Clinical trial NCT03751657
Conditions: Diabetes Mellitus, Type 2
Sponsor: Novo Nordisk A/S
Start date: 2018-11-29; Completion date: 2020-01-17
Enrollment: 247 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The study compares 2 medicines for people with type 2 diabetes: insulin 287 (a new medicine) and insulin glargine (a medicine doctors can already prescribe). The study doctors will test insulin 287 to see how well it works compared to insulin glargine. The study will also test if insulin 287 is safe. The study participants will either get insulin 287 or insulin glargine (100 units/mL) - which treatment the participants get is decided by chance. The participants will need to inject their selves every day about the same time. Once a week the participant will need to take 1 extra injection on the same day of the week. The participants will have 16 clinic visits and 14 phone calls with the study doctor. During the study, the doctors will ask you to: 1) measure your blood sugar every day with a blood glucose meter using a finger prick, 2) write down different information in a paper diary daily and return this to your doctor, 3) wear a medical device to measure your blood sugar all the time for 2 weeks 5 times during the study.

Detailed description:

Arms: arm 1: Participants will receive once weekly insulin 287 and once daily placebo in combination with metformin with or without dipeptidyl peptidase-4 inhibitors (DPP4i) during 26 weeks of treatment period. arm 2: Participants will receive once daily insulin glargine and once weekly placebo in combination with metformin with or without DPP4i during 26 weeks of treatment period.
Interventions: intervention 1: Insulin icodec intervention 2: Placebo (insulin 287) intervention 3: Metformin intervention 4: Dipeptidyl peptidase-4 inhibitors intervention 5: Insulin glargine intervention 6: Placebo (insulin glargine)
Intervention descriptions: intervention 1: Insulin 287 once weekly subcutaneous (s.c.) injections at the starting dose of 70 units. Dose adjustment was done for the individual patient based on the three pre-breakfast self-measured plasma glucose values measured on two days prior to titration and on the day of the contact. The insulin dose adjustment should aim to reach an SMPG of 3.9-6.0 mmol/L (70-108 mg/dL) intervention 2: Participants will receive once weekly s.c. injections of placebo equivalent to insulin 287. intervention 3: Metformin is considered as non investigational medicinal product. Subject will continue metformin at stable pre-trial dose. intervention 4: Dipeptidyl peptidase-4 inhibitors are considered as non investigational medicinal products. Subject will continue dipeptidyl peptidase-4 inhibitor at stable pre-trial dose. intervention 5: Insulin glargine (100 U/mL) once daily s.c. injections at the starting dose of 10 units. Dose adjustment will be done for the individual patient based on the three pre-breakfast self-measured plasma glucose values measured on two days prior to titration and on the day of the contact. The insulin dose adjustment should aim to reach an SMPG of 3.9-6.0 mmol/L (70-108 mg/dL). intervention 6: Participants will receive once daily s.c. injections of placebo equivalent to insulin glargine.

Protocol documents:
Prot_000.pdf: 
Cover Page for Protocol 
 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT03751657 
Sponsor trial ID: 
NN1436-4383 
Official title of study: 
An investigational trial comparing the efficacy and safety of 
once weekly NNC0148-0287 C (insulin 287) versus once daily 
insulin glargine, both in combination with metformin, with or 
without DPP-4 inhibitors, in insulin naïve subjects with type 2 
diabetes mellitus 
Document date: 
29 May 2020 
 


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List of contents
Protocol ...............................................................................................................................................
Log of protocol....................................................................................................................................
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16.1.1 Protocol and protocol amendments
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CONFIDENTIAL
 
 
 
 
 
Redacted protocol 
Includes redaction of personal identifiable information only. 
 
 
 
. 
 
 


Protocol
CONFIDENTIAL
Date:
25 June 2018
Novo Nordisk
Trial ID: NN1436-4383
Version:
1.0
Status:
Final
Page:
1 of 94
Protocol
Protocol title: An investigational trial comparing the efficacy and safety of once weekly 
NNC0148-0287 C (insulin 287) versus once daily insulin glargine, both in 
combination with metformin, with or without DPP-4 inhibitors, in insulin naïve 
subjects with type 2 diabetes mellitus
Substance: NNC0148-0287 C (insulin 287)
Universal Trial Number: U1111-1208-4124 
EUdraCT Number:2018-000322-63 
Trial phase: 2
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.
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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:
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Trial ID: NN1436-4383
Version:
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Status:
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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...................................................................................................................16
4.1
Primary, secondary and exploratory objectives ........................................................................16
4.1.1
Primary objective...................................................................................................16
4.1.2
Secondary objective...............................................................................................16
4.1.3
Exploratory objectives ...........................................................................................16
4.2
Primary estimand ....................................................................................................................17
4.2.1
Secondary estimand ...............................................................................................17
4.3
Primary, secondary and exploratory endpoints.........................................................................17
4.3.1
Primary endpoint ...................................................................................................17
4.3.2
Secondary endpoints ..............................................................................................17
4.3.2.1
Confirmatory endpoints....................................................................17
4.3.2.2
Supportive secondary endpoints .......................................................17
4.3.3
Exploratory endpoints............................................................................................19
5
Trial design ........................................................................................................................................19
5.1
Overall design.........................................................................................................................19
5.2
Subject and trial completion....................................................................................................20
5.3
End of trial definition..............................................................................................................20
5.4
Treatment emergent period......................................................................................................21
5.5
Scientific rationale for trial design...........................................................................................21
5.6
Justification for dose ...............................................................................................................22
6
Trial population .................................................................................................................................23
6.1
Inclusion criteria .....................................................................................................................23
6.2
Exclusion criteria ....................................................................................................................23
6.3
Lifestyle restrictions................................................................................................................24
6.4
Fasting requirements ...............................................................................................................25
6.5
Screen failures ........................................................................................................................25
6.6
Randomisation criteria ............................................................................................................25
7
Treatments .........................................................................................................................................25
7.1
Treatments administered .........................................................................................................25
7.1.1
Non-investigational medical products.....................................................................26
7.1.2
Auxiliary supplies..................................................................................................27
7.1.3
Medical devices .....................................................................................................27
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Trial ID: NN1436-4383
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7.2
Dose modification...................................................................................................................27
7.3
Method of treatment assignment..............................................................................................28
7.4
Blinding..................................................................................................................................28
7.5
Preparation/Handling/Storage/Accountability..........................................................................28
7.6
Treatment compliance.............................................................................................................29
7.7
Concomitant medication..........................................................................................................30
7.7.1
Ancillary treatment ................................................................................................30
7.8
Treatment after the end of the trial...........................................................................................30
8
Discontinuation/Withdrawal criteria ................................................................................................31
8.1
Discontinuation of trial treatment ............................................................................................31
8.2
Withdrawal from the trial ........................................................................................................32
8.2.1
Replacement of subjects.........................................................................................33
8.3
Lost to follow-up.....................................................................................................................33
9
Trial assessments and procedures .....................................................................................................33
9.1
Efficacy assessments...............................................................................................................34
9.1.1
Self-measured plasma glucose................................................................................34
9.1.2
Insulin dose ...........................................................................................................35
9.1.3
Flash Glucose Monitoring......................................................................................35
9.1.3.1
FGM Reader setting .........................................................................36
9.1.3.2
Fitting and removal of the FGM sensor.............................................36
9.1.3.3
Duration of FGM periods .................................................................37
9.1.3.4
Wearing of the FGM sensor..............................................................37
9.1.3.5
Transfer of FGM data.......................................................................37
9.1.4
Clinical efficacy laboratory assessments.................................................................37
9.2
Adverse events........................................................................................................................37
9.2.1
Time period and frequency for collecting AE and SAE information........................37
9.2.1.1
Event for adjudication ......................................................................39
9.2.2
Method of detecting AEs and SAEs .......................................................................40
9.2.3
Follow-up on AEs and SAEs..................................................................................40
9.2.4
Regulatory reporting requirements for SAEs ..........................................................40
9.2.5
Cardiovascular and death events.............................................................................41
9.2.6
Disease-related events and/or disease-related outcomes not qualifying for 
standard AE collection...........................................................................................41
9.2.7
Pregnancies and associated adverse events .............................................................41
9.2.8
Medical device incidents (including malfunctions).................................................42
9.2.9
Technical complaints .............................................................................................42
9.3
Treatment of overdose.............................................................................................................43
9.4
Safety assessments ..................................................................................................................43
9.4.1
Physical examinations............................................................................................44
9.4.2
Vital signs..............................................................................................................44
9.4.3
Electrocardiograms ................................................................................................45
9.4.4
Eye examination ....................................................................................................45
9.4.5
Clinical safety laboratory assessments....................................................................45
9.4.6
Immunogenicity assessments .................................................................................46
9.4.6.1
Assessments in case of suspicion of hypersensitivity reaction to 
trial product......................................................................................46
9.5
Pharmacokinetics ....................................................................................................................47
9.6
Pharmacodynamics .................................................................................................................47
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9.7
Genetics..................................................................................................................................47
9.8
Biomarkers .............................................................................................................................47
10
Statistical considerations ...................................................................................................................47
10.1
Sample size determination.......................................................................................................47
10.2
Definition of analysis sets........................................................................................................48
10.3
Statistical analyses ..................................................................................................................49
10.3.1
Primary endpoint ...................................................................................................50
10.3.2
Secondary endpoints ..............................................................................................52
10.3.3
Confirmatory secondary endpoints.........................................................................52
10.3.3.1
Supportive secondary endpoints .......................................................52
Efficacy endpoints .................................................................................................52
Safety endpoints ....................................................................................................53
10.3.3.2
Exploratory endpoints ......................................................................56
10.4
Pharmacokinetic and/or pharmacodynamic modelling .............................................................60
11
References ..........................................................................................................................................61
12
Appendices .........................................................................................................................................64
Abbreviations and Trademarks.......................................................................................64
Appendix 1
Clinical laboratory tests ...................................................................................................66
Appendix 2
Trial governance considerations......................................................................................68
Appendix 3
Adverse events: definitions and procedures for recording, evaluation, follow-up, 
Appendix 4
and reporting....................................................................................................................78
Contraceptive guidance and collection of pregnancy information .................................83
Appendix 5
Technical complaints: Definition and procedures for recording, evaluation, follow-
Appendix 6
up and reporting...............................................................................................................86
Retention of human biosamples.......................................................................................87
Appendix 7
Hypoglycaemic episodes...................................................................................................88
Appendix 8
Titration guideline............................................................................................................90
Appendix 9
Country-specific requirements ........................................................................................94
Appendix 10
Attachment I Global list of key staff and relevant departments and suppliers
Attachment II Country list of key staff and relevant departments
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Trial ID: NN1436-4383
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1
Synopsis
Rationale:
NNC0148-0287 formulation C (referred to as insulin 287) may provide an efficacious, safe and 
convenient once weekly alternative to once daily basal insulin, which could improve treatment 
adherence and quality of life for subjects with type 2 diabetes mellitus. 
The purpose of the present randomised, treat-to-target trial is to investigate efficacy and safety of 
once-weekly insulin 287 versus once-daily insulin glargine, both in combination with metformin 
with or without dipeptidyl peptidase-4 inhibitors, for 26 weeks in subjects with type 2 diabetes 
insufficiently controlled on metformin ±dipeptidyl peptidase-4 inhibitors. Glycated haemoglobin
(HbA1c) will be included as the primary endpoint since it is considered the most widely accepted 
measure of overall, long-term glucose control by the European Medicines Agency (EMA) and Food 
and Drug Administration (FDA) guidance documents.
Objectives and endpoints
Primary objective
To investigate the effect on glycaemic control after 26 weeks treatment of once weekly insulin 287 
versus once daily insulin glargine both in combination with metformin with or without dipeptidyl 
peptidase-4 inhibitors in insulin-naïve type 2 diabetes mellitus subjects inadequately treated with 
metformin with or without dipeptidyl peptidase-4 inhibitors.
Secondary objective
To investigate the safety and tolerability during 26 weeks of treatment with once weekly insulin 287 
versus once daily insulin glargine both in combination with metformin with or without dipeptidyl 
peptidase-4 inhibitors in insulin-naïve subjects with type 2 diabetes mellitus inadequately treated 
with metformin with or without dipeptidyl peptidase-4 inhibitors.
Primary endpoint
Change from baseline (visit 2, week 0) to week 26 (visit 28) in HbA1c (%-point and [mmol/mol])
Estimand
The primary estimand is defined as the treatment difference in change of HbA1c from baseline to 
week 26 between once weekly insulin 287 and once daily insulin glargine for all randomised 
subjects, if all subjects had adhered to treatment and did not receive ancillary treatment.
This is a ‘hypothetical’ estimand aiming to reflect the treatment effect for subjects that are actually 
able to take the drug during the intended treatment period.
Overall design:
This is a 26-week, randomised, double-blind, double-dummy, active-controlled, parallel-group, 
stratified, multicentre, multinational trial with 2 arms comparing the efficacy and safety of 
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Protocol
CONFIDENTIAL
Date:
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Novo Nordisk
Trial ID: NN1436-4383
Version:
1.0
Status:
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Page:
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treatment with insulin 287 once weekly versus insulin glargine once daily in insulin-naive subjects 
with type 2 diabetes mellitus inadequately controlled on metformin with or without dipeptidyl 
peptidase-4 inhibitors.
Subjects will be randomised in a 1:1 manner to receive once weekly insulin 287 and once daily 
placebo or once weekly placebo and once daily insulin glargine. The randomisation of subjects will 
be stratified based on use of dipeptidyl peptidase-4 inhibitors.
Key inclusion criteria:
!
Male or female, aged 18-75 years (both inclusive) at the time of signing informed consent.
!
Diagnosed with type 2 diabetes mellitus ≥ 180 days prior to the day of screening.
!
HbA1c of 7.0-9.5% (53-80 mmol/mol) (both inclusive) as assessed by central laboratory.
!
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):
a) Any metformin formulations ≥ 1500 mg or maximum tolerated or effective dose (as 
documented in subject's medical record) 
b) Any metformin formulations ≥ 1500 mg or maximum tolerated or effective dose (as 
documented in subject medical record) with DPP4i (≥ half of the maximum approved 
dose according to local label or maximum tolerated or effective dose (as documented in 
subject's medical records)
!
Insulin naïve. However, short term insulin treatment for a maximum of 14 days prior to the 
day of screening is allowed, as is prior insulin treatment for gestational diabetes.
!
Body mass index (BMI) ≤ 40.0 kg/m2
Key exclusion criteria:
!
Any episodes of diabetic ketoacidosis within the past 90 days prior to the day of screening 
and between screening and randomisation.
!
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.
!
Presently classified as being in New York Heart Association (NYHA) Class IV.
!
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. However, short 
term insulin treatment for a maximum of 14 days prior to the day of screening is allowed, as 
is prior insulin treatment for gestational diabetes.
!
Anticipated initiation or change in concomitant medications (for more than 14 consecutive 
days) known to affect weight or glucose metabolism (e.g. treatment with orlistat, thyroid 
hormones, or corticosteroids).
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Protocol
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Trial ID: NN1436-4383
Version:
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!
Uncontrolled and potentially unstable diabetic retinopathy or maculopathy. Verified by a 
pharmacologically pupil-dilated fundus examination performed by an ophthalmologist or 
another suitably qualified health care provider within the past 90 days prior to screening or 
in the period between screening and randomisation.
Randomisation criterion:
!
Subject able and willing to adhere to the protocol including self-administered daily 
injections using vial and syringe based on the Investigator’s judgment.
Number of subjects:
!
Number of subjects planned to be randomised: 250 subjects
!
Estimated number of subjects to complete the trial (on trial product): 215.
Treatment groups and duration:
The total trial duration for the individual subject will be approximately 33 weeks. The trial includes 
a 2 week screening period, followed by a 26-week randomised treatment period and a 5-week 
follow-up period. 
Trial products:
Investigational medical products:
!
Test product: 
o
NNC0148-0287 C 4200 nmol/mL in a 3 mL PDS290 pre-filled pen-injector with for 
subcutaneous injection
!
Reference therapies: 
o
Insulin glargine 100U/ml, 10 ml vials for subcutaneous injection
o
NNC0148-0287 C and insulin glargine placebo (double dummy trial)
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Protocol
     
Date:
25 June 2018
Status:
Final
Novo Nordisk
Trial ID: NN1436-4383
     
Version:
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2
Flowchart
Trial Periods
Screening
Randomisation
Treatment
End of 
treatment1
Follow up
Discontinuation 
phone contacts
(Px)
Discontinuation
follow-up
Visit (V)
Phone contact (P)
V1
V2
V3
V4
V5
V6
P7
V8
P9
V10 P11 V12 P13 V14 P15
P16
P17
V18 P19
P20
P21
V22 P23
P24
P25
V26 P27 V28 V29
FU1
V30
FU2
Every
4 
weeks
V28A
Time of visit (weeks)2
≤-2
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
28
31
26
Visit window (days)
±1
±1
±1
±1
±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 criterion
X
Concomitant illness/
medical history
X
Concomitant medication
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X3
X3
X3
X3
Demography4
X
Diabetes history/Diabetes 
complications
X
Date of Diagnosis of Diabetes
X
Childbearing potential
X
Tobacco use 5
X
Body measurements
Height
X
                                               
1 If subjects are discontinuing trial product prematurely they will be asked to attend the end of treatment visit (V28) as soon as possible and the follow up visits (V29 and 
V30) must be scheduled 2 and 5 weeks after discontinuation of trial product. After the follow-up period, the subjects discontinuing trial product prematurely should have 
phone contacts (Px) scheduled every 4 weeks until the discontinuation follow-up visit (28A) performed at week 26.
2 Time of visit is relative to randomisation (V2).
3 Only antidiabetic medication to be collected 
4 Demography consists of date of birth or year of birth and/or age, sex, ethnicity and race (according to local regulation).
5 Smoking is defined as smoking at least one cigarette or equivalent daily.
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Protocol
     
Date:
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Status:
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Novo Nordisk
Trial ID: NN1436-4383
     
Version:
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Trial Periods
Screening
Randomisation
Treatment
End of 
treatment1
Follow up
Discontinuation 
phone contacts
(Px)
Discontinuation
follow-up
Visit (V)
Phone contact (P)
V1
V2
V3
V4
V5
V6
P7
V8
P9
V10 P11 V12 P13 V14 P15
P16
P17
V18 P19
P20
P21
V22 P23
P24
P25
V26 P27 V28 V29
FU1
V30
FU2
Every
4 
weeks
V28A
Time of visit (weeks)2
≤-2
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
28
31
26
Visit window (days)
±1
±1
±1
±1
±1
±1
±1
±1
±1
±1
±1
±1
±1
±1
±1
±1
±1
±1
±1
±1
+3
+3
±3
Body weight6
X
X
X
X
X
EFFICACY
Glucose metabolism
HbA1c
X
X
X
X
X
X
X
X
X
Fasting plasma glucose
X
X
X
Fasting C-peptide
X
X
X
Self-measured plasma glucose 
(SMPG)7
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
9-point profile8
X
X
X
PK sampling
X
X
X
X
X
X
X
OTHER ASSESSMENTS
Flash glucose monitoring, 
fitting
X
X
X
X
X
Flash glucose monitoring, 
removal and upload
X
X
X
X
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
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
X
X
X
X
Technical complaints
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ECG9
X
X
                                               
6 Body weight should be measured fasting except for V1 and V28A.
7 Subjects will measure once daily pre-breakfast SMPG.
8 The 9-point profile must be performed  in the week prior to visits, on a day where the subject does not anticipate unusual strenuous exercise
9 ECG obtained within 2 weeks prior to V2 and V28 are acceptable if results are available for evaluation at the visits.
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Protocol
     
Date:
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Status:
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Trial ID: NN1436-4383
     
Version:
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Trial Periods
Screening
Randomisation
Treatment
End of 
treatment1
Follow up
Discontinuation 
phone contacts
(Px)
Discontinuation
follow-up
Visit (V)
Phone contact (P)
V1
V2
V3
V4
V5
V6
P7
V8
P9
V10 P11 V12 P13 V14 P15
P16
P17
V18 P19
P20
P21
V22 P23
P24
P25
V26 P27 V28 V29
FU1
V30
FU2
Every
4 
weeks
V28A
Time of visit (weeks)2
≤-2
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
28
31
26
Visit window (days)
±1
±1
±1
±1
±1
±1
±1
±1
±1
±1
±1
±1
±1
±1
±1
±1
±1
±1
±1
±1
+3
+3
±3
Eye Examination
X10
X11
Physical Examination
X
X
Vital signs
X
X
X
X
Biochemistry
X
X
X
X
X
X
X
X
Lipids
X
X
X
Free Fatty Acids
X
X
X
Haematology
X
X
X
X
Pregnancy test12
X
X
X
Antibodies
X
X
X
X
X
X
TRIAL MATERIAL
Drug accountability
X
X
X
X
X
X
X
Dispensing visit
X
X
X
X
X
X
Dose of trial insulin13
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X14
X
REMINDERS
Handout ID card
X
Attend visit fasting
X
X
X
                                               
10 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. 
11 Eye examinations performed within 2 weeks prior to V28 are acceptable if results are available for evaluation at the visit. For treatment-discontinued subjects, eye 
examination can be performed up to 2 weeks after V28.
12 For females of childbearing potential a serum pregnancy test must be performed at V1 and V30. At V2 and if a menstrual period is missed, a urine pregnancy test will 
be taken. 
13 The first 5 doses of once-weekly insulin 287 or once-weekly placebo will be taken at the site (V2 to V6).
14 The last dose of once weekly insulin/placebo must be taken 25 weeks after randomisation, whereas the last dose of the once daily insulin/placebo must be taken  26 
weeks after randomisation where the subjects come in for the end of treatment visit (V28). This is due to the longer half life of Insulin 287.
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Trial Periods
Screening
Randomisation
Treatment
End of 
treatment1
Follow up
Discontinuation 
phone contacts
(Px)
Discontinuation
follow-up
Visit (V)
Phone contact (P)
V1
V2
V3
V4
V5
V6
P7
V8
P9
V10 P11 V12 P13 V14 P15
P16
P17
V18 P19
P20
P21
V22 P23
P24
P25
V26 P27 V28 V29
FU1
V30
FU2
Every
4 
weeks
V28A
Time of visit (weeks)2
≤-2
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
28
31
26
Visit window (days)
±1
±1
±1
±1
±1
±1
±1
±1
±1
±1
±1
±1
±1
±1
±1
±1
±1
±1
±1
±1
+3
+3
±3
Hand out direction for use15
X
Training in trial product 
handling and titration
X16
X17
X
X
X
X
X
X
X
X
X
X
X
Hand out and instruct in BG 
meter 
X
IWRS session
X
X
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
X
X
Collect and review diary
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
End treatment
X
End of trial
X18
X
                                               
15 Directions for use can be handed out as needed at subsequent visits.
16 Subjects must be trained in the use of vial and syringe at V1, by having the subjects inject themselves with saline solution at site. If deemed necessary by the 
investigator, it could be considered to have the subjects inject themselves with saline solution at home between V1 and V2. At V2 the ability to self-administer daily 
injections will have to be assessed prior to randomisation.
17 Subjects must be trained in handling of the PDS290 pre-filled pen-injector at V2.
18 Not applicable for subjects discontinuing trial product prematurely, these will have “end of trial” at V28A.
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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 
which is designed for subcutaneous (s.c.) administration with the aim to develop a once weekly 
injectable basal insulin treatment. Currently the basal insulin products with the longest duration are 
administered once daily.
Research has shown that people with diabetes would prefer fewer injections and increased 
flexibility than provided by the current once-daily treatment regimen.1  Development of sustained 
release formulations or compounds with prolonged action has in several treatment areas been 
demonstrated to improve subject compliance and treatment outcomes. Hence, insulin 287 would be 
a convenient basal insulin which could improve treatment adherence and quality of life for subjects 
with type 2 diabetes mellitus (T2DM). 
The present randomised, treat-to-target trial will investigate efficacy and safety of once-weekly 
insulin 287 (formulation C) versus once-daily insulin glargine (IGlar), both in combination with 
metformin with or without dipeptidyl peptidase-4 inhibitors (DPP4i), for 26 weeks in subjects with 
type 2 diabetes insufficiently controlled on metformin ±DPP4i . HbA1c will be included as the 
primary endpoint since it is considered the most widely accepted measure of overall, long-term 
glucose control by the European Medicines Agency (EMA) and Food and Drug Administration 
(FDA) guidance documents.2, 3
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 premeal glucose target of 80–130 mg/dL (4.4–7.2 mmol/L) to achieve 
glycaemic control.4 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.2 Despite combination therapy and/or insulin treatment, a sizeable proportion of subjects 
remain poorly controlled.2
Improvement in long-term glucose control, as obtained with intensified insulin therapy, was shown 
in the UK Prospective Diabetes Study (UKPDS)5 to reduce the incidence of microvascular 
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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 (OADs), 
drug intensification, including insulin therapy, should not be delayed.6
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 and two 
multiple-dose trials in subjects with type 2 diabetes have been completed. The pharmacokinetics 
(PK) properties of subcutaneous insulin 287 (formulation C) 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 pharmacodynamics (PD) properties of s.c. insulin 287 (formulation C), 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 type 2 diabetes. No safety concerns were 
identified after multiple once-weekly dosing in the dose range of 12−24 nmol/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.7
Insulin glargine
Insulin glargine 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 is a widely used basal insulin world-wide and has therefore been selected as 
comparator in the current trial. For further details, please refer to the EMA Summary of Product 
Characteristics for insulin glargine (Lantus®)8, U.S. Label Information9 and manufactures label.
Metformin
Together with life style interventions metformin is considered a first-line antidiabetic therapy in 
subjects with T2DM.6 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 Metformin10 or locally approved Product 
Information.
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Dipeptidyl peptidase 4 inhibitors
Dipeptidyl peptidase 4 inhibitors (DPP4i) can be used as second line OADs in combination with 
Metformin11. DPP4i prevent the hydrolysis of incretin hormones, thereby increasing plasma 
concentrations of the active forms of glucagon-like peptide-1 (GLP-1) and glucose-dependent 
insulinotropic polypeptide (GIP). 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 (FHD) and multiple dose (MD) 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.12 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 insulin naïve subjects with type 2 diabetes insufficiently 
controlled on metformin ±DPP4i. For all subjects participating in this 26 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 LAI 287 describe undesirable clinical outcomes for which there is sufficient 
evidence that they are caused by LAI287. Potential risks in this section describe undesirable clinical 
outcomes for which there is scientific evidence to suspect the possibility of a causal relationship 
with LAI287, but where there is currently insufficient evidence to conclude that this association is 
causal.13
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, frequent blood glucose (BG) 
measurements will be made throughout drug exposure, and will prevent worsening of 
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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 formulation C of 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 9.4.6.1.
!
Hypersensitivity reactions
Severe systemic hypersensitivity reactions may potentially occur following injection of 
therapeutic proteins. No hypersensitivity reactions were reported in trial NN1436-4314 with 
optimised formulation C. 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 9.4.6.1.
!
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 optimised formulation C. 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 this trial blood samples will be analysed for serum antibodies against insulin 
287 at pre-dose time points and at the follow-up visit. 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 9.4.6.1.
!
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.
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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.7
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 type 1 diabetes and in the 
multiple dose trial in subjects with type 2 diabetes mellitus. No safety concerns have been observed 
with LAI287 formulation C; neither elevation in hepatic enzymes nor clinical consequences 
following antibody formation have been reported. With formulation C, 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 improved with the 
optimised formulation C and is anticipated to be favourable.7
4
Objectives and endpoints
4.1
Primary, secondary and exploratory objectives
4.1.1
Primary objective
To investigate the effect on glycaemic control after 26 weeks treatment of once weekly insulin 287 
versus once daily IGlar both in combination with metformin with or without DPP4i in insulin-naïve 
T2DM subjects inadequately treated with metformin with or without DPP4i.
4.1.2
Secondary objective
To investigate the safety and tolerability during 26 weeks of treatment with once weekly insulin 287
versus once daily IGlar both in combination with metformin with or without DPP4i in insulin-naïve 
subjects with T2DM inadequately treated with metformin with or without DPP4i.
4.1.3
Exploratory objectives
!
To investigate the pharmacokinetics (PK) of insulin 287 using population PK during 26 weeks 
of treatment in insulin naïve subjects with T2DM inadequately treated with metformin with or 
without DPP4i
!
To investigate the effect on glycaemic control (using 
FreeStyle Libre Pro) of insulin 
287 and IGlar during 26 weeks of treatment in insulin naïve subjects with T2DM inadequately 
treated with metformin with or without DPP4i
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4.2
Primary estimand 
The primary estimand is defined as the treatment difference in change of HbA1c from baseline to 
week 26 between once weekly insulin 287 and once daily IGlar for all randomised subjects, if all 
subjects had adhered to treatment and did not receive ancillary treatment.
This is a ‘hypothetical’ estimand aiming to reflect the treatment effect for subjects that are actually 
able to take the drug during the intended treatment period.
4.2.1
Secondary estimand
The secondary estimand is defined as the treatment difference in change of HbA1c from baseline to 
week 26 between once weekly insulin 287 and once daily IGlar for all randomised subjects, 
regardless of the treatment actually received. 
This estimand aims to reflect the treatment effect for all subjects regardless of treatment adherence, 
i.e., a ‘treatment policy’ estimand.
4.3
Primary, secondary and exploratory endpoints
4.3.1
Primary endpoint
Endpoint title
Time Frame 
Unit
Change in HbA1c
From baseline (V2) to week 
26 (V28)
%-point and 
[mmol/mol]
4.3.2
Secondary endpoints
4.3.2.1
Confirmatory endpoints 
Not applicable for this trial.
4.3.2.2
Supportive secondary endpoints
Supportive secondary efficacy endpoints
Endpoint title
Time Frame 
Unit
Change in fasting plasma 
glucose 
From baseline (V2) to week 
26 (V28)
[mmol/l]
9-point profile (individual 
SMPG values)
Week 26 (V28)
[mmol/l]
Change in mean of the 9-point 
profile, defined as the area 
From baseline (V2) to week 
26 (V28)
[mmol/l]
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under the profile
Fluctuations of the 9-point 
profile (defined as the 
integrated absolute distance 
from the mean profile value 
divided by measurement time)
Week 26 (V28)
[mmol/l]
Change in fasting C-peptide
From baseline (V2) to week 
26 (V28)
[mmol/l]
Change in body weight
From baseline  (V2) to week 
26 (V28)
Kilogram 
Weekly dose of insulin 287 
and weekly dose of  IGlar   
Week 24-26 (V26-V28)
U
Supportive secondary safety endpoints
Endpoint title
Time Frame 
Unit
Number of treatment emergent 
adverse events (TEAEs) 
From baseline (V2) to week 
31 (V30)
Number 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 (V2) to week 
26 (V28)
Number 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 (V2) to week 
26 (V28)
Number of events
Number of severe 
hypoglycaemic episodes (level 
3)
From baseline (V2) to week 
26 (V28)
Number of events
Change in anti-insulin 287 
antibodies level 
From baseline (V2) to week 
31 (V30)
%B/T* 
Change in anti-insulin 287 
antibody titres
From baseline (V2) to week 
31 (V30)
No unit
Change in cross-reactive anti-
human insulin antibody status 
From baseline (V2) to week 
31 (V30)
Positive/negative 
for cross-reactivity
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(positive/negative) 
* %B/T is % bound radioactivity-labelled insulin 287/Total added radioactivity-labelled 
insulin 287.
4.3.3
Exploratory endpoints
Endpoint title
Time Frame 
Unit
Insulin 287 concentrations, 
evaluated in a population PK 
analysis
From baseline (V2) to week 
26 (V28)
pmol/L
Time in target-range 3.9–7.8 
mmol/L (70-140 mg/dL) 
measured by flash glucose 
monitoring (FGM) (
 
FreeStyle Libre Pro) 
During the last 2 weeks of 
treatment (week 25 and 26)
Time unit
5
Trial design 
5.1
Overall design
This is a 26-week, randomised, double-blind, double-dummy, active-controlled, parallel-group, 
stratified, multicentre, multinational trial with 2 arms comparing the efficacy and safety of 
treatment with insulin 287 once weekly versus insulin glargine once daily in insulin-naive subjects 
with T2DM inadequately controlled on metformin with or without DPP4i.
Subjects will be randomised in a 1:1 manner to receive once weekly insulin 287 and once daily 
placebo or once weekly placebo and once daily insulin glargine. The randomisation of subjects will 
be stratified based on use of DPP4i.
The total trial duration for the individual subject will be approximately 33 weeks. The trial includes 
a 2 week screening period, followed by a 26-week randomised treatment period and a 5-week 
follow-up period. 
After screening, all eligible subjects will be randomised (1:1) to insulin 287 or insulin glargine at 
the randomisation visit (V2). During the 26-week treatment period, the subjects will have weekly 
contact with the site either at site visits or by phone. 
After 26 weeks of treatment the subjects will come in for their end-of-treatment visit. The end of-
treatment visit will be one week after the last dose of once weekly insulin/once weekly placebo and 
on the day of or the day after the last dose of once daily insulin/once daily placebo.
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The end of-treatment visit will be followed by two follow up visits (V29 and V30). The last follow 
up visit (V30) is scheduled to take place 6 weeks after the last dose of once weekly insulin/once 
weekly placebo and 5 weeks after the last dose of once daily insulin/once daily placebo.
The dose and dosing frequency of metformin with or without DPP4i should not be changed at any 
time during the trial, unless due to safety concerns.
Event adjudication will be performed for major adverse cardiovascular events (MACE) and 
hypersensitivity reactions (see section 9.2.1.1).
The overall trial design and visit schedule are outlined in the trial diagram Figure 5-1 and trial 
flowchart (section 2) respectively.
Figure 5-1
Trial Design
5.2
Subject and trial completion
250 subjects will be randomly assigned to trial product. The estimated number of subjects to 
complete the trial (on trial product) is 215.
Trial period completion for a subject:
Trial period completion is defined as when the randomised subject has completed the final 
scheduled visit V30, (‘end of trial' according to the flowchart, section 2).
'Date of trial completion' is the date the subject completed the final scheduled visit (V30).
Treatment period completion for a subject: 
Treatment period completion is defined as when the randomised subject has received the required 
treatment, and attended the 'end of treatment' visit (V28) according to the flowchart, section 2
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
Treatment emergent period 
The treatment emergent period represents the period where subjects are considered exposed to trial 
product. It starts at the first date of exposure to randomised treatment and ends at the last follow-up 
visit (FU2), thus includes a time period after last dose of randomised treatment corresponding to 
approximately 5 half-lives of insulin 287. Specifically, it ends at one of the following:
!
For subjects completing the trial: Last follow-up visit (FU2) 
!
For subjects who discontinue: Last follow-up visit (FU2) as defined in section 8.1
!
For subjects who discontinue, but do not attend FU2 visit: Last dosing day of randomised 
treatment + 5 weeks for glargine, and last dosing day of randomised treatment + 6 weeks for 
insulin 287
5.5
Scientific rationale for trial design
The trial is designed to investigate the effect on glycaemic control, safety and tolerability between a 
once-weekly insulin and a once-daily insulin, while minimising bias of the results. 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 has been chosen as comparator. 
The treatment arms will be blinded to increase the scientific value of the results as compared to an 
open design, thus avoiding bias from investigators and subjects. To ensure blinding between the two 
treatments with different duration of action and dosing frequency, a double-dummy approach is 
applied. The treatment duration of 26 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 as well as a sufficient maintenance period. The first 16 weeks will be defined as the 
titration period and the following 10 weeks until end-of-treatment as the maintenance period. 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 be insulin naïve, but all will use first line treatment metformin. 
Use of DPP4i in addition to metformin is allowed but not a requirement. Subjects will be stratified 
on use of DPP4i to ensure an equal distribution of subjects in both treatment arms. To include a 
more homogenous study population, other oral antidiabetic drugs are not allowed.
Titration of insulin 287 and IGlar are based on three pre-breakfast SMPG values measured on two 
days prior to titration and on the day of the contact.
Furthermore, to collect data to characterise the effect of insulin 287, FGM data will be collected 
during the trial.  
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 type 2 diabetes and related 
diseases, such as hypertension or dyslipidaemia. This is to avoid compromising the safety of the 
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subjects participating in the trial and to strengthen conclusions regarding the efficacy, safety and the 
PK properties of once-weekly insulin 287.
Furthermore, during the treatment period, the subjects will have weekly contacts with the site either 
at visits to the site or phone contacts and the first 5 administrations of once-weekly insulin 287 or 
once-weekly placebo will be done at the site. After the injections at the site, the subjects should stay 
at least one hour for observation. The last follow-up visit is planned to be 6 weeks after last once-
weekly insulin/once-weekly placebo dose allowing appropriate time for wash-out of trial drug, 
following at least 5 half-lives of insulin 287.
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. Some 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 with reference to premature discontinuation criteria, section 8.1
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 2877 and 
local label for insulin glargine. Relevant precautions have been implemented in the design and 
planned conduct of the trial in order to minimise the risks and inconveniences of participation in the 
trial. These precautions include thorough information regarding the correct administration of the 
trial products and gradual dose adjustment. 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. The double-dummy study design introduces a 
potential risk of mix-up between treatments. To minimise this risk, injections of the weekly insulin 
287/insulin 287 placebo will be performed at the site during the first month while the once daily 
injections are performed by the subjects at home. To further mitigate the risk, instructions will be 
given to consistently use the same thigh for injection, left for the once weekly injection and right for 
the once daily injection throughout the study period.
5.6
Justification for dose
Insulin glargine will be initiated at 10 units (U) once daily and insulin 287 will be initiated at 70U 
once weekly. One U of insulin 287 has similar glucose lowering effect as one U of a standard 
insulin analogue, such as insulin glargine, and therefore once-weekly dosing corresponds to 7 times 
the daily dose of the once daily comparator. Starting dose is based on insulin glargine label.
The starting dose is considered to be safe and conservative for insulin naïve subjects with type 2 
diabetes. The PK/PD properties of insulin 287 following 5 weeks of once weekly dosing in subjects 
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with type 2 diabetes (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 type 2 diabetes and no safety concerns were identified after multiple once-
weekly dosing in the dose range of 12−24 nmol/kg.
After randomisation at V2, subjects will start once daily and once-weekly injections on the same 
day. This treatment will continue until 25 weeks after randomisation. At this time point the last once 
weekly injection must be taken while the once daily injections are taken until 26 weeks after 
randomisation where the subjects come in for the end of treatment visit (V28). This is due to the 
longer half-life of Insulin 287. Further details 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
Subjects are eligible to be included in the trial only if all of the following criteria apply:
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 7.0-9.5% (53-80 mmol/mol) (both inclusive) as assessed by central laboratory.
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):
(a) Any metformin formulations ≥ 1500 mg or maximum tolerated or effective dose 
(as documented in subject's medical record) 
(b) Any metformin formulations ≥ 1500 mg or maximum tolerated or effective dose 
(as documented in subject medical record) with DPP4i (≥ half of the maximum 
approved dose according to local label or maximum tolerated or effective dose 
(as documented in subject's medical records) 
6. Insulin naïve. However, short term insulin treatment for a maximum of 14 days prior to the day 
of screening is allowed, as is prior insulin treatment for gestational diabetes.
7. Body mass index (BMI) ≤ 40.0 kg/m2
6.2
Exclusion criteria 
Subjects are excluded from the trial if any of the following criteria apply:
1. Known or suspected hypersensitivity to trial product(s) or related products. 
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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 adequate contraceptive methods (adequate contraceptive measures as 
required by local regulation or practice). 
For Czech Republic and Greece, please see Appendix 10 for country specific requirements.
4. Receipt of any investigational medicinal product within 90 days prior to the day of 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. 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.
8. Presently classified as being in New York Heart Association (NYHA) Class IV.
9. Planned coronary, carotid or peripheral artery revascularisation.
10. Renal impairment measured as estimated Glomerular Filtration Rate (eGFR) value of eGFR   
<60 ml/min/1.73 m2 as defined by KDIGO 2012 using the CKD-Epi for eGFR calculation*
11. Impaired liver function, defined as Alanine Aminotransferase (ALT) ≥ 2.5 times or Bilirubin 
>1.5 times upper normal limit at screening*
12. Inadequately treated blood pressure defined as Grade 3 hypertension or higher (Systolic ≥180 
mmHg or diastolic ≥110 mmHg) at screening.
13. 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. However, short term 
insulin treatment for a maximum of 14 days prior to the day of screening is allowed, as is prior 
insulin treatment for gestational diabetes.
14. Anticipated initiation or change in concomitant medications (for more than 14 consecutive days) 
known to affect weight or glucose metabolism (e.g. treatment with orlistat, thyroid hormones, or 
corticosteroids).
15. Uncontrolled and potentially unstable diabetic retinopathy or maculopathy. Verified by a 
pharmacologically pupil-dilated fundus examination performed by an ophthalmologist or 
another suitably qualified health care provider within the past 90 days prior to screening or in 
the period between screening and randomisation.
16. Presence or history of malignant neoplasms within the past 5 years prior to the day of screening. 
Basal and squamous cell skin cancer and any carcinoma in-situ are allowed.
*Result from the screening visit as provided by the central lab.
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 (if applicable) 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 and/or randomisation 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 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".
1) Subject able and willing to adhere to the protocol including self-administered daily injections 
using vial and syringe based on the Investigator’s judgment.
7
Treatments
7.1
Treatments administered
!
All investigational medical products (IMPs) are listed in table Table 7-1
!
Trial product must only be used, if it appears clear and colourless. 
!
Trial products must not be dispensed to any person not included in the trial
Table 7-1
Trial products provided by Novo Nordisk A/S
Trial product 
name:
NNC0148-0287 C 4200 nmol/mL or placebo 
(IMP, test product or double dummy)
Insulin glargine 100 U/mL or placebo
(IMP reference therapy or double dummy)
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Dosage form:
Solution for injection
Solution for injection
Route of 
administration:
Subcutaneously into the left thigh.
Rotation of injection site on the left thigh is 
recommended
Subcutaneously into the right thigh. 
Rotation of injection site on the right thigh is 
recommended.
Recommended 
initial dose.
Initial dose 70U.
For details refer to Appendix 9.
Initial dose 10U. 
For details refer to Appendix 9.
Dosing 
instructions:
Once weekly at the same day of the week, 
anytime during the day, preferably at the same 
time of the day.
For details on dose titration. See Appendix 9, 
Titration Guideline.
Once daily anytime of the day, preferably at the 
same time every day
For details on dose titration. See Appendix 9, 
Titration Guideline.
Packaging.
3 mL PDS290 pre-filled pen-injector.
10 ml vial 
!
After randomisation at V2, subjects will start once daily and once-weekly injections on the 
same day. During the treatment period, the subjects will have weekly contacts with the site 
either at visits to the site or phone contacts and the first 5 administrations of once-weekly 
insulin 287 or once-weekly placebo will be done at the site. After the injections at the site, 
the subjects should stay at least one hour for observation.
!
Once daily and once-weekly injections will continue until 25 weeks after randomisation. At 
this time point the last once weekly injection must be taken while the once daily injections 
are taken until 26 weeks after randomisation where the subjects come in for the end of 
treatment visit (V28).
!
Subjects must be trained in the use of vial and syringe at V1, by having the subjects inject 
themselves with saline solution at site. If deemed necessary by the investigator, it could be 
considered to have the subjects inject themselves with saline solution at home between V1 
and V2. At V2 the ability to self-administer daily injections will have to be assessed prior to 
randomisation.
!
Subjects must be trained in handling of the PDS290 pre-filled pen-injector at V2.
!
Training in handling the pen-injector and vials/syringes must be repeated during the trial as 
needed.
!
Subjects should be instructed to discard the injector needle and syringe after each injection 
and store the pen-injector without an injection needle attached. 
!
The investigator must document that directions for use (DFU) 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.
7.1.1
Non-investigational medical products
The oral antidiabetic drugs metformin and DPP4i are considered as Non Investigational Medicinal 
Products (NIMPs) and hence will not be provided by Novo Nordisk, unless required by local law 
and should be purchased or otherwise delivered to subjects in accordance with the local health plan.
For Slovakia, please see Appendix 10 for country specific requirements.
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7.1.2
Auxiliary supplies
The following will be provided by Novo Nordisk:
!
DFU for PDS290 pre-filled pen-injector and vials
!
Needles for PDS290 pre-filled pen-injectors. Only needles provided by Novo Nordisk must 
be used for administration of trial product. 
!
Syringes for injection of insulin glargine (for use with vial)
!
Diary
!
Blood glucose (BG) meter and related auxiliaries 
!
 FreeStyle Libre Pro supplies (sensor, reader, operator’s manual and user guides)
Subjects must be instructed in how to use the diary, FreeStyle Libre Pro and BG meter. The 
instruction should be repeated during the trial, as needed. 
For complaints related to the BG meter or the FreeStyle Libre Pro, the investigator must contact the 
device manufacturer’s technical support according to Operator’s Manuals provided with the 
devices.
7.1.3
Medical devices
Investigational medical device: 3 mL PDS290 pre-filled pen-injector
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 T2D has been verified by the notified body, 
. 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 in that there is no intent to use the results from 
this trial to support a new marketing application or extension of an existing marketing approval.
Training in the 3 mL PDS290 pre-filled pen-injector 
The subjects must be trained according to the direction for use in how to handle the PDS290 pen-
injector. Training must be repeated during the trial at regular intervals in order to ensure correct use 
of the PDS290 pen-injector. 
7.2
Dose modification 
Doses are adjusted according to plasma glucose values as described in Appendix 9 (Titration 
Guideline). 
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7.3
Method of treatment assignment
All subjects will be centrally randomised using IWRS and assigned to the next available treatment 
according to randomisation schedule. Subjects will be stratified based on use of DPP4i. Within each 
stratum, each subject will be randomly allocated to receive once weekly insulin 287 and once daily 
placebo or once weekly placebo and once daily insulin glargine.
Trial products will be dispensed at the trial visits summarised in the flowchart, section 2.
7.4
Blinding
This is a double-dummy, double-blinded trial. 
The following trial products will be packed blinded and are visually identical for the following trial 
product:
!
Insulin 287 or once weekly placebo, 3 mL PDS290 pre-filled pen-injector 
!
Insulin glargine or once daily placebo, 10 mL vial
The specific trial product for a subject will be assigned using the IWRS. The site will access the 
IWRS before the start and each dispensation of trial product administration for each subject. 
The IWRS is used for blind-breaking instructions. The blind may be broken in a medical emergency 
if knowing the actual treatment would influence the treatment of the subject. Novo Nordisk will be 
notified immediately after breaking the blind. The date when and reason why the blind was broken 
must be recorded in the source documentation.
Whenever the blind is broken, the person breaking the blind must print the "code break 
confirmation" notification generated by the IWRS and sign and date the document. 
When the blind is broken, the treatment allocation will be accessible to the investigator and the 
Novo Nordisk Global Safety department. If IWRS is not accessible at the time of blind break, the 
IWRS helpdesk should be contacted. Contact details are listed in Attachment I. 
If the blind has been broken by investigator, the subject must discontinue treatment with trial 
product and a treatment discontinuation session must be completed in IWRS. 
The laboratory responsible for pharmacokinetics and antibodies analyses and the responsible 
scientific monitor of bioanalysis at Novo Nordisk will have access to the treatment allocation in the 
IWRS. 
7.5
Preparation/Handling/Storage/Accountability
Only subjects enrolled in the trial may receive trial product and only authorised site staff may 
supply or administer trial product. 
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Storage conditions, in-use conditions and in-use time for trial products will be available on the 
product label and in the TMM. 
!
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 must confirm 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, controlled, and 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 TMM. 
!
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 subject must return all used and unused trial product including empty packaging 
materials during the trial as instructed by the investigator.
!
The investigator is responsible for drug accountability and record maintenance (i.e. receipt, 
accountability and final disposition records).
!
Drug accountability should be performed on a pen/vial 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 their compliance. The investigator should assess the compliance of the 
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 the SMPG profiles, dose and 
hypoglycaemia reporting. If a subject is found to be non-compliant the investigator will remind the 
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subject of the importance of following the instructions including taking the trial products as 
prescribed.
7.7
Concomitant medication
Any medication other than the trial product(s) that the subject is receiving at the time of the first 
visit (V1) or receives during the trial (incl. follow-up visits) must be recorded along with:
!
Trade name or generic name
!
Indication
!
Dates of administration including start and stop dates or continuation 
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.
!
Until end of treatment (V28) 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/DPP4i prior to end of treatment (V28), this is defined as ancillary treatment (see 
section 7.7.1)
!
For new anti-diabetic medication prescribed in the follow up period start date of current 
dose and total daily dose must also be recorded.
Changes in concomitant medication must be recorded at each visit. If a change is due to an
AE/SAE, then this must be reported according to Section 9.2.
7.7.1
Ancillary treatment 
Until end of treatment (V28) only randomised treatment (trial products and metformin with or 
without DPP4i) are allowed. Ancillary treatment is defined as any diabetes medication - other than 
randomised treatment (trial products and metformin with or without DPP4i) initiated due to for 
example safety reasons. It should be registered as concomitant medication (diabetes) in the
electronic case report form (eCRF). 
For subjects not treated with DPP4i prior to the randomisation, initiation of long term use of DPP4i 
is considered as ancillary treatment. A medication error (see Appendix 4) is as such not considered 
as ancillary treatment.
7.8
Treatment after the end of the trial 
When discontinuing trial products, either at the scheduled end of treatment visit (V28) or if trial 
product is discontinued, the subject should be transferred to a suitable marketed product at the 
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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.
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, attend the end of treatment
visit corresponding to V28 as soon as possible after discontinuation of trial product (preferably the 
same day) to collect the required data for the analysis of the primary endpoint. The two follow up 
visits must also be performed. FU1 must be scheduled at least 2 weeks (+3 days) after and FU2 
must be scheduled 5 weeks (+3 days) after discontinuation of the trial product respectively.
Once the two follow-up visits after discontinuation of trial product are completed the subject should 
be contacted by phone every 4 weeks. Information on antidiabetic medication must be collected and 
recorded in the eCRF. Phone contacts must be documented in the medical record and in the eCRF. 
The subject should finally come in for the discontinuation follow-up visit (V28A), 26 weeks after 
randomisation and have the assessments performed stated in the flow chart (section 2).
Final drug accountability must be done once the subject has discontinued the trial product and the 
premature discontinuation must be recorded in the IWRS through a treatment discontinuation 
session.
The reason for the premature discontinuation of trial product must be recorded in the eCRF.
Only subjects who withdraw consent will be considered as withdrawn from the trial. See section 8.2
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. Pregnancy
3. Intention of becoming pregnant
4. Simultaneous participation in another clinical trial of an approved or non-approved 
investigational medicinal product.
5. Lack of efficacy, defined as fulfilment of all 4 criteria below:
!
No reduction in HbA1c measured by central laboratory from randomisation (V2)  to visit 10, 
or to visit 14, or to visit 18, or to visit 22 or to visit 26 AND
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!
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
!
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
!
No treatable intercurrent cause (e.g. non-compliance) for the hyperglycaemia at the 
investigator’s judgment
See the flowchart 2 for data to be collected at the time of treatment discontinuation and follow-up 
and for any further evaluations that need to be completed.
The primary reason for discontinuation of trial product must be specified in the eCRF, 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 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 assessments performed according to V28 and come in for the follow up visits 
(V29 and V30). See the flowchart 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 
samples 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 reason(s) for withdrawing, the investigator must 
make a reasonable effort to ascertain the reason(s), while fully respecting the subject's rights. Where 
the reasons are obtained, the primary reason for withdrawal must be specified in the eCRF.
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8.2.1
Replacement of subjects
Subjects who discontinue trial product or withdraw from trial will not be replaced.
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'. 
9
Trial assessments and procedures
!
Trial procedures and their timing are summarised in the flowchart 2. 
!
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 
trial and giving contact details of relevant trial site staff. 
!
Adherence to the trial design requirements, including those specified in the flowchart, is 
essential and required for trial conduct. 
!
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. 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.
!
Repeat samples may be taken for technical issues and unscheduled samples or assessments 
may be taken for safety reasons. Please refer to Appendix 2 for further details on laboratory 
samples.
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!
Source data of clinical assessments performed and recorded in the eCRF 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, Libre Pro data, BG 
meter, pictures and ECG recordings. 
9.1
Efficacy assessments
Planned time points for all efficacy assessments are provided in the flowchart 2.
9.1.1
Self-measured plasma glucose 
At the screening visit (V1), subjects must be provided with a BG meter including auxiliaries and a 
diary as well as instructions for use. The subjects must be instructed in how to use the devices and 
the instruction should be repeated at regular intervals as indicated in the flowchart 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. 
The BG meter provided by Novo Nordisk must be used for the measurements required in the 
protocol, as described in the flow chart 2.
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 eCRF during or following the contact. If obtained via phone and a discrepancy 
is later detected, the values in the eCRF 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.
Selected titration data (e.g. certain SMPGs and insulin doses) will only be used during the trial for 
central titration surveillance, to ensure compliance with the titration guideline Appendix 9. Only 
SMPGs obtained as part of the 9-point profiles will be reported in the clinical trial report (CTR).
Once daily pre-breakfast SMPG
Subjects should perform daily pre-breakfast SMPG from randomisation visit (V2) to end of 
treatment visit (V28). These SMPG values should be performed in a fasting condition.
9-point SMPG profile
Subjects will be instructed to perform 9-point profiles in the week prior to visits as specified in 
section 2, on a day where the subject does not anticipate unusual strenuous exercise. 
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The SMPG values obtained should be recorded in the diary (including actual clock time and date of 
measurement) according to the time points listed below: 
!
Before breakfast 
!
90 minutes after the start of breakfast
!
Before lunch
!
90 minutes after the start of lunch
!
Before main evening meal (dinner)
!
90 minutes after the start of main evening meal (dinner)
!
At bedtime
!
At 4 am
!
Before breakfast the following day
SMPG values measured before breakfast should be performed in a fasting condition. 
The measurements will be used to evaluate the glucose profile.
9.1.2
Insulin dose
During the trial, starting at the randomisation visit (V2), subjects must be instructed to report date, 
dose and time of once weekly and date and dose of once daily insulin in the diary. 
The recommended insulin doses will be calculated by the investigator based on recommendations 
from the Titration Guideline (see Appendix 9). At each visit/phone contact the Investigator will 
titrate the subjects by making prescribed dose adjustments based on the recommendation from the 
diary, if applicable.
The Investigator must record the following in the eCRF:
!
Date, dose and injection time of once-weekly insulin/placebo 
!
Date and dose of once-daily insulin/placebo:
o
From V2 to V26: Insulin glargine/insulin glargine-placebo doses must be recorded 
two days prior to and on the day of the visit/contact.
o
From V26 to V28: Insulin glargine/insulin glargine-placebo doses must be recorded 
every day.
!
Prescribed doses of once-weekly and once-daily insulin/placebo i.e. what the investigator 
tells the subject to take
!
Reason for deviation from the recommended dose, if needed
For dosing of anti-diabetic medication prescribed in the follow up period please see section 7.7
9.1.3
Flash Glucose Monitoring
In order to evaluate the effect on glycaemic control at different time points during the trial, subjects 
will have FGM profiles generated 5 times during the trial. Please refer to the flowchart in section 2.
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The FGM system used in this trial will be the FreeStyle Libre Pro system which consists of two 
parts: 
!
the sensor, applied on the back of the subjects’ upper arm
!
the reader, a hand held device kept at site and used to download data stored on the sensor
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, which will be shown on the display of the reader upon download 
of sensor data. 
The FGM readings will be blinded to the subject as the reader will be kept at site.  
The FGM values generated should not be used for insulin dose titration and/or hypoglycaemic 
episodes reporting.
9.1.3.1
FGM Reader setting
Each site will receive 2 readers; one to activate all subjects’ sensors and download of their data and 
one as backup. 
The FGM reader must be set up before use. The set up includes:
!
Date and time setting
!
Entry of the target glucose range. The range 3.9–7.8 mmol/L (70-140 mg/dL) should be 
used.
Time and date as well as level of battery should be verified each time the reader is used. 
9.1.3.2
Fitting and removal of the FGM sensor
The sensor must be applied on the back of the upper arm of the subjects, using the sensor applicator 
as described in the Operator’s manual. When applied, a thin, flexible and sterile fibre is inserted just 
under the skin of the subjects, allowing the measurement of glucose concentration in the interstitial 
fluid. 
The sensor must be activated by holding the site reader within 4cm (1.5inch) of the sensor. 
Successful start of the sensor must be checked as described in the Operator’s manual.
The sensor will store the subject’s glucose readings every 15 minutes for up to 14 days. 
For further information on preparing, fitting, and removal of the FGM system, please refer to the 
Operator’s manual.
If a subject withdraws consent during one of the FGM periods, a site visit must be scheduled in 
order to remove the sensor and download data to the reader. 
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9.1.3.3
Duration of FGM periods
The sensor has an in-use period of 14 days and will automatically stop recording data 14 days after 
insertion and activation. 
Subjects must aim to use the sensor for 14 days.
In cases where the sensor is dislodged prematurely, the subject must be fitted with a new sensor as 
soon as possible. Additional fitting visit at site will not be considered an unscheduled visit. 
9.1.3.4
Wearing of the FGM sensor
Before each FGM periods, subjects must be instructed to follow the recommendations and 
limitations described in the Operator’s manual and user guide while wearing the FGM sensor.
Subjects must be instructed to remove the FGM sensor prior to any X-ray, Computerised 
Tomography (CT) scan, high-frequency electrical heat (diathermy) treatment or magnetic resonance 
imaging (MRI).
9.1.3.5
Transfer of FGM data
Data stored on the sensor must be downloaded at the site by holding the reader within 4cm (1.5inch) 
of the sensor. Data on the reader device must then be uploaded to the provided FGM Software 
program that allows upload of the FGM data from the reader, following the instructions from the 
user guide provided to sites. The upload will be documented by the system directly.
The following information must be recorded and transferred into the eCRF for every FGM period:
!
Serial number of the FGM sensor
!
Sensor fitting date and time
!
Sensor removal date and time
9.1.4
Clinical efficacy laboratory assessments
All protocol-required laboratory assessments, as defined in Appendix 2, must be conducted in 
accordance with the flowchart and the laboratory manual.
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 second follow-up visit (V30), at the time points specified in the flowchart. 
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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 learns 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.
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.
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 and hypoglycaemic episodes observed during the trial. The relevant specific events are listed 
in Table 9-1 and the reporting timelines in Figure 9-1.
Figure 9-1
Decision tree for determining the event type and the respective forms to 
complete with associated timelines:
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 upoad to Event 
Adjudiction 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
* Non-serious hypoglycaemic episodes should be reported on a dedicated 
hypoglycaemic form only.
No additional action
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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 Manual )
Acute coronary syndrome 
X
Cerebrovascular event 
X
Heart failure
X
Death 
X
Hypersensitivity
X
Injection site reactions
X
X
Medication error
X
Hypoglycaemic episodea
X
aRefer to Section 9.2.6for reporting details
For details about specific event forms, see Appendix 4
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 Table 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 (Table 9-1) selected based on 
predefined criteria (Appendix 4)
!
All AEs reported with a fatal outcome
2) Preferred term (PT) search (standardised screening): 
!
All AEs recorded in the eCRF 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 
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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. 
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 personal identifiers
and uploaded to the EAS as soon as possible and preferably within 4 weeks according to 
instructions in the Event Adjudication Site Manual. Specific labelling requirements apply to digital 
pictures (see section 9.4.6.1 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 eCRF 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, stabilisation, 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.
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Investigator safety reports must be prepared for suspected unexpected serious adverse reactions
(SUSARs) according to local regulatory requirements and Novo Nordisk policy and forwarded to 
investigators as necessary.
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 for standard
AE collection
The following Disease-Related Event (DRE) is common in subjects with T2DM and can be 
serious/life threatening:
!
Hypoglycaemic episodes
Definitions, classification and reporting requirements are described in Appendix 8. 
Hypoglycaemia
Non-serious hypoglycaemia must be reported on a hypoglycaemic episode form.
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)
Section not applicable for this trial. Refer to technical complaints in Section 9.2.9.
9.2.9
Technical complaints 
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 complaint form: ≤ 24 hours 
AE form: ≤ 24 hours 
SIF: ≤ 5 calendar days
Is it related  
to an SAE?
Technical complaint 
identified
Is it related
to an AE?
Yes
No
Technical complaint form
≤ 5 calendar days
Technical complaint form: 
≤ 5 calendar days
AE form: ≤ 5 calendar days
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. 
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9.3
Treatment of overdose
The overdose must be reported as a medication error. Refer to Section 9.2.1 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 has 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.
!
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 IB for insulin 287 and 
Summary of Product Characteristics for insulin glargine.8
9.4
Safety assessments
Planned time points for all safety assessments are provided in the flowchart 2.
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. 
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. 
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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 (V2) must be reported as an AE (see Section 9.2).
9.4.1
Physical examinations
!
A physical examination will include assessments of:
o
Head, ears, eyes, nose, throat, neck
o
Cardiovascular system
o
Respiratory system
o
Gastrointestinal system including mouth
o
Musculoskeletal system 
o
Central and peripheral nervous system
o
Skin 
!
Body measurements will also be measured and recorded as specified in the flowchart.
o
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.
o
Body weight should be assessed with the same equipment throughout the trial, if 
possible. 
o
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
o
From the body weight and height the BMI will be calculated in the eCRF.
!
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 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 
eCRF 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.
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9.4.3
Electrocardiograms
!
A 12-lead 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
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 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) and performed with pharmacologically dilated pupils.
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.
9.4.5
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 2.
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9.4.6
Immunogenicity assessments  
Blood samples to be analysed for serum antibodies against insulin 287 or insulin glargine will be 
drawn at pre-specified time points according to the flowchart in section 2. For details on blood 
sampling, serum preparation, storage, labelling and shipments please refer to the laboratory manual. 
Samples from the insulin 287 arm of the study will be analysed for anti-insulin 287 antibodies, and 
samples from the comparator arm will be analysed for anti-insulin glargine antibodies. Confirmed 
anti-insulin 287 or anti-insulin glargine antibody positive samples will have an antibody titre value 
determined, and will be further tested for cross-reactivity to endogenous insulin.
Residual anti-drug antibody samples may be used for exploratory investigation of antibodies or 
further development of anti-insulin antibody assays.
9.4.6.1
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: 
!
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. 
o
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
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The blood sampling should be repeated 2 – 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 hypersensitivity reaction.
9.5
Pharmacokinetics 
Blood samples will be used to evaluate the pharmacokinetics (PK) of insulin 287. PK samples will 
be collected at the visits outlined in the flowchart, section 2. The investigator must record the exact 
date and clock time for blood sampling in the eCRF. 
Each PK sample will be divided into 2 aliquots (one for pharmacokinetics and one for backup,). The 
back-up sample may be used to evaluate safety or efficacy aspects that address concerns arising 
during or after the trial.
Procedures for sampling, handling, storage, labelling, and shipments of the specimens must be 
performed in accordance with the laboratory manual. 
Bioanalysis of insulin 287 samples will be performed at a special laboratory using a validated15, 16
Luminescent Oxygen Channelling Immunoassay (LOCI) with a range of 500 – 100.000 pmol/L. 
The exact method will be described in a bioanalytical report. 
9.6
Pharmacodynamics 
Not applicable for this trial.
9.7
Genetics 
Not applicable for this trial.
9.8
Biomarkers 
Not applicable for this trial.
10 Statistical considerations
10.1
Sample size determination 
The primary estimand is defined as the treatment difference in change in HbA1c from baseline to 
week 26 between once weekly insulin 287 and once daily IGlar for all randomised subjects, if all 
subjects had adhered to treatment and did not receive ancillary treatment. This is a “hypothetical” 
estimand. This estimand aims to reflect the treatment effect for subjects that are actually able to take 
the drug during the intended treatment period. With the aim of evaluating proof of concept this 
estimand is considered relevant.
The sample size is determined such that the width of the two-sided 95% confidence interval (CI) for 
the treatment difference assuming normally distributed data in change from baseline to 26 weeks in 
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HbA1c is 0.5%-point. The standard deviation (SD) is expected to be 1.0%-point for all treatment 
arms based on observations with IGlar in insulin naïve T2DM trials (NN1250-3579, NN1250-3643 
and NN1250-3672). A total of 246 subjects will ensure the required width of the 95% CI. The total 
number of subjects to be randomised is rounded from 246 to 250 with 125 in each treatment arm.
The required width of the confidence interval is independent of the choice of estimand and 
sensitivity analyses since all randomised subjects will contribute to all analyses. The SD is assumed 
to be 1.0 based on observations from finalised clinical trials with IGlar in insulin naïve T2DM 
subjects. Since the assumed SD of 1 is to the conservative side it is assumed that the SD will not be 
further increased by the choice of estimand.
Table 10-1 displays sample sizes for various alternative standard deviations and widths of the 95% 
CI.
Table 10-1
Sample size for various standard deviations and widths of the confidence 
interval
Width of the 95% CI
SD
0.40
0.50
0.60
0.9
312
200
140
1.0
384
246
172
1.1
466
298
208
Sample size is computed for 1:1 randomisation. SD: standard deviation.
10.2
Definition of analysis sets
The following analysis sets are defined in accordance with the International Council for 
Harmonisation (ICH)-E9 guidance17.
!
Full Analysis Set (FAS): includes all randomised subjects. In exceptional cases, subjects 
may be eliminated from the full analysis set. In such cases the elimination will be justified 
and documented. The statistical evaluation of the FAS will follow the intention-to-treat 
(ITT) principle and subjects will contribute to the evaluation “as randomised”.
!
Safety Analysis Set (SAS): includes all subjects receiving at least one dose of the 
investigational product or comparator. Subjects in the safety set will contribute to the 
evaluation “as treated”.
Randomised subjects who are lost to follow up and where no exposure information of the 
investigational product or comparators is available after randomisation will be handled as 
unexposed.
The on-treatment observation period is defined as the period from date of first dose of randomised 
Investigational Medicinal Product (IMP) until the end of the treatment emergent period.
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The in-trial observation period is defined as the period from date of randomisation and until last 
scheduled subject-site contact (i.e. the end date is the last site/phone visit).
Before data are released for statistical analysis, a review of all data will take place to identify 
protocol deviations that could potentially affect the results. Any decision to exclude any subject or 
observation from the statistical analysis is the joint responsibility of the members of the sponsor 
study group. The subjects or observations to be excluded, and the reasons for their exclusion must 
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
If necessary, a SAP may be written in addition to the protocol, including a more technical and 
detailed elaboration of the statistical analyses. The SAP will be finalised before database lock.
Novo Nordisk will analyse and report data from all trial sites together.
All efficacy endpoints will be summarised using the full analysis set (FAS) and safety endpoints 
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 are summarised by arithmetic mean, SD, median, and minimum and maximum value. 
Selected endpoints, e.g. endpoints that are analysed log-transformed, will be reported with 
geometric mean and coefficient of variation in place of mean and SD. For measurements over time, 
mean values will be plotted to explore the trajectory over time. ‘On-treatment’ observed data will be 
used as the basis for plotting data if not otherwise specified. Mean profile for HbA1c will be plotted 
by time of treatment discontinuation and treatment in order to investigate discontinuation patterns. 
Data obtained after treatment discontinuation or initiation of ancillary treatment will be included 
using different plot symbols. In addition, selected endpoints will be summarised by empirical 
distribution plots, box plots, and plots of the mean change from baseline over time. For HbA1c, 
additional summary tables and plots based on ‘in-trial’ data will also be prepared.
Only endpoints derived after 26 weeks will be analysed statistically. In accordance with guidance18
endpoints will be assessed at frequent visits and also on subjects who discontinue treatment. If an 
assessment has been made both at screening and randomisation, and if not otherwise specified, the 
value from the randomisation visit will be used as the baseline value. If the value measured at the 
randomisation visit is missing and the assessment also has been made at screening, then the 
screening value will be used as the baseline value.
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 mean treatment effects 
using least square mean (LSMean) for absolute values, and change from baseline where applicable. 
The LSMean is either obtained by Rubin’s rule weighing together LSMeans from multiple 
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imputation estimations or obtained directly from estimation of a parameterised statistical model. In 
addition, estimated mean treatment difference (or ratio) will be presented together with the two-
sided 95% confidence interval and corresponding two-sided p-value.
In the statistical models explanatory factors will be coded as follows:
!
Treatment: Once weekly insulin 287, Once daily IGlar
!
DPP4i has 2 levels (yes and no)
!
Region has 2 levels (Europe and North America)
!
Visit: Planned visits for actual endpoint according to flowchart
The impact of protocol deviations and outliers may be investigated further in sensitivity analyses if 
deemed relevant.
10.3.1
Primary endpoint
The primary endpoint is change from baseline to week 26 in HbA1c.
Primary estimand
For the primary endpoint, the primary estimand is defined as the “hypothetical” estimand19.
The treatment difference between once weekly insulin 287 versus once daily IGlar in change from 
baseline to week 26 in HbA1c for all randomised subjects if all subjects had adhered to treatment 
and did not initiate ancillary treatment in subjects with T2DM inadequately treated with metformin 
with or without DPP4i.
The primary estimand will be estimated based on the FAS. This estimand aims to reflect the 
treatment effect for subjects that are actually able to take the drug during the intended treatment 
period. With the aim of evaluating proof of concept, this estimand is considered releva nt i.e. a de 
jure estimand addressing efficacy.
Subjects may start ancillary treatment during the trial. Hence, data obtained after occurrence of 
intercurrent event such as initiation of ancillary treatment and discontinuation of randomised 
treatment will not be included in the estimation of the primary estimand.
To estimate this estimand, change from baseline in HbA1c after 26 weeks will be analysed with the 
linear mixed model for repeated measurement (MMRM) method with an unstructured covariance 
matrix. All post baseline HbA1c measurements obtained on planned visits while the subject 
continues the randomised treatment will contribute to the analysis. Hence, data obtained after 
occurrence of the following two intercurrent events such as initiation of ancillary treatment and 
discontinuation of randomised treatment will not be included in the estimation of the primary 
estimand. This analysis has the underlying assumption that the missing data mechanism is ‘missing 
at random’. The model will include use of DPP4i (yes/no), region, treatment and visit as fixed 
factors and baseline HbA1c as covariate. Interactions between visit and all factors and covariates 
will also be included in the model. The estimated mean treatment difference and the confidence 
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interval will be presented together with the corresponding two-sided p-value. In the following, this 
MMRM method will be referred to as the standard MMRM method. 
Secondary estimand
The secondary estimand for the primary endpoint is the “treatment policy” estimand. 
The secondary estimand is defined as the treatment difference between once weekly insulin 287 
versus once daily IGlar in change from baseline to week 26 in HbA1c for all randomised subjects, 
regardless of the treatment actually received in subjects with T2DM inadequately treated with 
metformin with or without DPP4i. This estimand aims to reflect the treatment effect for all subjects 
regardless of treatment adherence, i.e. a de facto estimand addressing effectiveness.
This will be estimated using all HbA1c measurements obtained at week 26, also including 
measurements from subjects discontinuing their randomised treatment or initiating ancillary 
treatment. Missing HbA1c measurements at week 26 will be imputed from trial participants who are 
from the same randomised group, who have discontinued their randomised treatment and have an 
HbA1c  measurement at week 26.
This will be done as follows:
!
First, one thousand (1000) copies of the dataset will be generated.
!
Second, for each dataset copy, and each treatment group, an analysis of variance (ANOVA) 
model with baseline HbA1c value as a covariate will be fitted to the end of trial value for 
subjects having discontinued their randomised treatment and have an HbA1c measurement at 
week 26. The estimated parameters, and their variances, from the model will be used to 
impute missing values at end of trial in the same treatment group. The factors region and use 
of DPP4i are not considered in this step assuming the number of subjects to impute from 
will be low and that may lead the model does not meet the convergence criteria.
!
For each of the complete data sets, the change from baseline in HbA1c after 26 weeks will be 
analysed using an analysis of co-variance model with use of DPP4i (yes/no), region and 
treatment as fixed factor, and baseline HbA1c as covariate. The estimates and standard 
deviations for the 1000 data sets will be pooled to one estimate and associated SD using 
Rubin’s rule.
If less than 3 subjects have discontinued their randomised treatment and have an HbA1c
measurement at week 26 in any of the treatment groups, then the second step above will be carried 
out combining the two treatment arms and including treatment as factor in the model.
The estimated mean treatment difference and the confidence interval will be presented together with 
the corresponding two-sided p-value.
Sensitivity analysis
The following sensitivity analysis of the assumptions about the missing data will be carried out: for 
the primary estimand, a tipping point like type of analysis will be performed where subjects from 
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the Insulin 287 arm having no HbA1c measurement at week 26 are assumed to have a worse 
outcome compared to what was imputed in the primary analysis. This is done by adding a value Δi 
to the imputed HbA1c values in the Insulin 287 arm before analysing the data. The resulting 
estimated treatment differences and 95%CIs will be plotted as function of Δi to evaluate the 
robustness of the primary analysis results.
10.3.2
Secondary endpoints
10.3.3
Confirmatory secondary endpoints
Not applicable for this trial.
10.3.3.1
Supportive secondary endpoints
The supportive secondary endpoints will be addressed in terms of the frame work of the primary 
estimand only.
Efficacy endpoints
!
Change from baseline to week 26 in fasting plasma glucose
!
9-point profile (individual SMPG values) at week 26
!
Change from baseline to week 26 in mean of the 9-point profile, defined as the area under 
the profile
!
Fluctuations of the 9-point profile (defined as the integrated absolute distance from the mean 
profile value divided by measurement time)
!
Change from baseline to week 26 in fasting C-peptide
!
Change from baseline to week 26 in body weight
!
Weekly dose of insulin 287 and daily dose of IGlar at week 26
FPG, C-peptide and body weight – change from baseline after 26 weeks
Change from baseline in FPG and body weight will be analysed using the standard MMRM method 
with relevant baseline as the covariate.
Relative change from baseline in C-peptide will be analysed using the standard MMRM method. In 
this statistical analysis the endpoint will be log-transformed and so will the baseline covariate.
SMPG 9-point profile 
The following endpoints will be derived from self-measured plasma glucose,
1. 9-point profile (individual SMPG values)
2. Change from baseline to week 26 in mean of the 9-point profile, defined as the area under 
the profile 
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3. Fluctuations of the 9-point profile defined as the integrated absolute distance from the mean 
profile value divided by measurement time
A linear mixed effect model will be fitted to the 9-point SMPG profile data at week 26. The model 
will include treatment, region, use of DPP4i, time, the interaction between treatment and time, the 
interaction between region and time, and the interaction between use of DPP4i and time as fixed 
factors and subject as random effect. From the model mean profile by treatment and relevant 
treatment differences will be estimated and explored.
Change from baseline in mean of the 9-point profile, and fluctuation in 9-point profiles after 26 
weeks will be analysed separately using the standard MMRM method with relevant baseline as the 
covariate. Fluctuation in the 9-point profile will be logarithmically transformed before analysed.
Baseline fluctuation in the 9-point profile also will be log-transformed in the model.
Insulin dose
Insulin 287 dose and IGlar dose will be summarised by week.
The average insulin 287 dose derived from visit 26 to visit 28 versus average weekly IGlar dose 
derived from visit 26 to visit 28 will be logarithmically transformed and analysed based on standard 
MMRM method (except baseline as a covariate).
Safety endpoints
Number of treatment emergent adverse events from baseline to week 31
AEs will be coded using the most recent version of the Medical Dictionary for Regulatory 
Activities (MeDRA).
The treatment emergent period represents the period where subjects are considered exposed to trial 
product. It starts at the first date of exposure to randomised treatment and ends at the last follow-up 
visit (FU2), thus includes a time period after last dose of randomised treatment corresponding to 
approximately 5 half-lives of insulin 287. Specifically, it ends at one of the following:
!
For subjects completing the trial: Last follow-up visit (FU2) 
!
For subjects who discontinue: Last follow-up visit (FU2) as defined in section 8.1
!
For subjects who discontinue, but do not attend FU2 visit: Last dosing day of randomised 
treatment + 5 weeks for glargine, and last dosing day of randomised treatment + 6 weeks for 
insulin 287  
A treatment emergent adverse event (TEAE) is defined as an event that has onset date on or after 
the first day of exposure to randomised treatment and no later than the treatment emergent period. If 
the event has onset date before the first day of exposure on randomised treatment and increases in 
severity during the treatment period and until the treatment emergent period, then this event should 
also be considered as a TEAE.
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TEAEs are summarised descriptively, whereas non-TEAEs are presented in listings. TEAE data 
will be displayed 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 of 
exposure (R).
Summaries of TEAEs and of serious TEAEs will be presented as an overview including all AEs, 
serious AEs, number of deaths, AEs by severity, AEs by relation to treatment and AEs of special 
interest including AEs leading to treatment discontinuation or withdrawal.
Furthermore summary tables based on system organ class and preferred terms are made for:
!
All TEAEs
!
Serious TEAEs
!
TEAEs possibly or probably related to trial product
!
Severe, moderate and mild TEAEs
!
TEAEs reported by safety areas of interest
!
TEAEs with preferred term that are experienced by at least 5% (1%) of the subjects in any 
treatment arm or by at least 5% (1%) of all subjects
A listing for non-TEAEs with onset date before the first day of exposure to randomised treatment 
will be presented. A listing will also be presented for non-TEAEs collected after the treatment-
emergent period according to the definition of TEAE.
Additional summaries will be displayed for SAEs, including events collected after premature 
treatment discontinuation (“in-trial” summary).
Summary of number of treatment-emergent injection site reactions will be presented as an overview 
including all AEs, serious AEs, AEs by severity and AEs by relation to treatment and injection site 
reactions leading to treatment discontinuation or withdrawal. Furthermore summary table of 
injection site reaction based on system organ class and preferred terms will be made.
Hypoglycaemic episodes
For the definition and classification of hypoglycaemic episodes refer to Appendix 8. Data on 
treatment-emergent hypoglycaemic episodes are presented in terms of the number of subjects with 
at least one episode (N), the percentage of subjects with at least one episode (%), the number of 
episodes (E) and the event rate per 100 years of exposure (R).
Repeated SMPG measurements and/or symptoms (see Table 10-2), 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 
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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. 
Separate summaries will be made according to the level of hypoglycaemia, as recently 
recommended by the International Hypoglycaemia Study Group (2017 joint ADA/EASD position 
statement), ADA ‘Standards of Medical Care in Diabetes-2018’, ISPAD, Type 1 Diabetes 
Outcomes Program and ATTD congress. For references see Appendix 8.
The classification of hypoglycaemia is outlined in Table 10-2. The summaries are made for all and 
nocturnal (between 00:01 and 05.59 both inclusive) episodes respectively.
Table 10-2
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
The treatment emergent period represents the period where subjects are considered exposed to trial 
product. It starts at the first date of exposure to randomised treatment and ends at the last follow-up 
visit (FU2), thus includes a time period after last dose of randomised treatment corresponding to 
approximately 5 half-lives of insulin 287. Specifically, it ends at one of the following:
!
For subjects completing the trial: Last follow-up visit (FU2)
!
For subjects who discontinue: Last follow-up visit (FU2) as defined in section 8.1
!
For subjects who discontinue, but do not attend FU2 visit: Last dosing day of randomised 
treatment + 5 weeks for glargine, and last dosing day of randomised treatment + 6 weeks for 
insulin 287
Level 1 hypoglycaemic episodes, Level 2 and level 3 combined hypoglycaemic episodes, level 2 
hypoglycaemic episodes, and level 3 hypoglycaemic episodes after 26 weeks will be analysed 
separately by a negative binomial regression model with treatment, region and use of DPP4i 
(yes/no) as fixed factors and the log of time period (treatment-emergent) for which the 
hypoglycaemic episodes are considered as an offset.
The above analysis will be repeated for the following time points as below,
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1. Number of level 2 and level 3 combined hypoglycaemic episodes from baseline to week 31 
(Treatment emergent hypos)
2. Number of level 2 and level 3 combined hypoglycaemic episodes from baseline to week 16 
(Titration period)
3. Number of level 2  and level 3 combined hypoglycaemic episodes from week 17 to week  26 
(Maintenance period)
4. Number of level 2 hypoglycaemic episodes from baseline to week 31 (Treatment emergent 
hypos)
5. Number of level 2 hypoglycaemic episodes from baseline to week 16 (Titration period)
6. Number of level 2 hypoglycaemic episodes from week 17 to week  26 (Maintenance period)
7. Number of level 3 hypoglycaemic episodes from baseline to week 31 (Treatment emergent 
hypos)
8. Number of level 3 hypoglycaemic episodes from baseline to week 16 (Titration period)
9. Number of level 3 hypoglycaemic episodes from week 17 to week  26 (Maintenance period)
The number of nocturnal level 2 and level 3 combined hypoglycaemic episodes and number of level 
2 hypoglycaemic episodes, and number of level 3 hypoglycaemic episodes from:
!
baseline to 26 weeks
!
baseline to week 31
!
baseline to week 16 and
!
week 17 to week 26
will be analysed similarly.
Antibodies from baseline to 31 weeks
Change in anti-insulin 287 antibodies level, and change in anti-insulin 287 antibody titres will be 
summarised and tabulated. The correlation between change in values from baseline after 31 weeks 
of treatment in anti-insulin 287 antibodies level, and anti-insulin 287 antibody titres respectively to 
insulin dose at 26 weeks of treatment, HbA1c after 26 weeks of treatment and change from baseline 
after 26 weeks of treatment in HbA1c will be illustrated using scatter plots. The Pearson’s 
correlation coefficient will be tested and displayed in both table and the plots. Number and 
percentage of subjects positive for cross reactive antibodies will be tabulated by visit.
10.3.3.2
Exploratory endpoints
!
Insulin 287 concentrations, evaluated in a population PK analysis
!
Time in target-range 3.9-7.8 mmol/L (70–140 mg/dL) measured by flash glucose monitoring 
(FGM) (
 Free Style Libre Pro) during the last 2 weeks of treatment (week 25 and 
26)
The data accuracy may vary during the first 24 hours after sensor fitting, the FGM data from the 1st 
day (24h) of each sensor period will be excluded from analysis.
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10.3.7
Other analyses
Other efficacy tabulations:
HbA1c responders after 26 weeks (Yes/No)
Dichotomous outcome (responder=yes/non-responder=no) will be defined based on whether a 
subject has met a specific level of HbA1c < 7.0% after 26 weeks. Analysis of this responder 
outcome will be based on a logistic regression model with treatment, region and use of DPP4i as 
fixed factors and baseline HbA1c values as covariate.
For subjects who discontinue randomised treatment or start ancillary treatment, missing HbA1c data 
at 26 weeks are imputed by the MMRM method before applying the specific responder criteria.
HbA1c responders with minimal weight gain after 26 weeks
Responder for HbA1c with minimal weight gain after 26 weeks of treatment will be defined as:
!
HbA1c < 7.0% and change from baseline in body weight ≤ 3 %
Analysis of this responder outcome will be based on a logistic regression model with treatment, 
region and use of DPP4i as fixed factors and baseline HbA1c and baseline body weight values as 
covariates.
For subjects who discontinue randomised treatment or start ancillary treatment, missing HbA1c and 
body weight data at 26 weeks are imputed by the MMRM method before applying the specific 
responder criteria.
HbA1c responders without treatment-emergent clinically significant hypoglycaemic episodes 
and without treatment-emergent severe hypoglycaemic episodes after 26 weeks
Responder for HbA1c without treatment-emergent clinically significant hypoglycaemic episodes and 
without treatment-emergent severe hypoglycaemic episodes after 26 weeks of treatment will be 
defined as:
!
HbA1c < 7.0% and without treatment-emergent clinically significant hypoglycaemic 
episodes and without treatment-emergent severe hypoglycaemic episodes during the last 12 
weeks of treatment
Analysis of this outcome will be based on a logistic regression model with treatment, region and use 
of DPP4i as fixed factors and baseline HbA1c values as covariates, where subjects with less than 12 
weeks of treatment conservatively will be set to being non-responder.
For subjects who discontinue randomised treatment or start ancillary treatment, missing HbA1c data 
at 26 weeks are imputed based on the MMRM method before applying the specific responder 
criteria.
HbA1c responders without treatment-emergent severe hypoglycaemic episodes after 26 weeks
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Responder for HbA1c without treatment-emergent severe hypoglycaemic episodes after 26 weeks of 
treatment will be defined as:
!
HbA1c < 7.0% and without treatment-emergent severe hypoglycaemic episodes during the 
last 12 weeks of treatment
Analysis of this endpoint will be based on a logistic regression model with treatment, region and 
use of DPP4i as fixed factors and baseline HbA1c values as covariates, where subjects with less than 
12 weeks of treatment conservatively will be set to being non-responder.
For subjects who discontinue randomised treatment or start ancillary treatment, missing HbA1c data 
at 26 weeks are imputed based on the MMRM method before applying the specific responder 
criteria.
HbA1c responders without treatment-emergent clinically significant hypoglycaemic episodes 
and with minimal weight gain after 26 weeks
Responder for HbA1c without treatment-emergent clinically significant hypoglycaemic episodes and 
with minimal weight gain after 26 weeks of treatment will be defined as:
!
HbA1c < 7.0% without treatment-emergent clinically significant hypoglycaemic episodes 
during the last 12 weeks of treatment, and change from baseline in body weight ≤3 %
Analysis of this responder outcome will be based on a logistic regression model with treatment, 
region and use of DPP4i as fixed factors and baseline HbA1c and body weight values as covariates, 
where subjects with less than 12 weeks of treatment will conservatively be set to being non-
responder.
For subjects who discontinue randomised treatment or start ancillary treatment, missing HbA1c and 
body weight data at 26 weeks are imputed by the MMRM method before applying the specific 
responder criteria.
HbA1c responders without treatment-emergent severe hypoglycaemic episodes and with 
minimal weight gain after 26 weeks
Responder for HbA1c without treatment-emergent severe hypoglycaemic episodes and with minimal 
weight gain after 26 weeks of treatment will be defined as:
!
HbA1c < 7.0% without treatment-emergent severe hypoglycaemic episodes during the last 
12 weeks of treatment, and change from baseline in body weight ≤3 %
Analysis of this responder outcome will be based on a logistic regression model with treatment, 
region and use of DPP4i as fixed factors and baseline HbA1c and body weight values as covariates, 
where subjects with less than 12 weeks of treatment will conservatively be set to being non-
responder.
For subjects who discontinue randomised treatment or start ancillary treatment, missing HbA1c and 
body weight data at 26 weeks are imputed by the MMRM method before applying the specific 
responder criteria.
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Similar analyses as defined above will be carried out for responder targets replacing HbA1c <7.0% 
with HbA1c ≤6.5%.
FPG responder to treatment target after 26 weeks (Yes/No)
Dichotomous outcome (responder=yes/non-responder=no) will be defined based on whether a 
subject has met a specific target level of FPG ≤ 7.2 mmol/L (130 mg/dL) after 26 weeks. Analysis 
of this responder endpoint will be based on a logistic regression model with treatment, region and 
use of DPP4i as fixed factors and baseline FPG values as covariate.
For subjects who discontinue randomised treatment or start ancillary treatment, missing FPG data at 
26 weeks are imputed by the MMRM method before applying the specific responder criteria.
Similar analyses as defined above will be carried out for responder targets replacing <7.2 mmol/L 
(130 mg/dL) with ≤ 6 mmol/L (108 mg/dL).
Other safety tabulations:
Antibodies from baseline to 31 weeks
Number and percentage of subjects positive for anti-insulin 287 and anti-insulin glargine antibodies 
will be tabulated by visit. Anti-insulin glargine antibodies (both in %B/T and titres) will be 
summarised and tabulated. The correlation between change in titre values from baseline after 26 
weeks of treatment in anti-insulin glargine, to insulin dose after 26 weeks of treatment, HbA1c after 
26 weeks of treatment and change from baseline after 26 weeks of treatment in HbA1c will be 
illustrated using scatter plots. Also the Pearson's correlation coefficient will be tested and displayed 
in both table and the plots.
Clinical evaluation (ECG, eye examination and physical examination) change from baseline 
after 26 weeks
Eye examination (fundoscopy/fundus photography) and 12-lead ECG findings will be summarised 
descriptively, including:
!
Summaries for each visit
!
Shift tables from baseline to after 26 weeks
Laboratory assessment (Biochemistry and Haematology) - change from baseline after 26 
weeks
All laboratory parameters will be summarised descriptively including:
!
Summaries by visit
!
Shift tables from baseline to after 26 weeks
!
Proportion of subjects with measurements outside reference range by treatment and week
!
Box plots by time since randomisation
!
Listings of individual values outside reference ranges (abnormal values)
Lipids and vital signs
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Lipids and vital signs will be summarised by treatment.
Other exploratory tabulations:
Time in target-range measured by FGM, Libre Pro will be analysed using the standard MMRM 
method except baseline as a covariate for the following time in range,
!
Time in range 3.9–6.0 mmol/L (70-108 mg/dL)
!
Time in range 3.9–10.0 mmol/L (70-180 mg/dL)
!
Time spent < 3.0 mmol/L (54 mg/dL)
!
Time spent < 3.9 mmol/L (70 mg/dL)
!
Time spent > 10.0 mmol/L (180 mg/dL)
!
Time spent > 13.9 mmol/L (250 mg/dL)
Within subject variability as measured by CV%
The logarithm transformed FGM values will be analysed as repeated measures in a linear mixed 
model with treatment, use of DPP4i and region as fixed factors and subject as random factor. The 
model will assume independent within- and between-subject errors with variances depending on 
treatment. Within subject variability as measured by CV% for a treatment can be calculated from 
the corresponding residual variance ∀2 as % = (	
() −1) . The confidence interval for the 
CV ratio between treatments will be calculated using the delta method.
For population PK analysis refer section 10.4.
10.4
Pharmacokinetic and/or pharmacodynamic modelling
Insulin 287 serum concentration data will be used for a population PK analysis. The objective of the 
population PK analysis is to evaluate the effects of pre-specified covariates on serum concentrations 
of insulin 287.
The population PK analysis will be performed by Quantitative Clinical Pharmacology, Novo 
Nordisk A/S. A more technical and detailed elaboration of the population PK analysis will be given 
in a modelling analysis plan (MAP), which will be prepared before Database Lock (DBL). In brief, 
a previously developed PK model for insulin 287 will be applied. The absorption rate constant (Ka) 
in the model will be fixed, and the apparent clearance (CL/F) and the apparent volume of 
distribution (V/F) will be re-estimated. The covariates of interest will be incorporated into the PK 
model using criteria which will be specified in the MAP.
The population PK analysis will be reported in a separate modelling report, which will not be a part 
of the clinical trial report. The individual insulin 287 serum concentration data will be tabulated in 
the bioanalytical report (BAR).
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11 References
1.
Polonsky WH, Fisher L, Hessler D, Bruhn D, Best JH. Patient perspectives on once-weekly 
medications for diabetes. Diabetes Obesity & Metabolism. 2011;13(2):144-9.
2.
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.
3.
U.S. Department of Health and Human Services, Food and Drug Administration. Guidance 
for Industry. Diabetes Mellitus: Developing Drugs and Therapeutic Biologics for Treatment 
and Prevention, Draft Guidance. February 2008.
4.
American Diabetes Association. 6. Glycemic Targets: Standards of Medical Care in 
Diabetes-2018. Diabetes Care. 2018;41(Suppl 1):S55-S64.
5.
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.
6.
American Diabetes Association. Abridged for Primary Care Providers. Clin Diabetes. 
2018;36(1):14-37.
7.
Novo Nordisk A/S. Investigator's Brochure, NNC0148-0287 (insulin 287), NN1436, 
(edition 4). 2016.
8.
Sanofi-Aventis Groupe. Lantus®   (insulin glargine), EU Summary of Product 
Characteristics (SmPC). 01 Mar 2017.
9.
Food and Drug Administration. Lantus - U.S. Label information. 2015.
10.
Local SmPC for metformin, current version. 2008 2008.
11.
American Diabetes Association. 8. Pharmacologic Approaches to Glycemic Treatment: 
Standards of Medical Care in Diabetes-2018. Diabetes Care. 2018;41(Suppl 1):S73-S85.
12.
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.
13.
European Medicines Agency. Guideline on good pharmacovigilance practices (GVP). 
Module V – Risk management systems (Rev 1) (EMA/838713/2011 Rev 1). 15 Apr 2014.
14.
the European Economic Community. Medical Device Directive 93/42, Annex I. 1993.
15.
U.S. Department of Health and Human Services, Food and Drug Administration, Center for 
Drug Evaluation and Research (CDER), Center for Veterinary Medicine (CVM). Guidance 
for Industry. Bioanalytical Method Validation. 2001.
16.
European Medicines Agency (EMA) CfMPfHUC. Guideline on Bioanalytical Method 
Validation. EMEA/CHMP/19221/2009. 21 July 2011. 7/21/2011 2011.
17.
Little RJA, Rubin DB. Statistical analysis with missing data: New York: John Wiley & 
Sons. 1987.
18.
National Academy of Sciences (NAS). The Prevention and Treatment of Missing Data in 
Clinical Trials. Washington D.C.: The National Academies Press. 2010.
19.
Mallinckrodt CH, Lin Q, Lipkovich I, Molenberghs G. A structured approach to choosing 
estimands and estimators in longitudinal clinical trials. Pharm Stat. 2012;11(6):456-61.
20.
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.
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21.
ICH Harmonised Tripartite Guideline. Guideline for Good Clinical Practice E6(R2), Current 
Step 4 version. 09 Nov 2016.
22.
International Organization for Standardization. ISO 14155:2011, Clinical investigation of 
medical devices for human subjects - Good clinical practice. 01 Feb 2011.
23.
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.
24.
International Committee of Medicinal Journal Editors. Uniform Requirements for 
Manuscripts submitted to Biomedical Journals.: N Engl J Med; 1997 1997. p. 309-15.
25.
International Committee of Medical Journal Editors. Recommendations for the Conduct, 
Reporting, Editing and Publication of Scholarly Work in Medical Journals; current version 
available at www.icmje.org.
26.
De Angelis C, Drazen JM, Frizelle FA, Haug C, Hoey J, Horton R, et al. Clinical trial 
registration: a statement from the International Committee of Medical Journal Editors. N 
Engl J Med. 2004;351(12):1250-1.
27.
U.S. Food and Drug Administration. Food and Drug Administration Amendments Act of 
2007 as amended by the Final Rule "Clinical Trials Registration and Results Information 
Submission". 21 September 2016.
28.
The European Parliament and the Council of the European Council. Directive 2001/20/EC 
of the European Parliament and of the Council of 4 April 2001 on the approximation of the 
laws, regulations and administrative provisions of the Member States relating to the 
implementation of good clinical practice in the conduct of clinical trials on medicinal 
products for human use, article 11. Official Journal of the European Communities. 01 May 
2001.
29.
The European Parliament and the Council of the European Council. Regulation (EC) No 
726/2004 of the European Parliament and of the Council of 31 March 2004 laying down 
Community procedures for the authorisation and supervision of medicinal products for 
human and veterinary use and establishing a European Medicines Agency, article 57. 30 
April 2004.
30.
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.
31.
Jones TW, Group IHGW. Defining relevant hypoglycemia measures in children and 
adolescents with type 1 diabetes. Pediatr Diabetes. 2017.
32.
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.
33.
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.
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34.
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.
35.
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.
36.
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
BMI
body mass index
CRF
case report form
CTR
clinical trial report
DFU
directions for use
DPP-4i
dipeptidyl peptidase-4 inhibitor
DRE
disease related event
DUN
dispensing unit number
EAC
event adjudication committee
EAS
event adjudication system
ECG
Electrocardiogram
eCRF
electronic case report form
eGFR
estimated Glomerular Filtration Rate
EMA
European Medicines Agency
FAS
full analysis set
FDA
U.S. Food and Drug Administration
FDAAA
FDA Amendments Act
FGM
flash glucose monitoring
FPG
fasting plasma glucose
FSH
follicle-stimulating hormone 
GCP
Good Clinical Practice
HbA1c
glycated haemoglobin
ICH
International Council for Harmonisation
IEC
independent ethics committee
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IGlar
insulin glargine
IMP
investigational medicinal product
IRB
institutional review board
ITT
Intention to treat
IUD
intrauterine device
IUS
intrauterine hormone-releasing system 
IWRS
interactive web response system
LDL
low-density lipoprotein
MACE
major adverse cardiovascular event
NIMP
Non-investigational medical product
OAD
oral antidiabetic drug 
PCD
primary completion date
PD
pharmacodynamic
PG
plasma glucose
PK
pharmacokinetic
SAE
serious adverse event
SD
standard deviation
SMPG
self-measured plasma glucose
SUSAR
suspected unexpected serious adverse reaction
T½ 
half- life
T2DM
type 2 diabetes mellitus
TEAE
treatment emergent adverse event
TMM
trial materials manual
ULN
upper limit of normal
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 addit ional 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. 
!
PK samples will be destroyed at finalisation of the clinical trial report. 
!
Antibody samples and samples to assess systemic hypersensitivity reactions 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
!
Fasting C-peptide
NOTES :
1 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
!
Sodium
!
Bilirubin
Lipids
!
Cholesterol
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!
High density lipoprotein (HDL) cholesterol
!
Low density lipoprotein (LDL) 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
!
Anti-insulin 287 antibodies
!
Anti-insulin glargine antibodies
!
Pharmacokinetics
!
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 :
1Details 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 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 Helsinki20, applicable ICH Good Clinical Practice (GCP) Guideline21 and
ISO 1415522
!
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:
o
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
o
notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures
o
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
o
ensuring submission of the clinical trial report (CTR) synopsis to the IRB/IEC.
2) Financial disclosure
Investigators and subinvestigators 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 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 guidelines21, Declaration of Helsinki20 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 written 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 which will remain the 
same throughout the trial. Each site is assigned a 3-digit number and all subject numbers 
will start with the site 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 
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present trial to ensure standardised and objective assessment by an independent adjudication 
committee of experts within the specialty.
The cardiovascular events will be adjudicated in accordance with FDA requirements23. 
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 publications24.
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 Editors25.
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 publication(s) by investigator(s)
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)26, the Food and Drug Administration Amendment 
Act (FDAAA)27, European Commission Requirements(28, 29, ) and other relevant recommendations 
or regulations. If a subject requests to be included in the trial via the Novo Nordisk e-mail contact at 
these web sites, Novo Nordisk may disclose the investigator’s contact details to the subject. As a 
result of increasing requirements for transparency, some countries require public disclosure of 
investigator names and their affiliations.
The Primary Completion Date (PCD) is the last assessment of the primary endpoint, and is for this 
trial Last Subject First Treatment (LSFT) + 26 weeks corresponding to Visit 28. If the last subject is 
withdrawn early, the PCD is considered the date when the last subject randomised in the trial would 
have completed end of treatment Visit 28. The PCD determines the deadline for results disclosure at 
clinicaltrials.gov according to FDAAA.
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 FGM Libre Pro data). The 
investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the eCRF. 
!
The following will be provided as paper CRFs:
o
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:
o
AE forms 
o
Safety information forms 
o
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 
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staff after the date when the investigator signed the CRF, the CRF must be signed and dated 
again by the investigator.
!
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). 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 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 mu st 
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.
!
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 perio d. 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 completion. 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 and 
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 subinvestigator 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.
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. 
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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) for Poland, please see Appendix
10 for details.
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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.
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.
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 
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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):
Medication error:
A medication error concerning trial products is defined as:
!
Administration of wrong drug 
Note: Use of wrong DUN is not considered a medication error unless it results in a confirmed administration of 
wrong drug. 
!
Wrong route of administration, such as intramuscular instead of subcutaneous. 
!
Accidental administration of a lower or higher dose than intended. Accidental administration of a lower or 
higher dose than intended. i.e. dose which may lead to significant health consequences, as judged by the 
Investigator, irrespective of whether the SAE criteria are fulfilled or not; however, 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 
!
Ischaemic stroke
!
Haemorrhagic stroke
!
Undetermined stroke
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cord, or retinal vascular injury as 
a result of haemorrhage or 
infarction
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)
!
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 
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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.
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 a sequelae meets 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.
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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.
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.
Reporting of AEs for Non-Novo Nordisk medical devices provided by Novo Nordisk for use in the trial
Reporting of AEs on: 
 FreeStyle Libre Pro device and supplies or BG meter device and related auxiliaries 
All technical complaints on 
 FreeStyle Libre Pro and supplies or BG-meter, strips, lancets and control solutions 
must be reported directly to the supplier/manufacturer using the supplier reporting form within the timelines defined 
from supplier/manufacturer.
Contact details are provided in Attachment I to the protocol
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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
1. Premenarcheal 
2. 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.
3. Postmenopausal female
!
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high Follicle Stimulating Hormone (FSH) 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 FSH 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 in seminal fluid is unlikely.
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:
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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 b
! 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 (IUD)
! Intrauterine hormone-releasing System (IUS)
! 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.
!
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 
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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 Center, 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 
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 antibo dy 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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Protocol
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Date:
25 June 2018
Novo Nordisk
Trial ID: NN1436-4383
Version:
1.0
Status:
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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 IHSG30, ADA-2018 4, ISPAD31, Type 1 diabetes 
outcomes program32, ATTD33. Severe hypoglycaemia as defined by Seaquist34.
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 guidelines34.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 
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Version:
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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. 
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 fo llowing the return of PG to normal is considered sufficient evidence that 
the event was induced by a low PG concentration.34
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 the diary for 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.35 36
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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Date:
25 June 2018
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Trial ID: NN1436-4383
Version:
1.0
Status:
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Titration guideline
Appendix 9
Introduction
Titration guidelines have been developed, providing recommended dose adjustments at different 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 + insulin glargine-
placebo or insulin 287-placebo + insulin glargine.
Insulin 287 and insulin 287-placebo should be taken once weekly at the same day of the week. The 
starting dose will be 70U.
Insulin glargine and insulin glargine-placebo will be taken once daily anytime of the day preferably 
the same time every day. The starting dose will be 10U.
The treat-to-target approach will be applied in both treatments to optimise titration and glycaemic 
control throughout the trial.
There are no maximum or minimum doses.
Dose adjustment of trial products during the trial
Titration of insulin glargine and insulin glargine-placebo
After randomisation insulin glargine and insulin glargine-placebo doses will be adjusted once 
weekly by the investigator in connection with the scheduled visits/phone contacts as described 
below. Titrated dosed should be maintained until new titration or review is performed by the 
Investigator.
The dose adjustment will be based on the three pre-breakfast SMPG values measured on two days 
prior to titration and on the day of the contact.
If one or more SMPG values are missing, the dose adjustment should be performed on the 
remaining SMPG value(s). The insulin dose adjustment should aim to reach an SMPG of 3.9–6.0 
mmol/L (70–108 mg/dL).
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Trial ID: NN1436-4383
Version:
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Status:
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If there are no hypoglycaemic values in the pre-breakfast SMPGs value(s) the dose is adjusted 
according to Table 12-4. If there are hypoglycaemic values the dose is adjusted according to 
Table 12-5
Table 12-4
Insulin glargine and insulin glargine-placebo increase
Mean pre-breakfast SMPG
Dose adjustment
mmol/L
mg/dL
U
3.9 – 6.0
70 – 108
No adjustment
6.1 – 7.0
109 – 126
+ 2
> 7.0
> 126
+ 4
Table 12-5
Insulin glargine and insulin glargine-placebo reduction
Lowest pre-breakfast SMPG
Dose adjustment
mmol/L
mg/dL
U
3.0 – 3.8
54 – 69
- 2
< 3.0
< 54
- 4
Titration of insulin 287 and insulin 287-placebo
The dose adjustment will be based on the three fasting SMPG values measured on two days prior to 
titration and on the day of the contact.
If one or more SMPG values are missing, the dose adjustment should be performed on the 
remaining SMPG value(s). The insulin dose adjustment should aim to reach a SMPG of 3.9–6.0
mmol/L (70–108 mg/dL).
If there are no hypoglycaemic values in the fasting SMPGs value(s) the dose is adjusted according 
to Table 12-6. If there are hypoglycaemic values the dose is adjusted according to Table 12-7
Table 12-6
Insulin 287 and insulin 287-placebo increase
Mean pre-breakfast SMPG
Dose adjustment
mmol/L
mg/dL
U
3.9 – 6.0
70 – 108
No adjustment
6.1 – 7.0
109 – 126
+ 14
> 7.0
> 126
+ 28
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Protocol
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Date:
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Trial ID: NN1436-4383
Version:
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Status:
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Table 12-7
Insulin 287 and insulin 287-placebo reduction
Lowest pre-breakfast SMPG
Dose adjustment
mmol/L
mg/dL
U
3.0 – 3.8
54 – 69
- 14
< 3.0
< 54
- 28
Deviations from the algorithm
It is recommended that the algorithm is followed. The prescribed daily dose must always 
correspond to the prescribed weekly dose divided by 7. 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 eCRF by the investigator as applicable.
Missing dose guidance: 
The dosing window 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 measurement. 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 closest possible dose which can be 
divided with 7. 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 dosing should still be 
taken. Additional SMPG measurement should be performed to control BG.
Dose recommendation from V28 (end of treatment) and during follow up
If it is decided that the individual subject should continue on insulin from V28 it is recommended 
that the subject is switched 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 daily insulin glargine/insulin glargine-placebo dose
!
Calculate 50% of the latest weekly insulin 287/insulin 287-placebo dose divided by 7
!
Initiate the new daily basal insulin based on the lowest of the two calculated doses above
!
Consider titrating the basal insulin once or twice weekly in accordance with Table 12-4 and 
Table 12-5 during the follow up period
Data collection
The following data should be entered into the diary by the subject and reviewed by the investigator 
prior to the contact:
!
Per protocol pre-breakfast SMPG values measured since last visit/telephone contact
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Version:
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Status:
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!
Insulin glargine/insulin glargine-placebo and insulin 287/insulin 287-placebo doses taken 
prior to the visit/phone contact
The following should be entered by investigator into the eCRF within 24 hours after each contact:
!
Insulin glargine/insulin glargine-placebo and insulin 287/insulin 287-placebo 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 dose titration is entered into the diary and into the eCRF. 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.
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Trial ID: NN1436-4383
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Status:
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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 Greece: Adequate contraceptive measures are defined as combined hormonal contraception 
(containing oestrogen and progesterone), which suppress ovulation (oral, intravaginal, 
percutaneous), progesterone-only hormonal contraception which suppress ovulation (oral, 
injectable, implantable), intrauterine device, hormone-releasing intrauterine system, bilateral tubal 
occlusion, partner with vasectomy, sexual abstinence.
For Poland: Novo Nordisk carries liability for the trial exclusively in the scope defined by the 
applicable laws and in particular by the Civil Code and the Pharmaceutical Law dated 6 September 
2001 (uniform version Journal of Laws of 2008 No.45 item 271 with amendments). In order to 
support potential claims for liability attributable to the Trial, Novo Nordisk and investigator are 
covered by Insurance Policy issued according to applicable Polish law.
For Slovakia: It is necessary that the trial sponsor covers all costs for treatment of the disease 
studied. It is necessary to cover the whole diabetes medication payment, including metformin and 
DPP4i.
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Log of Protocols
INTERNAL USE ONLY
Date:
08 January 2020
Novo Nordisk
Trial ID: NN1436-4383
Version:
1.0
     
Status:
Final
     
Page:
1 of 1
Log of 4383 protocols
Please note that text in italics is only here to provide a full overview.
Date
Versions
Submitted
Comments
25-Jun-2018
1.0 
Yes
First version on the CTA
nD object ID: 
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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

SAP_001.pdf: 
Cover Page for Statistical Analysis Plan
Sponsor name:
Novo Nordisk A/S
NCT number
NCT03751657
Sponsor trial ID:
NN1436-4383
Official title of study:
An investigational trial comparing the efficacy and safety of
once weekly NNC0148-0287 C (insulin 287) versus once daily
insulin glargine, both in combination with metformin, with
or without DPP-4 inhibitors, in insulin naïve subjects with
type 2 diabetes mellitus
Document date:
20D\20


Link
List of contents
Statistical analysis plan......................................................................................................................
CONFIDENTIAL
Date:
Novo Nordisk
Version:
Status:
NNC0148-0287
Trial ID: NN1436-4383
Clinical Trial Report
Appendix 16.1.9
29 May 2020
1.0
Final
16.1.9 Documentation of statistical methods
1.0
.
CONFIDENTIAL
Redacted VWDWLVWLFDODQDO\VLVSODQ 
Includes redaction of personal identifiable information only. 
. 


Statistical Analysis Plan
CONFIDENTIAL
Date:
20 December 2019
Novo Nordisk
Trial ID: NN1436-4383
Version:
1.0
UTN: U1111-1208-4124
Status:
Final
EudraCT No.: 2018-000322-63
Page:
1 of 25
Statistical Analysis Plan
Trial ID: NN1436-4383
An investigational trial comparing the efficacy and safety of 
once weekly NNC0148-0287 C (insulin 287) versus once daily 
insulin glargine, both in combination with metformin, with 
or without DPP-4 inhibitors, in insulin naïve subjects with 
type 2 diabetes mellitus
Author
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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.
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:
20 December 2019
Novo Nordisk
Trial ID: NN1436-4383
Version:
1.0
UTN: U1111-1208-4124
Status:
Final
EudraCT No.: 2018-000322-63
Page:
2 of 25
Table of contents
Page
Table of contents.........................................................................................................................................2
List of abbreviations ...................................................................................................................................3
1
Introduction .........................................................................................................................................4
1.1
Trial information.......................................................................................................................4
1.2
Scope of the statistical analysis plan..........................................................................................5
2
Statistical considerations .....................................................................................................................5
2.1
Sample size determination.........................................................................................................5
2.2
Definition of analysis sets..........................................................................................................6
2.3
Definition of trial periods ..........................................................................................................7
2.4
Statistical analyses ....................................................................................................................8
2.4.1
Primary endpoint ...................................................................................................10
2.4.2
Secondary endpoints ..............................................................................................12
2.4.3
Confirmatory secondary endpoints.........................................................................12
2.4.3.1
Supportive secondary endpoints .......................................................12
2.4.3.2
Exploratory endpoints ......................................................................16
2.4.4
Other analyses .......................................................................................................16
2.5
Pharmacokinetic and/or pharmacodynamic modelling .............................................................20
2.6
Additional sensitivity analyses ................................................................................................20
3
Changes to the statistical analyses planned in the protocol..............................................................20
4
References ..........................................................................................................................................25
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Statistical Analysis Plan
CONFIDENTIAL
Date:
20 December 2019
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Trial ID: NN1436-4383
Version:
1.0
UTN: U1111-1208-4124
Status:
Final
EudraCT No.: 2018-000322-63
Page:
3 of 25
List of abbreviations
AE
adverse event
ANOVA
analysis of variance
CI
confidence interval
CRF
case report form
DPP4i
dipeptidyl peptidase-4 inhibitor
ECG
electrocardiogram
eCRF
electronic case report form
FAS
full analysis set
FGM
flash glucose monitoring
FPG
fasting plasma glucose
ICH
International Conference on Harmonisation of Technical Requirements
for Registration of Pharmaceuticals for Human Use
IGlar
insulin glargine
IWRS
interactive web response system
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
mixed model for repeated measurement
PK
pharmacokinetics
SAE
serious adverse event
SAP
statistical analysis plan
SAS
safety analysis set
SD
standard deviation
SMPG
self-measured plasma glucose
T2DM
type 2 diabetes mellitus

1.0
.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
20 December 2019
Novo Nordisk
Trial ID: NN1436-4383
Version:
1.0
UTN: U1111-1208-4124
Status:
Final
EudraCT No.: 2018-000322-63
Page:
4 of 25
1
Introduction
1.1
Trial information
This is a 26-week, randomised, double-blind, double-dummy, active-controlled, parallel-group, 
stratified, multicentre, multinational trial with 2 arms comparing the efficacy and safety of 
treatment with insulin 287 once weekly versus insulin glargine (IGlar) once daily in insulin-naïve 
subjects with type 2 diabetes mellitus (T2DM) inadequately controlled on metformin with or 
without dipeptidyl peptidase-4 inhibitors (DDP4i).
Subjects will be randomised in a 1:1 manner to receive once weekly insulin 287 and once daily 
placebo or once weekly placebo and once daily IGlar. The randomisation of subjects will be 
stratified based on use of DPP4i.
The total duration for the individual subject will be approximately 33 weeks. The trial includes a 2-
week screening period, followed by a 26-week randomised treatment period and a 5-week follow-
up period.
The overall trial design and visit schedule are outlined in the trial diagram Figure 1-1 and trial 
flowchart (protocol section 2), respectively.
Figure 1-1
Trial design
The primary objective is to investigate the effect on glycaemic control after 26 weeks treatment of 
once weekly insulin 287 versus once daily IGlar both in combination with metformin with or 
without DPP4i in insulin-naïve T2DM subjects inadequately treated with metformin with or without 
DPP4i.
The secondary objective is to investigate the safety and tolerability during 26 weeks of treatment 
with once weekly insulin 287 versus once daily IGlar both in combination with metformin with or 
without DPP4i in insulin-naïve subjects with T2DM inadequately treated with metformin with or 
without DPP4i.
The exploratory objectives are
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Statistical Analysis Plan
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Date:
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Trial ID: NN1436-4383
Version:
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UTN: U1111-1208-4124
Status:
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EudraCT No.: 2018-000322-63
Page:
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!
To investigate the pharmacokinetics (PK) of insulin 287 using population PK during 26 
weeks of treatment in insulin-naïve subjects with T2DM inadequately treated with 
metformin with or without DPP4i
!
To investigate the effect on glycaemic control (using
FreeStyle Libre Pro) of 
insulin 287 and IGlar during 26 weeks of treatment in insulin naïve subjects with T2DM 
inadequately treated with metformin with or without DPP4i
Subjects who prematurely discontinue trial product permanently or withdraw from the trial will be 
asked to attend the end of treatment visit (V28) as soon as possible and the follow-up visits (FU1 
and FU2) after 2 and 5 weeks, respectively. In case of premature trial product discontinuation, once 
the follow-up visits are completed the subject should be contacted by phone every 4 weeks and 
finally come in for the discontinuation follow-up visit (V28A) 26 weeks after randomisation.
For further details on handling of subjects who prematurely discontinue trial product permanently 
or withdraw from the trial and the trial in general, please see the trial protocol.
1.2
Scope of the statistical analysis plan
This statistical analysis plan (SAP) is based on the protocol An investigational trial comparing the 
efficacy and safety of once weekly NNC0148-0287 C (insulin 287) versus once daily insulin 
glargine, both in combination with metformin, with or without DPP-4 inhibitors, in insulin naïve 
subjects with type 2 diabetes mellitus, version 1.0 (dated 25 June 2018). Most of the statistical 
analyses and derivations of endpoints presented in this SAP are identical to those described in the 
protocol; some have been updated or added for technical or clinical reasons, but mostly the SAP 
contains clarifications for derivations, calculations of endpoints, and analyses. The changes to the 
statistical considerations proposed in this SAP and the reasons for the changes are described in 
section 3.
2
Statistical considerations
2.1
Sample size determination
The primary estimand is defined as the treatment difference in change in HbA1c from baseline to
week 26 between once weekly insulin 287 and once daily IGlar for all randomised subjects, if all
subjects had adhered to treatment and did not receive ancillary treatment. This is a “hypothetical”
estimand. This estimand aims to reflect the treatment effect for subjects that are actually able to take
the drug during the intended treatment period. With the aim of evaluating proof of concept this
estimand is considered relevant.
The sample size is determined such that the width of the two-sided 95% confidence interval (CI) for
the treatment difference assuming normally distributed data in change from baseline to 26 weeks in
HbA1c is 0.5%-point. The standard deviation (SD) is expected to be 1.0%-point for all treatment
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arms based on observations with IGlar in insulin naïve T2DM trials (NN1250-3579, NN1250-3643
and NN1250-3672). A total of 246 subjects with 123 in each treatment arm will ensure the required 
width of the 95% CI. The required width of the confidence interval is independent of the choice of 
estimand and sensitivity analyses since all randomised subjects will contribute to all analyses. The 
SD is assumed to be 1.0 based on observations from finalised clinical trials with IGlar in insulin 
naïve T2DM subjects. Since the assumed SD of 1 is to the conservative side it is assumed that the 
SD will not be further increased by the choice of estimand.
Table 2-1 displays sample sizes for various alternative standard deviations and widths of the 95%
CI.
Table 2-1
Sample size for various standard deviations and widths of the confidence 
interval
Width of the 95% CI
SD
0.40
0.50
0.60
0.9
312
200
140
1.0
386
246
172
1.1
466
298
208
Sample size is computed for 1:1 randomisation. SD: standard deviation.
2.2
Definition of analysis sets
The following analysis sets are defined in accordance with the International Council for 
Harmonisation (ICH)-E9 guidance1.
!
Full Analysis Set (FAS): includes all randomised subjects. In exceptional cases, subjects 
may be eliminated from the full analysis set. In such cases the elimination will be justified 
and documented. The statistical evaluation of the FAS will follow the intention-to-treat 
(ITT) principle and subjects will contribute to the evaluation “as randomised”.
!
Safety Analysis Set (SAS): includes all subjects receiving at least one dose of the 
investigational product or comparator. Subjects in the safety set will contribute to the 
evaluation “as treated”.
Randomised subjects who are lost to follow up and where no exposure information of the 
investigational product or comparators is available after randomisation will be handled as 
unexposed.
Before data are released for statistical analysis, a review of all data will take place to identify 
protocol deviations that could potentially affect the results. Any decision to exclude any subject or 
observation from the statistical analysis is the joint responsibility of the members of the sponsor 
study group. The subjects or observations to be excluded, and the reasons for their exclusion must 
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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.
2.3
Definition of trial periods
The in-trial 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. The end date is as defined above.
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.
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 observation period.
For adjudicated events it is the EAC determined onset date that determines if the event belongs to 
the on-treatment period.
The on-treatment without 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:
!
The last dose of trial product + 5 weeks for once daily insulin and + 6 weeks for once 
weekly insulin
!
Initiation of any diabetes treatment other than trial products and metformin +/- DPP4i
!
Increasing the dose of metformin or DPP4i
!
The end date of the on-treatment period if no ancillary treatment was initiated
The following will not be considered ancillary treatment:
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!
If a subject decreases the dose of background medication, or if a subject for a few days 
takes another antidiabetic drug other than randomised treatment or increases the dose of 
background medication due to reasons not related to the effect of randomised treatment, 
e.g.,
o
if antidiabetic treatment is given for an SAE
o
if a subject is hospitalised and it is against hospital policy to use trial products
o
if metformin or DPP4i is re-initiated after a few days without due to an AE or if 
removed entirely due to financial reasons
o
if a temperature deviation leaves trial product unavailable for distribution and 
administration
o
if a subject forgot trial medication while going on vacation and had to use other 
antidiabetic treatment while away
!
Antidiabetic drugs initiated after end of treatment visit
Baseline assessments are always included in the on-treatment without ancillary treatment period.
The ‘on-treatment without ancillary treatment’ observation period will be the primary observation 
period for efficacy evaluations. Safety will be evaluated based the ‘on-treatment’ observation 
periods unless otherwise specified.
Periods  considered as the titration period, the maintenance period, and the baseline to end of 
treatment period are used for certain hypoglycaemia tabulations. The titration period starts at the 
date of first dose of active trial product as recorded on the eCRF and ends on the date of week 16 
visit (V18) minus 1 day, the end of study date, the end of treatment visit date (V28), or the end of 
active treatment date, whichever comes first. The maintenance period starts at the date of week 16 
visit (V18) and ends on the end of treatment visit date (V28), the end of study date, or the end of 
active treatment date, whichever comes first. The maintenance period only exists if the end date for 
the titration period corresponds to the start date of the maintenance period. The baseline to end of 
treatment visit period starts at the date of first dose of active trial product as recorded on the eCRF 
and ends on the end of treatment visit date (V28) or the end of study date, whichever comes first.
2.4
Statistical analyses
Novo Nordisk will analyse and report data from all trial sites together.
All efficacy endpoints will be summarised using the full analysis set (FAS) and the ‘on-treatment 
without ancillary treatment’ observation period, albeit the primary endpoint will also be 
summarised using the ‘in-trial’ observation period. Safety endpoints will be summarised using the 
safety analysis set (SAS) and the ‘on-treatment’ observation period unless otherwise specified. All 
statistical analyses of efficacy and safety endpoints will be based on the FAS unless otherwise 
specified.
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Endpoints are summarised by arithmetic mean, SD, median, and minimum and maximum value. 
Selected endpoints, e.g. endpoints that are analysed log-transformed, will be reported with 
geometric mean and coefficient of variation in place of mean and SD. For measurements over time, 
mean values will be plotted to explore the trajectory over time for selected endpoints. ‘On-treatment
without ancillary treatment’ observed data will be used as the basis for plotting efficacy data while 
‘on-treatment’ observed data will be used as the basis for plotting safety data if not otherwise 
specified. Mean profile for HbA1c will be plotted by time of treatment discontinuation and treatment 
in order to investigate discontinuation patterns. Data obtained after treatment discontinuation or 
initiation of ancillary treatment will be included using different plot symbols. In addition, selected 
endpoints will be summarised by mean cumulative function plots, dot plots, box plots, and plots of 
the mean change from baseline over time. For HbA1c, additional summary tables and mean plots 
based on ‘in-trial’ data will also be prepared.
In accordance with guidance2, endpoints will be assessed at frequent visits and also on subjects who 
discontinue treatment. If an assessment has been made both at screening and randomisation, and if 
not otherwise specified, the value from the randomisation visit will be used as the baseline value. If 
the value measured at the randomisation visit is missing and the assessment also has been made at 
screening, then the screening value will be used as the baseline value.
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. For prematurely discontinued 
subjects, the discontinuation follow-up visit (V28A) 26 weeks after randomisation is reallocated to 
the end of treatment visit (V28) after performing the previous reallocation.
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 mean treatment effects 
using least square mean (LSMean) for absolute values, and change from baseline where applicable. 
The LSMean is either obtained by Rubin’s rule weighing together LSMeans from multiple
imputation estimations or obtained directly from estimation of a parameterised statistical model. In 
addition, estimated mean treatment difference (or ratio) will be presented together with the two-
sided 95% confidence interval and corresponding two-sided p-value.
In the statistical models, explanatory factors will be coded as follows:
!
Treatment: Once weekly insulin 287, Once daily IGlar
!
DPP4i has 2 levels (yes and no)
!
Region has 2 levels (Europe and North America)
!
Visit: Planned visits for actual endpoint according to flowchart
The impact of protocol deviations and outliers may be investigated further in sensitivity analyses if
deemed relevant.
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2.4.1
Primary endpoint
The primary endpoint is change from baseline to week 26 in HbA1c.
Primary estimand
For the primary endpoint, the primary estimand is defined as the “hypothetical” estimand3.
The treatment difference between once weekly insulin 287 versus once daily IGlar in change from 
baseline to week 26 in HbA1c for all randomised subjects if all subjects had adhered to treatment 
and did not initiate ancillary treatment in subjects with T2DM inadequately treated with metformin 
with or without DPP4i.
The primary estimand will be estimated based on the FAS. This estimand aims to reflect the 
treatment effect for subjects that are actually able to take the drug during the intended treatment 
period. With the aim of evaluating proof of concept, this estimand is considered relevant i.e. a de 
jure estimand addressing efficacy.
Subjects may start ancillary treatment during the trial. Hence, data obtained after occurrence of 
intercurrent event such as initiation of ancillary treatment and discontinuation of randomised 
treatment will not be included in the estimation of the primary estimand.
To estimate this estimand, change from baseline in HbA1c after 26 weeks will be analysed with the 
linear mixed model for repeated measurement (MMRM) method with an unstructured covariance 
matrix. All post baseline HbA1c measurements obtained on planned visits while the subject 
continues the randomised treatment and does not initiate ancillary treatment will contribute to the 
analysis. Hence, data obtained after initiation of ancillary treatment or discontinuation of 
randomised treatment will not be included in the estimation of the primary estimand. For definition 
of ancillary treatment, please see protocol section 7.7. For concomitant diabetes medication not 
considered to be ancillary treatment, please see section 2.3 above. This analysis has the underlying 
assumption that the missing data mechanism is ‘missing at random’. The model will include use of 
DPP4i (yes/no), region, treatment and visit as fixed factors and baseline HbA1c as covariate. 
Interactions between visit and all factors and covariates will also be included in the model. The 
estimated mean treatment difference and the confidence interval will be presented together with the 
corresponding two-sided p-value. In the following, this MMRM method will be referred to as the 
standard MMRM method.
Secondary estimand
The secondary estimand for the primary endpoint is the “treatment policy” estimand.
The secondary estimand is defined as the treatment difference between once weekly insulin 287 
versus once daily IGlar in change from baseline to week 26 in HbA1c for all randomised subjects, 
regardless of the treatment actually received in subjects with T2DM inadequately treated with 
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metformin with or without DPP4i. This estimand aims to reflect the treatment effect for all subjects 
regardless of treatment adherence, i.e. a de facto estimand addressing effectiveness.
This will be estimated using all HbA1c measurements obtained at week 26, also including
measurements from subjects discontinuing their randomised treatment or initiating ancillary 
treatment. Missing HbA1c measurements at week 26 will be imputed from trial participants who are 
from the same randomised group, who have discontinued their randomised treatment and have an 
HbA1c measurement at week 26.
This will be done as follows:
!
First, one thousand (1000) copies of the dataset will be generated.
!
Second, for each dataset copy, and each treatment group, an analysis of variance (ANOVA) 
model with baseline HbA1c value as a covariate will be fitted to the week 26 value based on
subjects having discontinued their randomised treatment and have an HbA1c measurement 
at week 26. The estimated parameters, and their variances, from the model will be used to 
impute missing values at week 26 in the same treatment group. The factors region and use 
of DPP4i are not considered in this step assuming the number of subjects to impute from 
will be low and that may lead the model to not meet the convergence criteria.
!
For each of the complete data sets, the change from baseline in HbA1c after 26 weeks will 
be analysed using an analysis of covariance model with use of DPP4i (yes/no), region and 
treatment as fixed factor, and baseline HbA1c as covariate. The estimates and standard 
deviations for the 1000 data sets will be pooled to one estimate and associated SD using 
Rubin’s rule.
If less than 3 subjects have discontinued their randomised treatment and have an HbA1c
measurement at week 26 in any of the treatment groups, then the second step above will be carried 
out combining the two treatment arms and including treatment as factor in the model.
The estimated mean treatment difference and the confidence interval will be presented together with 
the corresponding two-sided p-value.
Sensitivity analysis
The following sensitivity analysis of the assumptions about the missing data will be carried out: for 
the primary estimand, a tipping point like type of analysis will be performed where subjects from 
the Insulin 287 arm having no HbA1c measurement at week 26 are assumed to have a worse 
outcome compared to what was imputed in the primary analysis. This is done by adding a value Δi 
to the imputed HbA1c values in the Insulin 287 arm before analysing the data. The imputation is 
implemented as a multiple imputation in two steps. In the first step, intermittent missing HbA1c
values are imputed (1000 copies) for each treatment separately using a Markov Chain Monte Carlo 
method in order to obtain a monotone missing data pattern. In the second step, sequential multiple 
imputation of HbA1c values at week 4, 8, 12, 16, 20 and 26 for each dataset copy and each treatment 
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group is fitted using an analysis of covariance model with use of DPP4i (yes/no) and region as fixed 
factors, and baseline HbA1c and earlier HbA1c as covariates. For each of the complete data set, a
penalty is added to the imputed HbA1c values in the insulin 287 arm after which change from 
baseline in HbA1c after 26 weeks is derived and analysed using an analysis of covariance model 
with use of DPP4i (yes/no), region and treatment as fixed factor, and baseline HbA1c as covariate. 
For each penalty, the estimates and standard deviations for the 1000 data sets will be pooled to one 
estimate and associated SD using Rubin’s rule. The resulting estimated treatment differences and 
95% CIs will be plotted as function of Δi to evaluate the robustness of the primary analysis results.
2.4.2
Secondary endpoints
2.4.3
Confirmatory secondary endpoints
Not applicable for this trial.
2.4.3.1
Supportive secondary endpoints
The supportive secondary endpoints will be addressed in terms of the framework of the primary 
estimand only.
Efficacy endpoints
!
Change from baseline to week 26 in fasting plasma glucose
!
9-point profile (individual SMPG values) at week 26
!
Change from baseline to week 26 in mean of the 9-point profile, defined as the area under 
the profile divided by measurement time
!
Fluctuations of the 9-point profile (defined as the integrated absolute distance from the 
mean profile value divided by measurement time) at week 26
!
Fasting C-peptide at week 26
!
Change from baseline to week 26 in body weight
!
Weekly dose of insulin 287 and weekly dose of IGlar from visit 26 to visit 28
FPG and body weight – change from baseline after 26 weeks
Change from baseline in FPG and body weight will be analysed using the standard MMRM method 
with relevant baseline as the covariate.
Fasting C-peptide
Fasting C-peptide will be logarithmically transformed and analysed using the standard MMRM 
method but including relevant log-transformed baseline as the covariate.
SMPG 9-point profile
The following endpoints will be derived from self-measured plasma glucose,
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1. 9-point profile (individual SMPG values) at week 26
2. Change from baseline to week 26 in mean of the 9-point profile, defined as the area under 
the profile divided by measurement time
3. Fluctuations of the 9-point profile (defined as the integrated absolute distance from the mean 
profile value divided by measurement time) at week 26
A linear mixed effect model will be fitted to the 9-point SMPG profile data at week 26. The model 
will include treatment, region, use of DPP4i, time, the interaction between treatment and time, the 
interaction between region and time, and the interaction between use of DPP4i and time as fixed 
factors and subject as random effect.
Change from baseline in mean of the 9-point profile, and fluctuation in 9-point profiles after 26 
weeks will be analysed separately using the standard MMRM method with relevant baseline as the 
covariate. Fluctuation in the 9-point profile will be logarithmically transformed before analysed. 
Baseline fluctuation in the 9-point profile also will be log-transformed in the model.
Insulin dose
Insulin 287 dose and IGlar dose will be summarised by week.
Weekly dose from visit 26 to visit 28, i.e. the average weekly dose during the last two weeks of 
treatment, will be logarithmically transformed and analysed based on standard MMRM method but 
not including baseline as a covariate.
Safety endpoints
Number of treatment emergent adverse events from baseline to week 31
AEs will be coded using the most recent version of the Medical Dictionary for Regulatory 
Activities (MedDRA).
The treatment emergent period represents the period where subjects are considered exposed to trial 
product, i.e. it coincides with the on-treatment period as defined in section 2.2.
A treatment emergent adverse event is defined as 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 of exposure (R).
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Summaries of on-treatment AEs and of serious on-treatment AEs will be presented as an overview 
including all AEs, serious AEs, number of deaths, AEs by severity, AEs by relation to treatment and 
AEs of special interest including AEs leading to treatment discontinuation.
Furthermore, summary tables based on system organ class and preferred terms are made for the on-
treatment period for:
!
All AEs
!
Serious AEs
!
AEs possibly or probably related to trial product
!
Severe AEs
!
AEs reported by safety areas of interest
!
AEs with preferred term that are experienced by at least 5% of the subjects in any treatment 
arm or by at least 5% of all subjects
A listing for AEs occurring outside of the on-treatment period, i.e. with onset date before the first 
day of exposure to randomised treatment and AEs collected after the on-treatment period, will be 
presented.
Additional summaries will be displayed for SAEs, including events collected after premature 
treatment discontinuation (“in-trial” summary).
Summary of number of on-treatment injection site reactions will be presented as an overview 
including all AEs, serious AEs, AEs by severity and AEs by relation to treatment. Furthermore,
summary table of injection site reaction based on system organ class and preferred terms will be 
made.
Number of hypoglycaemic episodes
The definition and classification of hypoglycaemic episodes are outlined in Table 2-2. For further 
details, please refer to Appendix 8 in the protocol. Data on hypoglycaemic episodes are presented in 
terms of the number of subjects with at least one episode (N), the percentage of subjects with at 
least one episode (%), the number of episodes (E) and the event rate per 100 years of exposure (R). 
The summaries are made for all and nocturnal (between 00:01 and 05.59 both inclusive) episodes 
respectively.
Table 2-2
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
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Level
Glycaemic criteria
Description
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
Number of hypoglycaemic episodes, whenever analysed statistically, will be analysed by a negative 
binomial regression model with treatment, region and use of DPP4i (yes/no) as fixed factors and the 
log of time period for which the hypoglycaemic episodes are considered as an offset. In the 
following, this model will be referred to as the standard negative binomial regression model.
Level 1 hypoglycaemic episodes, level 2 and level 3 combined hypoglycaemic episodes, level 2
hypoglycaemic episodes, and level 3 hypoglycaemic episodes from baseline to end of treatment 
visit will be summarised and analysed separately by the standard negative binomial regression 
model to the extent data allows.
The above summaries will be repeated for the on-treatment period, the titration period and the 
maintenance period. The statistical analysis will be repeated for the following to the extent data 
allows,
1. Number of level 2 and level 3 combined hypoglycaemic episodes during the on-treatment 
period
2. Number of level 2 and level 3 combined hypoglycaemic episodes during the titration period
3. Number of level 2 and level 3 combined hypoglycaemic episodes during the maintenance 
period
4. Number of level 2 hypoglycaemic episodes during the on-treatment period
5. Number of level 2 hypoglycaemic episodes during the titration period
6. Number of level 2 hypoglycaemic episodes during the maintenance period
7. Number of level 3 hypoglycaemic episodes during the on-treatment period
8. Number of level 3 hypoglycaemic episodes during the titration period
9. Number of level 3 hypoglycaemic episodes during the maintenance period
The number of nocturnal level 2 and level 3 combined hypoglycaemic episodes and number of level
2 hypoglycaemic episodes, and number of level 3 hypoglycaemic episodes:
!
from baseline to end of treatment visit
!
during the on-treatment period
!
during the titration period
!
during the maintenance period
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will be analysed similarly to the extent data allows.
Antibodies from baseline to week 31
The following is to be prepared for both insulin 287 and insulin glargine. Anti-insulin antibody 
level, anti-insulin antibody titres and change from baseline in anti-insulin antibody titres will be 
summarised and tabulated. For anti-insulin antibody level, mean plots by treatment week will be 
prepared. The correlation between anti-insulin antibody titres and actual weekly basal insulin dose, 
HbA1c, and change from baseline in HbA1c, respectively, will be illustrated using mean plots by 
treatment week for quartiles of peak post baseline to week 31 titre values. The Spearman’s rank 
correlation coefficient between change in anti-insulin antibody titres at follow-up to actual weekly 
basal insulin dose during week 25 and week 26, HbA1c at week 26, change from baseline in HbA1c
at week 26, and level 2 and level 3 combined hypoglycaemic episodes during the on-treatment
period, respectively, will be derived and displayed in a table with the corresponding p-value for test 
of no correlation. Anti-insulin antibody status will be tabulated by visit, and anti-insulin antibody 
cross-reactivity to endogenous insulin status will be tabulated by visit for subjects positive for anti-
insulin antibodies. Shift table from baseline to week 26 and follow-up for cross-reactivity anti-
insulin antibody status will be prepared.
2.4.3.2
Exploratory endpoints
!
Insulin 287 concentrations, evaluated in a population PK analysis
!
Time in range 3.9-7.8 mmol/L (70–140 mg/dL) measured by flash glucose monitoring
(FGM) (
Free Style Libre Pro) during the last 2 weeks of treatment (week 25 and
26). The percentage of time spent in glycaemic range will be calculated as 100 times the 
number of recorded measurements in glycaemic range 3.9-7.8 mmol/L (70-140 mg/dL) 
divided by the total number of recorded measurements. It will be analysed using the 
standard MMRM method but not including baseline as a covariate.
Since the data accuracy may vary during the first 24 hours after sensor fitting, the FGM data from 
the 1st day (24h) of each sensor period will be excluded from analysis. Following the international 
consensus criteria4, it will be required that at least 70% of the planned FGM measurements during 
the last 2 weeks of treatment is available for endpoint data to be included in the analysis.
2.4.4
Other analyses
Other efficacy tabulations:
HbA1c responders after 26 weeks
Dichotomous outcome (responder=yes/non-responder=no) will be defined based on whether a
subject has met a specific level of HbA1c < 7.0% after 26 weeks. Analysis of this responder
outcome will be based on a logistic regression model with treatment, region and use of DPP4i as
fixed factors and baseline HbA1c as covariate.
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Date:
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Missing HbA1c (according to the primary estimand) are imputed by the standard MMRM method 
before applying the specific responder criterion.
HbA1c responders with minimal weight gain after 26 weeks
Responder will be defined as:
!
HbA1c < 7.0% and change from baseline in body weight < 3%
Analysis of this responder outcome will be based on a logistic regression model with treatment,
region and use of DPP4i as fixed factors and baseline HbA1c and baseline body weight as
covariates.
Missing HbA1c and body weight (according to the framework of the primary estimand) are imputed 
by the standard MMRM method before applying the specific responder criterion.
HbA1c responders after 26 weeks without severe or clinically significant hypoglycaemic 
episodes during the last 12 weeks of treatment
Responder will be defined as:
!
HbA1c < 7.0% and without severe or clinically significant hypoglycaemic episodes during 
the last 12 weeks of treatment
Analysis of this responder outcome will be based on a logistic regression model with treatment, 
region and use of DPP4i as fixed factors and baseline HbA1c as covariate.
Missing HbA1c (according to the primary estimand) are imputed by the standard MMRM method 
before applying the specific responder criterion. Subjects with less than 12 weeks of treatment 
without ancillary treatment will conservatively be set to being non-responder.
HbA1c responders after 26 weeks without severe hypoglycaemic episodes during the last 12 
weeks of treatment
Responder will be defined as:
!
HbA1c < 7.0% and without severe hypoglycaemic episodes during the last 12 weeks of 
treatment
Analysis of this responder outcome will be based on a logistic regression model with treatment, 
region and use of DPP4i as fixed factors and baseline HbA1c as covariate.
Missing HbA1c (according to the primary estimand) are imputed by the standard MMRM method 
before applying the specific responder criterion. Subjects with less than 12 weeks of treatment 
without ancillary treatment will conservatively be set to being non-responder.
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CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
20 December 2019
Novo Nordisk
Trial ID: NN1436-4383
Version:
1.0
UTN: U1111-1208-4124
Status:
Final
EudraCT No.: 2018-000322-63
Page:
18 of 25
HbA1c responders with minimal weight gain after 26 weeks and without severe or clinically 
significant hypoglycaemic episodes during the last 12 weeks of treatment
Responder will be defined as:
!
HbA1c < 7.0% without severe or clinically significant hypoglycaemic episodes during the 
last 12 weeks of treatment, and change from baseline in body weight < 3%
Analysis of this responder outcome will be based on a logistic regression model with treatment,
region and use of DPP4i as fixed factors and baseline HbA1c and body weight as covariates.
Missing HbA1c and body weight (according to the framework of the primary estimand) are imputed 
by the standard MMRM method before applying the specific responder criterion. Subjects with less 
than 12 weeks of treatment without ancillary treatment will conservatively be set to being non-
responder.
HbA1c responders with minimal weight gain after 26 weeks and without severe hypoglycaemic 
episodes during the last 12 weeks of treatment
Responder will be defined as:
!
HbA1c < 7.0% without severe hypoglycaemic episodes during the last 12 weeks of 
treatment, and change from baseline in body weight < 3%
Analysis of this responder outcome will be based on a logistic regression model with treatment,
region and use of DPP4i as fixed factors and baseline HbA1c and body weight as covariates.
Missing HbA1c and body weight (according to the framework of the primary estimand) are imputed 
by the standard MMRM method before applying the specific responder criterion. Subjects with less 
than 12 weeks of treatment without ancillary treatment will conservatively be set to being non-
responder.
Similar analyses as defined above will be carried out for responder targets replacing HbA1c <7.0%
with HbA1c ≤6.5%.
FPG responders after 26 weeks
Dichotomous outcome (responder=yes/non-responder=no) will be defined based on whether a
subject has met a specific target level of FPG ≤ 7.2 mmol/L (130 mg/dL) after 26 weeks. Analysis
of this responder outcome will be based on a logistic regression model with treatment, region and
use of DPP4i as fixed factors and baseline FPG as covariate.
Missing FPG (according to the framework of the primary estimand) are imputed by the standard 
MMRM method before applying the specific responder criterion.
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CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
20 December 2019
Novo Nordisk
Trial ID: NN1436-4383
Version:
1.0
UTN: U1111-1208-4124
Status:
Final
EudraCT No.: 2018-000322-63
Page:
19 of 25
Similar analyses as defined above will be carried out for responder targets replacing FPG ≤7.2 
mmol/L (130 mg/dL) with FPG ≤ 6 mmol/L (108 mg/dL).
Other safety tabulations:
Clinical evaluation (ECG, eye examination and physical examination) change from baseline
after 26 weeks
Eye examination (fundoscopy/fundus photography) and 12-lead ECG findings will be summarised
descriptively, including:
!
Summaries for each visit
!
Shift tables from baseline to after 26 weeks
Laboratory assessment (Biochemistry and Haematology) - change from baseline after 26
weeks
All laboratory parameters will be summarised descriptively including:
!
Summaries by visit
!
Box plots by time since randomisation
Lipids and vital signs
Lipids and vital signs will be summarised by treatment.
Other exploratory tabulations:
Time in range measured by FGM (
Free Style Libre Pro) during the last two weeks of 
treatment (week 25 and 26) will be analysed using the standard MMRM method but not including 
baseline as a covariate for the following time in range,
!
Time in range 3.9–6.0 mmol/L (70-108 mg/dL)
!
Time in range 3.9–10.0 mmol/L (70-180 mg/dL)
!
Time spent < 3.0 mmol/L (54 mg/dL)
!
Time spent < 3.9 mmol/L (70 mg/dL)
!
Time spent > 10.0 mmol/L (180 mg/dL)
!
Time spent > 13.9 mmol/L (250 mg/dL)
Within subject variability as measured by CV% during the last two weeks of treatment (week 25 
and 26) will be logarithmically transformed and analysed using an analysis of covariance model 
with treatment, region and use of DPP4i as fixed factors. Within subject variability will be 
calculated as the sample CV% of the recorded measurements.
For population PK analysis refer section 2.5.
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CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
20 December 2019
Novo Nordisk
Trial ID: NN1436-4383
Version:
1.0
UTN: U1111-1208-4124
Status:
Final
EudraCT No.: 2018-000322-63
Page:
20 of 25
2.5
Pharmacokinetic and/or pharmacodynamic modelling
Insulin 287 serum concentration data will be used for a population PK analysis. The objective of the
population PK analysis is to evaluate the effects of pre-specified covariates on serum concentrations
of insulin 287.
The population PK analysis will be performed by Quantitative Clinical Pharmacology, Novo
Nordisk A/S. A more technical and detailed elaboration of the population PK analysis will be given
in a modelling analysis plan (MAP), which will be prepared before Database Lock (DBL). In brief,
a previously developed PK model for insulin 287 will be applied. The absorption rate constant (Ka)
in the model will be fixed, and the apparent clearance (CL/F) and the apparent volume of
distribution (V/F) will be re-estimated. The covariates of interest will be incorporated into the PK
model using criteria which will be specified in the MAP.
The population PK analysis will be reported in a separate modelling report, which will not be a part
of the clinical trial report. The individual insulin 287 serum concentration data will be tabulated in
the bioanalytical report (BAR).
2.6
Additional sensitivity analyses
Seven subjects used an incorrect type of syringe for once daily IGlar or once daily placebo during 
varying time of the treatment period which led to administration of 2.5 times the prescribed dose of 
once daily IGlar or once daily placebo.
One of the seven subjects experienced level 1 hypoglycaemic episodes while on the incorrect type 
of syringe. If the subject who experienced level 1 hypoglycaemic episodes while on the incorrect 
type of syringe turns out to be randomised to IGlar after randomisation code break, a sensitivity 
analysis will be carried out by repeating the supportive statistical analysis for level 1 hypoglycaemic 
episodes from baseline to end of treatment visit but excluding this subject.
An increased dose of IGlar can potentially affect the development of anti-glargine antibodies. If any 
if the seven subjects turn out to be randomised to IGlar after randomisation code break, those who 
turn out to be randomised to IGlar will be excluded from an additional summary table of the change 
from baseline in anti-insulin glargine antibody titres by visit and an additional correlation analysis 
of the Pearson’s correlation coefficients.
3
Changes to the statistical analyses planned in the protocol
Sample size determination
Because of recruitment issues, it was decided to not round number of subjects to be randomised
from 246 to 250. Hence, the corresponding sentence has been deleted, and information about the 
number in each arm is included based on 246 subjects to be randomised.
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CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
20 December 2019
Novo Nordisk
Trial ID: NN1436-4383
Version:
1.0
UTN: U1111-1208-4124
Status:
Final
EudraCT No.: 2018-000322-63
Page:
21 of 25
The sample size for width of 95% CI of 0.40 and SD of 1.0 should have been 386 instead of the 
reported 384, as per sample size calculation. The number has been updated. However, this would 
not have affected the choice of sample size.
Definition of trial periods
A subsection including definition of trial periods has been added. The wording of the on-treatment 
period and the in-trial period have been updated with more details. Furthermore, a definition of the 
on-treatment without ancillary treatment period has been included to conceptualize the trial period 
described in the description of the primary estimand. A high-level description of what period will be 
of main interest for efficacy and safety evaluations has been included. Finally, the titration period, 
the maintenance period, and the baseline to end of treatment visit period have also been defined in 
more detail.
Ancillary treatment definition has been updated to reflect that only a dose increase of the 
background medication can be considered as ancillary treatment whereas the previous definition 
comprised any dose change. This is to reflect that ancillary treatment is considered as something 
extra on top of randomised treatment or the already taken background medication.
Statistical analyses
A summary with details on what analysis set and trial period to base summaries and analyses of 
efficacy and safety endpoints on have been included for easy reference. To align with what period 
summaries of efficacy and safety endpoints are to be based upon, efficacy data will be plotted for 
the on-treatment without ancillary treatment period and safety data will be plotted for the on-
treatment period.
Selected endpoints will not be summarised by empirical distribution plots. Hence, this has been 
deleted. Furthermore, only selected endpoints will have mean values plotted over time. Mean 
cumulative function plots and dot plots, however, will be used to summarise selected endpoints, 
which is why these have been added to the list of plot types. Furthermore, it has been specified that
the additional plots for HbA1c for ‘in-trial’ data are mean plots.
End of treatment assessments for withdrawn or prematurely discontinued subjects may be 
reallocated, as has been described.
Primary estimand
It had been specified that all post baseline HbA1c measurements obtained on planned visits while 
the subject continues the randomised treatment will contribute to the analysis. However, this needed 
to be updated to while the subject continues the randomised treatment and does not initiate ancillary 
treatment in order to align with the primary estimand.
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1.0
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CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
20 December 2019
Novo Nordisk
Trial ID: NN1436-4383
Version:
1.0
UTN: U1111-1208-4124
Status:
Final
EudraCT No.: 2018-000322-63
Page:
22 of 25
Reference to definition of ancillary treatment has been included together with reference to 
descriptive text on what concomitant diabetes medication is not to be considered ancillary 
treatment.
Secondary estimand
The analysis and imputation descriptions have been clarified for alignment with the secondary 
estimand.
Sensitivity analysis
A multiple imputation model mimicking the primary analysis has been specified for the tipping 
point analysis.
Efficacy endpoints
Change from baseline to week 26 in mean of the 9-point profile had been defined as the area under 
the profile while it should have been defined as the area under the profile divided by measurement 
time, which has been updated.
For fluctuation, timing of endpoint has been included to align with description of the other 
endpoints.
For fasting C-peptide, it has been clarified that it is fasting C-peptide at week 26 and not change 
from baseline to week 26 that is to be analysed.
Daily dose of IGlar has been updated to weekly dose of IGlar and dose at week 26 has been updated 
to dose during the last two weeks of treatment; endpoint description is now aligned with wording in 
protocol section 4.3.2.2 and the wording of analysis hereof.
Fasting C-peptide
Analysis description of fasting C-peptide has been included in its own subsection and wording is 
updated to reflect that fasting C-peptide should be analysed on log-scale.
SMPG 9-point profile
Change from baseline to week 26 in mean of the 9-point profile had been defined as the area under 
the profile while it should have been defined as the area under the profile divided by measurement 
time, which has been updated.
Insulin doses
Endpoint description has been updated to make the description clearer and to align wording with
that of other endpoints.
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CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
20 December 2019
Novo Nordisk
Trial ID: NN1436-4383
Version:
1.0
UTN: U1111-1208-4124
Status:
Final
EudraCT No.: 2018-000322-63
Page:
23 of 25
Number of treatment emergent adverse events from baseline to week 31
The on-treatment period corresponds to the treatment emergent period and the treatment emergent 
terminology will not be used in any outputs. Hence, redundant text has been deleted with reference 
to the description of the on-treatment period. Consequently, treatment emergent AEs are referred to 
as on-treatment AEs.
Summaries of on-treatment AEs, including on-treatment injection site reactions, leading to 
withdrawal from trial will not be produced as the end of trial form does not contain the information.
Furthermore, summary of on-treatment injection site reactions leading to treatment discontinuation 
will not be produced; the information is contained in an overall summary of on-treatment AEs 
leading to treatment discontinuation.
Summary tables based on system organ class and preferred terms are not to be made for moderate 
and mild on-treatment AEs or for on-treatment AEs with preferred term that are experienced by at 
least 1% of the subjects in any treatment arm or by at least 1% of all subjects. Consequently, this 
text has been deleted.
Text describing listing for AEs occurring outside of the on-treatment period has been rephrased and 
redundant text has been deleted.
Number of hypoglycaemic episodes
Details as to what hypoglycaemic episodes will be summarised and analysed have been provided, 
and the time period considered for each analysis have been made unambiguous with time periods 
now corresponding to the defined trial periods.
Antibodies from baseline to week 31
All outputs for antibody data are described in more detail in this section whereas the section under 
‘other safety tabulations’ has been deleted to make the description clear even though not all outputs 
in the updated section are relevant for the supportive secondary safety endpoints. Similar outputs 
are to be made for both insulin 287 and insulin glargine. Anti-insulin antibody %B/T level will be 
summarised and tabulated, but not change in anti-insulin antibody %B/T level. Correlation plots are 
illustrated using mean plots instead of scatter plots. Pearson’s correlation coefficient has been 
replaced by Spearman’s rank correlation coefficient due to the discrete nature of the titre values. 
The correlation coefficients are only to be derived for titre not %B/T level and should also be 
derived for correlation to the level 2 and level 3 combined hypoglycaemic episodes during the on-
treatment period while correlation to insulin dose has been updated to specify the dose during last 
two weeks of treatment to align with the dose endpoint. Finally, positive/negative summaries have 
been defined in more detail.
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CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
20 December 2019
Novo Nordisk
Trial ID: NN1436-4383
Version:
1.0
UTN: U1111-1208-4124
Status:
Final
EudraCT No.: 2018-000322-63
Page:
24 of 25
Exploratory endpoints
Time in range should be summarised based on percentage of time spent in range, not time unit as 
specified in protocol section 4.3.3. Furthermore, it has been specified that at least 70% of the 
planned FGM measurements within a sensor period need to be available to derive time in range 
within period.
Other efficacy tabulations
It has been clarified that missing values for whatever reason are imputed, not only missing values
due to subject discontinuing treatment or initiating ancillary treatment, but still according to the 
primary estimand.
In the responder outcome defined as HbA1c responders with minimal weight gain after 26 weeks 
and without clinically significant hypoglycaemic episodes during the last 12 weeks of treatment, 
severe hypoglycaemic episodes should have been included alongside clinically significant 
hypoglycaemic episodes. This has been updated and the endpoint now corresponds to a similar 
endpoint without minimal weight gain.
Definition of minimal weight gain after 26 weeks should have said change from baseline in body 
weight < 3% instead of ≤ 3%, which has now been updated. In description of FPG responder, target 
should have said ≤ 7.2 mmol/L instead of < 7.2 mmol/L, which has now been updated.
Other safety tabulations
For laboratory assessment, no shift table from baseline to after 26 weeks, proportion of subjects 
with measurement outside reference range by treatment and week, and listings of individual values 
outside reference ranges (abnormal values) will be produced after end of text reduction.
Similar to the exploratory endpoint of time in target-range, the exploratory tabulations of other time 
in range are to be based on the last two weeks of treatment, which has now been specified
It is not feasible to analyse FGM data as repeated measures in a linear mixed model. The analysis 
has been updated to analysis of covariance of the logarithmically transformed within subject CV for 
the last two weeks of treatments.
Additional sensitivity analyses
Additional sensitivity analyses have been added to explore impact of serious breach on potentially 
affected hypoglycaemic episodes data and antibody data.
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1.0
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CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
20 December 2019
Novo Nordisk
Trial ID: NN1436-4383
Version:
1.0
UTN: U1111-1208-4124
Status:
Final
EudraCT No.: 2018-000322-63
Page:
25 of 25
4
References
1.
Little RJA, Rubin DB. Statistical analysis with missing data: New York: John Wiley & 
Sons. 1987.
2.
National Academy of Sciences (NAS). The Prevention and Treatment of Missing Data in 
Clinical Trials. Washington D.C.: The National Academies Press. 2010.
3.
Mallinckrodt CH, Lin Q, Lipkovich I, Molenberghs G. A structured approach to choosing 
estimands and estimators in longitudinal clinical trials. Pharm Stat. 2012;11(6):456-61.
4.
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.
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