient admissions 
 Cumulative length of stay for inpatient admissions (days) 
 Number of ER encounters 
 Number of outpatient encounters 
 Number of medications 
 Occurrence of inpatient admission (yes/no) 
 Occurrence of ER encounter (yes/no) 
 Occurrence of outpatient encounter (yes/no) 
Diabetes related HCRU from baseline to year 2: 
 Number of diabetes related inpatient admissions 
 Cumulative length of stay for diabetes related inpatient admissions (days) 
 Number of diabetes related ER encounters 
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 Number of diabetes related outpatient encounters 
 Number of diabetes related medications 
 Occurrence of diabetes related inpatient admission (yes/no) 
 Occurrence of diabetes related ER encounter (yes/no) 
 Occurrence of diabetes related outpatient encounter (yes/no) 
3.3.3 Exploratory Endpoints 
Not applicable. 
  
4 
STUDY DESIGN 
4.1 
Overview 
This is a 2-year, multi-center, randomized, open label, parallel group, active comparator PCT 
comparing semaglutide versus SOC when added to up to 2 oral antidiabetic medications as 
treatment intensification among adult T2DM patients in the course of routine clinical practice. 
Patients will be randomized 1:1 to receive either semaglutide or SOC. 
The decision that further antidiabetic treatment intensification with an additional oral or 
injectable antidiabetic medication is indicated is at the discretion of the study physician and will 
be made prior to and independent of enrollment in this study. The study physician will have 
determined the patient’s suitability for treatment with semaglutide prior to inviting them to 
participate in the study. However, the determination to initiate semaglutide versus SOC will be 
made by randomization.  
Patients will be followed for 2 years, regardless of changes in antidiabetic treatment over the 
course of the study. Data collection will continue for the full 2 year study period unless a patient 
withdraws informed consent. Patients who enroll in the study agree to the release of health 
information, and to answer questions about their health during the course of the study. 
Additionally, medical and pharmacy claims data will be extracted for the 2 year study period, as 
well as up to 12 months prior to randomization as available. 
In keeping with the study objectives and pragmatic design to evaluate semaglutide versus SOC in 
real world, routine clinical practice, inclusion and exclusion criteria are minimally restrictive and 
there are few study-specific evaluations. Study physicians will follow and treat patients 
according to their routine clinical practice and judgement. All oral and injectable antidiabetic 
medications are allowed at the study physicians' discretion, with the exception of semaglutide in 
the SOC group. It is anticipated that patients will undergo medical evaluation at regular intervals 
over the course of the study duration as per standard of care, but the only dedicated study visits 
are at randomization, at year 1, and at year 2. The study will also capture clinical data collected 
at the sites during routine care visits, i.e., office visits and other patient contacts that occur as part 
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of routine clinical practice. Assessments will be conducted according to the study physician’s 
routine clinical practice, with a few study-specific assessments as described in section 5. The 
data available may differ from site to site and patient to patient. To ensure flexibility, the 
dedicated year 1 and year 2 study visits have a window of ±6 weeks. 
4.2 
Practice and Patient Selection 
The target population for this study consists of adult, commercially-insured, T2DM patients on 
up to 2 oral antidiabetic medications who are in need of treatment intensification with an 
additional antidiabetic oral or injectable medication. Physician practice and participant eligibility 
criteria were guided by feasibility data from the HealthCore Integrated Research Database 
(HIRDSM) prior to protocol development. 
Physician sites recruited for the study will be those who provide care for members of 
 
health plans, one of the largest healthcare insurance providers in the US. 
 provides 
medical coverage for roughly 1 in 8 Americans, and although this is mostly concentrated in the 
employer-supported, commercially-insured market, the data in the HIRD are overall 
representative of the entire US population. [7] Study site recruitment will target both primary 
care practitioners and specialized endocrinologists to reflect diverse treatment settings and 
patient populations. Potential sites will be evaluated regarding feasibility of their participation in 
the study, including having a T2DM population of 
 members to meet enrollment goals, 
based on the initial data analysis from the HIRD. Potential sites will be tiered based on their 
estimated number of eligible study patients, and outreach will begin with all sites that meet a pre-
determined minimum number of potentially eligible patients. Outreach and follow-up will be 
performed until the requisite number of physician sites is enrolled. Study-specific assessments 
have been kept to a minimum, thereby decreasing burden on study sites and increasing 
participation to a wide range of sites. 
4.2.1 Physician Practice Eligibility 
Participation of approximately 285 physician sites in the US, including both general practitioners 
and endocrinologists that have a T2DM population, is anticipated. Physician sites will be limited 
to those that participate in the care of patients who are actively enrolled in an
 
 
 health plan (hence forth referred to as 
 health plans). 
4.2.2 Patient Recruitment and Eligibility 
Eligible patients include adult T2DM patients whose physicians determine that they have 
inadequate glycemic control on 1 or 2 oral antidiabetic medications. Inadequate glycemic control 
is defined by the need for T2DM treatment intensification with an additional antidiabetic oral or 
injectable medication, as determined by the study physician. Patients 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 a broad population of adult T2DM patients 
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to generate data in a population that reflects the heterogeneity of a real world population treated 
in general practice, and support the study objectives to evaluate semaglutide versus SOC in real 
world, routine clinical practice. 
4.2.3 Patient Inclusion Criteria 
Patients 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. 
2. Male or female, age ≥ 18 years at the time of signing informed consent. 
3. Type 2 diabetes mellitus diagnosis. 
4. Treatment with either 1 or 2 oral antidiabetic medications. 
5. Current member of an 
 affiliated commercial health plan with pharmacy benefits. 
6. Recorded HbAlc value within last 90 days prior to randomization. 
7. Further intensification with an additional antidiabetic oral or injectable medication is 
indicated to achieve glycemic target at the discretion of the study physician according to 
approved labelling. 
4.2.4 Patient Exclusion Criteria 
Patients presenting with any of the following exclusion criteria will not be eligible for the study: 
1. Previous randomization in this study. 
2. Treatment with more than 2 oral antidiabetic medications or any injectable antidiabetic 
medication in a period of 30 days before the day of eligibility assessment. 
Temporary/emergency use of any type of insulin is allowed, as is prior insulin treatment 
for gestational diabetes.  
3. Contraindications to semaglutide according to the FDA approved label. 
4. Female who is pregnant, breastfeeding or intends to become pregnant. 
5. Participation in another clinical trial. 
4.2.5 Patient Enrollment 
Planned number of patients to be randomized: 2250 
Expected number of patients to complete the study after 52 weeks: 1687 
Expected number of patients to complete the study after 104 weeks: 1260 
4.2.6 Patient Randomization 
Study patients will be randomized to either semaglutide or SOC in a 1:1 ratio. The study design 
and patient randomization is depicted in Figure 1. 
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Figure 1 Study design diagram. Patients will be randomized in a 1:1 manner using centralized 
allocation to receive semaglutide or SOC as add-on to up to 2 oral antidiabetic medications.  
 
5 
STUDY PROCEDURES 
The study visit schedule is summarized in Appendix 1. 
5.1 
Enrollment Procedures 
The determination that a patient has inadequate glycemic control on up to 2 oral antidiabetic 
medications, and the subsequent decision to intensify antidiabetic treatment with an additional 
oral or injectable antidiabetic medication, will be made by the study physician during the course 
of routine clinical practice. Following the decision to initiate treatment intensification, the study 
physician will determine the patient’s suitability for the study. Suitability for the study will be 
assessed using the current inclusion and exclusion criteria, including the approved label for 
semaglutide. Only patients who are eligible for treatment intensification and have been found 
suitable for treatment with semaglutide, as determined by the study physician, are in scope for 
randomization. Prior to being randomized, patients must be willing to intensify with an 
antidiabetic medication, including GLP-1 receptor agonists. Study physicians will set and 
document an individualized HbA1c target for patients prior to randomization based on their 
clinical judgement and knowledge of the patient. To preserve the real-world nature of the study, 
patients will be approached for potential enrollment into the study when they present to their 
physician as part of their standard care. 
Informed consent will be obtained prior to any study related activities. The most recent HbA1c 
completed in the course of routine care up to 90 days prior to and including the date of 
randomization will be considered a baseline assessment and does not need to be repeated. 
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Study physicians or site personnel will collect patient characteristics and study data at each study 
visit as outlined in the Time and Events Schedule (Appendix 1), either directly from the patient 
or abstracted from the patient’s medical records, and enter them into the electronic Case Report 
Form (eCRF). 
5.2 
Randomization Visit 
Following informed consent and confirmation of inclusion/exclusion criteria, patients will be 
randomized to either semaglutide or SOC. Data collection at the randomization visit will include 
inclusion/exclusion criteria as well as the data outlined in the sections below. PRO and ClinRO 
questionnaires will also be administered (section 5.3). 
5.2.1 Patient Characteristics 
Baseline assessments at the randomization visit will include: demographic data, medical history, 
diabetes history including antidiabetic medications and diabetes complications, pre-specified 
concomitant medications related to cardiovascular risk, and clinical data (weight, height, HbA1c, 
SBP, DBP). Individualized HbA1c target will be set prior to randomization. The baseline HbA1c 
will be the patient’s most recent HbA1c within 90 days of randomization. 
5.2.2 Treatments 
To preserve the real-world nature of the study, the patient experience will be as close to routine 
care as possible. The study physician will be one of the patient’s own treating physicians, who 
may make treatment adjustments according to their clinical judgement. The study physician can 
make repeat prescriptions of the study drug as usual, which are collected by patients from the 
pharmacy of their choice. Patients will be randomized to either semaglutide or SOC. Treatment 
details will be recorded in the eCRF. 
Semaglutide Group 
Patients randomized to the semaglutide group will be prescribed commercially available 
semaglutide in a prefilled pen injector and will be instructed to initiate treatment with 
semaglutide according to the approved label. The study physician will determine the intended 
maintenance dose of semaglutide, as well as changes to the maintenance dose thereafter. Add-on, 
discontinuation or dose modification of antidiabetic medication, including semaglutide, during 
the study is allowed at the discretion of the study physician. 
Semaglutide Study Drug: For patients randomized to the semaglutide group, study drug is 
defined as semaglutide. 
SOC Group 
SOC is defined as commercially available oral or injectable antidiabetic medication (see current 
representative list below) other than semaglutide. Patients randomized to SOC will be prescribed 
and instructed to initiate commercially available antidiabetic medication according to the 
approved label and, if relevant for the specific antidiabetic medication, adjusted at the discretion 
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of the study physician. Patients randomized to SOC may discontinue SOC, add-on to the SOC or 
switch to another antidiabetic medication during the study, with the exception of semaglutide 
which is not allowed in the SOC group for the duration of the study. 
SOC Study Drug: For patients randomized to the SOC group, study drug is defined as the 
drug class of the first antidiabetic oral or injectable medication prescribed for treatment 
intensification following randomization. If a fixed dose combination (FDC) product is 
prescribed, one of the drugs will be chosen by the study physician to be the study drug. A 
patient randomized to the SOC treatment group will still be considered “on study drug” if 
they are taking a drug in the same class as their first study drug, even if it is not the same 
individual drug. This also applies to treatment intensification with a FDC product if one 
of the drugs is in the same class as the first study drug. 
Study Drug: Start/Stop, Discontinuations 
Study drug discontinuation is termination of the study drug. A patient can stop or start study drug 
throughout the study; therefore a patient’s study drug discontinuation status can change 
throughout the duration of the study. At any time during the duration of the study, if a patient is 
not taking study drug as defined, they will be considered “off study drug.” Conversely, at any 
time during the duration of the study, if a patient is taking study drug as defined, they will be 
considered “on study drug,” regardless of prior study drug discontinuations.  
If a participating patient becomes pregnant, the study physician will review the patient’s 
antidiabetic treatment regimen and make any changes necessary according to standard care of 
patients with T2DM during pregnancy. Semaglutide will be discontinued and will not be 
restarted unless the patient is no longer pregnant or breast-feeding. All study drug copay 
assistance will end.  
Copay assistance 
The study products will be handled and dispensed by the patients’ pharmacy(s) per their 
preference and health plan benefits. In order to minimize the impact of any differential in out-of-
pocket costs between the treatment groups, an out-of-pocket maximum will be provided by Novo 
Nordisk as part of the study. In both treatment groups, the patient’s copay will be up to the 
specified maximum for the study drug (as defined above) and ancillary needles (if required to 
administer the study drug). Copay assistance will only apply to the study drug as defined above 
(i.e., not to any subsequent add-on treatment or treatment changes outside the study drug 
definition). Because patients can start and stop study drug throughout the study, copay assistance 
may also start and stop throughout the study. For the duration of the study, any time a patient is 
“on study drug” they will receive copay assistance, and any time a patient is “off study drug” 
they will not receive copay assistance. The only exceptions are if a patient initiates prescription 
coverage through Medicare or Medicaid, at which point all copay assistance will end. 
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Products 
A current representative list of the products used in this study is below. All treatments will be 
used in accordance with local clinical practice and guidelines. Products with more than one 
active substance i.e., FDC products, can be used in this study. 
Semaglutide: Semaglutide in a prefilled pen (Ozempic®) 
Oral antidiabetic drugs: The oral antidiabetic drug classes included in this study are the 
commercially available options (listed in alphabetic order): 
 Alpha-glucosidase inhibitors 
 Dipeptidyl peptidase 4 (DPP-4) inhibitors 
 Meglitinides 
 Metformin 
 Sodium-glucose co-transporter 2 (SGLT-2) inhibitors 
 Sulfonylureas 
 Thiazolidinediones 
 Other 
o Bromocriptine 
o Colesevelam 
Injectable antidiabetic drugs: The injectable antidiabetic drug classes included in this study 
are the commercially available options (listed in alphabetic order): 
 GLP-1 RAs 
 Basal Insulin 
o Long acting insulin 
o Intermediate acting insulin including premix 
 Prandial Insulin 
o Short acting insulin 
o Rapid acting insulin 
 Other 
o Pramlintide 
Background medication: The (up to 2) oral antidiabetic medication(s) taken prior to 
randomization and treatment intensification is considered background medication. Patients may 
discontinue background medication at any time during the study. Patients may change the pre-
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study dose and frequency of background medication at any time during the study. Background 
medication will not be provided nor reimbursed by Novo Nordisk.   
5.3 
Patient Reported Outcomes, Clinician Reported Outcomes, and Diabetes 
Treatment Satisfaction 
Diabetes treatment satisfaction, generic health-related quality of life (HRQoL), work 
productivity, and patient and clinician global assessments will be assessed by the following 
instruments at randomization, year 1, and year 2. Patients will self-administer these instruments 
on paper. Site study personnel will review for completeness and enter responses into the eCRF. 
5.3.1 PRO and Treatment Satisfaction questionnaires 
5.3.1.1 Diabetes Treatment Satisfaction Questionnaire (DTSQ) [8] [9] [10] [11] 
The Diabetes Treatment Satisfaction Questionnaire (DTSQ) evaluates patient satisfaction with 
treatment. The DTSQ status version (DTSQs) will be completed at the randomization visit and 
the DTSQ change version (DTSQc) will be completed at the year 1 and year 2 dedicated study 
visits. 
5.3.1.2 Short Form 12-Item version 2 (SF-12 v2) Health Survey [12] 
The SF-12 v2 is a generic HRQoL questionnaire that assesses physical and mental functioning 
and overall HRQoL. The SF-12v2 standard 4-week recall period questionnaire will be completed 
at the randomization, year 1, and year 2 dedicated study visits. 
5.3.1.3 Work Productivity and Activity Impairment: General Health (WPAI-GH) 
Questionnaire [13] 
The WPAI-GH questionnaire assesses both absenteeism (i.e., work time missed) and 
presenteeism (i.e., impairment at work or reduced on-the-job effectiveness) as well as daily 
activity impairment (e.g., work around the house, shopping, exercising, childcare, studying) 
attributable to general health. The WPAI-GH will be administered at the randomization, year 1, 
and year 2 dedicated study visits. 
5.3.1.4 Patient Global Impression of Disease Severity (PGI-S) and Patient Global Impression 
of Change (PGI-C) 
The PGI-S is a 1-item measure that assesses the patient’s impression of disease severity based on 
their present diabetes symptoms, i.e., normal, mild, moderate, or severe, whereas the PGI-C 
assesses the patient’s impression of changes in diabetes symptoms, based on their diabetes 
symptoms now, compared with how they were before they began taking the study drug, i.e., very 
much better, much better, a little better, no change, a little worse, much worse, or very much 
worse. The PGI-S will be administered at the randomization visit and the PGI-C will be 
administered at the year 1 and year 2 dedicated study visits. 
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5.3.2 Clinician Global Impression of Disease Severity (CGI-S) and Clinician Global 
Impression of Change (CGI-C) 
The CGI-S is a 1-item measure that assesses the clinician’s impression of the patient’s disease 
severity, based on the patient’s present diabetes symptoms, i.e., normal, mild, moderate, or 
severe, whereas the CGI-C assesses the clinician’s impression of change in the patient’s diabetes 
symptoms, based on the patient’s diabetes symptoms now, compared with how they were before 
they began taking the study drug, i.e., very much better, much better, a little better, no change, a 
little worse, much worse, or very much worse. The study physician will complete the CGI-S at 
the randomization visit and the CGI-C at the year 1 and year 2 dedicated study visits. 
5.4 
Study Period 
Patients will be followed from randomization to end of study (EOS) at 2 years, during which 
study physicians or trained site personnel will collect study data and record it in the eCRF at 
dedicated study visits (randomization, year 1, year 2) and routine care visits. Patients will be 
followed for the full 2 year study period regardless of treatment changes or discontinuation 
during the study period, other than withdrawal of consent. If a patient leaves the 
 health 
plan network during the 2 year study period, administrative claims data will be collected from 
randomization through the date they leave the health plan. In this scenario, site-based study data 
collection will continue without change. 
On-study data collection at dedicated study visits and routine care visits (if available per local 
clinical practice) will include: clinical data (weight, HbA1c, SBP, DBP), treatment details (study 
drug, other antidiabetic medication, pre-specified concomitant medications related to 
cardiovascular risk, reasons for treatment discontinuation as applicable), hypoglycemia leading 
to inpatient admission or ER encounter, AEs leading to study drug discontinuation, pregnancy, 
and serious adverse events (SAEs). Additionally, PRO and ClinRO instruments will be 
completed at randomization, year 1, and year 2.  
EOS visit is 2 years (±6 weeks) after randomization. 
5.5 
Administrative Claims Data – HIRDSM 
In addition to prospectively collected clinical data and PROs, this study will also utilize claims 
data from the HIRD for all study patients. Data collected will include integrated medical claims, 
pharmacy claims, and health plan eligibility files for the 2 years after the respective patient’s 
study randomization. Extraction of this data will take place approximately 3 months after the last 
patient’s last visit (LPLV) to allow for data lags in the claims. Administrative claims data will 
also be collected for up to 12 months prior to study randomization, if available. The 
prospectively collected eCRF study data and claims data will be merged into one dataset via a 
study-specific patient identifier (ID) for analysis. 
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5.6 
Withdrawals 
5.6.1 Physician Practices 
Novo Nordisk and/or the Institutional Review Board (IRB) reserve the right to terminate the 
study any time. In this event, all data collection will end. After the collected data is received, 
study physicians will be compensated as contractually agreed. 
The IRB reserves the right to terminate participation of individual study sites at any time. 
Individual study sites may also be terminated for cause by Novo Nordisk per contractual 
agreement. In such cases, all data collection at terminated study sites will end. After the collected 
data is received, the study physicians will be compensated as contractually agreed. 
5.6.2 Patients 
Participation in the study is voluntary, and all patients are free to terminate their participation at 
any time. A patient will only be withdrawn from the study if they withdraw consent. In the event 
of study withdrawal, the study physician will record the reason for study withdrawal and 
continue to follow-up with the patient for any unresolved SAEs or pregnancies, if patient agrees. 
Upon patient 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 
Introduction 
Patients are randomized 1:1 to semaglutide or SOC. The data analyses for this study will be 
outlined in further detail in a Statistical Analysis Plan (SAP) developed prior to database lock at 
year 1. 
For continuous endpoints and categorical endpoints derived from continuous sources, the 
baseline value is defined as the last assessment taken prior to or at the randomization visit and 
before first use of study drug. 
If endpoint data is missing then any routine care data that are collected within ±10 weeks of the 
dedicated study visit will be used. 
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 semaglutide as compared to SOC (excluding semaglutide).  
The primary estimand for all objectives will be the “intention-to-treat” (ITT) estimand evaluating 
the effectiveness of randomized treatment intervention irrespective of adherence to this 
randomized intervention or changes to other antidiabetic medication during follow-up. The 
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purpose of this estimand is to quantify the expected effect size in the commercially-insured 
health plan population upon adoption of semaglutide as compared SOC (excluding semaglutide), 
and is as such relevant to inform and support appropriate market access and population based 
treatment guidance. 
The secondary estimand for all objectives with the exception of the adherence and persistence to 
treatment objective, is the “if all patients had adhered” estimand. This estimand evaluates the 
effect of randomized treatment intervention for all randomized patients if all patients had 
adhered to randomized treatment, regardless of changes to other (i.e., non-study drug) 
antidiabetic medication. The purpose of this estimand lies in quantifying the expected effect size 
for an individual patient in the commercially-insured health plan population who is prescribed, 
initiates, and continues treatment with semaglutide as compared to SOC (excluding 
semaglutide). The relevance of this effect measure is to inform decision making for individual 
patients and prescribing physicians. 
6.1.2 Confirmatory Endpoints and Hypotheses 
The primary endpoint is HbA1c <7.0% (53 mmol/mol) at year 1 (yes/no). This is a binary 
endpoint. Confirmatory secondary endpoints include:  
 Change in HbA1c (%-point) from baseline to year 1 
 HbA1c <7.0% (53 mmol/mol) at year 2 (yes/no) 
 Change in HbA1c (%-point) from baseline to year 2 
The primary and confirmatory endpoints will all be tested for superiority under multiplicity 
control via a hierarchical testing scheme according to the order given in the above bullet list. 
Confirmatory testing will only be performed for the primary estimand with the secondary 
estimand being supportive. The testing procedure will be stopped the first time an analysis fails 
to confirm superiority of the endpoint in question using a two-sided significance level of 5%. 
Superiority on HbA1c <7.0% will be evaluated with respect to the odds ratio (OR) (odds 
semaglutide / odds SOC): 
H0: OR≤1 against Ha: OR>1 
Superiority on change in HbA1c (year 1 – baseline; year 2 – baseline) will be evaluated with 
respect to the mean treatment difference (TD) (semaglutide – SOC):  
H0: TD≥0 against Ha: TD<0 
6.1.3 Study Populations 
The following analysis set will be defined: 
Full analysis set (FAS): Includes all randomized patients analyzed according to the treatment 
group to which they were assigned at randomization. 
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6.2 
Sample Size Determination  
6.2.1 Power and Sample Size for Primary Objective 
Assumptions for the sample size were based on input from the HIRD claims/laboratory results 
database. In line with the primary ITT estimand, the assumptions for the proportion of patients 
with HbA1c < 7.0% at year 1 and year 2, and for the change from baseline in HbA1c, were based 
on the claims/laboratory results data within the 
 population for all patients initiating 
treatment intensification, regardless of whether patients adhered to this treatment. Specifically, 
for semaglutide, assumptions were based on data for liraglutide and dulaglutide. For SOC, 
assumptions were based on all intensifications in the claims database. The study sample size of 
2,250 was calculated based on the following assumptions, informed from HIRD data: 10% 
difference in proportion patients with HbA1c < 7.0% at year 1 and year 2 (60% semaglutide 
versus 50% SOC), absolute difference in change from baseline HbA1c of 0.5%-point (SD=2.3%) 
between treatment groups, 90% power, and an overall alpha leve1 of 5%. Sample size 
calculations, including different sample size scenarios and a summary of the data from the 
HIRD, will be documented in the SAP. 
The proportion of missing data for the confirmatory endpoints was estimated to be 25% after one 
year and 44% after two years. In the sample size calculation, it was assumed that only non-
missing data at year 1 and year 2 would be used for the respective analyses. This is considered 
conservative, since the use of imputed data in the actual primary analysis (see 6.3) will increase 
the power. When accounting for missing data, randomizing 2250 patients will contribute 1687 
patients for the year 1 analyses and 1260 patients for the year 2 analyses, achieving a total power 
of 90% for confirming all 4 confirmatory hypotheses. The corresponding marginal powers for 
presence of HbA1c < 7.0% at year 1, change in HbA1c to 1 year, presence of HbA1c < 7.0% at 
year 2, and change in HbA1c to 2 years are 99%, 99%, 95%, and 97% respectively. 
6.3 
Statistical Analysis for the Primary Estimand 
The primary estimand will be estimated based on the FAS using data from all patients with 
observations at the dedicated study visit (year 1 for the primary endpoint), with the exception of 
patients who, in violation of the protocol, have initiated semaglutide in the SOC treatment group. 
The data collected following initiation of semaglutide from these patients will be censored and 
imputed together with missing data. The primary endpoint, HbA1c < 7.0%, will be analyzed with 
a logistic regression model with a logit link function, treatment as a categorical effect, and 
baseline HbA1c as covariate. From the model, the estimated OR (semaglutide versus SOC) will 
be presented. The underlying continuous endpoint of change in HbA1c will be analyzed using 
analysis of covariance (ANCOVA) that will include the same independent variables. From the 
model, the estimated mean difference in change from baseline to dedicated study visit 
(semaglutide versus SOC) will be presented. The estimated treatment effect from each of these 
analyses will be complemented with associated 95% confidence interval (CI) and two-sided p-
value for testing the null-hypothesis of no difference.  
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Prior to analysis, missing data will be imputed by multiple imputation on the continuous HbA1c 
scale and subsequently dichotomized for the primary endpoint. 500 complete data sets will be 
generated to adequately account for the uncertainty due to missing data. Missing endpoint data 
will be imputed separately by treatment group and based on patients who remained in the study 
according to study drug treatment status, i.e., according to whether these patients are on or off 
study drug at the dedicated study visit. Data will be imputed based on the assumption that, within 
treatment groups, patients with missing endpoint data will behave like patients with the same 
study drug treatment status at endpoint as the missing patients’ last registered treatment status 
prior to the missing endpoint. For example, for patients withdrawing from the study with an “off 
study drug” treatment status, data will be imputed based on the assumption that the withdrawn 
patients will behave like patients who remain in the study but are not receiving study drug at the 
dedicated study visit. Technically, the imputation model will be an ANCOVA for the endpoint 
data. The ANCOVA will include baseline HbA1c, diabetes duration, age, and sex as independent 
variables. After this model has been used to predict missing values, each of the now 500 
complete data sets will be analyzed as described above. Finally, the multiple analysis results will 
be combined using Rubin’s rule. [14] For the OR the results will be combined on the logarithm 
scale.   
Superiority for the primary endpoint, HbA1c <7.0% at year 1, will be considered established if 
the OR 95% CI is greater than 1, or similarly if the two-sided p-value is significant on a 5% level 
and the treatment OR is in favor of semaglutide. 
If the hierarchical testing scheme allows, superiority for change from baseline to dedicated study 
visit in HbA1c will be considered established if the 95% CI for the estimated treatment 
difference is smaller than 0, or similarly if the two-sided p-value is significant on a 5% level and 
the treatment difference is in favor of semaglutide. 
6.4 
Statistical Analysis for the Secondary Estimand 
The secondary estimand will be estimated based on the FAS. The analysis is similar to the 
primary analysis for the primary endpoint, but varies with regards to the data used and the 
imputation of missing data. Specifically, data will only be used from the subset of patients who 
are receiving study drug at the dedicated study visit (year 1 for the primary endpoint), in order to 
estimate the treatment effect if all patients had continued treatment. Patients who no longer are 
receiving study drug will be censored and imputed together with missing data. The same will 
apply to patients who, in violation of the protocol, have initiated semaglutide in the SOC group. 
Collectively, missing and censored data will be imputed separately by treatment group based on 
all patients who are on study drug at the dedicated study visit. Data will be imputed based on the 
assumption that withdrawn or censored patients behave like patients that remain in the study and 
continue on study drug. 
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The technical aspects of missing data imputation based on multiple imputation, the statistical 
analysis of the multiple complete data sets, and combination of the multiple results will be the 
same as that described for the primary estimand. 
6.5 
Supplementary Analyses 
The HbA1c analyses described for the two estimands above will be complemented with two 
complete case analyses based on the subset of patients without missing endpoint data, i.e., 
patients that do not have their endpoint imputed in the two analyses used for the primary and 
secondary estimand.  
Complete case analysis 
This analysis will be based only on patients with available measurements at the dedicated study 
visit including measurements irrespective of whether patients discontinued study drug or not. 
The analysis will use the same analysis model as described under the primary estimand. 
Complete case on-study drug analysis 
The analysis will be based only on patients with available measurements at the dedicated study 
visit including only measurements for patients still on study drug. The analysis will use the same 
analysis model as described under the primary estimand. 
6.6 
PRO Analysis 
PRO and physician assessments will be measured with the instruments described in Section 5.3. 
Analysis of these measures will address the secondary objective of this study to compare 
semaglutide versus SOC in the study’s patient population as is relates to PRO, i.e., treatment 
satisfaction, generic health outcomes, work productivity, and patient and physician global 
assessment measures, over one and two year observation periods. PRO analysis will 
descriptively summarize these measures at baseline, year 1, and year 2, as well as compare 
semaglutide versus SOC for change from baseline to year 1 and year 2. The continuous change 
from baseline endpoints will be analyzed using the same analysis approach as described under 
the complete case and complete case on-study drug analyses in Section 6.5. Details will be fully 
described in the SAP. 
6.7 
Safety Analysis 
SAEs and AEs will be collected as described in Section 7. No formal safety analyses are planned 
for this study. SAEs, AEs leading to study drug discontinuation, and pregnancies will be coded 
using Medical Dictionary for Regulatory Activities (MedDRA) and descriptively summarized by 
System Organ Class and Preferred Term (PT). 
6.8 
Other Analyses 
The following analyses are planned to further support the primary objective to compare 
semaglutide versus SOC in glycemic control. They will also address the secondary objectives of 
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this study to compare semaglutide versus SOC in the study’s patient population over one and two 
year observation periods as is relates to body weight loss, hypoglycemia, HCRU, and adherence 
and persistence to treatment. The binary and continuous endpoints that include HbA1c, weight, 
SBP, or DBP data will be analyzed using the same analysis approach as described under the 
primary estimand, secondary estimand, and supplementary analysis sections. All other endpoints 
will be analyzed using the same analysis approach as described under the complete case and 
complete case on-study drug analyses in Section 6.5. Further details of these analyses and details 
for analyses of other endpoint types will be fully described in the SAP. 
6.8.1 Supportive Analyses of Glycemic Control 
The proportion of patients achieving the secondary endpoints related to glycemic control at year 
1 as defined in section 3.3.2 (individualized HbA1c target, HbA1c <7.0% (53mmol/mol) or at 
least 1% point improvement in HbA1c from baseline, HbA1c target attainment per HEDIS 
criteria) will be compared between semaglutide and SOC treatment groups using the same 
analysis approach as described under the primary estimand, secondary estimand, and 
supplementary analysis sections. 
Additionally, derived outcome variables for supportive measures of glycemic control (Appendix 
2) will be utilized to support these analyses. 
6.8.2 Weight Loss 
Change in patient weight from baseline to year one will be calculated in pounds and percentage 
as defined in section 3.3.2. Mean change in weight will be compared between semaglutide and 
SOC treatment groups using the same analysis approach as described under the primary 
estimand, secondary estimand, and supplementary analysis sections. 
Additionally, derived outcome variables for supportive measures of body weight loss (Appendix 
2) will be utilized to support these analyses. 
6.8.3 Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) 
Change in patient SBP and DBP from baseline to year 1 and baseline to year 2 will be calculated 
as defined in section 3.3.2 and Appendix 2. Mean change in SBP and DBP will be compared 
between semaglutide and SOC treatment groups using the same analysis approach as described 
under the primary estimand, secondary estimand, and supplementary analysis sections. 
6.8.4 Hypoglycemia 
The number of hypoglycemic episodes leading to an inpatient admission or ER encounter will be 
reported by patients and compared by semaglutide and SOC treatment groups utilizing a negative 
binomial model. 
Additionally, derived outcome variables for supportive measures of hypoglycemia (Appendix 2) 
will be utilized to support these analyses. 
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6.8.5 Healthcare Resource Utilization (HCRU) 
HCRU analyses will compare all-cause and diabetes-related HCRU (inpatient admissions, ER 
encounters, outpatient encounters, and pharmacy utilization) as defined in section 3.3.2 from the 
HIRD by semaglutide and SOC treatment group from baseline to year 2.   
The details of claims data definitions and calculations will be fully described in the SAP. 
6.8.6 Adherence and Persistence to Treatment 
Adherence and persistence to the study drug will be calculated and compared between 
semaglutide and SOC treatment groups. 
Medication adherence refers to a patient’s conformance to the provider’s recommendation with 
respect to timing, dosage, and frequency of medication taken during the prescribed length of 
time. In claims, adherence is typically measured using either medication possession ratio (MPR) 
or proportion of days covered (PDC). 
Medication persistence refers to whether a patient stays on therapy or the time from initiation to 
discontinuation of therapy. In claims, persistence is typically defined as the duration of time from 
initiation of the therapy to discontinuation or switching, whichever comes first. 
Adherence and persistence will be further defined in the SAP.  
6.8.7 Antidiabetic Treatment Patterns 
Antidiabetic treatment patterns will be assessed and compared between semaglutide and SOC 
treatment groups. This analysis will summarize the number and classification type of antidiabetic 
medications taken during the study period.  
6.8.8 Exploratory Predictive Analysis 
An exploratory predictive analysis will be performed within and between the semaglutide and 
SOC treatment groups to identify predictors of treatment adherence and persistence and glycemic 
control. The objectives of the exploratory predictive analyses are to identify within and between 
treatment groups: 1) patients less likely to discontinue treatment and 2) patients more likely to 
reach clinical target.  
6.8.9 Evaluation of the Study Population 
To evaluate the generalizability of the study results, an analysis of the study population will be 
performed. The primary objective of this analysis is to evaluate the external validity of the study 
and to understand how the study population fits into the larger T2DM populations within study 
sites and 
 as a whole. Two claims-based T2DM patient populations will be described and 
compared to the study population: (1) commercially-insured 
 T2DM patients treated with 
up to 2 oral antidiabetic medications who undergo an antidiabetic treatment intensification, and 
(2) within the study sites, commercially-insured 
 T2DM patients treated with up to 2 oral 
antidiabetic medications who are not enrolled in the study, but who undergo an antidiabetic 
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treatment intensification. The analysis will compare the demographics, HCRU, and HbA1c 
between the study population and the two comparator populations during the 12 month period 
prior to randomization (for study population) or prior to a claims-based proxy for antidiabetic 
treatment intensification index date (for comparators). Additionally, treatment patterns of non-
enrolled T2DM patients within the practices from which the study patients are recruited will be 
evaluated to identify any relevant patterns of care suggesting channeling of certain types to 
patients away from the study. These analyses will help to contextualize study results within the 
T2DM population broadly. 
The details of this analysis will be fully described in the SAP. 
  
7 
Adverse Event Collection 
The principal study physician is responsible for monitoring the safety of participating patients. 
All SAEs reported by the patients during the study observational period are required to be 
documented on the appropriate SAE reporting form. For the purposes of this study, AEs that do 
not meet the definition of SAE will only be collected if they lead to study drug discontinuation. 
7.1 
Adverse Events 
An AE is defined as any untoward medical occurrence in a patient administered a pharmaceutical 
product or medical device, which does not necessarily have to have a causal relationship to the 
product of device. Study physicians will follow AEs that occur in any patient during this study in 
a manner consistent with routine clinical practice. For the purposes of this study, AEs that do not 
meet the definition of an SAE (section 7.2) will only be collected in the eCRF if they lead to 
study drug discontinuation. 
7.2 
Serious Adverse Events 
All AEs meeting the definition of SAE will be collected in the eCRF. SAEs will be reported 
from the time a patient is randomized until EOS at year 2, or until the patient withdraws from the 
study. An SAE is defined as any AE which results in at least one of the following outcomes: 
 Initial inpatient admission or prolongation of existing inpatient admission 
 A life-threatening event, i.e., an event in which the patient 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 
 Persistent or significant disability or incapacity 
 Congenital anomaly or birth defect in offspring 
 Death 
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 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 patient and may require 
medical or surgical intervention to prevent one of the other listed outcomes. 
7.2.1 Collection Period of Serious Adverse Events 
SAEs will be reported from the time a patient is randomized until EOS at year 2, or until the 
patient withdraws from the study. The principal study physician 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 patient 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. 
At each visit (both routine care visits and dedicated study visits), patients will be asked about 
AEs including hypoglycemic events, e.g. “Have you experienced any problems since the last 
contact?” 
If an investigator becomes aware of SAEs after EOS at year 2 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 patients 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 patient is randomized until EOS at year 2 or until 
the patient withdraws from the study. The principal study physician is responsible for alerting 
Novo Nordisk or its designee to any drug exposure during pregnancy within 14 days of the first 
knowledge of the pregnancy via the pregnancy reporting form. The study physician will follow 
the patient for the duration of the pregnancy. 
7.4 
Technical Complaints 
Technical complaints may be reported as per usual practice. However, any SAEs resulting from a 
technical complaint must be reported via EDC. 
 
8 
DATA COLLECTION 
8.1 
Data Sources 
Data sources include primary data collected prospectively by study sites at study visits 
(demographic and clinical data, patient-completed PRO data, and physician reported global 
assessments) as well as secondary data collection utilizing administrative claims data from the 
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HIRD.  In order to maintain patient confidentiality, each patient will be assigned a unique patient 
study ID number upon signing informed consent to use in place of patient name or any other 
identifying information (e.g., medical record number). Clinical study data, PROs/ClinROs and 
claims-derived variables will be integrated into one analysis dataset via this confidential patient 
ID. 
8.2 
Electronic Case Report Forms (eCRFs) 
All clinical study data will be collected at the physician office and entered into eCRF by trained 
site study personnel through a fully validated, 21 CFR 11 and HIPAA compliant EDC system.  
Patients 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.  
Some clinical assessments utilized in this study may be completed in the course of routine 
clinical practice by site personnel not affiliated with study (e.g., blood pressure), however any 
activities completed solely for the study (e.g., data entry, PRO administration) must be done by 
trained site study personnel. For example, a nurse not affiliated with the study may measure 
blood pressure as part of routine care. The data from this assessment may be used for this study, 
but must be extracted from the patient’s medical record and entered into the eCRF by trained site 
study personnel.  
The principal study physician has the ultimate responsibility for the collection and reporting of 
all clinical and patient data through the eCRFs, as well as ensuring that they are accurate and 
complete to the extent possible. 
8.3 
Year One Database Lock 
The primary analysis for this study is a year 1 analysis. Once data collection for year 1 has 
completed, a database lock and year 1 analysis will be performed. The year 1 analysis will not be 
integrated with HCRU and will be limited to year 1 endpoints derived from eCRF data, including 
PRO data. To maintain study integrity for the remaining study period, data from year 1 will be 
used for limited and confidential communications while complying with public disclosure 
requirements. All other analyses will be conducted following a second database lock once data 
collection for the entire study is 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 physician 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 
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potential study patients as well as the scientific integrity of the study. Site monitoring will be 
conducted by 
 staff.  
9.1.1 Institutional Review Board (IRB) 
The principal study physician will have prospective IRB approval of the study protocol, ICF, and 
any patient information or recruiting materials prior to commencement of any study activities at 
their site. In the case of a protocol amendment, the study physician 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 patients or others must be reported to the IRB as 
required. 
The principal study physician 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. The principal study physician must 
ensure that each study patient is informed of the study and authorizes release of health 
information prior to study-related activities. The study physician, or study personnel designated 
by the study physician, will obtain written informed consent from each patient prior to initiation 
of any study-related procedures. Each patient will be given a copy of the signed ICF. The 
principal study physician will retain the original signed ICF for each patient. 
The IRB must prospectively approve the ICF and any changes to the ICF during the course of the 
study before use. If a protocol amendment increases the potential risk to the patient, 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 patients entering the study as well as 
from currently enrolled patients 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 principal study physician must agree 
to maintain and allow access to required patient and study records. The principal study physician 
agrees to keep the identity of all participating patients (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). The principal study physician should retain records according 
to local regulations, or as specified in the Clinical Study Agreement, whichever is longer. 
 
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10 
PUBLICATION OF STUDY RESULTS 
All information related to this study is considered confidential information belonging to Novo 
Nordisk and 
 as consistent with contractual agreement. 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 with authorship 
following the International Committee of Medical Journal Editors (ICMJE) guidelines. 
Information regarding the study will be disclosed at clinicaltrials.gov and novonordisk-
trials.com. 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 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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REFERENCES 
 
[1]  International Council for Harmonisation of Technical Requirements for Pharmaceuticals 
for Human Use, "ICH Harmonised Draft Guideline: Estimands and Sensitivity Analysis in 
Clinical Trials E9(R1)," 2017. 
[2]  S. Inzucchi, R. Bergentstal, J. Buse and e. al., "Management of hyperglycemia in type 2 
diabetes, 2015: a patient-centered approach. Update to a position statement of the 
American Diabetes Association and the European Association for the Study of Diabetes," 
Diabetologia, vol. 58, no. 3, pp. 429-442, 2015.  
[3]  American Diabetes Association, "Diabetes advocacy. Sec. 15 In Standards of Medical Care 
in Diabetes - 2016," Diabetes Care, vol. 40, no. Suppl. 1, pp. S128-S129, 2016.  
[4]  Investigator's Brochure for s.c. Semaglutide (NN9535), Edition 12 or any updates hereof. 
2017.  
[5]  Health AwpfI: Why pharma needs to work differently with payers and INDs on RWE: 
Learnings from recent survey and symposium.  
[6]  "Standards of Medical Care in Diabetes-2017: Summary of Revisions," Diabetes Care, vol. 
40, no. Suppl 1, pp. S4-S5, 2017.  
[7]  T. Wasser, J. Ycas and O. Tunceli, "Applying Weighting Methodologies to a Commercial 
Database to Project US Census Demographic Data," The American Journal of Accountable 
Care, 2015.  
[8]  C. Bradley, "The Diabetes Treatment Satisfaction Questionnaire: DTSQ," in Handbook of 
Psychology and Diabetes: a guide to psychological measurement in diabetes research and 
practice, C. Bradley, Ed., Abingdon, Routledge, 1994, pp. 111-132. 
[9]  C. Bradley, "The Diabetes Treatment Satisfaction Questionnaire (DTSQ): change version 
for use alongside status version provides appropriate solution where ceiling effects occur," 
Diabetes Care, vol. 22, no. 3, pp. 530-532, 1999.  
[10] C. Bradley, "Patient perceptions of diabetes and diabetes therapy: assessing quality of life," 
Diabetes Metabolism Research and Reviews, vol. 18, pp. S64-S69, 2002.  
[11] C. Bradley, R. Plowright, J. Stewart, J. Valentine and E. Witthaus, "The Diabetes 
Treatment Satisfaction Questionnaire change version (DTSQc) evaluated in insulin 
glargine trials shows greater responsiveness to improvements than the original DTSQ," 
Health and Quality of Life Outcomes, vol. 5, no. 5, p. 57, 2007.  
[12] J. Ware, M. Kosinski and S. Keller, "A 12-item short-form health survey: construction of 
scales and preliminary tests of reliability and validity," Med Care, vol. 34, no. 3, pp. 220-
233, 1996.  
[13] M. Reilly, A. Zbrozek and E. Dukes, "The validity and reproducibility of a work 
productivity and activity impairment instrument," PharmacoEconomics, vol. 4, no. 5, pp. 
353-365, 1993.  
[14] R. Little and D. Rubin, Statistical analysis with missing data. J. Wiley, Ed., New York: 
John Wiley and Sons, 1987.  
 
 
 
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Appendix 1: Time and Events Schedule  
Study NN9535‐4416 
 
Dedicated Study visit, 
Randomization 
 
Routine Care  visits, 
Year 1 
Dedicated Study visit, 
Year 1 
Routine Care visits, 
Year 2 
Dedicated Study visit, 
Year 2 
Time of visit (Weeks)a 
0* 
0‐52** 
52±6 
52‐104** 
104±6 
PATIENT AND TREATMENT RELATED ASSESSMENTSb 
Informed consentc 
X 
 
 
 
 
Inclusion/Exclusion criteria 
X 
 
 
 
 
Demographics (date of birth, gender, race, 
ethnicity) 
X 
 
 
 
 
Selected medical history 
X 
 
 
 
 
Diabetes history and diabetes 
complications 
X 
 
 
 
 
Individualized HbA1c targetd 
X 
 
 
 
 
Type of glucose‐lowering medication 
including semaglutide 
X 
X 
X 
X 
X 
Concomitant cardiovascular medication
X 
X 
X 
X 
X 
Reason for discontinuation of any glucose 
lowering medication 
 
X 
X 
X 
X 
EFFECTIVENESS AND SAFETY RELATED ASSESSMENTS 
Body weight 
X 
X 
X
X 
X 
Height 
X 
 
 
 
 
SBP / DBP 
X 
X 
X 
X 
X 
HbA1c 
Xe 
X 
X
X 
X
SAEs, pregnancies, and AEs leading to 
study drug discontinuation 
 
X 
X 
X 
X 
Healthcare resource utilizationf 
 
X 
X 
X 
X 
Hypoglycemia leading to inpatient 
admission or ER encounter 
 
X 
X 
X 
X 
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Study NN9535‐4416 
 
Dedicated Study visit, 
Randomization 
 
Routine Care  visits, 
Year 1 
Dedicated Study visit, 
Year 1 
Routine Care visits, 
Year 2 
Dedicated Study visit, 
Year 2 
PROs and Physician Completed Assessments 
DTSQs 
X 
 
 
 
 
DTSQc 
 
 
X 
 
X 
SF‐12v2 
X 
 
X 
 
X 
WPAI‐GH 
X 
 
X 
 
X 
PGI‐S 
X 
 
 
 
 
PGI‐C 
 
 
X 
 
X 
CGI‐S 
X 
 
 
 
 
CGI‐C 
 
 
X 
 
X 
END OF STUDY 
End of study 
 
 
 
 
X 
* Eligibility assessment may take place up to 4 weeks prior to the randomization visit. If eligibility assessment 
occurs prior to the randomization visit, any changes in collected medical history, diabetes history, diabetes 
complications, glucose lowering medications and concomitant cardiovascular mediations will be collected at the 
randomization visit.  
** The year 1 and year 2 routine care visit windows are determined by the date of the patient’s dedicated year 1 
study visit. The year 1 routine care visit window will end immediately prior to the dedicated year 1 study visit. The 
year 2 routine care visit window will begin immediately following the dedicated year 1 study visit. 
 
Note: In this study, data will be collected from two different data sources: 
1) Data entered into the eCRF will be collected at dedicated study visits and routine care visits (if available 
per local clinical practice) and will include: demographics, selected medical history, diabetes medical 
history and diabetes complications, individualized HbA1c target, type of glucose-lowing medication, 
concomitant cardiovascular medication, reason for discontinuation of any glucose lowering medication, 
body weight, height, SBP, DBP, HbA1c, AEs leading to study drug discontinuation, SAEs, pregnancies and 
hypoglycemia leading to inpatient admission or ER encounter. Additionally, PRO and ClinRO data will be 
collected at the dedicated study visits and entered into the eCRF. 
2) Healthcare resource utilization and pharmacy prescription data will be extracted from the HIRD and will 
not be entered into the eCRF.  
 
a Routine care visits will follow standard of care frequency and any available data will be entered in the eCRF. 
b Assessments at dedicated study visits will be collected in eCRF. Assessments at routine care visits will be collected 
as available/according to local clinical practice in eCRF.  
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c Informed consent must be obtained before any study related activities. 
d Individualized HbA1c target must be set and documented prior to randomization. 
e The HbA1c value is based on historical data collected from the study physician and is the value closest to the date 
of randomization, within the last 90 days. 
f Data from the HIRD. Data will be extracted from the HIRD at the end of the study, but will include data from 
patient randomization through EOS or withdrawal. 
 
 
 
 
 
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Appendix 2: Additional Derived Outcome Variables for Supportive Analyses 
Supportive Measures of Glycemic Control 
 Individualized HbA1c target attained at year 2 (yes/no) 
 HbA1c <7.0% (53 mmol/mol) or at least 1% point improvement in HbA1c compared to 
baseline at year 2 (yes/no) 
 HbA1c <8.0% (64 mmol/mol) at year 1 (yes/no) 
 HbA1c <8.0% (64 mmol/mol) at year 2 (yes/no)  
 HbA1c <7.0% (53 mmol/mol) and no further antidiabetic medication intensification after 
randomization at year 1 (yes/no) 
 HbA1c <7.0% (53 mmol/mol) and no further antidiabetic medication intensification after 
randomization at year 2 (yes/no) 
 HbA1c target attainment per HEDIS criteria (<8.0% if age ≥65 years or with defined 
comorbidities, otherwise <7.0%) at year 2 (yes/no) 
 HbA1c <7.0% (53 mmol/mol) at year 1 in patients with HbA1c >9.0% at baseline 
(yes/no) 
 HbA1c <7.0% (53 mmol/mol) at year 2 in patients with HbA1c >9.0% at baseline 
(yes/no) 
 HbA1c <8.0% (64 mmol/mol) at year 1 in patients with HbA1c >9.0% at baseline 
(yes/no) 
 HbA1c <8.0% (64 mmol/mol) at year 2 in patients with HbA1c >9.0% at baseline 
(yes/no) 
Body Weight Loss 
 Change in body weight (%) from baseline to year 2 
 Change in body weight (lb) from baseline to year 2 
Blood Pressure 
 Change in SBP (mm Hg) from baseline to year 2 
 Change in DPB (mm Hg) from baseline to year 2 
Hypoglycemia 
 Reported hypoglycemia leading to inpatient admission or ER encounter during year 1 
(yes/no) 
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 
Reported hypoglycemia leading to inpatient admission or ER encounter during year 2 
(yes/no) 
Composite Variables 
 HbA1c <7.0% (53 mmol/mol) without experiencing hypoglycemia leading to inpatient 
admission or ER encounter and body weight loss of  ≥5% vs baseline at year 1 (yes/no) 
 Absolute HbA1c reduction of ≥0.5% without experiencing hypoglycemia leading to 
inpatient admission or ER encounter and a body weight loss of  ≥5% vs baseline at year 1 
(yes/no) 
 HbA1c <7.0% (53 mmol/mol) without experiencing hypoglycemia leading to inpatient 
admission or ER encounter and body weight loss of  ≥5% vs baseline at year 2 (yes/no) 
 Absolute HbA1c reduction of ≥0.5% without experiencing hypoglycemia leading to 
inpatient admission or ER encounter and a body weight loss of  ≥5% vs baseline at year 2 
(yes/no) 
 HbA1c <7.0% (53 mmol/mol) without experiencing hypoglycemia leading to inpatient 
admission or ER encounter and no body weight gain vs baseline at year 1 (yes/no) 
 HbA1c <7.0% (53 mmol/mol) without experiencing hypoglycemia leading to inpatient 
admission or ER encounter and no body weight gain vs baseline at year 2 (yes/no) 
Adherence to Treatment 
 Study drug medication adherence for the two years of the study, as measured by the 
medication possession ratio (MPR) 
 
 
 
 
 
 
 
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Appendix 3: Patient Reported Outcome Additional Information 
 
DTSQc 
The DTSQc provides a measure of how satisfied patients are with their current diabetes 
treatment compared with previous treatment. It consists of 8 questions, which are to be answered 
on a Likert scale from -3 to +3 (-3 = much less satisfied now to +3 = much more satisfied now), 
with 0 (midpoint), representing no change. Six questions are summed to produce a Total 
treatment satisfaction score. The remaining two questions concern perceived frequency of 
hyperglycemia and perceived frequency of hypoglycemia, respectively. The DTSQc Total 
treatment satisfaction score ranges from -18 to +18, with higher scores associated with greater 
treatment satisfaction. 
 
SF-12 v2 
The SF-12v2 is a 12-item generic health-related quality of life measure that assesses physical and 
mental functioning. The items will be scored using the scoring software that will be provided 
with the license. The following two summary scores are used as endpoints: Physical Component 
Summary (PCS) Score and Mental Component Summary (MCS) Score. The scores are norm-
scored such that the scores range from 0-100 with a mean of 50 and standard deviation of 10.  A 
higher score is associated with better quality of life and a lower score, poorer quality of life.  
 
WPAI-GH 
The WPAI-GH yields four types of scores: Absenteeism (work time missed), Presenteesism 
(impairment at work / reduced on-the-job effectiveness), Work productivity loss (overall work 
impairment / absenteeism plus presenteeism), and Activity Impairment. WPAI outcomes are 
expressed as percentages, with higher numbers indicating greater impairment and less 
productivity, i.e., worse outcomes (percent work time missed due to health, percent impairment 
while working due to health, percent overall work impairment due to health, percent activity 
impairment due to health). 
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Summary of Amendments and Updates 
 
Summary of Changes 
NN95359-4416 Protocol Version 2.0, dated 27MAR2019 
 
Number 
Section/Page 
 
Change 
Rationale 
1 
Global Change, 
Study Population 
Allow enrollment of patients 
treated with either 1 or 2 oral 
antidiabetic medications. 
  
Expand study population 
from patients treated with 
metformin monotherapy to 
patients treated with either 1 
or 2 oral antidiabetic 
medications to facilitate 
enrollment. 
 
2 
Global Change 
 
March 1327, 20182019 
 
Version 12.0 
 
Update protocol date and 
version. 
3 
Study Approvals, 
p. 2 
Name:  
 
 
Title:   
 
 
 
 
 
Study approval title update. 
4 
Study Approvals, 
p. 2 
Name:  
 
 
Title:  
 
Statistician 
 
Update to study statistician. 
5 
Patient 
Description,  
Synopsis, p. 7 
 
Eligible patients include adult 
T2DM patients on metformin 
monotherapy up to 2 oral 
antidiabetic medications whose 
physician deems that they have 
inadequate glycemic control and 
need treatment intensification 
with an additional antidiabetic 
oral or injectable medication. 
Update patient description 
to reflect expanded study 
population. 
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6 
Primary Objective 
 
Synopsis, p. 7 
 
Section 2.1, 
Primary Objective, 
p. 17 
The primary objective is to 
demonstrate superior long term 
effects of treatment with 
semaglutide compared to SOC 
both added to metformin up to 2 
oral antidiabetic medications on 
glycemic control when used as 
intensification in routine clinical 
practice in adult patients with 
T2DM. 
 
Update primary objective to 
reflect expanded study 
population. 
7 
Secondary 
Objective 
 
Synopsis, p. 7 
 
Section 2.2,  
Secondary 
Objectives, p. 17 
 
The secondary objectives are to 
compare the long term effect of 
semaglutide versus SOC both 
added to metformin up to 2 oral 
antidiabetic medications and 
used as intensification in routine 
clinical practice in adult patients 
with T2DM with regards to: 
 
Update secondary 
objectives to reflect 
expanded study population. 
8 
Study Design 
 
Synopsis, p. 7 
 
Section 4.1, Study 
Design Overview, 
p. 20 
This is a 2-year, multi-center, 
randomized, open label, parallel 
group, active comparator 
pragmatic clinical trial (PCT) 
comparing semaglutide versus 
SOC when added to metformin 
monotherapy up to 2 oral 
antidiabetic medications as 
treatment intensification among 
adult T2DM patients in the 
course of routine clinical 
practice. 
 
Update study design to 
reflect expanded study 
population. 
9 
Inclusion Criteria, 
#4 
 
Synopsis, p. 8 
 
Section 4.2.3, 
Patient Inclusion 
Criteria, p. 22 
 
4.) Treatment with metformin as 
antidiabetic monotherapy 
either 1 or 2 oral antidiabetic 
medications. 
 
Expand study population 
from patient treated with 
metformin monotherapy to 
patients treated with either 1 
or 2 oral antidiabetic 
medications to facilitate 
enrollment. 
 
10 
Inclusion Criteria, 
#5 
 
5.) Current member of an 
 affiliated 
Clarification of health plan 
requirements.  
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Synopsis, p. 8 
 
Section 4.2.3, 
Patient Inclusion 
Criteria, p. 22 
 
commercial health plan with 
pharmacy benefits. 
11 
Exclusion Criteria, 
#2 
 
Synopsis, p. 8 
 
Section 4.2.4, 
Patient Exclusion 
Criteria, p. 22 
 
2.) Treatment with more than 2 
oral antidiabetic medications 
or any injectable antidiabetic 
medication any medication 
for the indication of diabetes 
other than metformin in a 
period of 30 days before the 
day of eligibility assessment. 
Temporary/emergency use of 
any type of insulin is 
allowed, as is prior insulin 
treatment for gestational 
diabetes.  
 
Update exclusion criterion 
#2 to be consistent with 
inclusion criterion #4. 
12 
Section 1, 
Introduction, p. 16 
This local US study will enroll 
adult patients with T2DM who 
have inadequate glycemic 
control on metformin as their 
only up to 2 oral antidiabetic 
medications, as defined by the 
need for treatment intensification 
with an additional antidiabetic 
oral or injectable medication per 
the study physician´s discretion. 
 
Update description of study 
to reflect expanded study 
population. 
13 
Section 4.2, 
Practice and 
Patient Selection, 
p. 21 
The target population for this 
study consists of adult, 
commercially-insured, T2DM 
patients on metformin mono-
therapy up to 2 oral antidiabetic 
medications who are in need of 
treatment intensification with an 
additional antidiabetic oral or 
injectable medication. 
 
Update target population to 
reflect expanded study 
population. 
14 
Section 4.2, 
Practice and 
Patient Selection, 
p. 21 
 health plans serve a 
large population of T2DM 
patients. In feasibility data from 
the HIRD, the number of 
Delete data based on 
metformin monotherapy as 
it is not relevant to updated 
inclusion criteria. 
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patients with T2DM, at least one 
claim for metformin in the most 
recent 6 months, and without 
prior use of other antidiabetic 
drug classes (per study exclusion 
criterion #2), amounts to circa 
300,000 potential eligible 
patients distributed across 
61,803 unique providers. 
 
15 
Section 4.2.2, 
Patient 
Recruitment and 
Eligibility, p. 21 
Eligible patients include adult 
T2DM patients whose 
physicians determine that they 
have inadequate glycemic 
control on metformin 
antidiabetic monotherapy1 or 2 
oral antidiabetic medications. 
 
Update description of 
eligible patients to reflect 
expanded study population. 
16 
Figure 1, Study 
design, p. 23 
 
Figure 1 Study design 
diagram. Patients will be 
randomized in a 1:1 manner 
using centralized allocation to 
receive semaglutide or SOC as 
add-on to metformin up to 2 oral 
antidiabetic medications.  
 
Update description of study 
design to reflect expanded 
study population. 
17 
Section 5.1, 
Enrollment 
Procedures, p. 23 
 
The determination that a patient 
has inadequate glycemic control 
on metformin antidiabetic 
monotherapy up to 2 oral 
antidiabetic medications, and the 
subsequent decision to intensify 
antidiabetic treatment with an 
additional oral or injectable 
antidiabetic medication, will be 
made by the study physician 
during the course of routine 
clinical practice. 
 
Update enrollment 
procedures to reflect 
expanded study population. 
18 
Section 5.2.2, 
Treatments, p. 26 
 Metformin 
Add metformin to the list of 
oral antidiabetic drugs 
included in this study to 
reflect expanded study 
population. 
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19 
Section 5.2.2, 
Treatments, p. 26-
27 
Background medication: The 
(up to 2) oral antidiabetic 
medication(s) taken prior to 
randomization and treatment 
intensification following 
treatment is considered 
background medication: 
metformin. Patients may 
discontinue metformin 
background medication at any 
time during the study. Patients 
may change the pre-study dose 
and frequency of metformin 
background medication at any 
time during the study. 
Background medication will not 
be provided nor reimbursed by 
Novo Nordisk. 
 
Update description of 
background medication to 
reflect expanded study 
population. 
20 
Section 6.6, PRO 
Analysis, p. 33 
The continuous change from 
baseline endpoints will be 
analyzed using the same analysis 
approach as described under the 
complete case and complete case 
on-study drug analyses in 
primary estimand, secondary 
estimand, and supplementary 
analysis sSection 6.5. 
 
Update to planned PRO 
analyses, with no missing 
data imputation for PRO 
endpoints. 
21 
Section 6.8, Other 
Analyses, p. 34 
The binary and continuous 
endpoints that include HbA1c, 
weight, SBP, or DBP data will 
be analyzed using the same 
analysis approach as described 
under the primary estimand, 
secondary estimand, and 
supplementary analysis sections. 
All other endpoints will be 
analyzed using the same analysis 
approach as described under the 
complete case and complete case 
Update to planned analyses, 
with missing data 
imputation only for 
endpoints including HbA1c, 
weight, SBP, or DBP data. 
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on-study drug analyses in 
Section 6.5. 
 
22 
Section 6.8.9, 
Evaluation of 
Study Population, 
p. 35 
Two claims-based T2DM patient 
populations will be described 
and compared to the study 
population: (1) commercially-
insured 
 T2DM patients 
treated with metformin up to 2 
oral antidiabetic medications 
who undergo an antidiabetic 
treatment intensification, and (2) 
within the study sites, 
commercially-insured 
 
T2DM patients treated with 
metformin up to 2 oral 
antidiabetic medications who are 
not enrolled in the study, but 
who undergo an antidiabetic 
treatment intensification. 
 
Update claims-based 
comparator population to 
reflect expanded study 
population. 
 
CONFIDENTIAL


 
PROTOCOL No. NN9535-4416 – Novo Nordisk Semaglutide Study 
UTN: U1111-1207-6474 
 
 
 
   
 
 
 
 
 
Long term comparative effectiveness of once weekly 
semaglutide versus standard of care in a real world adult US 
population with type 2 diabetes - a randomized pragmatic 
clinical trial 
 
 
 
 
Trial ID NN9535-4416 
 
 
Novo Nordisk 
 
 
August 21, 2019 
 
Version 3.0 
 
 
 
 
 
 
Trial Phase: 4 
Investigational Substance: Semaglutide 
 
 
 
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STUDY APPROVALS 
Protocol No:  NN9535-4416 
21-AUG-2019 
 
Sponsor Approval: 
 
Name:  
 
Title:   
 
 
 
Novo Nordisk 
 
 
 
Signature:    
 
 
 
 
 
 
 
 
 
 
 
Date:  
 
 
 
 
 
 
Name:  
 
Title:  
 Statistician 
 
Novo Nordisk 
 
 
  
 
Signature:    
 
 
 
 
 
 
 
 
 
 
Date:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Principal Study Physician Agreement: 
 
I have read the protocol “Long term comparative effectiveness of once weekly semaglutide 
versus standard of care in a real world adult US population with type 2 diabetes - a randomized 
pragmatic clinical 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 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 
PRINCIPAL STUDY PHYSICIAN AGREEMENT ................................................................. 3 
TABLE OF CONTENTS ............................................................................................................. 4 
SYNOPSIS ..................................................................................................................................... 7 
LIST OF ABBREVIATIONS .................................................................................................... 11 
LIST OF DEFINITIONS ........................................................................................................... 14 
1 
INTRODUCTION............................................................................................................... 16 
1.1 
Background and Rationale .................................................................................................................................. 16 
2 
STUDY OBJECTIVES ....................................................................................................... 17 
2.1 
Primary Objective................................................................................................................................................... 17 
2.2 
Secondary Objectives ............................................................................................................................................ 17 
3 
STUDY ENDPOINTS ......................................................................................................... 17 
3.1 
Baseline ...................................................................................................................................................................... 17 
3.2 
Primary Endpoint ................................................................................................................................................... 17 
3.3 
Secondary Endpoints............................................................................................................................................. 18 
3.3.1 
Confirmatory Secondary Endpoints .............................................................................................................................. 18 
3.3.2 
Supportive Secondary Endpoints ................................................................................................................................... 18 
3.3.3 
Exploratory Endpoints ........................................................................................................................................................ 20 
4 
STUDY DESIGN ................................................................................................................. 20 
4.1 
Overview .................................................................................................................................................................... 20 
4.2 
Practice and Patient Selection ........................................................................................................................... 21 
4.2.1 
Physician Practices ............................................................................................................................................................... 21 
4.2.2 
Patient Recruitment and Eligibility ............................................................................................................................... 21 
4.2.3 
Patient Inclusion Criteria ................................................................................................................................................... 21 
4.2.4 
Patient Exclusion Criteria .................................................................................................................................................. 22 
4.2.5 
Patient Enrollment ................................................................................................................................................................ 22 
4.2.6 
Patient Randomization ........................................................................................................................................................ 22 
5 
STUDY PROCEDURES .................................................................................................... 23 
5.1 
Enrollment Procedures ........................................................................................................................................ 23 
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5.2 
Randomization Visit .............................................................................................................................................. 24 
5.2.1 
Patient Characteristics ........................................................................................................................................................ 24 
5.2.2 
Treatments ............................................................................................................................................................................... 24 
5.3 
Patient Reported Outcomes, Clinician Reported Outcomes, and Diabetes Treatment 
Satisfaction ............................................................................................................................................................................... 27 
5.3.1 
PRO and Treatment Satisfaction questionnaires ..................................................................................................... 27 
5.3.1.1 
Diabetes Treatment Satisfaction Questionnaire (DTSQ) [7] [8] [9] [10] .......................................... 27 
5.3.1.2 
Short Form 12-Item version 2 (SF-12 v2) Health Survey [11] .............................................................. 27 
5.3.1.3 
Work Productivity and Activity Impairment: General Health (WPAI-GH) Questionnaire [12]
 
27 
5.3.1.4 
Patient Global Impression of Disease Severity (PGI-S) and Patient Global Impression of 
Change (PGI-C) ................................................................................................................................................................................... 27 
5.3.2 
Clinician Global Impression of Disease Severity (CGI-S) and Clinician Global Impression of Change 
(CGI-C) 28 
5.4 
Study Period ............................................................................................................................................................. 28 
5.5 
Administrative Claims Data ................................................................................................................................ 28 
5.6 
Withdrawals ............................................................................................................................................................. 29 
5.6.1 
Physician Practices ............................................................................................................................................................... 29 
5.6.2 
Patients ....................................................................................................................................................................................... 29 
6 
STATISTICAL METHODS .............................................................................................. 29 
6.1 
Introduction ............................................................................................................................................................. 29 
6.1.1 
Estimands .................................................................................................................................................................................. 30 
6.1.2 
Confirmatory Endpoints and Hypotheses .................................................................................................................. 30 
6.1.3 
Study Populations .................................................................................................................................................................. 31 
6.2 
Sample Size Determination ................................................................................................................................. 31 
6.2.1 
Power and Sample Size for Primary Objective ......................................................................................................... 31 
6.3 
Statistical Analysis for the Primary Estimand ............................................................................................. 31 
6.4 
Statistical Analysis for the Secondary Estimand ......................................................................................... 32 
6.5 
Supplementary Analyses ..................................................................................................................................... 33 
6.6 
PRO Analysis ............................................................................................................................................................. 33 
6.7 
Safety Analysis ......................................................................................................................................................... 34 
6.8 
Other Analyses ......................................................................................................................................................... 34 
6.8.1 
Supportive Analyses of Glycemic Control ................................................................................................................... 34 
6.8.2 
Weight Loss .............................................................................................................................................................................. 34 
6.8.3 
Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)............................................................... 34 
6.8.4 
Hypoglycemia .......................................................................................................................................................................... 35 
6.8.5 
Healthcare Resource Utilization (HCRU) .................................................................................................................... 35 
6.8.6 
Adherence and Persistence to Treatment .................................................................................................................. 35 
6.8.7 
Antidiabetic Treatment Patterns .................................................................................................................................... 35 
6.8.8 
Exploratory Predictive Analysis ...................................................................................................................................... 35 
6.8.9 
Evaluation of the Study Population ............................................................................................................................... 36 
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7 
ADVERSE EVENT COLLECTION................................................................................. 36 
7.1 
Adverse Events ........................................................................................................................................................ 36 
7.2 
Serious Adverse Events ........................................................................................................................................ 36 
7.2.1 
Collection Period of Serious Adverse Events ............................................................................................................ 37 
7.3 
Pregnancy .................................................................................................................................................................. 37 
7.3.1 
Reporting Period of Pregnancy ....................................................................................................................................... 37 
7.4 
Technical Complaints ............................................................................................................................................ 38 
8 
DATA COLLECTION ....................................................................................................... 38 
8.1 
Data Sources ............................................................................................................................................................. 38 
8.2 
Electronic Case Report Forms (eCRFs) ........................................................................................................... 38 
8.3 
Year One Database Lock ....................................................................................................................................... 38 
9 
STUDY MANAGEMENT .................................................................................................. 39 
9.1 
Regulatory and Ethical Consideration ............................................................................................................ 39 
9.1.1 
Institutional Review Board (IRB) ................................................................................................................................... 39 
9.1.2 
Informed Consent .................................................................................................................................................................. 39 
9.2 
Record Retention and Access ............................................................................................................................. 40 
10 PUBLICATION OF STUDY RESULTS .......................................................................... 40 
11 INDEMNIFICATION ........................................................................................................ 40 
REFERENCES ............................................................................................................................ 41 
APPENDIX 1: TIME AND EVENTS SCHEDULE ................................................................ 42 
APPENDIX 2: ADDITIONAL DERIVED OUTCOME VARIABLES FOR SUPPORTIVE 
ANALYSES ................................................................................................................................. 45 
APPENDIX 3: PATIENT REPORTED OUTCOME ADDITIONAL INFORMATION .... 47 
SUMMARY OF AMENDMENTS AND UPDATES ............................................................... 48 
 
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SYNOPSIS 
Title: Long term comparative effectiveness of once weekly semaglutide versus standard of care in a 
real world US adult population with type 2 diabetes – a randomized pragmatic clinical trial 
Sponsor: Novo Nordisk 
Study Treatment: Semaglutide in a prefilled pen (Ozempic®) 
Active Ingredient: Semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1 RA) 
Comparator Treatment: Standard of Care (SOC) (excluding semaglutide) 
Trial ID:  NN9535-4416 
Study Physician Sites: Participation of approximately 200 physician sites, including both primary 
care practitioners and endocrinologists, that have a population of patients with the target indication, 
type 2 diabetes mellitus (T2DM), actively enrolled in a commercial or Medicare health plan with 
pharmacy benefits. 
Country: United States (US) 
Patients: Eligible patients include adult T2DM patients on up to 2 oral antidiabetic medications 
whose physician deems that they have inadequate glycemic control and need treatment intensification 
with an additional antidiabetic oral or injectable medication. 
Planned enrollment in this study is 1387. Patients will be randomized 1:1 to receive either 
semaglutide or SOC.  
Study Objectives: The objectives of this study are as follows: 
1.) The primary objective is to demonstrate superior long term effects of treatment with 
semaglutide compared to SOC both added to up to 2 oral antidiabetic medications on 
glycemic control when used as intensification in routine clinical practice in adult patients 
with T2DM. 
2.) The secondary objectives are to compare the long term effect of semaglutide versus SOC 
both added to up to 2 oral antidiabetic medications and used as intensification in routine 
clinical practice in adult patients with T2DM with regards to: 
a.
Weight loss
b.
Patient reported outcomes (PROs) and clinician reported outcomes (ClinROs)
c.
Hypoglycemia
d.
Healthcare Resource Utilization (HCRU)
e.
Adherence and persistence to treatment
Study Design: This is a 2-year, multi-center, randomized, open label, parallel group, active 
comparator pragmatic clinical trial (PCT) comparing semaglutide versus SOC when added to up to 2 
oral antidiabetic medications as treatment intensification among adult T2DM patients in the course of 
routine clinical practice. Patients will be randomized 1:1 to receive either semaglutide or SOC. The 
decision that further antidiabetic treatment intensification with oral or injectable antidiabetic 
medication is indicated is at the discretion of the study physician and will be made prior to and 
independent of enrollment in this study. The study physician will have determined the patient’s 
suitability for treatment with semaglutide prior to signing informed consent, but the determination to 
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initiate semaglutide versus SOC will be made by randomization. 
In keeping with the study objectives and pragmatic design to evaluate semaglutide versus SOC in real 
world, routine clinical practice, inclusion and exclusion criteria are minimally restrictive and there 
are few study-specific evaluations. Study physicians will follow and treat patients according to their 
routine clinical practice and judgement. All oral and injectable antidiabetic medications are allowed 
at the study physicians' discretion, with the exception of semaglutide in the SOC group. Patients will 
be followed for 2 years, regardless of changes in antidiabetic treatment over the course of the study. 
It is anticipated that patients will undergo medical evaluation at regular intervals over the course of 
the study duration as per standard of care, but the only dedicated study visits are at randomization, at 
year 1, and at year 2. The study will also capture clinical data collected at the sites during routine 
diabetic care visits, i.e., office visits and other patient contacts that occur as part of routine clinical 
practice. Assessments will be conducted according to the study physician’s routine clinical practice, 
with a few study-specific assessments as outlined in Study Procedures. Additionally, medical and 
pharmacy claims data will be captured utilizing the HealthCore Integrated Research Database 
(HIRDSM) for 
 patients or requested, via patient written authorization, from a set of other 
health insurers for non-
 patients for the 2 year study period. Claims data for the 12 months 
prior to randomization will also be collected if available. 
Participant Selection: 
Inclusion Criteria:   
Patients 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. 
2.) Male or female, age ≥ 18 years at the time of signing informed consent. 
3.) Type 2 diabetes mellitus diagnosis. 
4.) Treatment with either 1 or 2 oral antidiabetic medications. 
5.) Current member of a commercial or Medicare health plan with pharmacy benefits. 
6.) Recorded glycosylated hemoglobin A1c (HbAlc) value within the last 90 days prior to 
randomization. 
7.) Further intensification with an additional antidiabetic oral or injectable medication is 
indicated to achieve glycemic target at the discretion of the study physician according to 
approved labelling. 
Exclusion Criteria: 
Patients presenting with any of the following exclusion criteria will not be eligible for the study: 
1.) Previous randomization in this study. 
2.) Treatment with more than 2 oral antidiabetic medications or any injectable medication in a 
period of 30 days before the day of eligibility assessment. Temporary/emergency use of any 
type of insulin is allowed, as is prior insulin treatment for gestational diabetes.  
3.) Contraindications to semaglutide according to the FDA approved label. 
4.) Female who is pregnant, breastfeeding or intends to become pregnant. 
5.) Participation in another clinical trial. 
Study Procedures: 
 
Study physicians will identify eligible patients for participation. 
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 
Study physicians will obtain written informed consent from patients and if eligible, patients 
will be randomized to either semaglutide or SOC. 
 
Study data will be collected on electronic Case Report Forms (eCRFs) via an electronic data 
capture (EDC) system. 
 
Study physicians or site personnel will collect demographic, clinical (i.e., height, weight, 
systolic blood pressure (SBP), diastolic blood pressure (DBP)), medical and T2DM specific 
history, antidiabetic medications, and pre-specified concomitant medications related to 
cardiovascular risk data prior to or at randomization. Individualized HbA1c target will be set 
prior to randomization. 
 
Baseline HbA1c will be collected from physician sites during eligibility assessment and will 
be the value closest to the date of randomization, within 90 days. All post-randomization 
HbA1c values will be recorded as available per routine clinical practice during the 2 year 
study period. Post-randomization HbA1c values are required for the year 1 and year 2 
dedicated study visits. 
 
PROs and ClinROs will be completed at randomization, year 1, and year 2. 
 
Study physicians will collect patient data (HbA1c, study and antidiabetic medication 
changes, pre-specified concomitant medications related to cardiovascular risk, weight, SBP, 
DBP, hypoglycemic events leading to inpatient admission or emergency room (ER) 
encounter, adverse events (AEs) leading to study drug discontinuation, serious adverse 
events (SAEs), and pregnancies at the dedicated year 1 and year 2 study visits, as well as at 
any routine diabetic care visits during the 2 year study period.  Of note, AEs leading to study 
drug discontinuation or SAEs will be collected from all interactions with the patient, as well 
as if discovered when reviewing documents from healthcare encounters with other providers. 
 
Administrative medical claims, pharmacy claims and health plan eligibility data will be 
captured from the HIRD for 
 patients or requested, via patient written authorization, 
from a set of other health insurers for the duration of the 2 year study period. Claims data for 
the 12 months prior to study randomization will also be collected if available. This data will 
be used for HCRU measures, as well as adherence and persistence to treatment.  
Study Duration: Planned patient time on study will be 2 years. Administrative claims data will also 
be captured during this time period. Patients will be followed for the full 2 year study period 
regardless of changes in or discontinuation of antidiabetic treatment, other than withdrawal of 
consent. 
Questionnaires: Diabetes treatment satisfaction, generic health-related quality of life (HRQoL), 
work productivity, and patient and clinician global assessments will be measured at the 
randomization, year 1, and year 2 dedicated study visits. 
Statistical Analysis: Two estimands, each targeting a unique research question, have been defined to 
adequately describe the effect of semaglutide as compared to SOC (excluding semaglutide).  
The primary estimand for all objectives will be the “intention-to-treat” estimand evaluating the 
effectiveness of randomized treatment intervention, irrespective of adherence to this randomized 
intervention or changes to other antidiabetic medication. 
The secondary estimand for all objectives, with the exception of the adherence and persistence to 
treatment objective, is the “if all patients had adhered” estimand. This estimand evaluates the effect 
of randomized treatment intervention for all randomized patients if all patients had adhered to 
randomized treatment, regardless of changes to other antidiabetic medication. 
Baseline is defined as ≤ 90 days prior to randomization visit (week 0) for HbA1c. For secondary 
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endpoint assessments, baseline is defined as ≤ 4 weeks prior to the randomization visit (week 0). 
Primary completion date (PCD) is the date the last patient completes the year 1 dedicated study visit. 
The primary endpoint is binary, with success represented by an HbA1c <7.0% (53 mmol/mol) at year 
1 (yes/no). Confirmatory secondary endpoints include:  
 
Change in HbA1c (%-point) from baseline to year 1 
 
HbA1c <7.0% (53 mmol/mol) at year 2 (yes/no) 
 
Change in HbA1c (%-point) from baseline to year 2 
This study is designed to have 90% power to confirm superiority of the primary endpoint and 85% 
power to also confirm superiority of the first confirmatory secondary endpoint based on an analysis 
of the primary estimand for each of the endpoints.    
The confirmatory endpoints will all be tested under multiplicity control via a hierarchical testing 
scheme according to the order given in the above bullet list. 
The estimand informs choices about data foundation and statistical analysis including possible 
imputation of missing data, hereby ensuring that randomization is preserved as a sound basis for 
statistical inference; i.e., estimation of effect size, associated uncertainty, and statistical testing.  
The full analysis set (FAS) comprising all randomized patients will be the analysis population for 
evaluation of both the primary and secondary estimands. For both estimands, the primary endpoint, 
HbA1c <7.0%, will be analyzed using a logistic regression model with a logit link function and will 
include treatment and baseline HbA1c as independent variables. Continuous endpoints will be 
analyzed using analysis of covariance (ANCOVA) and will include the same independent variables. 
Prior to analysis, missing data will be imputed by multiple imputation on the continuous HbA1c scale 
and subsequently dichotomized for the primary endpoint. 
Supplementary Analyses: Two complete case analyses will complement the analyses for the 
primary and secondary estimands. The supplementary complete case analyses will be based on the 
subset of patients without missing endpoint data, i.e., patients that do not have their endpoint imputed 
in the two analyses used for the primary estimand and the secondary estimand, respectively.    
Secondary Analyses: Secondary analyses will compare semaglutide versus SOC treatment groups in 
terms of change in body weight, SBP, DBP, and PRO and ClinRO measures, based on the similar 
analysis methods as for the primary and secondary estimands. Similarly, binary endpoints and other 
secondary endpoints will be compared statistically between treatment groups, including HCRU and 
adherence/persistence to treatment measures, hypoglycemic events leading to inpatient admission or 
ER encounter, as well as composite measures of HbA1c, weight loss, and hypoglycemia. 
Safety: The principal study physician is responsible for monitoring the safety of participating 
patients. For the purposes of this study, AEs that do not meet the definition of an SAE will only be 
collected/recorded in the EDC if they lead to study drug discontinuation. Study physicians are 
responsible for reporting all SAEs and following the patient until the outcome of the SAE is closed 
out. All SAEs will be reported from randomization until end of study (EOS) at year 2 or patient study 
withdrawal. Study physicians are also responsible for recording all pregnancies in female patients 
from randomization until EOS at year 2 or patient study withdrawal. The patient 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  
ADA 
American Diabetes Association 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
eCCGs 
Electronic Case Report Form Completion Guidelines 
CFR 
Code of Federal Regulations 
CGI-C 
Clinical Global Impression of Change 
CGI-S 
Clinician Global Impression of Disease Severity 
CI 
Confidence Interval 
ClinRO 
Clinician Reported Outcome 
eCRF 
Electronic Case Report Form 
DBP 
Diastolic Blood Pressure 
DPP-4 
Dipeptidyl peptidase 4 
DTSQ 
Diabetes Treatment Satisfaction Questionnaire 
DTSQc 
Diabetes Treatment Satisfaction Questionnaire, change version 
DTSQs 
Diabetes Treatment Satisfaction Questionnaire, status version 
EASD 
European Association for the Study of Diabetes 
EDC 
Electronic Data Capture 
EOS 
End of Study 
ER 
Emergency Room 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FDC 
Fixed Dose Combination 
GCP 
Good Clinical Practice 
GLP-1 RA 
Glucagon-Like Peptide-1 Receptor Agonists 
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HbA1c 
Glycosylated Hemoglobin A1c 
HCRU 
Healthcare Resource Utilization 
HEDIS 
Healthcare Effectiveness Data and Information Set 
HIRDSM 
HealthCore Integrated Research Database 
HIPAA 
Health Insurance Portability and Accountability Act 
HRQoL 
Health-Related Quality of Life 
ICF 
Informed Consent Form 
ICMJE 
International Committee of Medical Journal Editors 
ID 
Identifier 
IRB 
Institutional Review Board 
ITT 
Intent to Treat 
LPLV 
Last Patient Last Visit 
LTFU 
Lost to Follow-Up 
MedDRA 
Medical Dictionary for Regulatory Activities 
MCS-12 
Mental Summary Component (of the Short Form 12-Item version 2) 
MPR 
Medication Possession Ratio 
OR 
Odds Ratio 
PCD 
Primary Completion Date 
PCS-12 
Physical Summary Component (of the Short Form 12-Item version 2) 
PCT 
Pragmatic Clinical Trial 
PDC 
Proportion Days Covered 
PGI-C 
Patient Global Impression of Change 
PGI-S 
Patient Global Impression of Disease Severity 
PRO 
Patient Reported Outcome 
PT 
Preferred Term 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
SD 
Standard Deviation 
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SF-12v2 
Short Form 12-Item version 2 
SGLT-2 
Sodium-Glucose Co-transporter 2 
SM 
Service Mark 
SOC 
Standard of Care 
SUSTAIN 
Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes 
T2DM 
Type 2 Diabetes Mellitus 
TD 
Treatment Difference 
US 
United States 
WPAI-GH 
Work Productivity and Activity Impairment, General Health 
 
 
 
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LIST OF DEFINITIONS 
 
Term 
Definition  
Administrative Claims 
Data 
Medical, pharmacy, and health plan eligibility data created in the 
processing of medical and pharmacy claims. The claims data utilized in 
this study are obtained from the HealthCore Integrated Research 
Database (HIRD) for 
 patients and requested, via patient 
written authorization, from a set of other health insurers for non-
 patients. 
Baseline 
Baseline refers to assessments conducted and patient data collected at 
or prior to randomization. Baseline HbAlc may be ≤ 90 days prior to 
randomization. Baseline for secondary endpoint assessments may be ≤ 
4 weeks prior to randomization. 
Baseline Endpoint 
For continuous endpoints and endpoints derived from continuous 
sources, the baseline value is defined as the last assessment taken prior 
to or at the randomization visit and before first use of study drug. 
Comparator Treatment 
Standard of Care (SOC) (excluding semaglutide); Commercially 
available oral or injectable antidiabetic medication, excluding 
semaglutide, prescribed at the discretion of the study physician for 
antidiabetic treatment intensification following randomization. 
Complete the Study 
Complete the study at 52 weeks: Patient has year 1 HbA1c data 
Complete the study at 104 weeks: Patient has year 2 HbA1c data 
Dedicated Study Visit 
One of three required study visits: randomization, year 1, and year 2. 
Enrollment 
Randomization 
Estimand 
The estimate targeted to address the research question posed by the 
study objective, i.e., “what is to be estimated.” [1] The estimand 
translates the study objective into a precise definition of the effect of 
treatment. 
Healthcare Resource 
Utilization (HCRU) 
Broad term encompassing use of healthcare services, including 
inpatient admissions, ER encounters, outpatient encounters including 
office visits, and pharmacy prescription fills. 
Index Date 
The date corresponding to an event of interest. In this study, index date 
is the date corresponding to a claims-based proxy for antidiabetic 
treatment intensification for 2 comparator populations, thus mimicking 
randomization date in the study population. 
Principal Study 
Physician 
Physician at study site who is responsible for the overall conduct and 
oversight of the study at their site, including: supervision of study 
personnel, monitoring the safety of all participating patients, ensuring 
the accurate and complete collection and reporting of study data, 
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continued review of the IRB study approval, and maintenance of study 
records. This term is analogous to “Investigator” in Good Clinical 
Practice (GCP) requirements.  
Randomization 
The point at which a patient is assigned by chance to either semaglutide 
or standard of care (SOC). 
Routine Diabetic Care 
Visit 
An office visit or other patient contact during the study period that 
occurs outside of the dedicated study visits (randomization, year 1, and 
year 2) according to routine clinical practice. 
Study Physician 
Physician at study site who participates in the conduct of the study. 
Study/Trial 
For the purposes of this protocol, study and trial are considered 
synonyms. Study is used throughout the body of the text as it reflects 
the post-regulatory approval setting and real world design. Trial is used 
in the title and in referring to the PCT acronym to maintain consistency 
with the industry standard Pragmatic Clinical Trial or PCT.  
Study Drug 
Study drug is the first antidiabetic oral or injectable medication 
prescribed for treatment intensification following randomization. A 
patient can start and stop study drug throughout the study. At any time 
during the duration of the study, if a patient is taking study drug as 
defined, they will be considered “on study drug” regardless of prior 
study drug discontinuations. 
 For the semaglutide treatment group, study drug is defined as 
semaglutide. 
 For the SOC treatment group, study drug is defined as the drug class 
of the first antidiabetic oral or injectable medication prescribed for 
treatment intensification following randomization. If a fixed dose 
combination (FDC) product is prescribed, one of the drugs will be 
chosen by the study physician to be the study drug. A patient 
randomized to the SOC treatment group will still be considered “on 
study drug” if they are taking a drug in the same drug class as their 
first study drug, even if it is not the same individual drug. This also 
applies to treatment intensification with a FDC product if one of the 
drugs is in the same drug class as the first study drug. 
Study Drug 
Discontinuations 
Study drug discontinuation is termination of the study drug. A patient 
can start and stop study drug throughout the study; therefore a patient’s 
study drug discontinuation status can change throughout the duration of 
the study. At any time during the duration of the study, if a patient is 
not taking study drug as defined, they will be considered “off study 
drug.” 
 
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1 
INTRODUCTION 
1.1 
Background and Rationale 
The American Diabetes Association (ADA) and European Association for the Study of Diabetes 
(EASD) position statement recommends a patient-centric approach to the selection of 
pharmacological treatment for type 2 diabetes mellitus (T2DM), including considerations on 
effectiveness, hypoglycemia risk, impact on body weight, side effects, costs, and patient 
preferences. [2] Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are recommended for 
the management of hyperglycemia in T2DM, primarily in combination with other antidiabetic 
medications. [2] [3] 
Semaglutide, a human GLP-1 analogue for once-weekly subcutaneous administration, has been 
shown to improve glycemic control in adults with T2DM as monotherapy when the use of 
metformin is considered inappropriate, or as add-on to other glucose lowering therapies 
including insulin. In the Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes 
(SUSTAIN) clinical development program, semaglutide demonstrated clinically relevant and 
superior glycemic control, as well as weight loss versus placebo and active comparators, both 
when used as mono- and combination therapy in inadequately controlled patients with T2DM. In 
addition, a significant reduction in cardiovascular risk was demonstrated for semaglutide versus 
placebo in patients with T2DM at high risk of cardiovascular events. The overall safety profile of 
semaglutide was consistent with the well-established GLP-1 RA safety profile. [4] 
Pragmatic clinical trials (PCTs) are designed and conducted to reflect patient outcomes and to 
investigate how a product is used and performs in routine clinical practice. This type of study 
compares two or more medical interventions that are directly relevant to clinical care and strives 
to assess those interventions’ effectiveness in real world practice. They use broad eligibility 
criteria and recruit patients from a variety of practice settings to ensure the inclusion of the type 
of patients whose care will be influenced by the study´s results. Such studies are increasingly 
important to generate evidence regarding real world treatment outcomes to inform and support 
appropriate market access. [5] 
The current local US study serves the purpose of evaluating the long term comparative 
effectiveness of semaglutide with existing commercially available antidiabetic medications in a 
real world population and in a variety of practice settings, thereby maximizing external validity 
while balancing the internal validity of a randomized controlled trial. This will generate data to 
complement the findings from the SUSTAIN clinical development program. Taken together, 
these findings may provide important evidence for decision making by clinicians, payers, and 
policy makers in routine clinical practice. 
This local US study will enroll adult patients with T2DM who have inadequate glycemic control 
on up to 2 oral antidiabetic medications, as defined by the need for treatment intensification with 
an additional antidiabetic oral or injectable medication per the study physician´s discretion. The 
current study targets patients at this particular treatment point because they represent the 
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population inadequately controlled on the current ADA recommended first lines of treatment of 
T2DM. The addition of a GLP-1 RA as second-line treatment is in line with the ADA guidance 
from 2017.  [6] In keeping with the ADA and EASD position statement recommending a patient-
centric approach to treatment selection for T2DM patients, in addition to comparative 
effectiveness, this study will also evaluate hypoglycemia risk, body weight, healthcare resource 
utilization (HCRU), patient reported outcomes (PROs), and clinician reported outcomes 
(ClinROs). Adverse events (AEs) leading to study drug discontinuation will also be collected.  
[2] 
  
2 
STUDY OBJECTIVES  
2.1 
Primary Objective 
The primary objective is to demonstrate superior long term effects of treatment with semaglutide 
compared to standard of care (SOC) both added to up to 2 oral antidiabetic medications on 
glycemic control when used as intensification in routine clinical practice in adult patients with 
T2DM.  
2.2 
Secondary Objectives 
The secondary objectives are to compare the long term effect of semaglutide versus SOC both 
added to up to 2 oral antidiabetic medications and used as intensification in routine clinical 
practice in adult patients with T2DM with regards to: 
 Weight loss 
 Patient reported outcomes (PROs) and clinician reported outcomes (ClinROs) 
 Hypoglycemia  
 Healthcare Resource Utilization (HCRU) 
 Adherence and persistence to treatment 
  
3 
STUDY ENDPOINTS 
3.1 
Baseline 
Baseline is defined as ≤ 90 days prior to randomization visit (week 0) for glycosylated 
hemoglobin A1c (HbA1c). For secondary endpoint assessments, baseline is defined as ≤ 4 weeks 
prior to the randomization visit (week 0). 
3.2 
Primary Endpoint 
Primary completion date (PCD) is the date the last patient completes the year 1 dedicated study 
visit. 
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The primary endpoint of this study is: 
 HbA1c <7.0% (53 mmol/mol) at year 1 (yes/no) 
3.3 
Secondary Endpoints 
3.3.1 Confirmatory Secondary Endpoints 
Confirmatory secondary endpoints of this study include: 
 Change in HbA1c (%-point) from baseline to year 1 
 HbA1c <7.0% (53 mmol/mol) at year 2 (yes/no)  
 Change in HbA1c (%-point) from baseline to year 2 
3.3.2 Supportive Secondary Endpoints 
Supportive secondary endpoints of this study include: 
 Individualized HbA1c target attained at year 1 (yes/no) 
 HbA1c <7.0% (53mmol/mol) or at least 1% point improvement in HbA1c compared to 
baseline at year 1 (yes/no) 
 HbA1c target attainment per Healthcare Effectiveness Data and Information Set (HEDIS) 
criteria (<8.0% if age ≥65 years or with defined comorbidities, otherwise <7.0%) at year 
1 (yes/no) 
 Change in body weight (lb) from baseline to year 1 
 Change in body weight (%) from baseline to year 1 
 Change in systolic blood pressure (SBP; mm Hg) from baseline to year 1 
 Change in diastolic blood pressure (DBP; mm Hg) from baseline to year 1 
 Time to first study drug discontinuation during 2 years (day) 
 Time to first treatment intensification (add-on) or change (switch) after randomization 
during 2 years (day) 
 Study drug medication adherence for the first year of the study, as measured by 
medication possession ratio (MPR) (%) 
 Number of hypoglycemic episodes leading to an inpatient admission or emergency room 
(ER) encounter from baseline to year 2 
 Diabetes Treatment Satisfaction Questionnaire, change version (DTSQc), Total treatment 
satisfaction score measured at year 1 
 DTSQc, Total treatment satisfaction score measured at year 2 
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 Change from baseline in Short Form 12-Item Version 2 Survey (SF-12 v2), Physical 
summary component (PCS-12) score at year 1 
 Change from baseline in SF-12 v2, PCS-12 score at year 2 
 Change from baseline in SF-12 v2, Mental summary component (MCS-12) score at year 
1 
 Change from baseline in SF-12 v2, MCS-12 score at year 2 
 Change from baseline in Work Productivity and Activity Impairment, General Health 
questionnaire (WPAI-GH) Absenteeism (work time missed) score at year 1 
 Change from baseline in WPAI-GH Absenteeism (work time missed) score at year 2 
 Change from baseline in WPAI-GH Presenteeism (impairment at work / reduced on-the-
job effectiveness) score at year 1 
 Change from baseline in WPAI-GH Presenteeism (impairment at work / reduced on-the-
job effectiveness) score at year 2 
 Change from baseline in WPAI-GH Work productivity loss (overall work impairment / 
absenteeism plus presenteeism) score at year 1 
 Change from baseline in WPAI-GH Work productivity loss (overall work impairment / 
absenteeism plus presenteeism) score at year 2 
 Change from baseline in WPAI-GH Activity Impairment score at year 1 
 Change from baseline in WPAI-GH Activity Impairment score at year 2 
All cause healthcare resource utilization (HCRU) from baseline to year 2: 
 Number of inpatient admissions 
 Cumulative length of stay for inpatient admissions (days) 
 Number of ER encounters 
 Number of outpatient encounters 
 Number of medications 
 Occurrence of inpatient admission (yes/no) 
 Occurrence of ER encounter (yes/no) 
 Occurrence of outpatient encounter (yes/no) 
Diabetes related HCRU from baseline to year 2: 
 Number of diabetes related inpatient admissions 
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 Cumulative length of stay for diabetes related inpatient admissions (days) 
 Number of diabetes related ER encounters 
 Number of diabetes related outpatient encounters 
 Number of diabetes related medications 
 Occurrence of diabetes related inpatient admission (yes/no) 
 Occurrence of diabetes related ER encounter (yes/no) 
 Occurrence of diabetes related outpatient encounter (yes/no) 
3.3.3 Exploratory Endpoints 
Not applicable. 
  
4 
STUDY DESIGN 
4.1 
Overview 
This is a 2-year, multi-center, randomized, open label, parallel group, active comparator PCT 
comparing semaglutide versus SOC when added to up to 2 oral antidiabetic medications as 
treatment intensification among adult T2DM patients in the course of routine clinical practice. 
Patients will be randomized 1:1 to receive either semaglutide or SOC. 
The decision that further antidiabetic treatment intensification with an additional oral or 
injectable antidiabetic medication is indicated is at the discretion of the study physician and will 
be made prior to and independent of enrollment in this study. The study physician will have 
determined the patient’s suitability for treatment with semaglutide prior to inviting them to 
participate in the study. However, the determination to initiate semaglutide versus SOC will be 
made by randomization.  
Patients will be followed for 2 years, regardless of changes in antidiabetic treatment over the 
course of the study. Data collection will continue for the full 2 year study period unless a patient 
withdraws informed consent. Patients who enroll in the study agree to the release of health 
information, and to answer questions about their health during the course of the study. 
Additionally, medical and pharmacy claims data will be extracted for the 2 year study period, as 
well as up to 12 months prior to randomization as available. 
In keeping with the study objectives and pragmatic design to evaluate semaglutide versus SOC in 
real world, routine clinical practice, inclusion and exclusion criteria are minimally restrictive and 
there are few study-specific evaluations. Study physicians will follow and treat patients 
according to their routine clinical practice and judgement. All oral and injectable antidiabetic 
medications are allowed at the study physicians' discretion, with the exception of semaglutide in 
the SOC group. It is anticipated that patients will undergo medical evaluation at regular intervals 
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over the course of the study duration as per standard of care, but the only dedicated study visits 
are at randomization, at year 1, and at year 2. The study will also capture clinical data collected 
at the sites during routine diabetic care visits, i.e., office visits and other patient contacts that 
occur as part of routine clinical practice. Assessments will be conducted according to the study 
physician’s routine clinical practice, with a few study-specific assessments as described in 
section 5. The data available may differ from site to site and patient to patient. To ensure 
flexibility, the dedicated year 1 and year 2 study visits have a window of ±6 weeks. 
4.2 
Practice and Patient Selection 
The target population for this study consists of adult T2DM patients on up to 2 oral antidiabetic 
medications who are in need of treatment intensification with an additional antidiabetic oral or 
injectable medication. To support study objectives, including claims analysis of HCRU, eligible 
patients will also be currently insured through a commercial health plan or Medicare with 
pharmacy benefits.  
Study site recruitment will target both primary care practitioners and specialized 
endocrinologists to reflect diverse treatment settings and patient populations. Potential sites will 
be evaluated regarding feasibility of their participation in the study, including having a T2DM 
population to meet enrollment goals. Potential sites will be tiered based on their estimated 
number of eligible study patients, and outreach will begin with all sites that meet a pre-
determined minimum number of potentially eligible patients. Outreach and follow-up will be 
performed until the requisite number of physician sites is enrolled. Study-specific assessments 
have been kept to a minimum, thereby decreasing burden on study sites and increasing 
participation to a wide range of sites. 
4.2.1 Physician Practices  
Participation of approximately 200 physician sites in the US, including both general practitioners 
and endocrinologists, is anticipated. 
4.2.2 Patient Recruitment and Eligibility 
Eligible patients include adult T2DM patients whose physicians determine that they have 
inadequate glycemic control on 1 or 2 oral antidiabetic medications. Inadequate glycemic control 
is defined by the need for T2DM treatment intensification with an additional antidiabetic oral or 
injectable medication, as determined by the study physician. Patients 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 a broad population of adult T2DM patients 
to generate data in a population that reflects the heterogeneity of a real world population treated 
in general practice, and support the study objectives to evaluate semaglutide versus SOC in real 
world, routine clinical practice. 
4.2.3 Patient Inclusion Criteria 
Patients must meet all of the following inclusion criteria to be eligible for the study: 
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1. Informed consent obtained before any study-related activities. Study-related activities are 
any procedures that are carried out as part of the study. 
2. Male or female, age ≥ 18 years at the time of signing informed consent. 
3. Type 2 diabetes mellitus diagnosis. 
4. Treatment with either 1 or 2 oral antidiabetic medications. 
5. Current member of a commercial or Medicare health plan with pharmacy benefits. 
6. Recorded HbAlc value within last 90 days prior to randomization. 
7. Further intensification with an additional antidiabetic oral or injectable medication is 
indicated to achieve glycemic target at the discretion of the study physician according to 
approved labelling. 
4.2.4 Patient Exclusion Criteria 
Patients presenting with any of the following exclusion criteria will not be eligible for the study: 
1. Previous randomization in this study. 
2. Treatment with more than 2 oral antidiabetic medications or any injectable antidiabetic 
medication in a period of 30 days before the day of eligibility assessment. 
Temporary/emergency use of any type of insulin is allowed, as is prior insulin treatment 
for gestational diabetes.  
3. Contraindications to semaglutide according to the FDA approved label. 
4. Female who is pregnant, breastfeeding or intends to become pregnant. 
5. Participation in another clinical trial. 
4.2.5 Patient Enrollment 
Planned number of patients to be randomized: 1387 
Expected number of patients to complete the study after 52 weeks: 1040 
Expected number of patients to complete the study after 104 weeks: 780 
4.2.6 Patient Randomization 
Study patients will be randomized to either semaglutide or SOC in a 1:1 ratio. The study design 
and patient randomization is depicted in Figure 1. 
 
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Figure 1 Study design diagram. Patients will be randomized in a 1:1 manner using centralized 
allocation to receive semaglutide or SOC as add-on to up to 2 oral antidiabetic medications.  
 
5 
STUDY PROCEDURES 
The study visit schedule is summarized in Appendix 1. 
5.1 
Enrollment Procedures 
The determination that a patient has inadequate glycemic control on up to 2 oral antidiabetic 
medications, and the subsequent decision to intensify antidiabetic treatment with an additional 
oral or injectable antidiabetic medication, will be made by the study physician during the course 
of routine clinical practice. Following the decision to initiate treatment intensification, the study 
physician will determine the patient’s suitability for the study. Suitability for the study will be 
assessed using the current inclusion and exclusion criteria, including the approved label for 
semaglutide. Only patients who are eligible for treatment intensification and have been found 
suitable for treatment with semaglutide, as determined by the study physician, are in scope for 
randomization. Prior to being randomized, patients must be willing to intensify with an 
antidiabetic medication, including GLP-1 receptor agonists. Study physicians will set and 
document an individualized HbA1c target for patients prior to randomization based on their 
clinical judgement and knowledge of the patient. To preserve the real-world nature of the study, 
patients will be approached for potential enrollment into the study through their physician if 
review of their medical history indicates that they may be eligible for the study. Outreach may 
occur when patients present to their physician as part of their standard care or through proactive 
contact of potentially eligible patients identified within the study physician’s practice. 
Informed consent will be obtained prior to any study related activities. The most recent HbA1c 
completed in the course of routine care up to 90 days prior to and including the date of 
randomization will be considered a baseline assessment and does not need to be repeated. 
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Study physicians or site personnel will collect patient characteristics and study data at each study 
visit as outlined in the Time and Events Schedule (Appendix 1), either directly from the patient 
or abstracted from the patient’s medical records, and enter them into the electronic Case Report 
Form (eCRF). 
5.2 
Randomization Visit 
Following informed consent and confirmation of inclusion/exclusion criteria, patients will be 
randomized to either semaglutide or SOC. Data collection at the randomization visit will include 
inclusion/exclusion criteria as well as the data outlined in the sections below. PRO and ClinRO 
questionnaires will also be administered (section 5.3). 
5.2.1 Patient Characteristics 
Baseline assessments at the randomization visit will include: demographic data, medical history, 
diabetes history including antidiabetic medications and diabetes complications, pre-specified 
concomitant medications related to cardiovascular risk, and clinical data (weight, height, HbA1c, 
SBP, DBP). Individualized HbA1c target will be set prior to randomization. The baseline HbA1c 
will be the patient’s most recent HbA1c within 90 days of randomization. 
5.2.2 Treatments 
To preserve the real-world nature of the study, the patient experience will be as close to routine 
care as possible. The study physician will be one of the patient’s own treating physicians, who 
may make treatment adjustments according to their clinical judgement. The study physician can 
make repeat prescriptions of the study drug as usual, which are collected by patients from the 
pharmacy of their choice. Patients will be randomized to either semaglutide or SOC. Treatment 
details will be recorded in the eCRF. 
Semaglutide Group 
Patients randomized to the semaglutide group will be prescribed commercially available 
semaglutide in a prefilled pen injector and will be instructed to initiate treatment with 
semaglutide according to the approved label. The study physician will determine the intended 
maintenance dose of semaglutide, as well as changes to the maintenance dose thereafter. Add-on, 
discontinuation or dose modification of antidiabetic medication, including semaglutide, during 
the study is allowed at the discretion of the study physician. 
Semaglutide Study Drug: For patients randomized to the semaglutide group, study drug is 
defined as semaglutide. 
SOC Group 
SOC is defined as commercially available oral or injectable antidiabetic medication (see current 
representative list below) other than semaglutide. Patients randomized to SOC will be prescribed 
and instructed to initiate commercially available antidiabetic medication according to the 
approved label and, if relevant for the specific antidiabetic medication, adjusted at the discretion 
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of the study physician. Patients randomized to SOC may discontinue SOC, add-on to the SOC or 
switch to another antidiabetic medication during the study, with the exception of semaglutide 
which is not allowed in the SOC group for the duration of the study. 
SOC Study Drug: For patients randomized to the SOC group, study drug is defined as the 
drug class of the first antidiabetic oral or injectable medication prescribed for treatment 
intensification following randomization. If a fixed dose combination (FDC) product is 
prescribed, one of the drugs will be chosen by the study physician to be the study drug. A 
patient randomized to the SOC treatment group will still be considered “on study drug” if 
they are taking a drug in the same class as their first study drug, even if it is not the same 
individual drug. This also applies to treatment intensification with a FDC product if one 
of the drugs is in the same class as the first study drug. 
Study Drug: Start/Stop, Discontinuations 
Study drug discontinuation is termination of the study drug. A patient can stop or start study drug 
throughout the study; therefore a patient’s study drug discontinuation status can change 
throughout the duration of the study. At any time during the duration of the study, if a patient is 
not taking study drug as defined, they will be considered “off study drug.” Conversely, at any 
time during the duration of the study, if a patient is taking study drug as defined, they will be 
considered “on study drug,” regardless of prior study drug discontinuations.  
If a participating patient becomes pregnant, the study physician will review the patient’s 
antidiabetic treatment regimen and make any changes necessary according to standard care of 
patients with T2DM during pregnancy. Semaglutide will be discontinued and will not be 
restarted unless the patient is no longer pregnant or breast-feeding. All study drug copay 
assistance will end.  
Copay assistance 
The study products will be handled and dispensed by the patients’ pharmacy(s) per their 
preference and health plan benefits. In order to minimize the impact of any differential in out-of-
pocket costs between the treatment groups, an out-of-pocket maximum will be provided by Novo 
Nordisk as part of the study. In both treatment groups, the patient’s copay will be up to the 
specified maximum for the study drug (as defined above) and ancillary needles (if required to 
administer the study drug). Copay assistance will only apply to the study drug as defined above 
(i.e., not to any subsequent add-on treatment or treatment changes outside the study drug 
definition). Because patients can start and stop study drug throughout the study, copay assistance 
may also start and stop throughout the study. For the duration of the study, any time a patient is 
“on study drug” they will receive copay assistance, and any time a patient is “off study drug” 
they will not receive copay assistance. The only exceptions are if a patient initiates prescription 
coverage through Medicaid, at which point all copay assistance will end. 
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Products 
A current representative list of the products used in this study is below. All treatments will be 
used in accordance with local clinical practice and guidelines. Products with more than one 
active substance i.e., FDC products, can be used in this study. 
Semaglutide: Semaglutide in a prefilled pen (Ozempic®) 
Oral antidiabetic drugs: The oral antidiabetic drug classes included in this study are the 
commercially available options (listed in alphabetic order): 
 Alpha-glucosidase inhibitors 
 Dipeptidyl peptidase 4 (DPP-4) inhibitors 
 Meglitinides 
 Metformin 
 Sodium-glucose co-transporter 2 (SGLT-2) inhibitors 
 Sulfonylureas 
 Thiazolidinediones 
 Other 
o Bromocriptine 
o Colesevelam 
Injectable antidiabetic drugs: The injectable antidiabetic drug classes included in this study 
are the commercially available options (listed in alphabetic order): 
 GLP-1 RAs 
 Basal Insulin 
o Long acting insulin 
o Intermediate acting insulin including premix 
 Prandial Insulin 
o Short acting insulin 
o Rapid acting insulin 
 Other 
o Pramlintide 
Background medication: The (up to 2) oral antidiabetic medication(s) taken prior to 
randomization and treatment intensification is considered background medication. Patients may 
discontinue background medication at any time during the study. Patients may change the pre-
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study dose and frequency of background medication at any time during the study. Background 
medication will not be provided nor reimbursed by Novo Nordisk.   
5.3 
Patient Reported Outcomes, Clinician Reported Outcomes, and Diabetes 
Treatment Satisfaction 
Diabetes treatment satisfaction, generic health-related quality of life (HRQoL), work 
productivity, and patient and clinician global assessments will be assessed by the following 
instruments at randomization, year 1, and year 2. Patients will self-administer these instruments 
on paper. Site study personnel will review for completeness and enter responses into the eCRF. 
5.3.1 PRO and Treatment Satisfaction questionnaires 
5.3.1.1 Diabetes Treatment Satisfaction Questionnaire (DTSQ) [7] [8] [9] [10] 
The Diabetes Treatment Satisfaction Questionnaire (DTSQ) evaluates patient satisfaction with 
treatment. The DTSQ status version (DTSQs) will be completed at the randomization visit and 
the DTSQ change version (DTSQc) will be completed at the year 1 and year 2 dedicated study 
visits. 
5.3.1.2 Short Form 12-Item version 2 (SF-12 v2) Health Survey [11] 
The SF-12 v2 is a generic HRQoL questionnaire that assesses physical and mental functioning 
and overall HRQoL. The SF-12v2 standard 4-week recall period questionnaire will be completed 
at the randomization, year 1, and year 2 dedicated study visits. 
5.3.1.3 Work Productivity and Activity Impairment: General Health (WPAI-GH) 
Questionnaire [12] 
The WPAI-GH questionnaire assesses both absenteeism (i.e., work time missed) and 
presenteeism (i.e., impairment at work or reduced on-the-job effectiveness) as well as daily 
activity impairment (e.g., work around the house, shopping, exercising, childcare, studying) 
attributable to general health. The WPAI-GH will be administered at the randomization, year 1, 
and year 2 dedicated study visits. 
5.3.1.4 Patient Global Impression of Disease Severity (PGI-S) and Patient Global Impression 
of Change (PGI-C) 
The PGI-S is a 1-item measure that assesses the patient’s impression of disease severity based on 
their present diabetes symptoms, i.e., normal, mild, moderate, or severe, whereas the PGI-C 
assesses the patient’s impression of changes in diabetes symptoms, based on their diabetes 
symptoms now, compared with how they were before they began taking the study drug, i.e., very 
much better, much better, a little better, no change, a little worse, much worse, or very much 
worse. The PGI-S will be administered at the randomization visit and the PGI-C will be 
administered at the year 1 and year 2 dedicated study visits. 
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5.3.2 Clinician Global Impression of Disease Severity (CGI-S) and Clinician Global 
Impression of Change (CGI-C) 
The CGI-S is a 1-item measure that assesses the clinician’s impression of the patient’s disease 
severity, based on the patient’s present diabetes symptoms, i.e., normal, mild, moderate, or 
severe, whereas the CGI-C assesses the clinician’s impression of change in the patient’s diabetes 
symptoms, based on the patient’s diabetes symptoms now, compared with how they were before 
they began taking the study drug, i.e., very much better, much better, a little better, no change, a 
little worse, much worse, or very much worse. The study physician will complete the CGI-S at 
the randomization visit and the CGI-C at the year 1 and year 2 dedicated study visits. 
5.4 
Study Period 
Patients will be followed from randomization to end of study (EOS) at 2 years, during which 
study physicians or trained site personnel will collect study data and record it in the eCRF at 
dedicated study visits (randomization, year 1, year 2) and routine diabetic care visits. Patients 
will be followed for the full 2 year study period regardless of treatment changes or 
discontinuation during the study period, other than withdrawal of consent. If a patient leaves 
their health plan during the 2 year study period, administrative claims data will be collected from 
randomization through the date they leave the health plan. If the patient switches to another 
health plan during the 2-year study period, an attempt may be made to collect administrative 
claims data from that plan as well. In these scenarios, site-based study data collection will 
continue without change. 
On-study data collection at dedicated study visits and routine diabetic care visits (if available per 
local clinical practice) will include: clinical data (weight, HbA1c, SBP, DBP), treatment details 
(study drug, other antidiabetic medication, pre-specified concomitant medications related to 
cardiovascular risk, reasons for treatment discontinuation as applicable), hypoglycemia leading 
to inpatient admission or ER encounter, AEs leading to study drug discontinuation, pregnancy, 
and serious adverse events (SAEs). Of note, AEs leading to study drug discontinuation or SAEs 
will be collected from all interactions with the patient, as well as if discovered when reviewing 
documents from healthcare encounters with other providers. Additionally, PRO and ClinRO 
instruments will be completed at randomization, year 1, and year 2.  
EOS visit is 2 years (±6 weeks) after randomization. 
5.5 
Administrative Claims Data
In addition to prospectively collected clinical data and PROs, this study will also utilize claims 
data from the HealthCore Integrated Research Database (HIRDSM) for 
 patients or 
requested, via patient written authorization, from a set of other health insurers for non-
 
patients. Data collected will include integrated medical claims, pharmacy claims, and health plan 
eligibility files for the 2 years after the respective patient’s study randomization. Final extraction 
of this data will take place approximately 3 months after the last patient’s last visit (LPLV) to 
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allow for data lags in the claims. Administrative claims data will also be collected for up to 12 
months prior to study randomization, if available. The prospectively collected eCRF study data 
and claims data will be merged into one dataset via a study-specific patient identifier (ID) for 
analysis. 
5.6 
Withdrawals 
5.6.1 Physician Practices 
Novo Nordisk and/or the Institutional Review Board (IRB) reserve the right to terminate the 
study any time. In this event, all data collection will end. After the collected data is received, 
study physicians will be compensated as contractually agreed. 
The IRB reserves the right to terminate participation of individual study sites at any time. 
Individual study sites may also be terminated for cause by Novo Nordisk per contractual 
agreement. In such cases, all data collection at terminated study sites will end. After the collected 
data is received, the study physicians will be compensated as contractually agreed. 
5.6.2 Patients 
Participation in the study is voluntary, and all patients are free to terminate their participation at 
any time. A patient will only be withdrawn from the study if they withdraw consent. In the event 
of study withdrawal, the study physician will record the reason for study withdrawal and 
continue to follow-up with the patient for any unresolved SAEs or pregnancies, if patient agrees. 
Upon patient withdrawal from the study, all data collection will end, but all study data collected 
up to withdrawal will be included in the study database. If a patient has not been in contact with 
the Prescribing Physician by the end of the 2 year study duration period and the site is not able to 
reach the patient after 3 contact attempts, the patient can be considered Lost To Follow-Up 
(LTFU). One of the 3 contact attempts should include a certified letter being sent to the patient.  
If a patient’s status is determined to be LTFU, this must be recorded on the End of Study eCRF. 
 
6 
STATISTICAL METHODS 
6.1 
Introduction 
Patients are randomized 1:1 to semaglutide or SOC. The data analyses for this study will be 
outlined in further detail in a Statistical Analysis Plan (SAP) developed prior to database lock at 
year 1. 
For continuous endpoints and categorical endpoints derived from continuous sources, the 
baseline value is defined as the last assessment taken prior to or at the randomization visit and 
before first use of study drug. 
If endpoint data is missing then any routine care data that are collected within ±10 weeks of the 
dedicated study visit will be used. 
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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 semaglutide as compared to SOC (excluding semaglutide).  
The primary estimand for all objectives will be the “intention-to-treat” (ITT) estimand evaluating 
the effectiveness of randomized treatment intervention irrespective of adherence to this 
randomized intervention or changes to other antidiabetic medication during follow-up. The 
purpose of this estimand is to quantify the expected effect size in the commercially-insured 
health plan population upon adoption of semaglutide as compared SOC (excluding semaglutide), 
and is as such relevant to inform and support appropriate market access and population based 
treatment guidance. 
The secondary estimand for all objectives with the exception of the adherence and persistence to 
treatment objective, is the “if all patients had adhered” estimand. This estimand evaluates the 
effect of randomized treatment intervention for all randomized patients if all patients had 
adhered to randomized treatment, regardless of changes to other (i.e., non-study drug) 
antidiabetic medication. The purpose of this estimand lies in quantifying the expected effect size 
for an individual patient in the commercially-insured health plan population who is prescribed, 
initiates, and continues treatment with semaglutide as compared to SOC (excluding 
semaglutide). The relevance of this effect measure is to inform decision making for individual 
patients and prescribing physicians. 
6.1.2 Confirmatory Endpoints and Hypotheses 
The primary endpoint is HbA1c <7.0% (53 mmol/mol) at year 1 (yes/no). This is a binary 
endpoint. Confirmatory secondary endpoints include:  
 Change in HbA1c (%-point) from baseline to year 1 
 HbA1c <7.0% (53 mmol/mol) at year 2 (yes/no) 
 Change in HbA1c (%-point) from baseline to year 2 
The primary and confirmatory endpoints will all be tested for superiority under multiplicity 
control via a hierarchical testing scheme according to the order given in the above bullet list. 
Confirmatory testing will only be performed for the primary estimand with the secondary 
estimand being supportive. The testing procedure will be stopped the first time an analysis fails 
to confirm superiority of the endpoint in question using a two-sided significance level of 5%. 
Superiority on HbA1c <7.0% will be evaluated with respect to the odds ratio (OR) (odds 
semaglutide / odds SOC): 
H0: OR≤1 against Ha: OR>1 
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Superiority on change in HbA1c (year 1 – baseline; year 2 – baseline) will be evaluated with 
respect to the mean treatment difference (TD) (semaglutide – SOC):  
H0: TD≥0 against Ha: TD<0 
6.1.3 Study Populations 
The following analysis set will be defined: 
Full analysis set (FAS): Includes all randomized patients analyzed according to the treatment 
group to which they were assigned at randomization. 
6.2 
Sample Size Determination  
6.2.1 Power and Sample Size for Primary Objective 
Assumptions for the sample size were based on input from the HIRD claims/laboratory results 
database. In line with the primary ITT estimand, the assumptions for the proportion of patients 
with HbA1c < 7.0% at year 1 and year 2, and for the change from baseline in HbA1c, were based 
on the claims/laboratory results data within the 
 population for all patients initiating 
treatment intensification, regardless of whether patients adhered to this treatment. Specifically, 
for semaglutide, assumptions were based on data for liraglutide and dulaglutide. For SOC, 
assumptions were based on all intensifications in the claims database. The study sample size of 
1,387 was calculated based on the following assumptions, informed from HIRD data: 10% 
difference in proportion patients with HbA1c < 7.0% at year 1 and year 2 (60% semaglutide 
versus 50% SOC), absolute difference in change from baseline HbA1c of 0.5%-point (SD=2.3%) 
between treatment groups, 90% power for confirming superiority of the primary endpoint, and an 
overall alpha leve1 of 5%. Sample size calculations, including different sample size scenarios 
and a summary of the data from the HIRD, will be documented in the SAP. 
The proportion of missing data for the confirmatory endpoints was estimated to be 25% after one 
year and 44% after two years. In the sample size calculation, it was assumed that only non-
missing data at year 1 and year 2 would be used for the respective analyses. This is considered 
conservative, since the use of imputed data in the actual primary analysis (see 6.3) will increase 
the power. When accounting for missing data, randomizing 1387 patients will contribute 1040 
patients for the year 1 analyses and 780 patients for the year 2 analyses, achieving a total power 
of 85% for confirming the two year 1 confirmatory hypotheses. The joint power for confirming 
all 4 confirmatory hypotheses is 58%. The corresponding marginal powers for presence of 
HbA1c < 7.0% at year 1, change in HbA1c to 1 year, presence of HbA1c < 7.0% at year 2, and 
change in HbA1c to 2 years are 90%, 94%, 80%, and 86% respectively. 
6.3 
Statistical Analysis for the Primary Estimand 
The primary estimand will be estimated based on the FAS using data from all patients with 
observations at the dedicated study visit (year 1 for the primary endpoint), with the exception of 
patients who, in violation of the protocol, have initiated semaglutide in the SOC treatment group. 
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The data collected following initiation of semaglutide from these patients will be censored and 
imputed together with missing data. The primary endpoint, HbA1c < 7.0%, will be analyzed with 
a logistic regression model with a logit link function, treatment as a categorical effect, and 
baseline HbA1c as covariate. From the model, the estimated OR (semaglutide versus SOC) will 
be presented. The underlying continuous endpoint of change in HbA1c will be analyzed using 
analysis of covariance (ANCOVA) that will include the same independent variables. From the 
model, the estimated mean difference in change from baseline to dedicated study visit 
(semaglutide versus SOC) will be presented. The estimated treatment effect from each of these 
analyses will be complemented with associated 95% confidence interval (CI) and two-sided p-
value for testing the null-hypothesis of no difference.  
Prior to analysis, missing data will be imputed by multiple imputation on the continuous HbA1c 
scale and subsequently dichotomized for the primary endpoint. 500 complete data sets will be 
generated to adequately account for the uncertainty due to missing data. Missing endpoint data 
will be imputed separately by treatment group and based on patients who remained in the study 
according to study drug treatment status, i.e., according to whether these patients are on or off 
study drug at the dedicated study visit. Data will be imputed based on the assumption that, within 
treatment groups, patients with missing endpoint data will behave like patients with the same 
study drug treatment status at endpoint as the missing patients’ last registered treatment status 
prior to the missing endpoint. For example, for patients withdrawing from the study with an “off 
study drug” treatment status, data will be imputed based on the assumption that the withdrawn 
patients will behave like patients who remain in the study but are not receiving study drug at the 
dedicated study visit. Technically, the imputation model will be an ANCOVA for the endpoint 
data. The ANCOVA will include baseline HbA1c, diabetes duration, age, and sex as independent 
variables. After this model has been used to predict missing values, each of the now 500 
complete data sets will be analyzed as described above. Finally, the multiple analysis results will 
be combined using Rubin’s rule. [13] For the OR the results will be combined on the logarithm 
scale.   
Superiority for the primary endpoint, HbA1c <7.0% at year 1, will be considered established if 
the OR 95% CI is greater than 1, or similarly if the two-sided p-value is significant on a 5% level 
and the treatment OR is in favor of semaglutide. 
If the hierarchical testing scheme allows, superiority for change from baseline to dedicated study 
visit in HbA1c will be considered established if the 95% CI for the estimated treatment 
difference is smaller than 0, or similarly if the two-sided p-value is significant on a 5% level and 
the treatment difference is in favor of semaglutide. 
6.4 
Statistical Analysis for the Secondary Estimand 
The secondary estimand will be estimated based on the FAS. The analysis is similar to the 
primary analysis for the primary endpoint, but varies with regards to the data used and the 
imputation of missing data. Specifically, data will only be used from the subset of patients who 
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are receiving study drug at the dedicated study visit (year 1 for the primary endpoint), in order to 
estimate the treatment effect if all patients had continued treatment. Patients who no longer are 
receiving study drug will be censored and imputed together with missing data. The same will 
apply to patients who, in violation of the protocol, have initiated semaglutide in the SOC group. 
Collectively, missing and censored data will be imputed separately by treatment group based on 
all patients who are on study drug at the dedicated study visit. Data will be imputed based on the 
assumption that withdrawn or censored patients behave like patients that remain in the study and 
continue on study drug. 
The technical aspects of missing data imputation based on multiple imputation, the statistical 
analysis of the multiple complete data sets, and combination of the multiple results will be the 
same as that described for the primary estimand. 
6.5 
Supplementary Analyses 
The HbA1c analyses described for the two estimands above will be complemented with two 
complete case analyses based on the subset of patients without missing endpoint data, i.e., 
patients that do not have their endpoint imputed in the two analyses used for the primary and 
secondary estimand.  
Complete case analysis 
This analysis will be based only on patients with available measurements at the dedicated study 
visit including measurements irrespective of whether patients discontinued study drug or not. 
The analysis will use the same analysis model as described under the primary estimand. 
Complete case on-study drug analysis 
The analysis will be based only on patients with available measurements at the dedicated study 
visit including only measurements for patients still on study drug. The analysis will use the same 
analysis model as described under the primary estimand. 
6.6 
PRO Analysis 
PRO and physician assessments will be measured with the instruments described in Section 5.3. 
Analysis of these measures will address the secondary objective of this study to compare 
semaglutide versus SOC in the study’s patient population as is relates to PRO, i.e., treatment 
satisfaction, generic health outcomes, work productivity, and patient and physician global 
assessment measures, over one and two year observation periods. PRO analysis will 
descriptively summarize these measures at baseline, year 1, and year 2, as well as compare 
semaglutide versus SOC for change from baseline to year 1 and year 2. The continuous change 
from baseline endpoints will be analyzed using the same analysis approach as described under 
the complete case and complete case on-study drug analyses in Section 6.5. Details will be fully 
described in the SAP. 
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6.7 
Safety Analysis 
SAEs and AEs will be collected as described in Section 7. No formal safety analyses are planned 
for this study. SAEs, AEs leading to study drug discontinuation, and pregnancies will be coded 
using Medical Dictionary for Regulatory Activities (MedDRA) and descriptively summarized by 
System Organ Class and Preferred Term (PT). 
6.8 
Other Analyses 
The following analyses are planned to further support the primary objective to compare 
semaglutide versus SOC in glycemic control. They will also address the secondary objectives of 
this study to compare semaglutide versus SOC in the study’s patient population over one and two 
year observation periods as is relates to body weight loss, hypoglycemia, HCRU, and adherence 
and persistence to treatment. The binary and continuous endpoints that include HbA1c, weight, 
SBP, or DBP data will be analyzed using the same analysis approach as described under the 
primary estimand, secondary estimand, and supplementary analysis sections. All other endpoints 
will be analyzed using the same analysis approach as described under the complete case and 
complete case on-study drug analyses in Section 6.5. Further details of these analyses and details 
for analyses of other endpoint types will be fully described in the SAP. 
6.8.1 Supportive Analyses of Glycemic Control 
The proportion of patients achieving the secondary endpoints related to glycemic control at year 
1 as defined in section 3.3.2 (individualized HbA1c target, HbA1c <7.0% (53mmol/mol) or at 
least 1% point improvement in HbA1c from baseline, HbA1c target attainment per HEDIS 
criteria) will be compared between semaglutide and SOC treatment groups using the same 
analysis approach as described under the primary estimand, secondary estimand, and 
supplementary analysis sections. 
Additionally, derived outcome variables for supportive measures of glycemic control (Appendix 
2) will be utilized to support these analyses. 
6.8.2 Weight Loss 
Change in patient weight from baseline to year one will be calculated in pounds and percentage 
as defined in section 3.3.2. Mean change in weight will be compared between semaglutide and 
SOC treatment groups using the same analysis approach as described under the primary 
estimand, secondary estimand, and supplementary analysis sections. 
Additionally, derived outcome variables for supportive measures of body weight loss (Appendix 
2) will be utilized to support these analyses. 
6.8.3 Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) 
Change in patient SBP and DBP from baseline to year 1 and baseline to year 2 will be calculated 
as defined in section 3.3.2 and Appendix 2. Mean change in SBP and DBP will be compared 
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between semaglutide and SOC treatment groups using the same analysis approach as described 
under the primary estimand, secondary estimand, and supplementary analysis sections. 
6.8.4 Hypoglycemia 
The number of hypoglycemic episodes leading to an inpatient admission or ER encounter will be 
reported by patients and compared by semaglutide and SOC treatment groups utilizing a negative 
binomial model. 
Additionally, derived outcome variables for supportive measures of hypoglycemia (Appendix 2) 
will be utilized to support these analyses. 
6.8.5 Healthcare Resource Utilization (HCRU) 
HCRU analyses will compare all-cause and diabetes-related HCRU (inpatient admissions, ER 
encounters, outpatient encounters, and pharmacy utilization) as defined in section 3.3.2 from 
claims data by semaglutide and SOC treatment group from baseline to year 2.   
The details of claims data definitions and calculations will be fully described in the SAP. 
6.8.6 Adherence and Persistence to Treatment 
Adherence and persistence to the study drug will be calculated and compared between 
semaglutide and SOC treatment groups. 
Medication adherence refers to a patient’s conformance to the provider’s recommendation with 
respect to timing, dosage, and frequency of medication taken during the prescribed length of 
time. In claims, adherence is typically measured using either medication possession ratio (MPR) 
or proportion of days covered (PDC). 
Medication persistence refers to whether a patient stays on therapy or the time from initiation to 
discontinuation of therapy. In claims, persistence is typically defined as the duration of time from 
initiation of the therapy to discontinuation or switching, whichever comes first. 
Adherence and persistence will be further defined in the SAP.  
6.8.7 Antidiabetic Treatment Patterns 
Antidiabetic treatment patterns will be assessed and compared between semaglutide and SOC 
treatment groups. This analysis will summarize the number and classification type of antidiabetic 
medications taken during the study period.  
6.8.8 Exploratory Predictive Analysis 
An exploratory predictive analysis will be performed within and between the semaglutide and 
SOC treatment groups to identify predictors of treatment adherence and persistence and glycemic 
control. The objectives of the exploratory predictive analyses are to identify within and between 
treatment groups: 1) patients less likely to discontinue treatment and 2) patients more likely to 
reach clinical target.  
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6.8.9 Evaluation of the Study Population 
To evaluate the generalizability of the study results, an analysis of the study population will be 
performed. The primary objective of this analysis is to evaluate the external validity of the study 
and to understand how the study population fits into the larger T2DM populations within study 
sites and a commercially-insured population as a whole. Two claims-based T2DM patient 
populations will be described and compared to the study population: (1) commercially-insured 
and Medicare Advantage 
 T2DM patients treated with up to 2 oral antidiabetic 
medications who undergo an antidiabetic treatment intensification, and (2) within the study sites, 
commercially-insured and Medicare Advantage 
 T2DM patients treated with up to 2 oral 
antidiabetic medications who are not enrolled in the study, but who undergo an antidiabetic 
treatment intensification. The analysis will compare the demographics, HCRU, and HbA1c 
between the study population and the two comparator populations during the 12 month period 
prior to randomization (for study population) or prior to a claims-based proxy for antidiabetic 
treatment intensification index date (for comparators). Additionally, treatment patterns of non-
enrolled T2DM patients within the practices from which the study patients are recruited will be 
evaluated to identify any relevant patterns of care suggesting channeling of certain types to 
patients away from the study. These analyses will help to contextualize study results within the 
T2DM population broadly. 
The details of this analysis will be fully described in the SAP. 
  
7 
Adverse Event Collection 
The principal study physician is responsible for monitoring the safety of participating patients. 
All SAEs reported by the patients during the study observational period are required to be 
documented on the appropriate SAE reporting form. For the purposes of this study, AEs that do 
not meet the definition of SAE will only be collected if they lead to study drug discontinuation. 
7.1 
Adverse Events 
An AE is defined as any untoward medical occurrence in a patient administered a pharmaceutical 
product or medical device, which does not necessarily have to have a causal relationship to the 
product of device. Study physicians will follow AEs that occur in any patient during this study in 
a manner consistent with routine clinical practice. For the purposes of this study, AEs that do not 
meet the definition of an SAE (section 7.2) will only be collected in the eCRF if they lead to 
study drug discontinuation. 
7.2 
Serious Adverse Events 
All AEs meeting the definition of SAE will be collected in the eCRF. SAEs will be reported 
from the time a patient is randomized until EOS at year 2, or until the patient withdraws from the 
study. An SAE is defined as any AE which results in at least one of the following outcomes: 
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 Initial inpatient admission or prolongation of existing inpatient admission 
 A life-threatening event, i.e., an event in which the patient 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 
 Persistent or significant disability or incapacity 
 Congenital anomaly or birth defect in offspring 
 Death 
 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 patient and may require 
medical or surgical intervention to prevent one of the other listed outcomes. 
7.2.1 Collection Period of Serious Adverse Events 
SAEs will be reported from the time a patient is randomized until EOS at year 2, or until the 
patient withdraws from the study. The principal study physician 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 patient 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. 
At each visit (both routine diabetic care visits and dedicated study visits), patients will be asked 
about AEs including hypoglycemic events, e.g. “Have you experienced any problems since the 
last contact?” Any SAE identified from any patient encounter or notation at any time must be 
reported. 
If an investigator becomes aware of SAEs after EOS at year 2 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 patients 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 patient is randomized until EOS at year 2 or until 
the patient withdraws from the study. The principal study physician is responsible for alerting 
Novo Nordisk or its designee to any drug exposure during pregnancy within 14 days of the first 
knowledge of the pregnancy via the pregnancy reporting form. The study physician will follow 
the patient for the duration of the pregnancy. 
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7.4 
Technical Complaints 
Technical complaints may be reported as per usual practice. However, any SAEs resulting from a 
technical complaint must be reported via EDC. 
 
8 
DATA COLLECTION 
8.1 
Data Sources 
Data sources include primary data collected prospectively by study sites at study visits 
(demographic and clinical data, patient-completed PRO data, and physician reported global 
assessments) as well as secondary data collection utilizing administrative claims data from health 
plans, as available.  In order to maintain patient confidentiality, each patient will be assigned a 
unique patient study ID number upon signing informed consent to use in place of patient name or 
any other identifying information (e.g., medical record number). Clinical study data, 
PROs/ClinROs and claims-derived variables will be integrated into one analysis dataset via this 
confidential patient ID. 
8.2 
Electronic Case Report Forms (eCRFs) 
All clinical study data will be collected at the physician office and entered into eCRF by trained 
site study personnel through a fully validated, 21 CFR 11 and HIPAA compliant EDC system.  
Patients 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.  
Some clinical assessments utilized in this study may be completed in the course of routine 
clinical practice by site personnel not affiliated with study (e.g., blood pressure), however any 
activities completed solely for the study (e.g., data entry, PRO administration) must be done by 
trained site study personnel. For example, a nurse not affiliated with the study may measure 
blood pressure as part of routine care. The data from this assessment may be used for this study, 
but must be extracted from the patient’s medical record and entered into the eCRF by trained site 
study personnel.  
The principal study physician has the ultimate responsibility for the collection and reporting of 
all clinical and patient data through the eCRFs, as well as ensuring that they are accurate and 
complete to the extent possible. 
8.3 
Year One Database Lock 
The primary analysis for this study is a year 1 analysis. Once data collection for year 1 has 
completed, a database lock and year 1 analysis will be performed. The year 1 analysis will not be 
integrated with HCRU and will be limited to year 1 endpoints derived from eCRF data, including 
PRO data. To maintain study integrity for the remaining study period, data from year 1 will be 
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used for limited and confidential communications while complying with public disclosure 
requirements. All other analyses will be conducted following a second database lock once data 
collection for the entire study is 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 physician 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 patients as well as the scientific integrity of the study. Site monitoring will be 
conducted by 
 staff.  
9.1.1 Institutional Review Board (IRB) 
The principal study physician will have prospective IRB approval of the study protocol, ICF, and 
any patient information or recruiting materials prior to commencement of any study activities at 
their site. In the case of a protocol amendment, the study physician 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 patients or others must be reported to the IRB as 
required. 
The principal study physician 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. The principal study physician must 
ensure that each study patient is informed of the study and authorizes release of health 
information prior to study-related activities. The study physician, or study personnel designated 
by the study physician, will obtain written informed consent from each patient prior to initiation 
of any study-related procedures. Each patient will be given a copy of the signed ICF. The 
principal study physician will retain the original signed ICF for each patient. 
The IRB must prospectively approve the ICF and any changes to the ICF during the course of the 
study before use. If a protocol amendment increases the potential risk to the patient, 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 patients entering the study as well as 
from currently enrolled patients if they are affected by the amendment, per IRB guidance. 
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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 principal study physician must agree 
to maintain and allow access to required patient and study records. The principal study physician 
agrees to keep the identity of all participating patients (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). The principal study physician should retain records according 
to local regulations, or as specified in the Clinical Study Agreement, whichever is longer. 
 
10 
PUBLICATION OF STUDY RESULTS 
All information related to this study is considered confidential information belonging to Novo 
Nordisk and 
 as consistent with contractual agreement. 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 with authorship 
following the International Committee of Medical Journal Editors (ICMJE) guidelines. 
Information regarding the study will be disclosed at clinicaltrials.gov and novonordisk-
trials.com. 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 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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REFERENCES 
 
[1]  International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use, "ICH Harmonised Draft Guidline: Estimands and 
Sensitivity Analysis in Clinical Trials E9(R1)," 2017. 
[2]  S. Izzucchi, R. Bergentstal, J. Buse and e. al., "Management of hyperglyacaemia in type 2 
diabetes, 2015: a patient-centred approach. Update to a position statement of the 
American Diabetes Association and the European Association for the Study of 
Diabetes," Diabetologia, vol. 58, no. 3, pp. 429-442, 2015.  
[3]  American Diabetes Association, "Diabetes advocacy. Sec. 15 In Standards of Medical 
Care in Diabetes - 2016," Diabetes Care, vol. 40, no. Suppl. 1, pp. S128-S129, 2016.  
[4]  Investigator's Brochure for s.c. Semaglutide (NN9535), Edition 12 or any updates hereof. 
2017.  
[5]  Health AwpfI: Why pharma needs to work differently with payers and INDs on RWE: 
Learnings from recent survey and symposium..  
[6]  "Standards of Medical Care in Diabetes-2017: Summary of Revisions," Diabetes Care, 
vol. 40, no. Suppl 1, pp. S4-S5, 2017.  
[7]  C. Bradley, "The Diabetes Treatment Satisfaction Questionnaire: DTSQ," in Handbook 
of Psychology and Diabetes: a guide to psychological measurement in diabetes research 
and practice, C. Bradley, Ed., Abingdon, Routledge, 1994, pp. 111-132. 
[8]  C. Bradley, "The Diabetes Treatment Satisfaction Questionnaire (DTSQ): change 
version for use alongside status version provides appropriate solution where ceiling 
effects occur," Diabetes Care, vol. 22, no. 3, pp. 530-532, 1999.  
[9]  C. Bradley, "Patient perceptions of diabetes and diabetes therapy: assessming quality 
of life," Diabetes Metabolism Research and Reviews, vol. 18, pp. S64-S69, 2002.  
[10] C. Bradley, R. Plowright, J. Stewart, J. Valentine and E. Witthaus, "The Diabetes 
Treatment Satisfaction Questionnaire change version (DTSQc) evaluated in insulin 
glargine trials shows greater responsiveness to improvements than the original 
DTSQ," Health and Quality of Life Outcomes, vol. 5, no. 5, p. 57, 2007.  
[11] J. Ware, M. Kosinski and S. Keller, "A 12-item short-form health survey: construction of 
scales and preliminary tests of reliability and validity," Med Care, vol. 34, no. 3, pp. 
220-233, 1996.  
[12] M. Reilly, A. Zbrozek and E. Dukes, "The validity and reproducibility of a work 
productivity and activity impairment instrument," PharmacoEconomics, vol. 4, no. 5, 
pp. 353-365, 1993.  
[13] R. Little and D. Rubin, Statistical analysis with missing data., J. Wiley, Ed., New York: 
John Wiley and Sons, 1987.  
[14] T. Wasser, J. Ycas and O. Tunceli, "Applying Weighting Methodologies to a Commercial 
Database to Project US Census Demographic Data," The American Journal of 
Accountable Care, 2015.  
 
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Appendix 1: Time and Events Schedule  
Study NN9535-4416 
 
Dedicated Study visit, 
Randomization 
 
Routine Diabetic Care  
visits, Year 1 
Dedicated Study visit, 
Year 1 
Routine Diabetic Care 
visits, Year 2 
Dedicated Study visit, 
Year 2 
Time of visit (Weeks)a 
0* 
0-52** 
52±6 
52-104** 
104±6 
PATIENT AND TREATMENT RELATED ASSESSMENTSb 
Informed consentc 
X 
 
 
 
 
Specific authorization forms for release of 
non-
 health plan claims data 
X 
 
X 
 
X 
Inclusion/Exclusion criteria 
X 
 
 
 
 
Demographics (date of birth, gender, race, 
ethnicity) 
X 
 
 
 
 
Selected medical history 
X 
 
 
 
 
Diabetes history and diabetes 
complications 
X 
 
 
 
 
Individualized HbA1c targetd 
X 
 
 
 
 
Type of glucose-lowering medication 
including semaglutidee 
X 
X 
X 
X 
X 
Concomitant cardiovascular medicatione 
X 
X 
X 
X 
X 
Reason for discontinuation of any glucose-
lowering medication 
 
X 
X 
X 
X 
EFFECTIVENESS AND SAFETY RELATED ASSESSMENTS 
Body weight 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
SBP / DBP 
X 
X 
X 
X 
X 
HbA1c 
Xf 
X 
X 
X 
X 
SAEs,g pregnancies, and AEs leading to 
study drug discontinuation 
 
X 
X 
X 
X 
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Study NN9535-4416 
 
Dedicated Study visit, 
Randomization 
 
Routine Diabetic Care  
visits, Year 1 
Dedicated Study visit, 
Year 1 
Routine Diabetic Care 
visits, Year 2 
Dedicated Study visit, 
Year 2 
Healthcare resource utilizationh 
 
X 
X 
X 
X 
Hypoglycemia leading to inpatient 
admission or ER encounter 
 
X 
X 
X 
X 
PROs and Physician Completed Assessments 
DTSQs 
X 
 
 
 
 
DTSQc 
 
 
X 
 
X 
SF-12v2 
X 
 
X 
 
X 
WPAI-GH 
X 
 
X 
 
X 
PGI-S 
X 
 
 
 
 
PGI-C 
 
 
X 
 
X 
CGI-S 
X 
 
 
 
 
CGI-C 
 
 
X 
 
X 
END OF STUDY 
End of study 
 
 
 
 
X 
* Eligibility assessment may take place up to 4 weeks prior to the randomization visit. If eligibility assessment 
occurs prior to the randomization visit, any changes in collected medical history, diabetes history, diabetes 
complications, glucose lowering medications and concomitant cardiovascular mediations will be collected at the 
randomization visit.  
** The year 1 and year 2 routine diabetic care visit windows are determined by the date of the patient’s dedicated 
year 1 study visit. The year 1 routine diabetic care visit window will end immediately prior to the dedicated year 1 
study visit. The year 2 routine diabetic care visit window will begin immediately following the dedicated year 1 
study visit. 
 
Note: In this study, data will be collected from two different data sources: 
1) Data entered into the eCRF will be collected at dedicated study visits and routine diabetic care visits (if 
available per local clinical practice) and will include: demographics, selected medical history, diabetes 
medical history and diabetes complications, individualized HbA1c target, type of glucose-lowing 
medication, concomitant cardiovascular medication, reason for discontinuation of any glucose lowering 
medication, body weight, height, SBP, DBP, HbA1c, AEs leading to study drug discontinuation, SAEs, 
pregnancies and hypoglycemia leading to inpatient admission or ER encounter. Of note, AEs leading to 
study drug discontinuation or SAEs will be collected from all interactions with the patient, as well as if 
discovered when reviewing documents from healthcare encounters with other providers. Additionally, PRO 
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and ClinRO data will be collected at the dedicated study visits and entered into the eCRF. 
2) Healthcare resource utilization and pharmacy prescription data will be extracted from health plan medical 
and pharmacy claims and will not be entered into the eCRF.  
 
a Routine diabetic care visits will follow standard of care frequency and any available data will be entered in the 
eCRF.  
b Assessments at dedicated study visits will be collected in eCRF. Assessments at routine diabetic care visits will be 
collected as available/according to local clinical practice in eCRF.  
c Informed consent must be obtained before any study related activities. 
d Individualized HbA1c target must be set and documented prior to randomization. 
e Medication data (glucose-lowering medications and/or concomitant cardiovascular medications) collected at study 
visits only include medications that are current at time of study visit. 
f The HbA1c value is based on historical data collected from the study physician and is the value closest to the date 
of randomization, within the last 90 days. 
g Any SAE identified from any encounter or notation at any time must be reported. 
h Data from health plan medical and pharmacy claims. Data will be extracted at the end of the study, but will include 
data from patient randomization through EOS or withdrawal. 
 
 
 
 
 
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Appendix 2: Additional Derived Outcome Variables for Supportive Analyses 
Supportive Measures of Glycemic Control 
 Individualized HbA1c target attained at year 2 (yes/no) 
 HbA1c <7.0% (53 mmol/mol) or at least 1% point improvement in HbA1c compared to 
baseline at year 2 (yes/no) 
 HbA1c <8.0% (64 mmol/mol) at year 1 (yes/no) 
 HbA1c <8.0% (64 mmol/mol) at year 2 (yes/no)  
 HbA1c <7.0% (53 mmol/mol) and no further antidiabetic medication intensification after 
randomization at year 1 (yes/no) 
 HbA1c <7.0% (53 mmol/mol) and no further antidiabetic medication intensification after 
randomization at year 2 (yes/no) 
 HbA1c target attainment per HEDIS criteria (<8.0% if age ≥65 years or with defined 
comorbidities, otherwise <7.0%) at year 2 (yes/no) 
 HbA1c <7.0% (53 mmol/mol) at year 1 in patients with HbA1c >9.0% at baseline 
(yes/no) 
 HbA1c <7.0% (53 mmol/mol) at year 2 in patients with HbA1c >9.0% at baseline 
(yes/no) 
 HbA1c <8.0% (64 mmol/mol) at year 1 in patients with HbA1c >9.0% at baseline 
(yes/no) 
 HbA1c <8.0% (64 mmol/mol) at year 2 in patients with HbA1c >9.0% at baseline 
(yes/no) 
Body Weight Loss 
 Change in body weight (%) from baseline to year 2 
 Change in body weight (lb) from baseline to year 2 
Blood Pressure 
 Change in SBP (mm Hg) from baseline to year 2 
 Change in DPB (mm Hg) from baseline to year 2 
Hypoglycemia 
 Reported hypoglycemia leading to inpatient admission or ER encounter during year 1 
(yes/no) 
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 
Reported hypoglycemia leading to inpatient admission or ER encounter during year 2 
(yes/no) 
Composite Variables 
 HbA1c <7.0% (53 mmol/mol) without experiencing hypoglycemia leading to inpatient 
admission or ER encounter and body weight loss of  ≥5% vs baseline at year 1 (yes/no) 
 Absolute HbA1c reduction of ≥0.5% without experiencing hypoglycemia leading to 
inpatient admission or ER encounter and a body weight loss of  ≥5% vs baseline at year 1 
(yes/no) 
 HbA1c <7.0% (53 mmol/mol) without experiencing hypoglycemia leading to inpatient 
admission or ER encounter and body weight loss of  ≥5% vs baseline at year 2 (yes/no) 
 Absolute HbA1c reduction of ≥0.5% without experiencing hypoglycemia leading to 
inpatient admission or ER encounter and a body weight loss of  ≥5% vs baseline at year 2 
(yes/no) 
 HbA1c <7.0% (53 mmol/mol) without experiencing hypoglycemia leading to inpatient 
admission or ER encounter and no body weight gain vs baseline at year 1 (yes/no) 
 HbA1c <7.0% (53 mmol/mol) without experiencing hypoglycemia leading to inpatient 
admission or ER encounter and no body weight gain vs baseline at year 2 (yes/no) 
Adherence to Treatment 
 Study drug medication adherence for the two years of the study, as measured by the 
medication possession ratio (MPR) 
 
 
 
 
 
 
 
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Appendix 3: Patient Reported Outcome Additional Information 
 
DTSQc 
The DTSQc provides a measure of how satisfied patients are with their current diabetes 
treatment compared with previous treatment. It consists of 8 questions, which are to be answered 
on a Likert scale from -3 to +3 (-3 = much less satisfied now to +3 = much more satisfied now), 
with 0 (midpoint), representing no change. Six questions are summed to produce a Total 
treatment satisfaction score. The remaining two questions concern perceived frequency of 
hyperglycemia and perceived frequency of hypoglycemia, respectively. The DTSQc Total 
treatment satisfaction score ranges from -18 to +18, with higher scores associated with greater 
treatment satisfaction. 
 
SF-12 v2 
The SF-12v2 is a 12-item generic health-related quality of life measure that assesses physical and 
mental functioning. The items will be scored using the scoring software that will be provided 
with the license. The following two summary scores are used as endpoints: Physical Component 
Summary (PCS) Score and Mental Component Summary (MCS) Score. The scores are norm-
scored such that the scores range from 0-100 with a mean of 50 and standard deviation of 10.  A 
higher score is associated with better quality of life and a lower score, poorer quality of life.  
 
WPAI-GH 
The WPAI-GH yields four types of scores: Absenteeism (work time missed), Presenteesism 
(impairment at work / reduced on-the-job effectiveness), Work productivity loss (overall work 
impairment / absenteeism plus presenteeism), and Activity Impairment. WPAI outcomes are 
expressed as percentages, with higher numbers indicating greater impairment and less 
productivity, i.e., worse outcomes (percent work time missed due to health, percent impairment 
while working due to health, percent overall work impairment due to health, percent activity 
impairment due to health). 
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Summary of Amendments and Updates 
 
Summary of Changes 
NN95359-4416 Protocol Version 2.0, dated 27MAR2019 
 
Number 
Section/Page 
 
Change 
Rationale 
1 
Global Change, 
Study Population 
Allow enrollment of patients treated 
with either 1 or 2 oral antidiabetic 
medications. 
  
Expand study population from 
patients treated with 
metformin monotherapy to 
patients treated with either 1 or 
2 oral antidiabetic medications 
to facilitate enrollment. 
 
2 
Global Change 
 
March 1327, 20182019 
 
Version 12.0 
 
Update protocol date and 
version. 
3 
Study Approvals, p. 
2 
Name:  
 
 
Title:   
 
 
 
 
Study approval title update. 
4 
Study Approvals, p. 
2 
Name:  
 
 
 
Title:  
 
 
Statistician 
 
Update to study statistician. 
5 
Patient Description,  
Synopsis, p. 7 
 
Eligible patients include adult 
T2DM patients on metformin 
monotherapy up to 2 oral 
antidiabetic medications whose 
physician deems that they have 
inadequate glycemic control and 
need treatment intensification with 
an additional antidiabetic oral or 
injectable medication. 
 
Update patient description to 
reflect expanded study 
population. 
6 
Primary Objective 
 
Synopsis, p. 7 
 
Section 2.1, Primary 
Objective, p. 17 
The primary objective is to 
demonstrate superior long term 
effects of treatment with 
semaglutide compared to SOC both 
added to metformin up to 2 oral 
antidiabetic medications on 
Update primary objective to 
reflect expanded study 
population. 
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glycemic control when used as 
intensification in routine clinical 
practice in adult patients with 
T2DM. 
 
7 
Secondary Objective 
 
Synopsis, p. 7 
 
Section 2.2,  
Secondary 
Objectives, p. 17 
 
The secondary objectives are to 
compare the long term effect of 
semaglutide versus SOC both added 
to metformin up to 2 oral 
antidiabetic medications and used 
as intensification in routine clinical 
practice in adult patients with 
T2DM with regards to: 
 
Update secondary objectives 
to reflect expanded study 
population. 
8 
Study Design 
 
Synopsis, p. 7 
 
Section 4.1, Study 
Design Overview, p. 
20 
This is a 2-year, multi-center, 
randomized, open label, parallel 
group, active comparator pragmatic 
clinical trial (PCT) comparing 
semaglutide versus SOC when 
added to metformin monotherapy 
up to 2 oral antidiabetic 
medications as treatment 
intensification among adult T2DM 
patients in the course of routine 
clinical practice. 
 
Update study design to reflect 
expanded study population. 
9 
Inclusion Criteria, 
#4 
 
Synopsis, p. 8 
 
Section 4.2.3, 
Patient Inclusion 
Criteria, p. 22 
 
4.) Treatment with metformin as 
antidiabetic monotherapy either 
1 or 2 oral antidiabetic 
medications. 
 
Expand study population from 
patient treated with metformin 
monotherapy to patients 
treated with either 1 or 2 oral 
antidiabetic medications to 
facilitate enrollment. 
 
10 
Inclusion Criteria, 
#5 
 
Synopsis, p. 8 
 
Section 4.2.3, 
Patient Inclusion 
Criteria, p. 22 
 
5.) Current member of an 
 
affiliated commercial health 
plan with pharmacy benefits. 
Clarification of health plan 
requirements.  
11 
Exclusion Criteria, 
#2 
 
Synopsis, p. 8 
 
2.) Treatment with more than 2 oral 
antidiabetic medications or any 
injectable antidiabetic 
medication any medication for 
the indication of diabetes other 
Update exclusion criterion #2 
to be consistent with inclusion 
criterion #4. 
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Section 4.2.4, 
Patient Exclusion 
Criteria, p. 22 
than metformin in a period of 
30 days before the day of 
eligibility assessment. 
Temporary/emergency use of 
any type of insulin is allowed, 
as is prior insulin treatment for 
gestational diabetes.  
12 
Section 1, 
Introduction, p. 16 
This local US study will enroll adult 
patients with T2DM who have 
inadequate glycemic control on 
metformin as their only up to 2 oral 
antidiabetic medications, as defined 
by the need for treatment 
intensification with an additional 
antidiabetic oral or injectable 
medication per the study 
physician´s discretion. 
Update description of study to 
reflect expanded study 
population. 
13 
Section 4.2, Practice 
and Patient 
Selection, p. 21 
The target population for this study 
consists of adult, commercially-
insured, T2DM patients on 
metformin mono-therapy up to 2 
oral antidiabetic medications who 
are in need of treatment 
intensification with an additional 
antidiabetic oral or injectable 
medication. 
Update target population to 
reflect expanded study 
population. 
14 
Section 4.2, Practice 
and Patient 
Selection, p. 21 
 health plans serve a large 
population of T2DM patients. In 
feasibility data from the HIRD, the 
number of patients with T2DM, at 
least one claim for metformin in the 
most recent 6 months, and without 
prior use of other antidiabetic drug 
classes (per study exclusion 
criterion #2), amounts to circa 
300,000 potential eligible patients 
distributed across 61,803 unique 
providers. 
Delete data based on 
metformin monotherapy as it 
is not relevant to updated 
inclusion criteria. 
15 
Section 4.2.2, 
Patient Recruitment 
and Eligibility, p. 21 
Eligible patients include adult 
T2DM patients whose physicians 
determine that they have inadequate 
glycemic control on metformin 
antidiabetic monotherapy1 or 2 oral 
antidiabetic medications. 
Update description of eligible 
patients to reflect expanded 
study population. 
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16 
Figure 1, Study 
design, p. 23 
 
Figure 1 Study design diagram. 
Patients will be randomized in a 1:1 
manner using centralized allocation 
to receive semaglutide or SOC as 
add-on to metformin up to 2 oral 
antidiabetic medications.  
 
Update description of study 
design to reflect expanded 
study population. 
17 
Section 5.1, 
Enrollment 
Procedures, p. 23 
 
The determination that a patient has 
inadequate glycemic control on 
metformin antidiabetic 
monotherapy up to 2 oral 
antidiabetic medications, and the 
subsequent decision to intensify 
antidiabetic treatment with an 
additional oral or injectable 
antidiabetic medication, will be 
made by the study physician during 
the course of routine clinical 
practice. 
 
Update enrollment procedures 
to reflect expanded study 
population. 
18 
Section 5.2.2, 
Treatments, p. 26 
 
Metformin 
Add metformin to the list of 
oral antidiabetic drugs 
included in this study to reflect 
expanded study population. 
 
19 
Section 5.2.2, 
Treatments, p. 26-27 
Background medication: The (up 
to 2) oral antidiabetic medication(s) 
taken prior to randomization and 
treatment intensification following 
treatment is considered background 
medication: metformin. Patients 
may discontinue metformin 
background medication at any time 
during the study. Patients may 
change the pre-study dose and 
frequency of metformin background 
medication at any time during the 
study. Background medication will 
not be provided nor reimbursed by 
Novo Nordisk. 
 
Update description of 
background medication to 
reflect expanded study 
population. 
20 
Section 6.6, PRO 
Analysis, p. 33 
The continuous change from 
baseline endpoints will be analyzed 
using the same analysis approach as 
described under the complete case 
and complete case on-study drug 
Update to planned PRO 
analyses, with no missing data 
imputation for PRO endpoints. 
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analyses in primary estimand, 
secondary estimand, and 
supplementary analysis sSection 
6.5. 
 
21 
Section 6.8, Other 
Analyses, p. 34 
The binary and continuous 
endpoints that include HbA1c, 
weight, SBP, or DBP data will be 
analyzed using the same analysis 
approach as described under the 
primary estimand, secondary 
estimand, and supplementary 
analysis sections. All other 
endpoints will be analyzed using 
the same analysis approach as 
described under the complete case 
and complete case on-study drug 
analyses in Section 6.5. 
 
Update to planned analyses, 
with missing data imputation 
only for endpoints including 
HbA1c, weight, SBP, or DBP 
data. 
22 
Section 6.8.9, 
Evaluation of Study 
Population, p. 35 
Two claims-based T2DM patient 
populations will be described and 
compared to the study population: 
(1) commercially-insured 
 
T2DM patients treated with 
metformin up to 2 oral antidiabetic 
medications who undergo an 
antidiabetic treatment 
intensification, and (2) within the 
study sites, commercially-insured 
 T2DM patients treated with 
metformin up to 2 oral antidiabetic 
medications who are not enrolled in 
the study, but who undergo an 
antidiabetic treatment 
intensification. 
 
Update claims-based 
comparator population to 
reflect expanded study 
population. 
 
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Summary of Changes 
NN95359-4416 Protocol Version 3.0, dated 21AUG2019 
 
Number 
Section/Page 
 
Change 
Rationale 
1 
Global Change, 
Study Population 
Allow enrollment of patients with 
any commercial or Medicare 
insurance with pharmacy benefits. 
  
Expand study population to 
facilitate enrollment. 
 
2 
Global Change 
 
March 27August 21 2019 
 
Version 32.0 
 
Update protocol date and 
version. 
3 
Study Approvals 
 
 
Update to project statistician. 
4 
Study Physician 
Sites, 
Synopsis, p. 7 
 
Section 4.2.1, 
Physician Practice 
Eligibility, p. 21 
 
Participation of approximately 285 
200 physician sites 
Reduction in number of sites 
necessary with expanded study 
population. 
5 
Study Physician 
Sites, 
Synopsis, p. 7 
 
…that have a population of patients 
with the target indication, type 2 
diabetes mellitus (T2DM), actively 
enrolled in an 
 affiliateda 
commercial or Medicare health plan 
with pharmacy benefits. 
 
Update description to reflect 
expanded study population. 
6 
Patients, 
Synopsis, p. 7 
Planned enrollment in this study is 
22501387. 
Reduction in planned 
enrollment based on updated 
power assumptions. 
 
7 
Global Change 
 
routine diabetic care visits 
Clarify data collection 
between study visits for sites. 
 
8 
Study Design, 
Synopsis, p. 8 
 
Study Procedures, 
Synopsis, p. 9 
Additionally, medical and 
pharmacy claims data will be 
captured utilizing the HealthCore 
Integrated Research Database 
(HIRDSM) for 
 patients or 
requested, via patient written 
authorization, from a set of other 
health insurers for non-
 
patients for the 2 year study period. 
HIRD Claims data for the 12 
months prior to randomization will 
Update to reflect expanded 
study population and 
collection of claims data from 
other health insurers. 
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Page 54 of 60 
also be collected if available. 
 
9 
Inclusion Criteria, 
#5 
 
Synopsis, p. 8 
 
Section 4.2.3, 
Patient Inclusion 
Criteria, p. 22 
 
5.) Current member of an 
 
affiliated a commercial or 
Medicare health plan with 
pharmacy benefits. 
Expand study population to 
facilitate enrollment. 
 
10 
Study Procedures, 
Synopsis, p. 9 
 
Appendix, Time and 
Events Schedule, 
Note 1, p. 43 
Of note, AEs leading to study drug 
discontinuation or SAEs will be 
collected from all interactions with 
the patient, as well as if discovered 
when reviewing documents from 
healthcare encounters with other 
providers. 
 
Clarification of AE leading to 
study drug discontinuation and 
SAE identification outside of 
routine diabetic care or 
dedicated study visits. 
11 
Statistical Analysis, 
Synopsis, p. 10 
This study is designed to have 90% 
power to jointly confirm superiority 
of the primary endpoint and 85% 
power to also confirm superiority of 
the above three first confirmatory 
secondary endpoints based on an 
analysis of the primary estimand for 
each of the endpoints. 
 
Update to power calculations. 
12 
List of Definitions, 
Administrative 
Claims Data, p. 14 
 
Medical, pharmacy, and health plan 
eligibility data created in the 
processing of medical and 
pharmacy claims. The claims data 
utilized in this study are obtained 
from the HealthCore Integrated 
Research Database (HIRD) for 
 patients and requested, via 
patient written authorization, from a 
set of other health insurers for non-
 patients. 
 
Updated definition to reflect 
expanded study population and 
collection of claims data.  
13 
Section 4.2, Practice 
and Patient 
Selection, p. 21 
The target population for this study 
consists of adult, commercially 
insured, T2DM patients on up to 2 
oral antidiabetic medications who 
are in need of treatment 
intensification with an additional 
antidiabetic oral or injectable 
medication. To support study 
objectives, including claims 
Update to reflect expanded 
study population. 
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analysis of HCRU, eligible patients 
will also be currently insured 
through a commercial health plan or 
Medicare with pharmacy benefits. 
14 
Section 4.2, Practice 
and Patient 
Selection, p. 21 
Physician practice and participant 
eligibility criteria were guided by 
feasibility data from the HealthCore 
Integrated Research Database 
(HIRDSM) prior to protocol 
development. 
Physician sites recruited for the 
study will be those who provide 
care for members of 
 health 
plans, one of the largest healthcare 
insurance providers in the US. 
 provides medical coverage 
for roughly 1 in 8 Americans, and 
although this is mostly concentrated 
in the employer-supported, 
commercially-insured market, the 
data in the HIRD are overall 
representative of the entire US 
population. [14] 
Update to reflect expanded 
study population and site 
selection. 
15 
Section 4.2, Practice 
and Patient 
Selection, p. 21 
Potential sites will be evaluated 
regarding feasibility of their 
participation in the study, including 
having a T2DM population of 
 members to meet 
enrollment goals, based on the 
initial data analysis from the HIRD. 
Update to reflect expanded 
study population and site 
selection. 
16 
Section 4.2.1, 
Physician Practices, 
p. 21
4.2.1 Physician Practices 
Eligibility 
Participation of approximately 
285200 physician sites in the US, 
including both general practitioners 
and endocrinologists that have a 
T2DM population, is anticipated. 
Physician sites will be limited to 
those that participate in the care of 
patients who are actively enrolled in 
an 
 
 
health plan 
(hence forth referred to as 
 
Update to reflect expanded 
study population and site 
selection. 
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health plans). 
 
17 
Section 4.2.5, 
Patient Enrollment, 
p. 22 
Planned number of patients to be 
randomized: 22501387 
Expected number of patients to 
complete the study after 52 weeks: 
16871040 
Expected number of patients to 
complete the study after 104 weeks: 
1260780 
 
Reduction in planned 
enrollment based on updated 
power assumptions. 
 
18 
Section 4.2.6, 
Patient 
Randomization, 
Figure 1, p. 23 
 
n=22501387 
Reduction in planned 
enrollment based on updated 
power assumptions. 
 
19 
Section 5.1, 
Enrollment 
Procedures, p. 23-24 
To preserve the real-world nature of 
the study, patients will be 
approached for potential enrollment 
into the study through their 
physician if review of their medical 
history indicates that they may be 
eligible for the study. Outreach may 
occur when they patients present to 
their physician as part of their 
standard care or through proactive 
contact of potentially eligible 
patients identified within the study 
physician’s practice. 
 
Clarification of patient 
recruitment and enrollment 
procedures. 
20 
Section 5.2.2, 
Treatments, Copay 
assistance, p. 26 
The only exceptions are if a patient 
initiates prescription coverage 
through Medicare or Medicaid, at 
which point all copay assistance 
will end. 
 
Update to reflect expanded 
study population and copay 
coverage for Medicare 
patients. 
21 
Section 5.4, Study 
Period, p. 28 
 
If a patient leaves their 
 
health plan network during the 2 
year study period, administrative 
claims data will be collected from 
randomization through the date they 
leave the health plan. If a patient 
switches to another health plan 
during the 2-year study period, an 
attempt may be made to collect 
administrative claims data from that 
plan as well. In this these scenarios, 
Update to reflect expanded 
study population and 
collection of claims data. 
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site-based study data collection will 
continue without change. 
 
22 
Section 5.5, 
Administrative 
Claims Data, p. 28 
5.1 Administrative Claims 
Data HIRDSM 
In addition to prospectively 
collected clinical data and PROs, 
this study will also utilize claims 
data from the HealthCore Integrated 
Research Database (HIRDSM) HIRD 
for all study 
 patients or 
requested, via patient written 
authorization, from a set of other 
health insurers for non-
 
patients. 
 
Update to reflect expanded 
study population and 
collection of claims data. 
23 
Section 5.5, 
Administrative 
Claims Data, p. 28 
Final Eextraction of this data will 
take place approximately 3 months 
after the last patient’s last visit 
(LPLV) to allow for data lags in the 
claims. 
 
Update to reflect expanded 
collection of claims data. 
24 
Section 5.6.2, 
Patients, p. 28 
If a patient has not been in contact 
with the Prescribing Physician by 
the end of the 2 year study duration 
period and the site is not able to 
reach the patient after 3 contact 
attempts, the patient can be 
considered Lost To Follow-Up 
(LTFU). One of the 3 contact 
attempts should include a certified 
letter being sent to the patient.  If a 
patient’s status is determined to be 
LTFU, this must be recorded on the 
End of Study eCRF. 
 
Added new language to clarify 
patients lost to follow-up. 
25 
Section 6.2.1, Power 
and Sample Size for 
the Primary 
Objective, p. 31 
 
The study sample size of 2,250 
1,387 was calculated based on the 
following assumptions,… 90% 
power for confirming superiority of 
the primary endpoint, and an overall 
alpha leve1 of 5%. 
 
Update to planned enrollment 
and power calculations. 
26 
Section 6.2.1, Power 
and Sample Size for 
the Primary 
Objective, p. 31 
 
When accounting for missing data, 
randomizing 2250 1387 patients 
will contribute 1687 1040 patients 
for the year 1 analyses and 1260 
780 patients for the year 2 analyses, 
achieving a total power of 90% 
Update to planned enrollment 
and power calculations. 
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85% for confirming the two year 1 
confirmatory hypotheses. The joint 
power for confirming all 4 
confirmatory hypotheses is 58%. 
The corresponding marginal powers 
for presence of HbA1c < 7.0% at 
year 1, change in HbA1c to 1 year, 
presence of HbA1c < 7.0% at year 
2, and change in HbA1c to 2 years 
are 99%90%, 99%94%, 95%80%, 
and 97%86% respectively. 
 
27 
Section 6.8.5, 
Healthcare Resource 
Utilization (HCRU), 
p. 35 
HCRU analyses will compare all-
cause and diabetes-related HCRU 
(inpatient admissions, ER 
encounters, outpatient encounters, 
and pharmacy utilization) as 
defined in section 3.3.2 from the 
HIRD claims data by semaglutide 
and SOC treatment group from 
baseline to year 2. 
 
Update to reflect expanded 
study population and 
collection of claims data. 
28 
Section 6.8.9, 
Evaluation of Study 
Population, p. 36 
The primary objective of this 
analysis is to evaluate the external 
validity of the study and to 
understand how the study 
population fits into the larger 
T2DM populations within study 
sites and 
 a commercially-
insured population as a whole. Two 
claims-based T2DM patient 
populations will be described and 
compared to the study population: 
(1) commercially-insured and 
Medicare Advantage 
 
T2DM patients treated with up to 2 
oral antidiabetic medications who 
undergo an antidiabetic treatment  
intensification, and (2) within the 
study sites, commercially-insured 
and Medicare Advantage T2DM 
patients treated with up to 2 oral 
antidiabetic medications who are 
not enrolled in the study, but who 
undergo an antidiabetic treatment 
intensification. 
 
Update to reflect expanded 
study population. 
29 
Section 7.2.1, 
Collection Period of 
Serious Adverse 
Any SAE identified from any 
patient encounter or notation at any 
time must be reported. 
Clarification of SAE 
identification outside of 
routine diabetic care or 
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Events, p. 37 
 
Appendix 1: Time 
and Events 
Schedule, Footnote 
g, p. 44 
 
 
dedicated study visits. 
30 
Section 8.1, Data 
Sources, p. 38 
Data sources include primary data 
collected prospectively by study 
sites at study visits (demographic 
and clinical data, patient-completed 
PRO data, and physician reported 
global assessments) as well as 
secondary data collection utilizing 
administrative claims data from the 
HIRD health plans, as available. 
 
Update to reflect expanded 
study population and 
collection of claims data. 
31 
References 
[7] T. Wasser, J. Ycas and O. 
Tunceli, "Applying Weighting 
Methodologies to a Commercial 
Database to Project US Census 
Demographic Data," The American 
Journal of Accountable Care, 2015. 
 
Reference no longer relevant 
with expanded study 
population. 
 
32 
Appendix 1: Time 
and Events 
Schedule, p. 42 
Specific authorization forms for 
release of non-
 health plan 
claims data 
Addition of claims release for 
non-
 patients to reflect 
expanded study population and 
collection of claims data. 
 
33 
Appendix 1: Time 
and Events 
Schedule, Note 2, p. 
43 
2) Healthcare resource utilization 
and pharmacy prescription data 
will be extracted from health 
plan medical and pharmacy 
claims the HIRD and will not 
be entered into the eCRF.  
 
Update to reflect expanded 
study population and 
collection of claims data. 
34 
Appendix 1: Time 
and Events 
Schedule, 
Medication 
Footnote, p. 44 
e Medication data (glucose-lowering 
medications and/or concomitant 
cardiovascular medications) 
collected at study visits only 
include medications that are current 
at time of study visit. 
 
Footnote clarifying time frame 
for medication data collected. 
35 
Appendix 1: Time 
and Events 
Schedule, Footnote 
f, p. 44 
hf Data from health plan medical 
and pharmacy claims the HIRD. 
Data will be extracted from the 
HIRD at the end of the study, but 
will include data from patient 
randomization through EOS or 
withdrawal. 
Update to reflect expanded 
study population and 
collection of claims data. 
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PROTOCOL No. NN9535-4416 – Novo Nordisk Semaglutide Study 
UTN: U1111-1207-6474 
Long term comparative effectiveness of once weekly 
semaglutide versus standard of care in a real world adult US 
population with type 2 diabetes - a randomized pragmatic 
clinical trial 
Trial ID NN9535-4416 
Novo Nordisk 
December 5, 2019 
Version 4.0 
Trial Phase: 4 
Investigational Substance: Semaglutide 
 
 
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Protocol No. NN9535-4416 
UTN: U1111-1207-6474 
 
Version 4.0; December 5, 2019 
CONFIDENTIAL 
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Principal Study Physician Agreement: 
 
I have read the protocol “Long term comparative effectiveness of once weekly semaglutide 
versus standard of care in a real world adult US population with type 2 diabetes - a randomized 
pragmatic clinical 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 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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CONFIDENTIAL 
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TABLE OF CONTENTS 
STUDY APPROVALS.................................................................................................................. 2 
PRINCIPAL STUDY PHYSICIAN AGREEMENT ................................................................. 3 
TABLE OF CONTENTS ............................................................................................................. 4 
SYNOPSIS ..................................................................................................................................... 7 
LIST OF ABBREVIATIONS .................................................................................................... 11 
LIST OF DEFINITIONS ........................................................................................................... 14 
1 
INTRODUCTION............................................................................................................... 16 
1.1 
Background and Rationale .................................................................................................................................. 16 
2 
STUDY OBJECTIVES ....................................................................................................... 17 
2.1 
Primary Objective................................................................................................................................................... 17 
2.2 
Secondary Objectives ............................................................................................................................................ 17 
3 
STUDY ENDPOINTS ......................................................................................................... 17 
3.1 
Baseline ...................................................................................................................................................................... 17 
3.2 
Primary Endpoint ................................................................................................................................................... 17 
3.3 
Secondary Endpoints............................................................................................................................................. 18 
3.3.1 
Confirmatory Secondary Endpoints .............................................................................................................................. 18 
3.3.2 
Supportive Secondary Endpoints ................................................................................................................................... 18 
3.3.3 
Exploratory Endpoints ........................................................................................................................................................ 20 
4 
STUDY DESIGN ................................................................................................................. 20 
4.1 
Overview .................................................................................................................................................................... 20 
4.2 
Practice and Patient Selection ........................................................................................................................... 21 
4.2.1 
Physician Practices ............................................................................................................................................................... 21 
4.2.2 
Patient Recruitment and Eligibility ............................................................................................................................... 21 
4.2.3 
Patient Inclusion Criteria ................................................................................................................................................... 22 
4.2.4 
Patient Exclusion Criteria .................................................................................................................................................. 22 
4.2.5 
Patient Enrollment ................................................................................................................................................................ 22 
4.2.6 
Patient Randomization ........................................................................................................................................................ 22 
5 
STUDY PROCEDURES .................................................................................................... 23 
5.1 
Enrollment Procedures ........................................................................................................................................ 23 
5.2 
Randomization Visit .............................................................................................................................................. 24 
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5.2.1 
Patient Characteristics ........................................................................................................................................................ 24 
5.2.2 
Treatments ............................................................................................................................................................................... 24 
5.3 
Patient Reported Outcomes, Clinician Reported Outcomes, and Diabetes Treatment 
Satisfaction ............................................................................................................................................................................... 27 
5.3.1 
PRO and Treatment Satisfaction questionnaires ..................................................................................................... 27 
5.3.1.1 
Diabetes Treatment Satisfaction Questionnaire (DTSQ) [7] [8] [9] [10] .......................................... 27 
5.3.1.2 
Short Form 12-Item version 2 (SF-12 v2) Health Survey [11] .............................................................. 27 
5.3.1.3 
Work Productivity and Activity Impairment: General Health (WPAI-GH) Questionnaire [12]
 
27 
5.3.1.4 
Patient Global Impression of Disease Severity (PGI-S) and Patient Global Impression of 
Change (PGI-C) ................................................................................................................................................................................... 27 
5.3.2 
Clinician Global Impression of Disease Severity (CGI-S) and Clinician Global Impression of Change 
(CGI-C) 28 
5.4 
Study Period ............................................................................................................................................................. 28 
5.5 
Administrative Claims Data ................................................................................................................................ 28 
5.6 
Withdrawals ............................................................................................................................................................. 29 
5.6.1 
Physician Practices ............................................................................................................................................................... 29 
5.6.2 
Patients ....................................................................................................................................................................................... 29 
6 
STATISTICAL METHODS .............................................................................................. 29 
6.1 
Introduction ............................................................................................................................................................. 29 
6.1.1 
Estimands .................................................................................................................................................................................. 30 
6.1.2 
Confirmatory Endpoints and Hypotheses .................................................................................................................. 30 
6.1.3 
Study Populations .................................................................................................................................................................. 31 
6.2 
Sample Size Determination ................................................................................................................................. 31 
6.2.1 
Power and Sample Size for Primary Objective ......................................................................................................... 31 
6.3 
Statistical Analysis for the Primary Estimand ............................................................................................. 31 
6.4 
Statistical Analysis for the Secondary Estimand ......................................................................................... 32 
6.5 
Supplementary Analyses ..................................................................................................................................... 33 
6.6 
PRO Analysis ............................................................................................................................................................. 33 
6.7 
Safety Analysis ......................................................................................................................................................... 34 
6.8 
Other Analyses ......................................................................................................................................................... 34 
6.8.1 
Supportive Analyses of Glycemic Control ................................................................................................................... 34 
6.8.2 
Weight Loss .............................................................................................................................................................................. 34 
6.8.3 
Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)............................................................... 34 
6.8.4 
Hypoglycemia .......................................................................................................................................................................... 35 
6.8.5 
Healthcare Resource Utilization (HCRU) .................................................................................................................... 35 
6.8.6 
Adherence and Persistence to Treatment .................................................................................................................. 35 
6.8.7 
Antidiabetic Treatment Patterns .................................................................................................................................... 35 
6.8.8 
Exploratory Predictive Analysis ...................................................................................................................................... 35 
6.8.9 
Evaluation of the Study Population ............................................................................................................................... 36 
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7 
ADVERSE EVENT COLLECTION................................................................................. 36 
7.1 
Adverse Events ........................................................................................................................................................ 36 
7.2 
Serious Adverse Events ........................................................................................................................................ 36 
7.2.1 
Collection Period of Serious Adverse Events ............................................................................................................ 37 
7.3 
Pregnancy .................................................................................................................................................................. 37 
7.3.1 
Reporting Period of Pregnancy ....................................................................................................................................... 37 
7.4 
Technical Complaints ............................................................................................................................................ 38 
8 
DATA COLLECTION ....................................................................................................... 38 
8.1 
Data Sources ............................................................................................................................................................. 38 
8.2 
Electronic Case Report Forms (eCRFs) ........................................................................................................... 38 
8.3 
Year One Database Lock ....................................................................................................................................... 38 
9 
STUDY MANAGEMENT .................................................................................................. 39 
9.1 
Regulatory and Ethical Consideration ............................................................................................................ 39 
9.1.1 
Institutional Review Board (IRB) ................................................................................................................................... 39 
9.1.2 
Informed Consent .................................................................................................................................................................. 39 
9.2 
Record Retention and Access ............................................................................................................................. 40 
10 PUBLICATION OF STUDY RESULTS .......................................................................... 40 
11 INDEMNIFICATION ........................................................................................................ 40 
REFERENCES ............................................................................................................................ 41 
APPENDIX 1: TIME AND EVENTS SCHEDULE ................................................................ 42 
APPENDIX 2: ADDITIONAL DERIVED OUTCOME VARIABLES FOR SUPPORTIVE 
ANALYSES ................................................................................................................................. 45 
APPENDIX 3: PATIENT REPORTED OUTCOME ADDITIONAL INFORMATION .... 47 
SUMMARY OF AMENDMENTS AND UPDATES ............................................................... 48 
 
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SYNOPSIS 
 
Title: Long term comparative effectiveness of once weekly semaglutide versus standard of care in a 
real world US adult population with type 2 diabetes – a randomized pragmatic clinical trial 
Sponsor: Novo Nordisk 
Study Treatment: Semaglutide in a prefilled pen (Ozempic®) 
Active Ingredient: Semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1 RA) 
Comparator Treatment: Standard of Care (SOC) (excluding semaglutide) 
Trial ID:  NN9535-4416 
Study Physician Sites: Participation of approximately 200 physician sites, including both primary 
care practitioners and endocrinologists, that have a population of patients with the target indication, 
type 2 diabetes mellitus (T2DM), actively enrolled in a commercial or Medicare health plan with 
pharmacy benefits. 
Country: United States (US) 
Patients: Eligible patients include adult T2DM patients on up to 2 oral antidiabetic medications, 
excluding oral semaglutide, whose physician deems that they have inadequate glycemic control and 
need treatment intensification with an additional antidiabetic oral or injectable medication. 
Planned enrollment in this study is 1387. Patients will be randomized 1:1 to receive either semaglutide 
s.c. or SOC.  
Study Objectives: The objectives of this study are as follows: 
1.) The primary objective is to demonstrate superior long term effects of treatment with 
semaglutide s.c. compared to SOC both added to up to 2 oral antidiabetic medications on 
glycemic control when used as intensification in routine clinical practice in adult patients with 
T2DM. 
2.) The secondary objectives are to compare the long term effect of semaglutide s.c. versus SOC 
both added to up to 2 oral antidiabetic medications and used as intensification in routine clinical 
practice in adult patients with T2DM with regards to: 
a. Weight loss 
b. Patient reported outcomes (PROs) and clinician reported outcomes (ClinROs) 
c. Hypoglycemia  
d. Healthcare Resource Utilization (HCRU) 
e. Adherence and persistence to treatment 
Study Design: This is a 2-year, multi-center, randomized, open label, parallel group, active comparator 
pragmatic clinical trial (PCT) comparing semaglutide s.c. versus SOC when added to up to 2 oral 
antidiabetic medications as treatment intensification among adult T2DM patients in the course of 
routine clinical practice. Patients will be randomized 1:1 to receive either semaglutide s.c. or SOC. The 
decision that further antidiabetic treatment intensification with oral or injectable antidiabetic 
medication is indicated is at the discretion of the study physician and will be made prior to and 
independent of enrollment in this study. The study physician will have determined the patient’s 
suitability for treatment with semaglutide s.c. prior to signing informed consent, but the determination 
to initiate semaglutide s.c. versus SOC will be made by randomization. 
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In keeping with the study objectives and pragmatic design to evaluate semaglutide s.c. versus SOC in 
real world, routine clinical practice, inclusion and exclusion criteria are minimally restrictive and there 
are few study-specific evaluations. Study physicians will follow and treat patients according to their 
routine clinical practice and judgement. All oral and injectable antidiabetic medications are allowed at 
the study physicians' discretion, with the exception of any formulation of semaglutide in the SOC group 
and oral semaglutide in the semaglutide group. Patients will be followed for 2 years, regardless of 
changes in antidiabetic treatment over the course of the study. 
It is anticipated that patients will undergo medical evaluation at regular intervals over the course of the 
study duration as per standard of care, but the only dedicated study visits are at randomization, at year 
1, and at year 2. The study will also capture clinical data collected at the sites during routine diabetic 
care visits, i.e., office visits and other patient contacts that occur as part of routine clinical practice. 
Assessments will be conducted according to the study physician’s routine clinical practice, with a few 
study-specific assessments as outlined in Study Procedures. Additionally, medical and pharmacy 
claims data will be captured utilizing the HealthCore Integrated Research Database (HIRDSM) for 
 patients or requested, via patient written authorization, from a set of other health insurers for 
non-
 patients for the 2 year study period. Claims data for the 12 months prior to randomization 
will also be collected if available. 
Participant Selection: 
Inclusion Criteria:   
Patients 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. 
2.) Male or female, age ≥ 18 years at the time of signing informed consent. 
3.) Type 2 diabetes mellitus diagnosis. 
4.) Treatment with either 1 or 2 oral antidiabetic medications. 
5.) Current member of a commercial or Medicare health plan with pharmacy benefits. 
6.) Recorded glycosylated hemoglobin A1c (HbAlc) value within the last 90 days prior to 
randomization. 
7.) Further intensification with an additional antidiabetic oral or injectable medication is indicated 
to achieve glycemic target at the discretion of the study physician according to approved 
labelling. 
Exclusion Criteria: 
Patients presenting with any of the following exclusion criteria will not be eligible for the study: 
1.) Previous randomization in this study. 
2.) Treatment with more than 2 oral antidiabetic medications, oral semaglutide, or any injectable 
medication in a period of 30 days before the day of eligibility assessment. 
Temporary/emergency use of any type of insulin is allowed, as is prior insulin treatment for 
gestational diabetes.  
3.) Contraindications to semaglutide according to the FDA approved label. 
4.) Female who is pregnant, breastfeeding or intends to become pregnant. 
5.) Participation in another clinical trial. 
Study Procedures: 
 
Study physicians will identify eligible patients for participation. 
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 
Study physicians will obtain written informed consent from patients and if eligible, patients 
will be randomized to either semaglutide s.c. or SOC. 
 
Study data will be collected on electronic Case Report Forms (eCRFs) via an electronic data 
capture (EDC) system. 
 
Study physicians or site personnel will collect demographic, clinical (i.e., height, weight, 
systolic blood pressure (SBP), diastolic blood pressure (DBP)), medical and T2DM specific 
history, antidiabetic medications, and pre-specified concomitant medications related to 
cardiovascular risk data prior to or at randomization. Individualized HbA1c target will be set 
prior to randomization. 
 
Baseline HbA1c will be collected from physician sites during eligibility assessment and will 
be the value closest to the date of randomization, within 90 days. All post-randomization 
HbA1c values will be recorded as available per routine clinical practice during the 2 year study 
period. Post-randomization HbA1c values are required for the year 1 and year 2 dedicated 
study visits. 
 
PROs and ClinROs will be completed at randomization, year 1, and year 2. 
 
Study physicians will collect patient data (HbA1c, study and antidiabetic medication changes, 
pre-specified concomitant medications related to cardiovascular risk, weight, SBP, DBP, 
hypoglycemic events leading to inpatient admission or emergency room (ER) encounter, 
adverse events (AEs) leading to study drug discontinuation, serious adverse events (SAEs), 
and pregnancies at the dedicated year 1 and year 2 study visits, as well as at any routine diabetic 
care visits during the 2 year study period. Of note, AEs leading to study drug discontinuation 
or SAEs will be collected from all interactions with the patient, as well as if discovered when 
reviewing documents from healthcare encounters with other providers. 
 
Administrative medical claims, pharmacy claims and health plan eligibility data will be 
captured from the HIRD for 
 patients or requested, via patient written authorization, 
from a set of other health insurers for the duration of the 2 year study period. Claims data for 
the 12 months prior to study randomization will also be collected if available. This data will 
be used for HCRU measures, as well as adherence and persistence to treatment.  
Study Duration: Planned patient time on study will be 2 years. Administrative claims data will also 
be captured during this time period. Patients will be followed for the full 2 year study period regardless 
of changes in or discontinuation of antidiabetic treatment, other than withdrawal of consent. 
Questionnaires: Diabetes treatment satisfaction, generic health-related quality of life (HRQoL), work 
productivity, and patient and clinician global assessments will be measured at the randomization, year 
1, and year 2 dedicated study visits. 
Statistical Analysis: Two estimands, each targeting a unique research question, have been defined to 
adequately describe the effect of semaglutide s.c. as compared to SOC (excluding semaglutide).  
The primary estimand for all objectives will be the “intention-to-treat” estimand evaluating the 
effectiveness of randomized treatment intervention, irrespective of adherence to this randomized 
intervention or changes to other antidiabetic medication. 
The secondary estimand for all objectives, with the exception of the adherence and persistence to 
treatment objective, is the “if all patients had adhered” estimand. This estimand evaluates the effect of 
randomized treatment intervention for all randomized patients if all patients had adhered to randomized 
treatment, regardless of changes to other antidiabetic medication. 
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Baseline is defined as ≤ 90 days prior to randomization visit (week 0) for HbA1c. For secondary 
endpoint assessments, baseline is defined as ≤ 4 weeks prior to the randomization visit (week 0). 
Primary completion date (PCD) is the date the last patient completes the year 1 dedicated study visit. 
The primary endpoint is binary, with success represented by an HbA1c <7.0% (53 mmol/mol) at year 
1 (yes/no). Confirmatory secondary endpoints include:  
 
Change in HbA1c (%-point) from baseline to year 1 
 
HbA1c <7.0% (53 mmol/mol) at year 2 (yes/no) 
 
Change in HbA1c (%-point) from baseline to year 2 
This study is designed to have 90% power to confirm superiority of the primary endpoint and 85% 
power to also confirm superiority of the first confirmatory secondary endpoint based on an analysis of 
the primary estimand for each of the endpoints.    
The confirmatory endpoints will all be tested under multiplicity control via a hierarchical testing 
scheme according to the order given in the above bullet list. 
The estimand informs choices about data foundation and statistical analysis including possible 
imputation of missing data, hereby ensuring that randomization is preserved as a sound basis for 
statistical inference; i.e., estimation of effect size, associated uncertainty, and statistical testing.  
The full analysis set (FAS) comprising all randomized patients will be the analysis population for 
evaluation of both the primary and secondary estimands. For both estimands, the primary endpoint, 
HbA1c <7.0%, will be analyzed using a logistic regression model with a logit link function and will 
include treatment and baseline HbA1c as independent variables. Continuous endpoints will be analyzed 
using analysis of covariance (ANCOVA) and will include the same independent variables. Prior to 
analysis, missing data will be imputed by multiple imputation on the continuous HbA1c scale and 
subsequently dichotomized for the primary endpoint. 
Supplementary Analyses: Two complete case analyses will complement the analyses for the primary 
and secondary estimands. The supplementary complete case analyses will be based on the subset of 
patients without missing endpoint data, i.e., patients that do not have their endpoint imputed in the two 
analyses used for the primary estimand and the secondary estimand, respectively.    
Secondary Analyses: Secondary analyses will compare semaglutide versus SOC treatment groups in 
terms of change in body weight, SBP, DBP, and PRO and ClinRO measures, based on the similar 
analysis methods as for the primary and secondary estimands. Similarly, binary endpoints and other 
secondary endpoints will be compared statistically between treatment groups, including HCRU and 
adherence/persistence to treatment measures, hypoglycemic events leading to inpatient admission or 
ER encounter, as well as composite measures of HbA1c, weight loss, and hypoglycemia. 
Safety: The principal study physician is responsible for monitoring the safety of participating patients. 
For the purposes of this study, AEs that do not meet the definition of an SAE will only be 
collected/recorded in the EDC if they lead to study drug discontinuation. Study physicians are 
responsible for reporting all SAEs and following the patient until the outcome of the SAE is closed 
out. All SAEs will be reported from randomization until end of study (EOS) at year 2 or patient study 
withdrawal. Study physicians are also responsible for recording all pregnancies in female patients from 
randomization until EOS at year 2 or patient study withdrawal. The patient 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  
ADA 
American Diabetes Association 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
eCCGs 
Electronic Case Report Form Completion Guidelines 
CFR 
Code of Federal Regulations 
CGI-C 
Clinical Global Impression of Change 
CGI-S 
Clinician Global Impression of Disease Severity 
CI 
Confidence Interval 
ClinRO 
Clinician Reported Outcome 
eCRF 
Electronic Case Report Form 
DBP 
Diastolic Blood Pressure 
DPP-4 
Dipeptidyl peptidase 4 
DTSQ 
Diabetes Treatment Satisfaction Questionnaire 
DTSQc 
Diabetes Treatment Satisfaction Questionnaire, change version 
DTSQs 
Diabetes Treatment Satisfaction Questionnaire, status version 
EASD 
European Association for the Study of Diabetes 
EDC 
Electronic Data Capture 
EOS 
End of Study 
ER 
Emergency Room 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FDC 
Fixed Dose Combination 
GCP 
Good Clinical Practice 
GLP-1 RA 
Glucagon-Like Peptide-1 Receptor Agonists 
HbA1c 
Glycosylated Hemoglobin A1c 
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HCRU 
Healthcare Resource Utilization 
HEDIS 
Healthcare Effectiveness Data and Information Set 
HIRDSM 
HealthCore Integrated Research Database 
HIPAA 
Health Insurance Portability and Accountability Act 
HRQoL 
Health-Related Quality of Life 
ICF 
Informed Consent Form 
ICMJE 
International Committee of Medical Journal Editors 
ID 
Identifier 
IRB 
Institutional Review Board 
ITT 
Intent to Treat 
LPLV 
Last Patient Last Visit 
LTFU 
Lost to Follow-Up 
MedDRA 
Medical Dictionary for Regulatory Activities 
MCS-12 
Mental Summary Component (of the Short Form 12-Item version 2) 
MPR 
Medication Possession Ratio 
OR 
Odds Ratio 
PCD 
Primary Completion Date 
PCS-12 
Physical Summary Component (of the Short Form 12-Item version 2) 
PCT 
Pragmatic Clinical Trial 
PDC 
Proportion Days Covered 
PGI-C 
Patient Global Impression of Change 
PGI-S 
Patient Global Impression of Disease Severity 
PRO 
Patient Reported Outcome 
PT 
Preferred Term 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
s.c. 
Subcutaneous 
SD 
Standard Deviation 
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SF-12v2 
Short Form 12-Item version 2 
SGLT-2 
Sodium-Glucose Co-transporter 2 
SM 
Service Mark 
SOC 
Standard of Care 
SUSTAIN 
Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes 
T2DM 
Type 2 Diabetes Mellitus 
TD 
Treatment Difference 
US 
United States 
WPAI-GH 
Work Productivity and Activity Impairment, General Health 
 
 
 
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LIST OF DEFINITIONS 
 
Term 
Definition  
Administrative Claims 
Data 
Medical, pharmacy, and health plan eligibility data created in the 
processing of medical and pharmacy claims. The claims data utilized in 
this study are obtained from the HealthCore Integrated Research 
Database (HIRD) for 
 patients and requested, via patient 
written authorization, from a set of other health insurers for non-
 patients. 
Baseline 
Baseline refers to assessments conducted and patient data collected at 
or prior to randomization. Baseline HbAlc may be ≤ 90 days prior to 
randomization. Baseline for secondary endpoint assessments may be ≤ 
4 weeks prior to randomization. 
Baseline Endpoint 
For continuous endpoints and endpoints derived from continuous 
sources, the baseline value is defined as the last assessment taken prior 
to or at the randomization visit and before first use of study drug. 
Comparator Treatment 
Standard of Care (SOC) (excluding semaglutide); Commercially 
available oral or injectable antidiabetic medication, excluding 
semaglutide, prescribed at the discretion of the study physician for 
antidiabetic treatment intensification following randomization. 
Complete the Study 
Complete the study at 52 weeks: Patient has year 1 HbA1c data 
Complete the study at 104 weeks: Patient has year 2 HbA1c data 
Dedicated Study Visit 
One of three required study visits: randomization, year 1, and year 2. 
Enrollment 
Randomization 
Estimand 
The estimate targeted to address the research question posed by the 
study objective, i.e., “what is to be estimated.” [1] The estimand 
translates the study objective into a precise definition of the effect of 
treatment. 
Healthcare Resource 
Utilization (HCRU) 
Broad term encompassing use of healthcare services, including 
inpatient admissions, ER encounters, outpatient encounters including 
office visits, and pharmacy prescription fills. 
Index Date 
The date corresponding to an event of interest. In this study, index date 
is the date corresponding to a claims-based proxy for antidiabetic 
treatment intensification for 2 comparator populations, thus mimicking 
randomization date in the study population. 
Principal Study 
Physician 
Physician at study site who is responsible for the overall conduct and 
oversight of the study at their site, including: supervision of study 
personnel, monitoring the safety of all participating patients, ensuring 
the accurate and complete collection and reporting of study data, 
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continued review of the IRB study approval, and maintenance of study 
records. This term is analogous to “Investigator” in Good Clinical 
Practice (GCP) requirements.  
Randomization 
The point at which a patient is assigned by chance to either semaglutide 
s.c. or standard of care (SOC). 
Routine Diabetic Care 
Visit 
An office visit or other patient contact during the study period that 
occurs outside of the dedicated study visits (randomization, year 1, and 
year 2) according to routine clinical practice. 
Study Physician 
Physician at study site who participates in the conduct of the study. 
Study/Trial 
For the purposes of this protocol, study and trial are considered 
synonyms. Study is used throughout the body of the text as it reflects 
the post-regulatory approval setting and real world design. Trial is used 
in the title and in referring to the PCT acronym to maintain consistency 
with the industry standard Pragmatic Clinical Trial or PCT.  
Study Drug 
Study drug is the first antidiabetic oral or injectable medication 
prescribed for treatment intensification following randomization. A 
patient can start and stop study drug throughout the study. At any time 
during the duration of the study, if a patient is taking study drug as 
defined, they will be considered “on study drug” regardless of prior 
study drug discontinuations. 
 For the semaglutide treatment group, study drug is defined as 
semaglutide s.c. 
 For the SOC treatment group, study drug is defined as the drug class 
of the first antidiabetic oral or injectable medication prescribed for 
treatment intensification following randomization. If a fixed dose 
combination (FDC) product is prescribed, one of the drugs will be 
chosen by the study physician to be the study drug. A patient 
randomized to the SOC treatment group will still be considered “on 
study drug” if they are taking a drug in the same drug class as their 
first study drug, even if it is not the same individual drug. This also 
applies to treatment intensification with a FDC product if one of the 
drugs is in the same drug class as the first study drug. 
Study Drug 
Discontinuations 
Study drug discontinuation is termination of the study drug. A patient 
can start and stop study drug throughout the study; therefore a patient’s 
study drug discontinuation status can change throughout the duration of 
the study. At any time during the duration of the study, if a patient is 
not taking study drug as defined, they will be considered “off study 
drug.” 
 
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1 
INTRODUCTION 
1.1 
Background and Rationale 
The American Diabetes Association (ADA) and European Association for the Study of Diabetes 
(EASD) position statement recommends a patient-centric approach to the selection of 
pharmacological treatment for type 2 diabetes mellitus (T2DM), including considerations on 
effectiveness, hypoglycemia risk, impact on body weight, side effects, costs, and patient 
preferences. [2] Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are recommended for 
the management of hyperglycemia in T2DM, primarily in combination with other antidiabetic 
medications. [2] [3] 
Semaglutide, a human GLP-1 analogue for once-weekly administration, has been shown to 
improve glycemic control in adults with T2DM as monotherapy when the use of metformin is 
considered inappropriate, or as add-on to other glucose lowering therapies including insulin. In 
the Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes (SUSTAIN) clinical 
development program, semaglutide demonstrated clinically relevant and superior glycemic 
control, as well as weight loss versus placebo and active comparators, both when used as mono- 
and combination therapy in inadequately controlled patients with T2DM. In addition, a 
significant reduction in cardiovascular risk was demonstrated for semaglutide versus placebo in 
patients with T2DM at high risk of cardiovascular events. The overall safety profile of 
semaglutide was consistent with the well-established GLP-1 RA safety profile. [4] 
Pragmatic clinical trials (PCTs) are designed and conducted to reflect patient outcomes and to 
investigate how a product is used and performs in routine clinical practice. This type of study 
compares two or more medical interventions that are directly relevant to clinical care and strives 
to assess those interventions’ effectiveness in real world practice. They use broad eligibility 
criteria and recruit patients from a variety of practice settings to ensure the inclusion of the type 
of patients whose care will be influenced by the study´s results. Such studies are increasingly 
important to generate evidence regarding real world treatment outcomes to inform and support 
appropriate market access. [5] 
The current local US study serves the purpose of evaluating the long term comparative 
effectiveness of semaglutide s.c. with existing commercially available antidiabetic medications 
in a real world population and in a variety of practice settings, thereby maximizing external 
validity while balancing the internal validity of a randomized controlled trial. This will generate 
data to complement the findings from the SUSTAIN clinical development program. Taken 
together, these findings may provide important evidence for decision making by clinicians, 
payers, and policy makers in routine clinical practice. 
This local US study will enroll adult patients with T2DM who have inadequate glycemic control 
on up to 2 oral antidiabetic medications (excluding oral semaglutide), as defined by the need for 
treatment intensification with an additional antidiabetic oral or injectable medication per the 
study physician´s discretion. The current study targets patients at this particular treatment point 
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because they represent the population inadequately controlled on the current ADA recommended 
first lines of treatment of T2DM. The addition of a GLP-1 RA as second-line treatment is in line 
with the ADA guidance from 2017. [6] In keeping with the ADA and EASD position statement 
recommending a patient-centric approach to treatment selection for T2DM patients, in addition 
to comparative effectiveness, this study will also evaluate hypoglycemia risk, body weight, 
healthcare resource utilization (HCRU), patient reported outcomes (PROs), and clinician 
reported outcomes (ClinROs). Adverse events (AEs) leading to study drug discontinuation will 
also be collected.  [2] 
  
2 
STUDY OBJECTIVES  
2.1 
Primary Objective 
The primary objective is to demonstrate superior long term effects of treatment with semaglutide 
s.c. compared to standard of care (SOC) both added to up to 2 oral antidiabetic medications on 
glycemic control when used as intensification in routine clinical practice in adult patients with 
T2DM.  
2.2 
Secondary Objectives 
The secondary objectives are to compare the long term effect of semaglutide s.c. versus SOC 
both added to up to 2 oral antidiabetic medications and used as intensification in routine clinical 
practice in adult patients with T2DM with regards to: 
 Weight loss 
 Patient reported outcomes (PROs) and clinician reported outcomes (ClinROs) 
 Hypoglycemia  
 Healthcare Resource Utilization (HCRU) 
 Adherence and persistence to treatment 
  
3 
STUDY ENDPOINTS 
3.1 
Baseline 
Baseline is defined as ≤ 90 days prior to randomization visit (week 0) for glycosylated 
hemoglobin A1c (HbA1c). For secondary endpoint assessments, baseline is defined as ≤ 4 weeks 
prior to the randomization visit (week 0). 
3.2 
Primary Endpoint 
Primary completion date (PCD) is the date the last patient completes the year 1 dedicated study 
visit. 
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The primary endpoint of this study is: 
 HbA1c <7.0% (53 mmol/mol) at year 1 (yes/no) 
3.3 
Secondary Endpoints 
3.3.1 Confirmatory Secondary Endpoints 
Confirmatory secondary endpoints of this study include: 
 Change in HbA1c (%-point) from baseline to year 1 
 HbA1c <7.0% (53 mmol/mol) at year 2 (yes/no)  
 Change in HbA1c (%-point) from baseline to year 2 
3.3.2 Supportive Secondary Endpoints 
Supportive secondary endpoints of this study include: 
 Individualized HbA1c target attained at year 1 (yes/no) 
 HbA1c <7.0% (53mmol/mol) or at least 1% point improvement in HbA1c compared to 
baseline at year 1 (yes/no) 
 HbA1c target attainment per Healthcare Effectiveness Data and Information Set (HEDIS) 
criteria (<8.0% if age ≥65 years or with defined comorbidities, otherwise <7.0%) at year 
1 (yes/no) 
 Change in body weight (lb) from baseline to year 1 
 Change in body weight (%) from baseline to year 1 
 Change in systolic blood pressure (SBP; mm Hg) from baseline to year 1 
 Change in diastolic blood pressure (DBP; mm Hg) from baseline to year 1 
 Time to first study drug discontinuation during 2 years (day) 
 Time to first treatment intensification (add-on) or change (switch) after randomization 
during 2 years (day) 
 Study drug medication adherence for the first year of the study, as measured by 
medication possession ratio (MPR) (%) 
 Number of hypoglycemic episodes leading to an inpatient admission or emergency room 
(ER) encounter from baseline to year 2 
 Diabetes Treatment Satisfaction Questionnaire, change version (DTSQc), Total treatment 
satisfaction score measured at year 1 
 DTSQc, Total treatment satisfaction score measured at year 2 
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 Change from baseline in Short Form 12-Item Version 2 Survey (SF-12 v2), Physical 
summary component (PCS-12) score at year 1 
 Change from baseline in SF-12 v2, PCS-12 score at year 2 
 Change from baseline in SF-12 v2, Mental summary component (MCS-12) score at year 
1 
 Change from baseline in SF-12 v2, MCS-12 score at year 2 
 Change from baseline in Work Productivity and Activity Impairment, General Health 
questionnaire (WPAI-GH) Absenteeism (work time missed) score at year 1 
 Change from baseline in WPAI-GH Absenteeism (work time missed) score at year 2 
 Change from baseline in WPAI-GH Presenteeism (impairment at work / reduced on-the-
job effectiveness) score at year 1 
 Change from baseline in WPAI-GH Presenteeism (impairment at work / reduced on-the-
job effectiveness) score at year 2 
 Change from baseline in WPAI-GH Work productivity loss (overall work impairment / 
absenteeism plus presenteeism) score at year 1 
 Change from baseline in WPAI-GH Work productivity loss (overall work impairment / 
absenteeism plus presenteeism) score at year 2 
 Change from baseline in WPAI-GH Activity Impairment score at year 1 
 Change from baseline in WPAI-GH Activity Impairment score at year 2 
All cause healthcare resource utilization (HCRU) from baseline to year 2: 
 Number of inpatient admissions 
 Cumulative length of stay for inpatient admissions (days) 
 Number of ER encounters 
 Number of outpatient encounters 
 Number of medications 
 Occurrence of inpatient admission (yes/no) 
 Occurrence of ER encounter (yes/no) 
 Occurrence of outpatient encounter (yes/no) 
Diabetes related HCRU from baseline to year 2: 
 Number of diabetes related inpatient admissions 
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 Cumulative length of stay for diabetes related inpatient admissions (days) 
 Number of diabetes related ER encounters 
 Number of diabetes related outpatient encounters 
 Number of diabetes related medications 
 Occurrence of diabetes related inpatient admission (yes/no) 
 Occurrence of diabetes related ER encounter (yes/no) 
 Occurrence of diabetes related outpatient encounter (yes/no) 
3.3.3 Exploratory Endpoints 
Not applicable. 
  
4 
STUDY DESIGN 
4.1 
Overview 
This is a 2-year, multi-center, randomized, open label, parallel group, active comparator PCT 
comparing semaglutide s.c. versus SOC when added to up to 2 oral antidiabetic medications as 
treatment intensification among adult T2DM patients in the course of routine clinical practice. 
Patients will be randomized 1:1 to receive either semaglutide s.c. or SOC. 
The decision that further antidiabetic treatment intensification with an additional oral or 
injectable antidiabetic medication is indicated is at the discretion of the study physician and will 
be made prior to and independent of enrollment in this study. The study physician will have 
determined the patient’s suitability for treatment with semaglutide s.c. prior to inviting them to 
participate in the study. However, the determination to initiate semaglutide s.c. versus SOC will 
be made by randomization.  
Patients will be followed for 2 years, regardless of changes in antidiabetic treatment over the 
course of the study. Data collection will continue for the full 2 year study period unless a patient 
withdraws informed consent. Patients who enroll in the study agree to the release of health 
information, and to answer questions about their health during the course of the study. 
Additionally, medical and pharmacy claims data will be extracted for the 2 year study period, as 
well as up to 12 months prior to randomization as available. 
In keeping with the study objectives and pragmatic design to evaluate semaglutide s.c. versus 
SOC in real world, routine clinical practice, inclusion and exclusion criteria are minimally 
restrictive and there are few study-specific evaluations. Study physicians will follow and treat 
patients according to their routine clinical practice and judgement. All oral and injectable 
antidiabetic medications are allowed at the study physicians' discretion, with the exception of 
any formulation of semaglutide in the SOC group and oral semaglutide in the semaglutide group. 
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It is anticipated that patients will undergo medical evaluation at regular intervals over the course 
of the study duration as per standard of care, but the only dedicated study visits are at 
randomization, at year 1, and at year 2. The study will also capture clinical data collected at the 
sites during routine diabetic care visits, i.e., office visits and other patient contacts that occur as 
part of routine clinical practice. Assessments will be conducted according to the study 
physician’s routine clinical practice, with a few study-specific assessments as described in 
section 5. The data available may differ from site to site and patient to patient. To ensure 
flexibility, the dedicated year 1 and year 2 study visits have a window of ±6 weeks. 
4.2 
Practice and Patient Selection 
The target population for this study consists of adult T2DM patients on up to 2 oral antidiabetic 
medications, excluding oral semaglutide, who are in need of treatment intensification with an 
additional antidiabetic oral or injectable medication. To support study objectives, including 
claims analysis of HCRU, eligible patients will also be currently insured through a commercial 
health plan or Medicare with pharmacy benefits.  
Study site recruitment will target both primary care practitioners and specialized 
endocrinologists to reflect diverse treatment settings and patient populations. Potential sites will 
be evaluated regarding feasibility of their participation in the study, including having a T2DM 
population to meet enrollment goals. Potential sites will be tiered based on their estimated 
number of eligible study patients, and outreach will begin with all sites that meet a pre-
determined minimum number of potentially eligible patients. Outreach and follow-up will be 
performed until the requisite number of physician sites is enrolled. Study-specific assessments 
have been kept to a minimum, thereby decreasing burden on study sites and increasing 
participation to a wide range of sites. 
4.2.1 Physician Practices  
Participation of approximately 200 physician sites in the US, including both general practitioners 
and endocrinologists, is anticipated. 
4.2.2 Patient Recruitment and Eligibility 
Eligible patients include adult T2DM patients whose physicians determine that they have 
inadequate glycemic control on 1 or 2 oral antidiabetic medications, excluding oral semaglutide. 
Inadequate glycemic control is defined by the need for T2DM treatment intensification with an 
additional antidiabetic oral or injectable medication, as determined by the study physician. 
Patients 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 a 
broad population of adult T2DM patients to generate data in a population that reflects the 
heterogeneity of a real world population treated in general practice, and support the study 
objectives to evaluate semaglutide s.c. versus SOC in real world, routine clinical practice. 
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4.2.3 Patient Inclusion Criteria 
Patients 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. 
2. Male or female, age ≥ 18 years at the time of signing informed consent. 
3. Type 2 diabetes mellitus diagnosis. 
4. Treatment with either 1 or 2 oral antidiabetic medications. 
5. Current member of a commercial or Medicare health plan with pharmacy benefits. 
6. Recorded HbAlc value within last 90 days prior to randomization. 
7. Further intensification with an additional antidiabetic oral or injectable medication is 
indicated to achieve glycemic target at the discretion of the study physician according to 
approved labelling. 
4.2.4 Patient Exclusion Criteria 
Patients presenting with any of the following exclusion criteria will not be eligible for the study: 
1. Previous randomization in this study. 
2. Treatment with more than 2 oral antidiabetic medications, oral semaglutide, or any 
injectable antidiabetic medication in a period of 30 days before the day of eligibility 
assessment. Temporary/emergency use of any type of insulin is allowed, as is prior 
insulin treatment for gestational diabetes.  
3. Contraindications to semaglutide according to the FDA approved label. 
4. Female who is pregnant, breastfeeding or intends to become pregnant. 
5. Participation in another clinical trial. 
4.2.5 Patient Enrollment 
Planned number of patients to be randomized: 1387 
Expected number of patients to complete the study after 52 weeks: 1040 
Expected number of patients to complete the study after 104 weeks: 780 
4.2.6 Patient Randomization 
Study patients will be randomized to either semaglutide s.c. or SOC in a 1:1 ratio. The study 
design and patient randomization is depicted in Figure 1. 
 
 
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Figure 1 Study design diagram. Patients will be randomized in a 1:1 manner using centralized 
allocation to receive semaglutide s.c. or SOC as add-on to up to 2 oral antidiabetic medications.  
 
5 
STUDY PROCEDURES 
The study visit schedule is summarized in Appendix 1. 
5.1 
Enrollment Procedures 
The determination that a patient has inadequate glycemic control on up to 2 oral antidiabetic 
medications, excluding oral semaglutide, and the subsequent decision to intensify antidiabetic 
treatment with an additional oral or injectable antidiabetic medication, will be made by the study 
physician during the course of routine clinical practice. Following the decision to initiate 
treatment intensification, the study physician will determine the patient’s suitability for the study. 
Suitability for the study will be assessed using the current inclusion and exclusion criteria, 
including the approved label for semaglutide s.c. Only patients who are eligible for treatment 
intensification and have been found suitable for treatment with semaglutide s.c., as determined 
by the study physician, are in scope for randomization. Prior to being randomized, patients must 
be willing to intensify with an antidiabetic medication, including GLP-1 receptor agonists. Study 
physicians will set and document an individualized HbA1c target for patients prior to 
randomization based on their clinical judgement and knowledge of the patient. To preserve the 
real-world nature of the study, patients will be approached for potential enrollment into the study 
through their physician if review of their medical history indicates that they may be eligible for 
the study. Outreach may occur when patients present to their physician as part of their standard 
care or through proactive contact of potentially eligible patients identified within the study 
physician’s practice. 
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Informed consent will be obtained prior to any study related activities. The most recent HbA1c 
completed in the course of routine care up to 90 days prior to and including the date of 
randomization will be considered a baseline assessment and does not need to be repeated. 
Study physicians or site personnel will collect patient characteristics and study data at each study 
visit as outlined in the Time and Events Schedule (Appendix 1), either directly from the patient 
or abstracted from the patient’s medical records, and enter them into the electronic Case Report 
Form (eCRF). 
5.2 
Randomization Visit 
Following informed consent and confirmation of inclusion/exclusion criteria, patients will be 
randomized to either semaglutide s.c. or SOC. Data collection at the randomization visit will 
include inclusion/exclusion criteria as well as the data outlined in the sections below. PRO and 
ClinRO questionnaires will also be administered (section 5.3). 
5.2.1 Patient Characteristics 
Baseline assessments at the randomization visit will include: demographic data, medical history, 
diabetes history including antidiabetic medications and diabetes complications, pre-specified 
concomitant medications related to cardiovascular risk, and clinical data (weight, height, HbA1c, 
SBP, DBP). Individualized HbA1c target will be set prior to randomization. The baseline HbA1c 
will be the patient’s most recent HbA1c within 90 days of randomization. 
5.2.2 Treatments 
To preserve the real-world nature of the study, the patient experience will be as close to routine 
care as possible. The study physician will be one of the patient’s own treating physicians, who 
may make treatment adjustments according to their clinical judgement. The study physician can 
make repeat prescriptions of the study drug as usual, which are collected by patients from the 
pharmacy of their choice. Patients will be randomized to either semaglutide s.c. or SOC. 
Treatment details will be recorded in the eCRF. 
Semaglutide Group 
Patients randomized to the semaglutide group will be prescribed commercially available 
semaglutide in a prefilled pen injector and will be instructed to initiate treatment with 
semaglutide s.c. according to the approved label. The study physician will determine the 
intended maintenance dose of semaglutide s.c., as well as changes to the maintenance dose 
thereafter. Add-on, discontinuation or dose modification of antidiabetic medication, including 
semaglutide s.c., during the study is allowed at the discretion of the study physician, with the 
exception of oral semaglutide, which is not allowed during the study period. 
Semaglutide Study Drug: For patients randomized to the semaglutide group, study drug is 
defined as semaglutide s.c. 
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SOC Group 
SOC is defined as commercially available oral or injectable antidiabetic medication (see current 
representative list below) other than semaglutide. Patients randomized to SOC will be prescribed 
and instructed to initiate commercially available antidiabetic medication according to the 
approved label and, if relevant for the specific antidiabetic medication, adjusted at the discretion 
of the study physician. Patients randomized to SOC may discontinue SOC, add-on to the SOC or 
switch to another antidiabetic medication during the study, with the exception of semaglutide 
which is not allowed in the SOC group for the duration of the study. 
SOC Study Drug: For patients randomized to the SOC group, study drug is defined as the 
drug class of the first antidiabetic oral or injectable medication prescribed for treatment 
intensification following randomization. If a fixed dose combination (FDC) product is 
prescribed, one of the drugs will be chosen by the study physician to be the study drug. A 
patient randomized to the SOC treatment group will still be considered “on study drug” if 
they are taking a drug in the same class as their first study drug, even if it is not the same 
individual drug. This also applies to treatment intensification with a FDC product if one 
of the drugs is in the same class as the first study drug. 
Study Drug: Start/Stop, Discontinuations 
Study drug discontinuation is termination of the study drug. A patient can stop or start study drug 
throughout the study; therefore a patient’s study drug discontinuation status can change 
throughout the duration of the study. At any time during the duration of the study, if a patient is 
not taking study drug as defined, they will be considered “off study drug.” Conversely, at any 
time during the duration of the study, if a patient is taking study drug as defined, they will be 
considered “on study drug,” regardless of prior study drug discontinuations.  
If a participating patient becomes pregnant, the study physician will review the patient’s 
antidiabetic treatment regimen and make any changes necessary according to standard care of 
patients with T2DM during pregnancy. Semaglutide will be discontinued and will not be 
restarted unless the patient is no longer pregnant or breast-feeding. All study drug copay 
assistance will end.  
Copay assistance 
The study products will be handled and dispensed by the patients’ pharmacy(s) per their 
preference and health plan benefits. In order to minimize the impact of any differential in out-of-
pocket costs between the treatment groups, an out-of-pocket maximum will be provided by Novo 
Nordisk as part of the study. In both treatment groups, the patient’s copay will be up to the 
specified maximum for the study drug (as defined above) and ancillary needles (if required to 
administer the study drug). Copay assistance will only apply to the study drug as defined above 
(i.e., not to any subsequent add-on treatment or treatment changes outside the study drug 
definition). Because patients can start and stop study drug throughout the study, copay assistance 
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may also start and stop throughout the study. For the duration of the study, any time a patient is 
“on study drug” they will receive copay assistance, and any time a patient is “off study drug” 
they will not receive copay assistance. The only exceptions are if a patient initiates prescription 
coverage through Medicaid or if a patient loses pharmacy coverage, at which point all copay 
assistance will end. 
Products 
A current representative list of the products used in this study is below. All treatments will be 
used in accordance with local clinical practice and guidelines. Products with more than one 
active substance i.e., FDC products, can be used in this study. 
Semaglutide: Semaglutide in a prefilled pen (Ozempic®) 
Oral antidiabetic drugs: The oral antidiabetic drug classes included in this study are the 
commercially available options (listed in alphabetic order): 
 Alpha-glucosidase inhibitors 
 Dipeptidyl peptidase 4 (DPP-4) inhibitors 
 Meglitinides 
 Metformin 
 Sodium-glucose co-transporter 2 (SGLT-2) inhibitors 
 Sulfonylureas 
 Thiazolidinediones 
 Other 
o Bromocriptine 
o Colesevelam 
Injectable antidiabetic drugs: The injectable antidiabetic drug classes included in this study 
are the commercially available options (listed in alphabetic order): 
 GLP-1 RAs 
 Basal Insulin 
o Long acting insulin 
o Intermediate acting insulin including premix 
 Prandial Insulin 
o Short acting insulin 
o Rapid acting insulin 
 Other 
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o Pramlintide 
Background medication: The (up to 2) oral antidiabetic medication(s) taken prior to 
randomization and treatment intensification is considered background medication. Patients may 
discontinue background medication at any time during the study. Patients may change the pre-
study dose and frequency of background medication at any time during the study. Background 
medication will not be provided nor reimbursed by Novo Nordisk.   
5.3 
Patient Reported Outcomes, Clinician Reported Outcomes, and Diabetes 
Treatment Satisfaction 
Diabetes treatment satisfaction, generic health-related quality of life (HRQoL), work 
productivity, and patient and clinician global assessments will be assessed by the following 
instruments at randomization, year 1, and year 2. Patients will self-administer these instruments 
on paper. Site study personnel will review for completeness and enter responses into the eCRF. 
5.3.1 PRO and Treatment Satisfaction questionnaires 
5.3.1.1 Diabetes Treatment Satisfaction Questionnaire (DTSQ) [7] [8] [9] [10] 
The Diabetes Treatment Satisfaction Questionnaire (DTSQ) evaluates patient satisfaction with 
treatment. The DTSQ status version (DTSQs) will be completed at the randomization visit and 
the DTSQ change version (DTSQc) will be completed at the year 1 and year 2 dedicated study 
visits. 
5.3.1.2 Short Form 12-Item version 2 (SF-12 v2) Health Survey [11] 
The SF-12 v2 is a generic HRQoL questionnaire that assesses physical and mental functioning 
and overall HRQoL. The SF-12v2 standard 4-week recall period questionnaire will be completed 
at the randomization, year 1, and year 2 dedicated study visits. 
5.3.1.3 Work Productivity and Activity Impairment: General Health (WPAI-GH) 
Questionnaire [12] 
The WPAI-GH questionnaire assesses both absenteeism (i.e., work time missed) and 
presenteeism (i.e., impairment at work or reduced on-the-job effectiveness) as well as daily 
activity impairment (e.g., work around the house, shopping, exercising, childcare, studying) 
attributable to general health. The WPAI-GH will be administered at the randomization, year 1, 
and year 2 dedicated study visits. 
5.3.1.4 Patient Global Impression of Disease Severity (PGI-S) and Patient Global Impression 
of Change (PGI-C) 
The PGI-S is a 1-item measure that assesses the patient’s impression of disease severity based on 
their present diabetes symptoms, i.e., normal, mild, moderate, or severe, whereas the PGI-C 
assesses the patient’s impression of changes in diabetes symptoms, based on their diabetes 
symptoms now, compared with how they were before they began taking the study drug, i.e., very 
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much better, much better, a little better, no change, a little worse, much worse, or very much 
worse. The PGI-S will be administered at the randomization visit and the PGI-C will be 
administered at the year 1 and year 2 dedicated study visits. 
5.3.2 Clinician Global Impression of Disease Severity (CGI-S) and Clinician Global 
Impression of Change (CGI-C) 
The CGI-S is a 1-item measure that assesses the clinician’s impression of the patient’s disease 
severity, based on the patient’s present diabetes symptoms, i.e., normal, mild, moderate, or 
severe, whereas the CGI-C assesses the clinician’s impression of change in the patient’s diabetes 
symptoms, based on the patient’s diabetes symptoms now, compared with how they were before 
they began taking the study drug, i.e., very much better, much better, a little better, no change, a 
little worse, much worse, or very much worse. The study physician will complete the CGI-S at 
the randomization visit and the CGI-C at the year 1 and year 2 dedicated study visits. 
5.4 
Study Period 
Patients will be followed from randomization to end of study (EOS) at 2 years, during which 
study physicians or trained site personnel will collect study data and record it in the eCRF at 
dedicated study visits (randomization, year 1, year 2) and routine diabetic care visits. Patients 
will be followed for the full 2 year study period regardless of treatment changes or 
discontinuation during the study period, other than withdrawal of consent. If a patient leaves 
their health plan during the 2 year study period, administrative claims data will be collected from 
randomization through the date they leave the health plan. If the patient switches to another 
health plan during the 2-year study period, an attempt may be made to collect administrative 
claims data from that plan as well. In these scenarios, site-based study data collection will 
continue without change. 
On-study data collection at dedicated study visits and routine diabetic care visits (if available per 
local clinical practice) will include: clinical data (weight, HbA1c, SBP, DBP), treatment details 
(study drug, other antidiabetic medication, pre-specified concomitant medications related to 
cardiovascular risk, reasons for treatment discontinuation as applicable), hypoglycemia leading 
to inpatient admission or ER encounter, AEs leading to study drug discontinuation, pregnancy, 
and serious adverse events (SAEs). Of note, AEs leading to study drug discontinuation or SAEs 
will be collected from all interactions with the patient, as well as if discovered when reviewing 
documents from healthcare encounters with other providers. Additionally, PRO and ClinRO 
instruments will be completed at randomization, year 1, and year 2.  
EOS visit is 2 years (±6 weeks) after randomization. 
5.5 
Administrative Claims Data 
In addition to prospectively collected clinical data and PROs, this study will also utilize claims 
data from the HealthCore Integrated Research Database (HIRDSM) for 
 patients or 
requested, via patient written authorization, from a set of other health insurers for non-
 
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patients. Data collected will include integrated medical claims, pharmacy claims, and health plan 
eligibility files for the 2 years after the respective patient’s study randomization. Final extraction 
of this data will take place approximately 3 months after the last patient’s last visit (LPLV) to 
allow for data lags in the claims. Administrative claims data will also be collected for up to 12 
months prior to study randomization, if available. The prospectively collected eCRF study data 
and claims data will be merged into one dataset via a study-specific patient identifier (ID) for 
analysis. 
5.6 
Withdrawals 
5.6.1 Physician Practices 
Novo Nordisk and/or the Institutional Review Board (IRB) reserve the right to terminate the 
study any time. In this event, all data collection will end. After the collected data is received, 
study physicians will be compensated as contractually agreed. 
The IRB reserves the right to terminate participation of individual study sites at any time. 
Individual study sites may also be terminated for cause by Novo Nordisk per contractual 
agreement. In such cases, all data collection at terminated study sites will end. After the collected 
data is received, the study physicians will be compensated as contractually agreed. 
5.6.2 Patients 
Participation in the study is voluntary, and all patients are free to terminate their participation at 
any time. A patient will only be withdrawn from the study if they withdraw consent. In the event 
of study withdrawal, the study physician will record the reason for study withdrawal and 
continue to follow-up with the patient for any unresolved SAEs or pregnancies, if patient agrees. 
Upon patient withdrawal from the study, all data collection will end, but all study data collected 
up to withdrawal will be included in the study database. If a patient has not been in contact with 
the Prescribing Physician by the end of the 2 year study duration period and the site is not able to 
reach the patient after 3 contact attempts, the patient can be considered Lost To Follow-Up 
(LTFU). One of the 3 contact attempts should include a certified letter being sent to the patient.  
If a patient’s status is determined to be LTFU, this must be recorded on the End of Study eCRF. 
 
6 
STATISTICAL METHODS 
6.1 
Introduction 
Patients are randomized 1:1 to semaglutide s.c. or SOC. The data analyses for this study will be 
outlined in further detail in a Statistical Analysis Plan (SAP) developed prior to database lock at 
year 1. 
For continuous endpoints and categorical endpoints derived from continuous sources, the 
baseline value is defined as the last assessment taken prior to or at the randomization visit and 
before first use of study drug. 
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If endpoint data is missing then any routine care data that are collected within ±10 weeks of the 
dedicated study visit will be used. 
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 semaglutide s.c. as compared to SOC (excluding semaglutide).  
The primary estimand for all objectives will be the “intention-to-treat” (ITT) estimand evaluating 
the effectiveness of randomized treatment intervention irrespective of adherence to this 
randomized intervention or changes to other antidiabetic medication during follow-up. The 
purpose of this estimand is to quantify the expected effect size in the commercially-insured 
health plan population upon adoption of semaglutide s.c. as compared SOC (excluding 
semaglutide), and is as such relevant to inform and support appropriate market access and 
population based treatment guidance. 
The secondary estimand for all objectives with the exception of the adherence and persistence to 
treatment objective, is the “if all patients had adhered” estimand. This estimand evaluates the 
effect of randomized treatment intervention for all randomized patients if all patients had 
adhered to randomized treatment, regardless of changes to other (i.e., non-study drug) 
antidiabetic medication. The purpose of this estimand lies in quantifying the expected effect size 
for an individual patient in the commercially-insured health plan population who is prescribed, 
initiates, and continues treatment with semaglutide s.c. as compared to SOC (excluding 
semaglutide). The relevance of this effect measure is to inform decision making for individual 
patients and prescribing physicians. 
6.1.2 Confirmatory Endpoints and Hypotheses 
The primary endpoint is HbA1c <7.0% (53 mmol/mol) at year 1 (yes/no). This is a binary 
endpoint. Confirmatory secondary endpoints include:  
 Change in HbA1c (%-point) from baseline to year 1 
 HbA1c <7.0% (53 mmol/mol) at year 2 (yes/no) 
 Change in HbA1c (%-point) from baseline to year 2 
The primary and confirmatory endpoints will all be tested for superiority under multiplicity 
control via a hierarchical testing scheme according to the order given in the above bullet list. 
Confirmatory testing will only be performed for the primary estimand with the secondary 
estimand being supportive. The testing procedure will be stopped the first time an analysis fails 
to confirm superiority of the endpoint in question using a two-sided significance level of 5%. 
Superiority on HbA1c <7.0% will be evaluated with respect to the odds ratio (OR) (odds 
semaglutide / odds SOC): 
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H0: OR≤1 against Ha: OR>1 
Superiority on change in HbA1c (year 1 – baseline; year 2 – baseline) will be evaluated with 
respect to the mean treatment difference (TD) (semaglutide – SOC):  
H0: TD≥0 against Ha: TD<0 
6.1.3 Study Populations 
The following analysis set will be defined: 
Full analysis set (FAS): Includes all randomized patients analyzed according to the treatment 
group to which they were assigned at randomization. 
6.2 
Sample Size Determination  
6.2.1 Power and Sample Size for Primary Objective 
Assumptions for the sample size were based on input from the HIRD claims/laboratory results 
database. In line with the primary ITT estimand, the assumptions for the proportion of patients 
with HbA1c < 7.0% at year 1 and year 2, and for the change from baseline in HbA1c, were based 
on the claims/laboratory results data within the 
 population for all patients initiating 
treatment intensification, regardless of whether patients adhered to this treatment. Specifically, 
for semaglutide, assumptions were based on data for liraglutide and dulaglutide. For SOC, 
assumptions were based on all intensifications in the claims database. The study sample size of 
1,387 was calculated based on the following assumptions, informed from HIRD data: 10% 
difference in proportion patients with HbA1c < 7.0% at year 1 and year 2 (60% semaglutide  
versus 50% SOC), absolute difference in change from baseline HbA1c of 0.5%-point (SD=2.3%) 
between treatment groups, 90% power for confirming superiority of the primary endpoint, and an 
overall alpha leve1 of 5%. Sample size calculations, including different sample size scenarios 
and a summary of the data from the HIRD, will be documented in the SAP. 
The proportion of missing data for the confirmatory endpoints was estimated to be 25% after one 
year and 44% after two years. In the sample size calculation, it was assumed that only non-
missing data at year 1 and year 2 would be used for the respective analyses. This is considered 
conservative, since the use of imputed data in the actual primary analysis (see 6.3) will increase 
the power. When accounting for missing data, randomizing 1387 patients will contribute 1040 
patients for the year 1 analyses and 780 patients for the year 2 analyses, achieving a total power 
of 85% for confirming the two year 1 confirmatory hypotheses. The joint power for confirming 
all 4 confirmatory hypotheses is 58%. The corresponding marginal powers for presence of 
HbA1c < 7.0% at year 1, change in HbA1c to 1 year, presence of HbA1c < 7.0% at year 2, and 
change in HbA1c to 2 years are 90%, 94%, 80%, and 86% respectively. 
6.3 
Statistical Analysis for the Primary Estimand 
The primary estimand will be estimated based on the FAS using data from all patients with 
observations at the dedicated study visit (year 1 for the primary endpoint), with the exception of 
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patients who, in violation of the protocol, have initiated semaglutide in the SOC treatment group. 
The data collected following initiation of semaglutide from these patients will be censored and 
imputed together with missing data. The primary endpoint, HbA1c < 7.0%, will be analyzed with 
a logistic regression model with a logit link function, treatment as a categorical effect, and 
baseline HbA1c as covariate. From the model, the estimated OR (semaglutide versus SOC) will 
be presented. The underlying continuous endpoint of change in HbA1c will be analyzed using 
analysis of covariance (ANCOVA) that will include the same independent variables. From the 
model, the estimated mean difference in change from baseline to dedicated study visit 
(semaglutide versus SOC) will be presented. The estimated treatment effect from each of these 
analyses will be complemented with associated 95% confidence interval (CI) and two-sided p-
value for testing the null-hypothesis of no difference.  
Prior to analysis, missing data will be imputed by multiple imputation on the continuous HbA1c 
scale and subsequently dichotomized for the primary endpoint. 500 complete data sets will be 
generated to adequately account for the uncertainty due to missing data. Missing endpoint data 
will be imputed separately by treatment group and based on patients who remained in the study 
according to study drug treatment status, i.e., according to whether these patients are on or off 
study drug at the dedicated study visit. Data will be imputed based on the assumption that, within 
treatment groups, patients with missing endpoint data will behave like patients with the same 
study drug treatment status at endpoint as the missing patients’ last registered treatment status 
prior to the missing endpoint. For example, for patients withdrawing from the study with an “off 
study drug” treatment status, data will be imputed based on the assumption that the withdrawn 
patients will behave like patients who remain in the study but are not receiving study drug at the 
dedicated study visit. Technically, the imputation model will be an ANCOVA for the endpoint 
data. The ANCOVA will include baseline HbA1c, diabetes duration, age, and sex as independent 
variables. After this model has been used to predict missing values, each of the now 500 
complete data sets will be analyzed as described above. Finally, the multiple analysis results will 
be combined using Rubin’s rule. [13] For the OR the results will be combined on the logarithm 
scale.   
Superiority for the primary endpoint, HbA1c <7.0% at year 1, will be considered established if 
the OR 95% CI is greater than 1, or similarly if the two-sided p-value is significant on a 5% level 
and the treatment OR is in favor of semaglutide. 
If the hierarchical testing scheme allows, superiority for change from baseline to dedicated study 
visit in HbA1c will be considered established if the 95% CI for the estimated treatment 
difference is smaller than 0, or similarly if the two-sided p-value is significant on a 5% level and 
the treatment difference is in favor of semaglutide. 
6.4 
Statistical Analysis for the Secondary Estimand 
The secondary estimand will be estimated based on the FAS. The analysis is similar to the 
primary analysis for the primary endpoint, but varies with regards to the data used and the 
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imputation of missing data. Specifically, data will only be used from the subset of patients who 
are receiving study drug at the dedicated study visit (year 1 for the primary endpoint), in order to 
estimate the treatment effect if all patients had continued treatment. Patients who no longer are 
receiving study drug will be censored and imputed together with missing data. The same will 
apply to patients who, in violation of the protocol, have initiated semaglutide in the SOC group. 
Collectively, missing and censored data will be imputed separately by treatment group based on 
all patients who are on study drug at the dedicated study visit. Data will be imputed based on the 
assumption that withdrawn or censored patients behave like patients that remain in the study and 
continue on study drug. 
The technical aspects of missing data imputation based on multiple imputation, the statistical 
analysis of the multiple complete data sets, and combination of the multiple results will be the 
same as that described for the primary estimand. 
6.5 
Supplementary Analyses 
The HbA1c analyses described for the two estimands above will be complemented with two 
complete case analyses based on the subset of patients without missing endpoint data, i.e., 
patients that do not have their endpoint imputed in the two analyses used for the primary and 
secondary estimand.  
Complete case analysis 
This analysis will be based only on patients with available measurements at the dedicated study 
visit including measurements irrespective of whether patients discontinued study drug or not. 
The analysis will use the same analysis model as described under the primary estimand. 
Complete case on-study drug analysis 
The analysis will be based only on patients with available measurements at the dedicated study 
visit including only measurements for patients still on study drug. The analysis will use the same 
analysis model as described under the primary estimand. 
6.6 
PRO Analysis 
PRO and physician assessments will be measured with the instruments described in Section 5.3. 
Analysis of these measures will address the secondary objective of this study to compare 
semaglutide versus SOC in the study’s patient population as is relates to PRO, i.e., treatment 
satisfaction, generic health outcomes, work productivity, and patient and physician global 
assessment measures, over one and two year observation periods. PRO analysis will 
descriptively summarize these measures at baseline, year 1, and year 2, as well as compare 
semaglutide versus SOC for change from baseline to year 1 and year 2. The continuous change 
from baseline endpoints will be analyzed using the same analysis approach as described under 
the complete case and complete case on-study drug analyses in Section 6.5. Details will be fully 
described in the SAP. 
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6.7 
Safety Analysis 
SAEs and AEs will be collected as described in Section 7. No formal safety analyses are planned 
for this study. SAEs, AEs leading to study drug discontinuation, and pregnancies will be coded 
using Medical Dictionary for Regulatory Activities (MedDRA) and descriptively summarized by 
System Organ Class and Preferred Term (PT). 
6.8 
Other Analyses 
The following analyses are planned to further support the primary objective to compare 
semaglutide versus SOC in glycemic control. They will also address the secondary objectives of 
this study to compare semaglutide versus SOC in the study’s patient population over one and two 
year observation periods as is relates to body weight loss, hypoglycemia, HCRU, and adherence 
and persistence to treatment. The binary and continuous endpoints that include HbA1c, weight, 
SBP, or DBP data will be analyzed using the same analysis approach as described under the 
primary estimand, secondary estimand, and supplementary analysis sections. All other endpoints 
will be analyzed using the same analysis approach as described under the complete case and 
complete case on-study drug analyses in Section 6.5. Further details of these analyses and details 
for analyses of other endpoint types will be fully described in the SAP. 
6.8.1 Supportive Analyses of Glycemic Control 
The proportion of patients achieving the secondary endpoints related to glycemic control at year 
1 as defined in section 3.3.2 (individualized HbA1c target, HbA1c <7.0% (53mmol/mol) or at 
least 1% point improvement in HbA1c from baseline, HbA1c target attainment per HEDIS 
criteria) will be compared between semaglutide and SOC treatment groups using the same 
analysis approach as described under the primary estimand, secondary estimand, and 
supplementary analysis sections. 
Additionally, derived outcome variables for supportive measures of glycemic control (Appendix 
2) will be utilized to support these analyses. 
6.8.2 Weight Loss 
Change in patient weight from baseline to year one will be calculated in pounds and percentage 
as defined in section 3.3.2. Mean change in weight will be compared between semaglutide and 
SOC treatment groups using the same analysis approach as described under the primary 
estimand, secondary estimand, and supplementary analysis sections. 
Additionally, derived outcome variables for supportive measures of body weight loss (Appendix 
2) will be utilized to support these analyses. 
6.8.3 Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) 
Change in patient SBP and DBP from baseline to year 1 and baseline to year 2 will be calculated 
as defined in section 3.3.2 and Appendix 2. Mean change in SBP and DBP will be compared 
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between semaglutide and SOC treatment groups using the same analysis approach as described 
under the primary estimand, secondary estimand, and supplementary analysis sections. 
6.8.4 Hypoglycemia 
The number of hypoglycemic episodes leading to an inpatient admission or ER encounter will be 
reported by patients and compared by semaglutide and SOC treatment groups utilizing a negative 
binomial model. 
Additionally, derived outcome variables for supportive measures of hypoglycemia (Appendix 2) 
will be utilized to support these analyses. 
6.8.5 Healthcare Resource Utilization (HCRU) 
HCRU analyses will compare all-cause and diabetes-related HCRU (inpatient admissions, ER 
encounters, outpatient encounters, and pharmacy utilization) as defined in section 3.3.2 from 
claims data by semaglutide and SOC treatment group from baseline to year 2.   
The details of claims data definitions and calculations will be fully described in the SAP. 
6.8.6 Adherence and Persistence to Treatment 
Adherence and persistence to the study drug will be calculated and compared between 
semaglutide and SOC treatment groups. 
Medication adherence refers to a patient’s conformance to the provider’s recommendation with 
respect to timing, dosage, and frequency of medication taken during the prescribed length of 
time. In claims, adherence is typically measured using either medication possession ratio (MPR) 
or proportion of days covered (PDC). 
Medication persistence refers to whether a patient stays on therapy or the time from initiation to 
discontinuation of therapy. In claims, persistence is typically defined as the duration of time from 
initiation of the therapy to discontinuation or switching, whichever comes first. 
Adherence and persistence will be further defined in the SAP.  
6.8.7 Antidiabetic Treatment Patterns 
Antidiabetic treatment patterns will be assessed and compared between semaglutide and SOC 
treatment groups. This analysis will summarize the number and classification type of antidiabetic 
medications taken during the study period.  
6.8.8 Exploratory Predictive Analysis 
An exploratory predictive analysis will be performed within and between the semaglutide and 
SOC treatment groups to identify predictors of treatment adherence and persistence and glycemic 
control. The objectives of the exploratory predictive analyses are to identify within and between 
treatment groups: 1) patients less likely to discontinue treatment and 2) patients more likely to 
reach clinical target.  
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6.8.9 Evaluation of the Study Population 
To evaluate the generalizability of the study results, an analysis of the study population will be 
performed. The primary objective of this analysis is to evaluate the external validity of the study 
and to understand how the study population fits into the larger T2DM populations within study 
sites and a commercially-insured population as a whole. Two claims-based T2DM patient 
populations will be described and compared to the study population: (1) commercially-insured 
and Medicare Advantage 
 T2DM patients treated with up to 2 oral antidiabetic 
medications, excluding oral semaglutide, who undergo an antidiabetic treatment intensification, 
and (2) within the study sites, commercially-insured and Medicare Advantage 
 T2DM 
patients treated with up to 2 oral antidiabetic medications, excluding oral semaglutide, who are 
not enrolled in the study, but who undergo an antidiabetic treatment intensification. The analysis 
will compare the demographics, HCRU, and HbA1c between the study population and the two 
comparator populations during the 12 month period prior to randomization (for study population) 
or prior to a claims-based proxy for antidiabetic treatment intensification index date (for 
comparators). Additionally, treatment patterns of non-enrolled T2DM patients within the 
practices from which the study patients are recruited will be evaluated to identify any relevant 
patterns of care suggesting channeling of certain types to patients away from the study. These 
analyses will help to contextualize study results within the T2DM population broadly. 
The details of this analysis will be fully described in the SAP. 
  
7 
ADVERSE EVENT COLLECTION 
The principal study physician is responsible for monitoring the safety of participating patients. 
All SAEs reported by the patients during the study observational period are required to be 
documented on the appropriate SAE reporting form. For the purposes of this study, AEs that do 
not meet the definition of SAE will only be collected if they lead to study drug discontinuation. 
7.1 
Adverse Events 
An AE is defined as any untoward medical occurrence in a patient administered a pharmaceutical 
product or medical device, which does not necessarily have to have a causal relationship to the 
product of device. Study physicians will follow AEs that occur in any patient during this study in 
a manner consistent with routine clinical practice. For the purposes of this study, AEs that do not 
meet the definition of an SAE (section 7.2) will only be collected in the eCRF if they lead to 
study drug discontinuation. 
7.2 
Serious Adverse Events 
All AEs meeting the definition of SAE will be collected in the eCRF. SAEs will be reported 
from the time a patient is randomized until EOS at year 2, or until the patient withdraws from the 
study. An SAE is defined as any AE which results in at least one of the following outcomes: 
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 Initial inpatient admission or prolongation of existing inpatient admission 
 A life-threatening event, i.e., an event in which the patient 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 
 Persistent or significant disability or incapacity 
 Congenital anomaly or birth defect in offspring 
 Death 
 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 patient and may require 
medical or surgical intervention to prevent one of the other listed outcomes. 
7.2.1 Collection Period of Serious Adverse Events 
SAEs will be reported from the time a patient is randomized until EOS at year 2, or until the 
patient withdraws from the study. The principal study physician 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 patient 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. 
At each visit (both routine diabetic care visits and dedicated study visits), patients will be asked 
about AEs including hypoglycemic events, e.g. “Have you experienced any problems since the 
last contact?” Any SAE identified from any patient encounter or notation at any time must be 
reported. 
If an investigator becomes aware of SAEs after EOS at year 2 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 patients 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 patient is randomized until EOS at year 2 or until 
the patient withdraws from the study. The principal study physician is responsible for alerting 
Novo Nordisk or its designee to any drug exposure during pregnancy within 14 days of the first 
knowledge of the pregnancy via the pregnancy reporting form. The study physician will follow 
the patient for the duration of the pregnancy. 
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7.4 
Technical Complaints 
Technical complaints may be reported as per usual practice. However, any SAEs resulting from a 
technical complaint must be reported via EDC. 
 
8 
DATA COLLECTION 
8.1 
Data Sources 
Data sources include primary data collected prospectively by study sites at study visits 
(demographic and clinical data, patient-completed PRO data, and physician reported global 
assessments) as well as secondary data collection utilizing administrative claims data from health 
plans, as available. In order to maintain patient confidentiality, each patient will be assigned a 
unique patient study ID number upon signing informed consent to use in place of patient name or 
any other identifying information (e.g., medical record number). Clinical study data, 
PROs/ClinROs and claims-derived variables will be integrated into one analysis dataset via this 
confidential patient ID. 
8.2 
Electronic Case Report Forms (eCRFs) 
All clinical study data will be collected at the physician office and entered into eCRF by trained 
site study personnel through a fully validated, 21 CFR 11 and HIPAA compliant EDC system.  
Patients 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.  
Some clinical assessments utilized in this study may be completed in the course of routine 
clinical practice by site personnel not affiliated with study (e.g., blood pressure), however any 
activities completed solely for the study (e.g., data entry, PRO administration) must be done by 
trained site study personnel. For example, a nurse not affiliated with the study may measure 
blood pressure as part of routine care. The data from this assessment may be used for this study, 
but must be extracted from the patient’s medical record and entered into the eCRF by trained site 
study personnel.  
The principal study physician has the ultimate responsibility for the collection and reporting of 
all clinical and patient data through the eCRFs, as well as ensuring that they are accurate and 
complete to the extent possible. 
8.3 
Year One Database Lock 
The primary analysis for this study is a year 1 analysis. Once data collection for year 1 has 
completed, a database lock and year 1 analysis will be performed. The year 1 analysis will not be 
integrated with HCRU and will be limited to year 1 endpoints derived from eCRF data, including 
PRO data. To maintain study integrity for the remaining study period, data from year 1 will be 
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used for limited and confidential communications while complying with public disclosure 
requirements. All other analyses will be conducted following a second database lock once data 
collection for the entire study is 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 physician 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 patients as well as the scientific integrity of the study. Site monitoring will be 
conducted by 
 staff.  
9.1.1 Institutional Review Board (IRB) 
The principal study physician will have prospective IRB approval of the study protocol, ICF, and 
any patient information or recruiting materials prior to commencement of any study activities at 
their site. In the case of a protocol amendment, the study physician 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 patients or others must be reported to the IRB as 
required. 
The principal study physician 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. The principal study physician must 
ensure that each study patient is informed of the study and authorizes release of health 
information prior to study-related activities. The study physician, or study personnel designated 
by the study physician, will obtain written informed consent from each patient prior to initiation 
of any study-related procedures. Each patient will be given a copy of the signed ICF. The 
principal study physician will retain the original signed ICF for each patient. 
The IRB must prospectively approve the ICF and any changes to the ICF during the course of the 
study before use. If a protocol amendment increases the potential risk to the patient, 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 patients entering the study as well as 
from currently enrolled patients if they are affected by the amendment, per IRB guidance. 
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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 principal study physician must agree 
to maintain and allow access to required patient and study records. The principal study physician 
agrees to keep the identity of all participating patients (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). The principal study physician should retain records according 
to local regulations, or as specified in the Clinical Study Agreement, whichever is longer. 
 
10 
PUBLICATION OF STUDY RESULTS 
All information related to this study is considered confidential information belonging to Novo 
Nordisk and 
 as consistent with contractual agreement. 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 with authorship 
following the International Committee of Medical Journal Editors (ICMJE) guidelines. 
Information regarding the study will be disclosed at clinicaltrials.gov and novonordisk-
trials.com. 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 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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glargine trials shows greater responsiveness to improvements than the original 
DTSQ," Health and Quality of Life Outcomes, vol. 5, no. 5, p. 57, 2007.  
[11] J. Ware, M. Kosinski and S. Keller, "A 12-item short-form health survey: construction 
of scales and preliminary tests of reliability and validity," Med Care, vol. 34, no. 3, pp. 
220-233, 1996.  
[12] M. Reilly, A. Zbrozek and E. Dukes, "The validity and reproducibility of a work 
productivity and activity impairment instrument," PharmacoEconomics, vol. 4, no. 5, 
pp. 353-365, 1993.  
[13] R. Little and D. Rubin, Statistical analysis with missing data., J. Wiley, Ed., New York: 
John Wiley and Sons, 1987.  
[14] T. Wasser, J. Ycas and O. Tunceli, "Applying Weighting Methodologies to a Commercial 
Database to Project US Census Demographic Data," The American Journal of 
Accountable Care, 2015.  
 
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Appendix 1: Time and Events Schedule  
Study NN9535-4416 
 
Dedicated Study visit, 
Randomization 
 
Routine Diabetic Care  
visits, Year 1 
Dedicated Study visit, 
Year 1 
Routine Diabetic Care 
visits, Year 2 
Dedicated Study visit, 
Year 2 
Time of visit (Weeks)a 
0* 
0-52** 
52±6 
52-104** 
104±6 
PATIENT AND TREATMENT RELATED ASSESSMENTSb 
Informed consentc 
X 
 
 
 
 
Specific authorization forms for release of 
non-
 health plan claims data 
X 
 
X 
 
X 
Inclusion/Exclusion criteria 
X 
 
 
 
 
Demographics (date of birth, gender, race, 
ethnicity) 
X 
 
 
 
 
Selected medical history 
X 
 
 
 
 
Diabetes history and diabetes 
complications 
X 
 
 
 
 
Individualized HbA1c targetd 
X 
 
 
 
 
Type of glucose-lowering medication 
including semaglutide s.c.e 
X 
X 
X 
X 
X 
Concomitant cardiovascular medicatione 
X 
X 
X 
X 
X 
Reason for discontinuation of any glucose-
lowering medication 
 
X 
X 
X 
X 
EFFECTIVENESS AND SAFETY RELATED ASSESSMENTS 
Body weight 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
SBP / DBP 
X 
X 
X 
X 
X 
HbA1c 
Xf 
X 
X 
X 
X 
SAEs,g pregnancies, and AEs leading to 
study drug discontinuation 
 
X 
X 
X 
X 
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Study NN9535-4416 
 
Dedicated Study visit, 
Randomization 
 
Routine Diabetic Care  
visits, Year 1 
Dedicated Study visit, 
Year 1 
Routine Diabetic Care 
visits, Year 2 
Dedicated Study visit, 
Year 2 
Healthcare resource utilizationh 
 
X 
X 
X 
X 
Hypoglycemia leading to inpatient 
admission or ER encounter 
 
X 
X 
X 
X 
PROs and Physician Completed Assessments 
DTSQs 
X 
 
 
 
 
DTSQc 
 
 
X 
 
X 
SF-12v2 
X 
 
X 
 
X 
WPAI-GH 
X 
 
X 
 
X 
PGI-S 
X 
 
 
 
 
PGI-C 
 
 
X 
 
X 
CGI-S 
X 
 
 
 
 
CGI-C 
 
 
X 
 
X 
END OF STUDY 
End of study 
 
 
 
 
X 
* Eligibility assessment may take place up to 4 weeks prior to the randomization visit. If eligibility assessment 
occurs prior to the randomization visit, any changes in collected medical history, diabetes history, diabetes 
complications, glucose lowering medications and concomitant cardiovascular mediations will be collected at the 
randomization visit.  
** The year 1 and year 2 routine diabetic care visit windows are determined by the date of the patient’s dedicated 
year 1 study visit. The year 1 routine diabetic care visit window will end immediately prior to the dedicated year 1 
study visit. The year 2 routine diabetic care visit window will begin immediately following the dedicated year 1 
study visit. 
 
Note: In this study, data will be collected from two different data sources: 
1) Data entered into the eCRF will be collected at dedicated study visits and routine diabetic care visits (if 
available per local clinical practice) and will include: demographics, selected medical history, diabetes 
medical history and diabetes complications, individualized HbA1c target, type of glucose-lowing 
medication, concomitant cardiovascular medication, reason for discontinuation of any glucose lowering 
medication, body weight, height, SBP, DBP, HbA1c, AEs leading to study drug discontinuation, SAEs, 
pregnancies and hypoglycemia leading to inpatient admission or ER encounter. Of note, AEs leading to 
study drug discontinuation or SAEs will be collected from all interactions with the patient, as well as if 
discovered when reviewing documents from healthcare encounters with other providers. Additionally, PRO 
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and ClinRO data will be collected at the dedicated study visits and entered into the eCRF. 
2) Healthcare resource utilization and pharmacy prescription data will be extracted from health plan medical 
and pharmacy claims and will not be entered into the eCRF.  
 
a Routine diabetic care visits will follow standard of care frequency and any available data will be entered in the 
eCRF.  
b Assessments at dedicated study visits will be collected in eCRF. Assessments at routine diabetic care visits will be 
collected as available/according to local clinical practice in eCRF.  
c Informed consent must be obtained before any study related activities. 
d Individualized HbA1c target must be set and documented prior to randomization. 
e Medication data (glucose-lowering medications and/or concomitant cardiovascular medications) collected at study 
visits only include medications that are current at time of study visit. 
f The HbA1c value is based on historical data collected from the study physician and is the value closest to the date 
of randomization, within the last 90 days. 
g Any SAE identified from any encounter or notation at any time must be reported. 
h Data from health plan medical and pharmacy claims. Data will be extracted at the end of the study, but will include 
data from patient randomization through EOS or withdrawal. 
 
 
 
 
 
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Appendix 2: Additional Derived Outcome Variables for Supportive Analyses 
Supportive Measures of Glycemic Control 
 Individualized HbA1c target attained at year 2 (yes/no) 
 HbA1c <7.0% (53 mmol/mol) or at least 1% point improvement in HbA1c compared to 
baseline at year 2 (yes/no) 
 HbA1c <8.0% (64 mmol/mol) at year 1 (yes/no) 
 HbA1c <8.0% (64 mmol/mol) at year 2 (yes/no)  
 HbA1c <7.0% (53 mmol/mol) and no further antidiabetic medication intensification after 
randomization at year 1 (yes/no) 
 HbA1c <7.0% (53 mmol/mol) and no further antidiabetic medication intensification after 
randomization at year 2 (yes/no) 
 HbA1c target attainment per HEDIS criteria (<8.0% if age ≥65 years or with defined 
comorbidities, otherwise <7.0%) at year 2 (yes/no) 
 HbA1c <7.0% (53 mmol/mol) at year 1 in patients with HbA1c >9.0% at baseline 
(yes/no) 
 HbA1c <7.0% (53 mmol/mol) at year 2 in patients with HbA1c >9.0% at baseline 
(yes/no) 
 HbA1c <8.0% (64 mmol/mol) at year 1 in patients with HbA1c >9.0% at baseline 
(yes/no) 
 HbA1c <8.0% (64 mmol/mol) at year 2 in patients with HbA1c >9.0% at baseline 
(yes/no) 
Body Weight Loss 
 Change in body weight (%) from baseline to year 2 
 Change in body weight (lb) from baseline to year 2 
Blood Pressure 
 Change in SBP (mm Hg) from baseline to year 2 
 Change in DPB (mm Hg) from baseline to year 2 
Hypoglycemia 
 Reported hypoglycemia leading to inpatient admission or ER encounter during year 1 
(yes/no) 
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 
Reported hypoglycemia leading to inpatient admission or ER encounter during year 2 
(yes/no) 
Composite Variables 
 HbA1c <7.0% (53 mmol/mol) without experiencing hypoglycemia leading to inpatient 
admission or ER encounter and body weight loss of  ≥5% vs baseline at year 1 (yes/no) 
 Absolute HbA1c reduction of ≥0.5% without experiencing hypoglycemia leading to 
inpatient admission or ER encounter and a body weight loss of  ≥5% vs baseline at year 1 
(yes/no) 
 HbA1c <7.0% (53 mmol/mol) without experiencing hypoglycemia leading to inpatient 
admission or ER encounter and body weight loss of  ≥5% vs baseline at year 2 (yes/no) 
 Absolute HbA1c reduction of ≥0.5% without experiencing hypoglycemia leading to 
inpatient admission or ER encounter and a body weight loss of  ≥5% vs baseline at year 2 
(yes/no) 
 HbA1c <7.0% (53 mmol/mol) without experiencing hypoglycemia leading to inpatient 
admission or ER encounter and no body weight gain vs baseline at year 1 (yes/no) 
 HbA1c <7.0% (53 mmol/mol) without experiencing hypoglycemia leading to inpatient 
admission or ER encounter and no body weight gain vs baseline at year 2 (yes/no) 
Adherence to Treatment 
 Study drug medication adherence for the two years of the study, as measured by the 
medication possession ratio (MPR) 
 
 
 
 
 
 
 
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Appendix 3: Patient Reported Outcome Additional Information 
 
DTSQc 
The DTSQc provides a measure of how satisfied patients are with their current diabetes 
treatment compared with previous treatment. It consists of 8 questions, which are to be answered 
on a Likert scale from -3 to +3 (-3 = much less satisfied now to +3 = much more satisfied now), 
with 0 (midpoint), representing no change. Six questions are summed to produce a Total 
treatment satisfaction score. The remaining two questions concern perceived frequency of 
hyperglycemia and perceived frequency of hypoglycemia, respectively. The DTSQc Total 
treatment satisfaction score ranges from -18 to +18, with higher scores associated with greater 
treatment satisfaction. 
 
SF-12 v2 
The SF-12v2 is a 12-item generic health-related quality of life measure that assesses physical and 
mental functioning. The items will be scored using the scoring software that will be provided 
with the license. The following two summary scores are used as endpoints: Physical Component 
Summary (PCS) Score and Mental Component Summary (MCS) Score. The scores are norm-
scored such that the scores range from 0-100 with a mean of 50 and standard deviation of 10.  A 
higher score is associated with better quality of life and a lower score, poorer quality of life.  
 
WPAI-GH 
The WPAI-GH yields four types of scores: Absenteeism (work time missed), Presenteesism 
(impairment at work / reduced on-the-job effectiveness), Work productivity loss (overall work 
impairment / absenteeism plus presenteeism), and Activity Impairment. WPAI outcomes are 
expressed as percentages, with higher numbers indicating greater impairment and less 
productivity, i.e., worse outcomes (percent work time missed due to health, percent impairment 
while working due to health, percent overall work impairment due to health, percent activity 
impairment due to health). 
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Summary of Amendments and Updates 
 
Summary of Changes 
NN95359-4416 Protocol Version 2.0, dated 27MAR2019 
 
Number 
Section/Page 
 
Change 
Rationale 
1 
Global Change, 
Study Population 
Allow enrollment of patients treated 
with either 1 or 2 oral antidiabetic 
medications. 
  
Expand study population from 
patients treated with 
metformin monotherapy to 
patients treated with either 1 or 
2 oral antidiabetic medications 
to facilitate enrollment. 
 
2 
Global Change 
 
March 1327, 20182019 
 
Version 12.0 
 
Update protocol date and 
version. 
3 
Study Approvals, p. 
2 
Name:  
 
 
Title:   
 
 
 
 
 
 
Study approval title update. 
4 
Study Approvals, p. 
2 
Name: 
 
 
 
Title:  
 
 
Statistician 
 
Update to study statistician. 
5 
Patient Description,  
Synopsis, p. 7 
 
Eligible patients include adult 
T2DM patients on metformin 
monotherapy up to 2 oral 
antidiabetic medications whose 
physician deems that they have 
inadequate glycemic control and 
need treatment intensification with 
an additional antidiabetic oral or 
injectable medication. 
 
Update patient description to 
reflect expanded study 
population. 
6 
Primary Objective 
 
Synopsis, p. 7 
 
Section 2.1, Primary 
Objective, p. 17 
The primary objective is to 
demonstrate superior long term 
effects of treatment with 
semaglutide compared to SOC both 
added to metformin up to 2 oral 
antidiabetic medications on 
Update primary objective to 
reflect expanded study 
population. 
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glycemic control when used as 
intensification in routine clinical 
practice in adult patients with 
T2DM. 
 
7 
Secondary Objective 
 
Synopsis, p. 7 
 
Section 2.2,  
Secondary 
Objectives, p. 17 
 
The secondary objectives are to 
compare the long term effect of 
semaglutide versus SOC both added 
to metformin up to 2 oral 
antidiabetic medications and used 
as intensification in routine clinical 
practice in adult patients with 
T2DM with regards to: 
 
Update secondary objectives 
to reflect expanded study 
population. 
8 
Study Design 
 
Synopsis, p. 7 
 
Section 4.1, Study 
Design Overview, p. 
20 
This is a 2-year, multi-center, 
randomized, open label, parallel 
group, active comparator pragmatic 
clinical trial (PCT) comparing 
semaglutide versus SOC when 
added to metformin monotherapy 
up to 2 oral antidiabetic 
medications as treatment 
intensification among adult T2DM 
patients in the course of routine 
clinical practice. 
 
Update study design to reflect 
expanded study population. 
9 
Inclusion Criteria, 
#4 
 
Synopsis, p. 8 
 
Section 4.2.3, 
Patient Inclusion 
Criteria, p. 22 
 
4.) Treatment with metformin as 
antidiabetic monotherapy either 
1 or 2 oral antidiabetic 
medications. 
 
Expand study population from 
patient treated with metformin 
monotherapy to patients 
treated with either 1 or 2 oral 
antidiabetic medications to 
facilitate enrollment. 
 
10 
Inclusion Criteria, 
#5 
 
Synopsis, p. 8 
 
Section 4.2.3, 
Patient Inclusion 
Criteria, p. 22 
 
5.) Current member of an 
 
affiliated commercial health 
plan with pharmacy benefits. 
Clarification of health plan 
requirements.  
11 
Exclusion Criteria, 
#2 
 
Synopsis, p. 8 
 
2.) Treatment with more than 2 oral 
antidiabetic medications or any 
injectable antidiabetic 
medication any medication for 
the indication of diabetes other 
Update exclusion criterion #2 
to be consistent with inclusion 
criterion #4. 
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Section 4.2.4, 
Patient Exclusion 
Criteria, p. 22 
 
than metformin in a period of 
30 days before the day of 
eligibility assessment. 
Temporary/emergency use of 
any type of insulin is allowed, 
as is prior insulin treatment for 
gestational diabetes.  
 
12 
Section 1, 
Introduction, p. 16 
This local US study will enroll adult 
patients with T2DM who have 
inadequate glycemic control on 
metformin as their only up to 2 oral 
antidiabetic medications, as defined 
by the need for treatment 
intensification with an additional 
antidiabetic oral or injectable 
medication per the study 
physician´s discretion. 
 
Update description of study to 
reflect expanded study 
population. 
13 
Section 4.2, Practice 
and Patient 
Selection, p. 21 
The target population for this study 
consists of adult, commercially-
insured, T2DM patients on 
metformin mono-therapy up to 2 
oral antidiabetic medications who 
are in need of treatment 
intensification with an additional 
antidiabetic oral or injectable 
medication. 
 
Update target population to 
reflect expanded study 
population. 
14 
Section 4.2, Practice 
and Patient 
Selection, p. 21 
 health plans serve a large 
population of T2DM patients. In 
feasibility data from the HIRD, the 
number of patients with T2DM, at 
least one claim for metformin in the 
most recent 6 months, and without 
prior use of other antidiabetic drug 
classes (per study exclusion 
criterion #2), amounts to circa 
300,000 potential eligible patients 
distributed across 61,803 unique 
providers. 
 
Delete data based on 
metformin monotherapy as it 
is not relevant to updated 
inclusion criteria. 
15 
Section 4.2.2, 
Patient Recruitment 
and Eligibility, p. 21 
Eligible patients include adult 
T2DM patients whose physicians 
determine that they have inadequate 
glycemic control on metformin 
antidiabetic monotherapy1 or 2 oral 
antidiabetic medications. 
 
Update description of eligible 
patients to reflect expanded 
study population. 
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16 
Figure 1, Study 
design, p. 23 
 
Figure 1 Study design diagram. 
Patients will be randomized in a 1:1 
manner using centralized allocation 
to receive semaglutide or SOC as 
add-on to metformin up to 2 oral 
antidiabetic medications.  
 
Update description of study 
design to reflect expanded 
study population. 
17 
Section 5.1, 
Enrollment 
Procedures, p. 23 
 
The determination that a patient has 
inadequate glycemic control on 
metformin antidiabetic 
monotherapy up to 2 oral 
antidiabetic medications, and the 
subsequent decision to intensify 
antidiabetic treatment with an 
additional oral or injectable 
antidiabetic medication, will be 
made by the study physician during 
the course of routine clinical 
practice. 
 
Update enrollment procedures 
to reflect expanded study 
population. 
18 
Section 5.2.2, 
Treatments, p. 26 
 
Metformin 
Add metformin to the list of 
oral antidiabetic drugs 
included in this study to reflect 
expanded study population. 
 
19 
Section 5.2.2, 
Treatments, p. 26-27 
Background medication: The (up 
to 2) oral antidiabetic medication(s) 
taken prior to randomization and 
treatment intensification following 
treatment is considered background 
medication: metformin. Patients 
may discontinue metformin 
background medication at any time 
during the study. Patients may 
change the pre-study dose and 
frequency of metformin background 
medication at any time during the 
study. Background medication will 
not be provided nor reimbursed by 
Novo Nordisk. 
 
Update description of 
background medication to 
reflect expanded study 
population. 
20 
Section 6.6, PRO 
Analysis, p. 33 
The continuous change from 
baseline endpoints will be analyzed 
using the same analysis approach as 
described under the complete case 
and complete case on-study drug 
Update to planned PRO 
analyses, with no missing data 
imputation for PRO endpoints. 
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analyses in primary estimand, 
secondary estimand, and 
supplementary analysis sSection 
6.5. 
 
21 
Section 6.8, Other 
Analyses, p. 34 
The binary and continuous 
endpoints that include HbA1c, 
weight, SBP, or DBP data will be 
analyzed using the same analysis 
approach as described under the 
primary estimand, secondary 
estimand, and supplementary 
analysis sections. All other 
endpoints will be analyzed using 
the same analysis approach as 
described under the complete case 
and complete case on-study drug 
analyses in Section 6.5. 
 
Update to planned analyses, 
with missing data imputation 
only for endpoints including 
HbA1c, weight, SBP, or DBP 
data. 
22 
Section 6.8.9, 
Evaluation of Study 
Population, p. 35 
Two claims-based T2DM patient 
populations will be described and 
compared to the study population: 
(1) commercially-insured 
 
T2DM patients treated with 
metformin up to 2 oral antidiabetic 
medications who undergo an 
antidiabetic treatment 
intensification, and (2) within the 
study sites, commercially-insured 
 T2DM patients treated with 
metformin up to 2 oral antidiabetic 
medications who are not enrolled in 
the study, but who undergo an 
antidiabetic treatment 
intensification. 
 
Update claims-based 
comparator population to 
reflect expanded study 
population. 
 
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Summary of Changes 
NN95359-4416 Protocol Version 3.0, dated 21AUG2019 
 
Number 
Section/Page 
 
Change 
Rationale 
1 
Global Change, 
Study Population 
Allow enrollment of patients with 
any commercial or Medicare 
insurance with pharmacy benefits. 
  
Expand study population to 
facilitate enrollment. 
 
2 
Global Change 
 
March 27August 21 2019 
 
Version 32.0 
 
Update protocol date and 
version. 
3 
Study Approvals 
 
 
 
Update to project statistician. 
4 
Study Physician 
Sites, 
Synopsis, p. 7 
 
Section 4.2.1, 
Physician Practice 
Eligibility, p. 21 
 
Participation of approximately 285 
200 physician sites 
Reduction in number of sites 
necessary with expanded study 
population. 
5 
Study Physician 
Sites, 
Synopsis, p. 7 
 
…that have a population of patients 
with the target indication, type 2 
diabetes mellitus (T2DM), actively 
enrolled in an 
 affiliateda 
commercial or Medicare health plan 
with pharmacy benefits. 
 
Update description to reflect 
expanded study population. 
6 
Patients, 
Synopsis, p. 7 
Planned enrollment in this study is 
22501387. 
Reduction in planned 
enrollment based on updated 
power assumptions. 
 
7 
Global Change 
 
routine diabetic care visits 
Clarify data collection 
between study visits for sites. 
 
8 
Study Design, 
Synopsis, p. 8 
 
Study Procedures, 
Synopsis, p. 9 
Additionally, medical and 
pharmacy claims data will be 
captured utilizing the HealthCore 
Integrated Research Database 
(HIRDSM) for 
 patients or 
requested, via patient written 
authorization, from a set of other 
health insurers for non-
 
patients for the 2 year study period. 
HIRD Claims data for the 12 
Update to reflect expanded 
study population and 
collection of claims data from 
other health insurers. 
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months prior to randomization will 
also be collected if available. 
 
9 
Inclusion Criteria, 
#5 
 
Synopsis, p. 8 
 
Section 4.2.3, 
Patient Inclusion 
Criteria, p. 22 
 
5.) Current member of an 
 
affiliated a commercial or 
Medicare health plan with 
pharmacy benefits. 
Expand study population to 
facilitate enrollment. 
 
10 
Study Procedures, 
Synopsis, p. 9 
 
Appendix, Time and 
Events Schedule, 
Note 1, p. 43 
Of note, AEs leading to study drug 
discontinuation or SAEs will be 
collected from all interactions with 
the patient, as well as if discovered 
when reviewing documents from 
healthcare encounters with other 
providers. 
 
Clarification of AE leading to 
study drug discontinuation and 
SAE identification outside of 
routine diabetic care or 
dedicated study visits. 
11 
Statistical Analysis, 
Synopsis, p. 10 
This study is designed to have 90% 
power to jointly confirm superiority 
of the primary endpoint and 85% 
power to also confirm superiority of 
the above three first confirmatory 
secondary endpoints based on an 
analysis of the primary estimand for 
each of the endpoints. 
 
Update to power calculations. 
12 
List of Definitions, 
Administrative 
Claims Data, p. 14 
 
Medical, pharmacy, and health plan 
eligibility data created in the 
processing of medical and 
pharmacy claims. The claims data 
utilized in this study are obtained 
from the HealthCore Integrated 
Research Database (HIRD) for 
 patients and requested, via 
patient written authorization, from a 
set of other health insurers for non-
 patients. 
 
Updated definition to reflect 
expanded study population and 
collection of claims data.  
13 
Section 4.2, Practice 
and Patient 
Selection, p. 21 
The target population for this study 
consists of adult, commercially 
insured, T2DM patients on up to 2 
oral antidiabetic medications who 
are in need of treatment 
intensification with an additional 
antidiabetic oral or injectable 
medication. To support study 
Update to reflect expanded 
study population. 
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objectives, including claims 
analysis of HCRU, eligible patients 
will also be currently insured 
through a commercial health plan or 
Medicare with pharmacy benefits. 
 
14 
Section 4.2, Practice 
and Patient 
Selection, p. 21 
Physician practice and participant 
eligibility criteria were guided by 
feasibility data from the HealthCore 
Integrated Research Database 
(HIRDSM) prior to protocol 
development. 
Physician sites recruited for the 
study will be those who provide 
care for members of 
 health 
plans, one of the largest healthcare 
insurance providers in the US. 
 provides medical coverage 
for roughly 1 in 8 Americans, and 
although this is mostly concentrated 
in the employer-supported, 
commercially-insured market, the 
data in the HIRD are overall 
representative of the entire US 
population. [14] 
 
Update to reflect expanded 
study population and site 
selection. 
15 
Section 4.2, Practice 
and Patient 
Selection, p. 21 
Potential sites will be evaluated 
regarding feasibility of their 
participation in the study, including 
having a T2DM population of 
 members to meet 
enrollment goals, based on the 
initial data analysis from the HIRD. 
 
Update to reflect expanded 
study population and site 
selection. 
16 
Section 4.2.1, 
Physician Practices, 
p. 21 
4.2.1 Physician Practices 
Eligibility 
Participation of approximately 
285200 physician sites in the US, 
including both general practitioners 
and endocrinologists that have a 
T2DM population, is anticipated. 
 
Physician sites will be limited to 
those that participate in the care of 
patients who are actively enrolled in 
an 
 
 
 
 health plan 
Update to reflect expanded 
study population and site 
selection. 
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(hence forth referred to as 
 
health plans). 
 
17 
Section 4.2.5, 
Patient Enrollment, 
p. 22 
Planned number of patients to be 
randomized: 22501387 
Expected number of patients to 
complete the study after 52 weeks: 
16871040 
Expected number of patients to 
complete the study after 104 weeks: 
1260780 
 
Reduction in planned 
enrollment based on updated 
power assumptions. 
 
18 
Section 4.2.6, 
Patient 
Randomization, 
Figure 1, p. 23 
 
n=22501387 
Reduction in planned 
enrollment based on updated 
power assumptions. 
 
19 
Section 5.1, 
Enrollment 
Procedures, p. 23-24 
To preserve the real-world nature of 
the study, patients will be 
approached for potential enrollment 
into the study through their 
physician if review of their medical 
history indicates that they may be 
eligible for the study. Outreach may 
occur when they patients present to 
their physician as part of their 
standard care or through proactive 
contact of potentially eligible 
patients identified within the study 
physician’s practice. 
 
Clarification of patient 
recruitment and enrollment 
procedures. 
20 
Section 5.2.2, 
Treatments, Copay 
assistance, p. 26 
The only exceptions are if a patient 
initiates prescription coverage 
through Medicare or Medicaid, at 
which point all copay assistance 
will end. 
 
Update to reflect expanded 
study population and copay 
coverage for Medicare 
patients. 
21 
Section 5.4, Study 
Period, p. 28 
 
If a patient leaves their 
 
health plan network during the 2 
year study period, administrative 
claims data will be collected from 
randomization through the date they 
leave the health plan. If a patient 
switches to another health plan 
during the 2-year study period, an 
attempt may be made to collect 
administrative claims data from that 
Update to reflect expanded 
study population and 
collection of claims data. 
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plan as well. In this these scenarios, 
site-based study data collection will 
continue without change. 
 
22 
Section 5.5, 
Administrative 
Claims Data, p. 28 
5.1 Administrative Claims 
Data HIRDSM 
In addition to prospectively 
collected clinical data and PROs, 
this study will also utilize claims 
data from the HealthCore Integrated 
Research Database (HIRDSM) HIRD 
for all study 
 patients or 
requested, via patient written 
authorization, from a set of other 
health insurers for non-
 
patients. 
 
Update to reflect expanded 
study population and 
collection of claims data. 
23 
Section 5.5, 
Administrative 
Claims Data, p. 28 
Final Eextraction of this data will 
take place approximately 3 months 
after the last patient’s last visit 
(LPLV) to allow for data lags in the 
claims. 
 
Update to reflect expanded 
collection of claims data. 
24 
Section 5.6.2, 
Patients, p. 28 
If a patient has not been in contact 
with the Prescribing Physician by 
the end of the 2 year study duration 
period and the site is not able to 
reach the patient after 3 contact 
attempts, the patient can be 
considered Lost To Follow-Up 
(LTFU). One of the 3 contact 
attempts should include a certified 
letter being sent to the patient.  If a 
patient’s status is determined to be 
LTFU, this must be recorded on the 
End of Study eCRF. 
 
Added new language to clarify 
patients lost to follow-up. 
25 
Section 6.2.1, Power 
and Sample Size for 
the Primary 
Objective, p. 31 
 
The study sample size of 2,250 
1,387 was calculated based on the 
following assumptions,… 90% 
power for confirming superiority of 
the primary endpoint, and an overall 
alpha leve1 of 5%. 
 
Update to planned enrollment 
and power calculations. 
26 
Section 6.2.1, Power 
and Sample Size for 
the Primary 
Objective, p. 31 
 
When accounting for missing data, 
randomizing 2250 1387 patients 
will contribute 1687 1040 patients 
for the year 1 analyses and 1260 
780 patients for the year 2 analyses, 
Update to planned enrollment 
and power calculations. 
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achieving a total power of 90% 
85% for confirming the two year 1 
confirmatory hypotheses. The joint 
power for confirming all 4 
confirmatory hypotheses is 58%. 
The corresponding marginal powers 
for presence of HbA1c < 7.0% at 
year 1, change in HbA1c to 1 year, 
presence of HbA1c < 7.0% at year 
2, and change in HbA1c to 2 years 
are 99%90%, 99%94%, 95%80%, 
and 97%86% respectively. 
 
27 
Section 6.8.5, 
Healthcare Resource 
Utilization (HCRU), 
p. 35 
HCRU analyses will compare all-
cause and diabetes-related HCRU 
(inpatient admissions, ER 
encounters, outpatient encounters, 
and pharmacy utilization) as 
defined in section 3.3.2 from the 
HIRD claims data by semaglutide 
and SOC treatment group from 
baseline to year 2. 
 
Update to reflect expanded 
study population and 
collection of claims data. 
28 
Section 6.8.9, 
Evaluation of Study 
Population, p. 36 
The primary objective of this 
analysis is to evaluate the external 
validity of the study and to 
understand how the study 
population fits into the larger 
T2DM populations within study 
sites and 
 a commercially-
insured population as a whole. Two 
claims-based T2DM patient 
populations will be described and 
compared to the study population: 
(1) commercially-insured and 
Medicare Advantage 
 
T2DM patients treated with up to 2 
oral antidiabetic medications who 
undergo an antidiabetic treatment  
intensification, and (2) within the 
study sites, commercially-insured 
and Medicare Advantage T2DM 
patients treated with up to 2 oral 
antidiabetic medications who are 
not enrolled in the study, but who 
undergo an antidiabetic treatment 
intensification. 
 
Update to reflect expanded 
study population. 
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29 
Section 7.2.1, 
Collection Period of 
Serious Adverse 
Events, p. 37 
 
Appendix 1: Time 
and Events 
Schedule, Footnote 
g, p. 44 
 
Any SAE identified from any 
patient encounter or notation at any 
time must be reported. 
 
Clarification of SAE 
identification outside of 
routine diabetic care or 
dedicated study visits. 
30 
Section 8.1, Data 
Sources, p. 38 
Data sources include primary data 
collected prospectively by study 
sites at study visits (demographic 
and clinical data, patient-completed 
PRO data, and physician reported 
global assessments) as well as 
secondary data collection utilizing 
administrative claims data from the 
HIRD health plans, as available. 
 
Update to reflect expanded 
study population and 
collection of claims data. 
31 
References 
[7] T. Wasser, J. Ycas and O. 
Tunceli, "Applying Weighting 
Methodologies to a Commercial 
Database to Project US Census 
Demographic Data," The American 
Journal of Accountable Care, 2015. 
 
Reference no longer relevant 
with expanded study 
population. 
 
32 
Appendix 1: Time 
and Events 
Schedule, p. 42 
Specific authorization forms for 
release of non-
 health plan 
claims data 
Addition of claims release for 
non-
 patients to reflect 
expanded study population and 
collection of claims data. 
 
33 
Appendix 1: Time 
and Events 
Schedule, Note 2, p. 
43 
2) Healthcare resource utilization 
and pharmacy prescription data 
will be extracted from health 
plan medical and pharmacy 
claims the HIRD and will not 
be entered into the eCRF.  
 
Update to reflect expanded 
study population and 
collection of claims data. 
34 
Appendix 1: Time 
and Events 
Schedule, 
Medication 
Footnote, p. 44 
e Medication data (glucose-lowering 
medications and/or concomitant 
cardiovascular medications) 
collected at study visits only 
include medications that are current 
at time of study visit. 
 
Footnote clarifying time frame 
for medication data collected. 
35 
Appendix 1: Time 
and Events 
Schedule, Footnote 
f, p. 44 
hf Data from health plan medical 
and pharmacy claims the HIRD. 
Data will be extracted from the 
HIRD at the end of the study, but 
Update to reflect expanded 
study population and 
collection of claims data. 
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will include data from patient 
randomization through EOS or 
withdrawal. 
 
 
 
 
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Summary of Changes 
NN95359-4416 Protocol Version 4.0, dated 05DEC2019 
 
Number 
Section/Page 
 
Change 
Rationale 
1 
Global Change, 
Patient Eligibility  
Oral semaglutide is not allowed as 
one of the 1-2 oral antidiabetic 
medications in patient eligibility 
criteria. 
 
Protocol update following 
approval oral formulation of 
semaglutide. 
 
2 
Global Change, 
Study Treatments 
Formulation of semaglutide for 
study is subcutaneous only. 
 
 
Oral semaglutide is not allowed 
in either treatment group during 
the study period. 
 
Protocol update following 
approval oral formulation of 
semaglutide. 
 
3 
Global Change 
 
August 21December 5, 2019 
 
Version 43.0 
 
Update protocol date and 
version. 
4 
Global Change, 
Study Treatments 
semaglutide s.c. 
 
 
Clarify formulation of 
semaglutide allowed for study 
treatment is subcutaneous 
only. 
 
5 
Study Approvals, p. 
2 
Name: 
 
 
 
Title:  
 
Statistician
 
 
 
Update to study statistician. 
6 
Patients, 
Synopsis, p. 7 
 
Section 4.2, Practice 
and Patient 
Selection, p. 21 
 
….adult T2DM patients on up to 2 
oral antidiabetic medications, 
excluding oral semaglutide, …. 
Update description of study 
population to reflect exclusion 
of oral semaglutide as one of 
the eligible antidiabetic 
medications patients can be on 
prior to eligibility assessment. 
 
7 
Study Design,  
 
Synopsis, p. 8 
 
Section 4.1, Study 
Design, p. 20 
All oral and injectable antidiabetic 
medications are allowed at the 
study physicians' discretion, with 
the exception of any formulation of 
semaglutide in the SOC group and 
oral semaglutide in the semaglutide 
group. 
 
Oral semaglutide is not 
allowed in either treatment 
group during the study period. 
 
8 
Exclusion Criteria, 
#2 
6.) Treatment with more than 2 
oral antidiabetic medications, 
Treatment with oral 
semaglutide is not allowed 
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Synopsis, p. 8 
 
Section 4.2.4, 
Patient Exclusion 
Criteria, p. 22 
 
oral semaglutide, or any 
injectable medication in a 
period of 30 days before the 
day of eligibility assessment. 
Temporary/emergency use of 
any type of insulin is allowed, 
as is prior insulin treatment for 
gestational diabetes 
 
prior to patient eligibility 
assessment. 
 
9 
Abbreviations, p. 12 
s.c. Subcutaneous 
Additional abbreviation. 
 
10 
Section 1.1, 
Background and 
Rationale, p. 16 
This local US study will enroll adult 
patients with T2DM who have 
inadequate glycemic control on up 
to 2 oral antidiabetic medications 
(excluding oral semaglutide), as 
defined by the need for treatment 
intensification with an additional 
antidiabetic oral or injectable 
medication per the study 
physician´s discretion. 
 
Update description of study 
population to reflect exclusion 
of oral semaglutide as one of 
the eligible antidiabetic 
medications patients can be on 
prior to eligibility assessment. 
 
11 
Section 4.2.2, 
Patient Recruitment 
and Eligibility, p. 21 
Eligible patients include adult 
T2DM patients whose physicians 
determine that they have inadequate 
glycemic control on 1 or 2 oral 
antidiabetic medications, excluding 
oral semaglutide. 
 
Update description of study 
population to reflect exclusion 
of oral semaglutide as one of 
the eligible antidiabetic 
medications patients can be on 
prior to eligibility assessment. 
 
 
12 
Section 4.2.6, 
Patient 
Randomization, 
Figure 1, p. 23 
 
Semaglutide s.c. once weekly 
Remove redundancy in 
treatment group label in Figure 
1. 
13 
Section 5.1, 
Enrollment 
Procedures, p. 23 
The determination that a patient has 
inadequate glycemic control on up 
to 2 oral antidiabetic medications, 
excluding oral semaglutide, and the 
subsequent decision to intensify 
antidiabetic treatment 
 
Oral semaglutide is not 
allowed as one of the 1-2 oral 
antidiabetic medications in 
patient eligibility criteria. 
 
14 
Section 5.2.2, 
Treatments, 
Semaglutide Group, 
p. 24 
Add-on, discontinuation or dose 
modification of antidiabetic 
medication, including semaglutide 
s.c., during the study is allowed at 
the discretion of the study 
physician, with the exception of 
Oral semaglutide is not 
allowed during the study 
period. 
 
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oral semaglutide, which is not 
allowed during the study period. 
15 
Section 5.2.2, 
Treatments, Copay 
assistance, p. 26 
The only exceptions are if a patient 
initiates prescription coverage 
through Medicaid or if a patient 
loses pharmacy coverage, at which 
point all copay assistance will end. 
Clarification of copay 
assistance. 
16 
Section 6.8.9, 
Evaluation of Study 
Population, p. 36 
Two claims-based T2DM patient 
populations will be described and 
compared to the study population: 
(1) commercially-insured and
Medicare Advantage 
T2DM patients treated with up to 2
oral antidiabetic medications,
excluding oral semaglutide, who
undergo an antidiabetic treatment
intensification, and (2) within the
study sites, commercially-insured
and Medicare Advantage 
T2DM patients treated with up to 2
oral antidiabetic medications,
excluding oral semaglutide, who are
not enrolled in the study, but who
undergo an antidiabetic treatment
intensification.
Update to claims-based 
comparator populations for 
evaluation of study population 
to exclude oral semaglutide 
use. 
CONFIDENTIAL

SAP_003.pdf: 
Cover Page for Statistical Analysis Plan 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT03596450 
Sponsor trial ID: 
NN9535-4416 
Official title of study: 
Long Term Comparative Effectiveness of Once Weekly 
Semaglutide Versus Standard of Care in a Real World Adult 
US Population With Type 2 Diabetes - a Randomized 
Pragmatic Trial 
Document date* 
26 October 2021 
*Document date refers to the date on which the document was most recently updated.
Note: The date in the footer of Page 2 is the date of compilation of the documents and not of an update to content.


Novo Nordisk  
Protocol No. NN953-4416 
 UTN: U1111-1207-6474 
Appendix 16.1.9 
Clinical Study Report   
Version 1.0; April 4, 2024 
16.1.9 Documentation of statistical methods 
16.1.9.1 Statistical Analysis Plan 
Redacted statistical analysis plan 
Includes redaction of personal identifiable information only. 
. 






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Statistical Analysis Plan for Long term comparative effectiveness of once weekly 
semaglutide versus standard of care in a real world adult US population with 
type 2 diabetes - a randomized pragmatic clinical trial 
 
 
 
 
 
 
Protocol No.  NN9535-4416 
 
 
Novo Nordisk 
 
 
 
June 30, 2020 
 
Version 2.0 
 
 
 
 
 
 
 
 
 
  
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Signature Page for Statistical Analysis Plan 
Protocol No:  NN9535-4416 
30-JUN-2020 
 
 Approval: 
 
Name:  
 
Title:    
, Research Biostatistics 
 
 
Signature:    
 
 
 
 
 
 
 
 
 
Date:  
 
 
 
 
 
Name:  
 
Title:    
 Scientist 
 
 
Signature:   
 
 
 
 
 
 
 
 
 
Date:  
 
 
 
 
 
 
Novo Nordisk Approval: 
 
Name:  
 
Title:  
 
 
 
 
Signature:   
 
 
 
 
 
 
 
 
Date:  
 
 
 
 
 
Name:  
 
Title:   
 
 
 
Signature:   
 
 
 
 
 
 
 
 
 
 
Date:  
 
 
 
DocuSign Envelope ID: FF833262-84F1-4369-9A7D-7B294A52C156
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04-Aug-2020
25-Aug-2020
25-Aug-2020
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TABLE OF CONTENTS 
Signature Page for Statistical Analysis Plan .............................................................................. 2 
TABLE OF CONTENTS ............................................................................................................. 3 
1.0 
INTRODUCTION............................................................................................................. 5 
2.0 
STUDY OBJECTIVES ..................................................................................................... 5 
2.1 
Primary Objective ..................................................................................................................... 5 
2.2 
Secondary Objectives ................................................................................................................ 5 
2.3 
Estimands ................................................................................................................................... 6 
2.3.1 
Primary Estimand .................................................................................................................... 6 
2.3.2 
Secondary Estimand ................................................................................................................ 6 
3.0 
STATISTICAL METHODOLOGY................................................................................ 6 
3.1 
General Considerations ............................................................................................................. 6 
3.2 
Study Populations ...................................................................................................................... 7 
3.2.1 
Analysis Population ................................................................................................................ 7 
3.2.2 
Safety Population .................................................................................................................... 7 
3.3 
Evaluation Schedule and Definitions ....................................................................................... 7 
3.4 
Confirmatory Endpoints and Hypotheses ............................................................................... 8 
3.5 
Sample Size Estimation ............................................................................................................. 9 
3.5.1 
Power and Sample Size for Primary Objective ....................................................................... 9 
3.6 
Missing Data ............................................................................................................................. 11 
3.7 
Data Definitions and Calculations .......................................................................................... 11 
3.7.1 
General .................................................................................................................................. 11 
3.7.2 
Demographics ....................................................................................................................... 11 
3.7.3 
Diabetes History .................................................................................................................... 11 
3.7.4 
Treatment Variables .............................................................................................................. 11 
3.7.4.1 
Semaglutide Study Drug ................................................................................................... 12 
3.7.4.2 
Standard of Care (SOC) Study Drug ................................................................................ 12 
3.7.4.3 
Treatment Intensification or Change ................................................................................ 13 
3.7.5 
Measures of Glycemic Control ............................................................................................. 13 
3.7.6 
Weight ................................................................................................................................... 13 
3.7.7 
Adherence and Persistence to Treatment .............................................................................. 14 
3.7.8 
Patient Reported Outcomes (PROs) ...................................................................................... 14 
3.7.8.1 
Diabetes Treatment Satisfaction Questionnaire (DTSQ) .................................................. 14 
3.7.8.2 
Short Form 12-Item Version 2 (SF-12 v2) ....................................................................... 16 
3.7.8.3 
Work Productivity and Activity Impairment, General Health (WPAI-GH) ..................... 16 
3.7.8.4 
Patient Global Impressions of Disease Severity (PGI-S) and Change (PGI-C) ................ 17 
3.7.8.5 
Clinician Global Impressions of Disease Severity (CGI-S) and Change (CGI-C) ........... 17 
3.7.9 
Healthcare Resource Utilization (HCRU) ............................................................................. 18 
3.8 
Examination of Subgroups ..................................................................................................... 20 
4.0 
STATISTICAL ANALYSES ......................................................................................... 20 
4.1 
Overview ................................................................................................................................... 20 
4.2 
Patient Disposition and Accountability ................................................................................. 20 
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4.3 
Demographics and Baseline Clinical Characteristics ........................................................... 21 
4.4 
Protocol Deviations .................................................................................................................. 21 
4.5 
Missing Value Imputation Methodology ............................................................................... 21 
4.5.1 
Primary Estimand Imputation Model .................................................................................... 21 
4.5.2 
Secondary Estimand Imputation Model ................................................................................ 22 
4.6 
Effectiveness Analysis.............................................................................................................. 22 
4.6.1 
Statistical Analysis for the Primary Estimand ....................................................................... 22 
4.6.2 
Statistical Analysis for the Secondary Estimand ................................................................... 23 
4.6.3 
Additional Analyses of Glycemic Control ............................................................................ 24 
4.6.3.1 
Descriptive Summaries of HbA1c .................................................................................... 24 
4.6.3.2 
Supportive Analyses of Glycemic Control ....................................................................... 24 
4.6.4 
Supplementary Analyses ....................................................................................................... 25 
4.6.4.1 
Complete Case Analysis ................................................................................................... 25 
4.6.4.2 
Complete Case On-Study Drug Analysis ......................................................................... 25 
4.7 
PRO Analysis ........................................................................................................................... 25 
4.8 
Concomitant Medications ....................................................................................................... 27 
4.9 
Other Analyses ......................................................................................................................... 27 
4.9.1 
Weight Loss .......................................................................................................................... 28 
4.9.2 
Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) ................................... 28 
4.9.3 
Hypoglycemia ....................................................................................................................... 28 
4.9.4 
Healthcare Resource Utilization (HCRU) ............................................................................. 28 
4.9.5 
Composite Endpoints ............................................................................................................ 29 
4.9.6 
Antidiabetic Treatment Patterns ............................................................................................ 30 
4.9.6.1 
Study Drug Regimen ........................................................................................................ 30 
4.9.6.2 
Adherence and Persistence to Treatment .......................................................................... 30 
4.9.6.3 
Other Antidiabetic Treatments .......................................................................................... 31 
4.10 
Study Site Recruitment and Participation ............................................................................ 31 
4.11 
Evaluation of the Study Population ....................................................................................... 32 
5.0 
SAFETY ........................................................................................................................... 34 
5.1 
AEs ............................................................................................................................................ 34 
5.2 
SAEs .......................................................................................................................................... 34 
5.3 
Pregnancy ................................................................................................................................. 34 
5.4 
Analysis ..................................................................................................................................... 34 
6.0 
Changes from Protocol ................................................................................................... 34 
7.0 
SAP Change Log ............................................................................................................. 36 
8.0 
APPENDIX A: Study Endpoints and Other Variables by Data Source .................... 41 
9.0 
APPENDIX B: 2018 HEDIS Criteria ............................................................................ 47 
10.0 
REFERENCES ................................................................................................................ 48 
 
 
 
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1.0 INTRODUCTION 
This document describes the Statistical Analysis Plan (SAP) for Protocol Number NN9535-4416, 
Long term comparative effectiveness of once weekly semaglutide versus standard of care in a 
real world adult US population with type 2 diabetes – a randomized pragmatic clinical trial. This 
is a 2-year, multi-center, randomized, open label, parallel group, active comparator pragmatic 
clinical trial (PCT) comparing semaglutide s.c. versus standard of care (SOC) when added to up 
to 2 oral antidiabetic medications as treatment intensification among adult type 2 diabetes 
mellitus (T2DM) patients in the course of routine clinical practice. 
This SAP is based on the most recent version of the protocol: Version 4.0, December 5, 2019. 
Protocol History: 
Number 
Version 
Date 
1.0 
Original Protocol 
March 13, 2018 
2.0 
Version 2.0 
March 27, 2019 
3.0 
Version 3.0 
August 21, 2019 
4.0 
Version 4.0 
December 5, 2019 
 
2.0 STUDY OBJECTIVES 
2.1 Primary Objective 
The primary objective is to demonstrate superior long term effects of treatment with semaglutide 
s.c. compared to SOC each added to up to 2 oral antidiabetic medications on glycemic control 
when used as intensification in routine clinical practice in adult patients with T2DM.  
2.2 Secondary Objectives 
The secondary objectives are to compare the long term effect of semaglutide s.c. versus SOC 
each added to up to 2 oral antidiabetic medications and used as intensification in routine clinical 
practice in adult patients with T2DM with regards to: 
• Weight loss 
• Patient reported outcomes (PROs) and clinician reported outcomes (ClinROs) 
• Hypoglycemia  
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• Healthcare Resource Utilization (HCRU) 
• Adherence and persistence to treatment 
2.3 Estimands 
The estimand informs choices about data foundation and statistical analysis including possible 
imputation of missing data, hereby ensuring that randomization is preserved as a sound basis for 
statistical inference; i.e. estimation of effect size, associated uncertainty and statistical testing. 
Two estimands, each targeting a unique research question, have been defined to adequately 
describe the effect of semaglutide s.c. as compared to SOC (excluding any semaglutide). 
2.3.1 Primary Estimand 
The primary estimand for all objectives will be the “intention-to-treat” (ITT) estimand evaluating 
the effectiveness of randomized treatment intervention irrespective of adherence to this 
randomized intervention or changes to other antidiabetic medication. 
2.3.2 Secondary Estimand 
The secondary estimand for all objectives with the exception of the adherence and persistence to 
treatment objective, is the “if all patients had adhered” estimand. This estimand evaluates the 
effect of randomized treatment intervention for all randomized patients if all patients had 
adhered to randomized treatment, regardless of changes to other antidiabetic medication. 
 
3.0 STATISTICAL METHODOLOGY 
3.1 General Considerations 
Statistical analyses will be performed using SAS® version 9.4 or higher computer software.  
Analyses will utilize prospectively collected data from study sites as well as secondary data 
collection utilizing administrative claims data from the HealthCore Integrated Research Database 
(HIRD®). Data from both sources will be integrated into one dataset for analysis. 
Patient flow, patient characteristics, treatments, and outcomes will be tabulated and summarized 
with descriptive statistics based on observed values only. All descriptive data summaries will 
include means, medians, standard deviation (SD), and ranges for continuous variables and 
absolute/relative frequencies for categorical data. In addition, for each variable the number 
(count) of values that are missing will also be reported for dedicated study visit data. Missing 
data are data that are planned and can be collected but are absent. Statistics will be summarized 
for the study population overall and by treatment arm. Two sets of descriptive summaries will be 
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produced: one based on the primary estimand (ITT) and one based on the secondary estimand 
(“if all patients had adhered”). 
Raw data (i.e., minimum and maximum values presented for range in continuous variables) will 
be reported out to the precision with which it was collected. Means will be reported to 1 decimal 
place more than the raw data. SD will be reported to 1 decimal place more than the mean.  
Percentages will be reported to 1 decimal place. Trailing zeros will be presented to maintain a 
consistent level of precision, e.g. 2.0 rather than 2. 
Inferential tests will be performed at the 5% level of significance (two-sided).  All p-values will 
be rounded to 3 decimal places. If a rounded p-value is 0.000 (i.e., the actual p-value is less than 
0.0005), then the p-value will be presented as ‘p< 0.001.’ 
3.2 Study Populations 
3.2.1 Analysis Population 
The following analysis set will be defined: 
Full analysis set (FAS): Includes all randomized patients analyzed according to the treatment 
group to which they were assigned at randomization. 
3.2.2 Safety Population 
The safety population includes all randomized patients initiated on study drug. 
3.3 Evaluation Schedule and Definitions 
Dedicated study visits are at randomization, at year 1, and at year 2. The study will also capture 
data collected at the sites during routine diabetic care visits, i.e., office visits and other patient 
contacts that occur as part of routine clinical practice. Routine diabetic care visits will occur per 
study physician’s routine clinical practice, therefore the number of visits and data available may 
differ from site to site and patient to patient. 
For analysis, baseline includes assessments conducted and patient data collected at or prior to 
randomization. Baseline is defined as ≤ 90 days prior to randomization visit (week 0) for HbA1c. 
For secondary endpoint assessments, baseline is defined as ≤ 4 weeks prior to the randomization 
visit (week 0). All baseline values will be derived from the last assessment taken prior to or at 
the randomization visit. 
The dedicated year 1 visit is at 52 weeks (±6 weeks) after randomization. Year 1 endpoint data 
will be derived from the dedicated year 1 study visit if the dedicated study visit is ±10 weeks of 
52 weeks post-randomization. If year 1 endpoint data is missing or outside of 52 ±10 weeks, then 
the routine diabetic care data closest to 52 weeks post-randomization ±10 weeks will be used. If 
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no routine diabetic care data are available 52 weeks post-randomization ±10 weeks, then year 1 
endpoint data will be considered missing and imputed as described in section 4.5, if applicable. 
The dedicated year 2/EOS visit is 104 weeks (±6 weeks) after randomization. Year 2 endpoint 
data will be derived from the dedicated year 2 study visit if the dedicated study visit is ±10 
weeks of 104 weeks post-randomization. If year 2 endpoint data is missing or outside of 104 ±10 
weeks, then the routine diabetic care data closest to 104 weeks post-randomization ±10 weeks 
will be used. If no routine diabetic care data are available 104 weeks post-randomization ±10 
weeks, then year 2 endpoint data will be considered missing and imputed as described in section 
4.5, if applicable. 
3.4 Confirmatory Endpoints and Hypotheses 
The primary endpoint is HbA1c <7.0% (53 mmol/mol) at year 1 (yes/no).  
Confirmatory secondary endpoints include:  
• Change in HbA1c (%-point) from baseline to year 1 
• HbA1c <7.0% (53 mmol/mol) at year 2 (yes/no) 
• Change in HbA1c (%-point) from baseline to year 2 
This study is designed to have 90% power to confirm superiority of the primary endpoint and 
85% power to also confirm superiority of the first confirmatory secondary endpoint based on 
primary estimand analyses. The primary and confirmatory secondary endpoints will all be tested 
for superiority under multiplicity control via a hierarchical testing scheme according to the order 
given in the above bullet list. Confirmatory testing will only be performed for the primary 
estimand with the secondary estimand being supportive. The testing procedure will be stopped 
the first time an analysis fails to confirm superiority of the endpoint in question using a two-
sided significance level of 5%. 
Superiority on HbA1c <7.0% at year 1 and at year 2 will be evaluated with respect to the odds 
ratio (OR) (odds semaglutide / odds SOC): 
H0: OR≤1 against Ha: OR>1 
Superiority on change in HbA1c (year 1 – baseline; year 2 – baseline) will be evaluated with 
respect to the mean treatment difference (TD) (semaglutide – SOC):  
H0: TD≥0 against Ha: TD<0 
Statistical analysis of all other endpoints will be unadjusted for multiplicity. 
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3.5 Sample Size Estimation 
3.5.1 Power and Sample Size for Primary Objective 
Assumptions for the sample size were based on input from the HIRD claims/laboratory results 
database. In line with the primary ITT estimand, the assumptions for the proportion of patients 
with HbA1c < 7.0% at year 1 and year 2, and for the change from baseline in HbA1c are based 
on the claims/laboratory results data within the 
 population for all patients initiating 
treatment intensification regardless of whether patients adhered to this treatment. Specifically, 
for semaglutide s.c., assumptions are based on data for liraglutide and dulaglutide. For SOC, 
assumptions are based on all intensifications in the claims database. The data from the claims 
database are shown in Table 3-1. Because the baseline HbA1c was higher in the all 
intensifications population compared to the liraglutide and dulaglutide groups, the assumptions 
used for the sample size calculation were adjusted accordingly. 
Table 3-1: HbAlc Change Data from 
 Population via HealthCore Integrated 
Research Database on Patients Intensifying Diabetes Treatment after Metformin 
Follow-
up 
Treatment 
intensification 
after 
metformin 
Number 
of 
patients 
with 
HbA1c 
Follow-
up data 
Proportion 
Patients 
Hba1c 
<7% at 
Follow-up 
Number 
of 
patients 
with 
Baseline 
and 
Follow-up 
HbA1c 
data 
HbA1c (%) 
Baseline 
mean 
HbA1c (%) 
Change from 
Baseline 
mean SD 
1y 
All 
intensifications 
6,522 
47% 
4,068 
8.9 
-1.54 
2.3 
dulaglutide 
411 
62% 
115 
8.6 
-1.47 
2.2 
liraglutide 
1,762 
62% 
394 
8.4 
-1.34 
2.0 
 2y 
All 
intensifications 
4,047 
49% 
2,401 
8.9 
-1.42 
2.3 
dulaglutide 
32 
71% 
≤10 
8.8 
-1.35 
1.2 
liraglutide 
893 
55% 
217 
8.6 
-1.24 
2.1 
Source: Data from the HealthCore Integrated Research Database. Data on file. 
 
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Table 3-2 presents several sample size scenarios together with assumptions and calculated 
power. The sample size calculation aimed for 90% power for confirming superiority of 
semaglutide s.c. versus SOC on the primary endpoint and 85% power to also confirm superiority 
of the first confirmatory secondary endpoint based on an analysis of the primary estimand for 
each of the endpoints. For the sample size calculation the likelihood ratio chi-square test was 
assumed for analyses of the binary presence of HbA1c < 7.0% endpoints and a t-test for the 
continuous change in HbA1c endpoints. An overall alpha level of 5% with two-sided tests was 
assumed. 
Table 3-2 Assumptions used in the sample size and calculated total power. 
Total 
Number 
Randomized 
Proportion Patients with 
HbA1c <7% at 1 and 2 Years HbA1c ETD 
at 1 and 2 
years 
HbA1c 
change SD 
Power 
total 
SOC 
Semaglutide 
1849 
50% 
60% 
0.5 
2.3 
80% 
2250 
50% 
58% 
0.5 
2.3 
72% 
2250 
50% 
60% 
0.5 
2.3 
90% 
2250 
50% 
60% 
0.5 
2.0 
93% 
2250 
50% 
60% 
0.4 
2.3 
77% 
ETD = Estimated Treatment Difference, SD=Standard Deviation 
Bold marked numbers indicate the chosen assumptions and numbers marked in underline indicate variations 
The proportion of missing data for the confirmatory endpoints was estimated to be 25% after one 
year and 44% after two years. In the sample size calculation, it was assumed that only non-
missing data at year 1 and year 2 would be used for the respective analyses. This is considered 
conservative, since the use of imputed data in the actual primary analysis (see 4.5) will increase 
the power. When accounting for missing data, randomizing 1387 patients will contribute 1040 
patients for the year 1 analyses and 780 patients for the year 2 analyses, achieving a total power 
of 85% for confirming the two year 1 confirmatory hypotheses.  The joint power for confirming 
all 4 confirmatory hypotheses is 58%. The corresponding marginal powers for presence of 
HbA1c < 7.0% at year 1, change in HbA1c to 1 year, presence of HbA1c < 7.0% at year 2, and 
change in HbA1c to 2 years are 90%, 94%, 80% and 86% respectively. 
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3.6 Missing Data 
Except where noted in section 4.5 for HbA1c, weight, systolic blood pressure (SBP), and 
diastolic blood pressure (DBP) endpoints, missing data will not be imputed and will be excluded 
from calculations. 
3.7 Data Definitions and Calculations 
3.7.1 General 
All absolute change from baseline variables will be calculated as: 
Change = Endpoint – Baseline 
All relative change from baseline variables will be calculated as: 
Relative Change (%) = [(Endpoint– Baseline)/Baseline] x 100 
If day and/or month is missing from dates, the first day of the month and/or the first month of the 
year will be assumed when calculating duration between dates. If imputation of an incomplete 
date associated with a post-randomization data element results in a date prior to randomization, 
the first day of the month immediately following randomization will be assumed. E.g., if the 
randomization date is 08/15/18 (mm/dd/yy) and the unknown date is 08/UNK/18 or UNK/10/18 
or UNK/UNK/18, the imputed date would be 09/01/18. 
The data sources for each endpoint and variables used in analysis are summarized in Appendix 
A. 
3.7.2 Demographics 
Age will be presented in years based on the patient’s birth date and randomization visit date. 
3.7.3 Diabetes History 
Duration of diabetes will be presented in years based on the patient’s diagnosis date and 
randomization visit date. 
3.7.4 Treatment Variables 
Study drug is defined as the first antidiabetic oral or injectable medication prescribed for 
treatment intensification following randomization. A patient can start and stop study drug 
throughout the study. At any time during the duration of the study, if a patient is taking study 
drug as defined, they will be considered “on study drug” regardless of prior study drug 
discontinuations. At any time during the duration of the study, if a patient is not taking study 
drug as defined, they will be considered “off study drug.” On and off study drug classification 
will be based on the eCRF data. 
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The first study drug discontinuation date will be defined as the date of the first time a patient 
discontinues study drug such that they are “off study drug.” 
For analysis of year 1 and year 2 endpoints, patients will categorized as “on study drug” or “off 
study drug” according to their study drug use at the endpoint visit, regardless of prior use/non-
use. If study drug status is missing for the year 1 or year 2 endpoint, the last registered study 
drug status prior to the endpoint visit will be used. 
3.7.4.1 
Semaglutide Study Drug 
For the semaglutide treatment group, study drug is defined as semaglutide s.c.. Therefore at any 
time during the study, patients randomized to the semaglutide group will be categorized as: 
On Study Drug: Taking Semaglutide s.c. (regardless of any other antidiabetic medication 
use or previous discontinuations) 
Off Study Drug: Not currently taking Semaglutide s.c. 
The following definitions will also apply to individual patient semaglutide s.c. dosing during the 
2 year study period, or until time of study drug discontinuation: 
Most Common: The dose associated with the longest period of use from randomization to 
year 2/EOS visit. 
Highest: The highest dose reported at any time from randomization to year 2/EOS visit. 
Final: The latest dose reported from randomization to year 2/EOS visit. 
3.7.4.2 
Standard of Care (SOC) Study Drug 
For the SOC treatment group, study drug is defined as the drug class of the first antidiabetic oral 
or injectable medication prescribed for treatment intensification following randomization 
(excluding any formulation of semaglutide). If a fixed dose combination (FDC) product is 
prescribed, one of the drugs will be specified by the study physician to be the study drug and 
on/off drug categorization will be based on the study physician specified drug only. Therefore, at 
any time during the study, patients randomized to the SOC treatment group will be categorized 
as: 
On Study Drug: Taking a drug in the same drug class as their first study drug, even if it is 
not the same individual drug (regardless of any other antidiabetic medication use or 
previous discontinuations except semaglutide). This also applies to treatment 
intensification with a FDC product if one of the drugs is in the same drug class as the first 
study drug. 
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Off Study Drug: Not currently taking a drug in the same drug class as their first study 
drug. 
3.7.4.3 
Treatment Intensification or Change 
Treatment intensification (add-on) or change (switch) in study drug after randomization will be 
identified and categorized. 
Treatment intensification is defined as initiation of an antidiabetic medication (besides the up to 
2 oral antidiabetic medication(s) taken prior to randomization) in addition to study drug, or 
initiation of more than one antidiabetic medication after discontinuation of study drug. 
The first treatment intensification date will be defined as the date of the first occurrence of an 
antidiabetic treatment intensification. 
Treatment change is defined as discontinuation of study drug and initiation of another 
antidiabetic medication (besides the up to 2 oral antidiabetic medication(s) taken prior to 
randomization). 
The first treatment change date will be defined as the date of the first occurrence of an 
antidiabetic treatment change. 
3.7.5 Measures of Glycemic Control 
Physicians will set a patient’s individualized HbA1c target prior to randomization. Achieving 
target at year 1 and year 2 is defined as: 
Endpoint HbA1c ≤ Individualized HbA1c target 
Attainment of the 2018 Healthcare Effectiveness Data and Information Set (HEDIS) HbA1c will 
be defined at year 1 and year 2 as: 
HbA1c <8.0% if age ≥ 65 years at endpoint or with defined comorbidities (Appendix B), 
else <7.0% 
HbA1c data for the HEDIS endpoints will be obtained from the eCRF. HEDIS 
comorbidities as defined in Appendix B will be obtained from the claims data and apply 
to the year prior to endpoint. HEDIS criteria at year 1 will be based on comorbidities 
identified between the randomization and year 1 visit. HEDIS criteria at year 2 will be 
based on comorbidities identified between the year 1 and year 2 visits. 
3.7.6 Weight 
No weight gain is defined as: Endpoint Weight ≤ Baseline Weight 
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3.7.7 Adherence and Persistence to Treatment 
Medication adherence refers to a patient’s conformance to the provider’s recommendation with 
respect to timing, dosage, and frequency of medication taken during the prescribed length of 
time. 
For this study, the medication possession ratio (MPR) will be used to assess adherence. MPR 
will be calculated for the study drug from claims data for baseline to year 1 and for baseline to 
year 2 as follows: 
MPR (%) = Sum of days supply for all prescription fills x 100 
Total number of days in time period 
 
MPR will be capped at 100%. 
Medication persistence refers to whether a patient stays on therapy or the time from initiation to 
discontinuation of therapy. Medication persistence will be assessed from baseline to year 2. 
For this study, medication persistence will be defined as duration of time in days from initiation 
of study drug to first study drug discontinuation from eCRF data as defined in section 3.7.4. 
A second persistence measure will be defined as duration of time in days from the date of 
initiation of study drug to the date of the first intensification or change in study drug as defined 
in section 3.7.4.3. 
3.7.8 Patient Reported Outcomes (PROs) 
3.7.8.1 
Diabetes Treatment Satisfaction Questionnaire (DTSQ) 
The Diabetes Treatment Satisfaction Questionnaire (DTSQ) is a validated instrument that is 
widely used in clinical trials and for routine clinical monitoring. It is useful in assessing 
outcomes of diabetes care. [1] The questionnaire consists of eight items -- six items assess 
treatment satisfaction, where each item is scored on a scale of 0–6, with six representing the 
greatest satisfaction, and two items assess the perceived frequency of hyperglycemia and 
hypoglycemia, also scored on a scale of 0-6, where “0” corresponds to none of the time and “6” 
corresponds to most of the time. 
The original DTSQ is now referred to as the status version (DTSQs) in order to distinguish it 
from the DTSQ change version (DTSQc), which was developed to overcome potential ceiling 
effects (i.e. where respondents score maximum or near-maximum satisfaction at baseline and can 
show little or no improvement at follow-up). [2] This study will use the DTSQs at randomization 
and the DTSQc at the dedicated year 1 and year 2 study visits. 
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Scoring the DTSQs  
The DTSQs has 8 items and produces the following measures:  
1. Treatment Satisfaction: Items 1, 4, 5, 6, 7 & 8 are summed to produce a Treatment 
Satisfaction score (range: 0 to 36). The higher the score, the greater the satisfaction with 
treatment.  
2. Individual satisfaction with treatment items (items 1, 4, 5, 6, 7 & 8) can be considered 
separately: All rated: 6 (very satisfied, convenient, flexible, etc.) to 0 (very dissatisfied, 
inconvenient, inflexible, etc.). The higher the score, the greater the satisfaction with each 
aspect of treatment.  
3. 'Perceived frequency of hyperglycemia' (item 2) & 'Perceived frequency of hypoglycemia' 
(item 3): Both rated: 6 (‘most of the time’) to 0 (‘none of the time’). Here, lower scores 
indicate blood glucose levels closer to the ideal. Higher scores indicate problems. 
Scoring the DTSQc  
The change version has the same 8 items as the status version, with a small alteration to the 
wording of Item 7. The DTSQc instructions and response options differ from those of the DTSQs 
and produce measures of relative change in satisfaction rather than measures of absolute 
satisfaction. 
1. Treatment Satisfaction (Change):  Items 1, 4, 5, 6, 7 and 8 are summed to produce a 
Treatment Satisfaction (change) score (range: +18 to –18). The higher the score, the greater 
the improvement in satisfaction with treatment; the lower the score, the greater the 
deterioration in satisfaction with treatment. A score of 0 represents no change.  
2. Individual satisfaction with treatment change items (items 1, 4, 5, 6, 7 and 8) can be 
considered separately: All rated: +3 ('much more satisfied', 'much more convenient', ‘much 
more flexible', etc.) to –3 ('much less satisfied', 'much less convenient', 'much less flexible', 
etc.). The higher the score, the greater the improvement in satisfaction with each aspect of 
treatment and the lower the score, the greater the deterioration in satisfaction with each 
aspect of treatment.  
3. Two remaining items ('Perceived change in frequency of hyperglycemia' (item 2) and 
'Perceived change in frequency of hypoglycemia' (item 3)) are treated individually: Both 
rated: +3 (‘much more of the time now’) to –3 (‘much less of the time now’). Here, negative 
scores indicate fewer problems with blood glucose levels. Positive scores indicate more 
problems than before. 
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3.7.8.2 
Short Form 12-Item Version 2 (SF-12 v2) 
The Short Form 12-item Version 2 (SF-12v2) is a generic health-related quality of live (HRQoL) 
measure that consists of 12 items from the Short Form 36-Item (SF-36) health survey and 
measures physical and mental dimensions of health. [3] Eight subscale scores (physical 
functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional, 
and mental health) and two summary scores (physical component summary (PCS) and mental 
component summary (MCS)) can be obtained using the proprietary scoring software provided by 
Optum. Scores are calculated as norm-based standardized scores ranging from 0 to 100 with 
means of 50 and SDs of 10, where a score of “0” indicates the lowest level of health measured by 
the scales, “100” indicates the highest level of health, and “50” indicates the mean or norm-score 
for the general US population. [4] 
For this study, the PCS-12 and MCS-12 summary scores will be used. The PCS-12 and MCS-12 
will be calculated at baseline, year 1, and year 2. Change from baseline will be calculated for the 
PCS-12 and MCS-12 at year 1 and year 2. 
3.7.8.3 
Work Productivity and Activity Impairment, General 
Health (WPAI-GH) 
The Work Productivity and Activity Impairment (WPAI) questionnaire is a 6-item instrument 
that measures absenteeism (work time missed), presenteeism (impairment at work / reduced on-
the-job effectiveness), work productivity loss (overall work impairment / absenteeism plus 
presenteeism), and activity impairment because of health problems in the past seven days. [5]  
There are two versions of the WPAI. In the general health version (WPAI:GH) individuals are 
asked questions about work and activity impairment due to health problems. In the specific 
health problem version (WPAI:SHP), individuals are asked questions concerning impairment 
due to a target health problem (e.g., arthritis). This study will use the general health version of 
the WPAI (WPAI:GH), per general guidelines from the website that indicate the general health 
version is more appropriate for a disease like diabetes. 
WPAI:GH Scoring Information 
General Information: 
In general, WPAI outcomes are expressed as impairment percentages, with higher numbers 
indicating greater impairment and less productivity, i.e., worse outcomes. The recall period is the 
past seven days, excluding the current day. 
Questions: 
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Q1 = currently employed (Yes=works full-/part-time; self-employed; works in family business; 
on vacation from paid employment/No=does not work for pay; only does volunteer work; 
usually works, but has been laid-off or unemployed during the past seven days; retired; seasonal 
workers not currently working) 
Q2 = hours missed due to health problems 
Q3 = hours missed for other reasons 
Q4 = hours actually worked 
Q5 = degree health affected productivity while working 
Q6 = degree health affected regular activities 
Scores: 
Multiply scores by 100 to express in percentages 
1. Percent work time missed due to health (Absenteeism): Q2/(Q2 + Q4) 
2. Percent impairment while working due to health (Presenteeism): Q5 /10 
3. Percent overall work impairment due to health (Work Productivity Loss): Q2/(Q2 + Q4) + 
[(1 – (Q2/(Q2 + Q4))) x (Q5/10)] 
4. Percent activity impairment due to health (Activity Impairment): Q6/10 
Absenteeism, presenteeism, work productivity loss, and activity impairment will be calculated at 
baseline, year 1, and year 2. Change from baseline will be calculated for each score at year 1 and 
year 2. 
3.7.8.4 
Patient Global Impressions of Disease Severity (PGI-S) and 
Change (PGI-C) 
The patient global impression of disease severity (PGI-S) is a single item that the patient will 
complete at the baseline randomization visit that assesses the patient’s perception of the severity 
of their diabetes at the time of the randomization visit. The patient global assessment of change 
(PGI-C) is a single item that the patient will complete at the dedicated year 1 and year 2 study 
visits that assesses their perception of their current disease status relative to the way it was before 
they started the study drug. 
3.7.8.5 
Clinician Global Impressions of Disease Severity (CGI-S) 
and Change (CGI-C) 
The clinician global impression of disease severity (CGI-S) is a single item that the clinician will 
complete after the patient’s baseline randomization visit that assesses the clinician’s perception 
of the patient’s severity of their diabetes at the randomization visit. The clinician global 
assessment of change (CGI-C) is a single item that the clinician will complete at the patient’s 
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dedicated year 1 and year 2 study visits that assesses the clinician’s perception of the patient’s 
current disease status relative to the way it was before they started the study drug. 
3.7.9 Healthcare Resource Utilization (HCRU) 
All-cause and T2DM-related HCRU will be defined from baseline to year 2. These data will 
come from the HIRD for 
 patients or requested from a set of other health insurers for 
non-
 patients. HCRU will include inpatient admissions, ER encounters, physician office 
visits (OV), other outpatient encounters, and pharmacy prescription fills. 
All medical claims (inpatient admissions, ER visits, physician OVs, or other outpatient 
encounters) will be included in the “all-cause” analysis. All pharmacy claims will be included in 
the “all-cause” HCRU. Inpatient admissions, ER visits, physician OVs, or other outpatient 
encounters will be considered to be “T2DM-related” if the associated medical claim(s) has an 
International Classification of Diseases, Tenth Revision (ICD-10) T2DM diagnosis code of 
E11.% in the primary position or secondary position. Pharmacy claims for antidiabetic 
medications will be included in the “T2DM-related” HCRU. 
• All-cause inpatient admission is defined by a claim or claims with inpatient place of 
service. Facility and provider claims are rolled into episodes with unique admission 
and discharge dates. ER visit claims on one day that are directly followed by an 
inpatient admission are considered as one inpatient admission and all HCRU from the 
encounter is combined. 
• T2MD-related inpatient admission is defined by a claim or claims with inpatient place 
of service and primary or secondary diagnosis of T2DM. Facility and provider claims 
are rolled into episodes with unique admission and discharge dates. ER visit claims 
on one day that are directly followed by an inpatient admission with a primary or 
secondary diagnosis of T2DM (regardless of the diagnoses associated with the ER 
visit claim) are considered as one T2MD-related inpatient admission and all HCRU 
from the encounter is combined. 
• All-cause ER visit is defined by a medical claim with ER place of service. 
• T2DM-related ER visit is defined by a medical claim with ER place of service and 
primary or secondary diagnosis of T2DM. 
• All-cause outpatient physician OV is defined by a medical claim with outpatient place 
of service and an evaluation and management (E&M) code that indicates physician 
OV. 
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• T2DM-related outpatient physician OV is defined by a medical claim with outpatient 
place of service and an E&M code that indicates physician OV with a primary or 
secondary diagnosis of T2DM. 
• All-cause other outpatient service is defined by a medical claim with outpatient place 
of service and code other than E&M, overall and by the following categories: 
o Tests – Lab 
o Imaging 
o Procedures 
o Occupational Therapy (OT)/Speech 
o Medication and Related Services 
o Durable Medical Equipment 
o Physician Other Services 
o Tests – Other 
o Other 
• T2DM-related other outpatient service is defined by a medical claim with outpatient 
place of service, with a primary or secondary diagnosis of T2DM, and code other than 
E&M, overall and by the following categories: 
o Tests – Lab 
o Imaging 
o Procedures 
o OT/Speech 
o Medication and Related Services 
o Durable Medical Equipment 
o Physician Other Services 
o Tests – Other 
o Other 
• All-cause pharmacy prescription fill is defined by a pharmacy claim. 
• T2DM-related pharmacy prescription fill is defined by a pharmacy claim for an 
antidiabetic medication. 
The length of stay (LOS) for individual all-cause and T2DM-related inpatient admissions is 
defined as: 
LOS (days) = Discharge Date – Admission Date 
The cumulative LOS will be the sum of all all-cause inpatient admissions and all T2DM-related 
inpatient admissions a patient experiences from baseline to year 2. 
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3.8 Examination of Subgroups 
Data will be presented overall and by treatment group. Additionally, subgroup analysis under the 
primary estimand (ITT) of the primary endpoint will be conducted on the following subgroups: 
• Age (<55 years versus ≥55 years) 
• Gender 
• Baseline HbA1c (<8.0% versus ≥8.0%) 
• Baseline body mass index (BMI) (<30 kg/m2, ≥30 kg/m2) 
• Duration of T2DM diagnosis at baseline (<5 years versus ≥5 years) 
 
4.0 STATISTICAL ANALYSES 
4.1 Overview 
The primary analysis for this study is a year 1 analysis. Once data collection for year 1 has 
completed, a database lock and year 1 analysis will be performed. The year 1 analysis will not be 
integrated with HCRU and will be limited to year 1 endpoints derived from eCRF data, including 
PRO data. The year 1 analysis results will be presented in a clinical study report and an internal 
results meeting. To maintain study integrity for the remaining study period, data from year 1 will 
be used for limited and confidential communications while complying with public disclosure 
requirements. All other analyses will be conducted following a second database lock once data 
collection for the entire study is complete. 
No changes to the study design will be made based on the results of the year 1 analysis.  
Descriptive summaries will be produced for both the primary (ITT) and secondary (“if all 
patients adhered”) estimands, with the exception of antidiabetic treatment patterns which will be 
based on the primary estimand only. All statistical analyses will be conducted under both the 
primary estimand (ITT) and secondary estimand (“if all patients had adhered”), with the 
exception of the adherence and persistence measures, which will be based on the primary 
estimand only. 
4.2 Patient Disposition and Accountability 
Patient disposition will be descriptively summarized for all randomized patients, including the 
number and percentage patients in the FAS and safety populations, patients who complete the 
dedicated year 2 study visit, and the primary reason for not completing the dedicated year 2 
study visit for patients who terminated participation in the study early. Summary metrics for 
number of screen failures by study site will also be presented. 
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4.3 Demographics and Baseline Clinical Characteristics 
Demographic and baseline clinical characteristics will be descriptively summarized for the FAS 
overall and by treatment group. For baseline comorbid conditions, the number and percentage of 
patients with at least one of the comorbid conditions collected in the study will also be 
summarized along with the relative frequencies of type of comorbid condition. The same 
approach will be followed for concomitant cardiovascular medications. In addition to eCRF data, 
type of insurance at randomization (obtained from claims) and geographic region (from study 
site location) will be summarized. 
4.4 Protocol Deviations 
Major protocol deviations will be summarized by type (informed consent, randomization error, 
inclusion/exclusion criteria error, unreported serious adverse events (SAEs), procedure not per 
protocol, study visit not per protocol, other). 
4.5 Missing Value Imputation Methodology 
Missing endpoint data will be imputed for HbA1c, weight, SBP, and DBP. The data of patients 
who, in violation of the protocol, initiate any formulation of semaglutide in the SOC treatment 
group, will be censored analytically following initiation of semaglutide. The patient will remain 
in the analysis, but data following their initiation of semaglutide will be censored and treated as 
missing. 
Prior to analysis of binary endpoints derived by dichotomizing HbA1c and body weight, missing 
data will be imputed by multiple imputation on the continuous scale and dichotomized as 
required for the endpoint. 500 complete data sets will be generated to adequately account for the 
uncertainty due to missing data. 
4.5.1 Primary Estimand Imputation Model 
Missing value imputation for the primary estimand will be based on data from all patients with 
observations at the endpoint visit (year 1 for the primary endpoint). Missing endpoint data will 
be imputed separately by treatment group and based on similar patients with available endpoint 
data according to study drug treatment status, i.e., according to whether these patients are on or 
off study drug at the endpoint visit. Data will be imputed based on the assumption that, within 
treatment groups, patients with missing endpoint data will behave like patients with the same 
study drug treatment status at endpoint as the missing patients’ last registered treatment status 
prior to the missing endpoint. For example, for patients with missing data who have discontinued 
treatment with study drug, data will be imputed based on the assumption that these patients will 
behave like patients with available data who are no longer receiving study drug. 
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Technically, the imputation model will be an analysis of covariance (ANCOVA) for the endpoint 
data. The ANCOVA will include the baseline value of the imputed variable (HbA1c, weight, 
SBP, or DBP), diabetes duration, age, and sex as independent variables. After this model has 
been used to predict missing values, each of the now 500 complete data sets will be analyzed as 
described for the primary analysis in section 4.6.1. Finally, the multiple analysis results will be 
combined using Rubin’s rule. [6] For the OR, the results will be combined on the logarithm 
scale. 
This process will be repeated for year 2 endpoints.   
4.5.2 Secondary Estimand Imputation Model 
Missing value imputation for the secondary estimand will be based only on data from the subset 
of patients who are receiving study drug (on study drug) at the endpoint visit (year 1 for the 
primary endpoint) in order to estimate the treatment effect if all patients had continued treatment. 
The endpoint data of patients who are not receiving study drug at the endpoint visit (off study 
drug) will be censored analytically and imputed together with missing data. Collectively, missing 
and censored data will be imputed separately by treatment group based on all patients who are on 
study drug at the endpoint visit. Data will be imputed based on the assumption that patients with 
missing data will behave like patients with available data who are on study drug. 
The technical aspects of missing data imputation based on multiple imputation, the statistical 
analysis of the multiple complete data sets, and combination of the multiple results will be the 
same as the ones described for the primary estimand. 
This process will be repeated for year 2 endpoints.  
4.6 Effectiveness Analysis 
4.6.1 Statistical Analysis for the Primary Estimand 
The primary effectiveness analysis is the primary estimand of the primary endpoint, HbA1c 
<7.0% at year 1, and confirmatory secondary endpoints of change in HbA1c (%-point) from 
baseline to year 1, HbA1c <7.0% at year 2, and change in HbA1c (%-point) at year 2. This 
analysis will be based on the FAS with missing data imputation as described in the primary 
estimand imputation model. 
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Year 1 Analysis 
The primary endpoint, HbA1c < 7.0% at year 1, will be analyzed with a logistic regression 
model with a logit link function, treatment as a categorical effect, and baseline HbA1c as 
covariate. From the model the estimated OR (semaglutide s.c. versus SOC) will be presented. 
The confirmatory secondary continuous endpoint of change in HbA1c (%-point) at year 1 will be 
analyzed using ANCOVA that will include the treatment and baseline HbA1c as independent 
variables. From the model, the estimated mean difference in change from baseline to endpoint 
visit (semaglutide s.c. versus SOC) will be presented. 
The estimated treatment effect from each of these analyses will be complemented with 
associated 95% CI and two-sided p-value for testing the null-hypothesis of no difference.  
Superiority for the primary endpoint, HbA1c <7.0% at year 1, will be considered established if 
the OR 95% confidence interval (CI) is greater than 1, or similarly if the two-sided p-value is 
significant on a 5% level and the treatment OR is in favor of semaglutide. 
If the hierarchical testing scheme allows, superiority for change in HbA1c from baseline to 
endpoint visit will be considered established if the 95% CI for the estimated treatment difference 
is smaller than 0, or similarly if the two-sided p-value is significant on a 5% level and the 
treatment difference is in favor of semaglutide. 
Year 2 Analysis 
The Year 1 analysis described above will be repeated for the confirmatory secondary endpoints 
of HbA1c <7.0% at year 2 and change in HbA1c (%-point) at year 2. If the hierarchical testing 
scheme allows, superiority will be tested first for HbA1c <7.0% at year 2 followed by change in 
HbA1c (%-point) at year 2 as described for the year 1 counterparts above. 
4.6.2 Statistical Analysis for the Secondary Estimand 
The primary effectiveness analysis will be repeated with the secondary estimand. This analysis 
will be based on the FAS with missing data imputation as described in the secondary estimand 
imputation model. With the exception of the data used and the imputation of missing data, which 
follows the secondary estimand, the statistical analysis is the same as the primary effectiveness 
analysis.  
The binary endpoints of HbA1c <7.0% at endpoint visit will be analyzed with a logistic 
regression model with a logit link function, treatment as a categorical effect, and baseline HbA1c 
as covariate. From the model the estimated OR (semaglutide s.c. versus SOC) and 95% CI will 
be presented. 
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The continuous endpoints of change in HbA1c (%-point) from baseline to endpoint visit will be 
analyzed using ANCOVA with treatment and baseline HbA1c as independent variables. From 
the model, the estimated mean difference in change from baseline to endpoint visit (semaglutide 
s.c. versus SOC) will be presented along with associated 95% CI. 
4.6.3 Additional Analyses of Glycemic Control 
4.6.3.1 
Descriptive Summaries of HbA1c 
Observed HbA1c values will be descriptively summarized at baseline, year 1, and year 2. 
Additionally, the following categories of observed HbA1c will be descriptively summarized at 
baseline, year 1, and year 2: 
• <7.0, 7.0-8.0, 8.1-9.0, 9.1-10.0, >10.0% 
• <8.0 versus ≥8.0% 
• <9.0 versus ≥9.0% 
4.6.3.2 
Supportive Analyses of Glycemic Control 
The following supportive endpoints of glycemic control are binary endpoints. These analyses 
will compare the proportion of patients achieving the secondary endpoints related to glycemic 
control between semaglutide and SOC treatment arms via a logistic regression model with a logit 
link function, treatment as a categorical effect, and baseline HbA1c as covariate. From the model 
the estimated OR (semaglutide s.c. versus SOC) will be presented. 
• Individualized HbA1c target attained at year 1 (yes/no) 
• HbA1c <7.0% (53mmol/mol) or at least 1% point improvement in HbA1c compared to 
baseline at year 1 (yes/no) 
• HbA1c target attainment per Healthcare Effectiveness Data and Information Set (HEDIS) 
criteria (<8.0% if age ≥65 years or with defined comorbidities, otherwise <7.0%) at year 1 
(yes/no) 
• Individualized HbA1c target attained at year 2 (yes/no) 
• HbA1c <7.0% (53 mmol/mol) or at least 1% point improvement in HbA1c compared to 
baseline at year 2 (yes/no) 
• HbA1c <8.0% (64 mmol/mol) at year 1 (yes/no) 
• HbA1c <8.0% (64 mmol/mol) at year 2 (yes/no)  
• HbA1c <7.0% (53 mmol/mol) and no further antidiabetic medication intensification after 
randomization at year 1 (yes/no) 
• HbA1c <7.0% (53 mmol/mol) and no further antidiabetic medication intensification after 
randomization at year 2 (yes/no) 
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• HbA1c target attainment per HEDIS criteria (<8.0% if age ≥65 years or with defined 
comorbidities, otherwise <7.0%) at year 2 (yes/no) 
• HbA1c <7.0% (53 mmol/mol) at year 1 in patients with HbA1c >9.0% at baseline (yes/no) 
• HbA1c <7.0% (53 mmol/mol) at year 2 in patients with HbA1c >9.0% at baseline (yes/no) 
• HbA1c <8.0% (64 mmol/mol) at year 1 in patients with HbA1c >9.0% at baseline (yes/no) 
• HbA1c <8.0% (64 mmol/mol) at year 2 in patients with HbA1c >9.0% at baseline (yes/no) 
4.6.4 Supplementary Analyses 
The HbA1c analyses described for the primary and secondary effectiveness analyses described 
above will be complemented with two complete case analyses based on the subset of patients 
without missing endpoint data, i.e., patients that do not have their endpoint imputed in the two 
analyses used for the primary and secondary estimand.  
4.6.4.1 
Complete Case Analysis 
This analysis will be based only on patients with available measurements at the dedicated study 
visit including measurements irrespective of whether patients discontinued study drug or not. 
The binary endpoints of HbA1c < 7.0% at year 1 and HbA1c < 7.0% at year 2 will be analyzed 
with a logistic regression model with a logit link function, treatment as a categorical effect, and 
baseline HbA1c as covariate. From the model the estimated OR (semaglutide s.c. versus SOC) 
will be presented  along with associated 95% CI. 
The continuous endpoints of change in HbA1c (%-point) at year 1 and change in HbA1c (%-
point) at year 2 will be analyzed using ANCOVA with treatment and baseline HbA1c as 
independent variables. From the model, the estimated mean difference in change from baseline 
to endpoint visit (semaglutide s.c. versus SOC) will be presented  along with associated 95% CI. 
4.6.4.2 
Complete Case On-Study Drug Analysis 
The analysis will be based only on patients with available measurements at the dedicated study 
visit including only measurements for patients still on study drug. Patients who discontinue study 
drug will be censored and missing data will not be imputed. The analysis will use the same 
analysis models as described for complete case analysis above. 
4.7 PRO Analysis 
PROs and ClinROs will be measured with the instruments described in section 3.7.8. Analysis of 
these measures will address the secondary objective of this study to compare semaglutide s.c. 
versus SOC in the study’s patient population as is relates to PROs and ClinROs, i.e., treatment 
satisfaction, generic health outcomes, work productivity, and patient and physician global 
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assessment measures, over one and two year observation periods. PRO analysis will 
descriptively summarize these measures at baseline, year 1 and year 2, as well as compare 
semaglutide s.c. versus SOC for change from baseline to year 1 and year 2.  
No imputation of missing PRO measures is planned. Therefore, the primary estimand for PRO 
analysis will be based on the FAS with endpoint data. The secondary estimand for PRO analysis 
will be based only on patients with endpoint data including only measurements for patients still 
on study drug. In the secondary estimand, patients who discontinue study drug will be censored 
and missing data will not be imputed. 
Data regarding all PROs will be reported for the entire sample by treatment group. Percentages 
of completed PROs will be reported as well. Descriptive statistics will be reported for aggregate 
scores for all appropriate measures by total score and subscale score(s) if applicable. 
Semaglutide and SOC treatment groups will be compared by independent t-tests for PRO 
measures in which the data are normally distributed or the Mann-Whitney U-test for PRO 
measures in which the data are not normally distributed. 
• Diabetes Treatment Satisfaction Questionnaire, change version (DTSQc), Total treatment 
satisfaction score measured at year 1 
• DTSQc, Total treatment satisfaction score measured at year 2 
• Change from baseline in Short Form 12-Item Version 2 Survey (SF-12 v2), Physical 
component summary (PCS-12) score at year 1 
• Change from baseline in SF-12 v2, PCS-12 score at year 2 
• Change from baseline in SF-12 v2, Mental component summary (MCS-12) score at year 
1 
• Change from baseline in SF-12 v2, MCS-12 score at year 2 
• Change from baseline in Work Productivity and Activity Impairment, General Health 
questionnaire (WPAI-GH) Absenteeism (work time missed) score at year 1 
• Change from baseline in WPAI-GH Absenteeism (work time missed) score at year 2 
• Change from baseline in WPAI-GH Presenteeism (impairment at work / reduced on-the-
job effectiveness) score at year 1 
• Change from baseline in WPAI-GH Presenteeism (impairment at work / reduced on-the-
job effectiveness) score at year 2 
• Change from baseline in WPAI-GH Work productivity loss (overall work impairment / 
absenteeism plus presenteeism) score at year 1 
• Change from baseline in WPAI-GH Work productivity loss (overall work impairment / 
absenteeism plus presenteeism) score at year 2 
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• Change from baseline in WPAI-GH Activity Impairment score at year 1 
• Change from baseline in WPAI-GH Activity Impairment score at year 2 
In addition to the above endpoints, PGI-S and CGI-S will be descriptively summarized at 
baseline overall and by treatment group. PGI-C and CGI-C will be descriptively summarized at 
year 1 and year 2 overall and by treatment group. 
During later analysis on the primary endpoints, PRO measures can be used in two ways: 
• Correlational analysis of the PRO measures with the dependent variable. These 
correlations will include the appropriate measure of Pearson’s ‘r’, Spearman’s rho, 
Kendall’s tau statistics or other appropriate measures that might fit the nature of the 
variable. 
• Should the correlational analysis from step 1 find that patient characteristics are linked to 
primary analysis endpoints, multivariate analysis or Logistic Regression will be 
conducted to determine if there are any patient related variables from the PROs that 
predict the effectiveness of therapy in combination with other clinical variables. Data 
reported will include model specifics (H-L Goodness of fit; R2, beta coefficients for each 
variable as well as ORs with 95% CIs.) 
4.8 Concomitant Medications 
The number and percentages patients reporting pre-specified concomitant cardiovascular 
medications during year 1 and during year 2 will be summarized for the population overall and 
by treatment group. 
4.9 Other Analyses 
The following analyses further support the primary objective to compare semaglutide s.c. versus 
SOC in glycemic control. They will address the secondary objectives of this study to compare 
semaglutide s.c. versus SOC in the study’s patient population over one and two year observation 
periods as is relates to body weight loss, hypoglycemia, HCRU, adherence and persistence to 
treatment, antidiabetic medication treatment patterns, and safety. 
Except where otherwise noted, the following analyses will be conducted for the primary 
estimand and the secondary estimand. For endpoints that do not include HbA1c, weight, SBP, or 
DBP, no missing data will be imputed. Therefore, the primary estimand for these endpoints will 
be based on the FAS with endpoint data. The secondary estimand for these endpoints will be 
based only on patients with endpoint data including only measurements for patients still on study 
drug. Patients who discontinue study drug will be censored and missing data will not be imputed. 
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4.9.1 Weight Loss 
Change in patient weight from baseline to endpoint will be calculated in absolute change 
(pounds) and relative change (percentage). Mean change in weight will be compared between 
semaglutide and SOC treatment groups following the ANCOVA model described for continuous 
endpoints in the primary (4.6.1) and secondary estimand (4.6.2). This analysis will be repeated 
for the complete case (4.6.4.1) and complete case on-study drug (4.6.4.2). 
• Change in body weight (%) from baseline to year 1 
• Change in body weight (lb) from baseline to year 1 
• Change in body weight (%) from baseline to year 2 
• Change in body weight (lb) from baseline to year 2 
4.9.2 Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) 
Absolute change in patient SBP and DBP from baseline to year 1 and baseline to year 2 will be 
calculated. Mean change in SBP and DBP will be compared between the semaglutide and SOC 
treatment groups following the ANCOVA model described for continuous endpoints in the 
primary (4.6.1) and secondary estimand (4.6.2). This analysis will be repeated for the complete 
case (4.6.4.1) and complete case on-study drug (4.6.4.2). 
4.9.3 Hypoglycemia 
The total number of hypoglycemic episodes leading to an inpatient admission or ER encounter 
will be summed per patient from baseline to year 2 and compared by semaglutide and SOC 
treatment groups utilizing a negative binomial model with fixed effect of treatment and baseline 
HbA1c as a covariate. Exploratory analysis will assess the impact of SOC study drug (defined in 
section 3.7.4.2) on the rate of hypoglycemia.  
Additionally, the frequency and percentage of patients reporting hypoglycemic episodes leading 
to an inpatient admission or ER encounter from baseline to year 1 and from baseline to year 2 
will be reported and compared between treatment groups via chi-square test. 
Hypoglycemic episodes that are considered SAEs will also be included in the safety analysis 
(section 5.4). 
4.9.4 Healthcare Resource Utilization (HCRU) 
HCRU analyses will compare all-cause and diabetes-related HCRU (inpatient admissions, ER 
encounters, physician OV, other outpatient encounters, and pharmacy utilization) as defined in 
section 3.7.9 from claims data by semaglutide and SOC treatment arm from baseline to year 2. 
The number of each type of encounter (all-cause and T2DM-related: inpatient admission, ER 
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encounter, physician OV, other outpatient encounter (overall and by specific categories listed in 
section 3.7.9), pharmacy prescription fills) a patient experiences from baseline to year 2 will be 
summed. 
HCRU will be summarized by setting (i.e., inpatient, ER, OV, outpatient, pharmacy) and cause 
(i.e., all-cause versus diabetes-related), for the study population overall and by treatment group. 
The occurrence (yes/no) and number of each type of encounter or prescription fill will be 
reported. LOS will be reported per admission and cumulative (baseline to year 2). LOS for 
inpatient admissions (days) per inpatient admission will be an encounter level analysis of the 
average inpatient admission LOS based on the total number of inpatient admissions; therefore, 
patients may contribute more than once. Statistics for cumulative LOS for inpatient admissions 
(days) will only be produced for patients with at least one inpatient admission. 
Treatment group comparisons will utilize the Student t-test for continuous variables and chi-
squared test (or Fisher’s exact test if outcome count less than 5) for categorical variables. 
4.9.5 Composite Endpoints 
The following composite endpoints will be analyzed with a logistic regression model with a logit 
link function, treatment as a categorical effect, and baseline HbA1c and baseline weight as 
covariates. This analysis will be repeated for the complete case (4.6.4.1) and complete case on-
study drug (4.6.4.2). 
• HbA1c <7.0% (53 mmol/mol) without experiencing hypoglycemia leading to inpatient 
admission or ER encounter and body weight loss of  ≥5% vs baseline at year 1 (yes/no) 
• Absolute HbA1c reduction of ≥0.5% without experiencing hypoglycemia leading to 
inpatient admission or ER encounter and a body weight loss of  ≥5% vs baseline at year 1 
(yes/no) 
• HbA1c <7.0% (53 mmol/mol) without experiencing hypoglycemia leading to inpatient 
admission or ER encounter and body weight loss of  ≥5% vs baseline at year 2 (yes/no) 
• Absolute HbA1c reduction of ≥0.5% without experiencing hypoglycemia leading to 
inpatient admission or ER encounter and a body weight loss of  ≥5% vs baseline at year 2 
(yes/no) 
• HbA1c <7.0% (53 mmol/mol) without experiencing hypoglycemia leading to inpatient 
admission or ER encounter and no body weight gain vs baseline at year 1 (yes/no) 
• HbA1c <7.0% (53 mmol/mol) without experiencing hypoglycemia leading to inpatient 
admission or ER encounter and no body weight gain vs baseline at year 2 (yes/no) 
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4.9.6 Antidiabetic Treatment Patterns 
4.9.6.1 
Study Drug Regimen 
Study drug regimen will be descriptively summarized by treatment arm. 
The SOC group’s randomized treatment regimen will be summarized by medication and class for 
study drug, i.e., the first antidiabetic medication prescribed for treatment intensification 
following randomization. 
For the semaglutide group, relative frequency by dose category (0.25, 0.5, 1.0 mg) will be 
calculated at randomization, year 1, and year 2. Additionally, the relative frequency by 
semaglutide dose category will be calculated for most common, highest, and final as defined in 
section 3.7.4.1. 
Treatment intensification and treatment change (definition 3.7.4.3) will also be descriptively 
summarized as follows: 
• Treatment intensification from baseline to year 1 (yes/no) 
• Treatment intensification from baseline to year 2 (yes/no) 
• Treatment change from baseline to year 1 (yes/no) 
• Treatment change from baseline to year 2 (yes/no) 
4.9.6.2 
Adherence and Persistence to Treatment 
Adherence and persistence to the study drug will be calculated and compared between 
semaglutide and SOC treatment groups. This analysis will be conducted for the primary estimand 
only. 
Study drug medication adherence will be summarized by the MPR (%) using the claims data. 
The MPR (%) for the first year of the study and the MPR (%) for the two year study period will 
be compared between treatment arms using the test of independent proportions. 
Medication persistence, as calculated using the eCRF data, will be summarized by: 
• Time to first study drug discontinuation during 2 years (day) 
• Time to first treatment intensification (add-on) or change (switch) after randomization 
during 2 years (day) 
Medication persistence measures will be compared between semaglutide and SOC treatment 
groups via the Cox proportional hazards model (with no covariates) to estimate the hazard ratio 
(HR) (semaglutide s.c. versus SOC) and 95% CI. Patients with no event will be censored at year 
2 or last contact if withdrawn or lost to follow-up. 
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4.9.6.3 
Other Antidiabetic Treatments 
Antidiabetic treatment patterns will be assessed and compared between semaglutide and SOC 
treatment groups. This analysis will summarize the number and classification type of antidiabetic 
medications taken during the study period.  
Descriptive statistics will be presented overall and by treatment group for the average number of 
antidiabetic medications patients report at randomization, year 1 and year 2. Relative frequencies 
of number of antidiabetic medications will also be summarized for randomization, year 1 and 
year 2. Relative frequencies by antidiabetic class will also be presented at randomization, year 1 
and year 2. 
4.10 Study Site Recruitment and Participation 
To contextualize the participating study sites within the pool of 
 providers, tables 
summarizing the identification, recruitment, and participation of providers will be presented. 
Site identification for this study begins with identifying the pool of potentially eligible patients in 
the HIRD using very broad claims-based inclusion/exclusion criteria: currently active members 
with at least one medical claim with an ICD-9 or ICD-10 diagnosis code for T2DM during the 
identification period, pharmacy carve-in benefits and pharmacy carve-out benefits at any time 
during the identification period, commercial plan coverage only, ≥18 years old, at least one 
pharmacy claim for metformin in the past 6 months, and no pharmacy claims for other 
antidiabetic medications within the past 30 days. These patients are then mapped back to the 
provider sites with which they had diabetes-related office visits during the identification period. 
From this process, a list of providers with number of potentially eligible patients is generated. 
The overall pool of 
 providers serving the target study population will be summarized 
with a table presenting patient densities by number of providers. 
A flow chart summarizing each step of the process will be produced to describe site recruitment 
and participation: 
1) Total number of providers with at least one potentially eligible patient identified. 
2) Total number of providers approached (I.e., providers who met predetermined threshold 
(x number of patients) for outreach.) 
3) Disposition of providers approached 
a. Interested, invited to participate 
b. Interested, rejected from participation 
c. Not Interested 
d. No Response 
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A table summarizing characteristics of providers (geographic region, provider specialty, and 
claims-based patient density) by disposition status will be produced. 
4.11 Evaluation of the Study Population 
To evaluate the generalizability of the study results, an analysis of the study population will be 
performed. The primary objective of this analysis is to evaluate the external validity of the study 
and to understand how the study population fits into the larger T2DM populations within study 
sites and commercially-insured population as a whole. Two claims-based T2DM patient 
populations will be described and compared to the study population: (1) all research-eligible 
commercially-insured and Medicare Advantage 
 T2DM patients treated with up to 2 oral 
antidiabetic medication, excluding oral semaglutide, who undergo an antidiabetic treatment 
intensification and (2) within the study sites, commercially-insured and Medicare Advantage 
 T2DM patients treated with up to 2 oral antidiabetic medications, excluding oral 
semaglutide, who are not enrolled in the study, but who undergo an antidiabetic treatment 
intensification.  
Identification of Claims-Based Comparator Populations 
The claims-based comparator populations and analysis will be based on data from the HIRD. 
Claims based inclusion/exclusion criteria will be imposed on the two comparator populations as 
best as can be identified via the claims data and available lab result data to reflect the 
inclusion/criteria of the study population. All patients meeting the inclusion/exclusion criteria for 
each of the claims-based T2DM populations will be included in the analysis. 
• Claims patient identification period = July 2018 until date last patient enrolled. (To align 
with the dates of the PCT study period). 
• Claims index date = Patient’s first prescription date associated with antidiabetic treatment 
intensification during the patient identification period. 
• Claims study period = July 2017 until 12 months following date of last patient enrolled. 
(To allow for 12 months of claims data before and after the identified antidiabetic 
treatment intensification.) 
Inclusion Criteria for Population #1 
• ≥ 1 medical claim with an ICD-10 diagnosis code for T2DM during patient identification 
period 
• A pharmacy claim(s) for 1 or 2 oral antidiabetic treatments, excluding oral semaglutide, 
as described in the PCT, during the patient identification period 
o First date of antidiabetic treatment pharmacy claim is index date 
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• ≥ 12 months medical and pharmacy eligibility prior to index date 
• Age ≥ 18 years on index date 
• HbA1c >7.0% within 90 days prior to and including index date 
Exclusion Criteria for Population #1 
•  Pharmacy claims for ≥2 oral antidiabetic medications, oral semaglutide, or any injectable 
antidiabetic medicationfor 30 days prior to index date. 
• Randomized into the current PCT. 
 
Inclusion Criteria for Population #2 
The inclusion criteria for population #2 will include all of the inclusion criteria as population #1, 
as well as: 
• Receiving antidiabetic treatment at a study site 
Exclusion Criteria for Population #2 
The exclusion criteria for population #2 is the same as the exclusion criteria for population #1. 
 
All analyses evaluating the study population will be descriptive only and will help to 
contextualize study results within the T2DM population broadly. All analyses will be based on 
the overall population only; analyses by treatment group will not be conducted. 
The analysis will descriptively compare the overall baseline demographics between the PCT 
study population and the two comparator populations. Baseline HbA1c (defined as closest HbAlc 
up to and including 90 days prior to randomization (for PCT population) or index date (for 
comparators)) will also be compared. 
Observed HCRU (all-cause and T2DM-related; inpatient, ER, outpatient physician OV, and 
other outpatient services, pharmacy utilizations) during the 12 month period prior to 
randomization (for study population) or prior to index date (for comparators) will also be 
compared between the PCT study population and the two comparator populations. The PCT 
study population for this comparison will be limited to study patients with 12 months of health 
plan eligibility prior to randomization.  
Additionally, treatment patterns of non-enrolled T2DM patients within the practices from which 
the study patients are recruited will be evaluated to identify any relevant patterns of care 
suggesting channeling of certain types of patients away from the study. This analysis be based on 
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the subset of patients with 12 months post-index data medical and pharmacy eligibility and will 
present the relative frequency of antidiabetic medications by class during the 12 months 
following randomization or index date for the PCT study population and comparator population 
#2. 
 
5.0 SAFETY 
5.1 AEs 
For the purpose of this study, AEs that do not meet the definition of an SAE (protocol section 
7.2) will only be required to be collected in the eCRF if they lead to study drug discontinuation. 
5.2 SAEs 
All AEs meeting the definition of an SAE (protocol section 7.2) will be collected in the eCRF. 
5.3 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 patients will be reported, along with pregnancy outcome and any AEs or 
SAEs observed in the fetus or newborn until 1 month of age.  
5.4 Analysis 
No formal safety analyses are planned for this study. SAEs and AEs leading to study drug 
discontinuation will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
and descriptively summarized by System Organ Class and Preferred Term (PT). Pregnancies 
occurring during the study will be also be descriptively summarized. 
 
6.0 Changes from Protocol 
The protocol specified conducting PRO Analysis (Protocol Section 6.6) and Other Analyses 
(Protocol Section 6.8) as described for the primary estimand, secondary estimand, and 
supplementary analysis (complete case and complete case on-study drug). However, missing 
data imputation will only be completed for HbA1c, weight, SBP, and DBP. Therefore, for 
endpoints that do not include HbA1c, weight, SBP, or DBP data, the primary estimand will be 
based on the FAS with endpoint data. The secondary estimand for these endpoints will be based 
only on patients with endpoint data including only measurements for patients still on study drug. 
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Patients who discontinue study drug will be censored and missing data will not be imputed. 
Supplementary analyses will not be completed for these endpoints. 
 
 
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7.0 SAP Change Log 
 
Summary of SAP Changes since First Patient First Visit 
 
Number 
Section/Page 
 
Change 
Rationale 
1 
 
Global Change, 
Study Population 
Allow enrollment of patients treated with 
either 1 or 2 oral antidiabetic medications 
Expand study population from 
patients treated with 
metformin monotherapy to 
patients treated with either 1 or 
2 oral antidiabetic medications 
to facilitate enrollment.  
2 
Global Change, 
Study Population 
Allow enrollment of patients with any 
commercial or Medicare insurance with 
pharmacy benefits. 
  
Expand study population to 
facilitate enrollment. 
 
3 
Global Change 
JulyMay 520, 20182020 
 
Version 12.0 
Update protocol date and 
version. 
 
4 
Study Approvals, 
p. 2 
Name:  
 
Title:    
 Research Biostatistics 
Name:  
 
Title:    
 Scientist 
 
Update to 
 study 
statistician. 
 
5 
Study Approvals, 
p. 2 
Name:  
 
Title:    
 
Name:  
  
Title:    
 
Update to Novo Nordisk study 
statistician. 
6 
Global Change,  
Study Treatments 
Semaglutide s.c. 
Clarify formulation of 
semaglutide allowed for study 
treatment is subcutaneous 
only. 
7 
Global Change 
 
routine diabetic care visits 
Clarify data collection 
between study visits for sites. 
 
8 
Global Change, 
Study Treatments 
…semaglutide s.c. as compared to SOC 
(excluding any semaglutide). 
 
No formulation of semaglutide 
is allowed in SOC group. 
Clarify that main study 
comparison excludes any 
formulation of semaglutide 
from the SOC group. 
 
9 
Section 1.0, 
Introduction 
This is a 2-year, multi-center, randomized, 
open label, parallel group, active comparator 
Update study design to reflect 
expanded study population. 
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pragmatic clinical trial (PCT) comparing 
semaglutide s.c. versus standard of care 
(SOC) when added to metformin 
monotherapyup to 2 oral antidiabetic 
medications as treatment intensification 
among adult type 2 diabetes mellitus (T2DM) 
patients in the course of routine clinical 
practice. 
10 
Section 2.1, 
Primary Objective 
The primary objective is to demonstrate 
superior long term effects of treatment with 
semaglutide s.c. compared to SOC each added 
to metformin up to 2 oral antidiabetic 
medications on glycemic control when used 
as intensification in routine clinical practice in 
adult patients with T2DM. 
Update primary objective to 
reflect expanded study 
population. 
11 
Section 2.2,  
Secondary 
Objectives 
 
The secondary objectives are to compare the 
long term effect of semaglutide s.c. versus 
SOC each added to metformin up to 2 oral 
antidiabetic medications and used as 
intensification in routine clinical practice in 
adult patients with T2DM with regards to: 
 
Update secondary objectives 
to reflect expanded study 
population. 
12 
Section 3.3, 
Evaluation 
Schedule and 
Definitions 
Year 2 endpoint data will be derived from the 
dedicated year 1 2 study visit if the dedicated 
study visit is ±10 weeks of 104 weeks post-
randomization. 
Correction 
13 
Section 3.4,  
Confirmatory 
Endpoint and 
Hypothesis 
This study is designed to have 90% power to 
jointly confirm superiority of the primary 
endpoint and 85% power to also confirm 
superiority of the first the above three 
confirmatory secondary endpoints based on 
primary estimand analyses. 
Update to power calculations. 
14 
Section 3.5.1  
Power and Sample 
Size for Primary 
Objective 
In line with the primary ITT estimand, the 
assumptions for the proportion of patients 
with HbA1c < 7.0% at year 1 and year 2, and 
for the change from baseline in HbA1c are 
based on the claims/laboratory results data 
within the 
 population for all patients 
initiating treatment intensification regardless 
of whether patients adhered to this treatment. 
Update to reflect protocol. 
15 
Section 3.5.1  
Power and Sample 
Size for Primary 
Objective 
The sample size calculation aimed for 90% 
power for simultaneously confirming 
superiority of semaglutide s.c. versus SOC on 
all of the primary endpoint and 85% power to 
also confirm superiority of the first 
Update to power calculations. 
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confirmatory secondary endpoint based on an 
analysis of the primary estimand for each of 
the endpointsthe secondary confirmatory 
endpoints at both year 1 and year 2 (4 
hypotheses in total). 
16 
Section 3.5.1  
Power and Sample 
Size for Primary 
Objective  
When accounting for missing data, 
randomizing 2250 1387 patients will 
contribute 1687 1040 patients for the year 1 
analyses and 1260 780 patients for the year 2 
analyses, achieving a total power of 90% 85% 
for confirming the two year 1 confirmatory 
hypotheses. The joint power for confirming 
all 4 confirmatory hypotheses is 58%. The 
corresponding marginal powers for presence 
of HbA1c < 7.0% at year 1, change in HbA1c 
to 1 year, presence of HbA1c < 7.0% at year 
2, and change in HbA1c to 2 years are 
99%90%, 99%94%, 95%80%, and 97%86% 
respectively. 
Update to planned enrollment 
and power calculations. 
17 
Section 3.7.4.2  
Standard of Care 
(SOC) Study Drug 
 
For the SOC treatment group, study drug is 
defined as the drug class of the first 
antidiabetic oral or injectable medication 
prescribed for treatment intensification 
following randomization (excluding any 
formulation of semaglutide). 
Semaglutide in any 
formulation is not allowed 
during the study period for the 
SOC group. 
18 
Section 3.7.4.3 
Treatment 
Intensification or 
Change 
Treatment intensification is defined as 
initiation of an antidiabetic medication 
(besides metforminthe up to 2 oral 
antidiabetic medication(s) taken prior to 
randomization) in addition to study drug, or 
initiation of more than one antidiabetic 
medication after discontinuation of study 
drug. 
Update definition to reflect 
expanded study population. 
19 
Section 3.7.4.3 
Treatment 
Intensification or 
Change 
Treatment change is defined as 
discontinuation of study drug and initiation of 
another antidiabetic medication (besides 
metforminthe up to 2 oral antidiabetic 
medication(s) taken prior to randomization). 
Update definition to reflect 
expanded study population. 
20 
Section 3.7.9 
Healthcare 
Resource 
Utilization 
(HCRU) 
These data will come from the HIRD for 
 patients or requested from a set of 
other health insurers for non-
 patients. 
Updated definition to reflect 
expanded study population and 
collection of claims data. 
21 
Section 4.5  
Missing endpoint data will be imputed for 
HbA1c, weight, SBP, and DBP. The data of 
Semaglutide in any 
formulation is not allowed 
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Missing Value 
Imputation 
Methodology 
patients who, in violation of the protocol, 
initiate any formulation of semaglutide in the 
SOC treatment group, will be censored 
analytically following initiation of 
semaglutide. The patient will remain in the 
analysis, but data following their initiation of 
semaglutide will be censored and treated as 
missing. 
during the study period for the 
SOC group. 
22 
Section 4.9.4  
Healthcare 
Resource 
Utilization 
(HCRU) 
HCRU analyses will compare all-cause and 
diabetes-related HCRU (inpatient admissions, 
ER encounters, physician OV, other 
outpatient encounters, and pharmacy 
utilization) as defined in section 3.7.9 from 
the HIRDclaims data by semaglutide and 
SOC treatment arm from baseline to year 2. 
Update to reflect expanded 
study population and 
collection of claims data. 
23 
Section 4.9.6.3 
Other Antidiabetic 
Treatments 
Background Medication 
Metformin dose will be descriptively 
summarized overall and by treatment group at 
randomization, year 1, and year 2. 
Other Antidiabetic Treatments 
… 
Descriptive statistics will be presented overall 
and by treatment group for the average 
number of antidiabetic medications patients 
report at randomization, year 1 and year 2. 
Relative frequencies of number of antidiabetic 
medications will also be summarized for 
randomization, year 1 and year 2. Relative 
frequencies by antidiabetic class will also be 
presented at randomization, year 1 and year 2. 
Update descriptive summary 
of other antidiabetic treatments 
to reflect expanded study 
population. 
24 
Section 4.11 
Evaluation of the 
Study Population 
The primary objective of this analysis is to 
evaluate the external validity of the study and 
to understand how the study population fits 
into the larger T2DM populations within 
study sites and 
 commercially-insured 
population as a whole. Two claims-based 
T2DM patient populations will be described 
and compared to the study population: (1) all 
research-eligible commercially-insured and 
Medicare Advantage 
 T2DM patients 
treated with metforminup to 2 oral 
antidiabetic medication, excluding oral 
semaglutide,  who undergo an antidiabetic 
treatment intensification and (2) within the 
study sites, commercially-insured and 
Update to reflect expanded 
study population. 
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Medicare Advantage 
 T2DM patients 
treated with metformin up to 2 oral 
antidiabetic medications, excluding oral 
semaglutide, who are not enrolled in the 
study, but who undergo an antidiabetic 
treatment intensification. 
25 
Section 4.11 
Evaluation of the 
Study Population 
Inclusion Criteria for Population #1 
• ≥ 1 medical claim with an ICD-10 diagnosis 
code for T2DM during patient identification 
period 
• ≥ 1 A pharmacy claim(s) for 1 or 2 oral 
antidiabetic treatments, excluding oral 
semaglutide, in addition to metformin, as 
described in the PCT, during the patient 
identification period 
o First date of antidiabetic 
treatment pharmacy claim is 
index date 
• ≥ 12 months medical and pharmacy 
eligibility prior to index date 
• ≥ 1 pharmacy claim for metformin in 6 
months prior to index date 
• Age ≥ 18 years on index date 
• HbA1c >7.0% within 90 days prior to and 
including index date 
Update to reflect expanded 
study population. 
26 
Section 4.11 
Evaluation of the 
Study Population 
Exclusion Criteria for Population #1 
• ≥ 1 pharmacy Pharmacy claims for ≥2 any 
oral antidiabetic medications, oral 
semaglutide, or any injectable antidiabetic 
medication other than metformin for 30 days 
prior to index date. 
• Randomized into the current PCT. 
Update to reflect expanded 
study population. 
 
 
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8.0 APPENDIX A: Study Endpoints and Other Variables by Data Source 
Endpoint/Variable 
Data Source 
eCRF 
Administrative 
Claims 
Study Drug Variables 
On/Off Study Drug 
X 
 
Treatment Intensification 
X 
 
Treatment Change 
X 
 
Antidiabetic treatment patterns 
X 
 
Primary Endpoint 
HbA1c <7.0% at year 1 (yes/no) 
X 
 
Confirmatory Endpoints 
Change in HbA1c (%-point) from baseline to year 1 
X 
 
HbA1c <7.0% at year 2 (yes/no) 
X 
 
Change in HbA1c (%-point) from baseline to year 1 
X 
 
Supportive Secondary Endpoint Assessment 
Individualized HbA1c target attained at year 1 (yes/no) 
X 
 
HbA1c <7.0% (53mmol/mol) or at least 1% point improvement in HbA1c 
compared to baseline at year 1 (yes/no) 
X 
 
HbA1c target attainment per Healthcare Effectiveness Data and 
Information Set (HEDIS) criteria (<8.0% if age ≥65 years or with defined 
comorbidities, otherwise <7.0%) at year 1 (yes/no) 
X 
X 
Change in body weight (lb) from baseline to year 1 
X 
 
Change in body weight (%) from baseline to year 1 
X 
 
Change in systolic blood pressure (SBP; mm Hg) from baseline to year 1 
X 
 
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Change in diastolic blood pressure (DBP; mm Hg) from baseline to year 1 
X 
 
Time to first study drug discontinuation during 2 years (day) 
X 
 
Time to first treatment intensification (add-on) or change (switch) after 
randomization during 2 years (day) 
X 
 
Study drug medication adherence for the first year of the study, as 
measured by medication possession ratio (MPR) (%) 
 
X 
Number of hypoglycemic episodes leading to an inpatient admission or 
emergency room (ER) encounter from baseline to year 2 
X 
 
Diabetes Treatment Satisfaction Questionnaire, change version (DTSQc), 
Total treatment satisfaction score measured at year 1 
X 
 
DTSQc, Total treatment satisfaction score measured at year 2 
X 
 
Change from baseline in Short Form 12-Item Version 2 Survey (SF-12 
v2), Physical component summary (PCS-12) score at year 1 
X 
 
Change from baseline in SF-12 v2, PCS-12 score at year 2 
X 
 
Change from baseline in SF-12 v2, Mental component summary (MCS-
12) score at year 1 
X 
 
Change from baseline in SF-12 v2, MCS-12 score at year 2 
X 
 
Change from baseline in Work Productivity and Activity Impairment, 
General Health questionnaire (WPAI-GH) Absenteeism (work time 
missed) score at year 1 
X 
 
Change from baseline in WPAI-GH Absenteeism (work time missed) 
score at year 2 
X 
 
Change from baseline in WPAI-GH Presenteeism (impairment at work / 
reduced on-the-job effectiveness) score at year 1 
X 
 
Change from baseline in WPAI-GH Presenteeism (impairment at work / 
reduced on-the-job effectiveness) score at year 2 
X 
 
Change from baseline in WPAI-GH Work productivity loss (overall work 
impairment / absenteeism plus presenteeism) score at year 1 
X 
 
Change from baseline in WPAI-GH Work productivity loss (overall work 
impairment / absenteeism plus presenteeism) score at year 2 
X 
 
Change from baseline in WPAI-GH Activity Impairment score at year 1 
X 
 
Change from baseline in WPAI-GH Activity Impairment score at year 2 
X 
 
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All cause HCRU from baseline to year 2 
Number of inpatient admissions 
 
X 
LOS for inpatient admissions (days) per inpatient admission 
 
X 
Cumulative length of stay for inpatient admissions (days) 
 
X 
Number of ER encounters 
 
X 
Number of physician OV  
 
X 
Number of other outpatient encounters (overall, and by category: Tests – 
Lab, Imaging, Procedures, OT/Speech, Medication and Related Services, 
Durable Medication Equipment, Physician Other Services, Tests – Other, 
Other)  
 
X 
Number of medications 
 
X 
Occurrence of inpatient admission (yes/no) 
 
X 
Occurrence of ER encounter (yes/no) 
 
X 
Occurrence of physician OV (yes/no) 
 
X 
Occurrence of other outpatient encounter (yes/no) (overall, and by 
category: Tests – Lab, Imaging, Procedures, OT/Speech, Medication and 
Related Services, Durable Medication Equipment, Physician Other 
Services, Tests – Other, Other) 
 
X 
Diabetes related HCRU from baseline to year 2 
Number of diabetes related inpatient admissions 
 
X 
LOS for diabetes related inpatient admissions (days) per diabetes related 
inpatient admission 
 
X 
Cumulative length of stay for diabetes related inpatient admissions (days) 
 
X 
Number of diabetes related ER encounters 
 
X 
Number of diabetes related physician OV 
 
X 
Number of diabetes related other outpatient encounters (overall, and by 
category: Tests – Lab, Imaging, Procedures, OT/Speech, Medication and 
Related Services, Durable Medication Equipment, Physician Other 
Services, Tests – Other, Other) 
 
X 
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Number of diabetes related medications 
 
X 
Occurrence of diabetes related inpatient admission (yes/no) 
 
X 
Occurrence of diabetes related ER encounter (yes/no) 
 
X 
Occurrence of diabetes related physician OV (yes/no) 
 
X 
Occurrence of diabetes related outpatient encounter (yes/no) (overall, and 
by category: Tests – Lab, Imaging, Procedures, OT/Speech, Medication 
and Related Services, Durable Medication Equipment, Physician Other 
Services, Tests – Other, Other) 
 
X 
Additional Derived Outcome Variables for Supportive Analyses 
Supportive Measures of Glycemic Control 
 
 
Individualized HbA1c target attained at year 2 (yes/no) 
X 
 
HbA1c <7.0% (53 mmol/mol) or at least 1% point improvement in HbA1c 
compared to baseline at year 2 (yes/no) 
X 
 
HbA1c <8.0% (64 mmol/mol) at year 1 (yes/no) 
X 
 
HbA1c <8.0% (64 mmol/mol) at year 2 (yes/no)  
X 
 
HbA1c <7.0% (53 mmol/mol) and no further antidiabetic medication 
intensification after randomization at year 1 (yes/no) 
X 
 
HbA1c <7.0% (53 mmol/mol) and no further antidiabetic medication 
intensification after randomization at year 2 (yes/no) 
X 
 
HbA1c target attainment per HEDIS criteria (<8.0% if age ≥65 years or 
with defined comorbidities, otherwise <7.0%) at year 2 (yes/no) 
X 
X 
HbA1c <7.0% (53 mmol/mol) at year 1 in patients with HbA1c >9.0% at 
baseline (yes/no) 
X 
 
HbA1c <7.0% (53 mmol/mol) at year 2 in patients with HbA1c >9.0% at 
baseline (yes/no) 
X 
 
HbA1c <8.0% (64 mmol/mol) at year 1 in patients with HbA1c >9.0% at 
baseline (yes/no) 
X 
 
HbA1c <8.0% (64 mmol/mol) at year 2 in patients with HbA1c >9.0% at 
baseline (yes/no) 
X 
 
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Body Weight Loss 
 
 
Change in body weight (%) from baseline to year 2 
X 
 
Change in body weight (lb) from baseline to year 2 
X 
 
Blood Pressure 
 
 
Change in SBP (mm Hg) from baseline to year 2 
X 
 
Change in DPB (mm Hg) from baseline to year 2 
X 
 
Hypoglycemia 
 
 
Reported hypoglycemia leading to inpatient admission or ER encounter 
during year 1 (yes/no) 
X 
 
Reported hypoglycemia leading to inpatient admission or ER encounter 
during year 2 (yes/no) 
X 
 
Composite Variables 
 
 
HbA1c <7.0% (53 mmol/mol) without experiencing hypoglycemia leading 
to inpatient admission or ER encounter and body weight loss of  ≥5% vs 
baseline at year 1 (yes/no) 
X 
 
Absolute HbA1c reduction of ≥0.5% without experiencing hypoglycemia 
leading to inpatient admission or ER encounter and a body weight loss of  
≥5% vs baseline at year 1 (yes/no) 
X 
 
HbA1c <7.0% (53 mmol/mol) without experiencing hypoglycemia leading 
to inpatient admission or ER encounter and body weight loss of  ≥5% vs 
baseline at year 2 (yes/no) 
X 
 
Absolute HbA1c reduction of ≥0.5% without experiencing hypoglycemia 
leading to inpatient admission or ER encounter and a body weight loss of  
≥5% vs baseline at year 2 (yes/no) 
X 
 
HbA1c <7.0% (53 mmol/mol) without experiencing hypoglycemia leading 
to inpatient admission or ER encounter and no body weight gain vs 
baseline at year 1 (yes/no) 
X 
 
HbA1c <7.0% (53 mmol/mol) without experiencing hypoglycemia leading 
to inpatient admission or ER encounter and no body weight gain vs 
baseline at year 2 (yes/no) 
X 
 
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Adherence to Treatment 
 
 
Study drug medication adherence for the two years of the study, as 
measured by the medication possession ratio (MPR) (%) 
 
X 
 
 
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9.0 APPENDIX B: 2018 HEDIS Criteria 
Denominator 
The eligible population.  
Note: The eligible population for the HbA1c Control <7% for a Selected 
Population indicator is reported after required exclusions are applied. 
Required exclusions 
for HbA1c Control  
<7% for a Selected 
Population indicator  
Exclude members who meet any of the following criteria: 
• 65 years of age and older as of December 31 of the measurement year. 
• CABG. Members who had CABG (CABG Value Set) in any setting during 
the measurement year or the year prior to the measurement year.  
• PCI. Members who had PCI (PCI Value Set), in any setting, during the 
measurement year or the year prior to the measurement year. 
• IVD. Members who met at least one of the following criteria during both the 
measurement year and the year prior to the measurement year. Criteria 
need not be the same across both years. 
– At least one outpatient visit (Outpatient Value Set) with an IVD diagnosis 
(IVD Value Set). 
– At least one acute inpatient encounter (Acute Inpatient Value Set) with 
an IVD diagnosis (IVD Value Set). 
• Thoracic aortic aneurysm. Members who met at least one of the following 
criteria during both the measurement year and the year prior to the 
measurement year. Criteria need not be the same across both years. 
– At least one outpatient visit (Outpatient Value Set), with a diagnosis of 
thoracic aortic aneurysm (Thoracic Aortic Aneurysm Value Set). 
– At least one acute inpatient encounter (Acute Inpatient Value Set), with a 
diagnosis of thoracic aortic aneurysm (Thoracic Aortic Aneurysm Value 
Set). 
• Any of the following, in any setting, any time during the member’s history 
through December 31 of the measurement year. 
– Chronic heart failure. A diagnosis of chronic heart failure (Chronic Heart 
Failure Value Set).  
– Prior MI. A diagnosis of MI (MI Value Set). 
– ESRD. ESRD (ESRD Value Set; ESRD Obsolete Value Set). 
– Chronic kidney disease (stage 4). Stage 4 chronic kidney disease (CKD 
Stage 4 Value Set). 
– Dementia. A diagnosis of dementia (Dementia Value Set; Frontotemporal 
Dementia Value Set).  
– Blindness. A diagnosis of blindness (Blindness Value Set).  
– Amputation (lower extremity). Lower extremity amputation (Lower 
Extremity Amputation Value Set). 
 
 
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10.0 REFERENCES 
 
[1] C. Bradley, "Diabetes Treatment Satistcation Questionnaire: DTSQ," in Handbook of 
Psychology and Diabetes: A Guide to Psychological Measurement in Diabetes Research 
and Practice, C. Bradley, Ed., Abington, Routledge, 1994, pp. 111-132. 
[2] C. Bradley, "The Diabetes Treatment Satisfaction Questionnaire (DTSQ): change version 
for use alongside status version provides appropriate solution where ceiling effects occur," 
Diabetes Care, vol. 22, no. 3, pp. 530-532, 1999.  
[3] J. Ware, M. Kosinski and S. Keller, "A 12-item short-form healch survey: construction of 
scales and preliminary tests of reliability and validity," Med Care, vol. 34, no. 3, pp. 220-
233, 1996.  
[4] J. Ware, M. Kosinski, D. Turner-Bowker and B. Gandek, How to score version 2 of the SF-
12 health survey (with a supplement documenting version 1), Lincoln, RI: QualityMetric, 
Incorporated, 2002.  
[5] M. Reilly, A. Zbrozek and E. Dukes, "The validity and reproducibility of a work 
productivity and activity impairment instrument," Pharmacoeconomics, vol. 4, no. 5, pp. 
353-365, 1993.  
[6] R. Little and D. Rubin, Statistical analysis with missing data, New York: John Wiley and 
Sons, 1987.  
 
 
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Statistical Analysis Plan for Long term comparative effectiveness of once weekly 
semaglutide versus standard of care in a real world adult US population with 
type 2 diabetes - a randomized pragmatic clinical trial 
 
 
 
 
 
 
Protocol No.  NN9535-4416 
 
 
Novo Nordisk 
 
 
 
October 26, 2021 
 
Version 3.0 
 
 
 
 
 
 
 
 
 
  
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Protocol No:  NN9535-4416 
26-OCT-2021 
 
 Approval: 
 
Name:  
 
Title:    
, Research Biostatistics 
 
 
Signature:
 
 
 
 
 
 
 
 
 
 
 
Date:  
 
 
 
 
 
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Title:    
 Scientist 
 
 
Signature: 
 
 
 
 
 
 
 
 
 
 
Date:  
 
 
 
 
 
 
Novo Nordisk Approval: 
 
Name:  
 
Title:  
 
 
 
 
Signature:
 
 
 
 
 
 
 
 
 
 
Date:  
 
 
 
 
 
Name:  
 
Title:   
 Innovative Trials 
 
 
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TABLE OF CONTENTS 
Signature Page for Statistical Analysis Plan .............................................................................. 2 
TABLE OF CONTENTS ............................................................................................................. 3 
1.0 
INTRODUCTION............................................................................................................. 5 
2.0 
STUDY OBJECTIVES ..................................................................................................... 5 
2.1 
Primary Objective ..................................................................................................................... 5 
2.2 
Secondary Objectives ................................................................................................................ 5 
2.3 
Estimands ................................................................................................................................... 6 
2.3.1 
Primary Estimand .................................................................................................................... 6 
2.3.2 
Secondary Estimand ................................................................................................................ 6 
3.0 
STATISTICAL METHODOLOGY................................................................................ 6 
3.1 
General Considerations ............................................................................................................. 6 
3.2 
Study Populations ...................................................................................................................... 7 
3.2.1 
Analysis Population ................................................................................................................ 7 
3.2.2 
Safety Population .................................................................................................................... 7 
3.3 
Evaluation Schedule and Definitions ....................................................................................... 7 
3.4 
Confirmatory Endpoints and Hypotheses ............................................................................... 8 
3.5 
Sample Size Estimation ............................................................................................................. 9 
3.5.1 
Power and Sample Size for Primary Objective ....................................................................... 9 
3.6 
Missing Data ............................................................................................................................. 11 
3.7 
Data Definitions and Calculations .......................................................................................... 11 
3.7.1 
General .................................................................................................................................. 11 
3.7.2 
Demographics ....................................................................................................................... 11 
3.7.3 
Diabetes History .................................................................................................................... 11 
3.7.4 
Treatment Variables .............................................................................................................. 11 
3.7.4.1 
Semaglutide Study Drug ................................................................................................... 12 
3.7.4.2 
Standard of Care (SOC) Study Drug ................................................................................ 12 
3.7.4.3 
Treatment Intensification, Change or Permanent Early Discontinuation ......................... 13 
3.7.5 
Measures of Glycemic Control ............................................................................................. 13 
3.7.6 
Weight ................................................................................................................................... 14 
3.7.7 
Adherence and Persistence to Treatment .............................................................................. 14 
3.7.8 
Patient Reported Outcomes (PROs) ...................................................................................... 14 
3.7.8.1 
Diabetes Treatment Satisfaction Questionnaire (DTSQ) .................................................. 14 
3.7.8.2 
Short Form 12-Item Version 2 (SF-12 v2) ....................................................................... 16 
3.7.8.3 
Work Productivity and Activity Impairment, General Health (WPAI-GH) ..................... 16 
3.7.8.4 
Patient Global Impressions of Disease Severity (PGI-S) and Change (PGI-C) ................ 17 
3.7.8.5 
Clinician Global Impressions of Disease Severity (CGI-S) and Change (CGI-C) ........... 18 
3.7.9 
Healthcare Resource Utilization (HCRU) ............................................................................. 18 
3.8 
Examination of Subgroups ..................................................................................................... 20 
4.0 
STATISTICAL ANALYSES ......................................................................................... 20 
4.1 
Overview ................................................................................................................................... 20 
4.2 
Patient Disposition and Accountability ................................................................................. 21 
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4.3 
Demographics and Baseline Clinical Characteristics ........................................................... 21 
4.4 
Protocol Deviations .................................................................................................................. 21 
4.5 
Missing Value Imputation Methodology ............................................................................... 21 
4.5.1 
Primary Estimand Imputation Model .................................................................................... 22 
4.5.2 
Secondary Estimand Imputation Model ................................................................................ 22 
4.6 
Effectiveness Analysis.............................................................................................................. 23 
4.6.1 
Statistical Analysis for the Primary Estimand ....................................................................... 23 
4.6.2 
Statistical Analysis for the Secondary Estimand ................................................................... 24 
4.6.3 
Additional Analyses of Glycemic Control ............................................................................ 24 
4.6.3.1 
Descriptive Summaries of HbA1c .................................................................................... 24 
4.6.3.2 
Supportive Analyses of Glycemic Control ....................................................................... 24 
4.6.4 
Supplementary Analyses ....................................................................................................... 25 
4.6.4.1 
Complete Case Analysis ................................................................................................... 25 
4.6.4.2 
Complete Case On-Study Drug Analysis ......................................................................... 26 
4.7 
PRO Analysis ........................................................................................................................... 26 
4.8 
Concomitant Medications ....................................................................................................... 27 
4.9 
Other Analyses ......................................................................................................................... 28 
4.9.1 
Weight Loss .......................................................................................................................... 28 
4.9.2 
Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) ................................... 28 
4.9.3 
Hypoglycemia ....................................................................................................................... 28 
4.9.4 
Healthcare Resource Utilization (HCRU) ............................................................................. 29 
4.9.5 
Composite Endpoints ............................................................................................................ 30 
4.9.6 
Antidiabetic Treatment Patterns ............................................................................................ 30 
4.9.6.1 
Study Drug Regimen ........................................................................................................ 30 
4.9.6.2 
Adherence and Persistence to Treatment .......................................................................... 31 
4.9.6.3 
Other Antidiabetic Treatments .......................................................................................... 31 
4.10 
Study Site Recruitment and Participation ............................................................................ 31 
4.11 
Evaluation of the Study Population ....................................................................................... 32 
5.0 
SAFETY ........................................................................................................................... 34 
5.1 
AEs ............................................................................................................................................ 34 
5.2 
SAEs .......................................................................................................................................... 34 
5.3 
Pregnancy ................................................................................................................................. 35 
5.4 
Analysis ..................................................................................................................................... 35 
6.0 
Changes from Protocol ................................................................................................... 35 
7.0 
SAP Change Log ............................................................................................................. 36 
8.0 
APPENDIX A: Study Endpoints and Other Variables by Data Source .................... 47 
9.0 
APPENDIX B: 2018 HEDIS Criteria ............................................................................ 53 
10.0 
REFERENCES ................................................................................................................ 54 
 
 
 
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1.0 INTRODUCTION 
This document describes the Statistical Analysis Plan (SAP) for Protocol Number NN9535-4416, 
Long term comparative effectiveness of once weekly semaglutide versus standard of care in a 
real world adult US population with type 2 diabetes – a randomized pragmatic clinical trial. This 
is a 2-year, multi-center, randomized, open label, parallel group, active comparator pragmatic 
clinical trial (PCT) comparing semaglutide s.c. versus standard of care (SOC) when added to up 
to 2 oral antidiabetic medications as treatment intensification among adult type 2 diabetes 
mellitus (T2DM) patients in the course of routine clinical practice. 
This SAP is based on the most recent version of the protocol: Version 4.0, December 5, 2019. 
Protocol History: 
Number 
Version 
Date 
1.0 
Original Protocol 
March 13, 2018 
2.0 
Version 2.0 
March 27, 2019 
3.0 
Version 3.0 
August 21, 2019 
4.0 
Version 4.0 
December 5, 2019 
 
2.0 STUDY OBJECTIVES 
2.1 Primary Objective 
The primary objective is to demonstrate superior long term effects of treatment with semaglutide 
s.c. compared to SOC each added to up to 2 oral antidiabetic medications on glycemic control 
when used as intensification in routine clinical practice in adult patients with T2DM.  
2.2 Secondary Objectives 
The secondary objectives are to compare the long term effect of semaglutide s.c. versus SOC 
each added to up to 2 oral antidiabetic medications and used as intensification in routine clinical 
practice in adult patients with T2DM with regards to: 
• Weight loss 
• Patient reported outcomes (PROs) and clinician reported outcomes (ClinROs) 
• Hypoglycemia  
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• Healthcare Resource Utilization (HCRU) 
• Adherence and persistence to treatment 
2.3 Estimands 
The estimand informs choices about data foundation and statistical analysis including possible 
imputation of missing data, hereby ensuring that randomization is preserved as a sound basis for 
statistical inference; i.e. estimation of effect size, associated uncertainty and statistical testing. 
Two estimands, each targeting a unique research question, have been defined to adequately 
describe the effect of semaglutide s.c. as compared to SOC (excluding any semaglutide). 
2.3.1 Primary Estimand 
The primary estimand for all objectives will be the “intention-to-treat” (ITT) estimand evaluating 
the effectiveness of randomized treatment intervention irrespective of adherence to this 
randomized intervention or changes to other antidiabetic medication. 
2.3.2 Secondary Estimand 
The secondary estimand for all objectives with the exception of the adherence and persistence to 
treatment objective, is the “if all patients had adhered” estimand. This estimand evaluates the 
effect of randomized treatment intervention for all randomized patients if all patients had 
adhered to randomized treatment, regardless of changes to other antidiabetic medication. 
 
3.0 STATISTICAL METHODOLOGY 
3.1 General Considerations 
Statistical analyses will be performed using SAS® version 9.4 or higher computer software.  
Analyses will utilize prospectively collected data from study sites as well as secondary data 
collection utilizing administrative claims data from the HealthCore Integrated Research Database 
(HIRD®). Data from both sources will be integrated into one dataset for analysis. 
Patient flow, patient characteristics, treatments, and outcomes will be tabulated and summarized 
with descriptive statistics based on observed values only. All descriptive data summaries will 
include means, medians, standard deviation (SD), and ranges for continuous variables and 
absolute/relative frequencies for categorical data. In addition, for each variable the number 
(count) of values that are missing will also be reported for dedicated study visit data. Missing 
data are data that are planned and can be collected but are absent. Statistics will be summarized 
for the study population overall and by treatment arm. Two sets of descriptive summaries will be 
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produced: one based on the primary estimand (ITT) and one based on the secondary estimand 
(“if all patients had adhered”). 
Raw data (i.e., minimum and maximum values presented for range in continuous variables) will 
be reported out to the precision with which it was collected. Means will be reported to 1 decimal 
place more than the raw data. SD will be reported to 1 decimal place more than the mean.  
Percentages will be reported to 1 decimal place. Trailing zeros will be presented to maintain a 
consistent level of precision, e.g. 2.0 rather than 2. 
Inferential tests will be performed at the 5% level of significance (two-sided).  All p-values will 
be rounded to 3 decimal places. If a rounded p-value is 0.000 (i.e., the actual p-value is less than 
0.0005), then the p-value will be presented as ‘p< 0.001.’ 
3.2 Study Populations 
3.2.1 Analysis Population 
The following analysis set will be defined: 
Full analysis set (FAS): Includes all randomized patients analyzed according to the treatment 
group to which they were assigned at randomization. 
3.2.2 Safety Population 
The safety population includes all randomized patients initiated on study drug analyzed 
according to the treatment group to which they received. 
3.3 Evaluation Schedule and Definitions 
Dedicated study visits are at randomization, at year 1, and at year 2. The study will also capture 
data collected at the sites during routine diabetic care visits, i.e., office visits and other patient 
contacts that occur as part of routine clinical practice. Routine diabetic care visits will occur per 
study physician’s routine clinical practice, therefore the number of visits and data available may 
differ from site to site and patient to patient. 
For analysis, baseline includes assessments conducted and patient data collected at or prior to 
randomization. Baseline is defined as ≤ 90 days prior to randomization visit (week 0) for HbA1c. 
For secondary endpoint assessments, baseline is defined as ≤ 4 weeks prior to the randomization 
visit (week 0). All baseline values will be derived from the last assessment taken prior to or at 
the randomization visit. 
The dedicated year 1 visit is at 52 weeks (±6 weeks) after randomization. Year 1 endpoint data 
will be derived from the dedicated year 1 study visit if the dedicated study visit is ±10 weeks of 
52 weeks post-randomization. If year 1 endpoint data is missing or outside of 52 ±10 weeks, then 
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the routine diabetic care data closest to 52 weeks post-randomization ±10 weeks will be used. If 
no routine diabetic care data are available 52 weeks post-randomization ±10 weeks, then year 1 
endpoint data will be considered missing and imputed as described in section 4.5, if applicable. 
The dedicated year 2/EOS visit is 104 weeks (±6 weeks) after randomization. Year 2 endpoint 
data will be derived from the dedicated year 2 study visit if the dedicated study visit is ±10 
weeks of 104 weeks post-randomization. If year 2 endpoint data is missing or outside of 104 ±10 
weeks, then the routine diabetic care data closest to 104 weeks post-randomization ±10 weeks 
will be used. If no routine diabetic care data are available 104 weeks post-randomization ±10 
weeks, then year 2 endpoint data will be considered missing and imputed as described in section 
4.5, if applicable. 
3.4 Confirmatory Endpoints and Hypotheses 
The primary endpoint is HbA1c <7.0% (53 mmol/mol) at year 1 (yes/no).  
Confirmatory secondary endpoints include:  
• Change in HbA1c (%-point) from baseline to year 1 
• HbA1c <7.0% (53 mmol/mol) at year 2 (yes/no) 
• Change in HbA1c (%-point) from baseline to year 2 
This study is designed to have 90% power to confirm superiority of semaglutide s.c. versus SOC 
on  the primary endpoint and 85% power to also confirm superiority of the first confirmatory 
secondary endpoint based on primary estimand analyses. The primary and confirmatory 
secondary endpoints will all be tested for superiority of semaglutide under multiplicity control 
via a hierarchical testing scheme according to the order given in the above bullet list. 
Confirmatory testing will only be performed for the primary estimand with the secondary 
estimand being supportive. The testing procedure will be stopped the first time an analysis fails 
to confirm superiority of semaglutide for the endpoint in question using a two-sided significance 
level of 5%. 
Superiority on HbA1c <7.0% at year 1 and at year 2 will be evaluated with respect to the odds 
ratio (OR) (odds semaglutide / odds SOC): 
H0: OR≤1 against Ha: OR>1 
Superiority on change in HbA1c (year 1 – baseline; year 2 – baseline) will be evaluated with 
respect to the mean treatment difference (TD) (semaglutide – SOC):  
H0: TD≥0 against Ha: TD<0 
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Statistical analysis of all other endpoints will be unadjusted for multiplicity. 
3.5 Sample Size Estimation 
3.5.1 Power and Sample Size for Primary Objective 
Assumptions for the sample size were based on input from the HIRD claims/laboratory results 
database. In line with the primary ITT estimand, the assumptions for the proportion of patients 
with HbA1c < 7.0% at year 1 and year 2, and for the change from baseline in HbA1c are based 
on the claims/laboratory results data within the 
 population for all patients initiating 
treatment intensification regardless of whether patients adhered to this treatment. Specifically, 
for semaglutide s.c., assumptions are based on data for liraglutide and dulaglutide. For SOC, 
assumptions are based on all intensifications in the claims database. The data from the claims 
database are shown in Table 3-1. Because the baseline HbA1c was higher in the all 
intensifications population compared to the liraglutide and dulaglutide groups, the assumptions 
used for the sample size calculation were adjusted accordingly. 
Table 3-1: HbAlc Change Data from 
 Population via HealthCore Integrated 
Research Database on Patients Intensifying Diabetes Treatment after Metformin 
Follow-
up 
Treatment 
intensification 
after 
metformin 
Number 
of 
patients 
with 
HbA1c 
Follow-
up data 
Proportion 
Patients 
Hba1c 
<7% at 
Follow-up 
Number 
of 
patients 
with 
Baseline 
and 
Follow-up 
HbA1c 
data 
HbA1c (%) 
Baseline 
mean 
HbA1c (%) 
Change from 
Baseline 
mean SD 
1y 
All 
intensifications 
6,522 
47% 
4,068 
8.9 
-1.54 
2.3 
dulaglutide 
411 
62% 
115 
8.6 
-1.47 
2.2 
liraglutide 
1,762 
62% 
394 
8.4 
-1.34 
2.0 
 2y 
All 
intensifications 
4,047 
49% 
2,401 
8.9 
-1.42 
2.3 
dulaglutide 
32 
71% 
≤10 
8.8 
-1.35 
1.2 
liraglutide 
893 
55% 
217 
8.6 
-1.24 
2.1 
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Source: Data from the HealthCore Integrated Research Database. Data on file. 
 
Table 3-2 presents several sample size scenarios together with assumptions and calculated 
power. The sample size calculation aimed for 90% power for confirming superiority of 
semaglutide s.c. versus SOC on the primary endpoint and 85% power to also confirm superiority 
of the first confirmatory secondary endpoint based on an analysis of the primary estimand for 
each of the endpoints. For the sample size calculation the likelihood ratio chi-square test was 
assumed for analyses of the binary presence of HbA1c < 7.0% endpoints and a t-test for the 
continuous change in HbA1c endpoints. An overall alpha level of 5% with two-sided tests was 
assumed. 
Table 3-2 Assumptions used in the sample size and calculated total power. 
Total 
Number 
Randomized 
Proportion Patients with 
HbA1c <7% at 1 and 2 Years HbA1c ETD 
at 1 and 2 
years 
HbA1c 
change SD 
Power 
total 
SOC 
Semaglutide 
1849 
50% 
60% 
0.5 
2.3 
80% 
2250 
50% 
58% 
0.5 
2.3 
72% 
2250 
50% 
60% 
0.5 
2.3 
90% 
2250 
50% 
60% 
0.5 
2.0 
93% 
2250 
50% 
60% 
0.4 
2.3 
77% 
ETD = Estimated Treatment Difference, SD=Standard Deviation 
Bold marked numbers indicate the chosen assumptions and numbers marked in underline indicate variations 
The proportion of missing data for the confirmatory endpoints was estimated to be 25% after one 
year and 44% after two years. In the sample size calculation, it was assumed that only non-
missing data at year 1 and year 2 would be used for the respective analyses. This is considered 
conservative, since the use of imputed data in the actual primary analysis (see 4.5) will increase 
the power. When accounting for missing data, randomizing 1387 patients will contribute 1040 
patients for the year 1 analyses and 780 patients for the year 2 analyses, achieving a total power 
of 85% for confirming the two year 1 confirmatory hypotheses.  The joint power for confirming 
all 4 confirmatory hypotheses is 58%. The corresponding marginal powers for presence of 
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HbA1c < 7.0% at year 1, change in HbA1c to 1 year, presence of HbA1c < 7.0% at year 2, and 
change in HbA1c to 2 years are 90%, 94%, 80% and 86% respectively. 
3.6 Missing Data 
Except where noted in section 4.5 for HbA1c, weight, systolic blood pressure (SBP), and 
diastolic blood pressure (DBP) endpoints, missing data will not be imputed and will be excluded 
from calculations. 
3.7 Data Definitions and Calculations 
3.7.1 General 
All absolute change from baseline variables will be calculated as: 
Change = Endpoint Visit – Baseline 
All relative change from baseline variables will be calculated as: 
Relative Change (%) = [(Endpoint Visit – Baseline)/Baseline] x 100 
If day and/or month is missing from dates, the first day of the month and/or the first month of the 
year will be assumed when calculating duration between dates. If imputation of an incomplete 
date associated with a post-randomization data element results in a date prior to randomization, 
the first day of the month immediately following randomization will be assumed. E.g., if the 
randomization date is 08/15/18 (mm/dd/yy) and the unknown date is 08/UNK/18 or UNK/10/18 
or UNK/UNK/18, the imputed date would be 09/01/18. 
The data sources for each endpoint and variables used in analysis are summarized in Appendix 
A. 
3.7.2 Demographics 
Age will be presented in years based on the patient’s birth date and randomization visit date. 
3.7.3 Diabetes History 
Duration of diabetes will be presented in years based on the patient’s diagnosis date and 
randomization visit date. 
3.7.4 Treatment Variables 
Study drug is defined as the first antidiabetic oral or injectable medication prescribed for 
treatment intensification following randomization. A patient can start and stop study drug 
throughout the study. At any time during the duration of the study, if a patient is taking study 
drug as defined, they will be considered “on study drug” regardless of prior study drug 
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discontinuations. At any time during the duration of the study, if a patient is not taking study 
drug as defined, they will be considered “off study drug.” On and off study drug classification 
will be based on the eCRF data. 
The first study drug discontinuation date will be defined as the date of the first time a patient 
discontinues study drug such that they are “off study drug.” 
For analysis of year 1 and year 2 endpoints, patients will be categorized as “on study drug” or 
“off study drug” according to their study drug use at the endpoint visit, regardless of prior 
use/non-use. If study drug status is missing for the year 1 or year 2 endpoint, the last registered 
study drug status prior to the endpoint visit will be used. 
3.7.4.1 
Semaglutide Study Drug 
For the semaglutide treatment group, study drug is defined as semaglutide s.c.. Therefore at any 
time during the study, patients randomized to the semaglutide group will be categorized as: 
On Study Drug: Taking Semaglutide s.c. (regardless of any other antidiabetic medication 
use or previous discontinuations) 
Off Study Drug: Not currently taking Semaglutide s.c. 
The following definitions will also apply to individual patient semaglutide s.c. dosing during the 
2 year study period, or until time of study drug discontinuation: 
Most Common: The dose associated with the longest period of use from randomization to 
year 2/EOS visit. 
Highest: The highest dose reported at any time from randomization to year 2/EOS visit. 
Final: The latest dose reported from randomization to year 2/EOS visit. 
3.7.4.2 
Standard of Care (SOC) Study Drug 
For the SOC treatment group, study drug is defined as the drug class of the first antidiabetic oral 
or injectable medication prescribed for treatment intensification following randomization 
(excluding any formulation of semaglutide). If a fixed dose combination (FDC) product is 
prescribed, one of the drugs will be specified by the study physician to be the study drug and 
on/off drug categorization will be based on the study physician specified drug only. Therefore, at 
any time during the study, patients randomized to the SOC treatment group will be categorized 
as: 
On Study Drug: Taking a drug in the same drug class as their first study drug, even if it is 
not the same individual drug (regardless of any other antidiabetic medication use or 
previous discontinuations except semaglutide). This also applies to treatment 
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intensification with a FDC product if one of the drugs is in the same drug class as the first 
study drug. 
Off Study Drug: Not currently taking a drug in the same drug class as their first study 
drug. 
3.7.4.3 
Treatment Intensification, Change or Permanent Early 
Discontinuation 
Treatment intensification (add-on), change (switch) in study drug, or permanent early 
discontinuation after randomization will be identified and categorized. 
Treatment intensification is defined as initiation of an antidiabetic medication (besides the up to 
2 oral antidiabetic medication(s) taken prior to randomization) in addition to study drug, or 
initiation of more than one antidiabetic medication after discontinuation of study drug. 
The first treatment intensification date will be defined as the date of the first occurrence of an 
antidiabetic treatment intensification. 
Treatment change is defined as discontinuation of study drug and initiation of another 
antidiabetic medication (besides the up to 2 oral antidiabetic medication(s) taken prior to 
randomization). 
The first treatment change date will be defined as the date of the first occurrence of an 
antidiabetic treatment change. 
Permanent early treatment discontinuation is defined as discontinuation of study drug as 
described in section 3.7.4 and no initiation of another antidiabetic medication (besides the up to 2 
oral antidiabetic medication(s) taken prior to randomization) for the remainder of the subject’s 
time in study. 
3.7.5 Measures of Glycemic Control 
Physicians will set a patient’s individualized HbA1c target prior to randomization. Achieving 
target at year 1 and year 2 is defined as: 
Endpoint Visit HbA1c ≤ Individualized HbA1c target 
Attainment of the 2018 Healthcare Effectiveness Data and Information Set (HEDIS) HbA1c will 
be defined at year 1 and year 2 as: 
HbA1c <8.0% if age ≥ 65 years at endpoint visit or with defined comorbidities 
(Appendix B), else <7.0% 
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HbA1c data for the HEDIS endpoints will be obtained from the eCRF. HEDIS 
comorbidities as defined in Appendix B will be obtained from the claims data and apply 
to the year prior to endpoint. HEDIS criteria at year 1 will be based on comorbidities 
identified between the randomization and year 1 visit. HEDIS criteria at year 2 will be 
based on comorbidities identified between the year 1 and year 2 visits. 
3.7.6 Weight 
No weight gain is defined as: Endpoint Visit Weight ≤ Baseline Weight 
3.7.7 Adherence and Persistence to Treatment 
Medication adherence refers to a patient’s conformance to the provider’s recommendation with 
respect to timing, dosage, and frequency of medication taken during the prescribed length of 
time. 
For this study, the medication possession ratio (MPR) will be used to assess adherence. MPR 
will be calculated for the study drug from claims data for baseline to year 1 and for baseline to 
year 2 as follows: 
MPR (%) = Sum of days supply for all prescription fills x 100 
Total number of days in time period 
 
MPR will be capped at 100%. 
Medication persistence refers to whether a patient stays on therapy or the time from initiation to 
discontinuation of therapy. Medication persistence will be assessed from baseline to year 2. 
For this study, medication persistence will be defined as duration of time in days from initiation 
of study drug to first study drug discontinuation from eCRF data as defined in section 3.7.4. 
A second persistence measure will be defined as duration of time in days from the date of 
initiation of study drug to the date of the first intensification or change in study drug as defined 
in section 3.7.4.3 or study drug discontinuation as defined in section 3.7.4, whichever occurs 
first. 
3.7.8 Patient Reported Outcomes (PROs) 
3.7.8.1 
Diabetes Treatment Satisfaction Questionnaire (DTSQ) 
The Diabetes Treatment Satisfaction Questionnaire (DTSQ) is a validated instrument that is 
widely used in clinical trials and for routine clinical monitoring. It is useful in assessing 
outcomes of diabetes care. [1] The questionnaire consists of eight items -- six items assess 
treatment satisfaction, where each item is scored on a scale of 0–6, with six representing the 
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greatest satisfaction, and two items assess the perceived frequency of hyperglycemia and 
hypoglycemia, also scored on a scale of 0-6, where “0” corresponds to none of the time and “6” 
corresponds to most of the time. 
The original DTSQ is now referred to as the status version (DTSQs) in order to distinguish it 
from the DTSQ change version (DTSQc), which was developed to overcome potential ceiling 
effects (i.e. where respondents score maximum or near-maximum satisfaction at baseline and can 
show little or no improvement at follow-up). [2] This study will use the DTSQs at randomization 
and the DTSQc at the dedicated year 1 and year 2 study visits. 
Scoring the DTSQs  
The DTSQs has 8 items and produces the following measures:  
1. Treatment Satisfaction: Items 1, 4, 5, 6, 7 & 8 are summed to produce a Treatment 
Satisfaction score (range: 0 to 36). The higher the score, the greater the satisfaction with 
treatment.  
2. Individual satisfaction with treatment items (items 1, 4, 5, 6, 7 & 8) can be considered 
separately: All rated: 6 (very satisfied, convenient, flexible, etc.) to 0 (very dissatisfied, 
inconvenient, inflexible, etc.). The higher the score, the greater the satisfaction with each 
aspect of treatment.  
3. 'Perceived frequency of hyperglycemia' (item 2) & 'Perceived frequency of hypoglycemia' 
(item 3): Both rated: 6 (‘most of the time’) to 0 (‘none of the time’). Here, lower scores 
indicate blood glucose levels closer to the ideal. Higher scores indicate problems. 
Scoring the DTSQc  
The change version has the same 8 items as the status version, with a small alteration to the 
wording of Item 7. The DTSQc instructions and response options differ from those of the DTSQs 
and produce measures of relative change in satisfaction rather than measures of absolute 
satisfaction. 
1. Treatment Satisfaction (Change):  Items 1, 4, 5, 6, 7 and 8 are summed to produce a 
Treatment Satisfaction (change) score (range: +18 to –18). The higher the score, the greater 
the improvement in satisfaction with treatment; the lower the score, the greater the 
deterioration in satisfaction with treatment. A score of 0 represents no change.  
2. Individual satisfaction with treatment change items (items 1, 4, 5, 6, 7 and 8) can be 
considered separately: All rated: +3 ('much more satisfied', 'much more convenient', ‘much 
more flexible', etc.) to –3 ('much less satisfied', 'much less convenient', 'much less flexible', 
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etc.). The higher the score, the greater the improvement in satisfaction with each aspect of 
treatment and the lower the score, the greater the deterioration in satisfaction with each 
aspect of treatment.  
3. Two remaining items ('Perceived change in frequency of hyperglycemia' (item 2) and 
'Perceived change in frequency of hypoglycemia' (item 3)) are treated individually: Both 
rated: +3 (‘much more of the time now’) to –3 (‘much less of the time now’). Here, negative 
scores indicate fewer problems with blood glucose levels. Positive scores indicate more 
problems than before. 
3.7.8.2 
Short Form 12-Item Version 2 (SF-12 v2) 
The Short Form 12-item Version 2 (SF-12v2) is a generic health-related quality of live (HRQoL) 
measure that consists of 12 items from the Short Form 36-Item (SF-36) health survey and 
measures physical and mental dimensions of health. [3] Eight subscale scores (physical 
functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional, 
and mental health) and two summary scores (physical component summary (PCS) and mental 
component summary (MCS)) can be obtained using the proprietary scoring software provided by 
Optum. Scores are calculated as norm-based standardized scores ranging from 0 to 100 with 
means of 50 and SDs of 10, where a score of “0” indicates the lowest level of health measured by 
the scales, “100” indicates the highest level of health, and “50” indicates the mean or norm-score 
for the general US population. [4] 
For this study, the PCS-12 and MCS-12 summary scores will be used. The PCS-12 and MCS-12 
will be calculated at baseline, year 1, and year 2. Change from baseline will be calculated for the 
PCS-12 and MCS-12 at year 1 and year 2. 
3.7.8.3 
Work Productivity and Activity Impairment, General 
Health (WPAI-GH) 
The Work Productivity and Activity Impairment (WPAI) questionnaire is a 6-item instrument 
that measures absenteeism (work time missed), presenteeism (impairment at work / reduced on-
the-job effectiveness), work productivity loss (overall work impairment / absenteeism plus 
presenteeism), and activity impairment because of health problems in the past seven days. [5]  
There are two versions of the WPAI. In the general health version (WPAI:GH) individuals are 
asked questions about work and activity impairment due to health problems. In the specific 
health problem version (WPAI:SHP), individuals are asked questions concerning impairment 
due to a target health problem (e.g., arthritis). This study will use the general health version of 
the WPAI (WPAI:GH), per general guidelines from the website that indicate the general health 
version is more appropriate for a disease like diabetes. 
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WPAI:GH Scoring Information 
General Information: 
In general, WPAI outcomes are expressed as impairment percentages, with higher numbers 
indicating greater impairment and less productivity, i.e., worse outcomes. The recall period is the 
past seven days, excluding the current day. 
Questions: 
Q1 = currently employed (Yes=works full-/part-time; self-employed; works in family business; 
on vacation from paid employment/No=does not work for pay; only does volunteer work; 
usually works, but has been laid-off or unemployed during the past seven days; retired; seasonal 
workers not currently working) 
Q2 = hours missed due to health problems 
Q3 = hours missed for other reasons 
Q4 = hours actually worked 
Q5 = degree health affected productivity while working 
Q6 = degree health affected regular activities 
Scores: 
Multiply scores by 100 to express in percentages 
1. Percent work time missed due to health (Absenteeism): Q2/(Q2 + Q4) 
2. Percent impairment while working due to health (Presenteeism): Q5 /10 
3. Percent overall work impairment due to health (Work Productivity Loss): Q2/(Q2 + Q4) + 
[(1 – (Q2/(Q2 + Q4))) x (Q5/10)] 
4. Percent activity impairment due to health (Activity Impairment): Q6/10 
Absenteeism, presenteeism, work productivity loss, and activity impairment will be calculated at 
baseline, year 1, and year 2. Change from baseline will be calculated for each score at year 1 and 
year 2. 
3.7.8.4 
Patient Global Impressions of Disease Severity (PGI-S) and 
Change (PGI-C) 
The patient global impression of disease severity (PGI-S) is a single item that the patient will 
complete at the baseline randomization visit that assesses the patient’s perception of the severity 
of their diabetes at the time of the randomization visit. The patient global assessment of change 
(PGI-C) is a single item that the patient will complete at the dedicated year 1 and year 2 study 
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visits that assesses their perception of their current disease status relative to the way it was before 
they started the study drug. 
3.7.8.5 
Clinician Global Impressions of Disease Severity (CGI-S) 
and Change (CGI-C) 
The clinician global impression of disease severity (CGI-S) is a single item that the clinician will 
complete after the patient’s baseline randomization visit that assesses the clinician’s perception 
of the patient’s severity of their diabetes at the randomization visit. The clinician global 
assessment of change (CGI-C) is a single item that the clinician will complete at the patient’s 
dedicated year 1 and year 2 study visits that assesses the clinician’s perception of the patient’s 
current disease status relative to the way it was before they started the study drug. 
3.7.9 Healthcare Resource Utilization (HCRU) 
All-cause and T2DM-related HCRU will be defined from baseline to year 2. These data will 
come from the HIRD for 
 patients or requested from a set of other health insurers for 
non-
 patients. HCRU will include inpatient admissions, ER encounters, physician office 
visits (OV), other outpatient encounters, and pharmacy prescription fills. 
All medical claims (inpatient admissions, ER visits, physician OVs, or other outpatient 
encounters) will be included in the “all-cause” analysis. All pharmacy claims will be included in 
the “all-cause” HCRU. Inpatient admissions, ER visits, physician OVs, or other outpatient 
encounters will be considered to be “T2DM-related” if the associated medical claim(s) has an 
International Classification of Diseases, Tenth Revision (ICD-10) T2DM diagnosis code of 
E11.% in the primary position or secondary position. Pharmacy claims for antidiabetic 
medications will be included in the “T2DM-related” HCRU. 
• All-cause inpatient admission is defined by a claim or claims with inpatient place of 
service. Facility and provider claims are rolled into episodes with unique admission 
and discharge dates. ER visit claims on one day that are directly followed by an 
inpatient admission are considered as one inpatient admission and all HCRU from the 
encounter is combined. 
• T2MD-related inpatient admission is defined by a claim or claims with inpatient place 
of service and primary or secondary diagnosis of T2DM. Facility and provider claims 
are rolled into episodes with unique admission and discharge dates. ER visit claims 
on one day that are directly followed by an inpatient admission with a primary or 
secondary diagnosis of T2DM (regardless of the diagnoses associated with the ER 
visit claim) are considered as one T2MD-related inpatient admission and all HCRU 
from the encounter is combined. 
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• All-cause ER visit is defined by a medical claim with ER place of service. 
• T2DM-related ER visit is defined by a medical claim with ER place of service and 
primary or secondary diagnosis of T2DM. 
• All-cause outpatient physician OV is defined by a medical claim with outpatient place 
of service and an evaluation and management (E&M) code that indicates physician 
OV. 
• T2DM-related outpatient physician OV is defined by a medical claim with outpatient 
place of service and an E&M code that indicates physician OV with a primary or 
secondary diagnosis of T2DM. 
• All-cause other outpatient service is defined by a medical claim with outpatient place 
of service and code other than E&M, overall and by the following categories: 
o Tests – Lab 
o Imaging 
o Procedures 
o Occupational Therapy (OT)/Speech 
o Medication and Related Services 
o Durable Medical Equipment 
o Physician Other Services 
o Tests – Other 
o Other 
• T2DM-related other outpatient service is defined by a medical claim with outpatient 
place of service, with a primary or secondary diagnosis of T2DM, and code other than 
E&M, overall and by the following categories: 
o Tests – Lab 
o Imaging 
o Procedures 
o OT/Speech 
o Medication and Related Services 
o Durable Medical Equipment 
o Physician Other Services 
o Tests – Other 
o Other 
• All-cause pharmacy prescription fill is defined by a pharmacy claim. 
• T2DM-related pharmacy prescription fill is defined by a pharmacy claim for an 
antidiabetic medication. 
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The length of stay (LOS) for individual all-cause and T2DM-related inpatient admissions is 
defined as: 
LOS (days) = Discharge Date – Admission Date 
The cumulative LOS will be the sum of all all-cause inpatient admissions and all T2DM-related 
inpatient admissions a patient experiences from baseline to year 2. 
3.8 Examination of Subgroups 
Data will be presented overall and by treatment group. Subgroup analyses under the primary 
estimand (ITT) of the primary endpoint and of the first confirmatory secondary endpoint (change 
in HbA1c from baseline to year 1) will be conducted on the following subgroups: 
• Age (<55 years versus ≥55 years) 
• Gender 
• Baseline HbA1c (<8.0% versus ≥8.0%) 
• Baseline body mass index (BMI) (<30 kg/m2, ≥30 kg/m2) 
• Duration of T2DM diagnosis at baseline (<5 years versus ≥5 years) 
Analysis of each subgroup will be based on a logistic regression model with logit link function 
for the primary endpoint and an ANCOVA model for the first confirmatory secondary endpoint.  
Models will also include treatment and subgroup as categorical effects, baseline HbA1c as 
covariate, and an interaction term composed of treatment and subgroup.   
 
Additionally, analysis of the above subgroups will be repeated for the treatment adherence and 
persistence endpoints using the FAS and an ANCOVA model for the adherence measures and a 
Cox proportional hazards model for the persistence measures.  Models will also include 
treatment and subgroup as categorical effects, and an interaction term composed of treatment and 
subgroup.  
 
For all interaction models, the estimated treatment effect for semaglutide s.c. versus SOC and 
95% confidence interval within each subgroup level and the p-value for the interaction term will 
be presented from each model.   
 
4.0 STATISTICAL ANALYSES 
4.1 Overview 
The primary analysis for this study is a year 1 analysis. Once data collection for year 1 has 
completed, a database lock and year 1 analysis will be performed. The year 1 analysis will not be 
integrated with HCRU and will be limited to year 1 endpoints derived from eCRF data, including 
PRO data. The year 1 analysis results will be presented in a clinical study report and an internal 
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results meeting. To maintain study integrity for the remaining study period, data from year 1 will 
be used for limited and confidential communications while complying with public disclosure 
requirements. All other analyses will be conducted following a second database lock once data 
collection for the entire study is complete. 
No changes to the study design will be made based on the results of the year 1 analysis.  
4.2 Patient Disposition and Accountability 
Patient disposition will be descriptively summarized for all randomized patients, including the 
number and percentage patients in the FAS and safety populations, patients who complete the 
dedicated year 2 study visit, and the primary reason for not completing the dedicated year 2 
study visit for patients who terminated participation in the study early. Summary metrics for 
number of screen failures by study site will also be presented. 
4.3 Demographics and Baseline Clinical Characteristics 
Demographic and baseline clinical characteristics will be descriptively summarized for the FAS 
overall and by treatment group. For baseline comorbid conditions, the number and percentage of 
patients with at least one of the comorbid conditions collected in the study will also be 
summarized along with the relative frequencies of type of comorbid condition. The same 
approach will be followed for concomitant cardiovascular medications. In addition to eCRF data, 
type of insurance at randomization (obtained from claims) and geographic region (from study 
site location) will be summarized. 
4.4 Protocol Deviations 
Major protocol deviations will be summarized by type (informed consent, randomization error, 
inclusion/exclusion criteria error, unreported serious adverse events (SAEs), procedure not per 
protocol, study visit not per protocol, other). 
4.5 Missing Value Imputation Methodology 
Missing endpoint data will be imputed for HbA1c, weight, SBP, and DBP. The data of patients 
who, in violation of the protocol, initiate any formulation of semaglutide in the SOC treatment 
group, will be censored analytically following initiation of semaglutide. The patient will remain 
in the analysis, but data following their initiation of semaglutide will be censored and treated as 
missing. 
Prior to analysis of binary endpoints derived by dichotomizing HbA1c and body weight, missing 
data will be imputed by multiple imputation on the continuous scale and dichotomized as 
required for the endpoint. 500 complete data sets will be generated to adequately account for the 
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uncertainty due to missing data. 
4.5.1 Primary Estimand Imputation Model 
Missing value imputation for the primary estimand will be based on data from all patients with 
observations at the endpoint visit (year 1 for the primary endpoint). Missing endpoint data will 
be imputed separately by treatment group and based on similar patients with available endpoint 
data according to study drug treatment status, i.e., according to whether these patients are on or 
off study drug at the endpoint visit, resulting in four separate imputation models. Data will be 
imputed based on the assumption that, within treatment groups, patients with missing endpoint 
data will behave like patients with the same study drug treatment status at endpoint as the 
missing patients’ last registered treatment status prior to the missing endpoint. For example, for 
patients with missing data who have discontinued treatment with study drug, data will be 
imputed based on the assumption that these patients will behave like patients with available data 
who are no longer receiving study drug. 
Technically, the imputation model will be an analysis of covariance (ANCOVA) for the endpoint 
data. The ANCOVA will include the baseline value of the imputed variable (HbA1c, weight, 
SBP, or DBP), diabetes duration, age, and sex as independent variables. After this model has 
been used to predict missing values, each of the now 500 complete data sets will be analyzed as 
described for the primary analysis in section 4.6.1. Finally, the multiple analysis results will be 
combined using Rubin’s rule. [6] For the OR, the results will be combined on the logarithm 
scale. 
This process will be repeated for year 2 endpoints.   
4.5.2 Secondary Estimand Imputation Model 
Missing value imputation for the secondary estimand will be based only on data from the subset 
of patients who are receiving study drug (on study drug) at the endpoint visit (year 1 for the 
primary endpoint) in order to estimate the treatment effect if all patients had continued treatment. 
The endpoint data of patients who are not receiving study drug at the endpoint visit (off study 
drug) will be censored analytically and imputed together with missing data. Collectively, missing 
and censored data will be imputed separately by treatment group based on all patients who are on 
study drug at the endpoint visit. Data will be imputed based on the assumption that patients with 
missing data will behave like patients with available data who are on study drug. 
The technical aspects of missing data imputation based on multiple imputation, the statistical 
analysis of the multiple complete data sets, and combination of the multiple results will be the 
same as the ones described for the primary estimand. 
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This process will be repeated for year 2 endpoints.  
4.6 Effectiveness Analysis 
4.6.1 Statistical Analysis for the Primary Estimand 
The primary effectiveness analysis is the primary estimand of the primary endpoint, HbA1c 
<7.0% at year 1, and confirmatory secondary endpoints of change in HbA1c (%-point) from 
baseline to year 1, HbA1c <7.0% at year 2, and change in HbA1c (%-point) at year 2. This 
analysis will be based on the FAS with missing data imputation as described in the primary 
estimand imputation model. 
Year 1 Analysis 
The primary endpoint, HbA1c < 7.0% at year 1, will be analyzed with a logistic regression 
model with a logit link function, treatment as a categorical effect, and baseline HbA1c as 
covariate. From the model the estimated OR (semaglutide s.c. versus SOC) will be presented. 
The confirmatory secondary continuous endpoint of change in HbA1c (%-point) at year 1 will be 
analyzed using ANCOVA that will include the treatment and baseline HbA1c as independent 
variables. From the model, the estimated mean difference in change from baseline to endpoint 
visit (semaglutide s.c. versus SOC) will be presented. 
The estimated treatment effect from each of these analyses will be complemented with 
associated 95% CI and two-sided p-value for testing the null-hypothesis of no difference.  
Superiority for the primary endpoint, HbA1c <7.0% at year 1, will be considered established if 
the OR 95% confidence interval (CI) is greater than 1, or similarly if the two-sided p-value is 
significant on a 5% level and the treatment OR is in favor of semaglutide. 
If the hierarchical testing scheme allows, superiority for change in HbA1c from baseline to 
endpoint visit will be considered established if the 95% CI for the estimated treatment difference 
is smaller than 0, or similarly if the two-sided p-value is significant on a 5% level and the 
treatment difference is in favor of semaglutide. 
Year 2 Analysis 
The Year 1 analysis described above will be repeated for the confirmatory secondary endpoints 
of HbA1c <7.0% at year 2 and change in HbA1c (%-point) at year 2. If the hierarchical testing 
scheme allows, superiority will be tested first for HbA1c <7.0% at year 2 followed by change in 
HbA1c (%-point) at year 2 as described for the year 1 counterparts above. 
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4.6.2 Statistical Analysis for the Secondary Estimand 
The primary effectiveness analysis will be repeated with the secondary estimand. This analysis 
will be based on the FAS with missing data imputation as described in the secondary estimand 
imputation model. With the exception of the data used and the imputation of missing data, which 
follows the secondary estimand, the statistical analysis is the same as the primary effectiveness 
analysis.  
The binary endpoints of HbA1c <7.0% at endpoint visit will be analyzed with a logistic 
regression model with a logit link function, treatment as a categorical effect, and baseline HbA1c 
as covariate. From the model the estimated OR (semaglutide s.c. versus SOC) and 95% CI will 
be presented. 
The continuous endpoints of change in HbA1c (%-point) from baseline to endpoint visit will be 
analyzed using ANCOVA with treatment and baseline HbA1c as independent variables. From 
the model, the estimated mean difference in change from baseline to endpoint visit (semaglutide 
s.c. versus SOC) will be presented along with associated 95% CI. 
4.6.3 Additional Analyses of Glycemic Control 
4.6.3.1 
Descriptive Summaries of HbA1c 
Observed HbA1c values will be descriptively summarized at baseline, year 1, and year 2. 
Additionally, the following categories of observed HbA1c will be descriptively summarized at 
baseline, year 1, and year 2: 
• <7.0, 7.0-<7.5, 7.5-<8.0, 8.0-<8.5, 8.5-<9.0, and ≥9.0% 
• <8.0 versus ≥8.0% 
• <9.0 versus ≥9.0% 
4.6.3.2 
Supportive Analyses of Glycemic Control 
The following supportive endpoints of glycemic control are binary endpoints. These analyses 
will compare the proportion of patients achieving the secondary endpoints related to glycemic 
control between semaglutide and SOC treatment arms via a logistic regression model with a logit 
link function, treatment as a categorical effect, and baseline HbA1c as covariate. From the model 
the estimated OR (semaglutide s.c. versus SOC) will be presented. 
• Individualized HbA1c target attained at year 1 (yes/no) 
• HbA1c <7.0% (53mmol/mol) or at least 1% point improvement in HbA1c compared to 
baseline at year 1 (yes/no) 
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• HbA1c target attainment per Healthcare Effectiveness Data and Information Set (HEDIS) 
criteria (<8.0% if age ≥65 years or with defined comorbidities, otherwise <7.0%) at year 1 
(yes/no) 
• Individualized HbA1c target attained at year 2 (yes/no) 
• HbA1c <7.0% (53 mmol/mol) or at least 1% point improvement in HbA1c compared to 
baseline at year 2 (yes/no) 
• HbA1c <8.0% (64 mmol/mol) at year 1 (yes/no) 
• HbA1c <8.0% (64 mmol/mol) at year 2 (yes/no)  
• HbA1c <7.0% (53 mmol/mol) and no further antidiabetic medication intensification after 
randomization at year 1 (yes/no) 
• HbA1c <7.0% (53 mmol/mol) and no further antidiabetic medication intensification after 
randomization at year 2 (yes/no) 
• HbA1c target attainment per HEDIS criteria (<8.0% if age ≥65 years or with defined 
comorbidities, otherwise <7.0%) at year 2 (yes/no) 
• HbA1c <7.0% (53 mmol/mol) at year 1 in patients with HbA1c >9.0% at baseline (yes/no) 
• HbA1c <7.0% (53 mmol/mol) at year 2 in patients with HbA1c >9.0% at baseline (yes/no) 
• HbA1c <8.0% (64 mmol/mol) at year 1 in patients with HbA1c >9.0% at baseline (yes/no) 
• HbA1c <8.0% (64 mmol/mol) at year 2 in patients with HbA1c >9.0% at baseline (yes/no) 
4.6.4 Supplementary Analyses 
The HbA1c analyses described for the primary and secondary effectiveness analyses described 
above will be complemented with two complete case analyses based on the subset of patients 
without missing endpoint data, i.e., patients that do not have their endpoint imputed in the two 
analyses used for the primary and secondary estimand.  
4.6.4.1 
Complete Case Analysis 
This analysis will be based only on patients with available measurements at the dedicated study 
visit including measurements irrespective of whether patients discontinued study drug or not. 
The binary endpoints of HbA1c < 7.0% at year 1 and HbA1c < 7.0% at year 2 will be analyzed 
with a logistic regression model with a logit link function, treatment as a categorical effect, and 
baseline HbA1c as covariate. From the model the estimated OR (semaglutide s.c. versus SOC) 
will be presented  along with associated 95% CI. 
The continuous endpoints of change in HbA1c (%-point) at year 1 and change in HbA1c (%-
point) at year 2 will be analyzed using ANCOVA with treatment and baseline HbA1c as 
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independent variables. From the model, the estimated mean difference in change from baseline 
to endpoint visit (semaglutide s.c. versus SOC) will be presented  along with associated 95% CI. 
4.6.4.2 
Complete Case On-Study Drug Analysis 
The analysis will be based only on patients with available measurements at the dedicated study 
visit including only measurements for patients still on study drug. Patients who discontinue study 
drug will be censored and missing data will not be imputed. The analysis will use the same 
analysis models as described for complete case analysis above. 
4.7 PRO Analysis 
PROs and ClinROs will be measured with the instruments described in section 3.7.8. Analysis of 
these measures will address the secondary objective of this study to compare semaglutide s.c. 
versus SOC in the study’s patient population as is relates to PROs and ClinROs, i.e., treatment 
satisfaction, generic health outcomes, work productivity, and patient and physician global 
assessment measures, over one and two year observation periods. PRO analysis will 
descriptively summarize these measures at baseline, year 1 and year 2, as well as compare 
semaglutide s.c. versus SOC for change from baseline to year 1 and year 2.  
No imputation of missing PRO measures is planned. The continuous change from baseline 
endpoints will be analyzed using the same analysis approach as described under the complete 
case and complete case on-study drug analyses in Section 4.6.4.  
Data regarding all PROs will be reported for the entire sample by treatment group. Percentages 
of completed PROs will be reported as well. Descriptive statistics will be reported for aggregate 
scores for all appropriate measures by total score and subscale score(s) if applicable. 
Semaglutide and SOC treatment groups will be compared by independent t-tests for PRO 
measures in which the data are normally distributed or the Mann-Whitney U-test for PRO 
measures in which the data are not normally distributed. 
• Diabetes Treatment Satisfaction Questionnaire, change version (DTSQc), Total treatment 
satisfaction score measured at year 1 
• DTSQc, Total treatment satisfaction score measured at year 2 
• Change from baseline in Short Form 12-Item Version 2 Survey (SF-12 v2), Physical 
component summary (PCS-12) score at year 1 
• Change from baseline in SF-12 v2, PCS-12 score at year 2 
• Change from baseline in SF-12 v2, Mental component summary (MCS-12) score at year 
1 
• Change from baseline in SF-12 v2, MCS-12 score at year 2 
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• Change from baseline in Work Productivity and Activity Impairment, General Health 
questionnaire (WPAI-GH) Absenteeism (work time missed) score at year 1 
• Change from baseline in WPAI-GH Absenteeism (work time missed) score at year 2 
• Change from baseline in WPAI-GH Presenteeism (impairment at work / reduced on-the-
job effectiveness) score at year 1 
• Change from baseline in WPAI-GH Presenteeism (impairment at work / reduced on-the-
job effectiveness) score at year 2 
• Change from baseline in WPAI-GH Work productivity loss (overall work impairment / 
absenteeism plus presenteeism) score at year 1 
• Change from baseline in WPAI-GH Work productivity loss (overall work impairment / 
absenteeism plus presenteeism) score at year 2 
• Change from baseline in WPAI-GH Activity Impairment score at year 1 
• Change from baseline in WPAI-GH Activity Impairment score at year 2 
In addition to the above endpoints, PGI-S and CGI-S will be descriptively summarized at 
baseline overall and by treatment group. PGI-C and CGI-C will be descriptively summarized at 
year 1 and year 2 overall and by treatment group. 
During later analysis on the primary endpoints, PRO measures can be used in two ways: 
• Correlational analysis of the PRO measures with the dependent variable. These 
correlations will include the appropriate measure of Pearson’s ‘r’, Spearman’s rho, 
Kendall’s tau statistics or other appropriate measures that might fit the nature of the 
variable. 
• Should the correlational analysis from step 1 find that patient characteristics are linked to 
primary analysis endpoints, multivariate analysis or Logistic Regression will be 
conducted to determine if there are any patient related variables from the PROs that 
predict the effectiveness of therapy in combination with other clinical variables. Data 
reported will include model specifics (H-L Goodness of fit; R2, beta coefficients for each 
variable as well as ORs with 95% CIs.) 
4.8 Concomitant Medications 
The number and percentages patients reporting pre-specified concomitant cardiovascular 
medications during year 1 and during year 2 will be summarized for the FAS overall and by 
treatment group. 
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4.9 Other Analyses 
The following analyses further support the primary objective to compare semaglutide s.c. versus 
SOC in glycemic control. They will address the secondary objectives of this study to compare 
semaglutide s.c. versus SOC in the study’s patient population over one and two year observation 
periods as is relates to body weight loss, hypoglycemia, HCRU, adherence and persistence to 
treatment, antidiabetic medication treatment patterns, and safety. 
The binary and continuous endpoints that include HbA1c, weight, SBP, or DBP data will be 
analyzed using the same analysis approach as described under the primary estimand, secondary 
estimand, and supplementary analysis sections. All other endpoints will be analyzed using the 
same analysis approach as described under the complete case and complete case on-study drug 
analyses in Section 4.6.4, except where otherwise noted.  
4.9.1 Weight Loss 
Change in patient weight from baseline to endpoint will be calculated in absolute change 
(pounds) and relative change (percentage). Mean change in weight will be compared between 
semaglutide and SOC treatment groups following the ANCOVA model described for continuous 
endpoints in the primary (4.6.1) and secondary estimand (4.6.2). This analysis will be repeated 
for the complete case (4.6.4.1) and complete case on-study drug (4.6.4.2). 
• Change in body weight (%) from baseline to year 1 
• Change in body weight (lb) from baseline to year 1 
• Change in body weight (%) from baseline to year 2 
• Change in body weight (lb) from baseline to year 2 
4.9.2 Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) 
Absolute change in patient SBP and DBP from baseline to year 1 and baseline to year 2 will be 
calculated. Mean change in SBP and DBP will be compared between the semaglutide and SOC 
treatment groups following the ANCOVA model described for continuous endpoints in the 
primary (4.6.1) and secondary estimand (4.6.2). This analysis will be repeated for the complete 
case (4.6.4.1) and complete case on-study drug (4.6.4.2). 
4.9.3 Hypoglycemia 
The total number of hypoglycemic episodes leading to an inpatient admission or ER encounter 
during year 1 (from baseline to year 1), during year 2 (from year 1 to year 2), and the cumulative 
sum per patient from baseline to year 2 will be compared by semaglutide and SOC treatment 
groups utilizing a negative binomial model with treatment group as a factor and baseline HbA1c 
as a covariate in the model and observation time included as an offset variable. Subjects 
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reporting one or more episodes during year 2 who missed the year 1 study visit will use the 
expected date of the year 1 study visit (365 days from date of randomization) in calculating 
observation time during year 2. Exploratory analysis will assess the impact of SOC study drug 
(defined in section 3.7.4.2) on the rate of hypoglycemia.  
Additionally, the frequency and percentage of patients reporting hypoglycemic episodes leading 
to an inpatient admission or ER encounter during year 1, during year 2, and cumulatively from 
baseline to year 2 will be reported and compared between treatment groups via chi-square test.  
The above described analyses will also be repeated separately for those hypoglycemic episodes 
leading to an inpatient admission only and for those hypoglycemic episodes leading to an ER 
encounter only.   
All analyses will be performed as described for the complete case (4.6.4.1) and complete case 
on-study drug (4.6.4.2). Hypoglycemic episodes that are considered SAEs will also be included 
in the safety analysis (section 5.4). 
4.9.4 Healthcare Resource Utilization (HCRU) 
HCRU analyses will compare all-cause and diabetes-related HCRU (inpatient admissions, ER 
encounters, physician OV, other outpatient encounters, and pharmacy utilization) as defined in 
section 3.7.9 from claims data by semaglutide and SOC treatment arm from baseline to year 2. 
The number of each type of encounter (all-cause and T2DM-related: inpatient admission, ER 
encounter, physician OV, other outpatient encounter (overall and by specific categories listed in 
section 3.7.9), pharmacy prescription fills) a patient experiences from baseline to year 2 will be 
summed. 
HCRU will be summarized by setting (i.e., inpatient, ER, OV, outpatient, pharmacy) and cause 
(i.e., all-cause versus diabetes-related), for the study population overall and by treatment group. 
The occurrence (yes/no) and number of each type of encounter or prescription fill will be 
reported. LOS will be reported per admission and cumulative (baseline to year 2). LOS for 
inpatient admissions (days) per inpatient admission will be an encounter level analysis of the 
average inpatient admission LOS based on the total number of inpatient admissions; therefore, 
patients may contribute more than once. Statistics for cumulative LOS for inpatient admissions 
(days) will only be produced for patients with at least one inpatient admission. 
Treatment group comparisons will utilize the Student t-test for continuous variables and chi-
squared test (or Fisher’s exact test if outcome count less than 5) for categorical variables. 
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4.9.5 Composite Endpoints 
The following composite endpoints will be analyzed with a logistic regression model with a logit 
link function, treatment as a categorical effect, and baseline HbA1c and baseline weight as 
covariates. This analysis will be performed as described for the complete case (4.6.4.1) and 
complete case on-study drug (4.6.4.2). 
• HbA1c <7.0% (53 mmol/mol) without experiencing hypoglycemia leading to inpatient 
admission or ER encounter and body weight loss of  ≥5% vs baseline at year 1 (yes/no) 
• Absolute HbA1c reduction of ≥0.5% without experiencing hypoglycemia leading to 
inpatient admission or ER encounter and a body weight loss of  ≥5% vs baseline at year 1 
(yes/no) 
• HbA1c <7.0% (53 mmol/mol) without experiencing hypoglycemia leading to inpatient 
admission or ER encounter and body weight loss of  ≥5% vs baseline at year 2 (yes/no) 
• Absolute HbA1c reduction of ≥0.5% without experiencing hypoglycemia leading to 
inpatient admission or ER encounter and a body weight loss of  ≥5% vs baseline at year 2 
(yes/no) 
• HbA1c <7.0% (53 mmol/mol) without experiencing hypoglycemia leading to inpatient 
admission or ER encounter and no body weight gain vs baseline at year 1 (yes/no) 
• HbA1c <7.0% (53 mmol/mol) without experiencing hypoglycemia leading to inpatient 
admission or ER encounter and no body weight gain vs baseline at year 2 (yes/no) 
4.9.6 Antidiabetic Treatment Patterns 
4.9.6.1 
Study Drug Regimen 
Study drug regimen will be descriptively summarized by treatment arm. 
The SOC group’s randomized treatment regimen will be summarized by medication and class for 
study drug, i.e., the first antidiabetic medication prescribed for treatment intensification 
following randomization. 
For the semaglutide group, relative frequency by dose category (0.25, 0.5, 1.0 mg) will be 
calculated at randomization, year 1, and year 2. Additionally, the relative frequency by 
semaglutide dose category will be calculated for most common, highest, and final as defined in 
section 3.7.4.1. 
Treatment intensification,treatment change and permanent early treatment discontinuation 
(definition 3.7.4.3) will also be descriptively summarized as follows: 
• Treatment intensification from baseline to year 1 (yes/no) 
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• Treatment intensification from baseline to year 2 (yes/no) 
• Treatment change from baseline to year 1 (yes/no) 
• Treatment change from baseline to year 2 (yes/no) 
• Treatment discontinuation from baseline to year 1 (yes/no) 
• Treatment discontinuation from baseline to year 2 (yes/no) 
4.9.6.2 
Adherence and Persistence to Treatment 
Adherence and persistence to the study drug will be calculated and summarized for the FAS and 
compared between semaglutide and SOC treatment groups.  
Study drug medication adherence will be summarized by the MPR (%) using the claims data. 
The MPR (%) for the first year of the study and the MPR (%) for the two year study period will 
be compared between treatment arms using a Student t-test. 
Medication persistence, as calculated using the eCRF data, will be summarized by: 
• Time to first study drug discontinuation during 2 years (day) 
• Time to first treatment intensification (add-on), change (switch) or discontination after 
randomization during 2 years (day), whichever occurs first 
Medication persistence measures will be compared between semaglutide and SOC treatment 
groups via the Cox proportional hazards model (with no covariates) to estimate the hazard ratio 
(HR) (semaglutide s.c. versus SOC), 95% CI, and p-value. Patients with no event will be 
censored at year 2 or last contact if withdrawn or lost to follow-up. 
4.9.6.3 
Other Antidiabetic Treatments 
Antidiabetic treatment patterns will be assessed and compared between semaglutide and SOC 
treatment groups. This analysis will summarize the number and classification type of antidiabetic 
medications taken during the study period.  
Descriptive statistics will be presented overall and by treatment group for the average number of 
antidiabetic medications patients report at randomization, year 1 and year 2. Relative frequencies 
of number of antidiabetic medications will also be summarized for randomization, year 1 and 
year 2. Relative frequencies by antidiabetic class will also be presented at randomization, year 1 
and year 2. 
4.10 Study Site Recruitment and Participation 
To contextualize the participating study sites within the pool of 
 providers, tables 
summarizing the identification, recruitment, and participation of providers will be presented. 
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Site identification for this study begins with identifying the pool of potentially eligible patients in 
the HIRD using very broad claims-based inclusion/exclusion criteria: currently active members 
with at least one medical claim with an ICD-9 or ICD-10 diagnosis code for T2DM during the 
identification period, pharmacy carve-in benefits and pharmacy carve-out benefits at any time 
during the identification period, commercial plan coverage only, ≥18 years old, at least one 
pharmacy claim for metformin in the past 6 months, and no pharmacy claims for other 
antidiabetic medications within the past 30 days. These patients are then mapped back to the 
provider sites with which they had diabetes-related office visits during the identification period. 
From this process, a list of providers with number of potentially eligible patients is generated. 
The overall pool of 
 providers serving the target study population will be summarized 
with a table presenting patient densities by number of providers. 
A flow chart summarizing each step of the process will be produced to describe site recruitment 
and participation: 
1) Total number of providers with at least one potentially eligible patient identified. 
2) Total number of providers approached (I.e., providers who met predetermined threshold 
(x number of patients) for outreach.) 
3) Disposition of providers approached 
a. Interested, invited to participate 
b. Interested, rejected from participation 
c. Not Interested 
d. No Response 
A table summarizing characteristics of providers (geographic region, provider specialty, and 
claims-based patient density) by disposition status will be produced. 
4.11 Evaluation of the Study Population 
To evaluate the generalizability of the study results, an analysis of the study population will be 
performed. The primary objective of this analysis is to evaluate the external validity of the study 
and to understand how the study population fits into the larger T2DM populations within study 
sites and commercially-insured population as a whole. Two claims-based T2DM patient 
populations will be described and compared to the study population: (1) all research-eligible 
commercially-insured and Medicare Advantage 
 T2DM patients treated with up to 2 oral 
antidiabetic medication, excluding oral semaglutide, who undergo an antidiabetic treatment 
intensification and (2) within the study sites, commercially-insured and Medicare Advantage 
 T2DM patients treated with up to 2 oral antidiabetic medications, excluding oral 
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semaglutide, who are not enrolled in the study, but who undergo an antidiabetic treatment 
intensification.  
Identification of Claims-Based Comparator Populations 
The claims-based comparator populations and analysis will be based on data from the HIRD. 
Claims based inclusion/exclusion criteria will be imposed on the two comparator populations as 
best as can be identified via the claims data and available lab result data to reflect the 
inclusion/criteria of the study population. All patients meeting the inclusion/exclusion criteria for 
each of the claims-based T2DM populations will be included in the analysis. 
• Claims patient identification period = July 2018 until date last patient enrolled. (To align 
with the dates of the PCT study period). 
• Claims index date = Patient’s first prescription date associated with antidiabetic treatment 
intensification during the patient identification period. 
• Claims study period = July 2017 until 12 months following date of last patient enrolled. 
(To allow for 12 months of claims data before and after the identified antidiabetic 
treatment intensification.) 
Inclusion Criteria for Population #1 
• ≥ 1 medical claim with an ICD-10 diagnosis code for T2DM during patient identification 
period 
• A pharmacy claim(s) for 1 or 2 oral antidiabetic treatments, excluding oral semaglutide, 
as described in the PCT, during the patient identification period 
o First date of antidiabetic treatment pharmacy claim is index date 
• ≥ 12 months medical and pharmacy eligibility prior to index date 
• Age ≥ 18 years on index date 
• HbA1c >7.0% within 90 days prior to and including index date 
Exclusion Criteria for Population #1 
•  Pharmacy claims for ≥2 oral antidiabetic medications, oral semaglutide, or any injectable 
antidiabetic medicationfor 30 days prior to index date. 
• Randomized into the current PCT. 
 
Inclusion Criteria for Population #2 
The inclusion criteria for population #2 will include all of the inclusion criteria as population #1, 
as well as: 
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• Receiving antidiabetic treatment at a study site 
Exclusion Criteria for Population #2 
The exclusion criteria for population #2 is the same as the exclusion criteria for population #1. 
 
All analyses evaluating the study population will be descriptive only and will help to 
contextualize study results within the T2DM population broadly. All analyses will be based on 
the overall population only; analyses by treatment group will not be conducted. 
The analysis will descriptively compare the overall baseline demographics between the PCT 
study population and the two comparator populations. Baseline HbA1c (defined as closest HbAlc 
up to and including 90 days prior to randomization (for PCT population) or index date (for 
comparators)) will also be compared. 
Observed HCRU (all-cause and T2DM-related; inpatient, ER, outpatient physician OV, and 
other outpatient services, pharmacy utilizations) during the 12 month period prior to 
randomization (for study population) or prior to index date (for comparators) will also be 
compared between the PCT study population and the two comparator populations. The PCT 
study population for this comparison will be limited to study patients with 12 months of health 
plan eligibility prior to randomization.  
Additionally, treatment patterns of non-enrolled T2DM patients within the practices from which 
the study patients are recruited will be evaluated to identify any relevant patterns of care 
suggesting channeling of certain types of patients away from the study. This analysis be based on 
the subset of patients with 12 months post-index data medical and pharmacy eligibility and will 
present the relative frequency of antidiabetic medications by class during the 12 months 
following randomization or index date for the PCT study population and comparator population 
#2. 
 
5.0 SAFETY 
5.1 AEs 
For the purpose of this study, AEs that do not meet the definition of an SAE (protocol section 
7.2) will only be required to be collected in the eCRF if they lead to study drug discontinuation. 
5.2 SAEs 
All AEs meeting the definition of an SAE (protocol section 7.2) will be collected in the eCRF. 
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5.3 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 patients will be reported, along with pregnancy outcome and any AEs or 
SAEs observed in the fetus or newborn until 1 month of age.  
5.4 Analysis 
No formal safety analyses are planned for this study. SAEs and AEs leading to study drug 
discontinuation will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
and descriptively summarized by System Organ Class and Preferred Term (PT). Pregnancies 
occurring during the study will be also be descriptively summarized. 
 
6.0 Changes from Protocol 
Version 1.0 of the protocol specified conducting PRO Analysis (Protocol Section 6.6) and Other 
Analyses (Protocol Section 6.8) as described for the primary estimand, secondary estimand, and 
supplementary analysis (complete case and complete case on-study drug). However, missing 
data imputation will only be completed for HbA1c, weight, SBP, and DBP. Therefore, for 
endpoints that do not include HbA1c, weight, SBP, or DBP data, endpoints will be analyzed 
using the same analysis approach as described under the complete case and complete case on-
study drug analyses in Section 4.6.4, except where otherwise noted.  Relevant text was corrected 
in NN95359-4416 Protocol Version 2.0, dated 27MAR2019. 
 
 
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7.0 SAP Change Log 
 
Summary of SAP Changes since First Patient First Visit 
NN9535-4416 SAP Version 2.0, dated 30JUN2020 
 
Number 
Section/Page 
 
Change 
Rationale 
1 
 
Global Change, 
Study Population 
Allow enrollment of patients treated with 
either 1 or 2 oral antidiabetic medications 
Expand study population from 
patients treated with 
metformin monotherapy to 
patients treated with either 1 or 
2 oral antidiabetic medications 
to facilitate enrollment.  
2 
Global Change, 
Study Population 
Allow enrollment of patients with any 
commercial or Medicare insurance with 
pharmacy benefits. 
  
Expand study population to 
facilitate enrollment. 
 
3 
Global Change 
JulyJune 530, 20182020 
 
Version 12.0 
Update SAP date and version. 
 
4 
Study Approvals, 
p. 2 
Name:  
 
Title:    
, Research Biostatistics 
Name:  
 
Title:    
 Scientist 
 
Update to 
 study 
statistician. 
 
5 
Study Approvals, 
p. 2 
Name:  
 
Title:    
 
Name:  
  
Title:    
 
Update to Novo Nordisk study 
statistician. 
6 
Global Change,  
Study Treatments 
Semaglutide s.c. 
Clarify formulation of 
semaglutide allowed for study 
treatment is subcutaneous 
only. 
7 
Global Change 
 
routine diabetic care visits 
Clarify data collection 
between study visits for sites. 
 
8 
Global Change, 
Study Treatments 
…semaglutide s.c. as compared to SOC 
(excluding any semaglutide). 
 
No formulation of semaglutide 
is allowed in SOC group. 
Clarify that main study 
comparison excludes any 
formulation of semaglutide 
from the SOC group. 
 
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9 
Section 1.0, 
Introduction 
This is a 2-year, multi-center, randomized, 
open label, parallel group, active comparator 
pragmatic clinical trial (PCT) comparing 
semaglutide s.c. versus standard of care 
(SOC) when added to metformin 
monotherapyup to 2 oral antidiabetic 
medications as treatment intensification 
among adult type 2 diabetes mellitus (T2DM) 
patients in the course of routine clinical 
practice. 
Update study design to reflect 
expanded study population. 
10 
Section 2.1, 
Primary Objective 
The primary objective is to demonstrate 
superior long term effects of treatment with 
semaglutide s.c. compared to SOC each added 
to metformin up to 2 oral antidiabetic 
medications on glycemic control when used 
as intensification in routine clinical practice in 
adult patients with T2DM. 
Update primary objective to 
reflect expanded study 
population. 
11 
Section 2.2,  
Secondary 
Objectives 
 
The secondary objectives are to compare the 
long term effect of semaglutide s.c. versus 
SOC each added to metformin up to 2 oral 
antidiabetic medications and used as 
intensification in routine clinical practice in 
adult patients with T2DM with regards to: 
 
Update secondary objectives 
to reflect expanded study 
population. 
12 
Section 3.3, 
Evaluation 
Schedule and 
Definitions 
Year 2 endpoint data will be derived from the 
dedicated year 1 2 study visit if the dedicated 
study visit is ±10 weeks of 104 weeks post-
randomization. 
Correction 
13 
Section 3.4,  
Confirmatory 
Endpoint and 
Hypothesis 
This study is designed to have 90% power to 
jointly confirm superiority of the primary 
endpoint and 85% power to also confirm 
superiority of the first the above three 
confirmatory secondary endpoints based on 
primary estimand analyses. 
Update to power calculations. 
14 
Section 3.5.1  
Power and Sample 
Size for Primary 
Objective 
In line with the primary ITT estimand, the 
assumptions for the proportion of patients 
with HbA1c < 7.0% at year 1 and year 2, and 
for the change from baseline in HbA1c are 
based on the claims/laboratory results data 
within the 
 population for all patients 
initiating treatment intensification regardless 
of whether patients adhered to this treatment. 
Update to reflect protocol. 
15 
Section 3.5.1  
The sample size calculation aimed for 90% 
power for simultaneously confirming 
superiority of semaglutide s.c. versus SOC on 
Update to power calculations. 
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Power and Sample 
Size for Primary 
Objective 
all of the primary endpoint and 85% power to 
also confirm superiority of the first 
confirmatory secondary endpoint based on an 
analysis of the primary estimand for each of 
the endpointsthe secondary confirmatory 
endpoints at both year 1 and year 2 (4 
hypotheses in total). 
16 
Section 3.5.1  
Power and Sample 
Size for Primary 
Objective  
When accounting for missing data, 
randomizing 2250 1387 patients will 
contribute 1687 1040 patients for the year 1 
analyses and 1260 780 patients for the year 2 
analyses, achieving a total power of 90% 85% 
for confirming the two year 1 confirmatory 
hypotheses. The joint power for confirming 
all 4 confirmatory hypotheses is 58%. The 
corresponding marginal powers for presence 
of HbA1c < 7.0% at year 1, change in HbA1c 
to 1 year, presence of HbA1c < 7.0% at year 
2, and change in HbA1c to 2 years are 
99%90%, 99%94%, 95%80%, and 97%86% 
respectively. 
Update to planned enrollment 
and power calculations. 
17 
Section 3.7.4.2  
Standard of Care 
(SOC) Study Drug 
 
For the SOC treatment group, study drug is 
defined as the drug class of the first 
antidiabetic oral or injectable medication 
prescribed for treatment intensification 
following randomization (excluding any 
formulation of semaglutide). 
Semaglutide in any 
formulation is not allowed 
during the study period for the 
SOC group. 
18 
Section 3.7.4.3 
Treatment 
Intensification or 
Change 
Treatment intensification is defined as 
initiation of an antidiabetic medication 
(besides metforminthe up to 2 oral 
antidiabetic medication(s) taken prior to 
randomization) in addition to study drug, or 
initiation of more than one antidiabetic 
medication after discontinuation of study 
drug. 
Update definition to reflect 
expanded study population. 
19 
Section 3.7.4.3 
Treatment 
Intensification or 
Change 
Treatment change is defined as 
discontinuation of study drug and initiation of 
another antidiabetic medication (besides 
metforminthe up to 2 oral antidiabetic 
medication(s) taken prior to randomization). 
Update definition to reflect 
expanded study population. 
20 
Section 3.7.9 
Healthcare 
Resource 
Utilization 
(HCRU) 
These data will come from the HIRD for 
 patients or requested from a set of 
other health insurers for non-
 patients. 
Updated definition to reflect 
expanded study population and 
collection of claims data. 
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21 
Section 4.5  
Missing Value 
Imputation 
Methodology 
Missing endpoint data will be imputed for 
HbA1c, weight, SBP, and DBP. The data of 
patients who, in violation of the protocol, 
initiate any formulation of semaglutide in the 
SOC treatment group, will be censored 
analytically following initiation of 
semaglutide. The patient will remain in the 
analysis, but data following their initiation of 
semaglutide will be censored and treated as 
missing. 
Semaglutide in any 
formulation is not allowed 
during the study period for the 
SOC group. 
22 
Section 4.9.4  
Healthcare 
Resource 
Utilization 
(HCRU) 
HCRU analyses will compare all-cause and 
diabetes-related HCRU (inpatient admissions, 
ER encounters, physician OV, other 
outpatient encounters, and pharmacy 
utilization) as defined in section 3.7.9 from 
the HIRDclaims data by semaglutide and 
SOC treatment arm from baseline to year 2. 
Update to reflect expanded 
study population and 
collection of claims data. 
23 
Section 4.9.6.3 
Other Antidiabetic 
Treatments 
Background Medication 
Metformin dose will be descriptively 
summarized overall and by treatment group at 
randomization, year 1, and year 2. 
Other Antidiabetic Treatments 
… 
Descriptive statistics will be presented overall 
and by treatment group for the average 
number of antidiabetic medications patients 
report at randomization, year 1 and year 2. 
Relative frequencies of number of antidiabetic 
medications will also be summarized for 
randomization, year 1 and year 2. Relative 
frequencies by antidiabetic class will also be 
presented at randomization, year 1 and year 2. 
Update descriptive summary 
of other antidiabetic treatments 
to reflect expanded study 
population. 
24 
Section 4.11 
Evaluation of the 
Study Population 
The primary objective of this analysis is to 
evaluate the external validity of the study and 
to understand how the study population fits 
into the larger T2DM populations within 
study sites and 
 commercially-insured 
population as a whole. Two claims-based 
T2DM patient populations will be described 
and compared to the study population: (1) all 
research-eligible commercially-insured and 
Medicare Advantage 
 T2DM patients 
treated with metforminup to 2 oral 
antidiabetic medication, excluding oral 
semaglutide,  who undergo an antidiabetic 
Update to reflect expanded 
study population. 
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treatment intensification and (2) within the 
study sites, commercially-insured and 
Medicare Advantage 
 T2DM patients 
treated with metformin up to 2 oral 
antidiabetic medications, excluding oral 
semaglutide, who are not enrolled in the 
study, but who undergo an antidiabetic 
treatment intensification. 
25 
Section 4.11 
Evaluation of the 
Study Population 
Inclusion Criteria for Population #1 
• ≥ 1 medical claim with an ICD-10 diagnosis 
code for T2DM during patient identification 
period 
• ≥ 1 A pharmacy claim(s) for 1 or 2 oral 
antidiabetic treatments, excluding oral 
semaglutide, in addition to metformin, as 
described in the PCT, during the patient 
identification period 
o First date of antidiabetic 
treatment pharmacy claim is 
index date 
• ≥ 12 months medical and pharmacy 
eligibility prior to index date 
• ≥ 1 pharmacy claim for metformin in 6 
months prior to index date 
• Age ≥ 18 years on index date 
• HbA1c >7.0% within 90 days prior to and 
including index date 
Update to reflect expanded 
study population. 
26 
Section 4.11 
Evaluation of the 
Study Population 
Exclusion Criteria for Population #1 
• ≥ 1 pharmacy Pharmacy claims for ≥2 any 
oral antidiabetic medications, oral 
semaglutide, or any injectable antidiabetic 
medication other than metformin for 30 days 
prior to index date. 
• Randomized into the current PCT. 
Update to reflect expanded 
study population. 
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Summary of SAP Changes since First Patient First Visit 
NN9535-4416 SAP Version 3.0, dated 26-OCT-2021 
 
Number 
Section/Page 
 
Change 
Rationale 
1 
 
Global Change 
June October 2630, 20210 
 
Version 23.0 
Update SAP date and 
version. 
2 
Study 
Approvals, p. 2 
Name: 
, 
 
Title:  
 
 
Name: 
 
 
Title:  
 Innovative Trials 
Update to Novo 
Nordisk 
 and 
study statistician. 
3 
Section 3.2.2, 
Safety 
Population 
The safety population includes all randomized patients 
initiated on study drug analyzed according to the 
treatment group to which they received. 
Text added to clarify 
definition of study 
population. 
4 
Section 3.4, 
Confirmatory 
Endpoints and 
Hypotheses 
This study is designed to have 90% power to confirm 
superiority of semaglutide s.c. versus SOC on of the 
primary endpoint and 85% power to also confirm 
superiority of the first confirmatory secondary endpoint 
based on primary estimand analyses. The primary and 
confirmatory secondary endpoints will all be tested for 
superiority of semaglutide under multiplicity control via 
a hierarchical testing scheme according to the order 
given in the above bullet list. Confirmatory testing will 
only be performed for the primary estimand with the 
secondary estimand being supportive. The testing 
procedure will be stopped the first time an analysis fails 
to confirm superiority of semaglutide of for the endpoint 
in question using a two-sided significance level of 5%. 
Text revised to 
clarify that references 
to ‘superiority’ 
specifically mean 
superiority of 
semaglutide s.c. in 
comparison to SOC. 
5 
Section 3.7.4.3, 
Treatment 
Intensification, 
Change or 
Permanent Early  
Discontinuation 
or Change 
Permanent early treatment discontinuation is defined as 
discontinuation of study drug as described in section 
3.7.4 and no initiation of another antidiabetic medication 
(besides the up to 2 oral antidiabetic medication(s) taken 
prior to randomization) for the remainder of the subject’s 
time in study. 
Section revised to 
include permanent 
early treatment 
discontinuation.  
6 
Section 3.7.7, 
Adherence and 
Persistence to 
Treatment 
A second persistence measure will be defined as duration 
of time in days from the date of initiation of study drug 
to the date of the first intensification or change in study 
drug as defined in section 3.7.4.3 or study drug 
discontinuation as defined in section 3.7.4, whichever 
occurs first. 
Text added to clarify 
the definition of the 
second persistence 
measure. 
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7 
Section 3.8, 
Examination of 
Subgroups 
Data will be presented overall and by treatment group. 
Additionally, sSubgroup analysis analyses under the 
primary estimand (ITT) of the primary endpoint and of 
the first confirmatory secondary endpoint (change in 
HbA1c from baseline to year 1) will be conducted on the 
following subgroups: 
• 
Age (<55 years versus ≥55 years) 
• 
Gender 
• 
Baseline HbA1c (<8.0% versus ≥8.0%) 
• 
Baseline body mass index (BMI) (<30 kg/m2, 
≥30 kg/m2) 
• 
Duration of T2DM diagnosis at baseline (<5 
years versus ≥5 years) 
 
Analysis of each subgroup will be based on a logistic 
regression model with logit link function for the primary 
endpoint and an ANCOVA model for the first 
confirmatory secondary endpoint.  Models will also 
include treatment and subgroup as categorical effects, 
baseline HbA1c as covariate, and an interaction term 
composed of treatment and subgroup.   
 
Additionally, analysis of the above subgroups will be 
repeated for the treatment adherence and persistence 
endpoints using the FAS and an ANCOVA model for the 
adherence measures and a Cox proportional hazards 
model for the persistence measures.  Models will also 
include treatment and subgroup as categorical effects, 
and an interaction term composed of treatment and 
subgroup.  
 
For all interaction models, the estimated treatment effect 
for semaglutide s.c. versus SOC and 95% confidence 
interval within each subgroup level and the p-value for 
the interaction term will be presented from each model. 
The analysis plan for 
the examination of 
subgroups was 
revised to include the 
first confirmatory 
endpoint (change in 
HbA1c from baseline 
to year 1).  In 
addition, further text  
added to describe the 
subgroup analysis for 
the treatment 
adherence and 
persistence measures 
noted in protocol 
Section 6.8.8 which 
were accidentally 
omitted in the 
previous version. 
8 
Section 4.1, 
Overview 
Descriptive summaries will be produced for both the 
primary (ITT) and secondary (“if all patients adhered”) 
estimands, with the exception of antidiabetic treatment 
patterns which will be based on the primary estimand 
only. All statistical analyses will be conducted under 
both the primary estimand (ITT) and secondary estimand 
(“if all patients had adhered”), with the exception of the 
Text removed.  
Specific details 
regarding which 
descriptive 
summaries and/or 
analyses will utilize 
the primary and 
secondary estimands 
are detailed within 
each subsection of 
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adherence and persistence measures, which will be based 
on the primary estimand only. 
Section 4.0 
(Statistical Analyses). 
9 
Section 4.5.1, 
Primary 
Estimand 
Imputation 
Model 
Missing endpoint data will be imputed separately by 
treatment group and based on similar patients with 
available endpoint data according to study drug 
treatment status, i.e., according to whether these patients 
are on or off study drug at the endpoint visit, resulting in 
four separate imputation models. 
Text added to note 
that the current 
approach will result 
in four separate 
imputation models. 
10 
Section 4.6.3.1, 
Descriptive 
Summaries of 
HbA1c 
Observed HbA1c values will be descriptively 
summarized at baseline, year 1, and year 2. Additionally, 
the following categories of observed HbA1c will be 
descriptively summarized at baseline, year 1, and year 2: 
• 
<7.0, 7.0-8.0, 8.1-9.0, 9.1-10.0, >10.0% 
• 
<7.0, 7.0-<7.5, 7.5-<8.0, 8.0-<8.5, 8.5-<9.0, and 
≥9.0% 
• 
<8.0 versus ≥8.0% 
• 
<9.0 versus ≥9.0% 
Cut-points use to 
categorized observed 
HbA1c were revised 
from 1.0% to 0.5% 
increments to 
facilitate the 
comparison with 
other clinical research 
studies.  
11 
Section 4.7,  
PRO Analysis 
No imputation of missing PRO measures is planned. The 
continuous change from baseline endpoints will be 
analyzed using the same analysis approach as described 
under the complete case and complete case on-study 
drug analyses in Section 4.6.4. Therefore, the primary 
estimand for PRO analysis will be based on the FAS 
with endpoint data. The secondary estimand for PRO 
analysis will be based only on patients with endpoint 
data including only measurements for patients still on 
study drug. In the secondary estimand, patients who 
discontinue study drug will be censored and missing data 
will not be imputed. 
Text revised to 
clarify the planned 
analysis of PRO data. 
12 
Section 4.8, 
Concomitant 
Medications 
The number and percentages patients reporting pre-
specified concomitant cardiovascular medications during 
year 1 and during year 2 will be summarized for the 
population FAS overall and by treatment group. 
Clarification 
13 
Section 4.9,  
Other Analyses 
The binary and continuous endpoints that include 
HbA1c, weight, SBP, or DBP data will be analyzed 
using the same analysis approach as described under the 
primary estimand, secondary estimand, and 
supplementary analysis sections. All other endpoints will 
be analyzed using the same analysis approach as 
described under the complete case and complete case on-
Revisions were made 
to the text to better 
align with protocol 
and to clarify the 
planned analyses for 
the endpoint 
measures. 
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study drug analyses in Section 4.6.4, except where 
otherwise noted. Except where otherwise noted, the 
following analyses will be conducted for the primary 
estimand and the secondary estimand. For endpoints that 
do not include HbA1c, weight, SBP, or DBP, no missing 
data will be imputed. Therefore, the primary estimand 
for these endpoints will be based on the FAS with 
endpoint data. The secondary estimand for these 
endpoints will be based only on patients with endpoint 
data including only measurements for patients still on 
study drug. Patients who discontinue study drug will be 
censored and missing data will not be imputed. 
 
14 
Section 4.9.3, 
Hypoglycemia 
The total number of hypoglycemic episodes leading to an 
inpatient admission or ER encounter during year 1 (from 
baseline to year 1), during year 2 (from year 1 to year 2), 
and the cumulative sum will be summed per patient from 
baseline to year 2 and will be compared by semaglutide 
and SOC treatment groups utilizing a negative binomial 
model with fixed effect of treatment group as a factor 
and baseline HbA1c as a covariate in the model and 
observation time included as an offset variable. Subjects 
reporting one or more episodes during year 2 who 
missed the year 1 study visit will use the expected date 
of the year 1 study visit (365 days from date of 
randomization) in calculating observation time during 
year 2. Exploratory analysis will assess the impact of 
SOC study drug (defined in section 3.7.4.2) on the rate 
of hypoglycemia.  
Additionally, the frequency and percentage of patients 
reporting hypoglycemic episodes leading to an inpatient 
admission or ER encounter during year 1 (from baseline 
to year 1), during year 2, and cumulatively from baseline 
to year 2 will be reported and compared between 
treatment groups via chi-square test.  
The above described analyses will also be repeated 
separately for those hypoglycemic episodes leading to an 
inpatient admission only and for those hypoglycemic 
episodes leading to an ER encounter only.   
Analysis plan 
updated to further 
defined in more detail 
the hypoglycemic 
endpoints and time 
periods to be 
assessed, and the 
statistical models to 
be used for analysis. 
 
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All analyses will be performed as described for the 
complete case (4.6.4.1) and complete case on-study drug 
(4.6.4.2).  
Hypoglycemic episodes that are considered SAEs will 
also be included in the safety analysis (section 5.4). 
15 
Section 4.9.5,  
Composite 
Endpoints 
This analysis will be repeated performed as described for 
the complete case (4.6.4.1) and complete case on-study 
drug (4.6.4.2). 
Correction.   
16 
Section 4.9.6.1,  
Study Drug 
Regimen 
Treatment intensification, and treatment change and 
permanent early treatment discontinuation (definition 
3.7.4.3) will also be descriptively summarized as 
follows: 
• 
Treatment intensification from baseline to year 1 
(yes/no) 
• 
Treatment intensification from baseline to year 2 
(yes/no) 
• 
Treatment change from baseline to year 1 
(yes/no) 
• 
Treatment change from baseline to year 2 
(yes/no) 
• 
Treatment discontinuation from baseline to year 
1 (yes/no) 
• 
Treatment discontinuation from baseline to year 
2 (yes/no) 
Section updated to 
include the analysis 
of permanent early 
treatment 
discontinuation. 
17 
Section 4.9.6.2,  
Adherence and 
Persistence to 
Treatment 
Adherence and persistence to the study drug will be 
calculated and summarized for the FAS and compared 
between semaglutide and SOC treatment groups. This 
analysis will be conducted for the primary estimand 
only. 
Clarification as to the 
analysis population to 
be used for the 
analysis of adherence 
and persistence to 
treatment. 
18 
Section 4.9.6.2,  
Adherence and 
Persistence to 
Treatment 
Study drug medication adherence will be summarized by 
the MPR (%) using the claims data. The MPR (%) for 
the first year of the study and the MPR (%) for the two 
year study period will be compared between treatment 
Correction made to 
the statistical test that 
will be used for the 
analysis of MPR.  
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arms using the a test of independent proportionsStudent 
t-test. 
19 
Section 4.9.6.2,  
Adherence and 
Persistence to 
Treatment 
Medication persistence, as calculated using the eCRF 
data, will be summarized by: 
• 
Time to first study drug discontinuation during 2 
years (day) 
• 
Time to first treatment intensification (add-on) 
or , change (switch) or discontination after 
randomization during 2 years (day), whichever 
occurs first 
Medication persistence measures will be compared 
between semaglutide and SOC treatment groups via the 
Cox proportional hazards model (with no covariates) to 
estimate the hazard ratio (HR) (semaglutide s.c. versus 
SOC), and 95% CI, and p-value. Patients with no event 
will be censored at year 2 or last contact if withdrawn or 
lost to follow-up. 
Text added to further 
define the analysis 
and presentation of 
medication 
persistence.  
20 
Section 6.0,  
Changes from 
Protocol 
The Version 1.0 of the protocol specified conducting 
PRO Analysis (Protocol Section 6.6) and Other Analyses 
(Protocol Section 6.8) as described for the primary 
estimand, secondary estimand, and supplementary 
analysis (complete case and complete case on-study 
drug). However, missing data imputation will only be 
completed for HbA1c, weight, SBP, and DBP. 
Therefore, for endpoints that do not include HbA1c, 
weight, SBP, or DBP data, endpoints will be analyzed 
using the same analysis approach as described under the 
complete case and complete case on-study drug analyses 
in Section 4.6.4, except where otherwise noted. the 
primary estimand will be based on the FAS with 
endpoint data. The secondary estimand for these 
endpoints will be based only on patients with endpoint 
data including only measurements for patients still on 
study drug. Patients who discontinue study drug will be 
censored and missing data will not be imputed. 
Supplementary analyses will not be completed for these 
endpoints. Relevant text was corrected in NN95359-
4416 Protocol Version 2.0, dated 27MAR2019. 
Section updated to 
note that relevant text 
was corrected in 
version 2.0 of the 
NN95359-4416 
Protocol, dated 
27Mar2019. 
 
 
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8.0 APPENDIX A: Study Endpoints and Other Variables by Data Source 
Endpoint/Variable 
Data Source 
eCRF 
Administrative 
Claims 
Study Drug Variables 
On/Off Study Drug 
X 
 
Treatment Intensification 
X 
 
Treatment Change 
X 
 
Antidiabetic treatment patterns 
X 
 
Primary Endpoint 
HbA1c <7.0% at year 1 (yes/no) 
X 
 
Confirmatory Endpoints 
Change in HbA1c (%-point) from baseline to year 1 
X 
 
HbA1c <7.0% at year 2 (yes/no) 
X 
 
Change in HbA1c (%-point) from baseline to year 1 
X 
 
Supportive Secondary Endpoint Assessment 
Individualized HbA1c target attained at year 1 (yes/no) 
X 
 
HbA1c <7.0% (53mmol/mol) or at least 1% point improvement in HbA1c 
compared to baseline at year 1 (yes/no) 
X 
 
HbA1c target attainment per Healthcare Effectiveness Data and 
Information Set (HEDIS) criteria (<8.0% if age ≥65 years or with defined 
comorbidities, otherwise <7.0%) at year 1 (yes/no) 
X 
X 
Change in body weight (lb) from baseline to year 1 
X 
 
Change in body weight (%) from baseline to year 1 
X 
 
Change in systolic blood pressure (SBP; mm Hg) from baseline to year 1 
X 
 
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Change in diastolic blood pressure (DBP; mm Hg) from baseline to year 1 
X 
 
Time to first study drug discontinuation during 2 years (day) 
X 
 
Time to first treatment intensification (add-on) or change (switch) after 
randomization during 2 years (day) 
X 
 
Study drug medication adherence for the first year of the study, as 
measured by medication possession ratio (MPR) (%) 
 
X 
Number of hypoglycemic episodes leading to an inpatient admission or 
emergency room (ER) encounter from baseline to year 2 
X 
 
Diabetes Treatment Satisfaction Questionnaire, change version (DTSQc), 
Total treatment satisfaction score measured at year 1 
X 
 
DTSQc, Total treatment satisfaction score measured at year 2 
X 
 
Change from baseline in Short Form 12-Item Version 2 Survey (SF-12 
v2), Physical component summary (PCS-12) score at year 1 
X 
 
Change from baseline in SF-12 v2, PCS-12 score at year 2 
X 
 
Change from baseline in SF-12 v2, Mental component summary (MCS-
12) score at year 1 
X 
 
Change from baseline in SF-12 v2, MCS-12 score at year 2 
X 
 
Change from baseline in Work Productivity and Activity Impairment, 
General Health questionnaire (WPAI-GH) Absenteeism (work time 
missed) score at year 1 
X 
 
Change from baseline in WPAI-GH Absenteeism (work time missed) 
score at year 2 
X 
 
Change from baseline in WPAI-GH Presenteeism (impairment at work / 
reduced on-the-job effectiveness) score at year 1 
X 
 
Change from baseline in WPAI-GH Presenteeism (impairment at work / 
reduced on-the-job effectiveness) score at year 2 
X 
 
Change from baseline in WPAI-GH Work productivity loss (overall work 
impairment / absenteeism plus presenteeism) score at year 1 
X 
 
Change from baseline in WPAI-GH Work productivity loss (overall work 
impairment / absenteeism plus presenteeism) score at year 2 
X 
 
Change from baseline in WPAI-GH Activity Impairment score at year 1 
X 
 
Change from baseline in WPAI-GH Activity Impairment score at year 2 
X 
 
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All cause HCRU from baseline to year 2 
Number of inpatient admissions 
 
X 
LOS for inpatient admissions (days) per inpatient admission 
 
X 
Cumulative length of stay for inpatient admissions (days) 
 
X 
Number of ER encounters 
 
X 
Number of physician OV  
 
X 
Number of other outpatient encounters (overall, and by category: Tests – 
Lab, Imaging, Procedures, OT/Speech, Medication and Related Services, 
Durable Medication Equipment, Physician Other Services, Tests – Other, 
Other)  
 
X 
Number of medications 
 
X 
Occurrence of inpatient admission (yes/no) 
 
X 
Occurrence of ER encounter (yes/no) 
 
X 
Occurrence of physician OV (yes/no) 
 
X 
Occurrence of other outpatient encounter (yes/no) (overall, and by 
category: Tests – Lab, Imaging, Procedures, OT/Speech, Medication and 
Related Services, Durable Medication Equipment, Physician Other 
Services, Tests – Other, Other) 
 
X 
Diabetes related HCRU from baseline to year 2 
Number of diabetes related inpatient admissions 
 
X 
LOS for diabetes related inpatient admissions (days) per diabetes related 
inpatient admission 
 
X 
Cumulative length of stay for diabetes related inpatient admissions (days) 
 
X 
Number of diabetes related ER encounters 
 
X 
Number of diabetes related physician OV 
 
X 
Number of diabetes related other outpatient encounters (overall, and by 
category: Tests – Lab, Imaging, Procedures, OT/Speech, Medication and 
Related Services, Durable Medication Equipment, Physician Other 
Services, Tests – Other, Other) 
 
X 
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SAP for Protocol No. NN9535-4416 
 
 
 
 
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Number of diabetes related medications 
 
X 
Occurrence of diabetes related inpatient admission (yes/no) 
 
X 
Occurrence of diabetes related ER encounter (yes/no) 
 
X 
Occurrence of diabetes related physician OV (yes/no) 
 
X 
Occurrence of diabetes related outpatient encounter (yes/no) (overall, and 
by category: Tests – Lab, Imaging, Procedures, OT/Speech, Medication 
and Related Services, Durable Medication Equipment, Physician Other 
Services, Tests – Other, Other) 
 
X 
Additional Derived Outcome Variables for Supportive Analyses 
Supportive Measures of Glycemic Control 
 
 
Individualized HbA1c target attained at year 2 (yes/no) 
X 
 
HbA1c <7.0% (53 mmol/mol) or at least 1% point improvement in HbA1c 
compared to baseline at year 2 (yes/no) 
X 
 
HbA1c <8.0% (64 mmol/mol) at year 1 (yes/no) 
X 
 
HbA1c <8.0% (64 mmol/mol) at year 2 (yes/no)  
X 
 
HbA1c <7.0% (53 mmol/mol) and no further antidiabetic medication 
intensification after randomization at year 1 (yes/no) 
X 
 
HbA1c <7.0% (53 mmol/mol) and no further antidiabetic medication 
intensification after randomization at year 2 (yes/no) 
X 
 
HbA1c target attainment per HEDIS criteria (<8.0% if age ≥65 years or 
with defined comorbidities, otherwise <7.0%) at year 2 (yes/no) 
X 
X 
HbA1c <7.0% (53 mmol/mol) at year 1 in patients with HbA1c >9.0% at 
baseline (yes/no) 
X 
 
HbA1c <7.0% (53 mmol/mol) at year 2 in patients with HbA1c >9.0% at 
baseline (yes/no) 
X 
 
HbA1c <8.0% (64 mmol/mol) at year 1 in patients with HbA1c >9.0% at 
baseline (yes/no) 
X 
 
HbA1c <8.0% (64 mmol/mol) at year 2 in patients with HbA1c >9.0% at 
baseline (yes/no) 
X 
 
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SAP for Protocol No. NN9535-4416 
 
 
 
 
Version 3.0; 26-OCT-2021 
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Body Weight Loss 
 
 
Change in body weight (%) from baseline to year 2 
X 
 
Change in body weight (lb) from baseline to year 2 
X 
 
Blood Pressure 
 
 
Change in SBP (mm Hg) from baseline to year 2 
X 
 
Change in DPB (mm Hg) from baseline to year 2 
X 
 
Hypoglycemia 
 
 
Reported hypoglycemia leading to inpatient admission or ER encounter 
during year 1 (yes/no) 
X 
 
Reported hypoglycemia leading to inpatient admission or ER encounter 
during year 2 (yes/no) 
X 
 
Composite Variables 
 
 
HbA1c <7.0% (53 mmol/mol) without experiencing hypoglycemia leading 
to inpatient admission or ER encounter and body weight loss of  ≥5% vs 
baseline at year 1 (yes/no) 
X 
 
Absolute HbA1c reduction of ≥0.5% without experiencing hypoglycemia 
leading to inpatient admission or ER encounter and a body weight loss of  
≥5% vs baseline at year 1 (yes/no) 
X 
 
HbA1c <7.0% (53 mmol/mol) without experiencing hypoglycemia leading 
to inpatient admission or ER encounter and body weight loss of  ≥5% vs 
baseline at year 2 (yes/no) 
X 
 
Absolute HbA1c reduction of ≥0.5% without experiencing hypoglycemia 
leading to inpatient admission or ER encounter and a body weight loss of  
≥5% vs baseline at year 2 (yes/no) 
X 
 
HbA1c <7.0% (53 mmol/mol) without experiencing hypoglycemia leading 
to inpatient admission or ER encounter and no body weight gain vs 
baseline at year 1 (yes/no) 
X 
 
HbA1c <7.0% (53 mmol/mol) without experiencing hypoglycemia leading 
to inpatient admission or ER encounter and no body weight gain vs 
baseline at year 2 (yes/no) 
X 
 
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SAP for Protocol No. NN9535-4416 
 
 
 
 
Version 3.0; 26-OCT-2021 
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Adherence to Treatment 
 
 
Study drug medication adherence for the two years of the study, as 
measured by the medication possession ratio (MPR) (%) 
 
X 
 
 
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SAP for Protocol No. NN9535-4416 
 
 
 
 
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9.0 APPENDIX B: 2018 HEDIS Criteria 
Denominator 
The eligible population.  
Note: The eligible population for the HbA1c Control <7% for a Selected 
Population indicator is reported after required exclusions are applied. 
Required exclusions 
for HbA1c Control  
<7% for a Selected 
Population indicator  
Exclude members who meet any of the following criteria: 
• 65 years of age and older as of December 31 of the measurement year. 
• CABG. Members who had CABG (CABG Value Set) in any setting during 
the measurement year or the year prior to the measurement year.  
• PCI. Members who had PCI (PCI Value Set), in any setting, during the 
measurement year or the year prior to the measurement year. 
• IVD. Members who met at least one of the following criteria during both the 
measurement year and the year prior to the measurement year. Criteria 
need not be the same across both years. 
– At least one outpatient visit (Outpatient Value Set) with an IVD diagnosis 
(IVD Value Set). 
– At least one acute inpatient encounter (Acute Inpatient Value Set) with 
an IVD diagnosis (IVD Value Set). 
• Thoracic aortic aneurysm. Members who met at least one of the following 
criteria during both the measurement year and the year prior to the 
measurement year. Criteria need not be the same across both years. 
– At least one outpatient visit (Outpatient Value Set), with a diagnosis of 
thoracic aortic aneurysm (Thoracic Aortic Aneurysm Value Set). 
– At least one acute inpatient encounter (Acute Inpatient Value Set), with a 
diagnosis of thoracic aortic aneurysm (Thoracic Aortic Aneurysm Value 
Set). 
• Any of the following, in any setting, any time during the member’s history 
through December 31 of the measurement year. 
– Chronic heart failure. A diagnosis of chronic heart failure (Chronic Heart 
Failure Value Set).  
– Prior MI. A diagnosis of MI (MI Value Set). 
– ESRD. ESRD (ESRD Value Set; ESRD Obsolete Value Set). 
– Chronic kidney disease (stage 4). Stage 4 chronic kidney disease (CKD 
Stage 4 Value Set). 
– Dementia. A diagnosis of dementia (Dementia Value Set; Frontotemporal 
Dementia Value Set).  
– Blindness. A diagnosis of blindness (Blindness Value Set).  
– Amputation (lower extremity). Lower extremity amputation (Lower 
Extremity Amputation Value Set). 
 
 
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10.0 REFERENCES 
 
[1] C. Bradley, "Diabetes Treatment Satistcation Questionnaire: DTSQ," in Handbook of 
Psychology and Diabetes: A Guide to Psychological Measurement in Diabetes Research 
and Practice, C. Bradley, Ed., Abington, Routledge, 1994, pp. 111-132. 
[2] C. Bradley, "The Diabetes Treatment Satisfaction Questionnaire (DTSQ): change version 
for use alongside status version provides appropriate solution where ceiling effects occur," 
Diabetes Care, vol. 22, no. 3, pp. 530-532, 1999.  
[3] J. Ware, M. Kosinski and S. Keller, "A 12-item short-form healch survey: construction of 
scales and preliminary tests of reliability and validity," Med Care, vol. 34, no. 3, pp. 220-
233, 1996.  
[4] J. Ware, M. Kosinski, D. Turner-Bowker and B. Gandek, How to score version 2 of the SF-
12 health survey (with a supplement documenting version 1), Lincoln, RI: QualityMetric, 
Incorporated, 2002.  
[5] M. Reilly, A. Zbrozek and E. Dukes, "The validity and reproducibility of a work 
productivity and activity impairment instrument," Pharmacoeconomics, vol. 4, no. 5, pp. 
353-365, 1993.  
[6] R. Little and D. Rubin, Statistical analysis with missing data, New York: John Wiley and 
Sons, 1987.  
 
 
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