Conditions: Diabetes Mellitus, Type 2
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 154
Healthy volunteers: no

Brief summary:
This study compares insulin 287 (a possible new medicine) to insulin glargine (a medicine doctors can already prescribe) in people with type 2 diabetes. Different ways of switching from the insulin which the participants are already on to insulin 287 are also compared. This is done to find the best way to switch to insulin 287. The participants will either get insulin 287 that they will have to inject once a week or insulin glargine that they will have to inject once a day. Which treatment any participant gets is decided by chance. The study will last for about 5 months (23 weeks). The participants will have 14 clinic visits and 6 phone calls with the study doctor. At 3 of the clinic visits participants will be asked not to eat or drink anything (except for water) in the last 8 hours before the visit. During the study, the doctor will ask the participants to: 1) measure their blood sugar every day with a blood sugar meter using a finger prick; 2) write down different information in a diary daily and return this to their study doctor. 3) wear a medical device (sensor) that measures the participants blood sugar all the time for 18 weeks (about 4 months) during the study.

Detailed description:

Arms:
arm 1: Participants will receive insulin 287 injections once weekly (OW). A unit to unit switch approach with an additional 100% loading dose of insulin 287 will be used. arm 2: Participants will receive insulin 287 injections OW. A unit to unit switch approach without loading dose of insulin 287 will be used. arm 3: Participants will receive insulin glargine U100 once daily (OD).

Interventions: intervention 1: Insulin icodec intervention 2: Insulin glargine U100
Intervention descriptions: intervention 1: Participants will receive subcutaneous (s.c.) injections of Insulin 287 OW for 16 weeks. intervention 2: Participants will receive s.c. injections of insulin glargine OD for 16 weeks

Protocol document:
Prot_000.pdf: 
Cover Page for Protocol 
 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT03922750 
Sponsor trial ID: 
NN1436-4466 
Official title of study: 
A trial comparing NNC0148-0287 C (insulin 287) versus 
insulin glargine U100, both in combination with metformin, 
with or without DPP4 inhibitors and with or without SGLT2 
inhibitors, in basal insulin treated subjects with type 2 diabetes 
mellitus 
Document date: 
28 May 2020 
 


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CONFIDENTIAL
 
 
 
 
 
Redacted protocol 
Includes redaction of personal identifiable information only. 
 
 
 
. 
 
 


Protocol
CONFIDENTIAL
Date:
29 November 2018
Novo Nordisk
Trial ID: NN1436-4466
Version:
1.0
Status:
Final
Page:
1 of 90
Protocol
Protocol title: A trial comparing NNC0148-0287 C (insulin 287) versus insulin glargine U100, 
both in combination with metformin, with or without DPP4 inhibitors, in basal 
insulin treated subjects with type 2 diabetes mellitus
Substance: NNC0148-0287 C (insulin 287)
Universal Trial Number: U1111-1219-5541 
EUdraCT Number: 2018-003407-18
Trial phase: 2a
In the following, Novo Nordisk A/S and its affiliates will be stated as “Novo Nordisk”.
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol
CONFIDENTIAL
Date:
29 November 2018
Novo Nordisk
Trial ID: NN1436-4466
Version:
1.0
Status:
Final
Page:
2 of 90
Table of Contents   
Page
Table of Contents........................................................................................................................................2
1
Synopsis................................................................................................................................................5
2
Flowchart .............................................................................................................................................8
3
Introduction .......................................................................................................................................12
3.1
Trial rationale..........................................................................................................................12
3.2
Background.............................................................................................................................12
3.3
Benefit-risk assessment ...........................................................................................................14
3.3.1
Benefits .................................................................................................................14
3.3.2
Risks......................................................................................................................14
3.3.3
Conclusion on the benefit risk profile.....................................................................16
4
Objectives and endpoints...................................................................................................................17
4.1
Primary, secondary and exploratory objectives ........................................................................17
4.1.1
Primary objective...................................................................................................17
4.1.2
Secondary objective...............................................................................................17
4.2
Primary, secondary and exploratory endpoints.........................................................................18
4.2.1
Primary endpoint ...................................................................................................18
4.2.2
Secondary endpoints ..............................................................................................18
4.2.2.1
Confirmatory secondary endpoints ...................................................18
4.2.2.2
Supportive secondary endpoints .......................................................18
5
Trial design ........................................................................................................................................20
5.1
Overall design.........................................................................................................................20
5.2
Subject and trial completion....................................................................................................21
5.3
End of trial definition..............................................................................................................21
5.4
Scientific rationale for trial design...........................................................................................22
5.5
Justification for dose ...............................................................................................................23
6
Trial population .................................................................................................................................24
6.1
Inclusion criteria .....................................................................................................................24
6.2
Exclusion criteria ....................................................................................................................25
6.3
Lifestyle restrictions................................................................................................................25
6.4
Fasting Requirements..............................................................................................................26
6.5
Screen failures ........................................................................................................................26
6.6
Randomisation criteria ............................................................................................................26
7
Treatments .........................................................................................................................................27
7.1
Treatments administered .........................................................................................................27
7.1.1
Background medication .........................................................................................27
7.1.2
Medical devices .....................................................................................................28
7.2
Dose modification...................................................................................................................29
7.3
Method of treatment assignment..............................................................................................29
7.4
Blinding..................................................................................................................................29
7.5
Preparation/Handling/Storage/Accountability..........................................................................30
7.6
Treatment compliance.............................................................................................................30
7.7
Concomitant medication..........................................................................................................31
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
29 November 2018
Novo Nordisk
Trial ID: NN1436-4466
Version:
1.0
Status:
Final
Page:
3 of 90
7.7.1
Concomitant medication (diabetes) ........................................................................31
7.8
Treatment after the end of the trial...........................................................................................31
8
Discontinuation/Withdrawal criteria ................................................................................................32
8.1
Discontinuation of trial treatment ............................................................................................32
8.2
Withdrawal from the trial ........................................................................................................33
8.2.1
Replacement of subjects.........................................................................................33
8.3
Lost to follow-up.....................................................................................................................34
9
Trial assessments and procedures .....................................................................................................35
9.1
Efficacy assessments...............................................................................................................35
9.1.1
Insulin Dose...........................................................................................................35
9.1.2
Self-measured plasma glucose................................................................................36
9.1.3
Continuous glucose monitoring (CGM)..................................................................36
9.1.4
Patient Reported Outcomes....................................................................................38
9.2
Adverse events........................................................................................................................38
9.2.1
Time period and frequency for collecting AE and SAE information........................38
9.2.1.1
Event for adjudication ......................................................................40
9.2.2
Method of detecting AEs and SAEs .......................................................................41
9.2.3
Follow-up on AEs and SAEs..................................................................................41
9.2.4
Regulatory reporting requirements for SAEs ..........................................................41
9.2.5
Cardiovascular and death events.............................................................................42
9.2.6
Disease-related events and/or disease-related outcomes not qualifying as an AE 
or SAE...................................................................................................................42
9.2.7
Pregnancies and associated adverse events .............................................................42
9.2.8
Medical device incidents (including malfunctions).................................................43
9.2.9
Technical complaints .............................................................................................43
9.3
Treatment of overdose.............................................................................................................44
9.4
Safety assessments ..................................................................................................................45
9.4.1
Physical examinations............................................................................................45
9.4.2
Vital signs..............................................................................................................46
9.4.3
Electrocardiograms ................................................................................................46
9.4.4
Clinical safety laboratory assessments....................................................................46
9.4.5
Assessments in case of suspicion of hypersensitivity reaction to trial product .........47
9.5
Eye Examination.....................................................................................................................47
9.6
Pharmacokinetics ....................................................................................................................48
9.7
Pharmacodynamics .................................................................................................................48
9.8
Genetics..................................................................................................................................48
9.9
Biomarkers .............................................................................................................................48
10
Statistical considerations ...................................................................................................................49
10.1
Sample size determination.......................................................................................................49
10.2
Definition of analysis sets........................................................................................................50
10.3
Statistical analyses ..................................................................................................................51
10.3.1
Primary endpoint ...................................................................................................52
10.4
Pharmacokinetic and/or pharmacodynamic modelling .............................................................53
11
References ..........................................................................................................................................54
12
Appendices .........................................................................................................................................56
Abbreviations and Trademarks.......................................................................................56
Appendix 1
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
29 November 2018
Novo Nordisk
Trial ID: NN1436-4466
Version:
1.0
Status:
Final
Page:
4 of 90
Clinical laboratory tests ...................................................................................................58
Appendix 2
Trial governance considerations......................................................................................60
Appendix 3
Adverse events: definitions and procedures for recording, evaluation, follow-up, 
Appendix 4
and reporting .....................................................................................................................................70
Contraceptive guidance and collection of pregnancy information .................................76
Appendix 5
Technical complaints: Definition and procedures for recording, evaluation, follow-
Appendix 6
up and reporting ................................................................................................................................79
Retention of human biosamples.......................................................................................80
Appendix 7
Hypoglycaemic episodes...................................................................................................81
Appendix 8
Titration guideline............................................................................................................83
Appendix 9
Country-specific requirements ........................................................................................90
Appendix 10
Attachment I Global list of key staff and relevant departments and suppliers
Attachment II Country list of key staff and relevant departments
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
29 November 2018
Novo Nordisk
Trial ID: NN1436-4466
Version:
1.0
UTN: U1111-1219-5541
Status:
Final
EUdraCT: 2018-003407-18
Page:
5 of 90
1
Synopsis
Rationale:
NNC0148-0287 formulation C (referred to as insulin 287) is a novel long-acting insulin analogue 
designed for subcutaneous (s.c.) administration, with the aim to develop a once weekly injectable 
basal insulin treatment with the potential of becoming a more convenient choice, and to improve 
treatment adherence, and quality of life, for subjects with type 2 diabetes mellitus.
The present trial, seeks to investigate the optimal switch algorithm for insulin 287 by examining the 
effect on glycaemic control and safety parameters of insulin 287 once weekly using either the ‘unit 
to unit switch’ (e.g. 30 U of once daily insulin glargine U100 switch to 210 U of once weekly 
insulin 287), or the ‘unit to unit switch with additional 100% loading dose’ (e.g. switch from 30 U 
of once daily insulin glargine U100 to 210 U of once weekly insulin 287 and additional 210 U of 
once weekly insulin 287 as 100% loading dose) compared to insulin glargine U100 once daily. 
Subjects with type 2 diabetes mellitus (T2DM) on a basal insulin analogue will be investigated 
during 16 weeks of treatment. The trial results will be used as guidance for the selection of the 
optimal switch approach of insulin 287 in the phase 3 development programme of insulin 287.
Objectives and endpoints
Primary objective
To compare the effect on glycaemic control of treatment with once weekly insulin 287 using 2 
different switch approaches versus once daily insulin glargine U100 both in combination with 
metformin ± DPP4 inhibitors (DPP4i) in basal insulin analogue treated T2DM subjects.
Secondary objective
To compare the safety and tolerability of once weekly insulin 287 using 2 different switch 
approaches versus once daily insulin glargine U100 both in combination with metformin ± DPP4i in 
basal insulin analogue treated T2DM subjects
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
29 November 2018
Novo Nordisk
Trial ID: NN1436-4466
Version:
1.0
UTN: U1111-1219-5541
Status:
Final
EUdraCT: 2018-003407-18
Page:
6 of 90
Overall design:
!
This is a 16 weeks exploratory, multicentre, randomised, open label, active-controlled, parallel-
group trial with 3 arms investigating the effect on glycaemic control and safety of treatment 
with once weekly insulin 287 using 2 different switch approaches (either ‘unit to unit switch’ 
approach, or ‘unit to unit switch with an additional 100% loading dose’ approach, versus once 
daily insulin glargine U100 in basal insulin analogue treated subjects with T2DM inadequately 
controlled on basal insulin analogue with metformin, with or without DPP4i.
!
Subjects will be randomized at V2 and stratified to one of the three treatment arms (1:1:1).
!
The trial will recruit subjects who are currently prescribed basal insulin along with metformin 
±DDP4i for the treatment for type 2 diabetes mellitus. 
The main inclusion criterions are:   
1. Male or female, aged 18-75 years (both inclusive) at the time of signing informed consent.
2. Diagnosed with type 2 diabetes mellitus ≥ 180 days prior to the day of screening.
3. HbA1c of 7.0-10.0% (53.0-85.8 mmol/mol) (both inclusive) as assessed by central laboratory. 
4. Treated with once daily or twice daily basal insulin analogue (insulin degludec, insulin detemir, 
insulin glargine U100 or U300, total daily dose of 10-50 U, both inclusive) ≥ 90 days prior to 
the day of screening.
5. Stable daily dose(s) for 90 days prior to the day of screening of any of the following anti-
diabetic drug(s) or combination regime(s):
!
Any metformin formulations ≥ 1500 mg or maximum tolerated or effective dose (as 
documented in subjects medical records)
!
Any metformin formulations ≥ 1500 mg or maximum tolerated or effective dose with 
DPP4i ≥ half of the maximum approved dose according to local label or maximum 
tolerated or effective dose (as documented in subjects medical records)
6. Body mass index (BMI) ≤ 40.0 kg/m2
The main exclusion criterions for this trial are:
1. Known or suspected hypersensitivity to trial product(s) or related products. 
2. Female who is pregnant, breast-feeding or intends to become pregnant or is of child-bearing 
potential and not using an adequate contraceptive method. 
3. Participation in any clinical trial of an approved or non-approved investigational medicinal 
product within 90 days before screening.
4. Any disorder, except for conditions associated with type 2 diabetes mellitus, which in the 
investigator’s opinion might jeopardise subject’s safety or compliance with the protocol.
5. Any episodes of diabetic ketoacidosis within the past 90 days prior to the day of screening and 
between screening and randomisation.
6. Known hypoglycaemic unawareness as indicated by the Investigator according to Clarke’s 
questionnaire question 8.
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
29 November 2018
Novo Nordisk
Trial ID: NN1436-4466
Version:
1.0
UTN: U1111-1219-5541
Status:
Final
EUdraCT: 2018-003407-18
Page:
7 of 90
7. Recurrent severe hypoglycaemic episodes within the last year as judged by the Investigator.
8. Myocardial infarction, stroke, hospitalisation for unstable angina pectoris or transient ischaemic 
attack within 180 days prior to the day of screening and between screening and randomisation.
!
There will be three treatment arms in this trial. Two of the arms will be insulin 287 arms and a 
third arm which will be for subjects on insulin glargine U100. 
Number of subjects:
200 subjects will be screened for this trial. 150 subjects will be randomized and put on trial product 
for the duration of the trial. 
Treatment groups and duration:
All subjects will be centrally randomised in a 1:1:1 manner, and assigned to receive either insulin 
287, 700 U/mL or insulin glargine 100 U/mL throughout the 16-week treatment period. The trial 
products will be provided as prefilled pens containing 3 mL solution for s.c. injection once weekly 
(insulin 287) and once daily (insulin glargine U100) respectively. 
The dose and dosing frequency of metformin ± DPP4i should not be changed at any time during the 
trial, unless due to safety concerns.
At the screening visit, Novo Nordisk will provide all subjects with a CGM device for continuous 
glucose monitoring and a BG meter for self-measuring of plasma glucose, during the first 18 weeks 
in the trial. Subjects will be carefully trained in handling of the trial product and devices, and will 
be closely monitored and retrained during the trial. 
When discontinuing trial products, either at the scheduled end of treatment visit (V18) or if trial 
product is discontinued prematurely, the subject should be transferred to a suitable marketed 
product at the discretion of the investigator. 
CONFIDENTIAL


Protocol
UTN: U1111-1219-5541
Date:
29 November 2018
Status:
Final
Novo Nordisk
Trial ID: NN1436-4466
EUdraCT: 2018-003407-18
Version:
1.0
Page:
8 of 90
2
Flowchart
Trial Periods
Screening
Randomisation
Treatment
End of treatment
Follow up
Discontinuation 
Follow up visit1
Visit (V)
Phone contact (P)
V1
V2 V3 V4 V5 V6 P7 V8 P9 V10 P11
V12
P13
V14 P15
V16
P17
V18
V19
FU1
V20
FU2
V18A
Time of visit (weeks)2
≤ -2
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
18
21
16
Visit window (days)
±1
±1
±1
±1 ±1 ±1 ±1
±1
±1
±1
±1
±1
±1
±1
±1
±1
+3
+3
±3
SUBJECT RELATED INFORMATION AND ASSESSMENTS
Informed consent
X
In/exclusion criteria
X
X
Randomisation criteria
X
Concomitantillness/medicalhistory3
X
Concomitant medication
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X4
X4
X4
Demography5
X
Diabetes history
X
Hypoglycaemia unawareness
X6
Date of Diagnosis of Diabetes
X
1 If subjects discontinue trial product prematurely they will be asked to attend the end of treatment visit (V18) as soon as possible and have the follow up visits scheduled 
3 weeks (V19) and 6 weeks (V20) after the last day of dosing for insulin 287 and 2 weeks (V19) and 5 weeks (V20) after the last day of dosing for insulin glargine. 
Subjects will be asked to stay in site contact and continue wearing CGM (changed weekly) throughout the remaining weeks, finalised by a last visit (V18A) 16 weeks 
after randomisation.
2 Time of visit is relative to randomisation (V2).
3 Diabetes complications should be reported under medical history case report form (CRF) form.
4 Only antidiabetic medication to be collected 
5 Demography consists of date of birth or year of birth and/or age, sex, ethnicity and race (according to local regulation).
6 Information on hypoglycaemia unawareness will be recorded according to Clarke's questionnaire, question 8. The investigator must ask the subject in the following 
way: "To what extent can you tell by your symptoms that your blood glucose is low?" Subjects answering 'never, rarely or sometimes' are considered to have impaired 
awareness of hypoglycaemia


Protocol
UTN: U1111-1219-5541
Date:
29 November 2018
Status:
Final
Novo Nordisk
Trial ID: NN1436-4466
EUdraCT: 2018-003407-18
Version:
1.0
Page:
9 of 90
Trial Periods
Screening
Randomisation
Treatment
End of treatment
Follow up
Discontinuation 
Follow up visit1
Visit (V)
Phone contact (P)
V1
V2 V3 V4 V5 V6 P7 V8 P9 V10 P11
V12
P13
V14 P15
V16
P17
V18
V19
FU1
V20
FU2
V18A
Time of visit (weeks)2
≤ -2
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
18
21
16
Visit window (days)
±1
±1
±1
±1 ±1 ±1 ±1
±1
±1
±1
±1
±1
±1
±1
±1
±1
+3
+3
±3
Childbearing potential
X
Tobacco use7
X
Body measurements
Height
X
Body weight
X
X
X
X
EFFICACY
Glucose metabolism
HbA1c
X
X
X 
X
X
X
X
Fasting plasma glucose
X
X
X
Self-measured plasma glucose (SMPG)8
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
OTHER ASSESSMENTS
Continuous glucose monitoring, fitting and training9
X
X
X
X
X
X
Continuous glucose monitoring, sensor check10
X
X
X
X
X
X
X
X
X
X
X
X
Continuous glucose monitoring, upload
X
X
X
X
X
X
X
X
X
X
X
X
Diabetes Treatment Satisfaction Questionnaire
X
X
Insulin Preference Questionnaire11
X
SAFETY
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hypoglycaemic episodes
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Technical complaints
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ECG12
X
X
7 Smoking is defined as smoking at least one cigarette or equivalent daily.
8 Subjects will measure once daily pre-breakfast SMPG. 
9 Subjects will be instructed by investigator to fit the CGM sensor on site at V1-V6. After V6, sensor should be changed by subjects.
10 At each phone contact or site visit, investigator should check if subject have correctly fitted sensor, and last sensor was only used for 7 days.
11 Only applicable for subjects randomised to insulin 287 arms.


Protocol
UTN: U1111-1219-5541
Date:
29 November 2018
Status:
Final
Novo Nordisk
Trial ID: NN1436-4466
EUdraCT: 2018-003407-18
Version:
1.0
Page:
10 of 90
Trial Periods
Screening
Randomisation
Treatment
End of treatment
Follow up
Discontinuation 
Follow up visit1
Visit (V)
Phone contact (P)
V1
V2 V3 V4 V5 V6 P7 V8 P9 V10 P11
V12
P13
V14 P15
V16
P17
V18
V19
FU1
V20
FU2
V18A
Time of visit (weeks)2
≤ -2
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
18
21
16
Visit window (days)
±1
±1
±1
±1 ±1 ±1 ±1
±1
±1
±1
±1
±1
±1
±1
±1
±1
+3
+3
±3
Eye Examination
X13
X14
Physical Examination
X
X
Vital signs
X
X
X
X
Biochemistry
X
X
X
X
X
X
Lipids
X
X
X
Haematology
X
X
X
X
Pregnancytest15
X
X
X
TRIAL MATERIAL
Drug accountability
X
X
X
X
X
Dispensing visit
X
X
X
X
Doseoftrialinsulin16
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X17
X
REMINDERS
Handout ID card
X
Attend visit fasting
X
X
X
Hand out direction for use18
X
Training in trial product, pen handling
X
X
X
X
X
X
X
X
X
X
Hand out and instruct in BG meter 
X
12 Electrocardiogram (ECG) obtained within 2 weeks prior to V2 and V18 are acceptable if results are available for evaluation at the visits.
13 Eye examination obtained within 90 days prior to V2 as part of routine practise may replace the screening assessment if results are available for evaluation at V2. 
14 Eye examinations performed within 2 weeks prior to V18 are acceptable if results are available for evaluation at the visit.
15 For females of childbearing potential a serum pregnancy test must be performed at V1 and V20. At V2 and if a menstrual period is missed anytime during the trial, a 
urine pregnancy test will be taken. If a urine pregnancy test is positive, a serum sample should be taken and sent to the central laboratory for analysis.
16 The first 5 doses of once weekly insulin 287 will be taken at the site (V2 to V6).
17 The last dose of once weekly insulin 287 must be taken 15 weeks after randomisation, whereas the last dose of the once daily insulin glargine U100 must be taken 16 
weeks after randomisation where the subjects come in for the end of treatment visit (V18). This is due to the longer half life of insulin 287.
18 Directions for use can be handed out as needed at subsequent visits.


Protocol
UTN: U1111-1219-5541
Date:
29 November 2018
Status:
Final
Novo Nordisk
Trial ID: NN1436-4466
EUdraCT: 2018-003407-18
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Trial Periods
Screening
Randomisation
Treatment
End of treatment
Follow up
Discontinuation 
Follow up visit1
Visit (V)
Phone contact (P)
V1
V2 V3 V4 V5 V6 P7 V8 P9 V10 P11
V12
P13
V14 P15
V16
P17
V18
V19
FU1
V20
FU2
V18A
Time of visit (weeks)2
≤ -2
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
18
21
16
Visit window (days)
±1
±1
±1
±1 ±1 ±1 ±1
±1
±1
±1
±1
±1
±1
±1
±1
±1
+3
+3
±3
IWRS session
X
X
X
X
X
X
Hand out and instruct in diary
X
X
X
X
X
X
X
X
X
X
X
X
X
Collect, review and transcribe diaries
X
X
X
X
X
X
X
X
X
X
X
X
X
End treatment
X
End of trial
X
X


Protocol
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3
Introduction
3.1
Trial rationale
NNC0148-0287 formulation C (referred to as insulin 287) is a novel long-acting insulin analogue 
designed for subcutaneous (s.c.) administration, with the aim to develop a once weekly injectable 
basal insulin treatment with the potential of becoming a more convenient choice, and to improve 
treatment adherence, and quality of life, for subjects with type 2 diabetes mellitus.
The present trial, seeks to investigate the optimal switch algorithm for insulin 287 by examining the 
effect on glycaemic control and safety parameters of insulin 287 once weekly using either the ‘unit 
to unit switch’ (e.g. 30 U of once daily insulin glargine U100 switch to 210 U of once weekly 
insulin 287), or the ‘unit to unit switch with additional 100% loading dose’ (e.g. switch from 30 U 
of once daily insulin glargine U100 to 210 U of once weekly insulin 287 and additional 210 U of 
once weekly insulin 287 as 100% loading dose) compared to insulin glargine U100 once daily. 
Subjects with type 2 diabetes mellitus (T2DM) on a basal insulin analogue will be investigated 
during 16 weeks of treatment. The trial results will be used as guidance for the selection of the 
optimal switch approach of insulin 287 in the phase 3 development programme of insulin 287.
3.2
Background
Diabetes mellitus
Diabetes mellitus is a metabolic disorder characterised by the presence of hyperglycaemia due to 
defective insulin secretion, insulin action or both. The chronic hyperglycaemia of diabetes mellitus 
is associated with significant long term sequelae, particularly damage, dysfunction and failure of 
various organs, especially the kidney, eye, nerves, heart and blood vessels.
Type 2 diabetes is a complex disorder which involves various degrees of decreased beta-cell 
function, peripheral insulin resistance and abnormal hepatic glucose metabolism. Glucose control in 
type 2 diabetes may deteriorate progressively over time. The American Diabetes Association 
(ADA) recommend a pre-meal glucose target of 80–130 mg/dL (4.4–7.2 mmol/L) to achieve 
glycaemic control.2 On average, after failure of diet and exercise alone, subjects require a new 
intervention with glucose-lowering agents every 3-4 years in order to obtain/retain good glycaemic 
control.3 Despite combination therapy and/or insulin treatment, a sizeable proportion of subjects 
remain poorly controlled.3
Improvement in long-term glucose control, as obtained with intensified insulin therapy, was shown 
in the UK Prospective Diabetes Study4 to reduce the incidence of microvascular complications and 
delay the progression of existing complications in people with T2DM. For subjects with T2DM 
who are not achieving glycaemic goals with oral antidiabetic drugs, drug intensification, including 
insulin therapy, should not be delayed.5
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Insulin 287
Insulin 287 is a novel long-acting basal insulin analogue with a terminal elimination half-life of 
approximately 196 hours (trial NN1436-4314). The molecule consists of a peptide backbone and a 
side-chain (coupled by acylation). The peptide backbone is more resistant towards proteolytical 
degradation compared to human insulin and the side chain gives a strong binding to albumin.
Insulin 287 has been formulated as a 4200 nmol/mL solution, equivalent to 700 units/mL, 
anticipating that the insulin 287 molecule is equipotent to once-daily basal insulins. A first human 
dose trial with single doses in healthy subjects and in subjects with type 1 diabetes mellitus (T1DM)
and two multiple-dose trials in subjects with T2DM have been completed. The PK properties of 
subcutaneous insulin 287 following 5 weeks of once weekly dosing in subjects with type 2 diabetes 
were investigated in trial NN1436-4314. This trial showed that insulin 287 exposure was well 
distributed across the dosing interval, with a PK profile suitable for once weekly dosing (the
geometric mean terminal t½ of insulin 287 was approximately 196 hours), and a peak around 16 
hours followed by a slow decline. 
For the pharmacodynamic (PD) properties of s.c. insulin 287, evaluated by glucose clamp, the 
glucose infusion rate response was evenly distributed across the dosing interval. In addition, insulin 
287 was well tolerated in subjects with T2DM. No safety concerns were identified after multiple 
once-weekly dosing in the dose range of 12−24 nmol/kg (2-4 U/kg). No serious or severe adverse 
events (AEs) were reported. No hypersensitivity reactions were reported.  
For further information on previous trials, please refer to the Investigators Brochure (IB).
Insulin glargine U100
Insulin glargine U100 is a once daily long-acting insulin analogue, indicated for treatment of 
diabetes mellitus in combination with oral antidiabetic agents and as part of a basal-bolus insulin 
regimen. Insulin glargine U100 is widely used basal insulin world-wide and has therefore been 
selected as comparator in the current trial. For further details, please refer to the European 
Medicines Agency (EMA) Summary of Product Characteristics for insulin glargine (Lantus®)6, U.S. 
Label Information7 and manufactures label.
Metformin
Together with life style interventions metformin is considered a first-line antidiabetic therapy in 
subjects with T2DM.5 Metformin is a product from the biguanide compound group. Metformin 
lowers plasma glucose levels without increasing the circulating insulin concentrations through 
lowering of the hepatic glucose output and increased insulin sensitivity. For further details, please 
refer to the EMA Summary of Products Characteristics for Metformin8 or locally approved Product 
Information.
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Trial ID: NN1436-4466
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Dipeptidyl peptidase 4 inhibitors
Dipeptidyl peptidase 4 inhibitors (DPP4i) can be used as second line oral anti-diabetic drugs in 
combination with Metformin.9 DPP4i prevent the hydrolysis of incretin hormones, thereby 
increasing plasma concentrations of the active forms of glucagon-like peptide-1 and glucose-
dependent insulinotropic polypeptide. Incretin hormones are released by the intestine throughout the 
day, and levels are increased in response to a meal. The incretins are part of an endogenous system 
involved in the physiologic regulation of glucose homeostasis. By enhancing active incretin levels, 
DPP4i increase insulin release and decrease glucagon levels in a glucose-dependent manner. For 
further details, please refer to the EMA Summary of Products Characteristics for the relevant DPP4i 
or locally approved Product Information.
3.3
Benefit-risk assessment
3.3.1
Benefits
Insulin 287 is currently in development for treatment of diabetes mellitus. Insulin 287 has in first 
human dose and multiple dose trials been shown to have a long and stable PK and PD profile 
supporting a once-weekly treatment. Currently available long-acting basal insulin products need to 
be administered once daily to provide 24-hour coverage. Research has shown that people with 
T2DM put value in reducing the number of insulin injections.10 Therefore, the compliance and 
quality of life are expected to increase by introducing a once-weekly basal insulin treatment.
The trial population will consist of subjects with type 2 diabetes insufficiently controlled on basal
insulin and, metformin ±DPP4i. For all subjects participating in this 16 week trial, the anticipated 
benefits include improved glycaemic control. Titration algorithms, specifying recommended 
adjustments of basal insulin dose at different plasma glucose levels, are used in order to ensure that 
subjects receive an optimal treatment. Subjects will receive intense medical care by means of close 
contact to the clinical sites with weekly contacts.
3.3.2
Risks
Identified risks for insulin 287 describe undesirable clinical outcomes for which there is sufficient 
evidence that they are caused by insulin 287. Potential risks in this section describe undesirable 
clinical outcomes for which there is scientific evidence to suspect the possibility of a causal 
relationship with insulin 287, but where there is currently insufficient evidence to conclude that this 
association is causal.11
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Date:
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Trial ID: NN1436-4466
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Identified risks
!
Hypoglycaemia
Hypoglycaemia is a common undesirable effect related to the pharmacological mechanism of 
insulin. To mitigate the risk of hypoglycaemia in this trial, blood glucose (BG) measurements will 
be made throughout the drug exposure period, and will prevent worsening of hypoglycaemia by 
early detection and administration of carbohydrates and medical treatment, if necessary.
Potential risks
!
Injection site reactions
Injection site reactions may occur with all injectable drugs. No injection site reactions were reported 
in trial NN1436-4314 with insulin 287. However, in this trial investigators and subjects will be 
asked to pay careful attention to injection site reactions at the place of injection; investigators 
should ensure careful monitoring and medical evaluation in case of injection site reaction 
occurrence. For further information on injection site reactions, please refer to Section 9.4.5.
!
Hypersensitivity reactions
Severe systemic hypersensitivity reactions may potentially occur following injection of therapeutic 
proteins.  No hypersensitivity reactions were reported in trial NN1436-4314 with insulin 287. 
During the treatment period in this trial, subjects will have weekly contacts with the site either at 
visits to the site or with phone contacts. Subjects and investigators will be instructed for signs and 
symptoms of allergic reactions and be instructed to contact the site immediately in case of signs of 
hypersensitivity. For further information on hypersensitivity reactions, please refer to Section 9.4.5.
!
Antibody formation leading to change in clinical effect
An increase in anti-insulin 287 specific antibodies and anti-human insulin antibodies were observed 
for some subjects in trial NN1436-4314 trial with insulin 287. No hypersensitivity reactions were 
observed in this trial. Moreover, in trial NN1436-4314 higher antibody levels seemed to be 
associated with a longer terminal half-life and reduced clearance for insulin 287. In case of a 
systemic hypersensitivity reaction, blood sampling for assessment of antibodies against insulin 287 
will be conducted. For more information, please refer to Section 9.4.5.
!
Increase in hepatic enzymes
Transient increases in hepatic enzymes upon initiation of s.c. insulin are considered as potential 
risks due to the pharmacological mechanism of insulin. An increase in hepatic enzyme was 
observed in nonclinical studies in rats and dogs. No clinically significant changes in hepatic 
biomarkers have been observed in humans following the administration of insulin 287. In this trial, 
measurements of hepatic biomarkers will be performed at frequent intervals.
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events of insulin 287 may be found in the investigator’s brochure and any updates 
hereof.
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Date:
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Trial ID: NN1436-4466
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3.3.3
Conclusion on the benefit risk profile
Based on the non-clinical and clinical development programme, it has been concluded that insulin 
287 is similar to human insulin with respect to pharmacological action and non-clinical safety. 
Insulin 287 was generally well tolerated within the evaluated dose ranges in the first-in-human, 
single dose escalation trial conducted in healthy subjects, in subjects with T1DM and in the multiple 
dose trial in subjects with T2DM. No safety concerns have been observed with insulin 287; neither 
elevation in hepatic enzymes nor clinical consequences following antibody formation have been 
reported. With insulin 287, no hypersensitivity reactions and injection site reactions were observed. 
To mitigate the risk of hypoglycaemia in this trial, frequent blood glucose measurements will be 
made throughout drug exposure. Therefore, it can be concluded that the risk to the subjects in this 
trial is considered low. The risk is acceptable in view of the benefits a basal insulin with a longer 
action profile than currently available would provide to subjects with diabetes. The overall benefit-
risk profile of insulin 287 is anticipated to be favourable.
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Protocol
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Date:
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Trial ID: NN1436-4466
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4
Objectives and endpoints
4.1
Primary, secondary and exploratory objectives
4.1.1
Primary objective
To compare the effect on glycaemic control of treatment with once weekly insulin 287 using two
different switch approaches versus once daily insulin glargine U100 both in combination with 
metformin ± DPP4i in basal insulin analogue treated T2DM subjects
4.1.2
Secondary objective
To compare the safety and tolerability of once weekly insulin 287 using 2 different switch 
approaches versus once daily insulin glargine U100 both in combination with metformin ± DPP4i in 
basal insulin analogue treated T2DM subjects
Primary estimand
The primary estimand is defined as the mean difference in ‘time in target range 3.9-10.0 mmol/L 
(70–180 mg/dL)’ during the last 2 weeks of treatment (week 15 and 16) between each of the 2 
different switch approaches of once weekly insulin 287 and once daily insulin glargine U100 for all 
randomised subjects, if all subjects had adhered to the randomised insulin treatment and had 70% of 
the planned continuous glucose monitoring (CGM) measurements recorded.
The following intercurrent events for the primary estimand will be handled by the hypothetical 
strategy: initiation of insulin treatment other than the randomised treatment, discontinuation of 
randomised insulin treatment, withdrawal from the trial, and recording of less than 70% of planned 
CGM measurements in the last two weeks of treatment. Other intercurrent events will be handled by 
the treatment policy strategy. This estimand aims to reflect the estimated treatment effect for 
subjects that had adhered to the planned insulin treatment during the planned treatment period.
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4.2
Primary, secondary and exploratory endpoints
4.2.1
Primary endpoint
Endpoint title*
Time frame
Unit
Time in target range 3.9–10.0 mmol/L (70-
180 mg/dL) measured using CGM
During the last 2 weeks of treatment 
(week 15 and 16)
Percent
*The primary endpoint is based on data recorded by continuous glucose monitoring (CGM) system, Dexcom G6 ®.
4.2.2
Secondary endpoints
4.2.2.1
Confirmatory secondary endpoints
Not applicable in this trial. 
4.2.2.2
Supportive secondary endpoints
Supportive secondary efficacy endpoints
Endpoint title 
Time frame
Unit
Change in HbA1c
From baseline week 0 (V2) to week 16 
(V18)
%-point 
Change in fasting plasma glucose (FPG)
From baseline week 0 (V2) to week 16 
(V18)
mmol/l 
Change in body weight
From baseline week 0 (V2) to week 16 
(V18)
Kg 
Weekly insulin dose**
During the last 2 weeks of treatment 
(week 15 and 16)
U
**Investigators will record administered insulin dose for both insulin glargine U100 and insulin 287 subjects. For 
insulin glargine U100, investigators will enter the daily administered doses in the CRF and for those on the insulin 287 
treatment, enter the weekly administered doses. 
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Supportive secondary safety endpoints
Endpoint title 
Time frame
Unit
Number of treatment emergent adverse 
events (TEAEs) 
From baseline week 0 (V2) to week 21 
(V20)
Count of 
events
Number of severe hypoglycaemic episodes 
(level 3)
From baseline week 0 (V2) to week 16 
(V18)
Count of 
events
Number of clinically significant 
hypoglycaemic episodes (level 2) (<3.0 
mmol/L (54 mg/dL), confirmed by BG meter) 
or severe hypoglycaemic episodes (level 3)
From baseline week 0 (V2) to week 16 
(V18)
Count of 
events
Number of hypoglycaemic alert episodes 
(level 1) (≥3.0 and <3.9 mmol/L (≥54 and 
<70 mg/dL), confirmed by BG meter)
From baseline week 0 (V2) to week 16 
(V18)
Count of 
events
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5
Trial design
5.1
Overall design
This is a 16 weeks exploratory, multicentre, randomised, open label, active-controlled, parallel-
group trial with 3 arms investigating the effect on glycaemic control and safety of treatment with 
once weekly insulin 287 using 2 different switch approaches (either ‘unit to unit switch with an 
additional 100% loading dose’ approach, referred in the trial design as arm A or ‘unit to unit switch’ 
approach, referred in the trial design as arm B) versus once daily insulin glargine U100 (arm C) in 
basal insulin analogue treated subjects with T2DM inadequately controlled on basal insulin 
analogue with metformin, with or without DPP4i. The overall trial design and visit schedule are 
outlined in Figure 5-1 and trial flowchart (see Section 2) respectively. 
Figure 5-1
Trial design
Subjects will be randomly allocated to receive once weekly insulin 287 using one of the 2 switch 
approaches (arm A and B) or once daily insulin glargine U100 (arm C). The randomisation will be
stratified based on prior basal insulin analogue twice daily treatment or insulin glargine U300 
treatment. The trial duration is approximately 23 weeks and consists 2 weeks of screening period, 
16 weeks of randomised treatment period, and 5 weeks follow-up period. The trial includes a 
screening visit (Visit 1) to assess subject’s eligibility. From screening visit (after signed informed 
consent) until randomisation, all subjects will be required to measure daily pre-breakfast self-
measured plasma glucose (SMPG) and have 10 days baseline continuous glucose monitoring
(CGM) profile collected. After screening, all eligible subjects will be randomised (1:1:1) at Visit 2. 
During the 16 weeks treatment period, subjects will have weekly contact with the site either at site 
visits (9 visits) or by phone (6 phone contacts). To evaluate the effect on glycaemic control, subjects 
will have CGM profiles collected during the 16 weeks treatment period. The CGM will be blinded 
for both subjects and investigator.     
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After 16 weeks of treatment subjects will come in for their end of treatment visit (V18). The end of 
treatment visit will be one week after the last dose of insulin 287 and on the day of or the day after 
the last dose of insulin glargine U100. This will be followed by 2 follow up visits (V19 and V20). 
The last follow up visit (V20) is scheduled to take place 6 weeks after the last dose of once weekly 
insulin 287 and 5 weeks after the last dose of once daily insulin glargine U100. This will allow for 
appropriate wash-out of trial drug, following at least 5 half-lives of insulin 287. 
The dose and dosing frequency of metformin ± DPP4i should not be changed at any time during the 
trial, unless due to safety concerns. This will be done at the discretion of the investigator. 
Event adjudication will be performed for major adverse cardiovascular events (MACE), death, and 
hypersensitivity reactions (see Section 9.2.1.1 and Appendix 4).
The follow-up period is 5 weeks.
5.2
Subject and trial completion
Approximately 200 subjects will be screened to achieve 150 subjects randomly assigned to trial 
product. The estimated number of subjects to complete the trial (on trial product) is 143.
Trial period completion for a subject:
Trial period completion is defined as when the randomised subject has completed the final 
scheduled visit V18 ('end of trial' according to the flowchart).
'Date of trial completion' is the date the subject completed the final scheduled visit (V20).
Treatment period completion for a subject: 
Treatment period completion is defined as when the randomised subject has received the 16 weeks 
required treatment, and attended the 'end of treatment' visit (V18) according to the flowchart.
Treatment emergent period for a subject:
The treatment emergent period represents the period where subjects are considered exposed to trial 
product. It starts at the first date of exposure to the randomised treatment and ends at the last 
follow-up visit (V20), thus includes a time period after last dose of randomised treatment 
corresponding to approximately 5 half-lives of insulin 287 once weekly dose.
For subjects who discontinues treatment, but do not attend the last follow up visit (V20): Last 
dosing day of randomised treatment + 5 weeks for insulin glargine U100 once daily, and last dosing 
day of randomised treatment + 6 weeks for insulin 287 once weekly.
5.3
End of trial definition
The end of the trial is defined as the date of the last visit of the last subject in the trial.
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5.4
Scientific rationale for trial design
The trial is designed to investigate the effect on glycaemic control and safety of once-weekly 
insulin 287 using two different switch algorithms with either a ‘unit to unit switch’, or a ‘unit to unit 
switch with an additional 100% loading dose’ versus once-daily insulin glargine U100 during 16 
weeks of treatment.
Currently, basal insulins with the longest duration are dosed once daily. In order to compare to well-
established and widely used basal insulin with once daily dosing, insulin glargine U100 has been 
chosen as comparator. The treatment arms will be open label as it was not considered feasible to 
blind the two insulin 287 arms and the insulin glargine U100 arm due to the high number of 
injections required to make a double-blind, double dummy trial resulting in an increased burden on 
the subjects.
The treatment duration of 16 weeks has been chosen as an adequate time to assess effect on 
glycaemic control as well as safety and tolerability. This duration will also allow for up-titrating the 
basal insulin. The treat-to-target approach has been chosen in order to ensure optimal titration of 
insulin based on self-measured plasma glucose (SMPG) values with the aim of improving HbA1c in 
the period.
Subjects included in the trial will already be on basal insulin treatment, ensuring trial population 
representative for the relevant patient group (see Section 6 regarding the subject population). All 
will use first line treatment metformin. Use of DPP4i in addition to metformin is allowed but not a 
requirement. To include a more homogenous study population, other oral antidiabetic drugs are not 
allowed.
Titration of insulin 287 and insulin glargine are based on three pre-breakfast SMPG values 
measured on two days prior to titration and on the day of the contact. CGM values will be used to 
generate profiles for evaluating the effect on glycaemic control.
To safeguard subjects, the inclusion and exclusion criteria defined in this trial will limit the trial 
population to subjects not suffering from underlying diseases other than T2DM and related diseases,
such as hypertension or dyslipidaemia. This is to avoid compromising the safety of the subjects 
participating in the trial and to strengthen conclusions regarding the efficacy and, safety of once-
weekly insulin 287.
During the treatment period, the subjects will have weekly contacts with the site either at site visits 
or phone contacts and the first 5 administrations of once-weekly insulin 287 will be done at the site. 
After the injections at the site, the subjects should stay at least one hour for observation. This 
applies only for those treated on the insulin 287 arms. The last follow-up visit is planned to be 6 
weeks after last dose of insulin 287, allowing appropriate time for wash-out of trial drug, following 
at least 5 half-lives of insulin 287.
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Ethical considerations 
All subjects must only be included after a thorough evaluation with regards to defined in- and 
exclusion criteria in order to ensure that subjects are eligible for trial treatment. Subjects will be 
treated with a treat-to-target insulin regimen anticipated to improve glycaemic control compared to 
their pre-trial treatment. To participate in the trial subjects will have to spend some extra time, as 
additional assessments and visits to the clinic are required. Three of the visits will also require that 
the subject is fasting for blood sampling. In case of lack of efficacy of trial product, the subject will 
be prematurely discontinued, see Section 8.1 regarding discontinuation of trial treatment.
The trial products may be associated with adverse reactions, of which hypoglycaemia is the most 
common. For further information, please refer to the Investigator’s Brochure for insulin 287 and 
local label for insulin glargine U100. Relevant precautions have been implemented in the design 
and planned conduct of the trial in order to minimise the risks and inconveniences of participation. 
These precautions include thorough information regarding the correct administration of the trial 
products and handling of the CGM device. The first 5 doses (V2-V6), along with handling and 
fitting of the CGM will be administered at the site by the site personnel. The insulin dose will be 
adjusted gradually and closely supervised. Furthermore, subjects will be informed about possible 
adverse reactions and inconveniences and will be instructed to contact the investigator in case of 
any concerns regarding the trial participation.
5.5
Justification for dose
Insulin glargine U100 will be initiated at the same dose as the pre-trial basal insulin and insulin 287 
will be initiated at 7 times the pre-trial basal insulin dose.
One unit (U) of Insulin 287 has similar glucose lowering effect as one U of insulin glargine U100, 
and therefore once-weekly dosing corresponds to 7 times the daily dose of the once daily 
comparator.
The PK/PD properties of Insulin 287 following 5 weeks of once weekly dosing in subjects with 
T2DM (trial NN1436-4314) showed that insulin 287 exposure was well distributed across the 
dosing interval, with a PK profile suitable for once weekly dosing. Insulin 287 was well tolerated in 
subjects with T2DM and no safety concerns were identified after multiple once-weekly dosing in 
the dose range of 12−24 nmol/kg (2-4 U/Kg).
For subjects randomised to insulin 287 100% loading dose arm: It takes 3-5 doses before reaching 
the full effect of insulin 287. Theoretically subjects may therefore need additional insulin to 
maintain glycaemic control the first weeks after initiation. Modelling data suggest that adding a 
100% loading dose may prevent deterioration of the glycaemic control during the first weeks of 
treatment without jeopardising safety. Therefore the approach of 100% loading dose has been 
chosen; hence no additional insulin is permitted after V2.
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To reduce the risk of subjects experiencing hypoglycaemia in the initial treatment phase subjects 
switching from a twice daily basal insulin regiment and a once daily regimen with insulin glargine 
U300 will have their dose reduced by 20%. This is applicable for all treatment arms.
After randomisation at V2, subjects will start once daily and once-weekly injections on the same 
day. This treatment will continue until 15 weeks after randomisation. At this time point the last once 
weekly injection must be taken while the once daily injections are taken until 16 weeks after 
randomisation where the subjects come in for the end of treatment visit (V18). This is due to the 
longer half-life of insulin 287. 
Further details on dose adjustment can be found in Appendix 9, titration guideline
6
Trial population
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known as 
protocol waivers or exemptions, is not permitted.
6.1
Inclusion criteria
For an eligible subject, all inclusion criteria must be answered “yes”. 
1. Informed consent obtained before any trial-related activities. Trial-related activities are any 
procedures that are carried out as part of the trial, including activities to determine suitability for 
the trial.
2. Male or female, aged 18-75 years (both inclusive) at the time of signing informed consent.
3. Diagnosed with type 2 diabetes mellitus ≥ 180 days prior to the day of screening.
4. HbA1c of 7.0-10.0% (53.0-85.8 mmol/mol) (both inclusive) as assessed by central laboratory. 
5. Treated with once daily or twice daily basal insulin analogue (insulin degludec, insulin detemir, 
insulin glargine U100 or U300, total daily dose of 10-50 U, both inclusive) ≥ 90 days prior to 
the day of screening.
6. Stable daily dose(s) for 90 days prior to the day of screening of any of the following anti-
diabetic drug(s) or combination regime(s):
!
Any metformin formulations ≥ 1500 mg or maximum tolerated or effective dose (as 
documented in subjects medical records)
!
Any metformin formulations ≥ 1500 mg or maximum tolerated or effective dose with 
DPP4i ≥ half of the maximum approved dose according to local label or maximum 
tolerated or effective dose (as documented in subjects medical records)
7. Body mass index (BMI) ≤ 40.0 kg/m2
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6.2
Exclusion criteria 
For an eligible subject, all exclusion criteria must be answered “no”. 
1. Known or suspected hypersensitivity to trial product(s) or related products. 
2. Previous participation in this trial. Participation is defined as signed informed consent. 
3. Female who is pregnant, breast-feeding or intends to become pregnant or is of child-bearing 
potential and not using an adequate contraceptive method.
For Czech Republic and Germany, please see country specific requirements in Appendix 10.
4. Participation in any clinical trial of an approved or non-approved investigational medicinal 
product within 90 days before screening.
5. Any disorder, except for conditions associated with type 2 diabetes mellitus, which in the 
investigator’s opinion might jeopardise subject’s safety or compliance with the protocol.
6. Any episodes of diabetic ketoacidosis within the past 90 days prior to the day of screening and 
between screening and randomisation.
7. Known hypoglycaemic unawareness as indicated by the Investigator according to Clarke’s 
questionnaire question 8.
8. Recurrent severe hypoglycaemic episodes within the last year as judged by the Investigator.
9. Myocardial infarction, stroke, hospitalisation for unstable angina pectoris or transient ischaemic 
attack within 180 days prior to the day of screening and between screening and randomisation.
10. Presently classified as being in New York Heart Association (NYHA) Class IV.
11. Planned coronary, carotid or peripheral artery revascularisation, between screening and 
randomisation.
12. Renal impairment measured as estimated Glomerular Filtration Rate (eGFR) value of eGFR   
<60 ml/min/1.73 m2 as defined by KDIGO 2012.
13. Impaired liver function, defined as Alanine Aminotransferase (ALT) ≥ 2.5 times or Bilirubin 
>1.5 times upper normal limit at screening
14. Inadequately treated blood pressure defined as Grade 3 hypertension or higher (Systolic ≥180 
mmHg or diastolic ≥110 mmHg) at screening.
15. Treatment with any medication for the indication of diabetes or obesity other than stated in the 
inclusion criteria within the past 90 days prior to the day of screening.
16. Uncontrolled and potentially unstable diabetic retinopathy or maculopathy. Verified by a fundus 
examination performed within the past 90 days prior to screening or in the period between 
screening and randomisation. Pharmacological pupil-dilation is a requirement unless using a 
digital fundus photography camera specified for non-dilated examination.
17. Presence or history of malignant neoplasms within 5 years prior to the day of screening. Basal 
and squamous cell skin cancer and any carcinoma in-situ are allowed
6.3
Lifestyle restrictions
Not applicable for this trial.
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6.4
Fasting Requirements
The subjects should be fasting when attending some of the visits, see flowchart, Section 2.
Fasting is defined as at least 8 hours without food and drink intake, except for water and other 
prescribed medication. Trial product and other glucose lowering agents should be withheld on the 
day of the fasting visit until blood sampling and body weight have been performed. Any other 
prescribed medication should be taken as usual. If the subject attends a fasting visit in a non-fasting 
state the blood sampling and body weight procedures should be re-scheduled to the next day.
6.5
Screen failures
Screen failures are defined as subjects who consent to participate in the clinical trial but are not 
eligible for participation according to in/exclusion criteria. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure subjects to meet 
requirements from regulatory authorities. Minimal information includes demography, screen failure 
details, eligibility criteria, and any serious adverse events (SAE). A screen failure session must be 
made in the interactive web response system (IWRS). 
Individuals who do not meet the criteria for participation in this trial may not be rescreened. Re-
sampling is not allowed if the subject has failed one of the inclusion criteria or fulfilled one of the 
exclusion criteria related to laboratory parameters. However, in case of technical issues (e.g. 
haemolysed or lost), re-sampling is allowed for the affected parameters. 
6.6
Randomisation criteria 
To be randomised, the randomisation criterion must be answered "yes".
!
Subject able and willing to adhere to the protocol including daily SMPG measurements and 
wearing CGM sensor based on the Investigator’s judgment.
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7
Treatments
7.1
Treatments administered
!
All investigational medical products (IMPs) are listed in Table 7-1
!
Trial product must only be used, if it appears clear and colourless. 
!
The investigator must document that directions for use are given to the subject orally and in 
writing at the first dispensing visit (as specified in the flowchart).
Table 7-1
Trial products provided by Novo Nordisk A/S
Trial product name and 
strength:
(NNC0148-0287 C)
4200 nmol/mL (insulin 287)
(Investigational medicinal 
product (IMP), test product)
Insulin glargine,
100 U/mL 
(IMP, reference therapy)
Dosage form & Route of 
administration:
solution for s.c. injection
solution for s.c. injection
Site of injection
Thigh
Thigh
Dosing instructions (see 
Appendix 9for titration 
guidelines):
Insulin 287 should be injected 
subcutaneously once weekly at 
the same day of the week, 
anytime during the day, 
preferably at the same time of 
the day throughout the trial.
Insulin glargine U100 should be 
injected subcutaneously once
daily at anytime of the day, but 
at the same time every day 
throughout the trial.
Packaging:
3 ml pre-filled PDS290 pen-
injector with 7U increments
3 mL SoloSTAR® pre-filled 
pen-injector with 1U 
increments.
For Germany: For country specific information please refer to Appendix 10.
7.1.1
Background medication
After randomisation subjects must continue their pre-trial oral anti-diabetic background medication 
with metformin ± DPP4i throughout the trial. The background medication must be maintained at the 
stable, pre-trial dose and at the same frequency during the entire treatment period unless due to 
safety concerns related to the background medication. In addition, the background medication:
!
is considered to be non-investigational medicinal product
!
will not be provided by Novo Nordisk A/S unless required by local law and should be purchased 
or otherwise delivered to subjects in accordance with local health plans
!
should be used in accordance with standard of care or local label in the individual country
!
any changes to the background medication must be updated in the case report form (CRF).
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7.1.2
Medical devices
PDS290 Pen Device
!
Insulin 287 will be provided in a PDS290 pre-filled pen with 7U increments, each pen-injector 
contains 3 ml insulin 287 corresponding to 2100 units, solution for injection.
!
The subjects must be trained according to the direction for use in how to handle the PDS290 
pen-injector when handed out the first time. 
!
Training must be repeated during the trial at regular intervals in order to ensure correct use of 
the PDS290 pen-injector.
!
The following should be emphasized: 
!
Always use a new needle for each injection as this will prevent contamination and ensure 
correct dose.
!
Only needles provided and/or approved by Novo Nordisk must be used for administration 
of trial product.
!
Remember to prime the pen-injector to ensure product flow
The PDS290 pen-injector to be used in this trial has not been approved for marketing. The PDS290 
pen-injector has been documented to be in compliance with the relevant essential requirements of 
Annex I of the Council directive 93/42/EEC 14, and compliance for the indication for use in adults 
with T2DM has been verified by the notified body, Lloyds. In this trial, the PDS290 pen-injector 
will be used in accordance with the verified intended use and indication for use.
The PDS290 pen-injector is not under investigation and there is no intent to use the results from this 
trial to support a new marketing application or extension of an existing marketing approval.
SoloSTAR Pen®
!
Insulin Glargine U100 will be provided as the marketed SoloSTAR® pen, containing 3 ml 
insulin glargine corresponding to 300U solution for injection. The pens will not be modified but 
labelled for clinical trial use.
!
The subjects must be trained according to the direction for use in how to handle the SoloSTAR
® pen when handed out the first time. 
!
Training must be repeated during the trial at regular intervals in order to ensure correct use of 
the SoloSTAR® pen.
!
The following should be emphasized:
!
Always use a new needle for each injection as this will prevent contamination and ensure 
correct dose.
!
Only needles provided and/or approved by Novo Nordisk must be used for administration 
of trial product.
!
Remember to prime the pen-injector to ensure product flow
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Continuous Glucose Monitoring (CGM)
For monitoring of continuous glucose during the first 18 weeks in the trial, Novo Nordisk will 
provide all subjects with a CGM device (sensor, transmitter, receiver, and guide).
A PC with internet connection must be available at site (same PC as used for the CRF system can 
be utilised). For further instruction and requirements, please see the user manual and guides 
provided.
Novo Nordisk will ensure that trial site staff receives appropriate training with regards to the use of 
the CGM devices. Furthermore site staff should familiarise themselves with the CGM user manual 
and guides before using the CGM devices. Subjects must be instructed in handling of the CGM and 
sensor change according to Section 9.1.3 as indicated in the flowchart, Section 2.
The CGM receiver should be collected at site at end of treatment visit (V18) and returned to Novo 
Nordisk after the trial.
Blood glucose meters
For self-measuring of blood glucose during the trial, Novo Nordisk will provide subjects with a BG 
meter at the screening visit (V1) including auxiliaries and instructions for use.
The subjects must be instructed in how to use the BG meter as indicated in the flowchart, Section 2. 
The BG meters use test strips calibrated to plasma values. Therefore, all measurements performed 
with capillary blood are automatically calibrated to plasma equivalent glucose values, which will be 
shown on the display
7.2
Dose modification
Doses are adjusted according to plasma glucose values as described in details in Titration guideline 
Appendix 9.
7.3
Method of treatment assignment
All subjects will be centrally randomised using an IWRS and assigned to the next available 
treatment according to randomisation schedule. Trial product will be dispensed at the trial visits 
summarised in the flowchart Section 2.
7.4
Blinding
This is an open-label trial. 
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7.5
Preparation/Handling/Storage/Accountability
Only subjects randomized in the trial may receive trial product and only authorised site staff may 
supply or administer trial product. The subject must return all used, partly used and unused trial 
product including empty packaging materials during the trial as instructed by the investigator.
!
The investigator must document, that directions for use are given to the subject verbally and in 
writing, at the first dispensing visit (V2). Directions for use can be handed out as needed at 
subsequent visits.
!
Conditions for storage are specified on the label and in the trial materials manual.
!
Each trial site will be supplied with sufficient trial products for the trial on an on-going basis, 
controlled by the IWRS. Trial product will be distributed to the trial sites, according to 
screening and randomisation.
!
The investigator is responsible for the confirmation of that appropriate temperature conditions 
have been maintained during transit, for all trial products received and any discrepancies are 
reported and resolved, before use of the trial products.
!
All trial products must be stored in a secure, access controlled, and temperature monitored 
(manual or automated) area in accordance with the labelled storage conditions, with access 
limited to the investigator and authorised site staff.
!
The investigator must inform Novo Nordisk immediately if any trial product has been stored 
outside specified conditions. Additional details regarding handling of temperature deviations 
can be found in the trial materials manual. 
!
Trial product that has been stored improperly must not be dispensed to any subject, before it has 
been evaluated and approved for further use by Novo Nordisk.
!
The investigator is responsible for drug accountability and record maintenance (i.e. receipt, 
accountability and final disposition records).
!
The subject should return all used, partly used and unused trial product including empty 
packaging materials, during the trial as instructed by the investigator.
!
Drug accountability should be performed on pen level and must be documented in the IWRS.
!
Destruction of trial products can be performed on an ongoing basis and will be done according 
to local procedures after accountability is finalised by the site and reconciled by the monitor. 
!
Destruction of trial products must be documented in the IWRS. 
!
All returned, expired or damaged trial products (for technical complaint samples see Appendix 
6) must be stored separately from non-allocated trial products. No temperature monitoring is 
required.
!
Non-allocated trial products including expired or damaged products must be accounted as 
unused, at the latest at closure of the trial site. 
7.6
Treatment compliance
Throughout the trial, the investigator will remind the subjects to follow the trial procedures and 
requirements to ensure subject compliance. The investigator should assess the compliance of the 
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subject at each contact (visit or phone contact) by evaluating the glycaemic control and adherence 
to the visit schedule, completion of the subject´s diary; including SMPG values, dose and 
hypoglycaemia reporting. If a subject is found to be non-compliant the investigator will remind the 
subject of the importance of following the instructions including taking the trial products as 
prescribed. Re-training will be provided as needed by the site.
To limit the risk of using multiple pens simultaneously, subjects randomised to insulin 287 and 
insulin glargine U100 will only receive the lowest possible amount of pen-injectors, still ensuring 
sufficient supplies, allowing for up-titration between the dispensing visits, see flowchart, Section 2.
7.7
Concomitant medication
Any medication other than the trial product that the subject is receiving at the time of the first visit 
(V1) or receives during the trial must be recorded along with:
!
Trade name or generic name
!
Indication
!
Dates of administration including start and stop dates
7.7.1
Concomitant medication (diabetes)
For metformin and DPP4i (if used), the following additional information must be recorded:
!
Start date of current dose and total daily dose. The dose should not be changed at any time 
during the trial, unless due to safety concerns
!
For new anti-diabetic medication prescribed in the follow up period, start date of current dose 
and total daily dose must also be recorded
Until end of treatment (V18) only randomised treatment (trial products and metformin with or 
without DPP4i) are allowed. If the investigator chooses to initiate other anti-diabetic medication, or 
change dose of metformin, or DPP4i prior to end of treatment (V18), this should be registered in the 
CRF as change in concomitant medication (diabetes). 
Changes in concomitant medication must be recorded at each visit. If a change is due to an adverse 
event (AE) or serious adverse event (SAE), then this must be reported according to Section 9.2
7.8
Treatment after the end of the trial
When discontinuing trial products, either at the scheduled end of treatment visit (V18) or if trial 
product is discontinued, the subject should be transferred to a suitable marketed product at the 
discretion of the investigator. If the switch to post-trial treatment includes a new insulin treatment, 
please refer to the titration guideline Appendix 9 for more information
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8
Discontinuation/Withdrawal criteria 
All efforts should be made to keep subjects on trial products.
The subject may be discontinued at any time during the trial, at the discretion of the investigator for 
safety, behavioural, compliance or administrative reasons. 
Efforts must be made to have the subjects, who discontinue trial product prematurely, attend the end 
of treatment visit (V18) and have the follow up visits V19 and V20 performed. Subjects should be 
asked to continue wearing CGM (changed weekly) throughout the remaining weeks, finalised by a 
last visit (V18A) 16 weeks after randomisation. To support the subjects with this, sites should stay 
in contact e.g. by phone calls or site visits to collect the required data for the analysis of the primary 
endpoint.
Only subjects who withdraw consent will be considered as withdrawn from the trial. Subjects must 
be educated about the continued scientific importance of their data, even if they discontinue trial 
product.
8.1
Discontinuation of trial treatment
The subject must be discontinued from trial product, if the following applies:
1. Safety concern related to trial product or unacceptable intolerability 
2. Included in the trial in violation of the inclusion and/or exclusion criteria
3. Pregnancy
4. Intention of becoming pregnant
5. Simultaneous participation in another clinical trial of an approved or non-approved 
investigational medicinal product.
6. Lack of efficacy, defined as fulfilment of all 4 criteria below:
a. No reduction in HbA1c measured by central laboratory from randomisation (V2) to visit 6, to 
visit 10, or to visit 14, AND
b. The pre-breakfast SMPG readings on 3 consecutive days higher than 240 mg/dL (13.3 
mmol/L) within the last two weeks period despite appropriate dose adjustments AND 
c. A confirmatory fasting plasma glucose (FPG) exceeding 240 mg/dL (13.3 mmol/L) measured 
by central laboratory. The subject should come in for an unscheduled visit as soon as 
possible (within one week). The next scheduled visit should not be awaited AND 
d. No treatable intercurrent cause (e.g. non-compliance) for the hyperglycaemia at the 
investigator’s judgment
If a subject is discontinued, the investigator must ask the subject if he/she is willing, as soon as 
possible, to have assessment performed according to end of treatment visit (V18) and to come in for 
the follow up visits V19 and V20. Subjects should be asked to continue wearing CGM (changed 
weekly) throughout the remaining weeks finalised by a last visit (V18A) 16 weeks after 
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randomisation. To support the subjects with this, sites should stay in contact e.g. by phone calls or 
site visits.
See the flowchart in Section 2 for data to be collected at the time of treatment randomisation and 
follow up visits V19, V20, and V18A.  
The primary reason for discontinuation of trial product must be specified in the CRF, and final drug 
accountability must be performed. A treatment discontinuation session must be made in the IWRS.
A subject who does not fulfil the eligibility (inclusion/exclusion/randomisation) criteria must not be 
randomised. Randomisation in violation of any of the eligibility criteria is Good Clinical Practice 
(GCP) non-compliance and must be reported to the sponsor without delay. This will be handled as 
an important protocol deviation, and the Independent Ethics Committee/Institutional Review Board
(IEC/IRB) and regulatory authorities must be notified according to local requirements. If there is no 
safety concerns, trial treatment may be continued or resumed at the discretion of the investigator 
after agreement with the sponsor's global medical expert.
8.2
Withdrawal from the trial
A subject may withdraw consent at any time at his/her own request. If a subject withdraws consent, 
the investigator must ask the subject if he/she is willing, as soon as possible, to have assessment 
performed according to end-of-treatment visit V18 and to come in for the follow up visits V19, and 
V20. See the flowchart in Section 2 for data to be collected. 
Final drug accountability must be performed even if the subject is not able to come to the trial site. 
A treatment discontinuation session must be made in the IWRS. 
If a subject withdraws from the trial, he/she may request destruction of any samples taken and not 
tested, and the investigator must document this in the medical record.
If the subject withdraws consent, Novo Nordisk may retain and continue to use any data collected 
before such a withdrawal of consent.
Although a subject is not obliged to give his/her reasons for withdrawing, the investigator must 
make a reasonable effort to ascertain the reasons, while fully respecting the subject's rights. Where 
the reasons are obtained, the primary reason for withdrawal must be specified in the end of trial 
form in the CRF.
8.2.1
Replacement of subjects
Subjects who discontinue trial product or withdraw from trial will not be replaced.
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8.3
Lost to follow-up
A subject will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the trial site. 
The following actions must be taken if a subject fails to return to the trial site for a required visit:
!
The site must attempt to contact the subject and reschedule the missed visit as soon as possible 
and counsel the subject on the importance of maintaining the assigned visit schedule and 
ascertain whether or not the subject wishes to and/or should continue in the trial.
!
Before a subject is deemed lost to follow-up, the investigator must make every effort to regain 
contact with the subject (where possible, at least three telephone calls and, if necessary, a 
certified letter to the subject's last known mailing address or local equivalent methods). These 
contact attempts should be documented in the subject's source document.
!
Should the subject continue to be unreachable, he/she will be considered to have withdrawn 
from the trial with a primary reason of lost to follow-up. 
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9
Trial assessments and procedures
Trial procedures and their timing are summarised in the flowchart in Section 2. Adherence to the
trial design requirements, including those specified in the flowchart, is essential and required for 
trial conduct.
!
Informed consent must be obtained before any trial related activity, see Appendix 3.
!
All screening evaluations must be completed and reviewed to confirm that potential subjects 
meet all eligibility criteria. 
!
The investigator will maintain a screening log to record details of all subjects screened and to 
confirm eligibility or record reason for screen failure, as applicable.
!
At screening, subjects will be provided with a card stating that they are participating in a clinical
trial and giving contact details of relevant trial site staff. 
!
All protocol-required laboratory assessments, as defined in Appendix 2, must be conducted in 
accordance with the flowchart in Section 2 and the laboratory manual.
!
Repeat samples may be taken for technical issues and unscheduled samples or assessments may 
be taken for safety reasons See Appendix 2 for further details on laboratory samples. 
!
Review of completed diaries, electrocardiograms (ECGs), laboratory reports, eye and physical 
examinations must be documented either on the documents (by signing and dating) or in the 
subject's source documents, including patient diaries. 
!
If clarification of entries or discrepancies in the diary is needed, the subject must be questioned 
and a conclusion made in the subject's source documents. Care must be taken not to bias the 
subject.
!
Source data of clinical assessments performed and recorded in the CRF must be available and 
will usually be in the subject’s medical records. Additional recording to be considered source 
data includes, but is not limited to diary data, laboratory reports, Dexcom G6 ® data, BG meter, 
pictures and electrocardiogram (ECG) recordings. 
For United States: Please refer to country specific information in Appendix 10.
9.1
Efficacy assessments
The efficacy laboratory assessments HbA1c and FPG are collected according to the time points 
provided in the flowchart, Section 2. For further details on laboratory tests see Appendix 2.
9.1.1
Insulin Dose
During the trial, starting at the screening visit (V1), subjects must be instructed to report daily 
SMPG measurements in the diary. 
From V2 subjects should be instructed to record insulin glargine U100 doses taken the last two days 
prior to titration and on the day of the contact, in the diary, exception being week 15 and 16 where 
doses must be collected every day. All insulin 287 doses must be entered in the diary. 
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At each visit or phone contact the Investigator will recommend to either titrate up or down or 
remain on the same dose based on the SMPG values measured on the two previous days and the day 
of the contact. The investigator must base the new recommended dose on the applicable titration 
algorithm assigned to that subject as per randomisation, see titration guideline Appendix 9, for 
further information.
The Investigator must record the following in the CRF:
!
Date, dose and injection time of insulin 287 or insulin glargine U100
!
Prescribed doses of insulin 287 and insulin glargine U100; i.e. what the investigator tells the 
subject to take
!
Reason for deviation from the recommended dose, as applicable
For dosing of anti-diabetic medication prescribed in the follow up period please see Section 7.7
9.1.2
Self-measured plasma glucose  
Subjects will be provided with a BG meter including auxiliaries as well as instructions for use. The 
subjects will be instructed in how to use the device and the instruction will be repeated at regular 
intervals as indicated in the flowchart, Section 2. 
The BG meters use test strips calibrated to plasma values. Therefore, all measurements performed 
with capillary blood are automatically calibrated to plasma equivalent glucose values, which will be 
shown on the display. 
Only the BG meter provided by Novo Nordisk should be used for the measurements required in the 
trial. 
Subjects should be instructed in how to record the results of the SMPG values in the diaries. The 
record of each SMPG value should include date, time and value. All data from the diary must be 
transcribed into the CRF during or following the contact. If obtained via phone and a discrepancy is 
later detected, the values in the CRF must be corrected.
Occasional review by the investigator of the BG meter values stored in the memory of the BG meter 
and correct reporting of these in the diary is advised in order to ensure adequacy of the data reported 
in the trial database. 
9.1.3
Continuous glucose monitoring (CGM)
As indicated in the flowchart (see Section 2), all subjects will wear CGM during screening and,
throughout the 16 week treatment period from V1 to V18. 
The CGM system used in this trial will be the Dexcom G6® which consists of three parts:
!
the sensor, applied under the skin on the subjects abdomen.
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!
the transmitter, which is placed on top of the sensor
!
the receiver, a hand held device used to store the data received from the transmitter
The sensor is pre-calibrated during manufacturing and requires no finger stick calibration during 
use. The sensor measurements performed in the interstitial fluid are automatically calibrated to 
plasma equivalent glucose values. The CGM readings will be blinded to both the subject and 
investigator and will not be used for any insulin dose titration or hypoglycaemic episode reporting. 
CGM fitting and training
The sensor must be applied under the skin of the subject’s lower abdomen, using the sensor 
applicator as described in the Operator’s user guide. When applied, a thin, flexible, and sterile fibre 
is inserted just under the skin of the subject, allowing the measurement of glucose concentration in 
the interstitial fluid.
For this trial the subject will change their CGM sensor at every site visit and phone contact (see 
flow chart Section 2) during the 18 week treatment period. The site staff will fit the sensor and 
transmitter on the subject during the first 6 clinic visits (V1 to V6). The site staffs are responsible 
for providing appropriate training during visit V1 to V6, to the subject on how to apply the sensor 
by themselves. 
From P7 to V18, including phone contacts (P7 to P15), the subject will change the sensor by 
themselves. At V10, the site will replace the transmitter during sensor change.
When a new sensor is applied to the subject it is important to enter the new sensor code into the 
receiver and to check that date and time is correct on the receiver. This will ensure that the sensor is 
calibrated to the receiver. 
For further information on fitting, and changing of the CGM parts, please refer to the user manual. 
If a subject withdraws consent during the trial, a site visit must be scheduled in order to remove the 
sensor and download the data from the receiver. At the end of the trial, the subject must return all 
CGM material, including any unused sensor, receiver and other materials to the site staff.
CGM sensor check
From P7 till V18, the site staff should ensure that the subject has correctly fitted the sensor, the 
receiver is working, and sensors are changed at every site visit and phone contact. This will be done 
in person during the clinic visit and over the phone during phone contacts.
CGM upload
Data stored on the receiver must be uploaded at the site to the provided CGM software program, 
following the instructions from the user guide provided to sites. 
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The upload will be documented by the system directly.
The following information must be recorded and transferred into the CRF for every CGM period:
!
Serial number of the CGM receiver
!
Sensor fitting date and time
!
Sensor removal date and time
9.1.4
Patient Reported Outcomes
There are two patient reported outcome questionnaires in this trial. They are: 
!
Diabetes Treatment Satisfaction Questionnaire (DTSQ)
!
Insulin Preference Questionnaire
All subjects (in all three arms of treatment) taking part in this trial will complete the Diabetes 
Treatment Satisfaction Questionnaire at V2 and V18. The questionnaire is in paper format and will 
be completed at site by the subject. 
Only subjects who are treated on the insulin 287 arms must also complete the Insulin Preference 
Questionnaire at V18 during their end of treatment clinic visit. 
9.2
Adverse events
The definitions of AEs and SAEs can be found in Appendix 4.
The investigator is responsible for detecting, documenting, recording and following up on events 
that meet the definition of an AE or SAE.
9.2.1
Time period and frequency for collecting AE and SAE information
All AEs will be collected from the first trial-related activity after obtaining informed consent and 
until the follow up visit/end of trial visit (V20), at the time points specified in the flowchart. 
All SAEs will be recorded and reported to Novo Nordisk or designee within 24 hours, as indicated 
in Appendix 4. The investigator must submit any updated SAE data to Novo Nordisk within 24 
hours of it being available.
Investigators are not obligated to actively seek for AE or SAE in former trial subjects. However, if 
the investigator becomes aware of any SAE, including a death, at any time after a subject has been 
discontinued from/completed the trial, and the investigator considers the event to be 
possibly/probably related to the investigational trial product or trial participation, the investigator 
must promptly notify Novo Nordisk.
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The method of recording, evaluating and assessing causality of AE and SAE and the procedures for 
completing and transmitting SAE reports are provided in Appendix 4. Care should be taken not to 
introduce bias when detecting AEs and/or SAEs. Open-ended and non-leading verbal questioning of 
the subject is the preferred method to inquire about events.
Timelines for reporting of AEs, and events for adjudication, are listed in Figure 9-1.
Some AEs require additional data collection via a specific event form. This includes medication 
errors observed during the trial. The relevant specific events are listed in Table 9-1and the reporting 
timelines in Figure 9-1.
AE identified
Is the event to be 
adjudicated
AE form ≤  24 hours
SIF ≤5 calendar days
Sign off ≤ 7 calendar days
Is the AE serious or 
non-serious?
AE form*
Is the AE listed as 
requiring a Specific Event 
Form to be completed?
Source data collection 
and upload to Event 
Adjudication System ≤4 
weeks
Non-serious
Serious
No
Yes
No additional action
No
Specific event form
For SAE:
≤14 calendar days
Yes
Timelines are from the awareness of an AE.
Queries and follow-up requests to be resolved ≤14 calendar days.
AE: Adverse Events, SAE: Serious Adverse Events, SIF: Safety Information Form
* NRQVHULRXVK\SRJO\FDHPLFHSLVRGHVVKRXOGEHUHSRUWHGRQDGHGLFDWHG
K\SRJO\FDHPLFIRUPRQO\
No additional action
Figure 9-1
Decision tree for determining the event type and the respective forms to 
complete with associated timelines
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Table 9-1
AEs requiring additional data collection (via specific event form), and events for 
adjudication
AE requiring additional data 
collection via event specific 
form 
(Appendix 4)
AE for adjudication requiring 
source document upload to Event 
Adjudication System (EAS)
(Section 9.2.1.1, Appendix 4 and 
Event Adjudication Site Manual )
Acute coronary syndrome 
X
Cerebrovascular event 
X
Heart failure
X
Death 
X
Hypersensitivity 
X
Injection site reactions
X
X
Medication error
X
Hypoglycaemic episode a,b
X
a Non-serious hypoglycaemic and hyperglycaemic episodes should be reported on dedicated hypoglycaemic and 
hyperglycaemic forms only.
b For details about specific event forms, see Section 9.2.6.
9.2.1.1
Event for adjudication
Event adjudication will be performed for adverse events in randomised subjects. The list of events 
for adjudication can be found in Figure 9-1 and the reporting timelines in Figure 9-1. These events 
are reviewed by an independent external event adjudication committee (EAC) in a blinded manner; 
refer to Appendix 3 for further details.
There are 3 ways to identify events relevant for adjudication as described below:
1. Investigator reported events for adjudication: 
!
All AEs reported with a relevant AE category (Figure 9-1) selected based on predefined 
criteria (Appendix 4)
!
All AEs reported with a fatal outcome
2. Preferred term search (standardised screening): 
!
All AEs recorded in the CRF but not directly reported by the investigator as requiring 
adjudication, will undergo screening to identify potential events for adjudication.
3. Event Adjudication Committee (EAC)-identified events: 
!
During review of source documents provided for another event for adjudication, the EAC 
may identify additional events in scope for adjudication that were not initially reported by 
the investigator. In these instances, the investigator will be notified of the newly identified 
event and has the option to report the EAC-identified event. Regardless of whether the 
investigator decides to report the event, it will undergo adjudication. 
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For all the scenarios listed above, investigator must collect copies of all relevant source documents 
specific to the event type as outlined in the Event Adjudication Site Manual. All source documents 
should be labelled with trial ID, subject number and AE number, anonymised of any treatment or
personal identifiers and uploaded to the Event Adjudication System (EAS) as soon as possible and 
preferably within 4 weeks according to instructions in the Event Adjudication Site Manual. Specific 
labelling and redaction requirements apply to digital pictures (see Section 9.4.5 and the Event 
Adjudication Site Manual for details). All follow up regarding source documents will be handled in 
the EAS. If no, or insufficient source documents are provided to the adjudication supplier, the 
investigator can be asked to complete a clinical narrative to be uploaded to the EAS.
If new information related to a reported event where source documents have previously been 
provided becomes available, it is the responsibility of the investigator to ensure that the new 
information is reflected in both the CRF and uploaded to the EAS.
The assessments made by both the EAC and the investigator will be analysed and included in the 
clinical trial report.
9.2.2
Method of detecting AEs and SAEs
Care should be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and non-
leading verbal questioning of the subject is the preferred method to inquire about events.
9.2.3
Follow-up on AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each subject at 
subsequent visits/contacts. All SAEs will be followed until resolution, stabilization, or if the event 
is otherwise explained (e.g. chronic condition) or the subject is lost to follow-up (as defined in
Section 8.3). Further information on follow-up procedures is given in Appendix 4.
9.2.4
Regulatory reporting requirements for SAEs
Prompt notification by the investigator to Novo Nordisk of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of subjects and the safety of a trial 
product under clinical investigation are met. 
Novo Nordisk has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a trial product under clinical investigation. Novo Nordisk 
will comply with country-specific regulatory requirements relating to safety reporting to the 
regulatory authority, IRB/IEC, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory requirements 
and Novo Nordisk policy and forwarded to investigators as necessary.
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An investigator who receives an investigator safety report describing a SAE or other specific safety 
information (e.g. summary or listing of SAEs), from Novo Nordisk will review and then file it 
along with the investigator's brochure and will notify the IRB/IEC, if appropriate according to local 
requirements.
9.2.5
Cardiovascular and death events
Cardiovascular and death events will be handled and reported according to AE/SAEs description in 
Section 9.2.1.
9.2.6
Disease-related events and/or disease-related outcomes not qualifying as an AE or 
SAE
The following Disease-Related Events (DREs) are common in subjects with T2DM and can be 
serious/life threatening:
!
Hypoglycaemic episodes
Definitions, classification and reporting requirements are described in Appendix 4.
Hypoglycaemia
Non-serious hypoglycaemia must be reported on a hypoglycaemic episode form only (refer to 
Figure 9-1).
If the hypoglycaemic episode fulfils the criteria for an SAE then in addition to the above, an AE 
form and a safety information form must also be filled in. One AE form and safety information 
form can cover several hypoglycaemic episode forms, if the subject has not recovered between the 
episodes.
9.2.7
Pregnancies and associated adverse events
Details of pregnancies in female subjects will be collected after the first-trial-related activity after 
obtaining informed consent and until the pregnancy outcome and the new born infant is one month 
of age.
If a pregnancy is reported in female subjects, the investigator should inform Novo Nordisk within 
14 calendar days of learning of the pregnancy and should follow the procedures outlined in 
Figure 9-2 and Appendix 5. 
Pregnancy outcome should be documented in the subject's medical record. Abnormal pregnancy 
outcome (e.g. spontaneous abortion foetal death, stillbirth, congenital anomalies and ectopic 
pregnancy) is considered an SAE.
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Maternal form 1b
 14 calendar days after birth
Maternal form 1a
 14 calendar days
After birth/
termination 
of pregnancy
No additional 
action
Normal outcome 
Maternal form 2  14 calendar days
Paternal form*1  14 calendar days
Abnormal outcome 
Pregnancy 
verified
*1 Further information collected on Paternal form for male partners of 
female subjects requires signing of specific informed consent .
AE/SAEs in connection with the pregnancy and in the foetus/newborn 
should follow the timelines in Figure 9.1.
Prior to 
birth or 
pregnancy 
termination 
For female subjects
Figure 9-2
Decision tree for determining the forms to complete with associated timelines 
for pregnancy. 
9.2.8
Medical device incidents (including malfunctions)
Refer to technical complaints in Section 9.2.9.
9.2.9
Technical complaints
Technical complaints will be collected for all trial products listed on the technical complaint (TC) 
form in the CRF.
The investigator must assess whether a technical complaint is related to an AE.
The definitions and reporting process for technical complaints can be found in Appendix 6.
Timelines for reporting technical complaints are listed in Figure 9-3. 
Technical Complaints related to the CGM devices or BG meters and associated auxiliaries must be 
reported directly to the supplier/manufacturer.
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Technical complaint form: KRXUV
AE form: KRXUV
SIF: FDOHQGDUGD\V
,VLWUHODWHG
WRDQ6$("
Technical complaint 
identified
,VLWUHODWHG
WRDQ$("
Yes
No
Technical complaint form
FDOHQGDUGD\V
Technical complaint form: 
FDOHQGDUGD\V
AE form: FDOHQGDUGD\V
No
Yes
AE: Adverse Event, SAE: Serious Adverse Event,  SIF: Safety Information Form
Figure 9-3
Decision tree for determining the forms to complete with associated timelines 
for technical complaints. 
9.3
Treatment of overdose
Accidental overdose must be reported as a medication error. Intentional overdose is considered 
abuse or misuse of trial product and must be reported as an AE. Refer to Section 9.2.1 and
Figure 9-1 for further details.
In the event of an overdose, the investigator should closely monitor the subject for overdose-related 
AE/SAE and laboratory abnormalities until the blood glucose is normalised and (or) 
signs/symptoms have been relieved. 
The administration of insulin, including an overdose of insulin, may result in hypoglycaemia. 
Symptoms usually occur suddenly and may include cold sweat, nervousness or tremor, anxious 
feelings, unusual tiredness, confusion, difficulty in concentration, excessive hunger, temporary 
vision changes, headache, nausea and palpitation. Prolonged or severe hypoglycaemia can lead to a 
loss of self-control, spasms, and/or unconsciousness and, in extreme cases, death. As with all long-
acting insulin preparations, their prolonged effect may delay recovery from a hypoglycaemic 
episode. 
A specific overdose for insulin 287 cannot be defined; however, hypoglycaemia may develop over 
sequential stages if the doses administered are too high relative to the subject’s requirements:
!
Mild hypoglycaemia can be treated by oral administration of glucose or sugary products.
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!
Severe hypoglycaemia, where the subject is not able to treat him/herself, can be treated by 
glucagon (0.5 to 1 mg) given intramuscularly or s.c. by a trained person, or by glucose 
given intravenously by a medical professional. Glucose must also be given intravenously, if 
the subject does not respond to glucagon within 10-15 minutes. If the subject has been 
unconscious, administration of oral carbohydrates is recommended for the subject upon 
regaining consciousness, in order to prevent a relapse.
Decisions regarding dose interruptions or modifications will be made by the investigator based on 
the clinical evaluation of the subject.
For more information on overdose, also consult the current version of Investigator’s Brochure (IB)
for insulin 287 and Summary of Product Characteristics for insulin glargine U100.6
9.4
Safety assessments 
Planned time points for all safety assessments and subject relation information are provided in the 
flowchart Section 2.
Medical history is a medical event that the subject has experienced in the past. Only relevant 
concomitant illness and medical history as judged by the investigator should be reported. 
A concomitant illness is any illness that is present at the start of the trial (i.e. at the first visit) or 
found as a result of a screening procedure or other trial procedures performed before exposure to 
trial product. 
The information collected for concomitant illness and medical history should include diagnosis, 
date of onset and date of resolution or continuation, as applicable.
In case of an abnormal and clinically significant finding, the investigator must record the finding on 
the Medical History/Concomitant Illness form if it is present at screening. Any new finding 
fulfilling the AE definition (see Appendix 4) during the trial and any clinically significant 
worsening from baseline (V1) must be reported as an AE (see Section 9.2).
For handling of hypoglycaemic episodes; see Appendix 8
9.4.1
Physical examinations
A physical examination will include assessments of:
!
Head, ears, eyes, nose, throat, neck
!
Cardiovascular system
!
Respiratory system
!
Gastrointestinal system including mouth
!
Musculoskeletal system 
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!
Central and peripheral nervous system
!
Skin 
Body measurements will also be measured and recorded as specified in the flowchart.
!
Body weight should be measured in kilogram (kg) or pounds (lb) without coat and shoes 
wearing only light clothing. Body weight will be recorded to one decimal.
!
Body weight should be assessed with the same equipment throughout the trial, if possible. 
!
Height should be assessed without shoes. Height is measured in centimetres (cm) or inches (in) 
at screening visit (V1) and recorded to the nearest whole number
!
From the body weight and height the BMI will be calculated in the CRF.
Investigators should pay special attention to clinical signs related to previous serious illnesses.
9.4.2
Vital signs
!
Pulse rate as well as diastolic and systolic blood pressure will be assessed.
!
Blood pressure and pulse measurements should be preceded by at least 5 minutes of rest for the 
subject in a quiet setting, in the same position at each of the 4 visits, without distractions (e.g. 
television, cell phones).
!
Blood pressure at screening will consist of 3 diastolic and systolic blood pressure measurements 
with intervals of at least 1 minute. All three readings must be entered in the CRF and the 
average of the 3 blood pressure readings will be calculated in the CRF. At the subsequent visits, 
the blood pressure should only be measured once.
!
Blood pressure and pulse measurements will be assessed with a completely automated device. 
Manual techniques will be used only if an automated device is not available.
9.4.3
Electrocardiograms
!
A 12-lead electrocardiogram (ECG) must be performed by the investigator or delegated staff as 
outlined in the flowchart, Section 2 using an ECG machine that automatically calculates the 
heart rate and measures PR, QRS, QT and QTc intervals. 
!
The ECG must be interpreted, signed and dated by the investigator to verify that the data has 
been reviewed. 
!
The ECG at screening must be done at the latest at V2 and the results interpreted by the 
investigator before randomisation in order to determine the eligibility of the subject. 
9.4.4
Clinical safety laboratory assessments
All protocol-required laboratory assessments, as defined in Appendix 2, must be conducted in 
accordance with the laboratory manual and the flowchart in Section 2.
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9.4.5
Assessments in case of suspicion of hypersensitivity reaction to trial product
Subjects and investigators will be instructed to detect signs and symptoms of hypersensitivity 
reactions to trial product:
!
Local reactions, including injection site reactions and 
!
Systemic reactions, including anaphylaxis
In the event of a hypersensitivity reaction: 
!
The subject should contact the site for advice on further action as soon as possible.
!
Treatment should be provided by the investigator according to local clinical practice.
Digital pictures
!
The investigator or the subject should take digital pictures of the hypersensitivity reaction at 
time of identification and thereafter as often as judged necessary by the investigator. 
!
The pictures should include subject identification number, date and time, time after dosing and a 
ruler for scaling. All pictures should be stored as part of source documentation at site. 
Additional blood samples
In the event of a systemic hypersensitivity reaction (defined in Appendix 4), as judged by the 
investigator, the subject should be called in as soon as possible to have additional blood samples 
taken in order to analyse the following parameters: 
!
Tryptase (optimal 0.5 – 2 hours post reaction)
!
Total IgE
!
Anti-NNC0148-0287 IgE antibodies 
!
Anti-NNC0148-0287 binding antibodies
!
Histamine release (basophil) assay 
!
Anti-human insulin IgE antibodies
The blood sampling should be repeated 2 to 4 weeks following the systemic hypersensitivity 
reaction. The results will be provided from the central laboratory and should be included in the 
documentation provided for event adjudication on the systemic and local hypersensitivity reaction.
Refer to Appendix 4 for further information about evaluation and reporting of hypersensitivity 
reactions. For information about sample retention; see Appendix 7. 
9.5
Eye Examination
Subjects with uncontrolled and potentially unstable diabetic retinopathy or maculopathy are not 
eligible as this indicates retinopathy that has recently progressed to a level that requires intervention 
or is approaching intervention, but has yet to be brought under control. Results of an eye 
examination performed by an ophthalmologist or another suitably qualified health care provider 
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(e.g. optometrist) must be available and evaluated by the investigator before randomisation to assess 
eligibility. 
The eye examination should be performed as a fundus photography (e.g. 2-field 60 degree or better, 
colour or red-free) or by slit-lamp biomicroscopy examination (e.g. using a pre-corneal or corneal 
contact lens examination). Pharmacological pupil-dilation is a requirement unless using a digital 
fundus photography camera specified for non-dilated examination. If the subject had such an eye 
examination performed within 90 days prior to screening, the investigator may base his/her 
evaluation upon the results of that examination. 
The examination must be repeated before randomisation if the subject has experienced worsening of 
visual function since the last examination. If the applicable eye examination was performed before 
the subject signed the informed consent form, it must be documented that the reason for performing 
the examination was not related to this trial. After randomisation an eye examination performed 
according to above must be performed as per the flowchart in Section 2. 
The investigator should indicate the outcome of each eye examination. Relevant findings prior to 
randomisation must be recorded as concomitant illness/medical history, while relevant findings 
occurring after randomisation should be reported as an AE, if applicable according to Section 9.2.
9.6
Pharmacokinetics
Not applicable for this trial.
9.7
Pharmacodynamics
Not applicable for this trial.
9.8
Genetics
Not applicable for this trial.
9.9
Biomarkers
Not applicable for this trial. 
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10 Statistical considerations 
10.1
Sample size determination 
The primary estimand is defined as the mean difference in ‘time in target range 3.9-10.0 mmol/L 
(70–180 mg/dL)’ during the last 2 weeks of treatment (week 15 and 16) between each of the 2 
different switch approaches of once weekly insulin 287 (arm A and B) and once daily insulin 
glargine U100 (arm C) for all randomised subjects, if all subjects had adhered to the randomised 
insulin treatment and had 70% of the planned CGM measurements recorded during the last two 
weeks of the planned treatment period (week 15 and 16). The following intercurrent events for the 
primary estimand will be handled by the hypothetical strategy: initiation of insulin treatment other 
than the randomised treatment (hereafter defined as rescue medication), discontinuation of 
randomised insulin treatment, recording of less than 70% of planned CGM measurements in the last 
two weeks of treatment, and withdrawal from the trial. Hence, measurements collected after these
intercurrent events are handled as missing data for the primary estimand.
The sample size calculation is based on the width of the 95% confidence interval (CI). Data from 
insulin degludec treated subjects in trial NN9068-3697 showed a standard deviation (SD) of 2.5 
hour for a 24h period after 26 weeks of treatment and for time in range defined as 3.9-10.0 mmol/L 
(70–180 mg/dL). NN9068-3697 was conducted in insulin naïve subjects with T2DM and used older 
CGM devices (iPro1 and iPro2). Another trial in T1DM subjects NN1250-3874 with insulin 
glargine U100 as comparator used the Dexcom SEVEN® PLUS CGM device which is considered 
more representative for the present trial as there have been notable improvements in the CGM-
devices. In this trial a SD of 3.0 hour in the last maintenance period was observed for time in range 
defined as 3.9-10.0 mmol/L (70–180 mg/dL). However, the titration periods were only four weeks 
in NN1250-3874. The SD for the current trial is assumed to be 3.0 based on observations from these 
two trials. Table 10-1 shows the width of the 95% confidence interval for any pairwise comparison 
that can be obtained with 80% probability for a range of sample sizes and assumed values of SD.
Table 10-1
Width of the 95% CI for various SD and number of subjects per treatment arm
Number per treatment arm
SD
40
50
60
2.5
2.4
2.1
1.9
3.0
2.9
2.5
2.3
3.5
3.3
3.0
2.7
CI: confidence interval. SD: standard deviation.
With 50 subjects randomised to each treatment arm in a 1:1:1 manner, the width of the 95% for any 
pairwise comparison is 2.5 h/24h with a probability of 80%. Two-and-a-half hour corresponds to 
approximately 10%-point for percent time in range.
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10.2
Definition of analysis sets
The following analysis sets will be defined:
Full analysis set (FAS): includes all randomised subjects. Subjects in the FAS will contribute to 
evaluation “as randomised”.
Safety analysis set (SAS): includes all subjects exposed to at least one dose of trial product. 
Subjects in the SAS will contribute to the evaluation based on the trial product received for the 
majority of the period they were on treatment. This will be referred to as contributing to the 
evaluation “as treated”. 
The relevant observations periods are
In-trial: This observation period represents the time period after randomisation where subjects are 
considered to be in the trial, regardless of discontinuation of trial product or initiation of rescue 
medication. The in-trial observation period starts at randomisation (as registered in IWRS) and ends 
at the date of: 
!
The last direct subject-site contact, which is scheduled to take place 6 weeks after planned last 
dose of once weekly trial product and 5 weeks after last dose of once daily trial product at a 
follow-up visit (phone visit) 
!
Withdrawal for subjects who withdraw their informed consent
!
The last subject-investigator contact as defined by the investigator for subjects who are lost to 
follow-up
!
Death for subjects who die before any of the above
!
For subjects not randomised but exposed to trial product the in-trial period starts at the date of 
first dose of trial product.
On-treatment: This observation period represents the time period where subjects are considered 
exposed to trial product. The observation period is a sub-set of the in-trial observation period. It 
starts at the date of first dose of trial product, the observation period ends at the first date of any of 
the following:
!
The follow-up visit (FU2)
!
The last date on trial product + 5 weeks for once daily insulin and +6 weeks for once weekly 
insulin
!
The end-date for the in-trial observation period
On-treatment without rescue medication: This observation period is a sub-set of the on-treatment 
observation period, where subjects are considered treated with randomised insulin product, and 
have not initiated a non-randomised inulin treatment. Specifically, the period starts at the date of 
first dose of trial product and ends at the first date of any of the following:
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!
The last dose of trial product + 5 weeks for once daily insulin and +6 weeks for once weekly 
insulin
!
Initiation of a non-randomised insulin treatment
The ’on-treatment without rescue medication’ observation period will be the primary observation 
period for efficacy evaluations. Safety will be evaluated based on the in -trial and the on-treatment 
observation periods unless otherwise specified.
Data points collected outside an observation period will be treated as missing in the analysis. 
Baseline data will always be included in an observation period. Before data are locked for statistical 
analysis, a review of all data will take place. Any decision to exclude either a subject or single 
observations from the statistical analysis is the joint responsibility of the members of the Novo 
Nordisk study group.
Exclusion of data from analyses will be used restrictively and normally no data should be excluded 
from the FAS. The subjects or observations to be excluded, and the reasons for their exclusion will 
be documented and signed by those responsible before database lock. The subjects and observations 
excluded from analysis sets, and the reason for this, will be described in the clinical trial report.
10.3
Statistical analyses
All efficacy endpoints will be summarised using the full analysis set (FAS) and safety assessments 
will be summarised using the safety analysis set (SAS).
All statistical analysis of efficacy and safety endpoints will be based on the FAS unless otherwise 
specified. Confirmatory analysis addressing the primary estimand will be based on on-treatment 
data without rescue medication.
Endpoints will be assessed at frequent visits and also for subjects who prematurely discontinue 
treatment. The baseline value is defined as the value from the randomisation visit. If this value is 
missing the last recorded value before randomisation visit will be used.
Laboratory values below the lower limit of quantification (LLOQ) will be set to ½LLOQ.
Presentation of results from a statistical analysis will include the estimated treatment means as well 
as estimated mean treatment difference (or ratio) together with the two-sided 95% confidence 
interval and corresponding two-sided p-value.
In the statistical models baseline value of the endpoint value will be included as a covariate and 
explanatory factors will be categorized as follows:
!
Treatment: switch approach with 100% loading dose, switch approach without loading dose, 
insulin glargine U100 
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10.3.1
Primary endpoint
The primary endpoint is ‘time in target range 3.9–10.0 mmol/L (70-180 mg/dL)’ during the last 2 
weeks of treatment (week 15 and 16). The percentage of time spent in glycaemic target range will 
be calculated as 100 times the number of recorded measurements in glycaemic target range 3.9–
10.0 mmol/L (70-180 mg/dL), both inclusive divided by the total number of recorded 
measurements. 
Following international consensus criteria14 it will be required that at least 70% of the planned 
CGM measurements, during the last two weeks of treatment is available, for endpoint data to be 
included in the analysis. 
The primary estimand will be estimated based on the Full Analysis Set (FAS) using measurements 
obtained while subjects are adhering to randomised treatment without initiation of rescue 
medication. Measurements obtained after initiation of rescue treatment and endpoint data from 
which the required 70% of the planned CGM measurements during the last two weeks of treatment 
are not available will be regarded as missing. Missing endpoint data will be imputed from trial 
participants who are from the same randomised group, and who have completed and adhered to 
their randomised insulin treatment without initiation of a non-randomised insulin treatment i.e., data 
will be imputed based on the assumption that, within treatment groups, subjects with missing 
endpoint data will behave like subjects completing randomised treatment. Specifically, the 
imputations and analyses will be carried out as follows: 
!
First, one thousand (1000) copies of the dataset will be generated for time in range.
!
Second, for each dataset copy, each assessment and each treatment group, an analysis of 
variance (ANOVA) model with baseline 'time in target range' as covariate will be fitted to the 
time in range values for subjects having completed their randomised treatment. The estimated 
mean, and variances, from the model will be used to impute missing values in the same 
treatment group.
!
For each of the complete data sets, the primary endpoint will be analysed using an ANOVA 
model with randomised treatment as fixed factor and baseline 'time in target range' as covariate, 
the analysis will be stratified according to pre-trial insulin treatment (twice daily or insulin 
glargine U300). The estimates and standard deviations for the 1000 data sets will be pooled to 
one estimate and associated standard deviation using Rubin’s rule.
!
Each pairwise treatment contrast with 95% CI will be presented.
Baseline ‘time in target range’ will be derived the same way as the primary endpoint.
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Efficacy endpoints
The secondary efficacy endpoints will be addressed in terms of the frame work of the primary 
estimand.
The secondary efficacy endpoints addressing glycaemic control and body weight will be analysed 
using the same model as specified for the primary model with the exception that baseline value of 
the endpoint will be used as covariate. Missing data will be imputed similarly as for the primary 
endpoint, but using a sequential approach where available data from scheduled visits during the trial 
are used to impute missing data for subsequent scheduled visits.
The insulin doses will be analysed log-transformed and without a covariate reflecting baseline dose 
but otherwise using the same statistical model as specified for the primary model. 
Safety endpoints
Adverse events
A treatment-emergent AE is an event that has onset date (or increase in severity) during the on-
treatment observation period. These will therefore be referred to as ‘on-treatment AEs’ hereafter. 
On-treatment AEs are summarised descriptively in terms of the number of subjects with at least one 
event (N), the percentage of subjects with at least one event (%), the number of events (E) and the 
event rate per 100 years (R). These summaries are replicated by outputs including all ‘in-trial’ AEs 
(i.e., AEs with onset date [or increase in severity] during the ‘in-trial’ observation period). 
The most frequent AEs will be defined as preferred terms that are experienced by at least 5% of the 
subjects in any of the treatment arms. 
All AEs will be coded using the most recent version of the Medical Dictionary for Regulatory 
Activities (MedDRA) coding.
Hypoglycaemic episodes
Hypoglycaemia endpoints will be summarized similarly to the treatment emergent AE's for the on-
treatment observation periods based on the SAS.
10.4
Pharmacokinetic and/or pharmacodynamic modelling
Not applicable for this trial. 
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11 References
1.
Clarke W, Jones T, Rewers A, Dunger D, Klingensmith GJ. Assessment and management of 
hypoglycemia in children and adolescents with diabetes. Pediatr Diabetes. 2009;10 Suppl 
12:134-45.
2.
American Diabetes Association. 6. Glycemic Targets: Standards of Medical Care in 
Diabetes-2018. Diabetes Care. 2018;41(Suppl 1):S55-S64.
3.
European Medicines Agency, Committee for Medicinal Products for Human Use (CHMP). 
Guideline on clinical investigation of medicinal products in the treatment or prevention of 
diabetes mellitus (CPMP/EWP/1080/00 Rev. 1). Adoption by CHMP. 14 May 2012.
4.
UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with 
sulphonylureas or insulin compared with conventional treatment and risk of complications 
in patients with type 2 diabetes (UKPDS 33). Lancet. 1998;352(9131):837-53, Erratum 
1999; 354: 602.
5.
American Diabetes Association. Abridged for Primary Care Providers. Clin Diabetes. 
2018;36(1):14-37.
6.
Sanofi-Aventis Groupe. Lantus®   (insulin glargine), EU Summary of Product 
Characteristics (SmPC). 01 Mar 2017.
7.
Food and Drug Administration. Lantus - U.S. Label information. 2015.
8.
Local SmPC for metformin, current version. 2008 2008.
9.
American Diabetes Association. 8. Pharmacologic Approaches to Glycemic Treatment: 
Standards of Medical Care in Diabetes-2018. Diabetes Care. 2018;41(Suppl 1):S73-S85.
10.
Hauber AB, Johnson FR, Sauriol L, Lescrauwaet B. Risking health to avoid injections: 
preferences of Canadians with type 2 diabetes. Diabetes Care. 2005;28(9):2243-5.
11.
European Medicines Agency. Guideline on good pharmacovigilance practices (GVP). 
Module V – Risk management systems (Rev 1) (EMA/838713/2011 Rev 1). 15 Apr 2014.
12.
Novo Nordisk A/S. Investigator's Brochure, NNC0148-0287 (Insulin 287), NN1436(T2D), 
(edition 5), or any updates hereof. 2018.
13.
Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 
Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. 
Kidney Int Suppl. 2013;3(1):1-150.
14.
Danne T, Nimri R, Battelino T, Bergenstal RM, Close KL, DeVries JH, et al. International 
Consensus on Use of Continuous Glucose Monitoring. Diabetes Care. 2017;40(12):1631-40.
15.
Little R, Rubin D. Statistical analysis with missing data. Sons. JW, editor. New York.: John 
Wiley & Sons. 1987.
16.
World Medical Association. Declaration of Helsinki - Ethical Principles for Medical 
Research Involving Human Subjects. Last amended by the 64th WMA General Assembly, 
Fortaleza, Brazil. 1 Oct 2013.
17.
ICH Harmonised Tripartite Guideline. Guideline for Good Clinical Practice E6(R2), Current 
Step 4 version. 09 Nov 2016.
18.
International Organization for Standardization. ISO 14155:2011, Clinical investigation of 
medical devices for human subjects - Good clinical practice. 01 Feb 2011.
19.
Hicks KA, Hung HMJ, Mahaffey KW, Mehran R, Nissen SE, Stockbridge NL, et al. 
Standardized Definitions for Cardiovascular and Stroke End Point Events in Clinical Trials 
(Draft). 20 Aug 2014.
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
International Committee of Medicinal Journal Editors. Uniform Requirements for
Manuscripts submitted to Biomedical Journals.: N Engl J Med; 1997 1997. p. 309-15.

International Committee of Medical Journal E. International Committee of Medical Journal
Editors (ICMJE): Uniform Requirements for Manuscripts Submitted to BiomedicalJournals: 
writing and editing for biomedical publication. Haematologica. 2004;89(3):264.

U.S. Department of Health and Human Services, Food and Drug Administration. Food and
DrugAdministration Amendments Act of 2007. Available from:
http://www.fda.gov/RegulatoryInformation/Legislation/SignificantAmendmentstotheFDCA
ct/FoodandDrugAdministrationAmendmentsActof2007/default.htm.
23.
European Commission Regulation for EudraCT. 2011 2011.
24.
International Hypoglycaemia Study Group. Glucose Concentrations of Less Than 3.0
mmol/L (54 mg/dL) Should Be Reported in Clinical Trials: A Joint Position Statement of
the American Diabetes Association and the European Association for the Study of Diabetes.
Diabetes Care. 2017;40(1):155-7.
25.
Jones TW, Group IHGW. Defining relevant hypoglycemia measures in children and
adolescents with type 1 diabetes. Pediatr Diabetes. 2017.
26.
Agiostratidou G, Anhalt H, Ball D, Blonde L, Gourgari E, Harriman KN, et al.
Standardizing Clinically Meaningful Outcome Measures Beyond HbA1c for Type 1
Diabetes: A Consensus Report of the American Association of Clinical Endocrinologists,
the American Association of Diabetes Educators, the American Diabetes Association, the
Endocrine Society, JDRF International, The Leona M. and Harry B. Helmsley Charitable
Trust, the Pediatric Endocrine Society, and the T1D Exchange. Diabetes Care.
2017;40(12):1622-30.
27.
Seaquist ER, Anderson J, Childs B, Cryer P, Dagogo-Jack S, Fish L, et al. Hypoglycemia
and diabetes: a report of a workgroup of the American Diabetes Association and the
Endocrine Society. Diabetes Care. 2013;36(5):1384-95.
28.
U.S. Department of Health and Human Services FaDA, ; Center for Drug Evaluation and
Research (CDER),; Center for Biologics Evaluation and Research (CBER),; Center for
Devices and Radiological Health (CDRH),. Guidance for Industry. Patient -Reported
Outcome Measures: Use in Medical Product Development to Support Labeling Claims.
2009.
29.
Stull DE, Leidy NK, Parasuraman B, Chassany O. Optimal recall periods for patient-
reported outcomes: challenges and potential solutions. Curr Med Res Opin. 2009;25(4):929-
42.
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12 Appendices
Abbreviations and Trademarks
Appendix 1
ADA
American Diabetes Association
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
BG
blood glucose
CGM
continuous glucose monitoring
CI
confidence interval
CRF
case report form
DUN
dispensing unit number
DPP4i
dipeptidyl peptidase 4 inhibitors
EAS
event adjudication system 
ECG
electrocardiogram
EMA
European Medicines Agency 
FAS
full analysis set
FPG
fasting plasma glucose
GCP
Good Clinical Practice
HbA1c
glycated haemoglobin
HRT
hormone replacement therapy
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
IMP
investigational medicinal product
IRB
Institutional Review Board
IWRS
interactive web response system
PD
pharmacodynamics
PG
plasma glucose
PK
pharmacokinetics
SAE
serious adverse event
SD
standard deviation
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SMPG
self-measured plasma glucose
T1DM 
type 1 diabetes mellitus 
T2DM 
type 2 diabetes mellitus 
WOCBP
woman of child bearing potential
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Clinical laboratory tests
Appendix 2
!
The tests detailed in Table 12-1 and Table 12-2 will be performed by the central laboratory, 
unless otherwise specified.
!
Additional tests may be performed at any time during the trial as determined necessary by the 
investigator or required by local regulations. Only laboratory samples specified in the protocol 
should be sent to the central laboratory for analysis; if additional laboratory sampling is needed, 
e.g. to follow up on AEs, this must be done at a local laboratory.
!
The investigator must review all laboratory results for concomitant illnesses and AEs.
!
Laboratory samples will be destroyed on an ongoing basis and no later than at finalisation of the 
clinical trial report. 
!
Samples to assess systemic hypersensitivity reactions will be stored as described in Appendix 7.
!
The laboratory equipment may provide analyses not requested in the protocol but produced 
automatically in connection with the requested analyses according to specifications in the 
laboratory standard operating procedures. Such data will not be transferred to the trial database, 
but abnormal values will be reported to the investigator. 
!
Antibody samples taken in case of a suspected hypersensitivity reaction related to the trial 
product will be stored as described in Appendix 7.
Table 12-1
Protocol-required efficacy laboratory assessments
Laboratory assessments
Parameters
Glucose metabolism 
!
FPG (Fasting plasma glucose)
!
HbA1c
NOTES :
a A FPG result < 3.9 mmol/L (70 mg/dL) in relation to planned fasting visits should not be reported as a hypoglycaemic 
episode but as an adverse event at the discretion of the investigator (Appendix 4).
Table 12-2
Protocol-required safety laboratory assessments
Laboratory assessments
Parameters
Haematology
!
Erythrocytes
!
Haematocrit
!
Haemoglobin
!
Leucocytes
!
Thrombocytes
!
Differential count (eosinophils, neutrophils, basophils, monocytes and 
lymphocytes) 
Biochemistry1
!
Alanine Aminotransferase (ALT) 
!
Albumin
!
Alkaline phosphatase
!
Aspartate Aminotransferase (AST)
!
Creatinine
!
Potassium
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!
Sodium
!
Bilirubin
Lipids
!
Cholesterol
!
High density lipoprotein (HDL) cholesterol
!
Low density lipoprotein cholesterol
!
Triglycerides
!
Free fatty acid
Pregnancy Testing
!
Serum or urine human chorionic gonadotropin (hCG) pregnancy test (for women 
of childbearing potential)
Other tests
!
eGFR calculated by the central laboratory based on the creatinine value using the 
CKD-EPI equation
!
Additional blood samples in case of a systemic hypersensitivity reaction: 
o
Tryptase 
o
Total IgE
o
Anti-NNC0148-0287 IgE antibodies  
o
Anti-NNC0148-0287 binding antibodies
o
Histamine release (basophil) assay 
o
Anti-human insulin IgE antibodies
Notes :
aDetails of required actions for increased liver parameters are given in Appendix 4 (Hy’s Law)
Trial-required laboratory assessments will be performed by a central laboratory, with the exception 
of: 
!
Urine pregnancy tests which are performed locally 
!
Anti-insulin 287 antibodies, anti-insulin glargine antibodies, pharmacokinetics and 
additional blood samples in case of a systemic and local hypersensitivity reaction which are 
performed at special lab.
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Trial governance considerations
Appendix 3
1) Regulatory and ethical considerations
!
This trial will be conducted in accordance with the protocol and with the following:
!
Consensus ethical principles derived from international guidelines including the Declaration of 
Helsinki16, applicable International Council for Harmonisation (ICH) Good Clinical Practice 
(GCP) Guideline17 and
ISO 1415518
!
Applicable laws and regulations
!
The protocol, informed consent form, investigator’s brochure (as applicable) and other relevant 
documents (e.g. advertisements), must be submitted to an IRB/IEC and reviewed and approved 
by the IRB/IEC before the trial is initiated.
!
Regulatory authorities will receive the clinical trial application, protocol amendments, reports 
on SAEs, and the clinical trial report according to national requirements.
!
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the trial design, except for changes necessary to eliminate an immediate safety 
hazard to trial subjects.
!
Before a trial site is allowed to start screening subjects, written notification from Novo Nordisk 
must be received.
!
The investigator will be responsible for:
!
providing written summaries of the status of the trial annually or more frequently in 
accordance with the requirements, policies, and procedures established by the IRB/IEC 
and/or regulatory authorities
!
notifying the IRB/IEC of SAEs or other significant safety findings as required by IRB/IEC 
procedures
!
providing oversight of the conduct of the trial at the site and adherence to requirements of 
ICH guidelines, the IRB/IEC, and all other applicable local regulations
!
ensuring submission of the clinical trial report synopsis to the IRB/IEC.
2) Financial disclosure
Investigators and sub-investigators will provide Novo Nordisk with sufficient, accurate financial 
information as requested to allow Novo Nordisk to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the trial and one 
year after completion of the trial.
For US trial sites: verification under disclosures per Code of Federal Regulations (CFR) of 
Financial Conflict of Interest.
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3) Informed consent process
!
The investigator or his/her representative will explain the nature of the trial to the subject and 
answer all questions regarding the trial.
!
The investigator must inform the subject about the long-term storage of additional blood 
samples e.g. for exploratory investigation of antibodies or further development of anti-insulin 
antibody assays or to assess systemic hypersensitivity reactions. The subject must be informed 
that he/she is free to refuse to participate and may withdraw consent to the long term storage of 
the additional blood samples at any time and for any reason during the storage period.
!
The investigator must ensure the subject ample time to come to a decision whether or not to 
participate in the trial. 
!
Subjects must be informed that their participation is voluntary.
!
Subjects will be required to sign and date a statement of informed consent that meets the 
requirements of local regulations, ICH guidelines17, Declaration of Helsinki16 and the IRB/IEC 
or trial site.
!
The medical record must include a statement that written informed consent was obtained before 
any trial related activity and the date when the written consent was obtained. The authorised 
person obtaining the informed consent must also sign and date the informed consent form before 
any trial related activity.
!
The responsibility of seeking informed consent must remain with the investigator, but the 
investigator may delegate the task of informing to a medically qualified person, in accordance 
with local requirements.
!
Subjects must be re-consented to the most current version of the informed consent form(s) 
during their participation in the trial.
!
A copy of the informed consent form(s) must be provided to the subject.
4) Information to subjects during trial
The site will be offered a communication package for the subject during the conduct of the trial. 
The package content is issued by Novo Nordisk. The communication package will contain written 
information intended for distribution to the subjects. The writt en information will be translated and 
adjusted to local requirements and distributed to and reviewed with the subject at the discretion of 
the investigator. The subject may receive a “welcome to the trial letter” and a “thank you for your 
participation letter” after completion of the trial. Further the subject may receive other written 
information during the trial. 
All written information to subjects must be sent to IRB/IEC for approval/favourable opinion and to 
regulatory authorities for approval or notification according to local regulations.
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5) Data protection
!
Subjects will be assigned a 6-digit unique identifier, a subject number. Any subject records or 
datasets that are transferred to Novo Nordisk will contain the identifier only; subject names or 
any information which would make the subject identifiable will not be transferred.
!
The subject and any biological material obtained from the subject will be identified by subject 
number, visit number and trial ID. Appropriate measures such as encryption or leaving out 
certain identifiers will be enforced to protect the identity of subjects as required by local, 
regional and national requirements. 
!
The subject must be informed that his/her personal trial related data will be used by Novo 
Nordisk in accordance with local data protection law. The disclosure of the data must also be 
explained to the subject. 
!
The subject must be informed that his/her medical records may be examined by auditors or 
other authorised personnel appointed by Novo Nordisk, by appropriate IRB/IEC members, and 
by inspectors from regulatory authorities.
6) Committee structure
Novo Nordisk safety committee
Novo Nordisk will constitute an internal insulin 287 safety committee to perform ongoing safety 
surveillance. The insulin 287 safety committee may recommend unblinding of any data for further 
analysis, and in this case an independent ad hoc group will be established in order to maintain the 
blinding of the trial personnel.
Event adjudication committee
An independent external EAC is established to perform ongoing blinded adjudication of selected 
AEs and death (see Table 9-1and Appendix 4). The EAC will evaluate events sent for adjudication 
using pre-defined definitions and guidelines in accordance with the EAC Charter. The evaluation is 
based on review of pre-defined clinical data collected by the investigational sites. 
The EAC is composed of permanent members covering all required medical specialities. EAC 
members must disclose any potential conflicts of interest and must be independent of Novo 
Nordisk. The EAC will have no authority to impact on trial conduct, trial protocol or amendments.
Hypersensitivity reactions were observed with previous Formulation A, which was subsequently 
optimised to the current Formulation C. No hypersensitivity reactions have so far been observed 
with Formulation C. However, event adjudication for hypersensitivity reactions (local reactions, 
including injection site reactions and systemic reactions, including anaphylaxis) is introduced in the 
present trial to ensure standardised and objective assessment by an independent adjudication 
committee of experts within the specialty.
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The cardiovascular events will be adjudicated in accordance with U.S. Food and Drug 
Administration requirements19. 
The AEs for adjudication are listed in Table 9-1 and Appendix 4.
Global expert panel
A global expert panel will consist of investigators participating in the trial in different countries and 
of designated Novo Nordisk employees. The panel will discuss and advice on global and local 
operational issues related to trial conduct.
7) Publication policy
The information obtained during the conduct of this trial is considered confidential, and may be 
used by or on behalf of Novo Nordisk for regulatory purposes as well as for the general 
development of the trial product. All information supplied by Novo Nordisk in connection with this 
trial shall remain the sole property of Novo Nordisk and is to be considered confidential 
information.
No confidential information shall be disclosed to others without prior written consent from Novo 
Nordisk. Such information shall not be used except in the performance of this trial.
The information obtained during this trial may be made available to other investigators who are 
conducting other clinical trials with the trial product, if deemed necessary by Novo Nordisk. 
Provided that certain conditions are fulfilled, Novo Nordisk may grant access to information 
obtained during this trial to researchers who require access for research projects studying the same 
disease and/or trial product studied in this trial.
Novo Nordisk may publish on its clinical trials website a redacted clinical trial report for this trial.
One investigator will be appointed by Novo Nordisk to review and sign the clinical trial report 
(signatory investigator) on behalf of all participating investigators. The signatory investigator will 
be appointed based upon the criteria defined by the International Committee of Medical Journal 
Editors for research publications.20
Communication of results
Novo Nordisk commits to communicate and disclose results of trials regardless of outcome. 
Disclosure includes publication of a manuscript in a peer-reviewed scientific journal, abstract 
submission with a poster or oral presentation at a scientific meeting or disclosure by other means. 
The results of this trial will be subject to public disclosure on external web sites according to 
international and national regulations. Novo Nordisk reserves the right to defer the release of data 
until specified milestones are reached, for example when the clinical trial report is available. This 
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includes the right not to release the results of interim analyses, because the release of such 
information may influence the results of the entire trial.
At the end of the trial, one or more scientific publications may be prepared collaboratively by the 
investigator(s) and Novo Nordisk. Novo Nordisk reserves the right to postpone publication and/or 
communication for up to 60 days to protect intellectual property.
In all cases the trial results will be reported in an objective, accurate, balanced and complete 
manner, with a discussion of the strengths and limitations. In the event of any disagreement on the 
content of any publication, both the investigators’ and Novo Nordisk opinions will be fairly and 
sufficiently represented in the publication.
Authorship
Novo Nordisk will work with one or more investigator(s) and other experts who have contributed to 
the trial concept or design, acquisition, analysis or interpretation of data to report the results in one 
or more publications.
Authorship of publications should be in accordance with the Recommendations for the Conduct, 
Reporting, Editing and Publication of Scholarly Work in Medical Journals by the International 
Committee of Medical Journal Editors.
All authors will be provided with the relevant statistical tables, figures, and reports needed to 
evaluate the planned publication. 
Where required by the journal, the investigator from each trial site will be named in an 
acknowledgement or in the supplementary material, as specified by the journal. 
Site-specific publications by investigators
For a multicentre clinical trial, analyses based on single-site data usually have significant statistical 
limitations and frequently do not provide meaningful information for healthcare professionals or 
subjects, and therefore may not be supported by Novo Nordisk. Thus, Novo Nordisk may deny a 
request or ask for deferment of the publication of individual site results until the primary manuscript 
is accepted for publication. In line with Good Publication Practice, such individual reports should 
not precede the primary manuscript and should always reference the primary manuscript of the trial.
Investigator access to data and review of results
As owner of the trial database, Novo Nordisk has the discretion to determine who will have access 
to the database.
Individual investigators will have their own research subjects' data, and will be provided with the 
randomisation code after results are available.
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8) Dissemination of clinical trial data
Information of the trial will be disclosed at clinicaltrials.gov and novonordisk-trials.com. It will also 
be disclosed according to other applicable requirements such as those of the International 
Committee of Medical Journal Editors (ICMJE), the Food and Drug Administration Amendment 
Act European Commission Requirements and other relevant recommendations or regulations. If 
a subject requests to be included in the trial via the Novo Nordisk e-mail contact at these web sites, 
Novo Nordisk may disclose the investigator’s contact details to the subject. As a result of increasing 
requirements for transparency, some countries require public disclosure of investigator names and 
their affiliations.
The Primary Completion Date is the last assessment of the primary endpoint, and is for this trial 
Last Subject First Treatment (LSFT) + 16 weeks corresponding to visit V18. If the last subject is 
withdrawn early, the Primary Completion Date is considered the date when the last subject would 
have completed visit V18. The Primary Completion Date determines the deadline for results 
disclosure at clinicaltrials.gov according to Food and Drug Administration Amendment Act.
9) Data quality assurance
Case Report Forms (CRFs)
!
Novo Nordisk or designee is responsible for the data management of this trial including quality 
checking of the data.
!
All subject data relating to the trial will be recorded on electronic CRFs unless transmitted 
electronically to Novo Nordisk or designee (e.g. laboratory and CGM Dexcom G6 ® data). The 
investigator is responsible for verifying that data entries are accurate and correct by physically
or electronically signing the CRF. 
!
The following will be provided as paper CRFs:
!
Pregnancy forms
!
The following will be provided as paper CRFs to be used when access to the CRF is revoked or 
the CRF is temporarily unavailable:
!
AE forms 
!
Safety information forms 
!
Technical complaint forms (also to be used to report complaints that are not subject related, 
e.g. discovered at trial site before allocation)
!
Corrections to the CRF data may be made by the investigator or the investigator’s delegated 
staff. An audit trail will be maintained in the CRF application containing as a minimum: the old 
and the new data, identification of the person entering the data, date and time of the entry and 
reason for the correction. If corrections are made by the investigator’s delegated staff after the 
date when the investigator signed the CRF, the CRF must be signed and dated again by the 
investigator.
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!
The investigator must ensure that data is recorded in the CRF as soon as possible, preferably 
within 5 working days after the visit. Once data has been entered, it will be available to Novo 
Nordisk for data verification and validation purposes.
Monitoring
!
The investigator must permit trial-related monitoring, audits, IRB/IEC review, and regulatory 
agency inspections and provide direct access to source data documents (original documents, 
data and records), including electronic medical records. Direct access includes permission to 
examine, analyse, verify and reproduce any record(s) and report(s) that are important to the 
evaluation of the trial. If the electronic medical record does not have a visible audit trail, the 
investigator must provide the monitor with signed and dated printouts. In addition the relevant 
trial site staff should be available for discussions at monitoring visits and between monitoring 
visits (e.g. by telephone). 
!
Trial monitors will perform ongoing source data verification to confirm that data entered into 
the CRF by authorised site personnel are accurate, complete and verifiable from source 
documents; that the safety and rights of subjects are being protected, to monitor drug 
accountability and collect completed paper CRF pages, if applicable, and that the trial is being 
conducted in accordance with the currently approved protocol and any other trial agreements, 
ICH GCP, and all applicable regulatory requirements.
!
Monitoring will be conducted using a risk based approach including risk assessment, monitoring 
plans, centralised monitoring (remote assessment of data by Novo Nordisk) and visits to trial 
sites. 
!
Monitors will review the subject’s medical records and other source data e.g. the diaries and 
PROs, to ensure consistency and/or identify omissions compared to the CRF. 
Protocol compliance
Deviations from the protocol should be avoided. If deviations do occur, the investigator must 
inform the monitor and the implications of the deviation must be reviewed and discussed.
Deviations must be documented and explained in a protocol deviation by stating the reason, date, 
and the action(s) taken. Some deviations, for which corrections are not possible, can be 
acknowledged and confirmed via edit checks in the CRF or via listings from the trial database. 
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10) Source documents
All data entered in the CRF must be verifiable in source documentation other than the CRF.
!
The original of the completed diaries must not be removed from the trial site.
!
Source documents provide evidence for the existence of the subject and substantiate the 
integrity of the data collected. Source documents are filed at the trial site.
!
Data reported on paper CRF or entered in the electronic CRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The investigator may need to request previous medical records or transfer records. 
Also, current medical records must be available. 
!
It must be possible to verify subject’s medical history in source documents such as subject’s 
medical record.
!
All subject data relating to the trial will be recorded on CRFs unless transmitted electronically 
to Novo Nordisk or designee (e.g. laboratory and diary data). The investigator is responsible for 
verifying that data entries are accurate and correct by physically or electronically signing the 
CRF.
!
The investigator must document any attempt to obtain external medical information by noting 
the date(s) when information was requested and who was contacted.
!
Definition of what constitutes source data can be found in a source document agreement at each 
trial site. There will only be one source document defined at any time for any data element.
11) Retention of clinical trial documentation
!
Records and documents, including signed informed consent forms, pertaining to the conduct of 
this trial must be retained by the investigator for 15 years after end of trial unless local 
regulations or institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of Novo Nordisk. No records 
may be transferred to another location or party without written notification to Novo Nordisk. 
!
The investigator must be able to access his/her trial documents without involving Novo Nordisk 
in any way. If applicable, electronic CRF and other subject data will be provided in an 
electronic readable format to the investigator before access is revoked to the systems and/or 
electronic devices supplied by Novo Nordisk. Site-specific CRFs and other subject data (in an 
electronic readable format or as paper copies or prints) must be retained by the trial site. If the 
provided electronic data (e.g. the CD-ROM) is not readable during the entire storage period, the 
investigator can request a new copy. A copy of all data will be stored by Novo Nordisk.
!
Subject’s medical records must be kept for the maximum period permitted by the hospital, 
institution or private practice
12) Trial and site closure
Novo Nordisk reserves the right to close the trial site or terminate the trial at any time for any 
reason at the sole discretion of Novo Nordisk. If the trial is suspended or terminated, the 
investigator must inform the subjects promptly and ensure appropriate therapy and follow-up. The 
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investigator and/or Novo Nordisk must also promptly inform the regulatory authorities and 
IRBs/IECs and provide a detailed written explanation.
Trial sites will be closed upon trial comple tion. A trial site is considered closed when all required 
documents and trial supplies have been collected and a trial site closure visit has been performed.
The investigator may initiate trial site closure at any time, provided there is reasonable cause a nd 
sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a trial site by Novo Nordisk or investigator may include but are not 
limited to:
!
failure of the investigator to comply with the protocol, the requirements of the IRB/IEC or local 
health authorities, Novo Nordisk procedures or GCP guidelines
!
inadequate recruitment of subjects by the investigator
!
discontinuation of further trial product development.
13) Responsibilities
The investigator is accountable for the conduct of the trial at his/her site and must ensure adequate 
supervision of the conduct of the trial at the trial site. If any tasks are delegated, the investigator 
must maintain a log of appropriately qualified persons to whom he/she has delegated specified trial-
related duties. The investigator must ensure that there is adequate and documented training for all 
staff participating in the conduct of the trial. It is the investigator’s responsibility to supervise the 
conduct of the trial and to protect the rights, safety, and well-being of the subjects. 
A qualified physician, who is an investigator or a sub-investigator for the trial, must be responsible 
for all trial-related medical decisions. 
The investigator is responsible for filing essential documents (i.e. those documents which 
individually and collectively permit evaluation of the conduct of a trial and the quality of the data 
produced) in the investigator trial master file. The documents, including the subject identification 
code list must be kept in a secure locked facility so that no unauthorized persons can get access to 
the data. 
The investigator will take all necessary technical and organisational safety measures to prevent 
accidental or wrongful destruction, loss or deterioration of data. The investigator will prevent any 
unauthorised access to data or any other processing of data against applicable law. The investigator 
must be able to provide the necessary information or otherwise demonstrate to Novo Nordisk that 
such technical and organisational safety measures have been taken.
During any period of unavailability, the investigator must delegate responsibility for medical care of 
subjects to a specific qualified physician who will be readily available to subjects during that time.
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If the investigator is no longer able to fulfil the role as investigator (e.g. if he/she moves or retires) a 
new investigator will be appointed in consultation with Novo Nordisk. 
The investigator and other site personnel must have sufficient English skills according to their 
assigned task(s).
14) Indemnity statement
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. 
Novo Nordisk accepts liability in accordance with: 
!
The Civil Code and the Pharmaceutical Law dated 6 September 2001 (uniform version Journal 
of Laws of 2008 No.45 item 271 with amendments).
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Adverse events: definitions and procedures for 
Appendix 4
recording, evaluation, follow-up, and reporting
AE definition
! An AE is any untoward medical occurrence in a clinical trial subject administered or using a medicinal product, 
whether or not considered related to the medicinal product or usage. 
! An AE can be any unfavourable and unintended sign, including an abnormal laboratory finding, symptom or disease 
(new or exacerbated) temporally associated with the use of a medicinal product. 
Note 1: This includes events related to the procedures involved (any procedure in the protocol).
Note 2: For users or other persons this is restricted to events related to the investigational medical device.
Events meeting the AE definition
! Any abnormal laboratory test results or safety assessments, including those that worsen from baseline, considered 
clinically significant in the medical and scientific judgment of the investigator.
! A clinical abnormal laboratory finding which is clinically significant, i.e. an abnormality that suggests a disease 
and/or organ toxicity and is of a severity that requires active management. Active management includes active 
treatment or further investigations, for example change of medicine dose or more frequent follow-up due to the 
abnormality
! Exacerbation of a chronic or intermittent pre-existing condition including either an increase in frequency and/or 
intensity of the condition.
! Signs, symptoms or the clinical sequelae of a suspected drug-drug interaction.
! Signs, symptoms or the clinical sequelae of a suspected overdose of trial product regardless of intent.
! A "lack of efficacy" or "failure of expected pharmacological action" per se will not be reported as an AE or SAE. 
Such instances will be captured in the efficacy assessments. However, the signs, symptoms and/or clinical sequelae 
resulting from lack of efficacy will be reported as AE or SAE if they fulfil the definition.
! Abuse and misuse of trial product must be reported as an AE.
! Abuse is defined as: Persistent or sporadic, intentional excessive use of a medicinal product, which is accompanied 
by harmful physical or psychological effects (e.g. overdose with the intention to cause harm)
! Misuse is defined as: Situations where the medicinal product is intentionally and inappropriately used not in 
accordance with the protocol or the terms of the marketing authorisation.
Events NOT meeting the AE definition 
! Pre-existing conditions, anticipated day-to-day fluctuations of pre-existing conditions, including those identified 
during screening or other trial procedures performed before exposure to trial product. 
! Note: pre-existing conditions should be recorded as medical history/concomitant illness.
! Pre-planned procedures, unless the condition for which the procedure was planned has worsened from the first trial 
related activity after the subject has signed the informed consent.
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Definition of an SAE
An SAE is an AE that fulfils at least one of the following criteria:
! Results in death
Is life-threatening
! The term 'life-threatening' in the definition of 'serious' refers to an event in which the subject was at risk of death at 
the time of the event. It does not refer to an event which hypothetically might have caused death, if it were more 
severe.
Requires inpatient hospitalisation or prolongation of existing hospitalisation
! Hospitalisation signifies that the subject has been detained at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or outpatient setting. 
Complications that occur during hospitalisation are AEs. If a complication prolongs hospitalisation or fulfils any 
other serious criteria, the event is serious. When in doubt as to whether “hospitalisation” occurred or was 
necessary, the AE should be considered serious.
! Hospitalisation for elective treatment of a pre-existing condition that did not worsen from baseline is not 
considered an AE.
Note:
! Hospitalisations for administrative, trial related and social purposes do not constitute AEs and should therefore not 
be reported as AEs or SAEs.
! Hospital admissions for surgical procedures, planned before trial inclusion, are not considered AEs or SAEs.
Results in persistent disability/incapacity
! The term disability means a substantial disruption of a person’s ability to conduct normal life functions.
! This definition is not intended to include experience of relatively minor medical significance such as uncomplicated 
headache, nausea, vomiting, diarrhoea, influenza, and accidental trauma (e.g. sprained ankle), which may interfere 
with or prevent everyday life functions but do not constitute a substantial disruption.
Is a congenital anomaly/birth defect
Important medical event:
Medical or scientific judgment should be exercised in deciding whether SAE reporting is appropriate in other situations. 
This includes important medical events that may not be immediately life-threatening or result in death or 
hospitalisation, but may jeopardise the subject or may require medical or surgical intervention to prevent one of the 
other outcomes listed in the above definition. These events should usually be considered serious and reported as SAEs 
using the important medical event criterion.
The following adverse events must always be reported as SAEs using the important medical event criterion, if no other 
seriousness criteria are applicable:
! Suspicion of transmission of infectious agents via the trial product. 
! Risk of liver injury defined as alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3 x UNL and 
total bilirubin >2 x UNL, where no alternative aetiology exists (Hy's law)
Description of AEs requiring additional data collection (via specific event form) and/or events for adjudication. 
AEs requiring additional data collection (via specific event form):
Injection site reaction
If an event of injection site reaction is observed the following additional information must be obtained if available on 
the injection site reaction form:
!
Symptoms associated with the event
!
Treatment given for the reaction
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!
Association with the trial product(s)
!
Relevant risk factors associated with the event
Additionally, the following information must be recorded on the injection site reaction form:
!
Timing and duration of the injection site reaction
!
Timing and dose of last injection prior to the onset of reaction
!
Relieve of symptoms
!
Information about the injection (incl. needle angle and site of reaction)
!
Skin condition before injection site reaction
!
Size of reaction
!
Needle information
Hypoglycaemic episode
See Appendix 8
Medication error: A medication error concerning trial products is defined as:
! Administration of wrong drug 
Note: Use of wrong dispensing unit number (DUN) is not considered a medication error unless it results in
administration of wrong drug
! Wrong route of administration, such as intramuscular instead of subcutaneous 
! Accidental administration of a lower or higher dose than intended. The administered dose must deviate from the 
intended dose to an extent where clinical consequences for the trial subject were likely to happen as judged by the 
investigator, although they did not necessarily occur
Events for adjudication
Event type
Description
Adjudication outcome
Acute coronary syndrome
Acute Coronary Syndrome 
conditions include all types of 
acute myocardial infarction and 
hospitalisation for unstable 
angina pectoris
!
Acute myocardial infarction 
(including subgroup 
classifications)
!
Hospitalisation for unstable 
angina pectoris
Cerebrovascular events
Episode of focal or global 
neurological dysfunction that 
could be caused by brain, spinal 
cord, or retinal vascular injury as 
a result of haemorrhage or 
infarction
!
Ischaemic stroke
!
Haemorrhagic stroke
!
Undetermined stroke
Heart failure
Presentation of the subject for an 
urgent, unscheduled 
clinic/office/emergency 
department visit or hospital 
admission, with a primary 
diagnosis of heart failure (new
episode or worsening of existing 
heart failure)
!
Heart failure hospitalisation
!
Urgent heart failure visit
Death
All cause death
!
Cardiovascular death 
(including undetermined 
cause of death)
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!
Non-Cardiovascular death
Hypersensitivity 
!
Local reactions, 
including injection site 
reactions  
!
Systemic reactions, 
including anaphylaxis
Hypersensitivity is defined as 
episodes of objectively 
reproducible symptoms or signs 
initiated by exposure to a 
defined stimulus at a dose 
tolerated by normal persons
Anaphylaxis is defined as 
serious hypersensitivity 
reactions that is rapid in onset 
and may cause death
!
Hypersensitivity reaction
AE and SAE recording
!
The investigator will record all relevant AE/SAE information in the CRF.
!
The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, and/or other 
clinical information. In such cases, the diagnosis (not the individual signs/symptoms) will be documented as 
the AE/SAE.
!
When an AE/SAE occurs, it is the responsibility of the investigator to review all documentation (e.g. hospital 
progress notes, laboratory and diagnostics reports) related to the event.
!
For all non-serious AEs the applicable forms should be signed when the event is resolved or at the end of the 
trial at the latest. For sign-off of SAE related forms refer to “SAE reporting via paper CRF” later in this 
section.
!
Novo Nordisk products used as concomitant medication if an AE is considered to have a causal relationship 
with a Novo Nordisk marketed product used as concomitant medication in the trial, it is important that the 
suspected relationship is reported to Novo Nordisk, e.g. in the alternative aetiology section on the safety 
information form. Novo Nordisk may need to report this adverse event to relevant regulatory authorities.
Assessment of severity
The investigator will assess intensity for each event reported during the trial and assign it to one of the following 
categories: 
!
Mild: An event that is easily tolerated by the subject, causing minimal discomfort and not interfering with 
everyday activities.
!
Moderate: An event that causes sufficient discomfort and interferes with normal everyday activities.
!
Severe: An event that prevents normal everyday activities.
Note: Severe is a category used for rating the intensity of an event; and both an AE and SAE can be assessed 
as severe. An event is defined as ‘serious’ when it meets at least one of the outcomes described in the 
definition of an SAE and not when it is rated as severe
Assessment of causality
The investigator is obligated to assess the relationship between trial product and the occurrence of each AE/SAE.
Relationship between an AE/SAE and the relevant trial product(s) should be assessed as: 
!
Probable - Good reason and sufficient documentation to assume a causal relationship.
!
Possible - A causal relationship is conceivable and cannot be dismissed.
!
Unlikely - The event is most likely related to aetiology other than the trial product.
Alternative aetiology, such as underlying disease(s), concomitant medication, and other risk factors, as well as the
temporal relationship of the event to trial product administration will be considered and investigated.
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The investigator should use the investigator’s brochure for insulin 287 and/or product information for marketed non-
Novo Nordisk's products, for the assessment. For each AE/SAE, the investigator must document in the medical records 
that he/she has reviewed the AE/SAE and has provided an assessment of causality.
There may be situations in which an SAE has occurred and the investigator has minimal information to include in the 
initial report. However, it is important that the investigator always makes an assessment of causality for every 
event before the initial transmission of the SAE data.
The investigator may change his/her opinion of causality in light of follow-up information and send a follow-up report 
with the updated causality assessment.
The causality assessment is one of the criteria used when determining regulatory reporting requirements.
Final outcome
The investigator will select the most appropriate outcome:
!
Recovered/resolved: The subject has fully recovered, or by medical or surgical treatment the condition has 
returned to the level observed at the first trial-related activity after the subject signed the informed consent.
!
Recovering/resolving: The condition is improving and the subject is expected to recover from the event. This 
term is only applicable if the subject has completed the trial or has died from another AE.
!
Recovered/resolved with sequelae: The subject has recovered from the condition, but with lasting effect due 
to a disease, injury, treatment or procedure. If sequelae meet an SAE criterion, the AE must be reported as an 
SAE.
!
Not recovered/not resolved: The condition of the subject has not improved and the symptoms are unchanged 
or the outcome is not known.
!
Fatal: This term is only applicable if the subject died from a condition related to the reported AE. Outcomes of 
other reported AEs in a subject before he/she died should be assessed as “recovered/resolved”, 
“recovering/resolving”, “recovered/resolved with sequelae” or “not recovered/not resolved”. An AE with a 
fatal outcome must be reported as an SAE.
!
Unknown: This term is only applicable if the subject is lost to follow-up.
Follow-up of AE and SAE
The investigator is obligated to perform or arrange for the conduct of supplemental measurements and/or evaluations as 
medically indicated or as requested by Novo Nordisk to elucidate the nature and/or causality of the AE or SAE as fully 
as possible (e.g. severe hypersensitivity reactions). This may include additional laboratory tests (e.g. skin prick test) or 
investigations, histopathological examinations, or consultation with other health care professionals.
New or updated information will be recorded in the CRF.
!
SAEs: All SAEs must be followed until the outcome of the event is “recovered/resolved”, “recovered/resolved 
with sequelae” or “fatal”, and until all queries have been resolved. Cases of chronic conditions, cancer or AEs 
ongoing at time of death (where death is due to another AE) may be closed with the outcome 
“recovering/resolving” or “not recovered/not resolved”. Cases can be closed with the outcome of 
“recovering/resolving” when the subject has completed the follow-up period and is expected by the 
investigator to recover.
The SAE follow-up information should only include new (e.g. corrections or additional) information and must 
be reported within 24 hours of the investigator’s first knowledge of the information. This is also the case for 
previously non-serious AEs which subsequently become SAEs.
!
Non-serious AEs: Non-serious AEs must be followed until the outcome of the event is “recovering/resolving”, 
“recovered/resolved” or “recovered/resolved with sequelae” or until the end of the follow-up period stated in 
the protocol, whichever comes first, and until all queries related to these AEs have been resolved. Cases of 
chronic conditions, cancer or AEs ongoing at time of death (where death is due to another AE) may be closed 
with the outcome “recovering/resolving” or “not recovered/not resolved”. Cases can be closed with the 
outcome of “recovering/resolving” when the subject has completed the follow-up period and is expected by the 
investigator to recover.
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The investigator must ensure that the recording of the worst case severity and seriousness of an event is kept 
throughout the trial. A worsening of an unresolved AE must be reported as follow up with re-assessment of 
severity and/or seriousness of the event.
SAE reporting via electronic CRF
!
Relevant forms (AE and safety information form) must be completed in the CRF. 
!
For reporting and sign-off timelines, see box below. 
!
If the CRF is unavailable for more than 24 hours, then the site will use the paper AE form and if the CRF is 
unavailable for more than 5 calendar days then the site will use the safety information form (see box below).
!
The site will enter the SAE data into the CRF as soon as it becomes available, see 9.2.1.
!
After the trial is completed at a given site, the CRF will be decommissioned to prevent the entry of new data or 
changes to existing data. If a site receives a report of a new SAE from a subject or receives updated data on a 
previously reported SAE after CRF decommission, then the site can report this information on a paper AE and 
safety information form (see box below) or to Novo Nordisk by telephone.
SAE reporting via paper CRF
! Relevant CRF forms (AE and safety information form) must be forwarded to Novo Nordisk either by fax, e-mail or 
courier.
! Initial notification via telephone is acceptable, although it does not replace the need for the investigator to complete 
the AE and safety information form within the designated reporting time frames (as illustrated in Figure 9-1):
! AE form within 24 hours.
! Safety information form within 5 calendar days. 
! Both forms must be signed within 7 calendar days.
! Contact details for SAE reporting can be found in the investigator trial master file.
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Contraceptive guidance and collection of pregnancy 
Appendix 5
information
It must be recorded in the CRF whether female subjects are of childbearing potential. 
Definitions
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile. 
Women in the following categories are not considered WOCBP
Premenarcheal 
Premenopausal female with one of the following:
!
Documented hysterectomy
!
Documented bilateral salpingectomy
!
Documented bilateral oophorectomy
Note: Documentation can come from the site personnel’s review of subject’s medical records, 
medical examination or medical history interview.
Postmenopausal female
!
A postmenopausal state is defined as no menses for 12 months without an alternative medical 
cause. A high follicle stimulating hormone level in the postmenopausal range may be used to 
confirm a postmenopausal state in women not using hormonal contraception or Hormonal 
Replacement Therapy (HRT). However, in the absence of 12 months of amenorrhea, a single 
follicle stimulating hormone measurement is insufficient. 
!
Females on HRT and whose menopausal status is in doubt will be required to use one of the 
non-hormonal highly effective contraception methods if they wish to continue their HRT during 
the trial. Otherwise, they must discontinue HRT to allow confirmation of postmenopausal status 
before trial enrolment.
Contraception guidance
Male subjects
No contraception measures are required for male subjects as the risk of teratogenicity/fetotoxicity 
caused by transfer of insulin 287 or insulin glargine U100 in seminal fluid is unlikely.
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Female subjects
Female subjects of childbearing potential are eligible to participate if they agree to use methods of 
contraception consistently and correctly as described in table(s) below:
Table 12-3
Highly effective contraceptive methods
Highly effective contraceptive methods that are user dependent a 
Failure rate of <1% per year when used consistently and correctly.
Combined (oestrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation  
! oral 
! intravaginal 
! transdermal 
Progestogen only hormonal contraception associated with inhibition of ovulation
! oral 
! injectable 
Highly effective methods that are user independent a 
Implantable progestogen only hormonal contraception associated with inhibition of ovulation 
! Intrauterine Device
! Intrauterine hormone-releasing System
! Bilateral tubal occlusion
Vasectomised partner 
A vasectomised partner is a highly effective contraception method provided that the partner is the sole male sexual 
partner of the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method of 
contraception should be used.
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse 
during the entire period of risk associated with the trial product. The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the trial and the preferred and usual lifestyle of the subject.
Notes: 
aFailure rates may differ from < 1% per year, if not used consistently and correctly. Use should be consistent with local 
regulations regarding the use of contraceptive methods for subjects participating in clinical trials. 
Pregnancy testing
!
WOCBP should only be included after a negative highly sensitive serum pregnancy test.
!
Urine Pregnancy testing should be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected.
Collection of pregnancy information
Female subjects who become pregnant 
!
Investigator will collect pregnancy information on any female subject, who becomes pregnant 
while participating in this trial.
!
Information will be recorded on the appropriate form and submitted to Novo Nordisk within 14 
calendar days of learning of a subject's pregnancy.
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!
Subject will be followed to determine the outcome of the pregnancy. The investigator will 
collect follow-up information on subject and neonate, which will be forwarded to Novo 
Nordisk. Generally, follow-up will not be required for longer than 1 month beyond the delivery 
date.
!
Any termination of pregnancy will be reported, regardless of foetal status (presence or absence 
of anomalies) or indication for procedure.
!
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy will be reported as an AE or SAE. 
!
A spontaneous abortion is always considered to be an SAE and will be reported as such.
!
Any SAE occurring as a result of a post-trial pregnancy which is considered possibly/probably 
related to the trial product by the investigator will be reported to Novo Nordisk as described in 
Appendix 4. While the investigator is not obligated to actively seek this information in former 
subjects, he or she may learn of an SAE through spontaneous reporting. 
!
Any female subject who becomes pregnant while participating in the trial will discontinue trial 
product. 
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Technical complaints: Definition and procedures for 
Appendix 6
recording, evaluation, follow-up and reporting 
Technical complaint definition 
A technical complaint is any written, electronic or oral communication that alleges product (medicine or device) 
defects. The technical complaint may be associated with an AE, but does not concern the AE itself.
Examples of technical complaints:
! Problems with the physical or chemical appearance of trial products (e.g. discoloration, particles or contamination).
! Problems with packaging material including labelling.
! Problems related to medical devices (e.g. to the injection mechanism, dose setting mechanism, push button or
interface between the pen-injector and the needle).
Time period for detecting technical complaints 
All technical complaints, which occur from the time of receipt of the product at trial site until the time of the last usage 
of the product, must be collected for products predefined on the technical complaint form. 
Reporting of technical complaints to Novo Nordisk
Contact details (fax, e-mail and address) for Customer Complaint Center –refer to Attachment I
Technical complaints must be reported on a separate technical complaint form:
1.
One technical complaint form must be completed for each affected DUN
2.
If DUN is not available, a technical complaint form for each batch, code or lot number must be completed
Timelines for reporting of technical complaints to Novo Nordisk
The investigator must complete the technical complaint form in the CRF within the timelines specified in Figure 9-3. If 
the CRF is unavailable or when reporting a technical complaint that is not subject related, the information must be 
provided on a paper form by fax, e-mail or courier to Customer Complaint Centre, Novo Nordisk, within the same 
timelines as stated above. When the CRF becomes available again, the investigator must enter the information on the 
technical complaint form in the CRF.
Follow-up of technical complaints 
The investigator is responsible for ensuring that new or updated information will be recorded on the originally 
completed form. 
Collection, storage and shipment of technical complaint samples
The investigator must collect the technical complaint sample and all associated parts that were packed in the same DUN 
and notify the monitor within 5 calendar days of obtaining the sample at trial site. The sample and all associated parts 
must be sent as soon as possible to Customer Complaint Center, Novo Nordisk, together with a copy of the completed 
technical complaint form. The technical complaint sample should contain the batch, code or lot number and, if 
available, the DUN. If the technical complaint sample is unobtainable, the reason must be stated on the technical 
complaint form. If several samples are shipped in one shipment, the sample and the corresponding technical complaint 
form should be kept together.
Storage of the technical complaint sample must be done in accordance with the conditions prescribed for the product.
Reporting of technical complaints for Novo Nordisk products not included in technical complaint form
Technical complaints on Novo Nordisk products not included in the technical complaint form should be reported to 
local Novo Nordisk affiliate with a reference to trial ID.
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Retention of human biosamples
Appendix 7
Anti-insulin 287 antibodies, anti-insulin glargine antibodies samples and samples to assess systemic 
and local hypersensitivity reactions (if taken) will be stored at a central bio-repository after end of 
trial and until marketing authorisation approval or until the research project terminates, but no 
longer than 15 years from end of trial after which they will be destroyed.
Antibody samples may be used for later analysis for further characterisation of antibody responses 
towards drug, if required by health authorities or for safety reasons, or for exploratory investigation 
of antibodies or further development of anti-insulin antibody assays.
The subject’s identity will remain confidential and the antibody samples will be identified only by 
subject number, visit number and trial identification number. No direct identification of the subject 
will be stored together with the samples.
Only Novo Nordisk staff and biorepository personnel will have access to the stored samples.
Subjects can contact the investigator if they wish to be informed about results derived from stored 
biosamples obtained from their own body.
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Trial ID: NN1436-4466
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Hypoglycaemic episodes
Appendix 8
Classification of hypoglycaemia
Classification of hypoglycaemia
Level
Glycaemic criteria
Description
Hypoglycaemia alert 
value (level 1)
< 3.9 mmol/L (70 mg/dL) 
and 
≥ 3.0 mmol/L (54 mg/dL)  
Sufficiently low for treatment with fast-acting 
carbohydrate and dose 
adjustment of glucose-lowering therapy
Clinically significant 
hypoglycaemia (level 2)
< 3.0 mmol/L (54 mg/dL)
Sufficiently low to indicate serious, clinically 
important hypoglycaemia
Severe hypoglycaemia 
(level 3)
No specific glucose 
threshold
Hypoglycaemia associated with severe 
cognitive impairment requiring
external assistance for recovery
Notes: Novo Nordisk terms adapted from IHSG24, ADA-2018 2, ISPAD25, Type 1 diabetes outcomes 
program26, ATTD14. Severe hypoglycaemia as defined by Seaquist27.
Reporting of hypoglycaemic episodes:
Plasma Glucose (PG) should always be measured by the study provided BG meter and recorded in 
the diary and CRF when a hypoglycaemic episode is suspected. 
PG values <3.9 mmol/L (70 mg/dL) should be reported as a hypoglycaemic episode according to 
the instructions below. When a subject experiences a hypoglycaemic episode, subject/investigator 
should record the general information in relation to the hypoglycaemia (timing, PG measurements, 
symptoms etc.) as described in the diary/CRF, respectively. In case a subject is not able to fill in the 
diary (e.g. in case of hospitalisation), the investigator should report the hypoglycaemic episode in
the hypoglycaemic episode CRF.
Upon onset of a hypoglycaemic episode the subject is recommended to measure PG every 15 
minutes until the SMPG value is ≥3.9 mmol/L (70 mg/dL) and in case of severe hypoglycaemia, 
that the condition have been resolved in accordance with current guidelines27.Furthermore, subjects 
should be encouraged to measure and follow their SMPG values 1-2 hours after the episode.
Repeated SMPG measurements and/or symptoms will by default be considered as one 
hypoglycaemic episode until a succeeding SMPG value is ≥ 3.9 mmol/L (70 mg/dL) and/or 
symptoms have been resolved. The episode should be reported as only one hypoglycaemic episode 
on the hypoglycaemic episode CRF. In case of several low SMPG values within the hypoglycaemic 
episode, the lowest value is the one that will be reported as the SMPG value for the hypoglycaemic 
episode but the start time of the episode will remain as the time for the first low SMPG value and/or 
symptom. The remaining values will be kept as source data in the diary. 
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If the severity of a hypoglycaemic episode changes, only one hypoglycaemic episode should be 
reported, reflecting the most severe degree of hypoglycaemia.
Regarding the question: “To feel better, did you need help to get a sugary drink, food, or 
medicine?” the investigator must instruct subjects that the answer should be “Yes”, if the episode is 
an event requiring assistance of another person to actively administer carbohydrate, glucagon, or 
take other corrective actions. PG concentrations may not be available during an event, but 
neurological recovery following the return of PG to normal is considered sufficient evidence that 
the event was induced by a low PG concentration.27
Additional information (e.g. description of symptoms, alleviation of symptoms, seizure or coma) in 
relation to severe hypoglycaemic episodes must be recorded in the hypoglycaemic episode CRF.
Diary Review
At each visit or phone contact, the investigator must review all SMPG values in the diary and 
identify any low SMPG values not reported as hypoglycaemic episodes. The subject must be 
questioned whether any of the low values were severe, i.e. whether the subject could have handled 
the episode (by getting a sugary drink and/or food) him/herself. If the subject could not have 
handled the episode him/herself, it has to be reported as a hypoglycaemic episode in the 
hypoglycaemic episode CRF describing that the subject could not have handled the episode 
him/herself. 
For low SMPG values for hypoglycaemic episodes where the subject could handle the episode 
him/herself: 
!
If a hypoglycaemic episode form in the diary is not completed by the subject within 7 calendar 
days of the SMPG measurement, the episode should be described in the source documents and 
reported by the investigator on a hypoglycaemic episode CRF with as much information as 
possible: Novo Nordisk will not query for additional data except for the start date and whether 
the subject could have handled the episode him/herself due to the decreased validity of such 
data.28 29
Re-training of subjects
The subject must be re-trained in how to report hypoglycaemic episodes if the investigator identifies 
low SMPG values not reported as hypoglycaemic episodes. The training should be documented by 
the investigator in source documents.
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Protocol
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Trial ID: NN1436-4466
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Titration guideline
Appendix 9
Introduction
Titration guidelines have been developed, providing recommended dose adjustments at different 
plasma glucose (PG) levels to ensure that subjects receive an optimal treatment. However, it is 
recognised that insulin treatment should be individualised and the specific titration algorithms may 
not be applicable in certain clinical situations. Hence, it is important that other information, such as 
symptoms of hypo/hyperglycaemia, previous response to dose adjustments, other glucose 
measurements and other indicators of the subject’s level of glycaemic control, is taken into 
consideration when decisions on dosing are made. The investigator is responsible for the treatment 
of the subjects and can therefore overrule the guidelines to avoid safety hazards.
Initiation of trial products
At randomisation eligible subjects will be randomised to receive insulin 287 or to receive insulin 
glargine U100.
Insulin 287 should be taken once weekly at the same day of the week. Dependent on randomisation 
and previous insulin regimen the subjects should either initiate insulin 287 with or without a 100% 
loading dose as follows:
A. If the subject prior to randomisation received a once daily regimen with insulin degludec, 
insulin detemir or insulin glargine U100 the initial dose of insulin 287 after randomisation 
should be according to the table below.
In Table 12-4, please find the calculated weekly doses for V2 and V3 based on current daily 
doses between 10 and 50U:
Weekly dose at randomisation 
visit (V2)
Weekly dose at V3
Without loading dose
Current daily dose x 7
Same dose as V2, then follow 
titration algorithm 
With additional 100% 
loading dose
Current daily dose x 7 x 2
Divide V2 dose by 2, then 
follow titration algorithm
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Table 12-4 Doses for subject that prior to randomisation received a once daily regimen with
insulin degludec, insulin detemir or insulin glargine U100
Current daily dose
V2 without loading dose
V3 without loading dose
V2 with loading dose
V3 with loading dose
10
70
70
140
70
11
77
77
154
77
12
84
84
168
84
13
91
91
182
91
14
98
98
196
98
15
105
105
210
105
16
112
112
224
112
17
119
119
238
119
18
126
126
252
126
19
133
133
266
133
20
140
140
280
140
21
147
147
294
147
22
154
154
308
154
23
161
161
322
161
24
168
168
336
168
25
175
175
350
175
26
182
182
364
182
27
189
189
378
189
28
196
196
392
196
29
203
203
406
203
30
210
210
420
210
31
217
217
434
217
32
224
224
448
224
33
231
231
462
231
34
238
238
476
238
35
245
245
490
245
36
252
252
504
252
37
259
259
518
259
38
266
266
532
266
39
273
273
546
273
40
280
280
560
280
41
287
287
574
287
42
294
294
588
294
43
301
301
602
301
44
308
308
616
308
45
315
315
630
315
46
322
322
644
322
47
329
329
658
329
48
336
336
672
336
49
343
343
686
343
50
350
350
700
350
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B. If the subject prior to randomisation received a twice daily regimen with any basal insulin 
analogue or an once daily regimen with insulin glargine U300, the total daily insulin dose prior 
to randomisation should be reduced by 20%. The initial doses of insulin 287 should be 
according to the table below.
Weekly dose at randomisation 
visit (V2)
Weekly dose at V3
Without loading dose
Current total daily dose x 0.8 x 7
Same dose as V2, then follow 
titration algorithm
With additional 100% 
loading dose
Current total daily dose x 0.8 x 7 x2
Divide V2 dose by 2, then 
follow titration algorithm
In Table 12-5, below, please find the calculated weekly doses for V2 and V3 based on current daily 
doses between 10 and 50U:
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Table 12-5 Doses for subjects that prior to randomisation received a twice daily regimen with 
any basal insulin analogue or a once daily regimen with insulin glargine U300
Current daily dose
V2: weekly dose 
without loading dose
V3 weekly dose without 
loading dose:
V2 weekly dose with 
loading dose
V3: weekly dose with 
loading dose
10
56
56
112
56
11
56
56
119
56
12
63
63
133
63
13
70
70
140
70
14
77
77
154
77
15
84
84
168
84
16
84
84
175
84
17
91
91
189
91
18
98
98
196
98
19
105
105
210
105
20
112
112
224
112
21
112
112
231
112
22
119
119
245
119
23
126
126
252
126
24
133
133
266
133
25
140
140
280
140
26
140
140
287
140
27
147
147
301
147
28
154
154
308
154
29
161
161
322
161
30
168
168
336
168
31
168
168
343
168
32
175
175
357
175
33
182
182
364
182
34
189
189
378
189
35
196
196
392
196
36
196
196
399
196
37
203
203
413
203
38
210
210
420
210
39
217
217
434
217
40
224
224
448
224
41
224
224
455
224
42
231
231
469
231
43
238
238
476
238
44
245
245
490
245
45
252
252
504
252
46
252
252
511
252
47
259
259
525
259
48
266
266
532
266
49
273
273
546
273
50
280
280
560
280
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Insulin glargine U100 should be taken once daily at any time of the day, but at the same time every 
day. 
If the subject prior to randomisation received a once daily regimen with insulin degludec, insulin 
detemir or insulin glargine U100 the initial dose at randomisation should be the same as prior to 
randomisation
If the subject prior to randomisation received a twice daily regimen with any basal insulin analogue 
or a once daily regimen with insulin glargine U300 the total daily insulin dose prior to 
randomisation should be reduced by 20% and taken once daily.
The treat-to-target approach will be applied to all three treatment arms to optimise glycaemic 
control throughout the trial. There are no maximum or minimum insulin doses.
Dose adjustment of trial products during the trial
After randomisation the trial products will be adjusted once weekly by the investigator in 
connection with the scheduled visits/phone contacts as described below.
The dose adjustment will be based on the three pre-breakfast SMPG values measured on the two 
days prior to titration and on the day of the contact, and in accordance with Table 12-6. If there are 
values below 4.4 mmol/L (80 mg/dL) the reduction will be based on the lowest SMPG value. If 
there are no low values the dose will be adjusted according to the mean of the SMPG values. If one 
or more SMPG values are missing, the dose adjustment should be performed on the remaining 
SMPG value(s).
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Table 12-6: Insulin glargine U100 and insulin 287 titration algorithm
Pre-breakfast SMPG
Insulin glargine U100 
dose adjustment
Insulin 287 dose 
adjustment
Value to use
mmol/L
mg/dL
U
U
Lowest of the 
SMPG values
<4.4
<80
–4
–28
Mean of the 
SMPG values
4.4–7.2
80–130
No adjustment
No adjustment
>7.2
>130
+4
+28
Deviations from the algorithm
It is recommended that the algorithm is followed. However, it is also important that the decision to 
adjust insulin doses is based on all relevant information. A reason for deviating from the algorithm 
should be entered into the CRF by the investigator as applicable.
Missing dose guidance for insulin 287
The dosing window for insulin 287 is ±1 day. 
!
If a dose is missed for ≤ 4 days after the planned dosing day, subjects should inject the 
planned full dose as soon as possible and perform control SMPG measurements. 
!
If the missing dose is observed from day 5 to day 7 (which is the next planned dosing day), 
subject should inject 50% of the missed dose rounded down to the nearest possible dose 
which can be divided with 7, e.g. if a subject forgot to take the prescribed dose of 77U, then 
50% of 77U is 38.5U and hence the dose should be rounded down to 35U. On day 7, the 
next scheduled full prescribed dose should still be taken. Additional SMPG measurement 
should be performed to control BG.
Dose recommendation from end of treatment (EOT) and during follow up for insulin 287
If it is decided that the individual subject should continue on insulin after EOT it is recommended 
that the subject is switched from insulin 287 to any available basal insulin at the discretion of the 
investigator. The initial post-trial basal dose is estimated as follows:
!
Calculate 50% of the latest weekly insulin 287 dose and divide by 7
!
Initiate the new daily basal insulin based on above calculated dose
!
Consider titrating the basal insulin once or twice weekly according to the pre-breakfast 
SMPG values and the local label of the chosen insulin
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Data collection
The following data should be entered into the diary every day by the subject and reviewed by the 
investigator during the clinic visit:
!
Per protocol pre-breakfast SMPG values measured since last visit/phone contact
!
Insulin glargine U100 doses taken the last two days prior to titration and on the day of the 
contact. Exception being week 15 and 16 where doses are collected every day. All insulin 287 
doses must be entered in the diary. 
The following should be entered by investigator into the CRF within 24 hours after each contact:
!
Per protocol pre-breakfast SMPG values measured since last visit/phone contact
!
Date, actual dose and injection time of insulin 287 since the last contact or date, actual dose and 
injection time of insulin glargine U100 taken the last two days prior to titration and on the day 
of the contact. Exception being week 15 and 16 where all daily doses are collected and must be 
entered into the CRF.   
!
Insulin glargine U100 or insulin 287 doses prescribed at this contact.
!
Reasons for deviation from the titration algorithms, if applicable
!
Hypoglycaemic episodes
Data surveillance
Surveillance of titration data will be performed centrally by Novo Nordisk in an unbiased or, if 
possible, a blinded manner. The data will be reviewed and significant changes from the titration 
algorithm will be followed up. 
It is important that data regarding titration is entered into the diary and into the CRF. If delays 
occur, action cannot be taken in due time before the subject’s next site visit/phone contact. The aim 
is to reduce the time periods in which a subject may receive suboptimal treatment.
The titration data should be reviewed by Novo Nordisk within 24 hours (on workdays). The 
reviewer may contact the investigator by e-mail or phone to clarify reasons for deviation or to 
request entry of missing data. When the investigator receives an inquiry, a response should be 
received at Novo Nordisk within 24 hours (on workdays).
In addition, Novo Nordisk will monitor changes in HbA1c. Novo Nordisk may visit or phone sites to 
discuss progress in glycaemic control and titration of individual subjects.
CONFIDENTIAL


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Date:
29 November 2018
Novo Nordisk
Trial ID: NN1436-4466
Version:
1.0
UTN: U1111-1219-5541
Status:
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EUdraCT: 2018-003407-18
Page:
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Country-specific requirements 
Appendix 10
For Czech Republic: Adequate contraceptive measures are always one highly reliable method 
(such as intrauterine device, sterilisation of one of the partners, hormonal birth control methods) 
plus one supplementary barrier method (such as condom, diaphragm) with a spermicide. In justified 
cases, this combination may be replaced with a double-barrier method with a spermicide. Total 
sexual abstinence may also be considered contraception. (Please note: Hormonal contraception 
should always be discussed with a gynaecologist).
For Germany: Section 6.2Exclusion criteria about pregnancy and use of contraceptive: 
Contraception requirements as per: CTFG guideline 
Section 7: Treatments: In section regarding trial products, please distinguish between IMPs and 
non-IMPs otherwise all Trial products are considered as IMPs and must be mentioned in the CTA.
Other: Subject's full Date of Birth is not allowed to be collected and must be shortened to Year of 
Birth.
For United States: Section 9 Trial assessments and procedures: For eye examinations: 
Funduscopy/fundusphotography will be performed by the Investigator or a local 
Ophthalmologist/Optometrist according to local practice
CONFIDENTIAL


Global and country key Novo Nordisk staff
Attachments I and II (if applicable) to the protocol are located in the Trial Master File.
Content: Global key staff and Country key staff
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CONFIDENTIAL


Protocol Amendment no 1
CONFIDENTIAL
Date:
01 February 2019
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Trial ID: NN1436-4466
Version:
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Status:
Final
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Protocol Amendment
no 1
to Protocol, version 2.0
dated 01 February 2019
Trial ID: NN1436-4466
Protocol title: A trial comparing NNC0148-0287 C (insulin 287) versus insulin glargine U100, 
both in combination with metformin, with or without DPP4 inhibitors and with or without 
SGLT2 inhibitors, in basal insulin treated subjects with type 2 diabetes mellitus
Trial phase: 2a
Applicable to all countries
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
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This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol Amendment no 1
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Date:
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Trial ID: NN1436-4466
Version:
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Status:
Final
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Table of Contents   "Double click to update Table of Content" 
1
Introduction including rationale for the protocol amendment...........................................................3
2
Changes ................................................................................................................................................3
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Protocol Amendment no 1
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Trial ID: NN1436-4466
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1
Introduction including rationale for the protocol amendment
Allowing few OADs (metformin and DPP4i) in the target population was to aim for a pure and 
homogeneous population. Current clinical practice however has moved towards increasing the use 
of other OADs as SGLT2i prior to initiating insulin. We therefore update the protocol to align with 
clinical practice. With allowing metformin, DPP4i and SGLT2i the protocol will closer reflect the 
clinical practice while at the same time securing a relatively homogeneous population.
2
Changes
In this protocol amendment:
!
Any new text is written in italics.
!
Any text deleted from the protocol is written using strike through.
Title, frontpage: 
A trial comparing NNC0148-0287 C (insulin 287) versus insulin glargine U100, both in 
combination with metformin, with or without DPP4 inhibitors and with or without SGLT2 
inhibitors, in basal insulin treated subjects with type 2 diabetes mellitus
Introduction, Background [3.2]:
sodium-glucose cotransporter 2 inhibitors (SGLT2i) 
SGLT2i can be used as second line OADs in combination with Metformin. SGLT2i provide insulin-
independent glucose lowering by blocking glucose reabsorption in the proximal renal tubule by 
inhibiting SGLT2. For further details, please refer to the EMA Summary of Products 
Characteristics for the relevant SGLT2i or locally approved Product Information.
Inclusion criteria [6]:
6.
Stable daily dose(s) for 90 days prior to the day of screening of any of the following anti-
diabetic drug(s) or combination regime(s):
o
Any metformin formulations ≥ 1500 mg or maximum tolerated or effective dose (as 
documented in subjects medical records).
o
Free or fixed combination therapy:  Metformin as outlined above  ± DPP4i ± 
SGLT2i is allowed:

DPP4i (≥ half of the maximum approved dose according to local label or 
maximum tolerated or effective dose)

SGLT2i (≥ half of the maximum approved dose according to local label or 
maximum tolerated or effective dose 
Objectives and endpoints, Primary objective [4.1.1.]:
CONFIDENTIAL


Protocol Amendment no 1
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Trial ID: NN1436-4466
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To compare the effect on glycaemic control of treatment with once weekly insulin 287 using two 
different switch approaches versus once daily insulin glargine U100 both in combination with 
metformin ± DPP4i ± SGLT2i in basal insulin analogue treated T2DM subjects
Objectives and endpoints, Secondary objective [4.1.2]:
To compare the safety and tolerability of once weekly insulin 287 using 2 different switch 
approaches versus once daily insulin glargine U100 both in combination with metformin ± DPP4i 
± SGLT2i in basal insulin analogue treated T2DM subjects
Trial design, overall design [5.1]
Subjects will be randomly allocated to receive once weekly insulin 287 using one of the 2 switch 
approaches (arm A and B) or once daily insulin glargine U100 (arm C). The randomisation will be 
stratified based on pre-trial insulin treatment and based on whether or not subjects are treated with 
SGLT2i. 
Statistical considerations, statistical analyses [10.3] 
In the statistical models baseline value of the endpoint value will be included as a covariate and 
explanatory factors will be categorized as follows:
!
Treatment: switch approach with 100% loading dose, switch approach without loading dose, 
insulin glargine U100 
!
Pre-trial insulin treatment: twice daily or insulin glargine U300: yes or no
!
SGLT2i use: yes or no
Statistical considerations, Primary endpoint [10.3.1]
!
First, one thousand (1000) copies of the dataset will be generated for time in range.
!
Second, for each dataset copy, each assessment and each treatment group, an analysis of 
variance (ANOVA) model with baseline 'time in target range' as covariate will be fitted to 
the time in range values for subjects having completed their randomised treatment. The 
estimated mean, and variances, from the model will be used to impute missing values in the 
same treatment group.
!
For each of the complete data sets, the primary endpoint will be analysed using an ANOVA 
model with randomised treatment, pre-trial insulin treatment and SGLT2i use (yes/no) as 
fixed factors and baseline ‘time in target range’ as covariate. The estimates and standard 
deviations for the 1000 data sets will be pooled to one estimate and associated standard 
deviation using Rubin’s rule.
Throughout protocol section 1-10: when mentioning backgound medication ± SGLT2i has been 
added.
END OF AMENDMENT 1
CONFIDENTIAL


Protocol Amendment no 2
CONFIDENTIAL
Date:
21 March 2019
Novo Nordisk
Trial ID: NN1436-4466
Version:
1.0
Status:
Final
Page:
1 of 6
Protocol Amendment
no 2
to Protocol, version 1.0
dated 29 November 2018
Trial ID: NN1436-4466
A trial comparing NNC0148-0287 C (insulin 287) versus insulin glargine U100,
both in combination with metformin, with or without DPP4 inhibitors, in basal
insulin treated subjects with type 2 diabetes mellitus
Trial phase: 2a
Applicable to Germany
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol Amendment no 2
CONFIDENTIAL
Date:
21 March 2019
Novo Nordisk
Trial ID: NN1436-4466
Version:
1.0
Status:
Final
Page:
2 of 6
Table of Contents   
1
Introduction including rationale for the protocol amendment...........................................................3
2
Changes ................................................................................................................................................3
2.1
Section 3.3.2 Risks....................................................................................................................3
2.2
Section 3.3.3 Conclusion on the benefit risk profile...................................................................5
2.3
Section 5.5 Justification for dose...............................................................................................5
2.4
Section 11 References ...............................................................................................................6
CONFIDENTIAL


Protocol Amendment no 2
CONFIDENTIAL
Date:
21 March 2019
Novo Nordisk
Trial ID: NN1436-4466
Version:
1.0
Status:
Final
Page:
3 of 6
1
Introduction including rationale for the protocol amendment
This protocol amendment is to update protocol version 1.0, dated 29 November 2018 to implement 
the objections received from the German Health Authority BfArM. 
This protocol is amended for the following reasons:
!
Inclusion of further clarification on the observation of hypersensitivity reactions in trial 
NN1436-4057. Explanation regarding different formulations of insulin 287 used in NN1436-
4057 (formulation A) and NN1436-4314 (formulation C). Confirmation that no hypersensitivity 
reactions have been observed with the current formulation C in trial NN1436-4314.
!
Additional information on introduction of event adjudication by an independent adjudication 
committee of experts for hypersensitivity reactions to ensure standardised and objective 
assessment.
!
Further explanation that the potency of one unit (U) of Insulin 287 corresponds to one unit (U) 
of Insulin glargine U100, considering the different dosing schemes. 
In this protocol amendment:
!
Any new text is written in italics.
!
Any text deleted from the protocol is written using strike through.
2
Changes
2.1
Section 3.3.2 Risks
Identified risks for insulin 287 describe undesirable clinical outcomes for which there is sufficient
evidence that they are caused by insulin 287. Potential risks in this section describe undesirable
clinical outcomes for which there is scientific evidence to suspect the possibility of a causal
relationship with insulin 287, but where there is currently insufficient evidence to conclude that this
association is causal.11
Identified risks
!
Hypoglycaemia
Hypoglycaemia is a common undesirable effect related to the pharmacological mechanism of
insulin. To mitigate the risk of hypoglycaemia in this trial, blood glucose (BG) measurements will
be made throughout the drug exposure period, and will prevent worsening of hypoglycaemia by
early detection and administration of carbohydrates and medical treatment, if necessary.
CONFIDENTIAL


Protocol Amendment no 2
CONFIDENTIAL
Date:
21 March 2019
Novo Nordisk
Trial ID: NN1436-4466
Version:
1.0
Status:
Final
Page:
4 of 6
Potential risks
!
Injection site reactions
Injection site reactions may occur with all injectable drugs. No injection site reactions were reported
in trial NN1436-4314 with insulin 287. However, in this trial investigators and subjects will be
asked to pay careful attention to injection site reactions at the place of injection; investigators
should ensure careful monitoring and medical evaluation in case of injection site reaction
occurrence. For further information on injection site reactions, please refer to Section 9.4.5.
!
Hypersensitivity reactions
Severe systemic hypersensitivity reactions may potentially occur following injection of therapeutic 
proteins. Multiple doses of once-weekly insulin 287 (previous formulation A) in the dose range of 9–
27 nmol/kg were generally well-tolerated by subjects with T2DM in trial NN1436-4057. However, 
the trial was put on hold due to 3 subjects experiencing hypersensitivity reactions. Trial NN1436 
4314 was very similar to trial NN1436-4057, but with an optimised formulation of insulin 287 
(formulation C) in subjects with T2DM. No hypersensitivity reactions were reported in trial 
NN1436-4314 with insulin 287. During the treatment period in this trial, subjects will have weekly 
contacts with the site either at visits to the site or with phone contacts. Subjects and investigators 
will be instructed for signs and symptoms of allergic reactions. and Subjects will be instructed to 
contact the site immediately in case of signs of hypersensitivity. For further information on 
hypersensitivity reactions, please refer to Section 9.4.5.
!
Antibody formation leading to change in clinical effect
An increase in anti-insulin 287 specific antibodies and anti-human insulin antibodies were observed
for some subjects in trial NN1436-4314 trial with insulin 287. No hypersensitivity reactions were
observed in this trial. Moreover, in trial NN1436-4314 higher antibody levels seemed to be
associated with a longer terminal half-life and reduced clearance for insulin 287. In case of a
systemic hypersensitivity reaction, blood sampling for assessment of antibodies against insulin 287
will be conducted. For more information, please refer to Section 9.4.5.
!
Increase in hepatic enzymes
Transient increases in hepatic enzymes upon initiation of s.c. insulin are considered as potential
risks due to the pharmacological mechanism of insulin. An increase in hepatic enzyme was
observed in nonclinical studies in rats and dogs. No clinically significant changes in hepatic
biomarkers have been observed in humans following the administration of insulin 287. In this trial,
measurements of hepatic biomarkers will be performed at frequent intervals.
More detailed information about the known and expected benefits and risks and reasonably
expected adverse events of insulin 287 may be found in the investigator’s brochure and any updates
hereof.
CONFIDENTIAL


Protocol Amendment no 2
CONFIDENTIAL
Date:
21 March 2019
Novo Nordisk
Trial ID: NN1436-4466
Version:
1.0
Status:
Final
Page:
5 of 6
2.2
Section 3.3.3 Conclusion on the benefit risk profile
Based on the non-clinical and clinical development programme, it has been concluded that insulin 
287 is similar to human insulin with respect to pharmacological action and non-clinical safety.
Hypersensitivity reactions were observed with a previous formulation A (see Investigator’s 
Brochure for insulin 28712), which was subsequently optimised to the current formulation C. No 
hypersensitivity reactions have been observed with the current formulation C in the concluded trial 
NN1436-4314.
Event adjudication for hypersensitivity reactions (local reactions, including injection site reactions 
and systemic reactions, including anaphylaxis) is introduced in the present trial to ensure 
standardised and objective assessment by an independent adjudication committee of experts within 
the specialty.
Insulin 287 was generally well tolerated within the evaluated dose ranges in the first-in-human, 
single dose escalation trial (NN1436-3955, previous formulation A), conducted in healthy subjects 
and in subjects with T1DM and as well as in the multiple dose trial in subjects with T2DM using 
formulation C (NN1436-4314).
No safety concerns have been observed with insulin 287; Neither elevation in hepatic enzymes nor 
clinical consequences following antibody formation have been reported with insulin 287. With 
insulin 287 formulation C, no hypersensitivity reactions and injection site reactions were observed 
in the completed trial. To mitigate the risk of hypoglycaemia in this trial, frequent blood glucose 
measurements will be made throughout drug exposure. Therefore, it can be concluded that the risk 
to the subjects in this trial is considered low. The risk is acceptable in view of the benefits a basal 
insulin with a longer action profile than currently available would provide to subjects with diabetes. 
The overall benefit-risk profile of insulin 287 is anticipated to be favourable.
2.3
Section 5.5 Justification for dose
Insulin glargine U100 will be initiated at the same dose as the pre-trial basal insulin and insulin 287 
will be initiated at 7 times the pre-trial basal insulin dose.
One unit (U) of Insulin 287 has similar glucose lowering effect as one U of insulin glargine U100, 
and therefore once-weekly dosing corresponds to 7 times the daily dose of the once daily 
comparator. The assumption of equipotency is supported by results from trial NN1436-4314: in the 
period 24–48 hours after dosing, i.e. around the time for maximum glucose-lowering effect, the 
relative bio-efficacy of insulin 287 compared to OD insulin degludec was 109% [81; 146], and in 
the last 24 hours of the weekly dosing interval it was 93% [63; 136]. The potency of insulin 
degludec and insulin glargine (U100) has previously shown to be comparable.30
CONFIDENTIAL


Protocol Amendment no 2
CONFIDENTIAL
Date:
21 March 2019
Novo Nordisk
Trial ID: NN1436-4466
Version:
1.0
Status:
Final
Page:
6 of 6
The PK/PD properties of Insulin 287 following 5 weeks of once weekly dosing in subjects with
T2DM (trial NN1436-4314) showed that insulin 287 exposure was well distributed across the
dosing interval, with a PK profile suitable for once weekly dosing. Insulin 287 was well tolerated in
subjects with T2DM and no safety concerns were identified after multiple once-weekly dosing in
the dose range of 12−24 nmol/kg (2-4 U/Kg).
For subjects randomised to insulin 287 100% loading dose arm: It takes 3-5 doses before reaching
the full effect of insulin 287. Theoretically subjects may therefore need additional insulin to
maintain glycaemic control the first weeks after initiation. Modelling data suggest that adding a
100% loading dose may prevent deterioration of the glycaemic control during the first weeks of
treatment without jeopardising safety. Therefore the approach of 100% loading dose has been
chosen; hence no additional insulin is permitted after V2.
To reduce the risk of subjects experiencing hypoglycaemia in the initial treatment phase subjects
switching from a twice daily basal insulin regiment and a once daily regimen with insulin glargine
U300 will have their dose reduced by 20%. This is applicable for all treatment arms.
After randomisation at V2, subjects will start once daily and once-weekly injections on the same
day. This treatment will continue until 15 weeks after randomisation. At this time point the last once
weekly injection must be taken while the once daily injections are taken until 16 weeks after
randomisation where the subjects come in for the end of treatment visit (V18). This is due to the
longer half-life of insulin 287.
Further details on dose adjustment can be found in Appendix 9, titration guideline
2.4
Section 11 References
11.
European Medicines Agency. Guideline on good pharmacovigilance practices (GVP).
Module V – Risk management systems (Rev 1) (EMA/838713/2011 Rev 1). 15 Apr 2014.
12.
Novo Nordisk A/S. Investigator's Brochure, NNC0148-0287 (Insulin 287), NN1436(T2D),
(edition 5), or any updates hereof. 2018.
30.
Novo Nordisk A/S. Tresiba ® (insulin degludec), EU Summary of Product Characteristics
(SmPC). Feb 2018.
CONFIDENTIAL


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CONFIDENTIAL


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Page 1 of 2 
NN1436-4466: Notification of error in document for Amendment 1, version 1.0 
to Protocol 1.0
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CONFIDENTIAL

SAP_001.pdf: 
Cover Page for Statistical Analysis Plan 
 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT03922750 
Sponsor trial ID: 
NN1436-4466 
Official title of study: 
A trial comparing NNC0148-0287 C (insulin 287) versus 
insulin glargine U100, both in combination with metformin, 
with or without DPP4 inhibitors and with or without SGLT2 
inhibitors, in basal insulin treated subjects with type 2 diabetes 
mellitus 
Document date: 
28 May 2020 
 


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CONFIDENTIAL
Redacted VWDWLVWLFDODQDO\VLVSODQ 
Includes redaction of personal identifiable information only. 
. 


Statistical Analysis Plan
CONFIDENTIAL
Date:
03 February 2020
Novo Nordisk
Trial ID: NN1436-4466
Version:
1.0
UTN: U1111-1219-5541
Status:
Final
EudraCT No.: 2018-003407-18
Page:
1 of 13
Statistical Analysis Plan
Trial ID: NN1436-4466
A trial comparing NNC0148-0287 C (insulin 287) versus 
insulin glargine U100, both in combination with metformin, 
with or without DPP4 inhibitors and with or without SGLT2 
inhibitors, in basal insulin treated subjects with type 2 
diabetes mellitus
Author
Biostatistics Aalborg 2
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Statistical Analysis Plan
CONFIDENTIAL
Date:
03 February 2020
Novo Nordisk
Trial ID: NN1436-4466
Version:
1.0
UTN: U1111-1219-5541
Status:
Final
EudraCT No.: 2018-003407-18
Page:
2 of 13
Table of contents   
Page
Table of contents.........................................................................................................................................2
List of abbreviations ...................................................................................................................................3
1
Introduction .........................................................................................................................................4
1.1
Trial information.......................................................................................................................4
1.2
Primary objective......................................................................................................................5
1.3
Secondary objective ..................................................................................................................5
1.4
Primary estimand ......................................................................................................................5
1.5
Scope of the statistical analysis plan..........................................................................................6
2
Statistical considerations .....................................................................................................................6
2.1
Sample size determination.........................................................................................................6
2.2
Definition of analysis sets..........................................................................................................7
2.3
Definitions of trial periods.........................................................................................................7
2.4
Statistical analyses ....................................................................................................................8
2.4.1
Primary endpoint .....................................................................................................9
2.4.2
Supportive secondary efficacy endpoints................................................................10
2.4.2.1
HbA1c, fasting plasma glucose (FPG), and body weight – change 
from baseline to week 16..................................................................10
2.4.2.2
Weekly insulin dose - during week 15 and 16...................................10
2.4.2.3
HbA1c responders............................................................................11
2.4.3
Supportive secondary safety endpoints...................................................................11
2.4.3.1
Adverse events.................................................................................11
2.4.3.2
Hypoglycaemic episodes ..................................................................11
2.4.4
Pharmacokinetic and/or pharmacodynamic modelling............................................11
3
Changes to the statistical analyses planned in the protocol..............................................................12
4
References ..........................................................................................................................................13
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
03 February 2020
Novo Nordisk
Trial ID: NN1436-4466
Version:
1.0
UTN: U1111-1219-5541
Status:
Final
EudraCT No.: 2018-003407-18
Page:
3 of 13
List of abbreviations
AACE
American Association of Clinical Endocrinologists
ADA
American Diabetes Association
AE
adverse event
ANCOVA
analysis of co-variance
CGM
continuous glucose monitoring
CI
confidence interval
DPP4i
dipeptidyl peptidase 4 inhibitors
EASD
European Association for the Study of Diabetes
FAS
full analysis set
FPG
fasting plasma glucose
IWRS
interactive web response system
LLOQ
lower limit of quantification
MCMC
Markov Chain Monte Carlo
SAP
statistical analysis plan
SAS
safety analysis set
SD
standard deviation
SGLT2i
sodium-glucose cotransporter 2 inhibitors
SMPG
self-measured plasma glucose
T2DM
type 2 diabetes mellitus
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
03 February 2020
Novo Nordisk
Trial ID: NN1436-4466
Version:
1.0
UTN: U1111-1219-5541
Status:
Final
EudraCT No.: 2018-003407-18
Page:
4 of 13
1
Introduction
1.1
Trial information
This is a 16 weeks exploratory, multicentre, randomised, open label, active-controlled, parallel-
group trial with 3 arms investigating the effect on glycaemic control and safety of treatment with 
once weekly insulin 287 using 2 different switch approaches (either ‘unit to unit switch with an 
additional 100% loading dose’ approach, referred in the trial design as arm A or ‘unit to unit switch’ 
approach, referred in the trial design as arm B) versus once daily insulin glargine U100 (arm C) in 
basal insulin analogue treated subjects with type 2 diabetes mellitus (T2DM) inadequately 
controlled on basal insulin analogue with metformin, with or without dipeptidyl peptidase 4 
inhibitors (DPP4i) and with or without sodium-glucose cotransporter 2 inhibitor (SGLT2i).
The overall trial design and visit schedule are outlined in Figure 1-1 and trial flowchart (see 
protocol Section 2) respectively. 
Figure 1-1
Trial design
The trial duration is approximately 23 weeks and consists of 2 weeks of screening period, 16 weeks 
of randomised treatment period, and 5 weeks of follow-up period. From screening visit (after signed 
informed consent; visit 1) until randomisation, all subjects will be required to measure daily pre-
breakfast self-measured plasma glucose (SMPG) and have a 10 day baseline continuous glucose 
monitoring (CGM) profile collected. At visit 2, after the screening period, all eligible subjects will 
be randomised (1:1:1), to receive once weekly insulin 287 using one of the 2 switch approaches 
(arm A and B) or once daily insulin glargine U100 (arm C). The randomisation will be stratified 
based on pre-trial insulin treatment regimen and based on whether subjects are treated with 
SGLT2i.
During the 16 weeks treatment period, subjects will have weekly contact with the site through either 
site visits (9 visits) or phone contacts (6 phone contacts). To evaluate the effect on glycaemic 
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
03 February 2020
Novo Nordisk
Trial ID: NN1436-4466
Version:
1.0
UTN: U1111-1219-5541
Status:
Final
EudraCT No.: 2018-003407-18
Page:
5 of 13
control, subjects will have CGM profiles collected during the 16 weeks treatment period. The CGM 
will be blinded for both subjects and investigator. 
After 16 weeks of treatment subjects will come in for their end of treatment visit (V18). The end of 
treatment visit will be one week after the last dose of insulin 287 and on the day of or the day after 
the last dose of insulin glargine U100. This will be followed by 2 follow up visits (V19 and V20). 
The last follow up visit (V20) is scheduled to take place 6 weeks after the last dose of once weekly 
insulin 287 and 5 weeks after the last dose of once daily insulin glargine U100. This will allow for 
appropriate wash-out of trial drug, following at least 5 half-lives of insulin 287. 
If a subject is prematurely discontinued from trial treatment, the investigator must ask the subject if 
he/she is willing, as soon as possible, to have assessment performed according to end of treatment 
visit (V18) and to come in for the follow up visits V19 and V20. Subjects should be asked to 
continue wearing CGM (changed weekly) throughout the remaining weeks finalised by a last visit 
(V18A) 16 weeks after randomisation. End of treatment assessments for withdrawn or prematurely 
discontinued subjects are reallocated to the nearest planned visit where the assessments were 
supposed to be taken, if this scheduled visit is at most 7 days apart and no assessment already exists 
at this visit.
1.2
Primary objective
To compare the effect on glycaemic control of treatment with once weekly insulin 287 using the 
two different switch approaches versus once daily insulin glargine U100 both in combination with 
metformin ± DPP4i ± SGLT2i in basal insulin analogue treated T2DM subjects.
1.3
Secondary objective
To compare the safety and tolerability of once weekly insulin 287 using 2 different switch 
approaches versus once daily insulin glargine U100 both in combination with metformin ± DPP4i ± 
SGLT2i in basal insulin analogue treated T2DM subjects.
1.4
Primary estimand
The primary estimand is defined as the mean difference in ‘time in target range 3.9-10.0 mmol/L 
(70–180 mg/dL)’ during the last 2 weeks of treatment (week 15 and 16) between each of the 2 
different switch approaches of once weekly insulin 287 and once daily insulin glargine U100 for all 
randomised subjects, if all subjects had adhered to the randomised insulin treatment and had 70% of 
the planned continuous glucose monitoring (CGM) measurements recorded.
The following intercurrent events for the primary estimand will be handled by the hypothetical 
strategy: initiation of insulin treatment other than the randomised treatment, discontinuation of 
randomised insulin treatment, withdrawal from the trial, and recording of less than 70% of planned 
CGM measurements in the last two weeks of treatment. Other intercurrent events will be handled by 
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
03 February 2020
Novo Nordisk
Trial ID: NN1436-4466
Version:
1.0
UTN: U1111-1219-5541
Status:
Final
EudraCT No.: 2018-003407-18
Page:
6 of 13
the treatment policy strategy. This estimand aims to reflect the estimated treatment effect for 
subjects that had adhered to the planned insulin treatment during the planned treatment period.
1.5
Scope of the statistical analysis plan
This statistical analysis plan (SAP) is based on the protocol A trial comparing NNC0148-0287 C 
(insulin 287) versus insulin glargine U100 both in combination with metformin, with or without 
DPP4 inhibitors and with or without SGLT2 inhibitors, in basal insulin treated subjects with type 2 
diabetes mellitus, version 2.0 (dated 01 February 2019).
It clarifies the statistical analyses described in the protocol with additions and corrections, which are 
described in Section 3. 
2
Statistical considerations
2.1
Sample size determination 
The sample size calculation is based on the width of the 95% confidence interval (CI). Data from 
insulin degludec treated subjects in trial NN9068-3697 showed a standard deviation (SD) of 2.5 
hour for a 24h period after 26 weeks of treatment and for time in range defined as 
3.9-10.0 mmol/L (70–180 mg/dL). NN9068-3697 was conducted in insulin naïve subjects with 
T2DM and used older CGM devices (iPro1 and iPro2). Another trial in type 1 diabetes mellitus 
(T1DM) subjects NN1250-3874 with insulin glargine U100 as comparator used the Dexcom 
SEVEN® PLUS CGM device which is considered more representative for the present trial as there 
have been notable improvements in the CGM-devices. In this trial a SD of 3.0 hour in the last 
maintenance period was observed for time in range defined as 3.9-10.0 mmol/L (70–180 mg/dL). 
However, the titration periods were only four weeks in NN1250-3874. The SD for the current trial 
is assumed to be 3.0 based on observations from these two trials. Table 2-1 shows the width of the 
95% confidence interval for any pairwise comparison that can be obtained with 80% probability for 
a range of sample sizes and assumed values of SD.
Table 2-1
Width of the 95% CI for various SD and number of subjects per treatment arm
Number per treatment arm
SD
40
50
60
2.5
2.4
2.1
1.9
3.0
2.9
2.5
2.3
3.5
3.3
3.0
2.7
CI: confidence interval. SD: standard deviation.
With 50 subjects randomised to each treatment arm in a 1:1:1 manner, the width of the 95% for any 
pairwise comparison is 2.5h/24h with a probability of 80%. Two-and-a-half hour corresponds to 
approximately 10%-points for percent time in range.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
03 February 2020
Novo Nordisk
Trial ID: NN1436-4466
Version:
1.0
UTN: U1111-1219-5541
Status:
Final
EudraCT No.: 2018-003407-18
Page:
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2.2
Definition of analysis sets
The following analysis sets will be defined:
Full analysis set (FAS): includes all randomised subjects. Subjects in the FAS will contribute to 
evaluation “as randomised”.
Safety analysis set (SAS): includes all subjects exposed to at least one dose of trial product. 
Subjects in the SAS will contribute to the evaluation based on the trial product received for the 
majority of the period they were on treatment. Any dose deviation will be ignored. This implies that 
subjects will contribute as randomised unless the subject receives insulin glargine instead of insulin 
287 or vice versa.
2.3
Definitions of trial periods
The relevant observation periods are:
In-trial: The in-trial observation period starts at randomisation (as registered in IWRS) and ends at 
the date of:
!
The last direct subject-site contact
!
Withdrawal for subjects who withdraw their informed consent
!
The last subject-investigator contact as defined by the investigator for subjects who are lost to 
follow-up (i.e. possibly an unscheduled phone visit)
!
Death for subjects who die before any of the above
For subjects not randomised but exposed to trial product the in-trial period starts at the date of first 
dose of trial product.
Baseline assessments are always included in the in-trial observation period. 
For adjudicated events it is the event adjudication committee (EAC) determined onset date that 
determines if the event belongs to the in-trial period. 
On-treatment: The on-treatment period starts at the date of first dose of trial product as recorded on 
the eCRF, and ends at the first date of any of the following:
!
The follow-up visit (FU2)
!
The last date on trial product + 5 weeks for once daily insulin and +6 weeks for once weekly 
insulin
!
The end-date for the in-trial observation period
Baseline assessments are always included in the on-treatment period. 
For adjudicated events it is the EAC determined onset date that determines if the event belongs to the 
on-treatment period.
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Statistical Analysis Plan
CONFIDENTIAL
Date:
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Trial ID: NN1436-4466
Version:
1.0
UTN: U1111-1219-5541
Status:
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EudraCT No.: 2018-003407-18
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On-treatment without rescue medication: This observation period is a sub-set of the on-treatment 
observation period. The on-treatment without rescue medication or ancillary treatment starts at the date 
of first dose of trial product as recorded on the eCRF and ends at the first date of any of the following: 
!
Initiation of a non-randomised insulin treatment (rescue medication)
!
The end date of the on-treatment period if no rescue medication was initiated.
The following will not be considered rescue medication:
!
If a subject takes an insulin other than randomised treatment for a few days due to reasons not 
related to the effect of the randomised treatment, e.g.,
o
if a subject is hospitalised and it is against hospital policy to use trial products 
o
if a temperature deviation leaves trial product unavailable for distribution and 
administration 
!
Insulin treatment initiated after end of treatment visit 
Baseline assessments are always included in the on-treatment without rescue medication/ancillary 
treatment period. 
The ’on-treatment without rescue medication’ observation period will be the primary observation 
period for efficacy evaluations. Safety will be evaluated based on the on-treatment observation 
periods unless otherwise specified.
Data points collected outside an observation period will be treated as missing in the analysis. 
Baseline data will always be included in an observation period. Before data are locked for statistical 
analysis, a review of all data will take place. Any decision to exclude either a subject or single 
observation from the statistical analysis is the joint responsibility of the members of the Novo 
Nordisk study group.
Exclusion of data from analyses will be used restrictively and normally no data should be excluded 
from the FAS. The subjects or observations to be excluded, and the reasons for their exclusion, will 
be documented and signed by those responsible before database lock. The subjects and observations 
excluded from analysis sets, and the reason for this, will be described in the clinical trial report.
2.4
Statistical analyses
All efficacy endpoints will be summarised using the full analysis set (FAS) and safety assessments 
will be summarised using the safety analysis set (SAS).
All statistical analyses of efficacy and safety endpoints will be based on the FAS unless otherwise 
specified.
Endpoints will be assessed at frequent visits also for subjects who prematurely discontinue 
treatment. The baseline value is defined as the value from the randomisation visit. If this value is 
missing the last recorded value before randomisation visit will be used. 
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Statistical Analysis Plan
CONFIDENTIAL
Date:
03 February 2020
Novo Nordisk
Trial ID: NN1436-4466
Version:
1.0
UTN: U1111-1219-5541
Status:
Final
EudraCT No.: 2018-003407-18
Page:
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Laboratory values below the lower limit of quantification (LLOQ) will be set to ½LLOQ.
Presentation of results from a statistical analysis will include the estimated treatment means as well 
as estimated mean treatment difference (or ratio) together with the two-sided 95% confidence 
interval and corresponding two-sided p-value.
The statistical models will include baseline values of the endpoint value as a covariate as well as
explanatory factors that are categorized as follows:
!
Treatment: switch approach with 100% loading dose, switch approach without loading dose,
insulin glargine U100
!
Pre-trial insulin treatment: twice daily basal insulin analogue or once daily insulin glargine
U300: yes or no
!
SGLT2i use: yes or no
2.4.1
Primary endpoint
The primary endpoint is ‘time in target range 3.9–10.0 mmol/L (70-180 mg/dL)’ during the last 2 
weeks of treatment (week 15 and 16)andwill be calculated as 100 times the number of recorded 
measurements in glycaemic target range 3.9–10.0 mmol/L (70-180 mg/dL), both inclusive,divided 
by the total number of recorded measurements.
Following international consensus criteria1it will be required that at least 70% of the planned CGM 
measurements, during the last two weeks of treatment is available, for endpoint data to be included 
in the analysis.
Baseline ‘time in target range3.9–10.0 mmol/L (70-180 mg/dL)’ will be computedinthe same way 
as the primary endpoint.Subjects with less than 72 hours corresponding to 864 measurements of 
CGM during the screening period will not have a baseline computed and hence will be excluded 
from theanalysis.
The primary estimand will be estimated based on the Full Analysis Set (FAS) using measurements 
obtained while subjects are adhering to randomised treatment without initiation of rescue 
medication. Measurements obtained after initiation of rescue treatment and endpoint data from 
which the required 70% of the planned CGM measurements during the last two weeks of treatment 
are not available will be regarded as missing. Missing endpoint data will be imputed from trial 
participants who are from the same randomised group, and who have completed and adhered to 
their randomised insulin treatment without initiation of a non-randomised insulin treatment i.e., data 
will be imputed based on the assumption that, within treatment groups, subjects with missing 
endpoint data will behave like subjects completing randomised treatment. Specifically, the 
imputations and analyses will be carried out as follows:
!
First, one thousand (1000) copies of the dataset will be generated for time in range.
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Statistical Analysis Plan
CONFIDENTIAL
Date:
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Novo Nordisk
Trial ID: NN1436-4466
Version:
1.0
UTN: U1111-1219-5541
Status:
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!
Second, for each dataset copy, each assessment and each treatment group, an analysis of 
covariance (ANCOVA) model with baseline 'time in target range' as covariate will be fitted to 
the time in range values for subjects having completed their randomised treatment. The 
estimated mean, and variances, from the model will be used to impute missing values in the 
same treatment group.
!
For each of the complete data sets, the primary endpoint will be analysed using an ANCOVA
model with randomised treatment, pre-trial insulin treatment and SGLT2i use (yes/no) as fixed 
factors and baseline ‘time in target range’ as covariate. The estimates and standard deviations 
for the 1000 data sets will be pooled to one estimate and associated standard deviation using 
Rubin’s rule2.
2.4.2
Supportive secondary efficacy endpoints
The secondary efficacy endpoints will be addressed in terms of the frame work of the primary 
estimand.
2.4.2.1
HbA1c, fasting plasma glucose (FPG), and body weight – change from baseline 
to week 16
The supportive secondary efficacy endpoints addressing glycaemic control and body weight will be 
analysed using the same model as specified for the primary endpoint with the exception that 
baseline value of the endpoint will be used as covariate.
The missing data will be imputed in the following way:
!
First, intermittent missing values will be imputed using a Markov Chain Monte Carlo (MCMC) 
method in order to obtain a monotone missing data pattern. The imputation is, as for the 
imputation of the primary analysis, done for each treatment arm separately and 1000 copies of 
the data set will be made.
!
Next, a sequential conditional regression approach for imputing monotone missing values at 
planned visits will be implemented beginning with the first assessment after baseline and 
sequentially continuing to the last planned assessment. Models will be fitted for each treatment 
arm (using observed and imputed data). The models include the baseline and post-baseline 
values of the corresponding endpoint, prior to the visit in question as covariates.
2.4.2.2
Weekly insulin dose - during week 15 and 16
Insulin doses will be summarised by weekly averages and the actual average insulin dose during the 
last two weeks of treatment (week 15 and 16) will be log-transformed and analysed without a 
covariate reflecting baseline dose but otherwise using the same statistical model as specified for the 
primary endpoint.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
03 February 2020
Novo Nordisk
Trial ID: NN1436-4466
Version:
1.0
UTN: U1111-1219-5541
Status:
Final
EudraCT No.: 2018-003407-18
Page:
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The missing data on dose will be imputed in the same way as missing data on glycaemic control and 
body weight. However, the model in the sequential conditional regression approach will not include 
a baseline value, but all values (observed or imputed) prior to the visit in question as covariates.
2.4.2.3
HbA1c responders
Two variables of dichotomous outcome (responder=yes/non-responder=no) will be defined based 
on whether a subject has met a specific level of HbA1c < 7% (American Diabetes Association 
(ADA) and European Association for the Study of Diabetes (EASD)), respectively, <6.5%
(American Association of Clinical Endocrinologists (AACE)) by treatment week.
Responders during the ‘on treatment without rescue medication’ period will be summarised and 
tabulated. No analysis will be performed.
2.4.3
Supportive secondary safety endpoints
2.4.3.1
Adverse events
A treatment-emergent AE is an event that has onset date (or increase in severity) during the on-
treatment observation period. These will therefore be referred to as ‘on-treatment AEs’ hereafter. 
On-treatment AEs are summarised descriptively in terms of the number of subjects with at least one 
event (N), the percentage of subjects with at least one event (%), the number of events (E) and the 
event rate per 100 years (R). These summaries are replicated by outputs including all ‘in-trial’ AEs 
(i.e., AEs with onset date [or increase in severity] during the ‘in-trial’ observation period). 
The most frequent AEs will be defined as preferred terms that are experienced by at least 5% of the 
subjects in any of the treatment arms. 
All AEs will be coded using the most recent version of the Medical Dictionary for Regulatory 
Activities (MedDRA) coding.
2.4.3.2
Hypoglycaemic episodes
Hypoglycaemia endpoints will be summarized similarly to the treatment emergent AE's for the ‘on-
treatment observation’ period as well as from baseline to the end of treatment visit based on the 
SAS.
2.4.4
Pharmacokinetic and/or pharmacodynamic modelling
Not applicable for this trial. 
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
03 February 2020
Novo Nordisk
Trial ID: NN1436-4466
Version:
1.0
UTN: U1111-1219-5541
Status:
Final
EudraCT No.: 2018-003407-18
Page:
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3
Changes to the statistical analyses planned in the protocol
Definition of ‘as treated’
Arm A and B of the trial design differ only in dosage at the first visit and so constructing a rule for 
when subjects should be considered as treated in arm A, respectively, arm B was difficult. Also 
since dosage deviations happens not only at randomisation, but any subsequent visits it was decided 
to ignore dose deviations when defining ‘as treated’. 
This implies that ‘as treated’ coincides with ‘as randomised’ unless the subject receives insulin 
Glargine instead of insulin 287 or vice versa.
Requirements for baseline CGM measurements
Due to a very low number of subjects with 70% or more of planned CGM measurements during the 
screening period it was decided that only subjects with less than 72 hours corresponding to 864 
measurements of CGM during the screening period will not have a baseline computed and hence 
will be excluded from the analysis. It is remarked that only 10 days of CGM measurements was 
planned during the screening period as only one devise per subject was distributed prior to baseline.
Definition of HbA1c responders
HbA1c responders have been defined in Section 2.4.2.3 since summary tabulations on this will be 
included in EoT.
Hypoglycaemic endpoint
Due to inconsistency between the protocol Section 4.2.2.2, stating that hypoglycaemic endpoints 
will be summarised based on ‘from baseline to week 16 (end of treatment)’, and protocol Section 
10.3.1, stating that hypoglycaemic endpoints will be summarised based on the ‘on treatment’ 
observation period, further details were specified in Section 2.4.3.2 stating that the hypoglycaemic 
endpoints will be summarised on both observation periods.
Primary analysis
Phrasing in the definition of the primary analysis in Section 2.4.1 has been modified from the 
protocol for added clarity. This has no implications on the analysis.
Supportive secondary efficacy endpoint
Detailed phrasing in the definition of the imputation method for glycaemic control, body weight and 
insulin dose endpoints in Section 2.4.2.1 have been added.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
03 February 2020
Novo Nordisk
Trial ID: NN1436-4466
Version:
1.0
UTN: U1111-1219-5541
Status:
Final
EudraCT No.: 2018-003407-18
Page:
13 of 13
Definition of ‘on-treatment without rescue medication’
The definition of the ‘on-treatment without rescue medication’ observation period has been 
modified in order to be a true subset of the ‘on-treatment’ observation period as also indicated in the 
protocol. See Section 2.3. This has no implications on the analysis.
4
References
1. Danne T, Nimri R, Battelino T, Bergenstal RM, Close KL, DeVries JH, et al. International 
Consensus on Use of Continuous Glucose Monitoring. Diabetes Care. 2017;40(12):1631-40.
2. Little R, Rubin D. Statistical analysis with missing data. Sons. JW, editor. New York.: John 
Wiley & Sons. 1987.
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