Clinical trial NCT02443155
Conditions: Diabetes Diabetes Mellitus, Type 1
Sponsor: Novo Nordisk A/S
Start date: 2015-11-10; Completion date: 2019-02-27
Enrollment: 308 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This trial is conducted globally. The aim of this trial is to assess the clinical proof-of-principle of NNC0114-0006 and liraglutide on preservation of beta-cell function in adult subjects with newly diagnosed type 1 diabetes mellitus.

Detailed description:

Arms: arm 1: None arm 2: None arm 3: None arm 4: None
Interventions: intervention 1: NNC0114-0006 intervention 2: liraglutide intervention 3: placebo
Intervention descriptions: intervention 1: NNC0114-0006 12 mg/kg administered i.v (intravenously) every 6 weeks. Subjects will continue their pre-trial insulin treatment intervention 2: Liraglutide 1.8 mg administered s.c. (subcutaneously) daily. Subjects will continue their pre-trial insulin treatment intervention 3: Placebo administered s.c (subcutaneously) or i.v ( intravenously). Subjects will continue their pre-trial insulin treatment

Protocol documents:
Prot_000.pdf: 
Cover Page for Protocol 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT02443155 
Sponsor trial ID: 
NN9828-4150 
Official title of study: 
A randomised, double-blind, double-dummy, placebo-
controlled, parallel-group, multi-centre clinical proof-of 
principle trial in adult subjects with newly diagnosed type 1 
diabetes mellitus investigating the effect of NNC0114-0006 
and liraglutide on preservation of beta-cell function 
Document date: 
17 September 2019 


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List of contents
Protocol ...............................................................................................................................................
Appendix A .........................................................................................................................................
Appendix B..........................................................................................................................................
Protocol amendment 1 .......................................................................................................................
Protocol amendment 2 .......................................................................................................................
Protocol amendment 3 .......................................................................................................................
Protocol amendment 4 .......................................................................................................................
Protocol amendment 5 .......................................................................................................................
Protocol amendment 6 .......................................................................................................................
Protocol amendment 7 .......................................................................................................................
Attachment I and II............................................................................................................................
CONFIDENTIAL
Date:
Novo Nordisk
Version:
Status:
NNC0114-0006
Trial ID: NN9828-4150
Clinical Trial Report
Appendix 16.1.1
 6HSWHPEHU 2019
1.0
Final
16.1.1 Protocol and protocol amendments
Redacted protocol 
Includes redaction of personal identifiable information only. 
. 


Protocol
CONFIDENTIAL
Date:
07 May 2015
Novo Nordisk
Trial ID: NN9828-4150 
Version:
2.0
UTN: U1111-1154-7172
Status:
Final
EudraCT no.: 2014-001215-39
Page:
1 of 141
Protocol
Trial ID: NN9828-4150
A randomised, double-blind, double-dummy, placebo-controlled, parallel-group 
multi-centre clinical proof-of-principle trial in adult subjects with newly 
diagnosed type 1 diabetes mellitus investigating the effect of NNC0114-0006 and 
liraglutide on preservation of beta-cell function
Trial phase: 2
Protocol originator
Name: 
Department: ClinOps 1, Insulin, GH & Devices
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol
CONFIDENTIAL
Date:
07 May 2015
Novo Nordisk
Trial ID: NN9828-4150 
Version:
2.0
UTN: U1111-1154-7172
Status:
Final
EudraCT no.: 2014-001215-39
Page:
2 of 141
Table of Contents
Page
Table of Contents..............................................................................................................................................2
Table of Figures................................................................................................................................................7
Table of Tables..................................................................................................................................................7
List of abbreviations.........................................................................................................................................8
1
Summary..................................................................................................................................................12
2
Flow chart ................................................................................................................................................16
3
Background information and rationale for the trial............................................................................26
3.1
Background information..............................................................................................................26
3.2
Rationale for the trial...................................................................................................................28
4
Objectives and endpoints........................................................................................................................30
4.1
Objectives ....................................................................................................................................30
4.2
Endpoints .....................................................................................................................................31
4.2.1
Primary endpoint........................................................................................................31
4.2.2
Supportive secondary endpoints ................................................................................31
4.2.2.1
Supportive secondary efficacy endpoints............................................31
4.2.2.2
Supportive secondary safety endpoints...............................................32
4.2.2.3
Supportive secondary biomarker endpoints ........................................33
4.2.2.4
Supportive secondary pharmacokinetic endpoints..............................33
5
Trial design ..............................................................................................................................................34
5.1
Type of trial .................................................................................................................................34
5.2
Rationale for trial design..............................................................................................................34
5.3
Treatment of subjects...................................................................................................................35
5.3.1
NNC0114-0006..........................................................................................................36
5.3.2
Liraglutide..................................................................................................................36
5.3.3
Insulin treatment ........................................................................................................37
5.3.4
Prohibited medication................................................................................................38
5.4
Treatment after discontinuation of trial product ..........................................................................39
5.5
Rationale for treatment ................................................................................................................39
6
Trial population.......................................................................................................................................40
6.1
Number of subjects......................................................................................................................40
6.2
Inclusion criteria ..........................................................................................................................40
6.3
Exclusion criteria.........................................................................................................................40
6.4
Randomisation criteria.................................................................................................................43
6.5
Temporary discontinuation of trial product .................................................................................43
6.6
Withdrawal criteria ......................................................................................................................44
6.7
Subject replacement.....................................................................................................................44
6.8
Rationale for trial population.......................................................................................................45
7
Milestones.................................................................................................................................................47
8
Methods and assessments .......................................................................................................................48
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
07 May 2015
Novo Nordisk
Trial ID: NN9828-4150 
Version:
2.0
UTN: U1111-1154-7172
Status:
Final
EudraCT no.: 2014-001215-39
Page:
3 of 141
8.1
Visit procedures...........................................................................................................................48
8.1.1
Informed consent .......................................................................................................48
8.1.2
Screening ...................................................................................................................48
8.1.3
Screening failures ......................................................................................................49
8.1.4
Re-screening/re-sampling ..........................................................................................49
8.1.5
Investigator’s assessment...........................................................................................49
8.1.6
Missed visits and unscheduled visits .........................................................................49
8.1.7
Withdrawn subjects....................................................................................................50
8.1.8
Fasting visits ..............................................................................................................50
8.2
Subject related information..........................................................................................................51
8.2.1
Concomitant illness and medical history...................................................................51
8.2.2
Concomitant medication............................................................................................51
8.2.3
Smoking status...........................................................................................................52
8.2.4
Abuse of alcohol and/or drugs...................................................................................52
8.2.5
Demography...............................................................................................................52
8.2.6
Diagnosis of diabetes.................................................................................................52
8.2.7
Diabetes treatment history .........................................................................................52
8.2.8
Family history of diabetes..........................................................................................52
8.2.9
Diabetes complications..............................................................................................52
8.3
Assessments for efficacy..............................................................................................................53
8.3.1
Mixed meal tolerance test..........................................................................................53
8.3.2
Self-measured blood glucose.....................................................................................55
8.3.3
4-point self-measured plasma glucose profiles..........................................................56
8.3.4
7-point profile ............................................................................................................56
8.3.5
Insulin doses ..............................................................................................................56
8.3.6
Carbohydrate intake per meal....................................................................................56
8.3.7
Patient reported outcomes (PROs).............................................................................57
8.4
Assessments for safety.................................................................................................................57
8.4.1
Adverse events...........................................................................................................57
8.4.2
Adverse Events requiring special forms in the eCRF................................................57
8.4.2.1
Pancreatitis ..........................................................................................58
8.4.2.2
Thyroid disease ...................................................................................58
8.4.2.3
Neoplasm.............................................................................................59
8.4.2.4
Hypersensitivity reactions...................................................................60
8.4.2.5
Injection/Infusion site reactions ..........................................................60
8.4.2.6
Hyperglycaemic episodes....................................................................61
8.4.2.7
Hypoglycaemic episodes.....................................................................63
8.4.3
Technical complaints.................................................................................................65
8.4.4
Body measurements...................................................................................................65
8.4.4.1
Height..................................................................................................65
8.4.4.2
Body weight ........................................................................................65
8.4.4.3
BMI .....................................................................................................66
8.4.5
Electrocardiogram......................................................................................................66
8.4.6
Eye examination ........................................................................................................67
8.4.7
Physical examination.................................................................................................67
8.4.8
Vital signs ..................................................................................................................68
8.5
Laboratory assessments ...............................................................................................................68
8.5.1
Laboratory assessments for efficacy..........................................................................69
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
07 May 2015
Novo Nordisk
Trial ID: NN9828-4150 
Version:
2.0
UTN: U1111-1154-7172
Status:
Final
EudraCT no.: 2014-001215-39
Page:
4 of 141
8.5.1.1
Glucose metabolism............................................................................69
8.5.1.2
Mixed meal tolerance test....................................................................69
8.5.1.3
Biomarkers ..........................................................................................69
8.5.1.4
Vitamin D (1,25 dehydroxy-calciferol)...............................................71
8.5.2
Laboratory assessments for safety .............................................................................71
8.5.2.1
Pregnancy test .....................................................................................71
8.5.2.2
Anti-drug antibodies............................................................................71
8.5.2.3
Total IgE..............................................................................................73
8.5.2.4
Biochemistry .......................................................................................73
8.5.2.5
Coagulation parameters.......................................................................74
8.5.2.6
Haematology .......................................................................................74
8.5.2.7
Cytokines.............................................................................................74
8.5.2.8
Urine dipstick......................................................................................74
8.5.2.9
Virus screen for hepatitis B and C.......................................................75
8.5.2.10
Tuberculosis screening test .................................................................75
8.5.2.11
Virus screen for Epstein-Barr virus.....................................................75
8.5.2.12
Virus screen for cytomegalovirus infection ........................................75
8.5.2.13
HIV......................................................................................................76
8.5.2.14
Hormones ............................................................................................76
8.5.2.15
Lipids...................................................................................................76
8.5.3
Other laboratory assessments.....................................................................................76
8.5.3.1
Genotype (optional).............................................................................76
8.5.3.2
Blood samples for long term retention (optional) ...............................76
8.5.3.3
Serum concentration of NNC0114-0006 for pharmacokinetics..........77
8.5.3.4
Plasma concentration of liraglutide for pharmacokinetics..................77
8.6
Other assessments........................................................................................................................78
8.6.1
Trial product administration NNC0114-0006............................................................78
8.6.2
Liraglutide/liraglutide placebo...................................................................................78
8.6.3
Subject e-diaries.........................................................................................................78
8.7
Subject compliance......................................................................................................................78
9
Trial supplies ...........................................................................................................................................80
9.1
Trial products...............................................................................................................................80
9.2
Labelling......................................................................................................................................81
9.3
Storage .........................................................................................................................................82
9.4
Drug accountability and destruction............................................................................................83
9.5
Auxiliary supplies and other deliveries........................................................................................83
10 Interactive voice/web response system ..................................................................................................84
11 Randomisation procedure and breaking of blinded codes..................................................................85
11.1
Breaking of blinded codes ...........................................................................................................85
12 Adverse events, and technical complaints and pregnancies................................................................86
12.1
Definitions ...................................................................................................................................86
12.2
Reporting of adverse events.........................................................................................................90
12.3
Follow-up of adverse events........................................................................................................93
12.4
Technical complaints and technical complaint samples ..............................................................94
12.4.1
Reporting of technical complaints .............................................................................94
12.4.2
Collection, storage and shipment of technical complaint samples ............................94
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
07 May 2015
Novo Nordisk
Trial ID: NN9828-4150 
Version:
2.0
UTN: U1111-1154-7172
Status:
Final
EudraCT no.: 2014-001215-39
Page:
5 of 141
12.5
Pregnancies..................................................................................................................................95
12.5.1
Pregnancies in female subjects ..................................................................................95
12.5.2
Pregnancies in female partners of male subjects .......................................................96
12.6
Precautions and/or overdose ........................................................................................................97
12.6.1
NNC0114-0006..........................................................................................................97
12.6.2
Liraglutide..................................................................................................................98
12.7
Committees related to safety........................................................................................................98
12.7.1
Novo Nordisk safety committee ................................................................................98
13 Case report forms....................................................................................................................................99
13.1
Corrections to case report forms..................................................................................................99
13.2
Case report form flow................................................................................................................100
13.3
E-diaries.....................................................................................................................................100
14 Monitoring procedures .........................................................................................................................101
14.1
Source data verification .............................................................................................................101
14.2
Titration Surveillance ................................................................................................................102
15 Data management..................................................................................................................................103
16 Computerised systems...........................................................................................................................104
17 Statistical considerations ......................................................................................................................105
17.1
Sample size calculation..............................................................................................................106
17.2
Definition of analysis sets..........................................................................................................107
17.3
Primary endpoint........................................................................................................................108
17.4
Secondary endpoints..................................................................................................................110
17.4.1
Supportive secondary endpoints ..............................................................................110
17.4.1.1
Efficacy endpoints.............................................................................110
17.4.1.2
Safety endpoints................................................................................113
17.4.1.3
Pharmacokinetic endpoints................................................................118
17.5
Interim analysis..........................................................................................................................120
17.6
Pharmacokinetic and/or pharmacodynamic modelling..............................................................120
17.7
Health economics and/or patient reported outcomes.................................................................121
18 Ethics......................................................................................................................................................122
18.1
Benefit-risk assessment of the trial............................................................................................122
18.2
Informed consent .......................................................................................................................124
18.3
Data handling.............................................................................................................................125
18.4
Information to subject during trial.............................................................................................125
18.5
Premature termination of the trial and/or trial site.....................................................................125
19 Protocol compliance..............................................................................................................................126
20 Audits and inspections ..........................................................................................................................127
21 Critical documents ................................................................................................................................128
22 Responsibilities......................................................................................................................................130
23 Reports and publications......................................................................................................................131
23.1
Communication of results..........................................................................................................131
23.1.1
Authorship ...............................................................................................................132
23.1.2
Site-specific publication(s) by investigator(s) .........................................................132
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
07 May 2015
Novo Nordisk
Trial ID: NN9828-4150 
Version:
2.0
UTN: U1111-1154-7172
Status:
Final
EudraCT no.: 2014-001215-39
Page:
6 of 141
23.2
Investigator access to data and review of results.......................................................................133
24 Retention of clinical trial documentation and human biospecimens................................................134
24.1
Retention of clinical trial documentation...................................................................................134
24.2
Retention of biospecimens.........................................................................................................134
25 Institutional Review Boards/Independent Ethics Committees and regulatory authorities............136
26 Indemnity statement .............................................................................................................................137
27 References..............................................................................................................................................138
Attachment I – Global list of key staff and relevant departments and suppliers
Attachment II – Country list of key staff and relevant departments
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
07 May 2015
Novo Nordisk
Trial ID: NN9828-4150 
Version:
2.0
UTN: U1111-1154-7172
Status:
Final
EudraCT no.: 2014-001215-39
Page:
7 of 141
Table of Figures
Page
Figure 5–1
Trial design.............................................................................................................................34
Figure 12–1
Initial reporting of AEs...........................................................................................................92
Figure 17–1
Novo Nordisk classification of hypoglycaemia...................................................................115
Figure 17–2
ADA classification of hypoglycaemia..................................................................................116
Table of Tables
Page
Table 5–1
Treatment arms.......................................................................................................................35
Table 5–2
Pre-meal SMPGs ....................................................................................................................38
Table 17–1
Power calculations................................................................................................................107
Table 17–2
Model terms for the statistical model for the primary endpoint ...........................................109
Table 17–3
Definition and calculation of PK endpoints..........................................................................119
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
07 May 2015
Novo Nordisk
Trial ID: NN9828-4150 
Version:
2.0
UTN: U1111-1154-7172
Status:
Final
EudraCT no.: 2014-001215-39
Page:
8 of 141
List of abbreviations
ADA
American Diabetes Association
AE
adverse event
ALAT
alanine aminotransferase
ASAT
aspartate aminotransferase
AUC
area under the curve
BG
blood glucose
CHO
carbohydrate
CI
confidence interval
CKD-EPI
Chronic Kidney Disease Epidemiology 
Collaboration
CLAE
clinical laboratory adverse event
Cmax
maximum concentration
CMV
cytomegalovirus
CPOP
clinical proof of principle
CRF
case report form
CT
calcitonin
CTR
clinical trial report
DAS
Disease Activity Score
DFU
direction for use 
DKA
diabetic ketoacidosis 
DTSQ
Diabetes Treatment Satisfaction Questionnaire 
DUN
dispensing unit number
EBV
Epstein-Barr virus 
ECG
electrocardiogram
eCRF
electronic case report form
eGFR
estimated glomerular filtration rate
ELISA
enzyme-linked immunosorbent assay 
EMA
European Medicines Agency
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
07 May 2015
Novo Nordisk
Trial ID: NN9828-4150 
Version:
2.0
UTN: U1111-1154-7172
Status:
Final
EudraCT no.: 2014-001215-39
Page:
9 of 141
FAS
full analysis set
FDA
U.S. Food and Drug Administration
FPFV
first patient first visit
FPG
fasting plasma glucose
GAD
glutamic acid decarboxylase
GCP
Good Clinical Practice
GLP-1
glucagon-like peptide-1
HbA1c
glycosylated haemoglobin
HBcAb
hepatitis B core antibody 
HBsAg
hepatitis B surface antigen 
HBsAb
Hepatitis B surface antibody 
HIV
human immunodeficiency virus 
HLA
human leucocyte antigen
IA2
islet antigen-2 
IAA
insulin autoantibodies
ICMJE 
International Committee of Medical Journal Editors
IgG
immunoglobulin G1 
IB
Investigator’s Brochure
ICH GCP
International Conference on Harmonisation Good 
Clinical Practice
IEC
independent ethics committee
IMP
investigational medicinal product
IRB
institutional review board
i.v.
intravenous(ly) 
IV/WRS
interactive voice/web response system
LADA
latent autoimmune diabetes of adults 
LPFV
last patient first visit
LPLV
last patient last visit
LSMeans
least square mean
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
07 May 2015
Novo Nordisk
Trial ID: NN9828-4150 
Version:
2.0
UTN: U1111-1154-7172
Status:
Final
EudraCT no.: 2014-001215-39
Page:
10 of 141
mAb
monoclonal antibody 
MAO
monoamine oxidase
MEN2
Multiple Endocrine Neoplasia Type 2
MESI
medical event of special interest
MMRM
mixed model for repeated measurements 
MMTT
mixed meal tolerance test 
MRT
mean residence time
NK
natural killer
NOD
non-obese-diabetic 
NPH
neutral protamine Hagedorn
NYHA
New York Heart Association
PBMCs
periphery blood mononuclear cells
PG
plasma glucose
PPG
postprandial glucose
RIP-LCMV-GP 
Rat-Insulin-Promoter-Lymphocytic-
Choriomeningitis-Glyco-Protein
PK
pharmacokinetic
PRO
patient reported outcome
RA
rheumatoid arthritis 
SAE
serious adverse event
SAP
statistical analysis plan
s.c.
subcutaneous(ly)
SD
standard deviation 
SF-36v2
Short Form Health Survey version 2 
SLE
systemic lupus erythematosus 
SMBG
self-measured blood glucose
SMPG
self-measured plasma glucose
SS
steady state
SUSAR
suspected unexpected serious adverse reaction
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
07 May 2015
Novo Nordisk
Trial ID: NN9828-4150 
Version:
2.0
UTN: U1111-1154-7172
Status:
Final
EudraCT no.: 2014-001215-39
Page:
11 of 141
TB
tuberculosis
T1DM
type 1 diabetes mellitus
T2DM
type 2 diabetes mellitus
TMM
Trial Materials Manual
Treg
regulatory T-cells 
TSH
Thyroid-stimulating hormone 
T-T-T
treat-to-target 
ZnT8
zinc-transporter 8 
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
07 May 2015
Novo Nordisk
Trial ID: NN9828-4150 
Version:
2.0
UTN: U1111-1154-7172
Status:
Final
EudraCT no.: 2014-001215-39
Page:
12 of 141
1
Summary
Objective(s) and endpoint(s):
Primary objective
The primary objective is to evaluate the effect of NNC0114-0006, liraglutide and the combination 
of NNC0114 0006 and liraglutide, compared to placebo, on preservation of beta-cell function  after
54 weeks of treatment in adult subjects with newly diagnosed type 1 diabetes mellitus (T1DM)
Secondary objectives
!
Objectives related to treatment period (from baseline to week 54):
!
To assess safety and tolerability of NNC0114-0006 and liraglutide in combination 
and alone in subjects with newly diagnosed T1DM 
!
To assess effect on glycaemic parameters (including insulin usage and insulin 
regimen) of NNC0114-0006 and liraglutide in combination and alone in subjects 
with newly diagnosed T1DM 
!
Objectives related to the post-treatment observation period (from week 54 to week 80):
!
To assess post-treatment safety and tolerability of NNC0114-0006 and liraglutide in 
combination and alone in subjects with newly diagnosed T1DM
!
To assess post-treatment effect on preservation of beta-cell function of 
NNC0114-0006 and liraglutide in combination and alone in subjects with newly 
diagnosed T1DM 
!
To assess post-treatment effect on glycaemic parameters (including insulin usage and 
insulin regimen) of NNC0114-0006 and liraglutide in combination and alone in 
subjects with newly diagnosed T1DM 
Primary endpoint
The primary endpoint is AUC0-4h for a mixed meal tolerance test (MMTT) stimulated C-peptide 
concentration-time curve at week 54 relative to baseline (defined as the MMTT performed at Visit 
2).
!
AUC0-4h, C-peptide, 54w/AUC0-4h, C-peptide, baseline
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
07 May 2015
Novo Nordisk
Trial ID: NN9828-4150 
Version:
2.0
UTN: U1111-1154-7172
Status:
Final
EudraCT no.: 2014-001215-39
Page:
13 of 141
Key secondary endpoints
!
Number of treatment emergent episodes of diabetic ketoacidosis (DKA) from first dose of 
trial product to week 54
!
Number of treatment emergent hypoglycaemic episodes according to the American Diabetes 
Association (ADA) and Novo Nordisk definitions from first dose of trial product to week 54
!
AUC0-4h for MMTT stimulated C-peptide concentration time curve at week 80 relative to 
baseline
!
AUC0-2h for MMTT stimulated C-peptide concentration time curve at week 54 and week 80
relative to baseline
!
Maximum MMTT stimulated C-peptide concentration (Cmax, C-peptide) at week 54 and week 
80 relative to baseline
!
Change in fasting C-peptide from baseline to week 54 and week 80
!
Change in HbA1c from baseline to week 54 and week 80
!
Change in fasting plasma glucose from baseline to week 54 and week 80
!
Total daily insulin dose in units per kg (three day average) at week 54 and week 80
Trial design:
The trial is a randomised, multi-centre, multinational, placebo-controlled, double-dummy, double-
blind, efficacy, safety and pharmacokinetic clinical proof of principle (CPOP) trial in subjects with 
newly diagnosed T1DM. The trial includes four parallel treatment groups, one with NNC0114-0006 
12 mg/kg intravenously every 6 week and liraglutide 1.8 mg subcutaneously daily, one with 
NNC0114-0006 12 mg/kg intravenously every 6 week, one with liraglutide 1.8 mg subcutaneously 
daily, and, one placebo arm randomised in a even ratio. The liraglutide dose may be reduced to 1.2 
mg, if 1.8 mg is not tolerated. Subjects will continue their pre-trial insulin treatment.
The randomisation will be stratified according to the non-fasting C-peptide value at screening. The 
stratification factor has two levels according to C-peptide value: ≥0.2 nmol/l to ≤0.6 nmol/l and 
>0.6 nmol/l. 
The exposure period for NNC0114-0006 and liraglutide in combination or alone is 54 weeks 
followed by a 26 weeks observation period. All groups will receive insulin treatment according to a 
treat-to-target regimen throughout the entire trial. 
Trial population:
304 adult subjects with newly diagnosed T1DM are required according to the sample size 
calculation. A maximum number of 314 subjects will be randomised.
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
07 May 2015
Novo Nordisk
Trial ID: NN9828-4150 
Version:
2.0
UTN: U1111-1154-7172
Status:
Final
EudraCT no.: 2014-001215-39
Page:
14 of 141
Key inclusion criteria:
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. T1DM (as diagnosed clinically*) ≤ 12 weeks prior to randomisation 
3. Male or female, aged 18-45 (both inclusive) at the time of signing the informed consent 
form
4. Non-fasting C-peptide ≥0.2 nmol/l
5. BMI ≥18.5 kg/m2
6. Presence of one or more islet specific auto antibodies (glutamic acid decarboxylase (GAD), 
islet antigen-2 (IA2) or zinc-transporter 8 (ZnT8)) at screening
7. Insulin dependence unless in temporary spontaneous remission (honeymoon period).
*The clinical diagnosis of T1DM is defined as by the following two paragraphs:
1. One or more of the following:
!
HbA1c ≥ 6.5% or 
!
fasting plasma glucose ≥ 7.0 mmol/l (126 mg/dl) or
!
a 2 hour plasma glucose ≥ 11.1 mmol/l (200 mg/dl) during an oral glucose tolerance test 
with a glucose load of 75 grams anhydrous glucose in water or 
!
classical symptoms of hyperglycaemia and a random plasma glucose ≥ 11.1 mmol/l (200 
mg/dl)1
In the absence of unequivocal hyperglycaemia, results should be confirmed by repeat 
testing.
2. In order to:
!
ensure that the aetiology is autoimmune, the clinical diagnosis needs to be confirmed by the 
presence of islet-specific auto-antibodies
!
exclude type 2 diabetes mellitus (T2DM) and latent autoimmune diabetes of adults (LADA)
the subjects should be without severe insulin resistance (i.e. total daily insulin dose larger 
than 1 U/kg per day at screening).
Key exclusion criteria:
1. Daily insulin usage > 1 U/kg per day at screening or use of continuous subcutaneous insulin 
infusion (CSII) 
2. History of recurrent (e.g. several times a year) of severe (e.g. pneumonia) or chronic 
infections or conditions predisposing to chronic infections (e.g., bronchiectasis and chronic 
osteomyelitis)
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
07 May 2015
Novo Nordisk
Trial ID: NN9828-4150 
Version:
2.0
UTN: U1111-1154-7172
Status:
Final
EudraCT no.: 2014-001215-39
Page:
15 of 141
3. History of severe systemic fungal infection within the past 12 months prior to screening 
unless treated and resolved with appropriate documented therapy 
4. Vaccination within 4 weeks before randomisation, Visit 3 (V3)
5. Receipt of any other concomitant medications or herbal products that can influence the 
immune system within 90 days prior to screening (V1)
6. History of pancreatitis (acute or chronic)
7. Family or personal history of Multiple Endocrine Neoplasia Type 2 (MEN2) or Medullary 
Thyroid Carcinoma (MTC)
8. Any past or current diagnosis of malignant neoplasms 
9. Known impairment of the immune system, except for T1DM
Assessments:
The primary efficacy assessment is MMTT stimulated C-peptide concentration at week 54.
The secondary efficacy assessments are HbA1c, and other glycaemic parameters (fasting plasma 
glucose, 4- and 7-point profiles) after 54 weeks of treatment and at week 80.
The key safety parameters include physical examination, adverse events, hypoglycaemia and 
hyperglycaemia episodes, blood pressure, pulse, electrocardiogram, biochemistry (including 
amylase and lipase), calcitonin, urine dipsticks, haematology and antibodies against NNC0114-
0006 and liraglutide.
Trial product(s):
The following trial products will be provided:
!
NNC0114-0006 C 100 mg/ml, in a 3.0 ml cartridge for i.v. infusion
!
NNC0114-0006 C 0 mg/ml, in a 3.0 ml cartridge for i.v. infusion
!
Liraglutide 6.0 mg/ml, in a 3 ml pre-filled injector for s.c. injection
!
Liraglutide placebo, in a 3 ml pre-filled injector for s.c. injection
NNC0114-0006 C 100 mg/ml or NNC0114-0006 C 0 mg/ml will be administered i.v. according to 
instructions. 
CONFIDENTIAL


Protocol
UTN: U1111-1154-7172
Date:
07 May 2015
Status:
Final
Novo Nordisk
Trial ID: NN9828-4150 
EudraCT no.: 2014-001215-39
Version:
2.0
Page:
16 of 141
2
Flow chart
Visit 1 to 37 procedures
Trial periods
S
R
Treatment
Visit type:
C: Clinic, P: Phone contact
C
C
C
C
C
C
C
P
P
C
P
P
C
P
C
P
C
P
C
P
C
P
C
P
C
P
C
P
C
Visit number
1
2
3
4
5
6
7
8
9
10
11
12
13
14,15
16
17,18
19
20-22
23
24
25
26-28
29
30
31
32-34
35
36
37
Timing of visit (weeks (W), or days 
(D) if specified)
-D28 to 
–D14
D-10 
0
1D
3D
W1
W2
W2 + 
1D
3
4
W4 + 
1D
W5
W6
W7,8
W9
W10,11
W12
W13-15
W16
W17
W18
W19-21
W22
W23
W24
W25-27
W28
W29
W30
Visit window (days)
±
4
±
1
±
1
±
1
±
1
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
SUBJECT RELATED
INFO/ASSESSMENTS
Informed consent
x
Genotyping consent, optional
x
Long term retention consent, optional
x
In/exclusion criteria
x
x
x
Randomisation
x
Randomisation criteria
x
Withdrawal criteria
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Dosing day exclusion criteria1
x
x
x
x
x
x
Abuse of alcohol
x
Abuse of drugs
x
Medical history
x
Concomitant illness
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
x
x
x
x
x
x
x
Demography
x


Protocol
UTN: U1111-1154-7172
Date:
07 May 2015
Status:
Final
Novo Nordisk
Trial ID: NN9828-4150 
EudraCT no.: 2014-001215-39
Version:
2.0
Page:
17 of 141
Trial periods
S
R
Treatment
Visit type:
C: Clinic, P: Phone contact
C
C
C
C
C
C
C
P
P
C
P
P
C
P
C
P
C
P
C
P
C
P
C
P
C
P
C
P
C
Visit number
1
2
3
4
5
6
7
8
9
10
11
12
13
14,15
16
17,18
19
20-22
23
24
25
26-28
29
30
31
32-34
35
36
37
Timing of visit (weeks (W), or days 
(D) if specified)
-D28 to 
–D14
D-10 
0
1D
3D
W1
W2
W2 + 
1D
3
4
W4 + 
1D
W5
W6
W7,8
W9
W10,11
W12
W13-15
W16
W17
W18
W19-21
W22
W23
W24
W25-27
W28
W29
W30
Visit window (days)
±
4
±
1
±
1
±
1
±
1
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
Diagnosis of diabetes
x
Diabetes treatment history
x
Pregnancy test2
x
Smoking habits
x
Family history of diabetes
x
Diabetes complications
x
Blood sample for genotyping 
(optional)
x
EFFICACY
Glucose metabolism
x
x
x
x
x
x
x
Meal test3
x
x
x
Self-measured plasma glucose:
7-point profile prior to visit
x
x
x
x
x
x
x
x
x
x
x
x
4-point profile prior to visit4
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
PRO questionnaires
x
x
Biomarkers:
Differential methylated INS DNA
x
x
x
x
Antibodies (autoantibodies)
x
x
x
x
x
Immunology
x
x
x
x
x
Vitamin D (1,25 dehydroxy-
x
x
x
x


Protocol
UTN: U1111-1154-7172
Date:
07 May 2015
Status:
Final
Novo Nordisk
Trial ID: NN9828-4150 
EudraCT no.: 2014-001215-39
Version:
2.0
Page:
18 of 141
Trial periods
S
R
Treatment
Visit type:
C: Clinic, P: Phone contact
C
C
C
C
C
C
C
P
P
C
P
P
C
P
C
P
C
P
C
P
C
P
C
P
C
P
C
P
C
Visit number
1
2
3
4
5
6
7
8
9
10
11
12
13
14,15
16
17,18
19
20-22
23
24
25
26-28
29
30
31
32-34
35
36
37
Timing of visit (weeks (W), or days 
(D) if specified)
-D28 to 
–D14
D-10 
0
1D
3D
W1
W2
W2 + 
1D
3
4
W4 + 
1D
W5
W6
W7,8
W9
W10,11
W12
W13-15
W16
W17
W18
W19-21
W22
W23
W24
W25-27
W28
W29
W30
Visit window (days)
±
4
±
1
±
1
±
1
±
1
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
calciferol
Dose of insulin administrations
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Carbohydrate intake
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
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
x
x
x
Hyperglycaemic episodes
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
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
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
x
x
x
x
x
x
x
Body measurements5
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
ECG
x6
x
x
x
x
x
Eye examination
x7
Physical examination
x
x
x
x
x
x
x
Vital signs
x
x
x
x
x
x
x
x
x
x
x
x
Antibodies:
Anti-NNC0114-0006 antibodies
x
x
x
Anti-liraglutide antibodies
x
x
x
IgE
x
x
x
x
x
Biochemistry
x
x
x
x
x
x
Coagulation parameters
x
x
x
x
x
x
Haematology
x
x
x
x
x
x


Protocol
UTN: U1111-1154-7172
Date:
07 May 2015
Status:
Final
Novo Nordisk
Trial ID: NN9828-4150 
EudraCT no.: 2014-001215-39
Version:
2.0
Page:
19 of 141
Trial periods
S
R
Treatment
Visit type:
C: Clinic, P: Phone contact
C
C
C
C
C
C
C
P
P
C
P
P
C
P
C
P
C
P
C
P
C
P
C
P
C
P
C
P
C
Visit number
1
2
3
4
5
6
7
8
9
10
11
12
13
14,15
16
17,18
19
20-22
23
24
25
26-28
29
30
31
32-34
35
36
37
Timing of visit (weeks (W), or days 
(D) if specified)
-D28 to 
–D14
D-10 
0
1D
3D
W1
W2
W2 + 
1D
3
4
W4 + 
1D
W5
W6
W7,8
W9
W10,11
W12
W13-15
W16
W17
W18
W19-21
W22
W23
W24
W25-27
W28
W29
W30
Visit window (days)
±
4
±
1
±
1
±
1
±
1
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
Cytokines
x
x
x
x
Urine dipsticks 
x
x
x
x
x
x
Hepatitis B
x
x
x
x
x
x
Hepatitis C
x
Tuberculosis screening test 
(QuantiFERON)
x
Epstein–Barr virus
x
x
x
x
x
x
CMV8
x
x
x
x
x
x
HIV
x
Hormones
x
x
x
Lipids
x
x
x
OTHER ASSESSMENTS
PK sampling
NNC0114-0006
x9
x
x
x
x
x
x
x
x
x
x
x
PK sampling
Liraglutide10
x
x
x
x
x
x
x
x
x
x
x
x
TRIAL MATERIAL
IV/IWRS
x
x
x
x
x
x
x
Administration and dispensing of 
trial product 
NNC0114-0006/placebo
x
x
x
x
x
x
Dispensing of liraglutide/placebo11
x
x
x
x
x
x


Protocol
UTN: U1111-1154-7172
Date:
07 May 2015
Status:
Final
Novo Nordisk
Trial ID: NN9828-4150 
EudraCT no.: 2014-001215-39
Version:
2.0
Page:
20 of 141
Trial periods
S
R
Treatment
Visit type:
C: Clinic, P: Phone contact
C
C
C
C
C
C
C
P
P
C
P
P
C
P
C
P
C
P
C
P
C
P
C
P
C
P
C
P
C
Visit number
1
2
3
4
5
6
7
8
9
10
11
12
13
14,15
16
17,18
19
20-22
23
24
25
26-28
29
30
31
32-34
35
36
37
Timing of visit (weeks (W), or days 
(D) if specified)
-D28 to 
–D14
D-10 
0
1D
3D
W1
W2
W2 + 
1D
3
4
W4 + 
1D
W5
W6
W7,8
W9
W10,11
W12
W13-15
W16
W17
W18
W19-21
W22
W23
W24
W25-27
W28
W29
W30
Visit window (days)
±
4
±
1
±
1
±
1
±
1
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
Drug accountability for IMP12
x
x
x
x
x
x
REMINDERS
Handout ID cards
x
Handout direction for use13
x
Handout and instruct in e-diary
x
Investigator review of e-diary
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Handout and instruct in BG meter
use
x
Attend fasting visit
x
x
x
x
x
x
x
Blood sample for long term 
retention (optional)
x
x
1. Only for NNC0114-0006
2. For woman of childbearing potential only. Blood sample at V1. For all subsequent visits a urine stick must only be measured for females of childbearing potential if a 
menstrual period is missed or as required by law. Austria: Urine-stick pregnancy test will be performed at all visits to the clinic
3. The MMTT may be re-scheduled twice within 10 days
4. 4-point profile will be used for T-T-T  
5. At V1 height and weight will be measured and BMI will be calculated via the eCRF. At the following visits only weight must be measured
6. A baseline ECG performed for any reason unrelated to the trial within 30 days prior to V1 is acceptable provided no clinical symptoms suggestive of cardiac disease 
have occurred in the meantime
7. A baseline fundoscopy/ fundus photography performed for any reason unrelated to the trial within 90 days prior to V3 is acceptable
8. Cytomegalovirus


Protocol
UTN: U1111-1154-7172
Date:
07 May 2015
Status:
Final
Novo Nordisk
Trial ID: NN9828-4150 
EudraCT no.: 2014-001215-39
Version:
2.0
Page:
21 of 141
9. PK sample for NNC0114-0006 (pre-dose and 1 hour sample after start of infusion)
10. PK sample at any time during the visit
11. Liraglutide/liraglutide placebo will be administered once daily
12. Investigational medicinal product
13. Injection of liraglutide will be trained at V3 and at following visits as needed.


Protocol
UTN: U1111-1154-7172
Date:
07 May 2015
Status:
Final
Novo Nordisk
Trial ID: NN9828-4150 
EudraCT no.: 2014-001215-39
Version:
2.0
Page:
22 of 141
Visit 38 to 90 procedures
Trial period
Treatment
Follow-up
Visit type:
C: Clinic, P: Phone contact
P
C
P
C
P
C
P
C
P
C
P
C
C
C
C
P
C
P
C
P
C
P
C
P
C
P
C
C
Visit number
38-40
41
42
43
44-46
47
48
49
50-52
53
54
55
56
57
58,59
60
61
62
63
64-68
69
70-73
74
75-77
78
79-88
89
901
Timing of visit 
(weeks (w), or days (D) if specified)                      
W31-33
W34
W35
W36
W37-39
W40
W41
W42
W43-45
W46
W47
W48
W48 + 
1D
W48 + 
3D
W49, 50
W51
W52
W53
W54
W55-59
W60
W61-64
W65
W66-68
W69
W70-79
W80
Visit window (days)
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
7
SUBJECT RELATED
INFO/ASSESSMENTS
Withdrawal criteria
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
Dosing day exclusion criteria2
x
x
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
x
x
x
x
x
x
Pregnancy test3
x
Diabetes complications
x
x
EFFICACY
Glucose metabolism
x
x
x
x
x
x
x
x
Meal test4
x
x
x
x
Self measured plasma glucose:
7-point profile prior to visit
x
x
x
x
x
x
x
x
4-point profile prior to visit5
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
PRO questionnaires
x
x
Biomarkers:
Differential methylated INS DNA
x
x
x
x
Antibodies (autoantibodies)
x
x
x
x
Immunology
x
x
x
x
Vitamin D (1,25 dehydroxy-calciferol)
x
x
x
x
Dose of insulin administrations
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Carbohydrate intake
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x


Protocol
UTN: U1111-1154-7172
Date:
07 May 2015
Status:
Final
Novo Nordisk
Trial ID: NN9828-4150 
EudraCT no.: 2014-001215-39
Version:
2.0
Page:
23 of 141
Trial period
Treatment
Follow-up
Visit type:
C: Clinic, P: Phone contact
P
C
P
C
P
C
P
C
P
C
P
C
C
C
C
P
C
P
C
P
C
P
C
P
C
P
C
C
Visit number
38-40
41
42
43
44-46
47
48
49
50-52
53
54
55
56
57
58,59
60
61
62
63
64-68
69
70-73
74
75-77
78
79-88
89
901
Timing of visit 
(weeks (w), or days (D) if specified)                      
W31-33
W34
W35
W36
W37-39
W40
W41
W42
W43-45
W46
W47
W48
W48 + 
1D
W48 + 
3D
W49, 50
W51
W52
W53
W54
W55-59
W60
W61-64
W65
W66-68
W69
W70-79
W80
Visit window (days)
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
7
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
x
x
Hyperglycaemic episodes
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
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
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
Body measurements
x
x
x
x
x
x
x
x
x
x
x
x
x
x
ECG
x
x
x
x
x
x
Eye examination6
x
x
Physical examination
x
x
x
x
x
x
Vital signs
x
x
x
x
x
x
x
x
x
Antibodies:
Anti-NNC0114-0006 antibodies
x
x
x
x
Anti-liraglutide antibodies
x
x
x
x
x
IgE
x
x
x
x
x
x
x
Biochemistry
x
x
x
x
x
x
Coagulation parameters
x
x
x
x
x
x
Haematology
x
x
x
x
x
x
Cytokines
x
x
x
x
x
x
Urine dipsticks 
x
x
x
x
x
x
Hepatitis B 
x
x
x
x
EBV
x
x
x
x
CMV
x
x
x
x


Protocol
UTN: U1111-1154-7172
Date:
07 May 2015
Status:
Final
Novo Nordisk
Trial ID: NN9828-4150 
EudraCT no.: 2014-001215-39
Version:
2.0
Page:
24 of 141
Trial period
Treatment
Follow-up
Visit type:
C: Clinic, P: Phone contact
P
C
P
C
P
C
P
C
P
C
P
C
C
C
C
P
C
P
C
P
C
P
C
P
C
P
C
C
Visit number
38-40
41
42
43
44-46
47
48
49
50-52
53
54
55
56
57
58,59
60
61
62
63
64-68
69
70-73
74
75-77
78
79-88
89
901
Timing of visit 
(weeks (w), or days (D) if specified)                      
W31-33
W34
W35
W36
W37-39
W40
W41
W42
W43-45
W46
W47
W48
W48 + 
1D
W48 + 
3D
W49, 50
W51
W52
W53
W54
W55-59
W60
W61-64
W65
W66-68
W69
W70-79
W80
Visit window (days)
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
7
Hormones
x
x
x
x
x
x
Lipids
x
x
x
x
x
x
OTHER ASSESSMENTS
PK sampling NNC0114-0006
x
x
x
7
x
x
x
x
x
x
x
x
x
x
PK sampling Liraglutide
x
x
x
x
x
x
x
x
TRIAL MATERIAL
IV/IWRS
x
x
x
x
x
Administration and dispensing of  trial 
product NNC0114-0006/placebo
x
x
x
Dispensing of liraglutide/placebo
x
x
x
Drug accountability for IMP
x
x
x
x
REMINDERS
Investigator review of e-diary
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Attend fasting visit
x
x
x
x
x
x
x
x
x
Blood sampling for long term retention
(optional)
x
x
End of dosing
x
8
x
9
Collection of e-diary
x
x
Collection of BG meter
x
x
End of trial
x
x
Sign off Casebook
x
x


Protocol
UTN: U1111-1154-7172
Date:
07 May 2015
Status:
Final
Novo Nordisk
Trial ID: NN9828-4150 
EudraCT no.: 2014-001215-39
Version:
2.0
Page:
25 of 141
1. Safety follow-up visit. To be conducted for subjects who have been withdrawn less than 14 weeks after last dose of NNC0114-0006/placebo. The visit should be 
conducted 15 weeks ± 1 week after last dose of NNC0114-0006/placebo
2. Only for NNC0014-0006
3. Blood sample at V63. A urine stick pregnancy test must be performed throughout the trial for females of childbearing potential if a menstrual period is missed or as 
required by local law. Austria: Urine-stick pregnancy test will be performed at all visits to the clinic
4. The MMTT may be re-scheduled twice within 10 days
5. 4-point profile will be used for T-T-T  
6. A fundoscopy/ fundus photography may be performed up to 2 weeks before or after V63 and up to 2 weeks before V89
7. PK sample for NNC0114-0006 (pre-dose and 1 hour sample after start of infusion)
8. Last dosing of NNC0114-0006/placebo
9. Last dosing of liraglutide/liraglutide placebo is the day prior to V63


Protocol
CONFIDENTIAL
Date:
07 May 2015
Novo Nordisk
Trial ID: NN9828-4150 
Version:
2.0
UTN: U1111-1154-7172
Status:
Final
EudraCT no.: 2014-001215-39
Page:
26 of 141
3
Background information and rationale for the trial
The trial will be conducted in compliance with this protocol, ICH GCP 2 and applicable regulatory 
requirements, and in accordance with the Declaration of Helsinki 3. 
In this document, the term investigator refers to the individual responsible for the overall conduct of 
the clinical trial at a trial site.
3.1
Background information
Type 1 diabetes mellitus
Type 1 diabetes mellitus (T1DM) is a disorder that arises following the selective autoimmune 
destruction of the insulin-producing beta-cells 4. A cure for T1DM would aim at ensuring that the 
necessary endogenous functional beta-cell mass required for adequate insulin production is 
preserved or increased. As the beta-cell destruction is immune-mediated in most cases, many efforts 
to stop or modify this destruction have focused on immunomodulatory, antigen-specific or anti-
inflammatory interventions. Genetically susceptible individuals can, following a putative 
environmental trigger, seroconvert and develop islet autoantibodies before the clinical diagnosis of 
T1DM. It is assumed, but never formally proven, that the beta-cell mass continuously decreases in 
an otherwise silent fashion before diagnosis. In single autoantibody-positive individuals there is no 
evidence of histopathological abnormalities (insulitis); only individuals with multiple 
autoantibodies have been shown to correspond with on-going insulitis and the multiple 
autoantibodies are a strong indicators of future progression toward clinical T1DM 4. At clinical 
diagnosis, most patients still harbour functional beta-cell mass as evidenced by their C-peptide level
4. It is hypothesised that a relatively modest recovery and/or preservation of beta-cell mass could re-
establish a pre-diagnosis ‘silent’ state.
NNC0114-0006
Interleukin-21(IL-21) is a multifunctional cytokine that plays a role in activation and differentiation 
of the immune system cells such as T-cells, B-cells, natural killer (NK) cells and some cell types of 
the myeloid lineage (macrophages and dendritic cells) 5,6. IL-21 is a secreted autocrine factor from 
T helper 17 (TH17) cells 5-7 and follicular TH cells 8, with function on both induction and persistence 
of these cells. Furthermore, IL-21 inhibits the generation of the regulatory T-cells (Treg). IL-21 is 
also essential for optimal B-cell proliferation, differentiation and antibody production 9.
The anti-IL-21 monoclonal antibody (mAb), NNC0114-0006 is a recombinant human mAb of the 
immunoglobulin G1 (IgG1) isotype with five amino acid substitutions to eliminate or reduce Fc-
effector functions, including activation of the classic complement pathway. NNC0114-0008 is the 
murine equivalent of NNC0114-0006. NNC0114-0006 binds to IL-21 with high affinity 
(disassociation constant, Kd = 0.19 pM), and neutralises IL-21 in cell-based assays with a half-
maximal inhibitory concentration (IC50) in the sub- or low nM range. NNC0114-0006 is not 
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
07 May 2015
Novo Nordisk
Trial ID: NN9828-4150 
Version:
2.0
UTN: U1111-1154-7172
Status:
Final
EudraCT no.: 2014-001215-39
Page:
27 of 141
expected to be engaged in antibody-dependent cellular cytotoxicity as it is not designed to target the 
cell membrane, but will bind soluble IL-21. It is hypothesised that inhibition of IL-21 in chronic 
inflammation is beneficial by restoring the balance between effector T-cells and Treg cells and also 
by inhibiting pathologic antibody production 5,6.
By binding to and neutralising IL-21, NNC0114-0006 is intended to reduce the inflammation 
mediated by IL-21. The multiple pathways affected by IL-21 suggest that NNC0114-0006 may have 
the potential to alter a wide range of chronic inflammatory conditions such as rheumatoid arthritis 
(RA), systemic lupus erythematosus (SLE), Crohn’s disease and T1DM. NNC0114-0006 has been 
administered in clinical trials to healthy subjects, subjects with RA, SLE or Crohn’s disease and no 
safety concerns have been raised. Statistically significant and clinically relevant improvements in 
Disease Activity Score (DAS) 28 (CRP) have been observed in patients with RA in the Clinical 
Proof of Principle (CPoP) trial (NN8828-3842), in which two intravenous (i.v.) doses of NNC0114-
0006 (12 mg/kg) were given 6 weeks apart. 
In accordance with the ICH M3 guideline76, reproductive and developmental studies have not been 
performed at this stage of development because developmental toxicity studies for mAbs can be 
performed in parallel with the conduct of phase 3 clinical trials. Full histopathological examination 
of both male and female reproductive organs was included in the 8 week, the 13 week and the 39-
week repeat-dose toxicity studies in cynomolgus monkeys. No treatment related effects were 
observed. Sexually mature animals were included the 39 week toxicity study.
Please refer to the current version of the NN9828 Investigator’s Brochure (IB), edition 1, 2015, and 
any updates hereof for further information about non-clinical data.
Liraglutide
Liraglutide is an analogue of the naturally occurring human hormone Glucagon-Like Peptide-1 
(GLP-1), and is suitable for once daily administration. GLP-1 is an incretin hormone secreted from 
the L-cells in the small intestine. An incretin hormone is a gut-derived peptide with important 
physiological function in augmenting post-prandial insulin secretion in response to ingestion of a 
meal. GLP-1 has a glucose dependent stimulatory effect on insulin and inhibitory effect on 
glucagon secretion from the pancreatic islets (i.e. when plasma glucose (PG) levels are above 
normal) 10. Liraglutide is the active ingredient used in the authorised product Victoza® pen-injector 
approved in more than 70 countries including EU, US, Canada, Japan and China for the treatment 
of T2DM in adults to achieve glycaemic control, in combination with metformin and/or metformin 
and sulphonylurea or a thiazolidinedione or insulin. Using the liraglutide pen-injector, the start dose 
is 0.6 mg and the dose is increased in 0.6 mg increments to a maximum of 1.8 mg. In brief, in 
healthy subjects and patients with T2DM the most prominent treatment effects of Victoza® are: 
a) glucose-dependent insulin synthesis and secretion 
b) decreased glucagon secretion in a glucose-dependent manner, 
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
07 May 2015
Novo Nordisk
Trial ID: NN9828-4150 
Version:
2.0
UTN: U1111-1154-7172
Status:
Final
EudraCT no.: 2014-001215-39
Page:
28 of 141
c) delay in gastric emptying,
d) decreased appetite and food intake.
Also, liraglutide does not seem to have an independent impact on renal clearance as assessed by 
eGFR in a clinical phase 3 setting 11.
In T1DM, the effect on glucose-dependent insulin synthesis and secretion may be limited by the 
pathophysiological nature of T1DM.
Please refer to the current version of the NN9211 IB, edition 3, 07 August 2013, and any updates 
hereof for further information about non-clinical data.
For an assessment of benefits and risks of the trial, see section 18.1.
3.2
Rationale for the trial
T1DM is caused by a chronic autoimmune response against the pancreatic beta-cells, which results 
in life-long exogenous insulin dependence. The precise aetiology of T1DM is currently unknown. 
Genetically susceptible individuals can, following a putative environmental trigger, seroconvert and 
develop islet autoantibodies. It is assumed, but has never been formally proven in man, that beta-
cell mass continuously decreases in an otherwise silent fashion before diagnosis. At clinical 
diagnosis, most patients still harbour a functional beta-cell mass as evidenced by their C-peptide 
levels and histology data from organ donors. It is hypothesized that a relatively modest recovery of 
beta-cell mass could re-establish a pre-diabetic state. Moreover, the Diabetes Control and 
Complications Trial firmly established that preservation of small amounts of endogenous insulin 
secretory capacity confers protection against long-term diabetic complications 12.
Targeting the autoimmune component of the disease in order to protect the beta-cells and preserve 
endogenous insulin secretion is a viable approach, provided that this can be done with an acceptable 
benefit/risk profile. Indeed, successful reversal to insulin independence has been achieved with 
potent immuno-suppressants such as cyclosporine or non-myeloablative stem cell therapy 13,14. 
Unfortunately, these treatments have considerable systemic side effects and therefore cannot be 
applied as a generalized intervention 15,16. Furthermore, the disease has a tendency to recur after 
treatment discontinuation. The latter is due to the accumulation of beta-cell antigen-specific 
memory T-cells, which can expand and react more efficiently, as soon as beta-cells are being 
augmented or re-introduced. Inhibition of IL-21 with NNC0114-0006 in T1DM may be beneficial 
by restoring the balance between effector T-cells and Treg cells. 
Current literature on exendin-4, a GLP-1 receptor agonist, suggest that combination with an 
immunomodulatory therapy may be a viable approach for preserving beta-cell function in T1DM 
since the combination of the two treatments appear to result in additive or synergistic effects 17-19.  
To this end, Novo Nordisk has conducted nonclinical studies to investigate the effect of NNC0114-
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
07 May 2015
Novo Nordisk
Trial ID: NN9828-4150 
Version:
2.0
UTN: U1111-1154-7172
Status:
Final
EudraCT no.: 2014-001215-39
Page:
29 of 141
0008 and liraglutide in late pre-diabetic and established diabetes and acute diabetes mouse models. 
Nonclinical data from the (non-obese-diabetic) NOD mouse model and the Rat-Insulin-Promoter-
Lymphocytic-Choriomeningitis-Glyco-Protein (RIP-LCMV-GP) mouse model for T1DM showed 
that when liraglutide was administrated as monotherapy, a significant but temporary decline in 
blood glucose (BG) levels was observed. After combined treatment with NNC0114 0006 and 
liraglutide, BG values were lowered and many treated mice remained normoglycemic when 
treatment with liraglutide was stopped, suggesting expansion or recovery of functional beta-cell 
mass. In summary, literature evidence and in-house in vivo studies provide a rationale for targeting 
both IL 21 and GLP 1 receptors through the combined use of NNC0114-0006 and liraglutide to 
preserve beta cell function in patients with T1DM.
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
07 May 2015
Novo Nordisk
Trial ID: NN9828-4150 
Version:
2.0
UTN: U1111-1154-7172
Status:
Final
EudraCT no.: 2014-001215-39
Page:
30 of 141
4
Objectives and endpoints
4.1
Objectives
Primary objective
The primary objective is to evaluate the effect of NNC0114-0006, liraglutide, and the combination 
of NNC0114 0006 and liraglutide, compared to placebo, on preservation of beta-cell function  after
54 weeks of treatment in adult subjects with newly diagnosed type 1 diabetes mellitus (T1DM)
Secondary objectives
!
Objectives related to treatment period (from baseline to week 54):
!
To assess safety and tolerability of NNC0114-0006 and liraglutide in combination 
and alone in subjects with newly diagnosed T1DM
!
To assess effect on glycaemic parameters (including insulin usage and insulin 
regimen) of NNC0114-0006 and liraglutide in combination and alone in subjects 
with newly diagnosed T1DM 
!
To assess pharmacokinetic (PK) properties of NNC0114-0006 and liraglutide in 
combination and alone in subjects with newly diagnosed T1DM
!
To explore biomarkers relevant for the effect of NNC0114-0006 and liraglutide in 
combination and alone in subjects with newly diagnosed T1DM
!
To assess disease burden and health status in subjects with newly diagnosed T1DM 
treated with NNC0114-0006 and liraglutide in combination and alone 
!
Objectives related to the post-treatment observation period (from week 54 to week 80):
!
To assess post-treatment safety and tolerability of NNC0114-0006 and liraglutide in 
combination and alone in subjects with newly diagnosed T1DM
!
To assess post-treatment effect on preservation of beta-cell function of 
NNC0114-0006 and liraglutide in combination and alone in subjects with newly 
diagnosed T1DM 
!
To assess post-treatment effect on glycaemic parameters (including insulin usage and 
insulin regimen) of NNC0114-0006 and liraglutide in combination and alone in 
subjects with newly diagnosed T1DM 
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
07 May 2015
Novo Nordisk
Trial ID: NN9828-4150 
Version:
2.0
UTN: U1111-1154-7172
Status:
Final
EudraCT no.: 2014-001215-39
Page:
31 of 141
!
To explore biomarkers relevant for the post-treatment effect of NNC0114-0006 and 
liraglutide in combination and alone in subjects with newly diagnosed T1DM
!
To assess post-treatment development of disease burden and health status in subjects 
with newly diagnosed T1DM treated with NNC0114-0006 and liraglutide in 
combination and alone
4.2
Endpoints
4.2.1
Primary endpoint
The primary endpoint is AUC0-4h for a mixed meal tolerance test (MMTT) stimulated C-peptide 
concentration-time curve at week 54 relative to baseline (defined as the MMTT performed at Visit 
2).
!
AUC0-4h, C-peptide, 54w/AUC0-4h, C-peptide, baseline
4.2.2
Supportive secondary endpoints
4.2.2.1
Supportive secondary efficacy endpoints
!
AUC0-4h for MMTT stimulated C-peptide concentration time curve at week 80 relative to 
baseline* 
!
AUC0-2h for MMTT stimulated C-peptide concentration time curve at week 54 and week 80
relative to baseline*
!
Maximum MMTT stimulated C-peptide concentration (Cmax, C-peptide) at week 54 and week 
80 relative to baseline*
!
AUC0-4h for MMTT stimulated plasma glucose concentration time curve at week 54 and 
week 80 relative to baseline
!
AUC0-2h for MMTT stimulated plasma glucose concentration time curve at week 54 and 
week 80 relative to baseline
!
Maximum MMTT stimulated plasma glucose concentration (Cmax, glucose) week 54 and week 
80 relative to baseline
!
Total daily insulin dose in units per kg (three day average) at week 54 and week 80* 
!
Number of insulin injections per day (three day average) at week 54 and week 80
!
Change in HbA1c from baseline to week 54 and week 80*
!
Change in fasting plasma glucose from baseline to week 54 and week 80*
!
Change in fasting C-peptide from baseline to week 54 and week 80*
!
Change in fasting glucagon from baseline to week 54 and week 80
!
7-point self-measured plasma glucose (SMPG) profiles. The following endpoints will be 
derived:
!
7-point profiles at week 54 and week 80
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
07 May 2015
Novo Nordisk
Trial ID: NN9828-4150 
Version:
2.0
UTN: U1111-1154-7172
Status:
Final
EudraCT no.: 2014-001215-39
Page:
32 of 141
!
Change in postprandial glucose (PPG)/prandial increment (breakfast, lunch, dinner
and average over the three meals) from baseline to week 54 and week 80
!
Change in mean of 7-point profiles from baseline to week 54 and week 80
!
Before breakfast SMPG at week 54 and week 80
!
Change in patient reported outcome (PRO) scores (SF36, Experience of Treatment Benefits
and Barriers, Diabetes Treatment Satisfaction Questionnaire (DTSQ)) from baseline to week
54 and week 80
* Key supportive secondary endpoint prospectively selected for disclosure (e.g. clinicaltrials.gov
and EudraCT)
4.2.2.2
Supportive secondary safety endpoints
!
Number of treatment emergent adverse events reported
!
from first dose of trial product to week 54
!
from week 54 to week 80
!
Number of treatment emergent hyperglycaemic episodes
!
from first dose of trial product to week 54
!
from week 54 to week 80
!
Number of treatment emergent episodes of diabetic ketoacidosis (DKA)
!
from first dose of trial product to week 54*
!
from week 54 to week 80
!
Number of subjects experiencing treatment emergent injection/infusion site reactions from
first dose of trial product and during treatment period (54 weeks) caused by:
!
NNC0114-0006/liraglutide/placebo injection/infusion
!
Number of treatment emergent hypoglycaemic episodes according to the American Diabetes
Association (ADA) and Novo Nordisk definitions
!
from first dose of trial product to week 54*
!
from week 54 to week 80
!
Change in body weight from baseline to week 54 and week 80
!
Diabetes complications (retinopathy and estimated glomeruli filtration rate) from baseline to
week 54 and week 80
!
Change in laboratory safety variables (haematology, biochemistry, coagulation, lipids, IgE,
urine dipsticks, cytokine panel, and hormones), vital signs, electrocardiograms (ECGs), eye-
examination and outcome of physical examination from baseline to week 54 and week 80
!
Change in anti-NNC0114-0006 antibodies from baseline to week 54 and week 80
!
Change in anti-liraglutide antibodies from baseline to week 54 and week 80
* Key supportive secondary endpoint prospectively selected for disclosure (e.g. clinicaltrials.gov
and EudraCT)
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
07 May 2015
Novo Nordisk
Trial ID: NN9828-4150 
Version:
2.0
UTN: U1111-1154-7172
Status:
Final
EudraCT no.: 2014-001215-39
Page:
33 of 141
4.2.2.3
Supportive secondary biomarker endpoints
!
Change in biomarker parameters from baseline to week 54 and week 80
!
T-cell profiling including islet-specific auto reactive CD8+ T-cells
!
IL-21
!
islets autoantibodies against glutamic acid decarboxylase (GAD), zinc-transporter 8
(ZnT8), islet antigen-2 (IA2), insulin autoantibody (IAA), isotypes of IAA and GAD
!
Change in differential methylated INS DNA in plasma from baseline to week 54 and week
80
!
Change in serum vitamin D (1,25 dehydroxy-calciferol) from baseline to week 54 and week
80
Differential methylated INS DNA and IL-21 will be analysed only if a functioning assay will be 
available in due time allowing to incorporate the analyses results in the database prior to database 
lock.
4.2.2.4
Supportive secondary pharmacokinetic endpoints
NNC0114-0006:
!
AUCτ, NNC0114-0006, area under the NNC0114-0006 time-concentration curve over a dosing
interval at steady state (SS) (defined as after last dose)
!
Terminal half-life (t½) after last dose of NNC0114-0006
!
Vss, NNC0114-0006, the apparent volume of distribution of NNC0114-0006 at steady-state
!
CLss, NNC0114-0006, clearance of NNC0114-0006 at steady state
!
MRT, NNC0114-0006, the mean residence time of NNC0114-0006
!
RA,AUC, NNC0114-0006, accumulation ratio of NNC114-0006 defined as AUC48-54 weeks/AUC0-6
weeks
!
Ctrough, NNC0114-0006, observed NNC0114-0006 concentration prior to dosing of
NNC0114-0006 at steady state
!
C1h, NNC0114-0006, observed NNC0114-0006 concentration 1 hour after dosing of
NNC0114-0006 at steady state
The following pharmacokinetic endpoints for liraglutide will be derived after the last dose 
administered at week 54:
!
C liraglutide, liraglutide concentration at steady state
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
07 May 2015
Novo Nordisk
Trial ID: NN9828-4150 
Version:
2.0
UTN: U1111-1154-7172
Status:
Final
EudraCT no.: 2014-001215-39
Page:
34 of 141
5
Trial design
5.1
Type of trial
The trial is a randomised, multi-centre, multinational, placebo-controlled, double-dummy, double-
blind, efficacy, safety and PK CPOP trial in subjects with newly diagnosed T1DMwith residual 
beta-cell function. The trial includes four parallel treatment groups, one with NNC0114-0006 12 
mg/kg i.v. every 6 week and liraglutide 1.8 mg s.c. daily,one with NNC0114-0006 12 mg/kg i.v. 
every 6 week, one with liraglutide 1.8 mg subcutaneously (s.c.) daily and, one placebo arm 
randomised in a evenratio. The randomisation will take place not more than 4 weeks from start of
screening(V1). The exposureperiod for NNC0114-0006 and liraglutide in combination or alone is 
54 weeks. The primary endpoint (C-peptide) is at week 54 as defined per U.S. FDA andEMA 
requirements20,21followed by a 26weeks observation period. All groups will receive insulin 
treatment according to a treat-to-target (T-T-T)regimen throughout the entire trial. SeeFigure 5–1
for theschematic trial design.
Figure 5–1
Trial design
5.2
Rationale for trial design
The rationale for the trial design, is to investigate the effect of NNC0114-0006 and liraglutide in 
combination on preservation of beta-cell function compared to placebo at week 54 in adult subjects 
with newly diagnosed T1DM with residual beta-cell function. In addition to the effect of the 
combination of NNC0114-0006 and liraglutide on preservation of beta-cell function, the trial will 
also generate data of treatment with either NNC0114-0006 or liraglutide compared to placebo on 
preservation of beta-cell function. The duration of the trial with 54 weeks of exposure of NNC0114-
0006 and/or liraglutide  has been chosen to align with the regulatory requirements from FDA and 
EMA. The length of the observation period of 26 weeks is chosen to give guidance for the further 
development program for the combination therapy of NNC0114-0006 and liraglutide. The FDA and 
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EMA guidelines advice that studies of products aimed at preservation of beta-cell function in 
recent-onset T1DM with remaining endogenous insulin reserve, should evaluate metabolic 
outcomes, such as stimulated C-peptide levels. Therefore the MMTT stimulated AUC0-4h C-peptide 
concentration has been chosen as the primary efficacy parameter.
The randomisation will be stratified according to non-fasting C-peptide level. The stratification 
factor has two levels according to C-peptide value: ≥0.2 nmol/l to ≤0.6 nmol/l and >0.6 nmol/l. 
There is no cap on the size of the strata. The effects of NNC0114-0006 on preservation of beta-cell 
function may depend on the level of the residual beta-cell function. The fasting C-peptide level is a 
marker of the residual beta-cell function and by stratifying for non-fasting C-peptide, the treatment 
arms are balanced with regards to the residual beta-cell function.
Clinical meaningful endpoints have been included such as number of treatment emergent 
hypoglycaemic episodes, insulin injections per day, and change in HbA1c. Furthermore, other 
secondary end-points e.g. total insulin usage and fasting values of glucose, insulin, glucagon and C-
peptide have been included to describe effect of treatments on the glucose metabolism and insulin 
usage.
A multi-centre and multinational design has been chosen to ensure that the results are applicable for 
subjects with different demographic characteristics.
5.3
Treatment of subjects
The subjects in the trial will be randomised in a blinded manner to receive one of the following 
treatment arms:
Table 5–1
Treatment arms
Treatment arms Treatment start (V3)
1st dose escalation (V7)
liraglutide
2nd dose escalation (V10)
liraglutide
1
NNC0114-0006 12 mg/kg1 i.v.
+ liraglutide 0.6 mg s.c.
NNC0114-0006 12 mg/kg 
i.v. + liraglutide 1.2 mg s.c.
NNC0114-0006 12 mg/kg i.v.
+ liraglutide 1.8 mg2 s.c.
2
NNC0114-0006 12 mg/kg i.v. +
liraglutide placebo s.c.
NNC0114-0006 12 mg/kg
i.v. + liraglutide placebo s.c.
NNC0114-0006 12 mg/kg i.v.
+ liraglutide placebo s.c.
3
Liraglutide 0.6 mg s.c. + 
NNC0114-0006 C 0 mg/ml i.v.
Liraglutide 1.2 mg s.c. +
NNC0114-0006 C 0 mg/ml 
i.v.
Liraglutide 1.8 mg s.c. + 
NNC0114-0006 C 0 mg/ml
i.v.
4
NNC0114-0006 C 0 mg/ml i.v.
+ liraglutide placebo s.c.
NNC0114-0006 C 0 mg/ml 
i.v.+ liraglutide placebo s.c.
NNC0114-0006 C 0 mg/ml
i.v. + liraglutide placebo s.c.
1. The dose is fixed so the dose is both the maximum and the minimum dose.
2. The maximum dose after dose escalation is 1.8 mg however if this is not tolerated it is allowed to reduce the dose to
1.2 mg. This is the lowest accepted dose.
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5.3.1
NNC0114-0006
NNC0114-0006 C 100 mg/ml and NNC0114-0006 C 0 mg/ml will be administered as an i.v. 
infusion every 6 weeks (first administration Week 0 and last administration Week 48) at the trial 
sites. The i.v. infusion of NNC0114-0006 C 100 mg/ml or NNC0114-0006 C 0 mg/ml will be 
administered according to instructions as detailed in the Trial Materials Manual (TMM). Subjects 
will remain at the clinical trial site for at least 2 hours after completion of NNC0114-0006 C 100 
mg/ml or NNC0114-0006 C 0 mg/ml administration to be observed for AEs. On days with MMTT 
the administration of NNC0114-0006/placebo, may be done during the MMTT. 
Dosing day exclusion criteria
The infusion of NNC0114-0006 must be postponed if there are symptoms or signs of infection, 
which in the opinion of the investigator are clinically significant (e.g. fever, pneumonia or tonsillitis
or unspecific viral infection).
If NNC0114-0006 cannot be given within 2 weeks after the scheduled visit this should be recorded 
as a missed dosing in the electronic case report form (eCRF). The next NNC0114-0006 dose will be 
given as planned.
5.3.2
Liraglutide
Liraglutide and liraglutide placebo will be self-administered s.c. either in the abdomen, thigh or 
upper arm daily with a pen-injector around the same time of the day, when the most convenient 
time of the day has been chosen. The last dose of liraglutide will be administered at the day prior to 
the Visit 63 (week 54). 
Liraglutide and insulin should not be injected in close physical proximity.
Initiation and escalation of liraglutide/liraglutide placebo
All subjects will initiate 0.6 mg liraglutide or 0.1 ml liraglutide placebo1 treatment on the day of 
randomisation. As the target dose is 1.8 mg liraglutide or 0.3 ml liraglutide placebo, the dose will be 
escalated in increments of 0.6 mg liraglutide or 0.1 ml liraglutide placebo every 2 weeks until 1.8 
mg liraglutide or 0.3 ml liraglutide placebo has been reached. In case of in-tolerable liraglutide side 
effects related to the dose escalation, it is acceptable to reduce the dose to the previous dose level 
for up to an additional 2 weeks. If 1.8 mg liraglutide or 0.3 ml liraglutide placebo is not tolerated 
due to side effects, the dose can be reduced to 1.2 mg liraglutide or 0.2 ml liraglutide placebo, 
which is considered to be the lowest acceptable dose. If 1.2 or 0.2 ml liraglutide placebo is not 
tolerated, the subject must be withdrawn (see Section 6.5).
1 The pen-injector has a dose scale of 0.6, 1.2 and 1.8 mg which will equal 0.1,0.2 and 0.3 ml liraglutide placebo on the dose scale.
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Missed doses of liraglutide/liraglutide placebo before target dose is reached
If any dose is missed by the subject ≤3 consecutive days before reaching the target dose of 1.8 mg 
or 0.3 ml placebo (1.2 mg or 0.2 ml placebo, if higher dose is not tolerated), it must be documented 
in the medical record and the investigator should discuss the importance of treatment compliance 
with the subject. After having missed liraglutide doses for ≤ 3 days the subject must be re-initiated 
on the dose the subject was taking prior to the missed doses. The dose escalation should be 
performed as originally planned.
If any dose is missed by the subject > 3 consecutive days at any time point it must be documented 
in the medical record and the investigator should discuss the importance of treatment compliance 
with the subject. The subject must be re-initiated on 0.6 mg liraglutide/placebo and dose escalation 
should be every 2 weeks. 
Missed doses of liraglutide/liraglutide placebo after target dose is reached
After reaching the target dose of 1.8 mg or 0.3 ml placebo (1.2 mg or 0.2 ml placebo, if higher dose 
is not tolerated), dose and dose frequency should not be changed at any time during the treatment 
period.
If any dose is missed by the subject ≤3 consecutive days it must be documented in the medical 
record and the investigator should discuss the importance of treatment compliance with the subject. 
After having missed liraglutide doses ≤3 days the subject must be re-initiated on the target dose. 
If any dose is missed by the subject > 3 consecutive days at any time point it must be documented 
in the medical record and the investigator should discuss the importance of treatment compliance 
with the subject. The subject must be re-initiated on 0.6 mg liraglutide/placebo and dose escalation 
should be every 2 weeks. 
5.3.3
Insulin treatment
Subject will continue on their current insulin treatment after they have been randomised. Subjects 
will be trained in diabetes self-care including carbohydrate counting before and atrandomisation 
and whenever needed during the course of the study in order to achieve the most optimal diabetes 
control. 
During the trial subjects will receive insulin treatment in order to achieve metabolic control 
according to the insulin titration guideline (Appendix A). This insulin treatment will be handled by 
the local trial sites in collaboration with Novo Nordisk’s Insulin Titration Group. It is acceptable to 
pause or stop insulin treatment if the investigator assesses that the subject is in remission. 
Glucagon can beused as rescue medication for the treatment of severe hypoglycaemia. The 
investigator or designee will ensure training has been conducted.
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Insulin reduction on the day of liraglutide/ liraglutide placebo initiation and escalation
As it is a blinded trial, when liraglutide/ liraglutide placebo is initiated, the total daily pre-
randomisation insulin dose should be reduced by 25 % for a minimum of 24 hours after the 
initiation of liraglutide/ liraglutide placebo. The reduction in the total daily insulin dose may come 
from reduction in basal and/or bolus insulin dose. The advice is to maintain the ratio between basal 
and bolus insulin when reducing insulin on the day of liraglutide/ liraglutide placebo initiation and 
escalation. A change of the ratio should be based on reaching the pre-meal SMPG targets. The pre-
randomisation dose is the average of the previous three consecutive day’s insulin dose. Thereafter 
the insulin dose should be adjusted according to the glucose target in Table 5–2.
When escalating to 1.2 mg and 1.8 mg liraglutide/ liraglutide placebo, the total daily insulin doses 
should be reduced by 10 % for a minimum of 24 hours after the escalation of liraglutide/ liraglutide 
placebo dose. The total daily dose is the average of the previous three consecutive days’ insulin 
dose. The reduction in the total daily insulin dose may come from reduction in basal and/or bolus 
insulin dose. Thereafter, the insulin dose should be adjusted according to the glucose target in Table 
5–2.
Table 5–2
Pre-meal SMPGs
Pre-breakfast/pre-meal SMPG
mmol/L
mg/dl
4.0-6.0
71-108
5.3.4
Prohibited medication
The following medications must not be used during the treatment period (week 0-54):
1. Systemically corticosteroids, monoamine oxidase (MAO) inhibitors, systemic non-selective
beta-blockers and growth hormone
2. Medications or herbal products that can influence the glucose homeostasis (except for
insulin) and/or the immune system. It is up to the investigator to judge which herbal
products influence on the glucose homeostasis
3. Treatment with any medication for the indication of diabetes or obesity other than insulin
and trial medication.
The following medications must not be used during the trial period (week 0-80):
1. Live vaccines
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5.4
Treatment after discontinuation of trial product
When discontinuing trial products the subject will continue their usual insulin treatment at the 
discretion of the investigator.
5.5
Rationale for treatment
The concept of combining immunotherapy with another agent was recently tested in the NOD 
recent onset diabetes model using a combination regimen of anti-IL-21 (NNC0114-0008) and 
liraglutide. These experiments used a two-week course of 5 injections at 25 mg/kg of NNC0114-
0008 combined with daily liraglutide administration. In the spontaneous NOD mouse model, the 
first experiment resulted in potent remission from hyperglycaemia in established T1DM, with 
statistically better efficacy as compared to each respective monotherapy. In a repeat study, however, 
the efficacy of NNC0114-0008 monotherapy was equivalent to the combination therapy, and an 
additive effect could not be demonstrated. Finally, in the induced RIP-LCMV-GP mouse model the 
combination treatment outperformed both monotherapies. All together the animal data suggest that 
a combination regimen of NNC0114-0006 and liraglutide may preserve beta-cell function 
synergistically in T1DM patients. The non-clinical data from the NOD mice and RIP-LCMV-GP 
model suggest that more than two doses of NNC0114-0006 need to be administered to get a clinical 
significant effect. 
The intravenous route for administration of NNC0114-0006 has been chosen to ensure the beta-
cells are adequately exposed to NNC0114-0006. The dosage of 12 mg/kg i.v. every 6 weeks (2 
doses in total) has in the NN8828-3842 trial in patients with RA shown efficacy and an acceptable 
safety profile. The efficacy was only established on the primary endpoint. The trial will generate 
data for beta-cell function every 12 weeks, which will allow to evaluate when an effect will start.
Measurement of the effect by doing a MMTT has been chosen to comply with FDA 20 and EMA 21
guidelines, where primary endpoint should be measured after one year. The length of the 
observation period of 26 weeks is chosen to give guidance for the further development program for 
the combination therapy of NNC0114-0006 and liraglutide.
Liraglutide is the active ingredient used in the authorised product Victoza® for the treatment of 
T2DM. Liraglutide is given subcutaneously once daily at a starting dose of 0.6 mg daily, and the 
therapeutic dose is 1.2 mg or 1.8 mg. 1.8 mg liraglutide is the maximal approved dose, and 
therefore this dose has been chosen as the preferred one. 
Due to the nature of the development of T1DM and the progressive decline in beta-cell function and 
non-fasting C-peptide over time, only a randomised parallel-group design will make comparison to 
the natural course of the disease development (placebo) possible during the administration period.
There is currently no approved comparator available for beta-cell function preservation after onset 
of T1DM. Thus placebo is the relevant comparator.
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6
Trial population
6.1
Number of subjects 
Number of subjects planned to be screened: 600
Number of subjects planned to be randomised: 304
Maximum number of subjects to be randomised: 314
Number of subjects expected to complete the trial (defined as reaching primary endpoint): 240
6.2
Inclusion criteria
For an eligible subject, all inclusion criteria must be answered “yes”. 
1. Informed consent obtained before any trial-related activities. Trial-related activities are any
procedures that are carried out as part of the trial, including activities to determine suitability
for the trial
2. Type 1 diabetes mellitus (as diagnosed clinically*) ≤ 12 weeks prior to randomisation
3. Male or female, aged 18-45 years (both inclusive) at the time of signing informed consent
4. Non-fasting C-peptide ≥0.2 nmol/l
5. BMI ≥18.5 kg/m2
6. Presence of one or more islet specific auto antibodies (glutamic acid decarboxylase (GAD),
islet antigen-2 (IA2) or zinc-transporter 8 (ZnT8)) at screening
7. Insulin dependence unless in temporary spontaneous remission (honeymoon period).
*See Section 6.8 for the clinical diagnosis.
6.3
Exclusion criteria
For an eligible subject, all exclusion criteria must be answered “no”. 
1. Known or suspected hypersensitivity to trial products or related products
2. Previous participation in this trial. Participation is defined as signed the informed consent.
3. Female who is pregnant, breast-feeding or intends to become pregnant or is of child-bearing
potential not using adequate contraceptive methods (adequate contraceptive measures, as
required by local regulations or practice)
For Ireland: Adequate contraceptive measures are defined as established use of combined
oral contraceptives, injected or implanted hormonal methods of contraception, sterilisation,
IUD or intrauterine system or consistent use of barrier methods together with the use of
spermicide and sexual abstinence.
For Sweden: Adequate contraceptive measures are: oral (except low-dose gestagen
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(lynestrenol and norestisteron)), injectable, or implanted hormonal contraceptives, 
intrauterine device, intrauterine system (for example, progestin-releasing coil), 
vasectomized male (with appropriate postvasectomy documentation of the absence of sperm 
in the ejaculate).
For United Kingdom: Adequate contraceptive measures are defined as established use of 
oral, injected or implanted hormonal methods of contraception, sterilisation, IUD or 
intrauterine system, or consistent use of barrier methods together with the use of spermicide, 
and sexual abstinence.
4. Male of reproductive age who or whose partner(s) is not using adequate contraceptive 
methods (adequate contraceptive measures, as required by local regulation or practice)
5. Participation in another interventional clinical trial within 5 half-life of the product(s) and if 
unknown then 3 months before randomisation (V3)
6. Severe diabetic ketoacidosis (defined as confirmed blood pH below 7.2) within 2 weeks 
prior to randomisation (V3)
7. Daily insulin usage > 1 U/kg per day at screening (V1) or use of continuous subcutaneous 
insulin infusion (CSII)
8. History of recurrent (e.g. several times a year) of severe (e.g. pneumonia) or chronic 
infections or conditions predisposing to chronic infections (e.g., bronchiectasis and chronic 
osteomyelitis)
9. History of severe systemic fungal infection within the past 12 months prior to screening 
(V1) unless treated and resolved with appropriate documented therapy 
10. Vaccination within 4 weeks before randomisation (V3)
11. Requiring a vaccine during treatment or within 60 days after last dose of NNC0114-0006 
with the exception of influenza vaccination according to local diabetes treatment 
requirements. The influenza vaccine can be given 3 weeks after a dose of NNC0114-0006 
and 2 weeks before next dose of NNC0114-0006 
12. Evidence of herpes zoster resolved less than 2 months prior to screening (V1)
13. History of disseminated or complicated herpes zoster
14. Evidence of or cytomegalovirus infection (CMV) resolved less than 2 months prior to 
screening (V1)
15. Serologic evidence of acute infection with CMV, defined as a positive CMV IgM
16. A positive QuantiFERON®-TB Gold test (test may be repeated if result is inconclusive) 
throughout the trial
17. A history of active tuberculosis (TB) within the last 3 years from screening even if treated 
effectively
18. History of active TB more than 3 years prior to screening if there is no documentation that 
the prior anti-TB treatment was appropriate in duration and type 
19. Household contact with a person with active TB, unless appropriate isoniazid prophylaxis 
for TB was previously given
20. Positive serology for hepatitis B documented by any of the following:
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!
Positive test for hepatitis B surface antigen (HBsAg)
!
Positive test for hepatitis B core antibody (HBcAb)
–
Note: Hepatitis B surface antibody (HBsAb) positivity without HBcAb positivity
indicates vaccination against hepatitis B and is not exclusionary with prior history of
vaccination
21. Positive test results for hepatitis C virus (HCV) as documented by any of the following:
!
Anti-HCV antibody positivity (as assessed by an enzyme immunoassay)
!
Presence of HCV ribonucleic acid (RNA) in serum
22. Positive test for current Epstein-Barr virus (EBV) infection as documented by :
!
Presence of IgM EBV antibodies
23. Human immunodeficiency virus (HIV) 1 or 2 antibodies
24. Subjects presently classified as being in NYHA Class IV (New York Heart Association
(NYHA))
25. Inadequately treated blood pressure as defined as Class 2 hypertension or higher
(Systolic≥160mmHg or diastolic ≥100 mmHg) in accordance with National High Blood
Pressure Education Program, 7th Joint National Committee and ESH/ESC 2013 guidelines
26. Within the past 180 days prior to screening (V1) any of the following: Myocardial
infarction, stroke or hospitalization for unstable angina and/or transient ischemic attack
27. Renal impairment estimated glomerular filtration rate (eGFR) <60ml/min as per (Chronic
Kidney Disease Epidemiology Collaboration) CKD-EPI 22
28. History of pancreatitis (acute or chronic)
29. Family or personal history of Multiple Endocrine Neoplasia Type 2 (MEN2) or Medullary
Thyroid Carcinoma (MTC)
30. Impaired liver function, defined as alanine aminotransferase (ALAT) or aspartate
aminotransferase (ASAT) ≥2.5 times upper limit of normal at screening (V1)
31. One or more screening (V1) laboratory values as stated:
!
Haemoglobin <6.2 mmol/l (10.0 g/dl)
!
Neutrophils <2x109/l
!
Leucocytes <3.5x109/l
!
Thrombocytes <100x109/l
!
Alkaline phosphatase (ALP) >2 times the UNL
!
Creatinine >2 times the UNL
!
Bilirubin >1.5 times the UNL
!
Calcitonin ≥ 50 ng/l
!
Any other laboratory abnormality that might, in the judgment of the investigator,
place the subject at unacceptable risk for participation in this trial
32. Proliferative retinopathy or maculopathy requiring acute treatment as verified by dilated
fundoscopy or fundus photography performed within 90 days prior to randomisation (V3)
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33. Current treatment with any of the following: Systemically corticosteroids, MAO inhibitors,
systemic non-selective beta-blockers or growth hormone
34. Receipt of any other concomitant medications or herbal products that can influence the
immune system within 90 days prior to screening (V1)
35. Treatment with any medication for the indication of obesity in a period of 90 days before
screening (V1)
36. Currently planned surgical procedures which may impair the subjects eligibility to
participate
37. Currently planned coronary, carotid or peripheral artery revascularisation
38. Any past or current diagnosis of malignant neoplasms
39. Known impairment of the immune system, except for T1DM
40. Donation or loss of >400 ml of blood within 8 weeks prior to randomisation or longer, if
required by local regulation
41. History of alcohol or drug abuse within the last 5 years or abuse that, in the investigator’s
opinion, might compromise the subject’s compliance or safety while participating in the trial
and/or ability to complete the trial.
All laboratory parameters listed in the in- and exclusion criteria will be analysed at a central 
laboratory.
6.4
Randomisation criteria
1. Absence of major bacterial infections within 4 weeks prior to randomisation (V3), (e.g.,
pneumonia and meningitis)
2. Absence of any symptoms or signs of an infection, which in the opinion of the investigator
is clinically significant
To be randomised, all randomisation criteria must be answered “yes”.
If one or more randomisation criteria are answered “no”, the subject should be offered to have the 
randomisation visit re-scheduled not later than 12 weeks after the diagnosis of T1DM. 
6.5
Temporary discontinuation of trial product
If the investigator suspects acute pancreatitis, trial products should be discontinued until 
confirmatory tests have been conducted and appropriate treatment should be initiated. If tests reveal 
that a subject does not have acute pancreatitis, re-initiation of liraglutide should be managed 
according to Section 5.3. 
Furthermore the subject can be temporarily discontinued of the NNC0114-0006 in case of an 
infection which is considered by the investigator to cause a safety concern.
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Temporary discontinuation of treatment with investigational product will not lead to withdrawal 
from the trial. However if 2 consecutive NNC0114-0006 doses are missed the subject should be 
withdrawn from the trial.
6.6
Withdrawal criteria
The subject may withdraw at will at any time. The subject may be withdrawn from the trial at the 
discretion of the investigator due to a safety concern or if judged non-compliant with trial 
procedures. Furthermore Novo Nordisk may decide to stop the trial, part of the trial or a trial site at 
any time.
The subject must be withdrawn if the following applies:
1. Included in the trial in violation of the inclusion and/or exclusion criteria and/or randomised
in violation of the randomisation criteria
2. Participation in another clinical trial throughout the trial
3. If 2 consecutive NNC0114-0006 doses are missed
4. Subjects switching to an insulin pump at any time point during trial participation
5. If, during the trial, the randomised liraglutide/ liraglutide placebo dose of 1.2 mg/day or
corresponding placebo volume after dose escalation is not tolerated
6. Hypoglycaemia and/or hyperglycaemia with ketosis during the treatment period posing a
safety concern, as judged by the investigator
7. Acute pancreatitis. Subjects that are diagnosed with acute pancreatitis during the trial (as a
minimum 2 of the following diagnostic criteria)
1. Severe acute upper abdominal pain,
2. Amylase and/or lipase >3x UNL or
3. Characteristic findings on ultrasound/computerised axial tomography
(CT)/magnetic resonance imaging (MRI)
8. Initiation of any prohibited medication (see Section 5.3.4).
9. Calcitonin ≥ 50 ng/l before week 54
10. Pregnancy
11. Intention of becoming pregnant
12. Unintended weight loss before week 54 posing a safety issue as judged by the investigator
13. Acute EBV or CMV infection before week 54 confirmed by central laboratory
14. Hepatitis B infection before week 54 confirmed by central laboratory
If a subject is withdrawn from the trial please see Section 8.1.7 for which visits the subject should 
attend.
6.7
Subject replacement
Subjects who are withdrawn will not be replaced.
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6.8
Rationale for trial population 
T1DM is a disease affecting all age groups with the highest incidences seen in children and 
adolescent below 19 years of age 23. A large proportion of the target population includes children 
and adolescents with newly diagnosed T1DM as well as young adults (below 30 years of age). Data 
from Sweden indicate that newly diagnosed patients with T1DM from18 years of age to 35 years of 
age and patients with LADA above 35 years of age are expected to outnumber patients with T1DM 
younger than 18 years of age at least by a factor of three in the future 24. Since NNC0114-0006 has 
not previously been administered to subjects below the age of 18 years or in subjects with newly 
diagnosed T1DM and the FDA and EMA recommends testing in adults prior to testing in a pediatric
population, the first clinical trial will include subjects with newly diagnosed T1DM from 18 to 45 
years of age. The reason for excluding subjects >45 years is to minimize the risk of including 
subjects with LADA. The destruction of beta-cells in LADA subjects progresses more slowly than 
in other types of T1DM. The decline of beta-cell function occurs more rapid in young versus older 
newly diagnosed T1DM subjects. The high age limit has been chosen as a trade-off between being 
able to recruit subjects to the trial and the lower decline of beta-cell function with increasing age.
As stated above, the functional beta-cell mass continuously decreases in an otherwise silent fashion 
before clinical diagnosis of T1DM. However, most patients still have functional beta-cell mass as 
evidenced by their C-peptide level at diagnosis 25. It is therefore hypothesized that a relatively 
modest recovery of beta-cell mass could re-establish a pre-diagnostic ‘silent’ state of T1DM. In 
order to ensure that patients with a residual beta-cell mass potentially can achieve a clinically 
meaningful improvement in glucose control, the peak or mean non-fasting C-peptide level needs to 
be above 0.2 nmol/l 26 within 12 weeks after onset of T1DM and that the subjects are metabolic 
stable (defined as no severe DKA, (confirmed pH below 7.2) within the last 2 weeks prior to 
screening).
The clinical diagnosis of T1DM is defined by the following two paragraphs:
1. One or more of the following:
!
HbA1c ≥ 6.5% or 
!
fasting plasma glucose ≥ 7.0 mmol/l (126 mg/dl) or
!
a 2 hour plasma glucose ≥ 11.1 mmol/l (200 mg/dl) during an oral glucose tolerance test 
with a glucose load of 75 grams anhydrous glucose in water or 
!
classical symptoms of hyperglycaemia and a random plasma glucose ≥ 11.1 mmol/l (200 
mg/dl)1
In the absence of unequivocal hyperglycamia, results should be confirmed by repeat testing.
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2. In order to:
!
ensure that the aetiology is autoimmune, the clinical diagnosis needs to be confirmed by the
presence of islet-specific auto-antibodies
!
exclude T2DM and LADA the subjects should be without severe insulin resistance (i.e. total
daily insulin dose larger than 1 U/kg per day at screening).
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Date:
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Trial ID: NN9828-4150 
Version:
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7
Milestones
Planned duration of recruitment period (i.e. FPFV – LPFV ): 18 month
End of trial is defined as LPLV.
For United Kingdom:
Planned date for LPLV: 27-Nov-2018
Recruitment:
Recruitment will be monitored on an ongoing basis by the sponsor. Prior to the initiation visit all 
trial sites should have a recruitments mitigation plan in place detailing how many subjects they can 
recruit within a certain period. If a trial site has not enrolled the number of subjects according to the 
recruitment mitigation plan, the remaining subjects may be reallocated. 
The screening and randomisation rate will be followed closely via the interactive voice/web 
response system (IV/WRS) in order to estimate when to stop screening. All investigators will be 
notified immediately when the recruitment periods ends, after which no further subjects may be 
screened and the IV/WRS will be closed for further screening. All subjects included in the 
screening period and eligible for randomisation can be randomised.
Trial registration:
Information of the trial will be disclosed at clinicaltrials.gov and novonordisk-trials.com. According 
to the Novo Nordisk Code of Conduct for Clinical Trial Disclosure 27, it will also be disclosed 
according to other applicable requirements such as those of the International Committee of Medical 
Journal Editors (ICMJE) 28, the Food and Drug Administration Amendment Act (FDAAA) 29,
European Commission Requirements 30,31 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.
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Trial ID: NN9828-4150 
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8
Methods and assessments
8.1
Visit procedures
Throughout the trial the investigator should ensure working in accordance with (ICH GCP) 2 and 
local regulations. The investigator must ensure that trial procedures are performed as described in 
the protocol. Any discrepancies will result in protocol and/or GCP deviations and the investigator 
must take appropriate action to avoid recurrence of the detected discrepancies. 
The following sections describe the assessments and procedures that must be performed during this 
trial. The timing of the assessments and procedures are specified in the flow chart Section 2.
The investigator must keep a subject screening log, a subject identification code list and a subject 
enrolment log. The subject screening log and subject enrolment log may be combined in one list 
and may be generated from the IV/WRS.
In addition the investigator must keep a log of staff and delegations of task(s) at the site. The 
investigator must sign the log of staff and the delegation of task(s) at site at the time of delegation.
8.1.1
Informed consent
Before screening takes place, subjects must be provided with oral and written information about the 
trial and the procedures involved. Subjects will be fully informed, orally and in writing about their 
responsibilities and rights while participating in the trial, as well as about the possible advantages 
and disadvantages when participating in the trial. Subjects will have the opportunity to ask 
questions and have ample time to consider participation. The informed consent process may take 
place before the screening visit (Visit 1).
Subjects who wish to participate in the trial must sign and date the subject information/informed 
consent for the trial before any trial related procedures (see Section 18.2). All subjects must be 
provided with a copy of their own signed and dated informed consent form.
8.1.2
Screening
At screening (V1), subjects will be provided with a card stating that they are participating in a trial 
and giving contact address(es) and telephone number(s) of relevant trial site staff. Subjects should 
be instructed to return the card to the investigator at the last trial visit or to destroy the card after the 
last visit.
Each subject will be assigned a unique 6-digit subject number which will remain the same 
throughout the trial. 
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8.1.3
Screening failures
If any inclusion criteria are answered no or any exclusion criteria are answered yes, the subject is a 
screening failure.
For screening failures the screening failure form in the electronic case report form (eCRF) must be 
completed with the reason for not continuing in the trial. Serious adverse events from screening 
failures must be transcribed by the investigator into the eCRF. Follow-up of serious adverse events 
(SAEs) must be carried out according to Section 12.3. A screening failure session must be made in 
the IV/WRS. The case book must be signed after all queries are closed. 
8.1.4
Re-screening/re-sampling
Re-sampling or re-screening is NOT allowed if the subject has failed one of the inclusion or 
exclusion criteria related to laboratory parameters. 
However if the tuberculosis screening test at Visit 1 is inconclusive re-tests can be performed. The 
repeat test results must be available for evaluating the subject’s eligibility before Visit 3. 
8.1.5
Investigator’s assessment
It is the responsibility of the investigator or delegated staff to review the e-diaries, PROs, ECGs, 
eye examinations (fundoscopy/ fundus photography), laboratory reports etc. This must be 
documented with the investigator or delegated staff’s dated signature either on the front page of the 
documents and/or in the subject’s medical records. The signed documents must be retained at the 
investigator site as source documentation.
8.1.6
Missed visits and unscheduled visits
If a visit is missed every effort should be made to ensure information is collected at a telephone 
contact. Subjects will be invited for the next scheduled visit according to the visit schedule.
If the investigator asks to subject to have a test described in the protocol re- done (e.g extra blood 
sample if some of the blood sample values are out of range) this should be recorded as an 
unscheduled visit and an unscheduled visit form must be completed. 
If the subject attends the clinic and some of the tests have to be re-scheduled (e.g. in a non-fasting 
state at a fasting visit) the re-scheduled tests should NOT be recorded as an unscheduled visit. In 
this case blood samples will have a different date of collection than the rest of the assessments. 
Likewise  re-scheduling of the MMTT and dosing of NNC0114-0006/placebo should not be 
recorded as an unscheduled visit. Temporary discontinuation of trial product
A temporary discontinuation is when the subject temporarily discontinues trial product after 
randomisation see Section 6.5
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8.1.7
Withdrawn subjects
If a subject is withdrawn from the trial during the treatment period (week 0-54), the investigator 
must aim to undertake procedures similar to those for Visit 63 as soon as possible and perform the
safety follow up visit (Visit 90) 15 ±1 weeks after last dose of NNC0114-0006. Subjects will be 
instructed to use appropriate pregnancy prevention until 15 weeks after last dose of NNC0114-
0006. The end-of-trial form must be completed, and final drug accountability must be performed 
even if the subject is not able to come to the trial site. A withdrawal session must be made in the 
IV/WRS. The case book must be signed after all queries have been closed.
If a subject is withdrawn from the trial during the observation period (week 55-80), the investigator 
must aim to undertake procedures similar to those for Visit 89 as soon as possible and the safety 
follow up visit (Visit 90) 15 ±1 weeks after last dose of NNC0114-0006. Subjects withdrawn 14 
weeks or more after last dose of NNC0114-0006 should not attend Visit 90. The end-of-trial form
must be completed. A withdrawal session must be made in the IV/WRS. The case book must be 
signed after all queries have been closed. 
Additional follow-up of subjects due to adverse events (AEs) or pregnancy is described in Section 
12.3 and 12.5.
If subjects fails to return for these visits or is unable to do so, every effort should be made by the 
investigator to contact him/her by phone or by sending appropriate correspondence (i.e., certified 
letter) that will become part of the investigators’ file to record that efforts were made to reach the 
subject.
Although a subject is not obliged to give his/her reason(s) for withdrawing from a trial, 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 not completing the trial 
must be specified on the end-of-trial form in the eCRF.
If new information becomes available which the safety committee at Novo Nordisk concludes 
would compromise the safety of the subjects, the trial will be permanently discontinued. In such 
cases, the subjects will still need follow-up visits as described above, i.e. at discontinuation and at 
15 weeks ± 1 week after last dosage of NNC0114-0006 dosage for safety reasons.
8.1.8
Fasting visits
The subject should attend selected visits fasting (see Section 2).
Fasting is defined as no food or drink intake for at least 6 hours, except water. Trial products and 
any medication which should be taken with or after a meal should be withheld on the day of the 
visit until blood sampling and body weight measurements have been performed. 
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If the subject is not fasting as required on days where fasting blood sampling should be drawn all
blood samples (both fasting and non-fasting) must be re-scheduled within the visit window and the 
date for the fasting blood samples must be recorded in the eCRF. All other assessments can be 
performed even though the subject is not fasting. Re-scheduling of fasting blood samples is not 
considered as an unscheduled visit.
8.2
Subject related information
The timing of the assessments is specified in the flow chart Section 2.
8.2.1
Concomitant illness and medical history
A concomitant illness is any illness that is present at the start of the trial (i.e. at the screening visit
(V1)) or found as a result of a screening procedure. The disease under investigation (T1DM) should 
not be entered as it is captured under diagnosis of diabetes.
Medical history is a medical event that the subject has experienced in the past. Only relevant 
medical history should be reported.
The information collected for concomitant illness and medical history should include diagnosis, 
date of onset and date of resolution or continuation, as applicable.
Any change to a concomitant illness should be recorded during the trial. A clinically significant 
worsening of a concomitant illness must be reported as an AE. 
8.2.2
Concomitant medication
A concomitant medication is any medication, other than the NNC0114-0006, liraglutide and 
insulin, which is taken during the trial, including the screening and follow-up periods. Information 
on insulin treatment is recorded in diabetes treatment history see Section 8.2.7 and in the e-diary see 
Section 8.6.3. 
Details of any concomitant medication must be recorded at the first visit. Changes in concomitant 
medication must be recorded at each visit as they occur. 
The information collected for each concomitant medication includes trade name or generic name, 
start date and stop date or continuation. 
If a change is due to an AE, then this must be reported according to Section 12. If the change 
influences the subject’s eligibility to continue in the trial, the monitor must be informed.
For restrictions regarding concomitant medication, please refer to Section 5.3.
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8.2.3
Smoking status
Details of smoking status must be recorded at the first visit. Smoking is defined as smoking at least 
one cigarette, cigar or pipe daily. The collected information should include whether or not the 
subject smokes or has smoked.
8.2.4
Abuse of alcohol and/or drugs
Subject will be asked if he/she has a history of alcohol and/or drug abuse or is currently abusing 
alcohol and/or drugs. In case of a history of alcohol and/or drug abuse, duration of abuse in years 
and the year of end of abuse should be recorded in the eCRF.
8.2.5
Demography
The following information has to be recorded:
!
Date of birth, unless not permitted by local regulations
!
Age
!
Sex
!
Race, unless not permitted by local regulations
!
Ethnicity, unless not permitted by local regulations
8.2.6
Diagnosis of diabetes
The following information has to be recorded:
!
Date of diagnosis of T1DM
8.2.7
Diabetes treatment history
The following information has to be recorded:
!
Start date of current diabetes treatment
!
Number of severe hypoglycaemic episodes since diagnosis
8.2.8
Family history of diabetes
The following information has to be recorded:
!
Is there a family history of diabetes (Y/N)
!
Indicate the relation to the subject
!
Type of diabetes
8.2.9
Diabetes complications
The following information has to be recorded (Y/N):
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!
Diabetic retinopathy
!
Diabetic neuropathy
!
Diabetic nephropathy
!
Other
8.3
Assessments for efficacy
The timing of the assessments and procedures are specified in the flow chart Section 2.
8.3.1
Mixed meal tolerance test
The subject will have a MMTT performed at certain visits, as outlined in Section 2.
Instructions prior to MMTT visits
The subject should be instructed to:
!
Follow normal routine on the days prior to the MMTT visit regarding eating however the
subject should attend the MMTT visit fasting
!
Follow normal exercise and refrain from hard exercise (comparable to and exceeding 5 km
running or weightlifting) 24 hours prior to the MMTT
!
Minimise physical activity in the morning of the MMTT to the extent possible
!
Refrain from intake of alcohol and use of medications that affect motility (i.e. prokinetics,
anticholinergic, tricyclic antidepressants) 24 hours prior to the MMTT
!
Not to take their basal insulin after 22.00 the evening before the MMTT visit
!
Subjects who normally take basal insulin in the morning should bring their basal insulin to
the MMTT
!
Not to take any bolus insulin later than 2 hours prior to the MMTT
!
Remember to bring their bolus insulin to the MMTT visits (to be given after MMTT)
!
Take liraglutide/liraglutide placebo at the same time as usual both the day before the MMTT
visit and on the day of the MMTT
!
Remember to bring their liraglutide/liraglutide placebo to the MMTT visits, if applicable
!
Remember to bring their BG meter provided for this trial
!
Remember the importance of having BG on target
Preparation and conduct of the MMTT
The MMTT will be initiated in the morning after fasting for at least 6 hours. The NNC0114-
0006/placebo may be given during the MMTT. 
Subjects will be instructed not to take basal insulin after 22.00 the evening before the MMTT. 
Receipt of insulin boluses is allowed until 2 hours prior to the MMTT. 
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The plasma glucose value measured at the site before the MMTT must be ≤9.0 mmol/l (162 mg/dl) 
in order to avoid hyperglycaemia during the MMTT. Therefore if the plasma glucose value 
measured at the site is > 9.0 mmol/l (162 mg/dl) the subject may receive bolus insulin and the 
MMTT can be performed after 2 hours if a plasma glucose value ≤9.0 mmol/l (162 mg/dl) is 
confirmed. The MMTT may also be re-scheduled within 1-10 days. Re-scheduling of the MMTT is 
not considered as an unscheduled visit. Two rescheduling’s are allowed per MMTT visit. If this is 
not possible the MMTT must be reported as not done. All other assessments at the visit should be 
conducted as planned including dosing of NNC0114-0006/placebo. 
If plasma glucose value measured at the site before the MMTT is ≤3.9 mmol/l (70 mg/dl), the
MMTT will be rescheduled within 1-10 days. Re-scheduling of the MMTT is not considered as an 
unscheduled visit. Two rescheduling’s are allowed per MMTT visit. If this is not possible the 
MMTT must be reported as not done. All other assessments at the visit should be conducted as 
planned including dosing of NNC0114-0006/placebo. 
All plasma glucose values to be measured at site must be measured with a validated BG instrument. 
The BG meters handed out to the subjects should not be used for this purpose.
The subject’s body weight must be measured before intake of the standardised liquid meal. The 
standardised liquid meal will be provided by Novo Nordisk. The subject must consume 6 ml/kg
(maximum 360 ml) of the standardised liquid meal as quickly as possible and within 12 minutes. 
The investigator should confirm that the subject consumed the required amount in the eCRF. 
Blood samples (11-point profile) will be collected 10 minutes prior to the meal (-10) at meal start 
(0), and at 15, 30, 60, 90, 120, 150, 180, 210 and 240 minutes after meal start. The blood samples 
will be assayed for C-peptide and plasma glucose. During the MMTT plasma glucose will be 
monitored on a validated plasma glucose instrument. If the glucose level exceeds 16.7 mmol/l (300
mg/dl) plasma ketones (betahydroxybutyrate) should be measured on a BG meter.
The subject is allowed to go to the toilet. The number of visits to the toilet should be limited. The 
subjects are allowed to drink water 2 hours after start of the MMTT. The amount of ingested water 
should be limited.
Precautions during the MMTT
In case the plasma glucose exceeds 16.7 mmol/l (300 mg/dl) and plasma ketones > 0.6 mmol/l and 
≤ 1.5mmol/l (only measured if plasma glucose is above 16.7 mmol/l (300 mg/dl)), the MMTT can 
be stopped at the discretion of the investigator and rescue insulin treatment may be initiated if 
deemed necessary. 
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If the plasma ketone level is above 1.5 mmol/l presenting a risk of ketoacidosis, the MMTT must
be stopped and appropriate treatment should be initiated. The plasma ketone level should be 
controlled as long as it is above 1.5 mmol/l.
In case of hypoglycaemia during the MMTT (plasma glucose value <3.9 mmol/l (70 mg/dl)), the 
MMTT can be stopped at the discretion of the investigator and rescue treatment according to local 
practice can be initiated. 
After the MMTT
The subjects may have a meal after the last blood sample has been taken. 
It is up to the discretion of the investigator to decide if subjects who normally takes basal insulin in 
the morning should take their basal insulin after the MMTT. Bolus insulin will be allowed jointly 
with the post-test meal, as applicable. 
Documentation of the MMTT
The following has to be recorded:
!
Date of mixed meal tolerance test
!
Was the subject fasting prior to intake of liquid meal (Y/N)
!
Did the subject withhold the insulin treatment as required prior to the MMTT (Y/N)
!
Was the last SMPG measurement at the site before start of the meal within the acceptable 
range (4.0-9.0 mmol/l)
!
Code number(s) of the liquid meal 
!
Meal time. Actual time for the start and stop
!
How much volume of the liquid meal was ingested (ml)
!
Actual time points for the blood samples
!
Was the MMTT stopped prematurely and reason for stopping
8.3.2
Self-measured blood glucose 
At Visit 2, subjects will be provided with a BG meter including lancets, plasma-calibrated test strips 
and control solutions as well as instructions for use (control solutions will only be provided if they 
are needed, requested or required according to local requirements or procedures). The subjects will 
be instructed in how to use the device, the instruction will be repeated as necessary during the trial. 
The blood glucose meter 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. 
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Subjects will be instructed in how to record the results of the self-measured blood glucose (SMBGs)
in the e-diaries. The record of each SMBG will include date, time point (e.g. before breakfast, 
before lunch, etc.) and value. BG should always be measured when a hypo- or hyperglycaemic 
episode is suspected. Hypoglycaemic and hyperglycaemic episodes will be recorded by the subject 
in the e-diary (see Section 8.6.3). The investigator may ask the subject to perform additional SMPG 
measurements if needed for any safety reason. 
8.3.3
4-point self-measured plasma glucose profiles
Subjects will be instructed to perform SMPG measurements before breakfast, before lunch, before 
dinner and at bedtime daily to allow optimal insulin titration. The plasma glucose levels, the date
and the time point of all measurements will be recorded for each time point stated in the e-diary. 
8.3.4
7-point profile
Subjects will be instructed to perform SMPG measurements before and 90 minutes after the start of 
breakfast, lunch, dinner and at bedtime. Measurements will be performed according to the flowchart 
in Section 2. The plasma glucose levels, the date and the time point for all measurements will be 
recorded for each time point stated in the e-diary.
The 7-point plasma glucose profile includes one before breakfast measurement, one before lunch,
one before dinner and one at bedtime measurement. These measurements are the same needed for 
the 4-point profile.
8.3.5
Insulin doses
Subjects will be instructed in how to record the insulin doses in the e-diaries. Each record should 
include date, time point (e.g. before breakfast, before lunch etc.), value, units and type (basal or 
bolus) of insulin.
Insulin doses will be collected on a daily basis to allow optimal insulin titration.
If a subjects reports an actual bolus insulin dose that deviates from the prescribed bolus insulin dose 
the subject will be asked to report a reason for this deviation in the e-diary.
8.3.6
Carbohydrate intake per meal
Subjects whowill betitratedaccording to the principle of flexible insulin therapy (seeAppendix A) 
will be instructed in how to record the carbohydrate intakein the e-diary.Each record should 
include date, time point (e.g. breakfast lunch etc.) and grams of carbohydrate. The carbohydrate 
intake will be collected on a daily basis, if applicableto allow optimal insulin titration.
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8.3.7
Patient reported outcomes (PROs)
The following questionnaires will be used in the trial to investigate the impact of the treatment on 
subject’s overall health related quality of life and their treatment experience and satisfaction:
!
36-Item Short Form Health Survey version 2 (SF-36v2)
!
Diabetes-Specific Health Beliefs: Experience of Treatment Benefits and Barriers – Type 1
(ETBB)
!
Diabetes Treatment Satisfaction Questionnaire - status (DTSQs)
The questionnaires have to be completed by the subjects at selected visits (see Section 2).
The questionnaires must be completed by the subject him/herself on paper and should preferably be 
completed after conclusion of all fasting activities but before any other visit-related activities. It will 
take the subject approximately 15 minutes to answer all the questions.
The questionnaires will be supplied in a linguistically validated version for all languages relevant 
for this trial. 
It is the responsibility of the investigator or delegated staff to review the completed PRO 
questionnaires for (and ensure reporting of) any potential AEs. Review of PROs must be 
documented on the designated signature sheet on the documents and/or in the subject’s medical 
record. 
If clarification of entries or discrepancies in the PRO is needed, the subject must be questioned and 
a conclusion made in the subject’s medical record. Care must be taken not to bias the subject
Data from the questionnaires will be transferred into the eCRF by the investigator or delegated staff. 
8.4
Assessments for safety
The timing of the assessments and procedures are specified in the flow chart Section 2.
8.4.1
Adverse events
AEs must be recorded at each visit in accordance with the procedures outlined in Section 12.2 and 
12.3.
8.4.2
Adverse Events requiring special forms in the eCRF 
For some AEs the investigator must fill in special forms in the eCRF. The AEs that require special 
forms in the eCRF are 
!
Pancreatitis
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!
Thyroid disease
!
Neoplasm
!
Hypersensitivity reactions
!
Injection/Infusion site reactions
If the subject experiences a hyperglycaemic or hypoglycaemic episode the subject should report this 
in the e-diary.
Hyperglycaemia and hypoglycaemia will only be reported on an AE form if they fulfil the criteria 
of a SAE.
In case any of these events fulfil the criteria for a SAE, please report accordingly (see Section 12.1)
Some events may require additional assessments as described in the following section. 
8.4.2.1
Pancreatitis
If an event of pancreatitis (or clinical suspicion of pancreatitis) is observed during the trial, this 
must be recorded as an AE and on a specific Pancreatitis event form in the eCRF. The following 
information must be reported if available: 
!
Signs and symptoms of pancreatitis
!
Specific laboratory test supporting a diagnosis of pancreatitis:
–
Amylase
–
Lipase
–
ALAT and ASAT
–
Bilirubin
–
Alkaline Phosphatase
!
Imaging performed and consistency with pancreatic disease
!
Complications to the event
!
Relevant risk factors for pancreatic disease including
–
History of gall-stones
–
History of pancreatitis
–
Family history of pancreatitis
–
Trauma
8.4.2.2
Thyroid disease
If an event of thyroid disease, including any thyroid neoplasms is observed during the trial, this 
must be recorded as an AE and on a specific thyroid disease event form in the eCRF. The following 
information must be reported if available: 
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!
History of thyroid disease
!
Signs and symptoms leading to investigations of thyroid disease
!
Specific laboratory tests describing Thyroid function including :
–
Thyroid-stimulating hormone (TSH)
–
Total and free T3 and T4 and Free Thyroid Index
–
Calcitonin
–
Thyroid Peroxiodase antibodies
–
Thyroglobulin and Thyroglobulin antibody
–
Thyroid Stimulating Hormone receptor antibody
!
Diagnostic imaging performed and any prior imaging supporting the disease history
!
Pathologic examinations
!
Treatment given for the condition
!
Risk factors identified
!
Family history of thyroid disease
Thyroidectomy and genetic testing
For Israel:the following is not applicable.
In case a subject is to undergo a thyroidectomy (partial or total) for any reason during the trial, the
subject will be asked to inform the investigator prior to the operation. Prior to the thyroidectomy,
the subject will be asked to consent to the following:
If assessment of the thyroid gland confirms C-cell pathology (i.e., hyperplastic or neoplastic
thyroid C-cells) a blood sample is collected and analysedto identify germline RET gene mutations
associated with MEN2syndrome if allowed by local law. The blood sample should be collected at 
the first visit tothe clinic after the confirmation of C-cell pathology. The identification of the gene
mutations will be performed by the central laboratory (for details please see Attachment I).
The blood sample will be destroyed after analysis.
8.4.2.3
Neoplasm
All events of neoplasm (excluding thyroid neoplasm which should be recorded according to Section 
8.4.2.2) must be reported including malignant neoplasm, in situ neoplasm and benign neoplasm 
observed during the trial. This must be recorded as an AE and on a specific neoplasm event form in 
the eCRF. The following information must be reported if available: 
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!
Type of neoplasm
!
Symptoms leading to identification of event
!
Diagnostic imaging
!
Pathological examination results
!
Treatment for the event
!
Participation in screening programs
!
Risk factors associated to the event
8.4.2.4
Hypersensitivity reactions
If suspicion of a hypersensitivity reaction occurs the subjects should be instructed to contact the site 
staff as soon as possible for further guidance.
All events of hypersensitivity reactions must be reported as an AE and on a specific hypersensitivity 
reaction event form in the eCRF. The following information must be obtained: 
!
Signs and symptoms associated to the event
!
Time of appearance after administration of trial drug
!
If any relevant immunological tests has been performed and type and result of test
!
If any treatment was given for the reaction
!
Any previous  history of similar reactions
!
Any relevant risk or confounding factors identified
Treatment should be according to local practice.
In the event of a severe immediate hypersensitivity reaction to trial product, blood sampling for 
special laboratory assessment of anti-NNC0114-0006 and anti-liraglutide IgE antibodies and anti-
NNC0114-0006 and anti-liraglutide binding antibodies should be conducted at 2 weeks and 
between 3 and 6 month after the event. 
In the event of an immediate systemic hypersensitivity reaction to trial product it is recommended 
locally to test for tryptase (total and/or mature tryptase) within 3 hours of the reaction. Moreover, a 
baseline tryptase measurement is necessary ~1 week after the immediate severe hypersensitivity 
reaction due to individual to individual variation in tryptase baseline concentration.
Tryptase concentrations (if measured) as well as anti-NNC0114-0006 and anti-liraglutide IgE 
antibodies will not be reported to the trial database but be reported to Novo Nordisk Safety 
Operations for inclusion in the ARGUS Safety database. Results will be included in the narratives.
8.4.2.5
Injection/Infusion site reactions
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All events of injection site/Infusion site reactions caused by NNC0114-0006 and liraglutide must be 
reported as an AE and on a specific injection site reaction event form in the eCRF. The following 
information must be obtained: 
!
Type of reaction – local or generalised
!
Symptoms associated to the event
!
Treatment for the event
!
Association with the trial product(s)
!
Risk factors associated to the event
Treatment should be according to local practice.
8.4.2.6
Hyperglycaemic episodes
A hyperglycaemic episode is defined as, and confirmed by PG values >16.7 mmol/l (300 mg/dl).
PG should always be measured when there is a suspicion of a hyperglycaemic episode. Multiple 
(>1) hyperglycaemic values of SMPG >16.7 mmol/l (300 mg/dl) are considered as one 
hyperglycaemic episode until the SMPG is <16.7 mmol/L (300 mg/dl). One episode is set to a 
maximum of 24 h for the first SMPG >16.7 mmol/l (300 mg/dl).
All PG values >16.7 mmol/l (300 mg/dl) should be recorded by the subject in the e-diary from visit 
2 to visit 89. 
The recording should include the following information (layman-language will be used in the e-
diary to phrase the respective questions ensuring that subjects understand the questions): 
!
Date and time of hyperglycaemic episode
!
The PG level before treating the episode
!
Blood ketone value before treating the episode
!
Date, time and dose of last liraglutide/placebo administration prior to the episode
!
Date, time and dose of last basal insulin administration prior to the episode
!
Date, time and dose of last bolus insulin administration prior to the episode
!
Whether the episode was symptomatic
!
Where there any factors contributing to the hyperglycaemic episode?
!
Recent changes in diet 
!
Concomitant infection
!
Recently missed  or reduced dose of  insulin
!
Other
!
Unknown
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The subject should measure his/her plasma ketones when plasma glucose values >16.7 mmol/l (300 
mg/dl). Subjects will be instructed in how to record the results of the ketone values in the provided 
e-diaries and should only record the ketone values based on the glucometer measurements.
If the hyperglycaemic episode fulfils the criteria for an SAE then an AE form and a SIF must also 
be completed in the eCRF.
Assessments in case of suspicion of treatment emergent hyperglycaemia and diabetic 
ketoacidosis
Inadequate dosing or discontinuation of insulin treatment may lead to hyperglycaemia and DKA. 
Usually the first symptoms of hyperglycaemia develop gradually over a period of hours or days. 
Symptoms may include: increased thirst, dry mouth, increased frequency of urination, headache, 
fatigue, blurred vision, or even nausea, vomiting, abdominal pain, drowsiness, flushed dry skin, loss 
of appetite, flushing, confusion, difficulty breathing as well as acetone odour of breath. Untreated 
hyperglycaemia eventually lead to DKA, which is potentially lethal. Illness, such as infections and 
fever may lead to increased insulin requirement.
If a subject suspects hyperglycaemia, the subject must perform plasma glucose measurement 
immediately. If SMPG > 16.7 mmol/l (300 mg/dl), plasma ketones should be measured.
Normally, ketone levels are expected to be less than 0.6 mmol/l. Ketone levels may increase if a 
person fasts, exercises vigorously or has diabetes and becomes ill. If plasma ketone levels are 
higher than 1.5 mmol/l, subjects will be instructed to contact the site staff immediately for advice 
and assistance. 
If the investigator suspects DKA, confirmatory tests and appropriate treatment should be initiated. 
A DKA is confirmed if at a minimum three of the following 5 diagnostic criteria are present 32:
1. PG > 13.9 mmol/l (250 mg/dl)
2. Arterial pH < 7.30
3. Serum Bicarbonate < 18 mEq/l
4. Serum Ketones: Positive. If available, measurement of plasma hydroxybutyrate may be useful for 
diagnosis 3-hydroxybutyrate > 1.5 mmol/l
5. Urine Ketones: Positive 
Confirmed cases of DKA must be reported as SAEs by completion of an AE and SIF in the eCRF 
and should be followed-up with investigations of potential precipitating causes of DKA (i.e. 
infection/stroke/acute myocardial infarction/pancreatitis).
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8.4.2.7
Hypoglycaemic episodes
Blood glucose should always be measured and recorded when a hypoglycaemic episode is 
suspected.
All plasma glucose values:
!
≤ 3.9 mmol/l (70 mg/dl) or  
!
> 3.9 mmol /l (70 mg/dl) occurring in conjunction with hypoglycaemic symptoms 
should be reported according to the instructions below throughout the trial from visit 2 to visit 89. 
Upon onset of a hypoglycaemic episode the subject is recommended to measure blood glucose 
every 15 minutes in accordance to current guidelines 33.
A SMPG ≤3.9 mmol/l (70 mg/dl) or hypoglycaemic symptoms must trigger a hypoglycaemic 
episode form to be completed by the subject.  Repeated SMPG measurements and/or symptoms will 
per default be considered as one hypoglycaemic episode until a succeeding measurement is >3.9 
mmol/l (70 mg/dl) or symptoms have been resolved.  One hypoglycaemic episode form is to cover 
these measurements and/or symptoms. However, each hypoglycaemic episode form will cover a 
period of maximum 60 minutes after onset of a hypoglycaemic episode. 
In case of several low SMPG values within the 60 minute interval, the lowest value is the one that 
will be reported as the SMPG value for the hypoglycaemic episode but the start time of the episode 
will remain as the time for the first SMPG value and/or symptom.
If a new low SMPG value is measured or the subject still has symptoms more than 60 minutes after
the first reported low SMPG value it is considered as a new episode and a new hypoglycaemic 
episode form is to be filled in.
The record should include the following information (layman-language will be used in the e-diary 
to phrase the respective questions ensuring that subjects understand the questions): 
!
Date and time of hypoglycaemic episode 
!
The plasma glucose level before treating the episode (if available) and any follow up 
measurements.  (The lowest value measured during the hypoglycaemic episode will be 
reported as the SMPG value for the episode, the remaining values will be kept as source 
data).
!
Whether the episode was symptomatic (Yes/No).  (A hypoglycaemic episode starting as 
non-symptomatic should be updated to symptomatic if the subject experiences symptoms 
later during the episode. The subjects are therefore to be prompted whether there are 
changes to symptoms for each low SMPG value within the 60 minutes period). 
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!
Whether the subject was able to treat him/herself   (If the severity of a hypoglycaemic
episode aggravates, only one hypoglycaemic episode should be reported reflecting the most
severe condition. The subjects are therefore to be prompted whether they are able to self-
treat (Yes or No) for each low SMPG value within the 60 minutes period).
!
Date, time and dose of last liraglutide/placebo administration prior to the episode
!
Date, time and dose of last basal insulin administration prior to the episode
!
Date, time and dose of last bolus insulin administration prior to the episode
!
Date and time of last main meal prior to episode
!
Whether the episode occurred in relation to physical activity
!
Any sign of fever or other disease
!
Whether the subject was asleep when the episode occurred
If yes, whether the symptoms of the episode woke up the subject
The answer to the question: "Was subject able to treat him/herself?" must be answered "No" for an 
episode requiring assistance of another person to actively administer carbohydrate, glucagon, or 
take other corrective actions. Plasma glucose concentrations may not be available during an event, 
but neurological recovery following the return of plasma glucose to normal is considered sufficient 
evidence that the event was induced by a low plasma glucose concentration 33. 
Oral carbohydrates should not be given if the subject is unconscious.
If the question "Was the subject able to treat him/herself?" is answered "No", the following 
information should be recorded:
!
Who helped manage the episode (medical person or non-medical person)
!
Where the treatment was administered (in clinic/ emergency room/ hospital or other. If the
subject was treated in clinic/ emergency room/ hospital whether they were transported in an
ambulance or not)
!
Type of treatment provided by other person (i.e. oral carbohydrates, glucagon, IV glucose or
other)
!
Were symptoms alleviated after administration of treatment?
!
Factors contributing to the episode (i.e. physical activity, missed meal, diet changed,
medication error (i.e. overdose, mix-up between products), miscalculation of insulin dose,
other or unknown)
!
Did the subject experience seizure?
!
Was the subject unconscious/comatose?
!
Did the subject experience any of the following symptoms 34:
–
Autonomic: sweating, trembling, hunger or palpitations
–
Neuroglycopenic: confusion, drowsiness, speech difficulty, visual disturbances, odd
behaviour, impaired balance or incoordination
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–
General malaise: headache or malaise
!
Did the subject experience other symptoms?
The Investigator must review the e-diary data for correct reporting of SMPGs and hypoglycaemic 
episodes at each contact. If the investigator experiences missing data in the diary, the subject must 
be questioned whether there have been any severe hypoglycaemic episodes since the last visit i.e. 
any hypoglycaemic episodes where the subject was not able to self-treat. Any severe 
hypoglycaemic episodes must be reported on a hypoglycaemic episode form.  
Non-severe hypoglycaemic episodes not having a hypoglycaemic episode form completed within 7 
days since the SMPG measurement will not be reported retrospectively and missing data points for 
non-severe hypoglycaemic episodes will generally not be questioned by the investigator or queried 
by Novo Nordisk due to subject’s short recall of non-severe hypoglycaemic episodes35,36.  
The subject must be re-trained in how to report hypoglycaemic episodes if the investigator identifies 
unreported hypoglycaemic episodes. 
If the hypoglycaemic episode fulfils the criteria for an SAE and/or a medical event of special 
interest (MESI) then an AE form and a safety information form must also be filled in, see section 
12.1
8.4.3
Technical complaints
Technical complaints must be recorded in accordance with the procedures outlined in Section 12.4. 
The following information has to be recorded:
!
Product
!
Code no
!
DUN
!
Onset date of technical complaint
!
Description of the technical complaint
8.4.4
Body measurements
8.4.4.1
Height
Height without shoes should be measured in meters (m) or inches (in) and recorded with two 
decimals at screening (V1).
8.4.4.2
Body weight
Body weight should be measured and recorded according to Section 2.
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Version:
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Body weight should be measured in kilograms (kg) or pounds (lb) and should be recorded with one 
decimal in the eCRF. The body weight should be measured with an empty bladder, without shoes 
and only wearing light clothes.
Body weight should be measured using a calibrated scale. The same scale should preferably be used 
throughout the trial.
8.4.4.3
BMI
BMI will be calculated at the first visit by the eCRF using the equation:
BMI kg/m2 = Body weight (kg)/ (Height (m) x Height (m)) or (kg/m2 = (lb/in2 x 703))
8.4.5
Electrocardiogram 
A 12-lead ECG must be performed locally by the investigator or delegated staff at the time points 
specified in Section 2. The ECG print out must be interpreted, signed and dated by the investigator.
The evaluation must follow the categories:
!
Normal
!
Abnormal
–
Was the result clinically significant? (Yes/No)
A baseline ECG performed for any reason unrelated to the trial within 30 days prior to Visit 1 is 
acceptable provided no clinical symptoms suggestive of cardiac disease have occurred in the 
meantime. If the ECG is performed before the subject has signed the informed consent form, it must 
be documented in the medical records that the reason for performing the procedure was not related 
to this trial.
Any abnormal, clinical significant findings at screening visit (Visit 1) must be recorded as 
concomitant illness. 
Any clinical significant worsening from Visit 1 must be recorded as an AE (see Section 12.1)
In the treatment period of the trial the following information has to be recorded:
!
Overall interpretation
!
Heart rate
!
PR interval
!
QRS duration
!
QTc interval
!
RR interval
In the observation period of the trial the following information has to be recorded:
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!
Overall interpretation
8.4.6
Eye examination
Dilated fundoscopy or fundus photography should be performed by the investigator, a local 
ophthalmologist or an optometrist according to local practice at the visits specified in Section 2. 
Result of the dilated fundoscopy/ fundus photography will be interpreted locally by the investigator 
in relation to the trial. The evaluation must be documented, signed and dated.
The evaluation must follow the categories:
!
Normal
!
Abnormal
–
Was the result clinically significant? (Yes/No)
Any abnormal, clinical significant findings at randomisation visit (Visit 3) must be recorded as 
concomitant illness. 
Any clinical significant worsening from Visit 3 must be recorded as an AE (see Section 12.1)
If an eye examination has been performed within 90 days prior to Visit 3 as part of routine practice, 
and if the results are available prior to randomisation (Visit 3), the procedure does not have to be 
repeated, provided no worsening of visual function has occurred in the meantime. The investigator 
must still interpret, sign and date the fundoscopy/ fundus photography results. If the fundoscopy/ 
fundus photography is performed before the subject has signed the informed consent form, it must 
be documented in the subjects medical records that the reason for performing the procedure was not 
related to this trial. At Visit 63 the fundoscopy/ fundus photography may be performed in a time 
window of 2 weeks prior and 2 weeks after the visit and at Visit 89 the fundoscopy/ fundus 
photography may be performed 2 weeks prior to the visit.
8.4.7
Physical examination
Physical examination will be performed at selected visits according to Section 2. The examination 
will include:
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!
General appearance
!
Head, ears, eyes, nose, throat, neck
!
Respiratory system
!
Cardiovascular system
!
Gastrointestinal system incl. mouth
!
Musculoskeletal system
!
Central and peripheral nervous system
!
Skin
!
Lymph node palpation
!
Thyroid gland
Any abnormal, clinically significant findings at screening visit (Visit 1) must be recorded as 
concomitant illness.
Any clinically significant worsening from Visit 1 must be reported as an AE (see Section 12).
8.4.8
Vital signs
The following vital signs will be assessed at selected visits according to Section 2:
!
Systolic and diastolic blood pressure (mmHg). Subjects should rest in a sitting position for 5
minutes
!
Pulse. Subjects should rest in a sitting position for 5 minutes
!
Body temperature, ear
!
Respiratory rate (breath/minutes)
!
Overall interpretation of vital signs
Any abnormal, clinically significant findings at screening visit (Visit 1) must be recorded as 
concomitant illness.
Any clinically significant worsening from Visit 1 must be reported as an AE (see Section 12.1).
8.5
Laboratory assessments
The timing of the blood samples are outlined in the flow chart (see Section 2). Laboratory 
assessments can be done at another day than on the day of the actual visit as long as it is within the 
visit window.
Review of laboratory reports must be documented either on the document and/or in the subject’s 
medical record.
The laboratory equipment may provide analyses not requested in the protocol but produced 
automatically in connection with the requested analyses according to specifications in the laboratory 
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standard operating procedures. Such data will not be transferred to the trial database, but abnormal 
values will be reported to the investigator. The investigator must review all laboratory results for 
concomitant illnesses and AEs and report these according to this protocol. 
In the case of an ‘abnormal, clinically significant’ finding, the investigator must comment in the 
subject notes and, if it occurs at screening visit (Visit 1), record this on the concomitant 
illness/medical history form. 
Any clinically significant worsening after Visit 1 must be reported as an AE (see Section 12.1). 
All blood samples will be sent to the central laboratory. Instructions for obtaining samples, handling 
conditions including coding in order to keep subject identity confidential, storage, blood sampling, 
storage and shipping will be described in a trial specific laboratory manual supplied by the central
laboratory. Some samples will be shipped to the central laboratory, from where they will be shipped 
to specialised laboratories for analysis. It will be specified below if samples are analysed at site or at 
a specialised laboratory, all other samples will be analysed at the central laboratory.
8.5.1
Laboratory assessments for efficacy
8.5.1.1
Glucose metabolism
The following will be analysed:
!
HbA1c will be measured according to Section 2, except at Visit 1.
!
Fasting plasma glucose (FPG) will be measured according to Section 2, except at Visit 1.
For the measurement of FPG the subject must be fasting according to Section 8.1.8.
!
Fasting glucagon will be measured according to Section 2, except at Visit 1. For the
measurement of fasting glucagon the subject must be fasting according to Section 8.1.8.
!
Fasting C-peptide will be measured according to Section 2, except at Visit 1. For the
measurement of C-peptide the subject must be fasting according to Section 8.1.8.
!
PG (non-fasting) will be measured at Visit 1.
!
C-peptide (non-fasting ) will be measured at Visit 1.
8.5.1.2
Mixed meal tolerance test
Please refer to Section 8.3.1 for details on the samples for the 11 points C-peptide and glucose 
profiles.
8.5.1.3
Biomarkers
Differentially methylated INS DNA
Minimally invasive methods to determine episodes of beta-cell death could be a valuable tool for 
patient stratification in clinical trials, assessing clinical response to therapy, and directing patient 
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care. When beta-cells die, they release insulin (INS) DNA that can be measured in serum. Though 
the INS gene can be detected in cells other than beta-cells, the methylation status of this gene is 
tissue-dependent, e.g., beta-cell-derived INS is hypomethylated. The differentially methylated INS 
DNA assay is hypothesized to identify waves of beta-cell death by measuring the ratio of 
methylated to unmethylated insulin DNA, thus providing a method of assessing beta-cell loss.
Samples will be drawn according to Section 2. This hypothesis-testing assay will be used by a 
specialised lab if a functioning assay is available in due time to ensure analysis and results ready for 
data base lock. If no functional assay is available the samples will be destroyed. 
Antibodies (autoantibodies) & isotypes
The autoantibodies are used to confirm the clinical diagnosis of TD1M at screening and the 
assessments during the trial will give information of disease development. Further during the trial, 
isotypes of anti-insulin (IAA) and of anti-GAD autoantibodies will also be determined. Isotypes 
will change over time as the diabetes-associated immune response progresses or is modified by 
therapy. Therefore, autoantibody isotypes will provide information regarding the immune and 
disease status of an individual.
Autoantibodies will be drawn according to Section 2. The following autoantibodies will be 
analysed:
!
Anti-GAD
!
Anti-ZnT8
!
Anti-IA2
!
Anti-IAA, excepted at Visit 1
Additionally, isotypes for anti-IAA and –GAD will be evaluated, excepted at Visit 1.
Anti-IAA and –GAD isotypes will be analysed at a specialised laboratory and only if the sample is 
positive for anti-IAA or anti-GAD antibodies. These results will be reported to the investigator at 
the end of the trial.
Immunology
T1DM is mediated by immune destruction of the islets, characterised by T-cell infiltrate and 
detectable autoantibodies in the periphery. Additionally, IL-21 is an important immune-modifying 
cytokine that has been demonstrated to impact B- and T-cell compartments. The assays proposed 
will assess the disease- and treatment-associated effects on the immune response mediating T1D.
Samples will be drawn according to Section 2. The investigator must record the date and the exact 
time for sampling the blood. 
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The following will be analysed:
!
T-cell profiling including islet-specific auto reactive CD8+ T-cells
!
IL-21, excepted at Visit 2
The blood sampling for assessment of T-cell profiling including islet-specific auto reactive CD8+ 
T-cells should preferably be performed at about the same time of day for a given subject.
Blood sampling for the assessment of Il-21 should be taken pre-dose of the NNC0114-0006 
administration. IL-21 will be analysed at a specialised laboratory only if a functioning assay is 
available in due time to ensure analyses and results are ready for data base lock. The investigator 
will receive the results of the immunology assessments at the end of the trial. If no functional assay 
is available the samples will be destroyed. 
The periphery blood mononuclear cells (PBMCs) used for the analyses of the T-cell profiling 
including islet-specific auto reactive CD8+ T-cells will be stored for up to 15 years for potential 
future assessments if the subject has consented to it (see Section 24.2).
8.5.1.4
Vitamin D (1,25 dehydroxy-calciferol)
Samples for Vitamin D (1,25 dehydroxy-calciferol) will be drawn according to Section 2. 
8.5.2
Laboratory assessments for safety
8.5.2.1
Pregnancy test
A human chorionic gonadotropin serum pregnancy test will be performed at Visit 1 and 63 on all 
women where childbearing potential has not been ruled out by for example measuring FSH levels.
Urine pregnancy test will be performed for females of childbearing potential at any time during the 
trial if a menstrual period is missed or required by local law. If a subject during a phone contact 
reports missing menstrual period, an unscheduled visit should be scheduled as soon as possible to 
have a urine pregnancy test performed. Urine pregnancy kits will be supplied by the central 
laboratory. The test will be performed at site.
For Austria: A monthly urine pregnancy test is mandatory for female subjects of childbearing 
potential.
8.5.2.2
Anti-drug antibodies 
Assessment of antibodies against liraglutide and NNC0114-0006 (anti-drug antibodies) in serum 
will be performed at specialised laboratories according to Section 2. 
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Samples for the determination of anti-drug antibodies must be drawn in a fasting state to minimise 
interference of endogenous GLP-1. During the treatment period samples must be drawn prior to 
administrating trial products. 
The investigators will not receive the results until the trial is completed and unblinded. A detailed 
description of the assay methods will be included in the antibody analysis report at the end of the 
study.
Antibody samples may be retained until drug approval by FDA and/or EMA. The retained antibody 
samples may be used for further characterisation for antibody responses towards drug if required by 
health authorities or for safety reasons. At end of trial the specialised laboratories responsible for 
the anti-drug antibodies analysis will arrange the transfer of samples to Novo Nordisk for storage. 
Anti-drug antibodies are stable for many years when stored frozen (e.g. -20 degrees Celsius), and 
further characterisation is therefore possible. Samples will only be used for further characterisation 
if required by the authorities (FDA and/or EMA) or for safety reasons.
Anti-liraglutide antibodies
The screening analysis of serum samples for antibodies against liraglutide will be done in the two 
arms dosed with liraglutide at Visit 3, 19, 31, 43, 63, 69, and 89 or 90. However all subjects will 
have blood samples drawn to avoid unblinding. The assay is a validated RIA. Samples positive for 
anti-liraglutide antibodies will furthermore be characterised for cross-reactivity to native GLP-1.
At Visit 69, 89 and 90 positive anti-liraglutide antibody samples from the screening analysis will in 
addition be analysed for in vitro neutralising effect by comparison to Visit 3 (before drug exposure) 
in a cell-based assay. Furthermore, antibody positive samples from the screening analysis that 
cross-react with native GLP-1 will be analysed for in vitro neutralising effect towards native GLP-1 
in a cell-based assay.
Anti-NNC0114-0006 antibodies
The screening analysis of serum samples for antibodies against NNC0114-0006 will be done in the 
two arms dosed with NNC01114-0006 at Visit 3, 19, 31, 43, 63, 89 and 90. However all subjects 
will have blood samples drawn to avoid unblinding. The assay is a validated bridging antibody 
assay. Samples positive for anti-NNC0114-0006 antibodies will furthermore be characterised for 
specificity to the constant region with mutations and the variable region.
The neutralising effect of anti-NNC0114-0006 antibodies will be evaluated by correlating results to 
PK data and the specificity of anti-drug antibodies (towards the constant region with mutations and 
the variable region). 
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Protocol
CONFIDENTIAL
Date:
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Trial ID: NN9828-4150 
Version:
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UTN: U1111-1154-7172
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8.5.2.3
Total IgE
Total IgE will measured according to Section 2. 
8.5.2.4
Biochemistry
The following will be analysed according to Section 2:
!
ALAT
!
Albumin
!
Alkaline phosphatase
!
Amylase
!
ASAT
!
Bilirubins, total
!
Calcium (albumin corrected)
!
Chloride
!
Creatinine kinase
!
Creatinine
!
Gamma glutamyltransferase
!
CRP
!
Estimated GFR, only at Visit 1, 63 and 89
!
Lactate dehydrogenase
!
Lipase
!
Magnesium
!
Phosphate
!
Potassium
!
Sodium
!
Total proteins
!
Urea (blood urea nitrogen)
!
Uric acid
eGFR will be calculated by the central laboratory based on the creatinine value using the CKD-EPI 
equation as this indirect measurement of GFR has a median difference with direct measurement of 
GFR of 2.5 ml/min 37.
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Date:
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Trial ID: NN9828-4150 
Version:
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8.5.2.5
Coagulation parameters
The following will be analysed according to Section 2:
!
INR
!
D-dimer
8.5.2.6
Haematology
The following will be analysed according to Section 2:
!
Erythrocytes
!
Haematocrit
!
Haemoglobin
!
Leucocytes
!
Mean corpuscular haemoglobin
!
Mean corpuscular haemoglobin, conc.
!
Mean corpuscular volumen
!
Thrombocytes
!
Differential count:
!
Eosinophils
!
Neutrophils
!
Basophils
!
Lymphocytes
!
Monocytes
8.5.2.7
Cytokines
The following will be analysed according to Section 2:
!
Cytokine panel (IL-6, IL-10, IL-17, IFN∀, TNF-#)
The investigators will not receive the results until the trial is completed.
8.5.2.8
Urine dipstick
Urinalysis will be performed from a sample of mid-stream urine by means of a stick at the trial site. 
The following will be assessed according to Section 2 and result reported in the eCRF:
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Trial ID: NN9828-4150 
Version:
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!
Erythrocyte
!
Glucose
!
Ketone
!
Leucocyte
!
Nitrite
!
pH
!
Protein
!
Specific gravity
The urine sticks provided by the central laboratory may include more parameters than requested for 
this protocol. Such data will not be recorded in the eCRF. The investigator must review all results 
on the urine stick for concomitant illnesses and AEs and report these according to Section 8.2.1 and 
12.
8.5.2.9
Virus screen for hepatitis B and C
The following assessments will be performed according to Section 2:
!
HBcAb
!
HBsAb
!
HBsAg
!
Anti-HCV antibody, assessed by an enzyme immunoassay
!
HCV-RNA
8.5.2.10
Tuberculosis screening test
A QuantiFERON®-TB Gold test will be performed at Visit 1.
If the test is inconclusive  retests can be performed. The repeat test results must be available for 
evaluating the subject’s eligibility before Visit 3. 
8.5.2.11
Virus screen for Epstein-Barr virus
Blood samples will be drawn according to Section 2 for assessment of:
!
IgM EBV antibodies
!
IgG EBV nuclear antigen
8.5.2.12
Virus screen for cytomegalovirus infection
The following will be analysed according to Section 2:
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Date:
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Trial ID: NN9828-4150 
Version:
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UTN: U1111-1154-7172
Status:
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!
CMV IgM
!
CMV IgG
8.5.2.13
HIV
The following  will be analysed at Visit 1:
!
HIV1 antibodies
!
HIV2 antibodies
8.5.2.14
Hormones
The following will be analysed according to Section 2:
!
TSH, excepted at Visit 19, 43 and 55
!
Calcitonin
For actions to be taken if calcitonin is ≥ 10 ng/L, please refer to AppendixB.
8.5.2.15
Lipids
The following will be analysedaccording to Section 2:
!
Cholesterol
!
Free fatty acids
!
HDL cholesterol
!
LDL cholesterol
!
Triglycerides
8.5.3
Other laboratory assessments
8.5.3.1
Genotype (optional)
For Israel: the following is not applicable.
Blood samples for genotyping will be collected and analysed for human leucocyte antigen (HLA)
class I, provided the subject has given separate written informed consent. The samples will be 
stored as described in Section 24.2.
8.5.3.2
Blood samples for long term retention (optional)
For Israel: the following is not applicable.
Provided the subject has given a separate written informed consent, specific blood samples will be 
collected and serum stored for up to 15 years for potential future assessments see Section 24.2. 
Since new biomarkers related to TD1M and/or to safety, efficacy, or mechanism of action of 
NNC0114-0006 and liraglutide may evolve during the conduct of the trial, potential future 
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Date:
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Trial ID: NN9828-4150 
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assessment on stored samples may be related to safety, e.g. infections, efficacy or mode of action of 
NNC0114-0006 and liraglutide as well as to TD1M. 
8.5.3.3
Serum concentration of NNC0114-0006 for pharmacokinetics
PK samples will be taken according to Section 2. At Visit 3 and 55, samples will be taken pre-dose 
(up to 60 min before) and 1 hour after start of the infusion. At NNC0114-0006 dosing visits, the
sample should be taken pre-dose. The investigator must record the date and the exact time for 
sampling the blood. 
Serum will be analysed by use of an enzyme-linked immunosorbent assay (ELISA) specific for 
NNC0114-0006. The ELISA is validated for human serum samples.
All samples from subjects receiving active treatment with NNC0114-0006 will be analysed for 
NNC0114-0006. For subjects receiving placebo or liraglutide treatment only, the samples taken 1 
hour after the start of infusion at Visit 3 will be analysed in order to verify the placebo treatment. If 
the NNC0114-0006 concentration in this sample is above the lower limit of quantification (LLOQ), 
all samples from that subject will also be analysed. A copy of the subject treatment allocation report 
will be forwarded to the laboratory before any analyses are started.
The analysis will be performed by a specialised laboratory. Investigators will not receive the results 
until the trial is completed and unblinded.
The PK samples will be retained until the clinical trial report (CTR) has been finalised. The samples 
will be stored at the specialised laboratory.
8.5.3.4
Plasma concentration of liraglutide for pharmacokinetics
A single blood sample for PK will be drawn and assayed for plasma concentrations of liraglutide at 
the visits specified in Section 2. The investigator must record the date and the exact time for 
sampling the blood. The sample can be taken at any time during the visit. Plasma will be analysed 
by use of an enzyme-linked immunosorbent assay (ELISA) specific for liraglutide. The ELISA is 
validated for human plasma samples 
All samples from subjects receiving active treatment with liraglutide will be analysed for 
liraglutide. For subjects receiving placebo treatment or NNC0114-0006 only, samples taken at Visit 
6 will be analysed in order to verify the placebo treatment. If the liraglutide concentration in this 
sample is above the lower limit of quantification (LLOQ), all samples from the subject will also be 
analysed.
A copy of the subject treatment allocation report will be forwarded to the laboratory before any 
analyses are started.
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Date:
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Trial ID: NN9828-4150 
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The analysis will be performed by a specialised laboratory. Investigators will not receive the results 
until the trial is completed and unblinded. 
The PK samples will be retained until the CTR has been finalised. The samples will be stored at the 
specialised laboratory.
8.6
Other assessments
8.6.1
Trial product administration NNC0114-0006 
Investigators must report the exact volume of NNC0114-0006  in the eCRF after each infusion. 
Each record should also include date and start and stop time of the infusion.
8.6.2
Liraglutide/liraglutide placebo
Subjects will be instructed to report the dose (0.6, 1.2 or 1.8 mg) as indicated on the pen in their e-
diary on a daily basis. Each record should also include date, time and injection site.
8.6.3
Subject e-diaries
The subjects will be provided with an e-diary at Visit 2. The investigator or delegated will train the 
subject in the use of the e-diary according to the provided instructions. 
The following information will be collected in the e-diaries:
!
Liraglutide/placebo doses (see Section 8.6.2)
!
4-point profiles (see Section 8.3.3)
!
7-point profiles (see Section 8.3.4)
!
Insulin doses (see Section 8.3.5)
!
Reasons for deviating from the prescribed bolus insulin dose
!
Carbohydrate (CHO) intake per meal (CHO-counting subjects only) (see Section 8.3.6)
!
Hypoglycaemic episodes (see Section 8.4.2.7)
!
Hyperglycaemic episodes including ketone data (see Section 8.4.2.6)
Review of e-diaries must be documented. Please refer to Section 13.3.
8.7
Subject compliance
Throughout the trial, the investigator will remind the subjects to follow the trial procedures and 
requirements to ensure subject compliance. If a subject is found to be non-compliant, the 
investigator will remind the subject of the importance of following the instructions given including 
taking the trial products as prescribed. Substantial failure to comply with the prescribed dose 
regimen can lead to withdrawal at the discretion of the investigator.
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Trial ID: NN9828-4150 
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Treatment compliance:
Throughout the trial the treatment compliance will be assessed by monitoring of drug accountability 
as specified in Section 9.4. The unused/used liraglutide pens code numbers will be assessed against 
the dispensed code numbers and in case of discrepancies the subject must be asked.
The target dose of liraglutide or placebo is 1.8 mg. If 1.8 mg per day is not tolerated, the subject can 
stay on 1.2 mg per day. 
Subjects are asked to report the actual daily dose in the e-dairy. Prior to or during each visit/phone 
contact the investigator or delegated staff should review the subject’s compliance with regards to 
liraglutide/placebo treatment. If the subject has missed a dose completely or not administered the 
expected dose the investigator or delegated staff should ask the subject for the reason for non-
compliance and discuss the importance of treatment compliance. 
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Date:
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Trial ID: NN9828-4150 
Version:
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9
Trial supplies
Trial supplies comprise trial products and auxiliary supplies. Additional details regarding trial 
supplies can be found in the TMM. 
Trial products must not be dispensed to any person not included in the trial. 
9.1
Trial products
The following IMPs for treatment at site will be provided by Novo Nordisk A/S Denmark:
!
NNC0114-0006 C 100 mg/ml, 3 ml cartridges
!
NNC0114-0006 C 0 mg/ml, 3 ml cartridges
Trial cartridge will be packed blinded and will appear similar.
NNC0114-0006 C 100 mg/ml /NNC0114-0006 C 0 mg/ml appear clear to slightly opalescent and 
colourless/slightly yellow essentially free from visible particles. If this is not the case or the liquid is 
cloudy it must not be used.
The following IMPs for treatment at home will be provided by Novo Nordisk A/S Denmark:
!
Liraglutide 6.0 mg/ml, 3 ml pre-filled pen-injector
!
Liraglutide placebo, 3 ml pre-filled pen-injector
Liraglutide /Liraglutide placebo will be packed blinded and are visually identical.
Liragutide 6 mg/ml /Liragutide placebo appear clear and colourless or almost colourless. If this is 
not the case the liquid must not be used. 
The following trial products will be provided by Novo Nordisk A/S, Denmark:
Trial product
Strength
Dosage form
Route of 
administration
Container/
delivery device 
NNC0114-0006 C 100 
mg/ml 
100 mg/ml 
3 ml cartridge
i.v.
Cartridge
NNC0114-0006 C 0 
mg/ml 
0 mg/ml
Liraglutide  6.0 mg/ml
6.0 mg/ml
3 ml pre-filled 
pen
s.c.
3 ml pre-filled 
pen/pen-injector
Liraglutide placebo
0 mg/ml
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Date:
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Trial ID: NN9828-4150 
Version:
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The following non-IMPs are used in this trial:
!
Insulin:
During the trial subjects will receive insulin treatment in order to achieve a metabolic 
control according to the insulin titration guideline. Subjects will continue their pre-trial 
insulin treatment. Thus treatment will be considered background treatment. Preferably the 
type and/or brand of basal and bolus insulin should not be changed throughout the trial.
Insulin will not be provided by Novo Nordisk.
!
Glucagon
Glucagon will be used as rescue medication for the treatment of severe hypoglycaemia.
Glucagon will not be provided by Novo Nordisk.
9.2
Labelling
The trial products will be labelled in accordance with Annex 13 38, local regulations and trial 
requirements.
Each trial site will be supplied with sufficient trial products for the trial on an on-going basis 
controlled by the IWRS. Dispensing unit numbers (DUNs) will be distributed to the trial sites 
according to enrolment and randomisation. 
For NNC0114-0006 C 100 mg/ml / NNC0114-0006 C 0 mg/ml i.v. infusion, an instruction for 
handling will be described in the TMM.
For Liraglutide 6.0 mg/ml/Liraglutide placebo a direction for use (DFU) will be provided to the 
sites. The investigator must document that direction for use is given to the subject orally and in 
writing at the first dispensing visit (Visit 3). The investigator may give the DFU to the subject at 
subsequent visits, if needed.
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Trial ID: NN9828-4150 
Version:
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UTN: U1111-1154-7172
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9.3
Storage 
Trial product
Storage 
conditions
(not-in-use)
In-use conditions
In-use time*
NNC0114-0006 C 100 mg/ml
Store in a 
refrigerator
(2°C to 8°C)
Protect from light
Do not freeze
Below 30°C
Protect from light
Do not freeze
For 6 hours
NNC0114-0006 C 0 mg/ml
Trial product
Storage 
conditions
(not-in-use)
In-use conditions
In-use time**
Liraglutide 
6.0 mg/ml, 3 ml pre-filled 
pen 
Store in a 
refrigerator
(2°C to 8°C)
Protect from light
Do not freeze
Store below 30°C
US:
15-30° or in a 
refrigerator (2°C-
8°C)
CA:
At room 
temperature not 
above 30°C or in 
a refrigerator (2°-
8°C)
Protect from light
Do not freeze
1 month 
US:
For 30 days
CA:
For 30 days 
Liraglutide placebo
3 ml pre-filled pen 
*In-use time starts after removal from the refrigerator at site. The dosing should be performed 
within 6 hours after the trial product is removed from the refrigerator. 
** In-use time starts when first dose is taken 
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Trial ID: NN9828-4150 
Version:
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The investigator must ensure the availability of proper storage conditions, and also record and 
evaluate the temperature. The investigator must inform Novo Nordisk immediately if any trial 
product has been stored outside specified conditions (e.g. outside temperature range).
Trial product that has been stored improperly must not be dispensed to any subject before it has 
been evaluated and approved for further use by Novo Nordisk. The investigator must take 
appropriate action to ensure correct storage.
9.4
Drug accountability and destruction
Drug accountability is the responsibility of the investigator.
Returned trial product (used/partly used or unused including empty packaging material) can be 
stored at room temperature and must be stored separately from non-allocated trial product.
The trial products will be dispensed to each subject as required according to treatment group. The 
IWRS will allocate trial product to the subject at randomisation and each dispensing visit. The 
correct dispensing unit number(s) (DUN(s)) must be dispensed to the subject. The investigator or 
delegated person is responsible for ensuring that:
!
Drug accountability for NNC0114-0006 C 100 mg/ml / NNC0114-0006 C 0 mg/ml is 
performed on a cartridge level using the IWRS drug accountability module
!
Drug accountability for Liraglutide 6.0 mg/ml/Liraglutide placebo is performed on a pen 
level using the IWRS drug accountability module 
!
Subjects are instructed to return all used, partly used and unused trial product including 
empty packaging material at each dispensing visit and at end of treatment visit
Due to the formulation of NNC0114-0006 C 100 mg/ml, NNC0114-0006 C 0 mg/ml, Liraglutide 
6.0 mg/ml, Liraglutide placebo it is not possible for the monitors to verify drug accountability on a 
volume level. 
Destruction will be done according to local procedures after accountability is finalised and verified 
by the monitor. Destruction of products must be documented.
9.5
Auxiliary supplies and other deliveries
The following auxiliary supplies will be provided by Novo Nordisk and specified in the TMM:
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Trial ID: NN9828-4150 
Version:
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!
Needles for pre-filled pen injector
!
BG meters to measure plasma glucose levels and to measure blood ketone levels, when 
needed including 
!
lancets, plasma-calibrated test strips and control solutions
!
control solutions will only be provided if they are needed, requested or required 
according to local requirements or procedures.
!
Mixed meals
!
Set for the infusion of NNC0114-0006
10
Interactive voice/web response system
A trial-specific IV/WRS will be set up which can be accessed at any time via the internet or 
telephone. Access to the IV/WRS must be restricted to and controlled by authorised persons. 
IV/WRS is used for:
!
Screening
!
Screening failure
!
Randomisation
!
Medication arrival
!
Dispensing
!
Withdrawal
!
Completion
!
Code break
!
Drug accountability
!
Data change
IV/WRS user manuals will be provided to each trial site.
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Trial ID: NN9828-4150 
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11 Randomisation procedure and breaking of blinded codes
This trial is double-blind. A randomisation session will be carried out for all subjects using the 
IV/WRS. At the randomisation visit (Visit 3) subjects meeting all inclusion and randomisation 
criteria and none of the exclusion criteria will be centrally randomised to one of the 4 parallel 
treatment groups in a 1:1:1:1 manner to:
!
NNC0114-0006 C 100 mg/ml 12 mg/kg i.v. every 6 weeks and liraglutide 1.8 mg s.c. daily
!
NNC0114-0006 C 100 mg/ml 12 mg/kg i.v. every 6 weeks and liraglutide placebo 0 mg s.c.
daily
!
NNC0114-0006 C 0 mg/ml i.v. every 6 weeks and liraglutide 1.8 mg s.c. daily
!
NNC0114-0006 C 0 mg/ml i.v. every 6 weeks and liraglutide placebo 0 mg s.c. daily
The randomisation will be stratified according to non-fasting C-peptide levels: 
!
non-fasting  C-peptide ≥ 0.2 nmol/l to ≤0.6 nmol/l
!
non-fasting  C-peptide >0.6 nmol/l
11.1
Breaking of blinded codes
The IV/WRS will notify Novo Nordisk (monitor and the Global Safety department) immediately 
after the code is broken.
The code for a particular subject may be broken in a medical emergency if knowing the actual 
treatment would influence the treatment of the subject. Whenever a code is broken the person 
breaking the code must print the Code Break Confirmation Notification generated by the IV/WRS, 
record the reason, and sign and date the document.
When the code is broken, the treatment allocation will be accessible tothe investigator and the 
Novo Nordisk Global Safety department. If IV/WRS is not accessible at thetime of code break the 
IV/WRS helpdesk should be contacted. Contact details are listed in Attachment I.
If the code has been broken the subject must be withdrawn from the trial and a withdrawal session 
must be completed in IV/WRS.
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12 Adverse events, and technical complaints and pregnancies
12.1
Definitions
Adverse event 
An adverse event (AE) is any untoward medical occurrence in a subject administered a product, and 
which does not necessarily have a causal relationship with this treatment. 
An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory 
finding), symptom or disease temporally associated with the use of a product, whether or not 
considered related to the product. 
An AE includes:
!
A clinically significant worsening of a concomitant illness.
!
A clinical laboratory adverse event (CLAE): a clinical laboratory abnormality 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.
The following should not be reported as AEs:
!
Pre-existing conditions, including those found as a result of screening procedures (pre-
existing conditions should be reported as 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.
!
Non-serious hypoglycaemia is an AE, but is reported on a hypoglycaemic episode form
instead of on an AE form, see Section 8.4.2.7.
!
Non-serious hyperglycaemia is an AE, but is reported on a hyperglycaemic episode form
instead of on an AE form, see Section 8.4.2.6.
The following three definitions are used when assessing an AE:
!
Severity
–
Mild - no or transient symptoms, no interference with the subject's daily activities.
–
Moderate - marked symptoms, moderate interference with the subject's daily activities.
–
Severe - considerable interference with the subject's daily activities; unacceptable.
!
Causality
Relationship between an AE and the relevant trial product(s):
–
Probable - Good reason and sufficient documentation to assume a causal relationship.
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–
Possible - A causal relationship is conceivable and cannot be dismissed.
–
Unlikely - The event is most likely related to aetiology other than the trial product.
!
Final 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 sequela 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 fatal outcome must be reported 
as an SAE.
–
Unknown - This term is only applicable if the subject is lost to follow-up.
Serious adverse event
A serious adverse event (SAE) is an experience that at any dose results in any of the following:
!
Death.
!
A life-threateninga experience.
!
In-patient hospitalisationb or prolongation of existing hospitalisation.
!
A persistent or significant disability or incapacityc.
!
A congenital anomaly or birth defect.
!
Important medical events that may not result in death, be life threateninga or require 
hospitalisationb may be considered an SAE when - based on appropriate medical judgement 
- they may jeopardise the subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in the definition of SAEd. 
Suspicion of transmission of infectious agents via the trial product must always be 
considered an SAE. 
a.
The term "life threatening" in the definition of SAE refers to an event in which the subject was 
at risk of death at the time of the event. It does not refer to an event which hypothetically might 
have caused death if it was more severe.
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b. The term "hospitalisation" is used when a subject: 
–
Is admitted to a hospital or in-patient, irrespective of the duration of physical stay, or 
–
Stays at the hospital for treatment or observation for more than 24 hours
Medical judgement must always be exercised, and when in doubt, the hospital contact should be 
regarded as a hospitalisation. 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.
c.
A substantial disruption of a subject's ability to conduct normal life functions (e.g. following the 
event or clinical investigation the subject has significant, persistent or permanent change, 
impairment, damage or disruption in his/her body function or structure, physical activity and/or 
quality of life).
d. For example intensive treatment in an emergency room or at home of allergic bronchospasm, 
blood dyscrasiasis or convulsions that do not result in hospitalisation, or development of drug 
dependency or drug abuse.
Severe infections should be reported as SAEs ( i.e. should be reported as an “important medical 
event”, if not fulfilling other SAE criteria like “hospitalisation”).
Non-serious adverse event
A non-serious AE is any AE which does not fulfil the definition of an SAE.
Adverse Events requiring additional information
In this trial the following AEs require the completion of an additional eCRF page:
1. Hypersensitivity reactions
2. Injection/Infusion site reaction 
3. Neoplasm
4. Pancreatitis
5. Thyroid Disease
The following events should be reported on in the e-diary by the subjects. They should only be 
reported on an AE form if they fulfil the criteria of an SAE.
1. Hyperglycaemic episodes 
2. Hypoglycaemic episodes
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Medical event of special interest
A medical event of special interest (MESI) is an event which, in the evaluation of safety, has a 
special focus. A MESI is an AE (SAE or non-serious AE) which fulfils one or more of the below 
defined MESI criteria.
1. Medication errors concerning trial products:
–
Administration of wrong drug or use of wrong device. Note: Use of wrong DUN is not
considered a medication error
–
Wrong route of administration, such as intramuscular instead of subcutaneous.
–
Administration of an overdose with the intention to cause harm (e.g. suicide attempt).
–
Accidental administration of a lower or higher dose than intended. 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.
Note: A drug pause should not be reported as a medication error.
Trial specific AEs.
Severe infections should be reported as SAEs ( i.e. should be reported as an “important medical 
event”, if not fulfilling other SAE criteria like “hospitalisation”).
Any infection requiring hospitalisation and/or which based upon appropriate medical judgement, is
considered to be:
i.
More severe, longer-lasting or harder-to-treat than generally expected (e.g. for ear
infections, pneumonia, meningitis, bronchitis, sinusitis or skin infections)
ii.
An infection with unusual localization
iii.
Re-activation of a latent infection (e.g. JC polyomavirus (progressive multifocal
leukoencephalopathy), Epstein-Barr virus, varicella-zoster virus (herpes zoster),
herpes-simplex virus)
iv.
An opportunistic infection defined as an infection caused by an organism that does
not normally cause disease but may occur in people with weakened immune systems.
These micro-organisms may (but not exclusively) include:
!
Acinetobacter baumanni
!
Aspergillus sp.
!
Blastoschizomyces capitatus
!
Candida albicans
!
Clostridium difficile
!
Cryptococcus neoformans
!
Cryptosporidium
!
Cytomegalovirus
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!
Geomyces destructans
!
Histoplasma capsulatum
!
Isospora belli
!
Kaposi's Sarcoma caused by Human herpesvirus 8 (HHV8), also called
Kaposi's sarcoma-associated herpesvirus (KSHV)
!
Legionnaires' Disease (Legionella pneumophila)
!
Microsporidium
!
Mycobacterium Tuberculosis
!
Mycobacterium avium complex (MAC) (Nontuberculosis Mycobacterium)
!
Pneumocystis jirovecii, previously known as Pneumocystis carinii f. hominis
!
Pseudomonas aeruginosa
!
Staphylococcus aureus
!
Streptococcus pneumoniae
!
Streptococcus pyogenes
!
Trichosporon beigelii
!
Toxoplasma gondii
Technical complaint
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:
!
The physical or chemical appearance of trial products (e.g. discoloration, particles or
contamination)
!
The packaging material (e.g. leakage, cracks, rubber membrane issues or errors in labelling
text)
!
Problems related to devices (e.g. to the injection mechanism, dose setting mechanism, push
button or interface between the pen and the needle)
12.2
Reporting of adverse events
All events meeting the definition of an AE must be collected and reported. This includes events 
from the first trial-related activity after the subject has signed the informed consent2 until the end of 
the post-treatment follow-up period (26 weeks after the end of treatment). The events must be 
recorded in the applicable eCRF forms in a timely manner, see timelines below and Figure 12–1. 
During each contact with the trial site staff, the subject must be asked about AEs and technical 
complaints, for example by asking: "Have you experienced any problems since the last contact?"
2 With the exception of hyperglycaemic and hypoglycamic episodes for which reporting starts at V2.
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All AEs, either observed by the investigator or subject, must be reported by the investigator and 
evaluated. Novo Nordisk assessment of expectedness is performed according to the following 
reference documents: 
!
NN9211 IB, edition 3, 07 August 2013 and updates thereto
!
NN9828 IB, edition 1, 2015 and updates thereto
All AEs must be recorded by the investigator on an AE form. The investigator should report the 
diagnosis, if available. If no diagnosis is available, the investigator should record each sign and
symptom as individual AEs using separate AE forms.
For SAEs a safety information form must be completed in addition to the AE form. If several 
symptoms or diagnoses occur as part of the same clinical picture, one safety information form can 
be used to describe all the SAEs. 
MESIs, regardless of seriousness, must be reported using both the AE form and the safety 
information form and an MESI form. The MESI form is a form tailored to collect specific 
information related to the individual MESI.
The AE form for a non-serious AE not fulfilling the MESI criteria should be signed when the event 
is resolved or at the end of the trial.
Timelines for initial reporting of AEs:
The investigator must complete the following forms in the eCRF within the specified timelines:
!
SAEs: The AE form within 24 hours and the safety information form within 5 calendar
days of the investigator's first knowledge of the SAE.
Both forms must be signed within 7 calendar days from the date the information was entered 
in the eCRF.
!
For SAEs with additional data collection: in addition also the specific event form within 
14 calendar days of the investigator's first knowledge of the AE.
!
Non-serious AEs with additional data collection: The AE form and the specific event 
form within 14 calendar days of the investigator's first knowledge of the event
!
SAEs fulfilling the MESI criteria: In addition to above, the MESI form within 14 
calendar days of the investigator's first knowledge of the AE. 
!
Non-serious AE fulfilling the MESI criteria: The AE form, and safety information form 
and MESI form within 14 calendar days of the investigator's first knowledge of the event.
If the eCRF is unavailable, the concerned AE information must be reported on paper forms and sent 
to Novo Nordisk by fax, e-mail or courier within the same timelines as stated above. When the 
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eCRF becomes available again, the investigator must enter the information on the appropriate forms 
in the eCRF.
Contact details (fax, telephone, e-mail and address) are provided in the investigator trial master file. 
An AE is 
observed and 
reported 
It is an SAE
complete:
!
AE form ≤ 24 hours
!
SIF ≤ 5 calendars days
It is a non-serious AE
complete:
!
AE form
Fulfilling 
seriousness 
criteria?
Additional 
data 
collection 
requeried?
Additional 
data collection 
required?
Complete ≤ 14 calendar 
days:
!
Specific event form
!
For medication Error
(MESI): Medication
Error form
No additional forms to 
be completed
Complete ≤ 14 calendar 
days: 
!
Specific event form
!
For Medication Error
(MESI):  SIF and
Medication Error
form
Yes
No
Yes
No
Yes
No
AE: Adverse Event
SIF: safety information form
All timelines are from the investigator’s
first knowledge of the event
Addtional data collection described in chapter 8.4.2
Figure 12–1
Initial reporting of AEs
Reporting of trial product-related SUSARs by Novo Nordisk:
Novo Nordisk will notify the investigator of trial product-related suspected unexpected serious 
adverse reactions (SUSARs) in accordance with local requirements and GCP 2. In addition, the 
investigator will be informed of any trial-related SAEs that may warrant a change in any trial 
procedure.
In accordance with regulatory requirements, Novo Nordisk will inform the regulatory authorities, 
including EMA, of trial product-related SUSARs. In addition, Novo Nordisk will inform the 
IRBs/IECs of trial product-related SUSARs in accordance with local requirement and GCP 2, unless 
locally this is an obligation of the investigator.
Novo Nordisk products used as concomitant medication:
If a SAE and/or MESI 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.
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12.3
Follow-up of adverse events
The investigator must record follow-up information by updating the forms in the eCRF. 
Follow up information must be reported to Novo Nordisk according to the following:
!
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.
!
Non-serious AE fulfilling the MESI criteria: Non-serious AE fulfilling the MESI criteria 
must be followed as specified for non-serious AEs. Follow-up information on MESIs should 
only include new (e.g. corrections or additional) information and must be reported within 14 
calendar days of the investigator’s first knowledge of the information. This is also the case 
for previously reported non-serious AEs which subsequently fulfil the MESI criteria. 
The investigator must ensure that 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.
Queries or follow-up requests from Novo Nordisk must be responded to within 14 calendar days
from the date of receipt of the request, unless otherwise specified in the follow-up request.
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12.4
Technical complaints and technical complaint samples
12.4.1
Reporting of technical complaints
All technical complaints on any of the following products:
!
NNC0114-0006 C100 mg/ml, 3 ml cartridges
!
NNC0114-0006 C 0 mg/ml, 3ml cartridges
!
Liraglutide 6.0 mg/ml, 3 ml pre-filled pen-injector
!
Liraglutide placebo 3 ml pre-filled pen-injector
!
Needles
which occur from the time of first usage of the product until the time of the last usage of the 
product, must be collected and reported to Customer Complaint Center, Novo Nordisk.
Contact details (fax, e-mail and address) are provided in Attachment I to the protocol.
The investigator must assess whether the technical complaint is related to any AEs, SAEs, and/or
MESI.
Technical complaints must be reported on a separate technical complaint form. A technical 
complaint form for each code or lot number or for each DUN must be completed.
The investigator must complete the technical complaint form in the eCRF within the following 
timelines of the trial site obtaining knowledge of the technical complaint:
!
Technical complaint assessed as related to an SAE within 24 hours
!
All other technical complaints within 5 calendar days
If the eCRF 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 eCRF becomes 
available again, the investigator must enter the information on the technical complaint form in the 
eCRF.
12.4.2
Collection, storage and shipment of technical complaint samples
The investigator must collect the technical complaint sample and notify the monitor within 5 
calendar daysof obtaining the sample at trial site. The monitor must coordinate the shipment to 
Customer Complaint Center, Novo Nordisk (the address is provided in Attachment I) and ensure 
that the sample is sent as soon as possible. Aprint or copy of the technical complaint form must be 
sent with the sample.
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The investigator must ensure that the technical complaint sample contains the code number and, if 
available, the DUN.
If the technical complaint sample is unobtainable, the investigator must specify on the technical 
complaint form why it is unobtainable. 
Storage of the technical complaint sample must be done in accordance with the conditions 
prescribed for the product. The shipment of the technical complaint sample should be done in 
accordance with the same conditions as for storage (see Section 9). 
12.5
Pregnancies
12.5.1
Pregnancies in female subjects
Female subjects must be instructed to notify the investigator immediately if they become pregnant 
during the trial. The investigator must report any pregnancy in subjects who have received trial 
product(s).
The investigator must follow the pregnancy until the pregnancy outcome and the newborn infant is 
one month of age.
The investigator must report information about the pregnancy, pregnancy outcome, and health of 
the newborn infant(s), as well as AEs in connection with the pregnancy, and AEs in the foetus and 
newborn infant.
The following must be collected and reported by the investigator to Novo Nordisk - electronically 
(e.g. in PDF format), or by fax or courier:
1. Reporting of pregnancy information
Information about the pregnancy and pregnancy outcome/health of the newborn infant(s) has to
be reported on Maternal Form 1A and 1B, respectively.
When the pregnancy outcome is abnormal (i.e. congenital anomalies, foetal death including 
spontaneous abortion and/or any anomalies of the foetus observed at gross examination or 
during autopsy), and/or when a congenital anomaly is diagnosed within the first month, further 
information has to be reported for the female subject on Maternal Form 2. In addition, 
information from the male partner has to be reported on the Paternal Form, after an informed 
consent has been obtained from the male partner. 
Initial reporting and follow-up information must be reported within 14 calendar days of the 
investigator's first knowledge of initial or follow-up information. 
2. Reporting of AE information
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The investigator has to report AEs in connection with the pregnancy as well as in the foetus and 
newborn infant(s). The SAEs that must be reported include abnormal outcome, such as foetal 
death (including spontaneous abortion), and congenital anomalies (including those observed at 
gross examination or during autopsy of the foetus), as well as other pregnancy complications 
fulfilling the criteria of an SAE.
Forms and timelines for reporting AEs:
Non-serious AEs: 
–
Paper AE form* within 14 calendar days of the investigator's first knowledge of the 
initial or follow-up information to the non-serious AE.
SAEs: 
–
Paper AE form* within 24 hours of the investigator's first knowledge of the SAE.
–
Paper safety information form within 5 calendar days of the investigator's first 
knowledge of the SAE.
–
SAE follow-up information to the AE form and/or safety information form within 24 
hours of the investigator's first knowledge of the follow-up information.
*
It must be clearly stated in the AE diagnosis field on the AE form if the event occurred in 
the subject, foetus or newborn infant.
Any queries or follow-up requests from Novo Nordisk to non-serious AEs, SAEs and pregnancy 
forms must be responded to by the investigator within 14 calendar days from the date of receipt of 
the request, unless otherwise specified in the follow-up request.
12.5.2
Pregnancies in female partners of male subjects
Male subjects must be instructed to notify the investigator if their female partner becomes pregnant 
during the trial, except in the screening period. At the last scheduled visit, male subjects must be 
asked if their female partner has become pregnant.
If a female partner has become pregnant during the trial, the investigator must follow-up on the 
pregnancy outcome and until the newborn infant is one month of age, irrespective of whether the 
trial is completed or not. The investigator must ask the male subject and assess, if the pregnancy 
outcome is normal or abnormal. 
When the pregnancy outcome is normal this information is recorded in the subject's medical record 
only, no further information is collected and reported to Novo Nordisk. When the pregnancy 
outcome is abnormal (i.e. congenital anomalies, foetal death including spontaneous abortion and/or 
any anomalies of the foetus observed at gross examination or during autopsy), the following must 
be reported by the investigator to Novo Nordisk electronically (e.g. in PDF format) or by fax:
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1. Reporting of pregnancy information
Information from the male subject has to be reported on the Paternal Form. Furthermore,
information from the female partner (including information about the pregnancy outcome and
health status of the infant until the age of one month) has to be reported on the Maternal Forms
1A, 1B and 2, after an informed consent has been obtained from the female partner.
Initial reporting and follow-up information must be reported within 14 calendar days of the 
investigator's first knowledge of initial or follow-up information. 
2. Reporting of AE information
The following AEs in the foetus and newborn infant have to be reported:
–
Non-serious AEs evaluated as possible/probably related to the father's treatment with the
trial product(s).
–
SAEs in the foetus and newborn infant - whether or not related to the father's treatment
with the trial product(s). This includes an abnormal outcome - such as foetal death
(including spontaneous abortion) and congenital anomalies (including those observed at
gross examination or during autopsy of the foetus).
Forms and timelines for reporting AEs:
Please see Section 12.5.1, point 2, "Forms and timelines for reporting AEs:". 
Any queries or follow-up requests from Novo Nordisk to non-serious AEs, SAEs and pregnancy 
forms must be responded to by the investigator within 14 calendar days from the date of receipt of 
the request, unless otherwise specified in the follow-up request.
12.6
Precautions and/or overdose
12.6.1
NNC0114-0006
Because of the early stage of clinical development of NNC0114-0006, no special warnings or 
precautions can be formulated at present. No clinically relevant safety findings have been observed 
in the non-clinical studies, or by the limited clinical safety data emerged to date, that would 
conclude any specific recommendations, e.g. on AE or laboratory monitoring.
Administration of NNC0114-0006 must take place in an environment where access to resuscitation 
equipment (i.e. ventilation balloon and medication for treatment of hypersensitivity reactions) is 
available in case of an acute reaction/or development of other unpredicted, serious or life-
threatening reactions. Written emergency procedures must be in place, and the clinical staff 
responsible for dosing and monitoring the subjects must be adequately trained in emergency 
procedures.
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To date, no subjects have accidentally been overdosed with NNC0114-0006, as no subjects have 
received doses of NNC0114-0006 exceeding the dose level of any planned dose ranges in the FHD 
trial. The highest dose level tested in the FHD trial was 25 mg/kg administered i.v. and this dose 
level was well tolerated in both healthy subjects, subjects with RA and subjects with Crohn’s 
Disease. In case of an overdose, treatment with NNC0114-0006 should be suspended and 
appropriate medical supportive treatment of clinical signs should be given.
For further information, please refer to the current version of the NN9828 IB.
12.6.2
Liraglutide
When initiating treatment with liraglutide, the subject may in some cases experience loss of 
fluids/dehydration, e.g. in case of vomiting, nausea or diarrhoea, sometimes with a decrease in 
kidney function. It is important to avoid dehydration by drinking enough fluids.
From clinical trials and marketed use overdoses have been reported up to 40 times the 
recommended maintenance dose (72 mg). Events reported included severe nausea and severe 
vomiting. None of the reports included severe hypoglycaemia. All patients recovered without 
complications.
For further information, please refer to the current version of the NN9211 IB.
12.7
Committees related to safety
12.7.1
Novo Nordisk safety committee
Novo Nordisk will constitute an internal NN9828 safety committee to perform ongoing safety 
surveillance of clinical trials with NNC0114-0006, including this trial.
The safety committee will conduct on-going monitoring of blinded safety data (all reported adverse 
events, selected safety laboratory parameters, including calcitonin, amylase and lipase).
If safety signals are observed either based on immediate review of serious adverse events reported, 
or based on periodic review of all other adverse events and above mentioned laboratory parameters 
collected during the trial, the safety committee will take appropriate measures to safeguard the 
subjects.
The NN9828 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.
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13 Case report forms
Novo Nordisk will provide a system for the electronic case report forms (eCRF). This system and 
support services to the system will be provided by an external supplier.
Ensure that all relevant questions are answered, and that no empty data field exists. If a test or an 
assessment has not been done and will not be available, or if the question is irrelevant (e.g. is not 
applicable), indicate this according to the data entry instructions.
The following will be provided as paper CRFs:
!
Pregnancy forms
In addition paper AE forms, safety information forms and technical complaint forms will be 
provided. These must be used when access to the eCRF is revoked or if the eCRF is unavailable. 
On the paper CRF forms print legibly, using a ballpoint pen. Ensure that all questions are answered, 
and that no empty data blocks exist. Ensure that no information is recorded outside the data blocks. 
If a test/assessment has not been done and will not be available, indicate this by writing "ND" (not 
done) in the appropriate answer field in the CRF. If the question is irrelevant (e.g. is not applicable) 
indicate this by writing "NA" (not applicable) in the appropriate answer field. Further guidance can 
be obtained from the instructions in the CRF.
The investigator must ensure that all information is consistent with the source documentation. By 
electronically signing the case book in the eCRF, the investigator confirms that the information in 
the eCRF and related forms is complete and correct.
13.1
Corrections to case report forms 
For eCRFs:
Corrections to the eCRF data may be made by the investigator or the investigator's delegated staff.
An audit trail will be maintained in the eCRF application containing as a minimum: the old and the 
new data, identification of the person entering the data, date and time of the entry and reason for the 
correction.
If corrections are made by the investigator's delegated staff after the date the investigator has signed 
the case book, the case book must be signed and dated again by the investigator.
For paper CRFs
Corrections to the data in CRFs may only be made by drawing a straight line through the incorrect 
data and then writing the correct entry next to the data that was crossed out. Each correction must 
be initialled, dated and explained (if necessary). 
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13.2
Case report form flow 
The investigator must ensure that data is recorded in the eCRF as soon as possible, preferably 
within 5 days after the visit. Once data has been entered, it will be available to Novo Nordisk for 
data verification and validation purposes. Queries will be generate in the eCRF on an ongoing basis, 
and the investigator should solve these queries preferable within 3 business days.
At the end of the trial the investigator must ensure that all remaining data have been entered into the 
eCRF no later than 24 hours after the last visit at the trial site to ensure the planned lock of the 
database. In addition queries must be solved immediately in order to ensure the planned lock of the 
database.
Site specific eCRF data (in an electronic readable format) will be provided to the trial site before 
access to the eCRF is revoked. This data must be retained at the trial site.
When access to update the AE form in the eCRF application is removed, the investigator must 
record any AE follow-up information, if required, on the paper CRFs provided.
Laboratory reports will be retained at the sites. 
13.3
E-diaries
At visit 2 the subjects will be provided with an e-diary device for electronic recording of data  as 
specified in Section 8.6.3 after subjects have been trained in the use of the device. The e-diary 
device will be returned by the subjects at the EOT visit. The e-diary and related support services 
will be supplied by a vendor that will be working under the direction and supervision of Novo 
Nordisk. 
The e-diary will contain built in edit checks, to ensure that all relevant questions are answered. All 
data entered will be transferred automatically from the device to the database, where they are kept 
as a certified copy of source data.  
The e-diary device is not intended to support the subsequent review and modification of completed 
entries. If corrections to transferred data are needed, a query flow will be initiated. Data in the e-
diary will be viewable to relevant sites and Novo Nordisk personnel on a secure, password 
protected web portal. Data will be transferred to the Novo Nordisk trial database at defined 
intervals. 
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14 Monitoring procedures 
During the course of the trial, the monitor will visit the trial site to ensure that the protocol is 
adhered to, that all issues have been recorded, to perform source data verification and to monitor 
drug accountability. The first monitoring visit will be performed as soon as possible after FPFV at 
the trial site and no later than 4 weeks after. The monitoring visit intervals will depend on the 
outcome of the remote monitoring of the eCRFs, the trial site's recruitment rate and the compliance 
of the trial site to the protocol and GCP, but will not exceed 12 weeks.
14.1
Source data verification
The monitor must be given direct access to source 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).
All data must be verifiable in source documentation other than the eCRF.
For all data recorded the source document must be defined in a source document agreement at each 
trial site. There must only be one source defined at any time for any data element. The investigator 
should make a reasonable effort to obtain additional information from external sources e.g. primary 
physician and other hospitals/departments to collect information required to evaluate all in- and 
exclusion criteria if not available in the subject’s medical record at the trial site and if not part of the 
screening assessments performed.
Considering the electronic source data environment, it is accepted that the earliest practically 
retainable record should be considered as the location of the source data and therefore transcription
to the e-diary from glucometer is considered the source document for recordings of glucometer. 
Source data generated by the trial site can be corrected by another person than the person entering 
the source data if accepted by local regulations; any correction must be explained, signed and dated 
by the person making the correction.
The original PROs must not be removed from the trial site.
Data recorded in the subject’s e-diary is considered source data with respect to:
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!
Date, time, dose and injection site of liraglutide
!
4-point profiles
!
7-point profiles
!
Date, time point (e.g. before breakfast, before lunch etc.), value, units and type (basal or
bolus) of insulin doses
!
Reasons for deviating the prescribed insulin dose
!
Carbohydrate intake per meal (CHO-counting subjects only)
!
Hypoglycaemic episodes
!
Hyperglycaemic episodes including ketone data
The monitor will ensure that the eCRFs are completed on an ongoing basis and within agreed 
timelines and that paper CRFs are collected.
The following data will be source data verified for screening failures: 
!
Date for obtaining informed consent.
!
Screen failure reason
Monitors must review the subject's medical records and other source data  to ensure consistency 
and/or identify omissions compared to the eCRF. If discrepanciesare found, the investigator must 
be questioned about these.
A follow-up letter (paper or electronic) will be sent to the investigator following each monitoring 
visit. This should address any action to be taken.
14.2
Titration Surveillance
Surveillance of insulin titration will be performed centrally by an independent Novo Nordisk 
Titration Group not otherwise involved in the conduct of the trial. Surveillance will be performed 
on an ongoing basis throughout the trial. Details are described in Appendix A.
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15 Data management
Data management is the responsibility of Novo Nordisk. Data management may be delegated under 
an agreement of transfer of responsibilities to a contract research organisation (CRO). 
Appropriate measures, including encryption of data files containing person identifiable data, will be 
used to ensure confidentiality of subject data, when they are transmitted over open networks. 
Data from central laboratories will be transferred electronically from the laboratory performing the 
analyses. In cases where data is transferred via non-secure electronic networks, data will be 
encrypted during transfer.
The subject and any biological material obtained from the subject will be identified by subject 
number and trial ID. Appropriate measures such as encryption or leaving out certain identifiers will 
be enforced to protect the identity of subjects in all presentations and publications as required by 
local, regional and national requirements.
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16 Computerised systems
Novo Nordisk will capture and process clinical data using computerised systems that are described 
in Novo Nordisk Standard Operating Procedures and IT architecture documentation. The use and 
control of these systems are documented.
Investigators working on the trial may use their own electronic systems to capture source data. 
Novo Nordisk will collect information on practical use of these systems within the conduct of this 
trial.
The e-diary software and hardware implementation are compliant with the requirements of FDA 21 
CFR Part 1139. After trial finalisation, each trial site will be supplied with electronic media 
containing site-specific subject records including the subjects’ diaries and audit trail including any 
data additions and corrections made. Novo Nordisk will furthermore retain and securely store 
copies of all archived documents and data.
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17 Statistical considerations
If necessary, a statistical analysis plan (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.
Based on the statistical model, treatment means or geometric means (LSMeans) and treatment 
comparisons (i.e. treatment differences or treatment ratios) will be presented with 95% confidence 
intervals (CI) and p-values for the two-sided test of no treatment difference. A significance level of 
5% will be used. All pairwise treatment differences (or ratios) will be presented. No adjustment for 
multiple testing will be performed.
Some endpoints will be summarised for the treatment period, for the observation period and for the 
entire trial period (i.e. the treatment period together with the observation period)
The treatment period and the observation period will be derived for completed subjects as
!
The start of the treatment period will be the date of first trial product administration
!
The end of the treatment period will be the day before the visit at week 54 (i.e. the day 
before visit 63)
!
The start of the observation period will be the day after the end of the treatment period
!
The end of the observation period will be the date of the last visit
For withdrawn subjects the date of last contact will be the maximum of the date of the last visit and 
the withdrawal date. The treatment period and the observation period will be derived for withdrawn 
subjects as
!
The start of the treatment period will be defined as described for completed subjects
!
The end of the treatment period will be as defined for competed subjects if this date is 
before or on the date of last contact. Otherwise the end of the treatment period will be the 
date of last contact
!
An observation period will only be defined if the date of last contact is after the end of the 
treatment period
–
The start of the observation period will be defined as for completed subjects
–
The end of the observation period will be the date of last contact
For endpoints evaluated as change from baseline and/or for baseline adjustment in the statistical 
analyses, baseline will be defined as the information recorded at the Visit 3 (randomisation). If no 
measurement is available at Visit 3, then the information recorded at Visit 2 will be used as the 
baseline. Furthermore, if no measurement is available at Visit 2, then the information recorded at 
Visit 1 will be used as the baseline.
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As there is no previous experience with NNC0114-0006 in subjects with T1DM, the defined 
endpoints and analyses may be supplemented with additional endpoints or analyses such that a 
better evaluation of the effect and safety of NNC0114-0006 can be obtained.
17.1
Sample size calculation
This is a phase 2 trial and the first Novo Nordisk trial of NNC0114-0006 in subjects with newly 
diagnosed T1DM. Therefore the knowledge on treatment effects and on the standard deviation of 
the primary endpoint is limited. 
The statistical power calculations have been done under the following assumptions
!
The primary endpoint is AUC0-4h for a MMTT stimulated C-peptide concentration-time
curve at week 54 relative to baseline, i.e. AUC0-4h, C-peptide, 54w/AUC0-4h, C-peptide, baseline. The
primary endpoint will be log-transformed in the statistical analysis and this will be denoted
ln(AUC0-4h,C-peptide,∆54w). Thus, AUC0-4h, C-peptide,∆54w is the proportion of AUCC-peptide that is
preserved after 54 weeks relative to the level at baseline. E.g. a reduction of AUCC-peptide of
35% corresponds to a preservation of 65% and value of the ln(AUC0-4h,C -peptide,∆54w) is
ln(0.65)=-0.431.
!
The residual standard deviation of ln(AUC0-4h, C-peptide, Δ54w) in the model described above
may depend on the treatment. Based on the results of Herold et al. 40 the standard deviation
is assumed to be 1 in the placebo group and 0.5 in the group treated with NNC0114-0006 in
combination with liraglutide.
!
The expected preservation in the placebo treated patients is 65%, based on the results of
Herold et al. 40 who found a mean of 70% decline in AUCC-peptide over a 24-months period.
Assuming a linear decline, the mean 12-months decline would be 35%, i.e. a preservation of
65%. The statistical power calculations have been done assuming three levels of treatment
effects for NNC0114-0006 in combination with liraglutide; a preservation of 85% and 95%
and 98%, respectively.
Table 17–1 shows the statistical power for the test of no treatment effect if the true mean 
preservation is 85%, 95% or 98% in the group treated with NNC0114-0006 in combination with 
liraglutide and 65% in the placebo group when the numbers of completers are 40, 60 or 80, 
respectively using a two-sided test and 5% level of significance. The rows corresponding to the 
chosen number of (completing) subjects are highlighted.
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Date:
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Version:
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Table 17–1
Power calculations
True treatment effect (preservation)
N (completers per group)
Statistical power
85%
40
0.320
85%
60
0.451
85%
80
0.566
95%
40
0.561
95%
60
0.740
95%
80
0.854
98%
40
0.628
98%
60
0.804
98%
80
0.903
Assuming a preservation of 98% and a SD of 0.5 for NNC0114-0006 in combination with 
liraglutide and a preservation of 65% and a SD of 1 for placebo, then the power will be 80.4% with 
60 subjects completing the trial in each of the two treatment arms.
17.2
Definition of analysis sets
The following analysis sets are defined in accordance with the ICH-E9 41 guidance:
!
The full analysis set (FAS) will include all randomised subjects. Only in exceptional cases
subjects may be excluded from the FAS. In such cases the reason for exclusion 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 treated’.
!
The PK analysis set will include all randomised subjects with at least one valid PK
measurement. Subjects in the PK analysis set will contribute to the evaluation ‘as treated’.
!
The safety analysis set will include all subjects receiving at least one dose of randomised
treatment. Subjects in the safety analysis set will contribute to the evaluation ‘as treated’.
Analyses of efficacy and biomarker endpoints will be based on the FAS. Analyses of the PK 
endpoints will be based on the PK analysis set. Analyses of safety endpoints will be based on the 
safety analysis set.
Before the database is locked and ready for statistical analysis a review of all data will take place. 
Extreme values and outliers will be identified by the study group during programming and data 
review according to ICH-E9 41 using a fake randomisation. In addition, protocol deviations, which 
may potentially affect the results, will be identified and it will be evaluated if subjects and/or data 
should be excluded from analysis.
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Obviously erroneous data points may be excluded from the analyses or re-analysed (in case of e.g. 
serum concentrations). The decision to re-analyse or exclude data points from the statistical analysis 
is the joint responsibility of the study group. Furthermore, the individual PK profiles with fake 
subject numbers and the individual profiles for C-peptide and plasma glucose from the MMTT will 
be examined prior to database lock to establish whether it is possible to calculate all endpoints. If 
samples are missing that are important for the derivation of the endpoints, certain endpoints will not 
be calculated and they will be excluded from the analysis. In these cases, the subjects, observations 
or endpoints to be excluded and the reason for their exclusion will be documented prior to database 
lock. The subjects and observations excluded from analysis and the reason for exclusion will also be 
described in the clinical trial report.
The impact of protocol deviations and outliers may be investigated further in sensitivity analyses, if 
deemed relevant.
17.3
Primary endpoint
The primary endpoint is AUC0-4h for a MMTT stimulated C-peptide concentration-time curve at 
week 54 relative to baseline: AUC0-4h, C-peptide, 54w/AUC0-4h, C-peptide, baseline.
More specifically, AUC0-4h, C-peptide, t at time ‘t’ will be determined as the area from 0 to 4 hours 
under the C-peptide concentration profile after a MMTT using the trapezoidal method based on 
observed concentration values and actual measurement times. If the MMTT is stopped before 4 
hours due to hyperglycaemia or hypoglycaemia, the last measured C-peptide concentration will be 
carried forward for calculation of the primary endpoint. If the MMTT is stopped before 4 hours it 
will most likely be due to hyperglycaemia as hypoglycaemia is not expected when a high amount of 
carbohydrates are ingested. Using LOCF will result in an overestimated AUC since the C-peptide 
response is expected to be at the maximum level during hyperglycaemia. Furthermore, the risk of 
hyperglycaemia during MMTT will be higher in the placebo group if the active treatments have an 
effect on beta-cell preservation. Thus, LOCF is considered as a conservative approach.
The AUC0-4h for MMTT stimulated C-peptide is derived at baseline and at 12, 24, 36, and 54 weeks 
and is denoted AUC0-4h, C-peptide, t, where t is the time of the assessment. Thus, t=54 weeks 
corresponds to the primary endpoint.
Let yit denote the value of AUC0-4h, C-peptide,∃t evaluated relative to baseline at time t for subject i, i.e. 
yit = AUC0-4h, C-peptide,∃t = AUC0-4h, C-peptide, t/AUC0-4h, C-peptide, baseline
yit will be analysed using a multiplicative repeated measurements model including all available 
assessments over time with treatment, stratum and sex as factors and ln(AUC0-4h, C-peptide, baseline) and 
age at baseline as covariates (see Table 17–2). The interaction between all variables and visit 
(week) will be included in the model.
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Table 17–2
Model terms for the statistical model for the primary endpoint
Model term
Description
ln(yit)
dependent variable, subject i, time t
ln(AUC0-4h, C-peptide, baseline)
fixed effect covariate with a visit dependent coefficient
Visit
fixed effect factor corresponding to time t=12w, 24w, 36w, 54w
Treatment
fixed effect interaction term between treatment and visit (i.e. the treatment effect is 
not assumed the same for all visits), with treatment as a factor with 4 levels: 
NNC0114-0006 in combination with liraglutide, NNC0114-0006, liraglutide and 
placebo 
Stratum
fixed effect interaction term between stratum and visit, with stratum as a factor with 
two levels according to non-fasting C-peptide measurement at screening: 0.2-0.6 
nmol/l and >0.6 nmol/l
Age
fixed effect covariate with a visit dependent coefficient
Sex
fixed effect interaction term between sex and visit
The variance-covariance matrix for the repeated measurements for each subject will be unstructured 
and may depend on treatment, if an assumption of equal variance-covariance matrix between 
treatments turns out not to be reasonable. 
From the model, least square means (LSMeans) for each treatment group at selected time points, 
including week 54 will be estimated, and mean differences between treatment groups in log-
transformed AUC0-4h, C-peptide,∃t at these time points will be estimated. These estimates will be back-
transformed to the original scale to represent treatment (geometric) means and treatment (geometric 
mean) ratios with 95% CIs.
The primary endpoint will be summarised using descriptive statistics and presented graphically.
Sensitivity analyses
The following sensitivity analyses will be made
!
To assess the impact of the subjects for whom the MMTT is stopped before 4 hours due to
hyperglycaemia or hypoglycaemia, a sensitivity analysis will be performed excluding these
subjects
!
An analysis using last observation carried forward (LOCF) of the primary endpoint. The
analysis will be made using a normal linear regression model for the log-transformed
primary endpoint with treatment, stratum and sex as fixed factors and age and baseline value
(log-transformed) as covariates
!
An analysis based on the subjects completing the treatment period (i.e. completing the visit
at week 54). The analysis will be made using a normal linear regression model for the log-
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transformed primary endpoint with treatment, stratum and sex as fixed factors and age and 
baseline value (log-transformed) as covariates
Exploratory analyses
An exploratory analysis will be made to investigate a potential interaction between treatment and 
stratum for the primary endpoint. The analysis will be made by adding the interaction between 
stratum, treatment and visit as a factor in the mixed model for repeated measurements (MMRM)
described for the primary endpoint. The treatment means and the treatment ratios at selected time 
points including week 54 will be presented with 95% CIs for each stratum separately. 
The effect of the biomarkers at baseline and high resolution HLA (class I) genotyping on the 
primary endpoint will be explored one variable at a time.
For continuous variables, the analysis will be made by adding the biomarker at baseline (log-
transformed) as a fixed effect covariate with a coefficient that depends on visit and treatment to the 
MMRM described for the primary endpoint. The estimated effect of the variable at selected time 
points including week 54 will be presented with a 95% CI for each treatment.
For categorical variables, the analysis will be made by adding a fixed effect interaction term 
between the variable, treatment and visit to the MMRM described for the primary endpoint. The 
treatment means and the treatment ratios at selected time points including week 54 with 95% CIs 
will be presented for each category of the variable.
An exploratory analysis will be made to investigate a potential effect of the concentration of 
liraglutide on the primary endpoint using data from the two groups of subjects treated with 
liraglutide. This analysis will be made by adding the log-transformed concentration of liraglutide 
measured on the visit corresponding to the last MMTT as a covariate in the analysis using LOCF 
for the primary endpoint.
17.4
Secondary endpoints
17.4.1
Supportive secondary endpoints
17.4.1.1
Efficacy endpoints
Endpoints derived from the mixed meal tolerance test
The endpoints based on the mixed meal tolerance test will be derived from the individual C-peptide 
concentration-time curves and from the individual plasma glucose concentration-time curves. The 
AUC endpoints will be derived using the same approach as described for the primary endpoint. The 
Cmax endpoints will be derived as the ratio between the Cmax at the relevant time points.
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The endpoints will be analysed using a similar model as applied for the primary endpoint except 
that the corresponding value at baseline will be included as a covariate. 
The endpoints will be summarised using descriptive statistics and presented graphically. The C-
peptide concentration-time curves and the plasma glucose concentration-time curves will be 
presented graphically. 
Insulin dose
The total daily insulin dose will be derived as the average of the doses reported on the three days 
prior to the visit. 
The endpoints will be analysed using a similar model as applied for the primary endpoint except 
that the dose at baseline will be included as a covariate. The analysis will be made on the original 
scale (i.e. without log-transformation). Consequently, treatment means (LSMeans) and treatment 
differences will be presented with 95% CIs.
The endpoints will be summarised using descriptive statistics and presented graphically.
Number of insulin injections
The number of insulin injections will be derived as the average of the reported number on the three 
days prior to the visit. The endpoints will be summarised using descriptive statistics.
HbA1c, FPG, fasting C-peptide and fasting glucagon
The HbA1c and FPG endpoints will be analysed using a similar model as described for the primary 
endpoint except that the corresponding value at baseline will be included as a covariate and the 
analysis will be made on the original scale (i.e. without the log-transformation). Consequently, 
treatment means (LSMeans) and treatment differences will be presented with 95% CIs.
The fasting C-peptide and fasting glucagon endpoints will be analysed using a similar model as 
described for the primary endpoint except that the corresponding value at baseline will be included 
as a covariate. The values will be log-transformed prior to analysis, i.e. the change will be 
calculated for the log-transformed data and the log-transformed value at baseline will be included as 
a covariate.
The endpoints will be summarised using descriptive statistics and presented graphically.
Self-measured plasma glucose profiles
The 7-point SMPG profile will include a pre-meal measurement and a measurements 90 minutes 
after start of meal for breakfast lunch and dinner as well a measurement at bedtime.
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The 4-point SMPG profile will be used for titration of the insulin dose and will include a pre-meal 
measurement for breakfast, lunch and dinner and a measurement at bedtime.
7-point profiles at week 54 and week 80
A normal linear mixed effect model will be fitted to the 7-point SMPG profile data at week 54. The 
model will include treatment, time-point, the interaction between treatment and time-point, sex and 
stratum as fixed factors, age as a covariate and subject as a random effect. The variance-covariance 
matrix will be unstructured and may depend on treatment if an assumption of equal variance-
covariance matrix between treatments turn out not to be reasonable. From this model the treatment 
differences at each time-point will be estimated and explored.
The same analysis will be made using the 7-point SMPG profile data at week 80.
The 7-point SMPG profiles will be summarised using descriptive statistics and presented 
graphically.
Change in prandial increment and change in mean of 7-point profile
The prandial increment at a meal will be calculated as the post-meal measurement minus the pre-
meal measurement. The prandial increment will be calculated for breakfast, lunch and dinner 
separately. The average over the three meals will also be calculated. The mean of the 7-point SMPG 
profile will be calculated as the mean of all 7 points.
The endpoints will be analysed using a similar model as described for the primary endpoint except 
that the corresponding value at baseline will be included as a covariate and the analysis will be 
made on the original scale. Consequently, treatment means (LSMeans) and treatment differences 
will be presented with 95% CIs.
The endpoints will be summarised using descriptive statistics and presented graphically.
Before breakfast SMPG
The within-subject variability will be evaluated using the before breakfast measurements from 4-
point SMPG profiles at week 54 and week 80.
A normal liner mixed effect model will be fitted to the before breakfast SMPG values at week 54. 
The model will include treatment, sex and stratum as fixed factors, age as a covariate and subject as 
a random effect. The model will assume independent within- and between-subject error variances 
depending on treatment. The within-subject variance will be presented for each treatment with the 
95% CI. The 95% CI will be calculated using the delta method.
The same analysis will be made for the before breakfast SMPG values at week 80.
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PRO endpoints
Data collected with the PRO questionnaires (SF-36v2, Experience of Treatment Benefits and 
Barriers, and DTSQ (status)) will be scored according to the instruments’ respective scoring 
algorithms into the following endpoints (domains)
!
For Experience of Treatment Benefits and Barriers:
–
’Perceived benefits’
–
’Perceived barriers’
!
For Diabetes Treatment Satisfaction Questionnaire (status):
–
’Treatment satisfaction’
–
‘Perceived frequency of hypoglycaemia’
–
‘Perceived frequency of hyperglycaemia’
!
For SF-36v2:
–
‘Physical Component Summary’ score
–
‘Mental Component Summary’ score
–
‘Physical functioning’
–
‘Role-physical’
–
‘Bodily pain’
–
‘General health’
–
‘Vitality’
–
‘Social functioning’
–
‘Role-emotional’
–
’Mental health’
The PRO endpoints will be summarised using descriptive statistics.
Biomarker endpoints
The biomarker endpoints will be analysed using a similar model as described for the primary 
endpoint except that the corresponding value at baseline will be included as a covariate and the 
analysis will be made on the original scale. Consequently, treatment means (LSMeans) and 
treatment differences will be presented with 95% CIs. If the model assumptions are not fulfilled 
then transformations of the data will be considered, e.g. the change will be calculated on the log-
transformed data and the log-transformed value at baseline will be included as a covariate.
The biomarker endpoints will be summarised using descriptive statistics and presented graphically.
17.4.1.2
Safety endpoints
Adverse events, DKA episodes and infusion/injection site reactions
All adverse events (including  DKA episodes and infusion/injection site reactions) will be coded 
using the latest version of Medical Dictionary for Regulatory Activities (MedDRA). An adverse 
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event will be defined as treatment emergent if the onset of the adverse event occurs on or after the 
first day of trial product administration.
Treatment emergent adverse events will be summarised by system organ class, preferred term, 
seriousness, severity and relation to trial product. Separate summaries will be made for treatment 
emergent DKA episodes and for treatment emergent infusion/injection site reactions. The 
summaries will be made for the treatment period, for the observation period and for the entire trial 
period. 
Additional information will be recorded on special eCRF pages for selected adverse events. This 
information will be listed.
All adverse events will be listed and separate listings will be made for DKA episodes and 
infusion/injection site reactions.
Hyperglycaemic episodes
Hyperglycaemic episodes will be defined as treatment emergent if the onset occurs on or after the 
first day of trial product administration.
The number of treatment emergent hyperglycaemic episodes will be summarised by treatment. The 
summaries will be made for the treatment period, for the observation period and for the entire trial 
period.
Hypoglycaemic episodes
Classification of Hypoglycaemia: 
Treatment emergent: hypoglycaemic episodes will be defined as treatment emergent if the onset of 
the episode occurs on or after the first day of trial product administration, and no later than 1 day 
after the date of last contact.
Nocturnal hypoglycaemic episodes: are episodes occurring between 00:01 and 05.59 both inclusive.
Hypoglycaemic episodes are classified according to the Novo Nordisk classification of 
hypoglycaemia (see Figure 17–1) and the ADA classification of hypoglycaemia (see Figure 17–2).
Novo Nordisk classification of hypoglycaemia
In normal physiology, symptoms of hypoglycaemia occur below a plasma glucose level of 3.1 
mmol/l (56 mg/dl) 42.Therefore, Novo Nordisk has included hypoglycaemia with plasma glucose 
levels below this cut-off point in the definition of blood glucose (BG) confirmed hypoglycaemia.
Novo Nordisk uses the following classification (see Figure 17–1) in addition to the ADA 
classification: 
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!
Severe hypoglycaemia according to the ADA classification 33.
!
Symptomatic BG confirmed hypoglycaemia: An episode that is BG confirmed by plasma
glucose value <3.1 mmol/l (56 mg/dl) with symptoms consistent with hypoglycaemia.
!
Asymptomatic BG confirmed hypoglycaemia: An episode that is BG confirmed by plasma
glucose value <3.1 mmol/l (56 mg/dl) without symptoms consistent with hypoglycaemia.
!
Severe or BG confirmed symptomatic hypoglycaemia: An episode that is severe according to
the ADA classification 33 or BG confirmed by a plasma glucose value <3.1 mmol/l (56 mg/dl)
with symptoms consistent with hypoglycaemia.
!
BG confirmed hypoglycaemia: An episode that is BG confirmed by a plasma glucose value <3.1
mmol/l (56 mg/dl) with or without symptoms consistent with hypoglycaemia.
!
Severe or BG confirmed hypoglycaemia: An episode that is severe according to the ADA
classification 33 or BG confirmed by a plasma glucose value <3.1 mmol/l (56 mg/dl) with or
without symptoms consistent with hypoglycaemia.
Hypoglycaemic
episode
PG ≤ 3.9 mmol/l 
(70 mg/dl) 
or 
Alleviation of 
symptoms 
or
Seizure, coma or 
fatal 
SMBG
measurement
PG < 3.1 mmol/l
(56 mg/dl)
with symptoms
PG < 3.1 mmol/l
(56 mg/dl)
without
symptoms
Symptomatic BG 
confirmed 
hypoglycaemia
Asymptomatic BG 
confirmed 
hypoglycaemia
Yes
No
Severe or 
BG confirmed 
symptomatic 
hypoglycaemia
BG confirmed 
hypoglycaemia
Severe or BG 
confirmed 
hypoglycaemia
Note: Glucose measurements are performed with capillary blood calibrated to plasma equivalent glucose values
Subject 
able to 
treat him/
herself
Severe 
hypoglycaemia
(ADA 2013)
Figure 17–1
Novo Nordisk classification of hypoglycaemia
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ADA classification 33 of hypoglycaemia
! Severe hypoglycaemia: An episode requiring assistance of another person to actively administer
carbohydrate, glucagon, or take other corrective actions. Plasma glucose concentrations may
not be available during an event, but neurological recovery following the return of plasma
glucose to normal is considered sufficient evidence that the event was induced by a low plasma
glucose concentration.
! Asymptomatic hypoglycaemia: An episode not accompanied by typical symptoms of
hypoglycaemia, but with a measured plasma glucose concentration ≤ 3.9 mmol/l (70 mg/dl).
! Documented symptomatic hypoglycaemia: An episode during which typical symptoms of
hypoglycaemia are accompanied by a measured plasma glucose concentration ≤ 3.9 mmol/l (70
mg/dl).
! Pseudo-hypoglycaemia: An episode during which the person with diabetes reports any of the
typical symptoms of hypoglycaemia with a measured plasma glucose concentration > 3.9
mmol/l (70 mg/dl) but approaching that level.
! Probable symptomatic hypoglycaemia: An episode during which symptoms of hypoglycaemia
are not accompanied by a plasma glucose determination but that was presumably caused by a
plasma glucose concentration ≤ 3.9 mmol/l (70 mg/dl).
Hypoglycaemic 
episode 
PG ≤ 3.9 mmol/l 
(70 mg/dl) 
or 
Alleviation of 
symptoms 
or
Seizure, coma or 
fatal 
SMBG
measurement
Asymptomatic 
hypoglycaemia
Documented 
symptomatic 
hypoglycaemia
Pseudo-
hypoglycaemia
Probable 
symptomatic 
hypoglycaemia
No
Yes
No measurement 
with symptoms
PG > 3.9 mmol/l 
(70 mg/dl)
with symptoms
PG ≤3.9 mmol/l 
(70 mg/dl)
with symptoms
PG ≤3.9 mmol/l 
(70 mg/dl)
without symptoms
No
Yes
Note: Glucose measurements are performed with capillary blood calibrated to plasma equivalent glucose values
Subject 
able to 
treat him/
herself
Severe 
hypoglycaemia
(ADA 2013)
Figure 17–2
ADA classification of hypoglycaemia
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Date:
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Analysis of hypoglycaemic episodes
The number of treatment emergent hypoglycaemic episodes will be summarised by treatment. 
Separate summaries will be made for the Novo Nordisk and for the ADA classifications and for 
nocturnal episodes. The summaries will be made for the treatment period, for the observation period 
and for the entire trial period.
The total number of treatment emergent severe or BG confirmed symptomatic hypoglycaemic 
episodes will be analysed using a negative binominal regression model with a log link function, and 
the logarithm of the exposure time as an offset. The model will include treatment, stratum and sex 
as factors and age as a covariate. The treatment ratio will be estimated and the corresponding two-
sided 95% CI will be calculated. The analysis will be made for the treatment period, for the 
observation period and for the entire trial period.
The total number of treatment emergent nocturnal severe or BG confirmed symptomatic 
hypoglycaemic episodes will be analysed using the same model as above. The analysis will be made 
for the treatment period, for the observation period and for the entire trial period.
To the extent that data allows, additional analyses may be performed for the other classes of 
hypoglycaemic episodes using the same model as described above.
Sensitivity analyses will be made (for each analysed class of hypoglycaemia) comparing number 
and individual rates of hypoglycaemic episodes, respectively, using the Wilcoxon-Mann-Whitney 
method. This will be made for all different pairs of treatments.
Body weight
The body weight endpoints will be analysed using a similar model as described for the primary 
endpoint except that the body weight at baseline will be included as a covariate and the analysis will 
be made on the original scale. Consequently, treatment means (LSMeans) and treatment differences 
will be presented with 95% CIs.
Body weight endpoints will be summarised using descriptive statistics and presented graphically.
Diabetes complications, eye examination and physical examination
The endpoints for eGFR will be analysed using a similar model as described for the primary 
endpoint except that the corresponding value at baseline will be included as a covariate and the 
analysis will be made on the original scale. Consequently, treatment means (LSMeans) and 
treatment differences will be presented with 95% CIs. If the model assumptions are not fulfilled 
then transformations of the data will be considered, e.g. the change will be calculated on the log-
transformed data and the log-transformed value at baseline will be included as a covariate.
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The endpoints will be summarised. The endpoints for eGFR will be presented graphically.
Laboratory safety variables (haematology, biochemistry, coagulation, lipids, IgE, urine 
dipsticks, cytokine panel and hormones)
The laboratory safety variables will be flagged if outside the reference range and abnormal values 
will be listed.
The endpoints for the laboratory safety variables will be summarised and the numerical variables 
will be presented graphically.
The endpoints for amylase and lipase will be analysed using a similar model as described for the 
primary endpoint except that the corresponding value at baseline will be included as a covariate. 
The individual values will be log-transformed prior to analysis, i.e. the change will be calculated on 
the log-transformed data and the log-transformed value at baseline will be included as a covariate. 
The endpoints for TSH, IgE and cytokine panel will be analysed using a similar model as described 
for the primary endpoint except that the corresponding value at baseline will be included as a 
covariate and the analysis will be made on the original scale. Consequently, treatment means 
(LSMeans) and treatment differences will be presented with 95% CIs. If the model assumptions are 
not fulfilled then transformations of the data will be considered, e.g. the change will be calculated 
on the log-transformed data and the log-transformed value at baseline will be included as a 
covariate.
Vital signs and ECG
The systolic blood pressure, diastolic blood pressure and pulse endpoints will be analysed using a 
similar model as described for the primary endpoint except that the corresponding value at baseline 
will be included as a covariate and the analysis will be made on the original scale. Consequently, 
treatment means (LSMeans) and treatment differences will be presented with 95% CIs.
The endpoints will be summarised. The numerical endpoints will be presented graphically.
Anti-NNC0114-0006 antibodies and anti-liraglutide antibodies
The endpoints will be summarised and presented graphically.
17.4.1.3
Pharmacokinetic endpoints
The PK endpoints described in Table 17–3 will be derived from the individual NNC0114-0006 
concentration-time curves after the first dose and after the last dose of NNC0114-0006. 
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Furthermore, the trough concentration prior to dosing and the concentration 1 hour after dosing will 
be determined for NNC0114-0006 and the liraglutide concentration will be determined for 
liraglutide at the visits specified in Section 2.
Table 17–3
Definition and calculation of PK endpoints
Endpoint
Description
Calculation
AUCτ, NNC0114-0006
Area under the NNC0114-0006 
concentration-time curve over a dosing 
interval at steady state (SS) (defined as 
after last dose)
AUCτ, NNC0114-0006 will be derived as the area 
under the concentration-time curve using the 
linear trapezoidal technique based on observed 
values and actual measurement times between 0 
and 6 weeks (after the last dose).
Missing values will be imputed using linear 
interpolation, possibly using measurements after 
6 weeks. If the end time of the interval (i.e. 6 
weeks) is after the time of the last quantifiable 
concentration, tz, and the terminal rate constant, 
λz, can be determined then AUCτ, NNC0114-0006 will 
be derived as the sum of AUC0-tz, NNC0114-0006 and 
AUCtz-6 weeks, NNC0114-0006, where 
AUCtz-6 weeks,NNC0114-0006 will be approximated 
using estimated values from the linear regression 
model applied for estimation of λz. If λz cannot be 
determined, then AUC0-tz, NNC0114-0006 will be used 
instead of AUCτ, NNC0114-0006.
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Date:
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Endpoint
Description
Calculation
λz
Terminal rate constant for NNC0114-
0006 (this is not an endpoint but it is 
used for calculation of some 
endpoints)
The terminal rate constant λz will be determined 
through linear regression with the logarithm to 
concentration as the response variable and actual 
measurement time as the explanatory variable. 
Valid observations from the terminal part of the 
curve, which is approximately linear, will be used 
for the determination. 
t½
Terminal serum half-life after last dose 
of NNC0114-0006
Calculated as log(2)/λz
Vss, NNC0114-0006
The apparent volume of distribution of 
NNC0114-0006 at steady-state
Calculated as MRTNNC0114-0006 * CLSS, NNC0114-0006
CLss, NNC0114-0006
Clearance of NNC0114-0006 at steady 
state
Calculated as dose/AUCτ, NNC0114-0006
MRTNNC0114-0006
The mean residence time of 
NNC0114-0006
Calculated as
MRT
= AUMC + τ ∗AUC
AUC
where
AUC = AUC + AUC − AUC
and
AUMC = 
( − )( + )


RA,AUC, NNC0114-0006
Accumulation ratio of NNC114-0006 
defined as AUC48-54 weeks/AUC0-6 weeks
AUC48-56 weeks will be calculated as described for 
AUCτ, NNC0114-0006.
AUC0-6 weeks will be calculated using a similar 
approach except that extrapolation using λz will 
not be made
The PK endpoints will be summarised using descriptive statistics. The PK data will be presented 
graphically.
17.5
Interim analysis
No formal interim analysis has been planned.
17.6
Pharmacokinetic and/or pharmacodynamic modelling
PK data for anti-IL-21, PD data for C peptide (reflecting beta cell function) from the Meal 
Tolerance Tests, and other pharmacodynamic markers may be used for population PK and PK/PD 
modelling if relevant to support dose selection and trial design of potential future trials. This 
exploratory analysis will not be reported in the Clinical Trial Report.
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17.7
Health economics and/or patient reported outcomes
Please refer to Section 17.4.1.1 for a description of the PRO endpoints. The results will be included 
in the clinical trial report.
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18 Ethics
18.1
Benefit-risk assessment of the trial
NNC0114-0006 has been developed for treatment of chronic inflammatory and autoimmune 
diseases. A total of approximately 158 healthy subjects and subjects with RA, SLE, and Crohn’s 
Disease have received active treatment, either as single doses or multiple doses (up to 4 doses in 
total). The safety profile generated by non-clinical safety studies and the clinical trials conducted 
have not raised any safety concerns. For the completed trials in subjects with RA (including at total 
of 114 subjects) and in subjects with Crohn’s Disease (including a total 53 subjects), a tendency 
towards an increased risk of mild infections when treated with NNC0114-0006 compared to 
placebo was observed. No pattern in time to onset or duration of these events has been identified; 
however a potential risk of mild infections in relation to treatment with NNC0114-0006 is present.
Theoretical risks when treating with NNC0114-0006 include immunogenicity, local infusion 
reactions, hypersensitivity reactions and AEs associated with the inhibition of IL-21-mediated 
signalling such as other (severe and opportunistic) infections and malignancies. As with other anti-
inflammatory therapies, suppression of the immune system may carry an inherent risk of 
compromising host immunity. In the non-clinical safety studies in cynomolgus monkeys, a 
decreased antibody response to immunisation with specific antigens has been observed in 
accordance with the expected pharmacology of NNC0114-0006. Therefore a decreased response to 
vaccinations cannot be excluded. In alignment with labels of other immune-modulatory compounds, 
administrations of live vaccines are excluded during clinical trials.
The concept of combining immunotherapy with another agent was recently tested in the NOD 
recent onset diabetes model using a combination regimen of anti-IL-21 (NNC0114-0008) and 
liraglutide. These experiments used a two-week course of 5 injections at 25 mg/kg of NNC0114-
0008 combined with daily liraglutide administration. In the spontaneous NOD mouse model, the 
first experiment resulted in potent remission from hyperglycaemia in established T1DM, with 
statistically better efficacy as compared to each respective monotherapy. In a repeat study, however, 
the efficacy of NNC0114-0008 monotherapy was equivalent to the combination therapy, and an 
additive effect could not be demonstrated. Finally, in the induced RIP-LCMV mouse model the 
combination treatment outperformed both monotherapies. This suggest that combination treatment 
with liraglutide and NNC0114-006 may preserve beta-cell functions in humans. 
The safety profile of liraglutide is well characterised for use in T2DM, for which indication it has 
been approved and marketed as Victoza®. Liraglutide is generally well tolerated by both healthy 
subjects, obese subjects and subjects with T2DM. AEs related to the gastrointestinal organ system 
were found to be the most common, with nausea being the most frequently reported AE in subjects 
treated with liraglutide. In the clinical development program 42% had one or more gastrointestinal 
related event. The gastrointestinal AEs were most frequent in the early part of the treatment period. 
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Episodes of hypoglycaemia were infrequent due to the glucose-dependent mode-of-action of 
liraglutide. There have been few reported events of acute pancreatitis. Subjects should be informed 
of the characteristic symptom of acute pancreatitis: persistent, severe abdominal pain. If pancreatitis 
is suspected, liraglutide, and other potentially suspect medicinal products should be discontinued. If 
the diagnosis of pancreatitis is confirmed the subject must be withdrawn as described in Section 6.6. 
If a pancreatitis can be excluded all previously discontinued treatments can be re-initiated. 
Novo Nordisk is currently investigating the safety and potential benefits of liraglutide as adjunct 
treatment to insulin in subjects with established T1DM. The emerging safety data generated during 
these ongoing clinical trials with liraglutide in T1DM is being reviewed on an ongoing basis.
Relevant precautions have been implemented in the design and planned conduct of this trial in order 
to minimise the risks. Patient safety will be monitored closely by recording adverse events, 
measuring safety laboratory parameters, local tolerability and antibody development against 
NNC0114-0006 and liraglutide. Adverse events will be evaluated with respect to seriousness, 
severity, time of onset, duration, frequency and outcome, and all safety data generated during the 
present trial will be reviewed on an ongoing basis. 
There will be benefits from a public health point of view and from an individual point of view.
Public health point benefits:
Despite great advances in diabetes care, T1DM is still associated with considerable morbidity and 
premature mortality. T1DM develops when the immune system destroys the insulin-producing 
pancreatic beta-cells. NNC0114-0006 in combination with liraglutide administered to subjects with 
T1DM is expected to provide a new, attractive treatment option for newly diagnosed T1DM
subjects aiming at sustained preservation of endogenous insulin production. Patient benefits could 
consequently include a decrease or elimination of the requirement for administration of exogenous 
insulin and a reduction of both short and long term diabetes complications while improving the 
quality of life.
Individual benefits:
Subjects will get a state-of-art metabolic control during the trial. Subjects will be trained in diabetes 
self-care including carbohydrate counting before and around randomisation and whenever needed in 
order to achieve the most optimal diabetes control. During the trial subjects will receive insulin 
treatment in order to achieve a metabolic control according to the insulin titration guideline.
It is concluded that the potential benefits from participating in the trial outweighs the potential risks. 
The safety profiles of NNC0114-0008 and liraglutide generated from the non-clinical studies and 
clinical trials have not revealed any safety issues that should prohibit administration of either 
NNC0114-0006 or liraglutide to subjects with early onset ofT1DM. The results from this trial are 
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assumed to contribute to the development of new improved treatments for subjects with newly 
diagnosed T1DM.
18.2
Informed consent
In seeking and documenting informed consent, the investigator must comply with applicable 
regulatory requirement(s) and adhere to ICH GCP 2 and the requirements in the Declaration of 
Helsinki 3.
Before any trial-related activity, the investigator must give the subject verbal and written 
information about the trial and the procedures involved in a form that the subject can read and 
understand. 
The subjects must be fully informed of their rights and responsibilities while participating in the 
trial as well as possible disadvantages of being treated with the trial products.
The investigator must ensure the subject ample time to come to a decision whether or not to 
participate in the trial. 
A voluntary, signed and personally dated informed consent must be obtained from the subject 
before any trial-related activity.
The responsibility for seeking informed consent must remain with the investigator, but the 
investigator may delegate the task to a medically qualified person, in accordance with local 
requirements. The written informed consent must be signed and personally dated by the person who 
seeks the informed consent before any trial-related activity.
If information becomes available that may be relevant to the subject’s willingness to continue 
participating in the trial, the investigator must inform the subject in a timely manner, and a revised 
written subject information must be provided and a new informed consent must be obtained.
If the subject agrees to have blood samples taken for genotyping (see Section 8.5.3.1) a separate 
signed informed consent form will be obtained from the subject.
Furthermore if the subject agrees to have a blood sample taken for long term storage of human 
samples (see Section 8.5.3.2) and/or to have some of the blood stored from the T-cell profiling islet-
specific auto reactive CD8+ T-cells samples (see Section 8.5.1.3) a separate signed informed 
consent form will be obtained from the subject.
In case a subject undergoes a thyroidectomy, a separate informed consent will be obtained for 
collection of a blood sample for genetic testing (see Section 8.4.2.2 )
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In case of abnormal outcome of a pregnancy a separate informed consent will be obtained (see 
Section 12.5.1 and 12.5.2.
18.3
Data handling
If the subject is withdrawn from the trial or lost to follow up, then the subject’s data will be handled 
as follows:
!
Data already collected and data collected at the end-of-trial visit and the last safety follow-
up visit (Visit 90) will be retained by Novo Nordisk, entered into the database and used for
the trial report.
!
Safety events will be reported to Novo Nordisk and regulatory authorities according to
local/national requirements.
If data is used, it will always be in accordance with local regulations and IRBs/IECs.
18.4
Information to subject during trial
The site will be offered a communication package to the subject during the conduct of the trial. The 
package content is issued by Novo Nordisk. The communication package will contain the letters 
intended for distribution to the subjects. The letters will be translated and adjusted to local 
requirements and distributed to the subject by 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 letters or other material 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.
18.5
Premature termination of the trial and/or trial site
Novo Nordisk, the IRBs/IECs or a regulatory authority may decide to stop the trial, part of the trial 
or a trial site at any time, but agreement on procedures to be followed must be obtained.
If a trial is suspended or prematurely terminated, the investigator must inform the subjects promptly 
and ensure appropriate therapy and follow-up. The investigator and/or Novo Nordisk must also 
promptly inform the regulatory authorities and IRBs/IECs and provide a detailed written 
explanation. 
If, after the termination of the trial, the benefit-risk analysis changes, the new evaluation must be 
provided to the IRBs/IECs in case it has an impact on the planned follow-up of subjects who have 
participated in the trial. If it has an impact, the actions needed to inform and protect the subjects 
should be described.
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19 Protocol compliance
Deviations from the protocol should be avoided.
If deviations do occur, the investigator must inform the monitor and the implications of the 
deviation must be reviewed and discussed.
Deviations must be documented and explained in a protocol deviation by stating the reason, date, 
and the action(s) taken. Some deviations, for which corrections are not possible, can be 
acknowledged and confirmed via edit checks in the eCRF or via listings from the clinical database.
Documentation on protocol deviations must be kept in the investigator's trial master file and 
sponsor trial master file.
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Version:
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UTN: U1111-1154-7172
Status:
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20 Audits and inspections
Any aspect of the clinical trial may be subject to audits conducted by Novo Nordisk or inspections 
from domestic or foreign regulatory authorities or from IRBs/IECs. Audits and inspections may 
take place during or after the trial. The investigator and the site staff as well as Novo Nordisk staff 
have an obligation to cooperate and assist in audits and inspections. This includes giving auditors 
and inspectors direct access to all source documents and other documents at the trial site relevant to 
the clinical trial. This includes permission to examine, analyse, verify and reproduce any record(s) 
and report(s) that are relevant to the evaluation of the trial.
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Trial ID: NN9828-4150 
Version:
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21
Critical documents
Before a trial site is allowed to start screening subjects, the following documents must be available 
to Novo Nordisk:
!
Regulatory approval and/or acknowledgement of notification as required 
!
Approval/favourable opinion from IRBs/IECs clearly identifying the documents reviewed as 
follows: protocol, any protocol amendments, subject information/informed consent form, 
any other written information to be provided to the subject and subject recruitment materials
!
List of IRB/IEC members and/or constitution (or a general assurance number/statement of 
compliance)
!
Curricula vitae of investigator and sub-investigator(s) (current, dated and signed - must 
include documented GCP training or a certificate)
!
Signed receipt of Investigator's Brochures
!
Signed and dated Agreement on Protocol
!
Signed and dated agreement on protocol amendment, if applicable
!
Contract, signed by the investigator and/or appropriate parties on behalf of the investigator’s 
site and Novo Nordisk
!
Source document agreement
!
Central laboratory certification and normal ranges
!
Insurance statement, if applicable
!
Financial disclosure form from investigator and sub-investigator(s)
Only applicable for US trial sites: 
!
For US trial sites: verification under disclosures per Code of Federal Regulations (CFR) of 
Financial Conflict of Interest
!
For US trial sites: FDA form 1572 must be completed and signed by the investigator at each 
site
FDA form 1572:
For US sites:
!
Intended for US sites
!
Conducted under the IND
!
All US investigators, as described above, will sign FDA Form 1572
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Date:
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Version:
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For sites outside the US:
!
Intended for participating sites outside of the US
!
Not conducted under the IND
!
All investigators outside of the US will not sign FDA form 1572
Novo Nordisk will analyse and report data from all sites together if more than one site is involved in 
the trial.
By signing the protocol, each investigator agrees to comply fully with ICH GCP 2, applicable 
regulatory requirements and the Declaration of Helsinki 3. 
By signing the protocol, each investigator also agrees to allow Novo Nordisk to make investigator's 
name and information about site name and address publically available if this is required by 
national or international regulations.
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Date:
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Status:
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22 Responsibilities
The investigator is accountable for the conduct of the trial at his/her 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 training 
for all staff participating in the conduct of the trial. It is the investigator's responsibility to supervise 
the conduct of the trial and to protect the rights, safety, and well-being of the subjects.
A qualified physician, who is an investigator or a sub-investigator for the trial, must be responsible 
for all trial-related medical decisions.
The investigator must ensure adequate supervision of the conduct of the trial at the trial site. 
The investigator will follow instructions from Novo Nordisk when processing data.
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 should be kept in a secure locked facility, so 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. 
The investigator and other site personnel must have sufficient English skills according to their 
assigned task(s).
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23 Reports and publications
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 physicians who are conducting other 
clinical trials with the trial product, if deemed necessary by Novo Nordisk. Provided that certain 
conditions are fulfilled, Novo Nordisk may grant access to information obtained during this trial to 
researchers who require access for research projects studying the same disease and/or trial product 
studied in this trial.
Novo Nordisk may publish on its clinical trials website a redacted clinical trial report for this trial.
One investigator will be appointed by Novo Nordisk to review and sign the clinical trial report 
(signatory investigator) on behalf of all participating investigators. The signatory investigator will 
be appointed based upon the criteria defined by the International Committee of Medical Journal 
Editors for research publications 43. 
23.1
Communication of results
Novo Nordisk commits to communicating, and otherwise making available for public disclosure, 
results of trials regardless of outcome. Public disclosure includes publication of a paper in a 
scientific journal, abstract submission with a poster or oral presentation at a scientific meeting, or 
disclosure by other means.
The results of this trial will be subject to public disclosure on external web sites according to 
international and national regulations, as reflected in the Novo Nordisk Code of Conduct for 
Clinical Trial Disclosure 27.
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 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.
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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. All authors will be given the relevant 
statistical tables, figures, and reports needed to evaluate the planned publication. 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.
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. 
Novo Nordisk maintains the right to be informed of plans by any investigator to publish and to 
review any scientific paper, presentation, communication or other information concerning the 
investigation described in this protocol. Any such communication must be submitted in writing to 
Novo Nordisk before submission for comments. Comments will be given within four weeks from 
receipt of the planned communication.
23.1.1
Authorship
Authorship of publications should be in accordance with the Uniform Requirements of the 
International Committee of Medical Journal Editors 43 (ICMJE) (sometimes referred to as the 
Vancouver Criteria).
At the end of the trial, one or more publications (abstracts, posters manuscripts) will be prepared for 
submission to scientific congresses and peer-reviewed journals in collaboration between Novo 
Nordisk and investigator(s) appointed by Novo Nordisk. These investigator(s) must meet the 
ICMJE authorship criteria to be named authors on publications.
23.1.2
Site-specific publication(s) by investigator(s)
For a multi-centre 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. It is a Novo Nordisk policy that 
such individual reports do not precede the primary manuscript and should always reference the 
primary manuscript of the trial.
Novo Nordisk reserves the right to prior review of such publications. Further to allow for the 
primary manuscript to be published as the first, Novo Nordisk asks for deferment of publication of 
individual site results until the primary manuscript is accepted for publication. As Novo Nordisk 
wants to live up to the industry publication policy, submission of a primary publication will take 
place no later than 18 months after trial completion.
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23.2
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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24 Retention of clinical trial documentation and human biospecimens
24.1
Retention of clinical trial documentation
Subject's medical records must be kept for the maximum period permitted by the hospital, 
institution or private practice.
The investigator must agree to archive the documentation (this includes both electronic and paper-
based records) pertaining to the trial in an archive after completion or discontinuation of the trial if 
not otherwise notified. The investigator should not destroy any documents without prior permission 
from Novo Nordisk. If the investigator cannot archive the documents at the trial site, Novo Nordisk 
can refer the investigator to an independent archive provider that has a system in place to allow only 
the investigator to access the files.
The investigator must be able to access his/her trial documents without involving Novo Nordisk in 
any way. Site-specific CRFs and other subject data (in an electronic readable format or as paper 
copies or prints) will be provided to the investigator before access is revoked to the systems and/or 
electronic devices supplied by Novo Nordisk. These data must be retained by the trial site. If the 
provided 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.
Novo Nordisk will maintain Novo Nordisk documentation pertaining to the trial for as long as the 
product is on the market plus 20 years. 
The files from the trial site/institution must be retained for 15 years after the completion of the trial, 
or longer if required by local regulations or Novo Nordisk. In any case trial files cannot be
destroyed until the trial site/institution is notified by Novo Nordisk. The deletion process must 
ensure confidentiality of data and must be done in accordance with local regulatory requirements.
24.2
Retention of biospecimens
The trial will involve collection of biospecimens to be stored in central archives. Blood samples for 
genotyping (see Sections 8.5.3.1), long term storage (see Section 8.5.3.2) and PBMCs (see Section 
8.5.1.3) will be stored for up to 15 years for potential future assessments. As new biomarkers 
related to the disease and/or safety, efficacy, or mechanism of action of trial products may evolve 
during the conduct of the trial, the analyses of the stored biospecimens may also include biomarkers 
that are unknown at present or have not been included in the scientific hypotheses at initiation of the 
trial. After the end of trial the central laboratory will arrange the transfer of samples to an appointed 
storage facility. Novo Nordisk will have access to the samples.
None of the data will be identified by name. Blood samples will be identified only by a subject 
number, a visit number and a trial identification number. The trial staff is responsible for 
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maintaining a code list which links to the subject number. The code list must be kept for at least 15 
years. The code list may be reviewed by Novo Nordisk staff including auditors or representatives 
from regulatory authorities, but no copies will be made of this list.
Potential consequences for the subject and their relatives 
The results of the potential additional genotyping (other than HLA) and of potential analysis of long 
term storage samples and PBMCs will not have any medical consequences for the subjects or their 
relatives and the results will be reported in separate documents, hence will therefore not be included 
in the CTR.
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25 Institutional Review Boards/Independent Ethics Committees and 
regulatory authorities
IRB/IEC:
Written approval or favourable opinion must be obtained from IRB/IEC prior to commencement of 
the trial.
During the trial, the investigator or Novo Nordisk, as applicable, must promptly report the 
following to the IRB/IEC, in accordance with local requirements: updates to Investigator's 
Brochures, unexpected SAEs where a causal relationship cannot be ruled out, protocol amendments 
according to local requirements, deviations to the protocol implemented to eliminate immediate 
hazards to the subjects, new information that may affect adversely the safety of the subjects or the 
conduct of the trial (including new benefit-risk analysis in case it will have an impact on the 
planned follow-up of the subjects), annually written summaries of the trial status, and other 
documents as required by the local IRB/IEC.
The investigator must ensure submission of the clinical trial report synopsis to the IRB/IEC.
Protocol amendments must not be implemented before approval or favourable opinion according to 
local regulations, unless necessary to eliminate immediate hazards to the subjects.
The investigator must maintain an accurate and complete record of all submissions made to the 
IRB/IEC. The records must be filed in the investigator trial master file and copies must be sent to 
Novo Nordisk.
Regulatory Authorities:
Regulatory authorities will receive the clinical trial application, protocol amendments, reports on 
SAEs, and the clinical trial report according to national requirements.
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26 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:
For Austria: Arzneimittelgesetz (BGBL Nr. 185/1983) last amended with BGBl. I Nr. 48/2013   
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27 References
1 Standards of medical care in diabetes--2015. Diabetes Care 2015; 38 Suppl 1:S8-16.
2 International Conference on Harmonisation. ICH Harmonised Tripartite Guideline. Guideline 
for Good Clinical Practice. E6 (R1), Step 4.  10 Jun 1996. 
3 World Medical Association. Declaration of Helsinki. Ethical Principles for Medical Research 
Involving Human Subjects. Last amended by the 64th WMA General Assembly, Fortaleza, 
Brazil. October 2013.  1996. 
4 Atkinson MA, Eisenbarth GS, Michels AW. Type 1 diabetes. Lancet 2014; 383(9911):69-82.
5 Spolski R, Leonard WJ. Interleukin-21: Basic Biology and Implications for Cancer and 
Autoimmunity. Annual Review of Immunology 2008; 26(1).
6 Spolski R, Kashyap M, Robinson C, Yu Z, Leonard WJ. IL-21 signaling is critical for the 
development of type I diabetes in the NOD mouse. Proc Natl Acad Sci U S A 2008; 
105(37):14028-14033.
7 Brandt K, Singh PB, Bulfone-Paus S, Ruckert R. Interleukin-21: A new modulator of 
immunity, infection, and cancer. Cytokine & Growth Factor Reviews 2007; 18(3-4):223-232.
8 Chtanova T, Tangye SG, Newton R, Frank N, Hodge MR, Rolph MS et al. T Follicular Helper 
Cells Express a Distinctive Transcriptional Profile, Reflecting Their Role as Non-Th1/Th2 
Effector Cells That Provide Help for B Cells. J Immunol 2004; 173(1):68-78.
9 Spolski R, Leonard WJ. Interleukin-21: a double-edged sword with therapeutic potential. Nat 
Rev Drug Discov 2014; 13(5):379-395.
10 Kieffer TJ, Habener JL. The glucagon-like peptides. Endocr Rev 1999; 20(6):876-913.
11 Trial NN2211-3916. Clinical Trial Report: Efficacy and safety of liraglutide versus placebo as 
add-on to existing diabetes medication in subjects with type 2 diabetes and moderate renal 
impairment. 14 Feb 2014.
12 The effect of intensive treatment of diabetes on the development and progression of long-term 
complications in insulin-dependent diabetes mellitus. The Diabetes Control and 
Complications Trial Research Group. N Engl J Med 1993; 329(14):977-986.
13 Stiller CR, Dupre J, Gent M, Jenner MR, Keown PA, Laupacis A et al. Effects of cyclosporine 
immunosuppression in insulin-dependent diabetes mellitus of recent onset. Science 1984; 
223(4643):1362-1367.
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14 Voltarelli JC, Couri CE, Stracieri AB, Oliveira MC, Moraes DA, Pieroni F et al. Autologous 
nonmyeloablative hematopoietic stem cell transplantation in newly diagnosed type 1 diabetes 
mellitus. JAMA 2007; 297(14):1568-1576.
15 Parving HH, Tarnow L, Nielsen FS, Rossing P, Mandrup-Poulsen T, Osterby R et al. 
Cyclosporine nephrotoxicity in type 1 diabetic patients. A 7-year follow-up study. Diabetes 
Care 1999; 22(3):478-483.
16 Kroll JL, Beam C, Li S, Viscidi R, Dighero B, Cho A et al. Reactivation of latent viruses in 
individuals receiving rituximab for new onset type 1 diabetes. J Clin Virol 2013; 57(2):115-
119.
17 Ogawa N, List JF, Habener JF, Maki T. Cure of overt diabetes in NOD mice by transient 
treatment with anti-lymphocyte serum and exendin-4. Diabetes 2004; 53(7):1700-1705.
18 Yang Z, Chen M, Carter JD, Nunemaker CS, Garmey JC, Kimble SD et al. Combined 
treatment with lisofylline and exendin-4 reverses autoimmune diabetes. Biochem Biophys Res 
Commun 2006; 344(3):1017-1022.
19 Sherry NA, Chen W, Kushner JA, Glandt M, Tang Q, Tsai S et al. Exendin-4 improves 
reversal of diabetes in NOD mice treated with anti-CD3 monoclonal antibody by enhancing 
recovery of beta-cells. Endocrinology 2007; 148(11):5136-5144.
20 FDA Guidance for Industry Diabetes Mellitus: Developing Drugs and Therapeutic Biologics 
for Treatment and Prevention, Draft Guidance. 13 Feb 2008.
21 EMA/CPMP/EWP/1080/00 Rev.1 Guideline on clinical investigation of medicinal products in 
the treatment of diabetes mellitus. 15 Nov 2012.
22 KDIGO Clinical Practice Guideline for Glomerulonephritis. 1 Jun 2012.
23 Dabelea D, Mayer-Davis EJ, Saydah S, Imperatore G, Linder B, Divers J et al. Prevalence of 
type 1 and type 2 diabetes among children and adolescents from 2001 to 2009. JAMA 2014; 
311(17):1778-1786.
24 Lernmark A, Larsson HE. Immune therapy in type 1 diabetes mellitus. Nat Rev Endocrinol 
2013; 9(2):92-103.
25 Pozzilli P, Visalli N, Buzzetti R, Cavallo MG, Marietti G, Hawa M et al. Metabolic and 
immune parameters at clinical onset of insulin-dependent diabetes: a population-based study. 
IMDIAB Study Group. Immunotherapy Diabetes. Metabolism 1998; 47(10):1205-1210.
26 Palmer JP, Fleming GA, Greenbaum CJ, Herold KC, Jansa LD, Kolb H et al. C-peptide is the 
appropriate outcome measure for type 1 diabetes clinical trials to preserve beta-cell function: 
report of an ADA workshop, 21-22 October 2001. Diabetes 2004; 53(1):250-264.
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27 Novo Nordisk: http://www.novonordisk-trials.com/website/content/how-we-disclose-trial-
information.aspx 2015.
28 De AC, 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):1250-1251.
29 Food and Drug Administration Amendments Act of 2007.  27 Sep 2007. 
30 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. May 2001. 2001.
31 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. Official Journal 
of the European Communities. April 2001. 2001.
32 Kitabchi AE, Umpierrez GE, Miles JM, Fisher JN. Hyperglycemic crises in adult patients with 
diabetes. Diabetes Care 2009; 32(7):1335-1343.
33 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):1384-1395.
34 McAulay V, Deary IJ, Frier BM. Symptoms of hypoglycaemia in people with diabetes. Diabet 
Med 2001; 18(9):690-705.
35 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):929-942.
36 FDA Guidance for Industry  Patient-Reported Outcome Measures: Use in Medical Product 
Development to Support Labeling Claims . Dec 2009.
37 Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF, III, Feldman HI et al. A new 
equation to estimate glomerular filtration rate. Ann Intern Med 2009; 150(9):604-612.
38 European Union; The rules governing medicinal products in the European Union, volume 4, 
Annex 13, Manufacture of Investigational Medicinal Products - Brussels, July 2003.  
39 Food and Drug Administration. Food and Drug Administration: Code of Federal Regulations,
21 CFR Part 11, Electronic Records, Electronic Signatures.   2009. 
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40 Herold KC, Gitelman SE, Ehlers MR, Gottlieb PA, Greenbaum CJ, Hagopian W et al. 
Teplizumab (anti-CD3 mAb) treatment preserves C-peptide responses in patients with new-
onset type 1 diabetes in a randomized controlled trial: metabolic and immunologic features at 
baseline identify a subgroup of responders. Diabetes 2013; 62(11):3766-3774.
41 ICH E9 guidelines: Statistical principles for clinical trials, step 4 version, 1998, 
CPMP/ICH/363/96.  1-35. 5 Feb 1998. 
42 Schwartz NS, Clutter WE, Shah SD, Cryer PE. Glycemic thresholds for activation of glucose 
counterregulatory systems are higher than the threshold for symptoms. J Clin Invest 1987; 
79(3):777-781.
43 International Committee of Medical Journal Editors. Recommendations for the Conduct, 
Reporting, Editing, and Publication of Scholarly Work in Medical Journals. 16 Dec 2014.
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Protocol appendix A
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Appendix A: Insulin Titration Guideline
A randomised, double-blind, double-dummy, placebo-
controlled, parallel-group multi-centre clinical proof-of-
principle trial in adult subjects with newly diagnosed type 1 
diabetes mellitus investigating the effect of NNC0114-0006 and 
liraglutide on preservation of beta-cell function
Trial phase: 2
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol appendix A
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Table of Contents
Page
Table of Contents..............................................................................................................................................2
1
Introduction...............................................................................................................................................3
2
Treatment regimens..................................................................................................................................4
2.1
Injection area..................................................................................................................................4
2.2
Time of injection............................................................................................................................4
3
Initiation and titration ..............................................................................................................................5
3.1
Insulin at trial initiation..................................................................................................................5
3.2
Titration of basal insulin (not applicable on liraglutide/placebo initiation and escalation 
days)...............................................................................................................................................5
3.3
Initiation of a second basal insulin dose during the trial................................................................6
3.4
Titration of bolus insulin (not applicable on liraglutide/placebo initiation and escalation 
days)...............................................................................................................................................6
3.4.1
Carbohydrate counting - subjects following principles of flexible bolus insulin 
therapy .........................................................................................................................6
3.4.2
Bolus dosing - subjects using the algorithm ................................................................7
3.5
Insulin reduction on the days of liraglutide/placebo initiation and dose escalations.....................8
3.6
Deviations from the algorithm.......................................................................................................8
4
Data collection ...........................................................................................................................................9
5
Review procedure....................................................................................................................................10
6
References................................................................................................................................................11
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1
Introduction
The goal of insulin therapy is to achieve near normoglycaemia, i.e. to reach a pre-defined HbA1c
level with a low rate of hypoglycaemic episodes and as little weight gain as possible. Several trials 
have shown that this is difficult to achieve, unless plasma glucose (PG) values are intensively 
monitored and the insulin dose(s) frequently adjusted 1-6.
To ensure treatment uniformity between the sites, as well as to ensure that subjects receive an 
optimal treatment, titration algorithms have been developed specifying recommended dose 
adjustments at different PG levels.
It is recognised that treatments differ between different regions and countries. Likewise, specific 
titration guidelines may not be applicable in certain clinical situations. 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 should always use his 
clinical judgement to avoid safety hazards. The investigator is responsible for the treatment of the 
subjects and can therefore overrule the guideline.
To optimise and maintain glycaemic control, the investigator should, throughout the trial be at least
in weekly contact with the subjects to assist the subjects in adjusting insulin doses and to ensure the 
subject’s welfare.
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2
Treatment regimens
There are no maximum or minimum insulin doses defined(see section 5.3.3 of the protocol).
2.1
Injection area
The insulin types used in this trial should be injected subcutaneously in accordance with local 
labelling. The chosen region should be the same throughout the trial. Rotation of injection sites 
within a given region is recommended.
2.2
Time of injection
Bolus insulin (regular human insulin or fast-acting insulin analogues) should be administered with 
the main meals (2-4 times daily) according to local labelling.
Basal insulin, neutral protamine Hagedorn (NPH) insulin or long-acting insulin analogues, should 
be administered once or twice daily in accordance with local labelling. Please note that insulin 
glargine and insulin degludec should only be administered once daily.
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3
Initiation and titration
Please note the request for insulin reduction during the liraglutide/placebo dose escalation period 
described in section 3.5.
3.1
Insulin at trial initiation
All subjects will continue their current insulin regimen after randomisation.
3.2
Titration of basal insulin (not applicable on liraglutide/placebo initiation and
escalation days)
After the liraglutide/placebo dose initiation and escalation days, basal insulinwill be adjusted 
weeklyby the investigator in connection with the scheduledvisit/phone contacts. 
For subjects receiving basal insulinonce daily the dose should be increasedbased on the mean pre-
breakfast SMPGvalues measured on the day of the contact and 2days prior to the contactin 
accordance with Table 1.If one of the SMPG values <4.0 mmol/l(< 71 mg/dl) the dose should be 
reduced according to Table 2.
For subjects receiving basal insulintwice daily the evening dose should be adjusted according to 
pre-breakfast SMPG values measured on the day of the contact and 2 days prior to the contactand 
the morning dose should be adjustedaccording to the pre-dinnerSMPG values measured 3days 
prior to the contact according to 
Tableand Table 2.
Table 1
Basal insulin increase
Mean pre-breakfast/pre-dinner SMPG
Dose adjustment
mmol/l
mg/dl
U
4.0 – 6.0
71 – 108
No adjustment
6.1 – 10.0
109 – 180
+ 2
10.1 – 15.0
181 – 270
+ 4
> 15.0
> 270
+ 6
CONFIDENTIAL


Protocol appendix A
CONFIDENTIAL
Date:
07 May 2015
Novo Nordisk
Trial ID: NN9828-4150
Version:
2.0
UTN: U1111-1154-7172
Status:
Final
EudraCT No.: 2014-001215-39
Page:
6 of 11
Table 2
Basal insulin reduction
Lowest pre-breakfast/pre-dinner SMPG
Dose adjustment
mmol/l
mg/dl
U
3.1 – 3.9
56 – 70
- 2
<3.1
< 56
- 4
3.3
Initiation of a second basal insulin dose during the trial
It is recommended that basal insulin is not changed from a once daily to a twice daily regimen 
during the liraglutide dose escalation period. Thereafter a second dose can be initiated at the 
investigator’s discretion except for insulin glargine and insulin degludec which should only be 
dosed once daily. Adjustment of the second dose should be done in accordance with the principles 
described in section 3.2.
3.4
Titration of bolus insulin (not applicable on liraglutide/placebo initiation and
escalation days)
Bolus insulin (mealtime) should be adjusted according to section 3.4.1, if the subject follows the 
principles of flexible insulin therapy and according to section 3.4.2, if the subject follows the bolus 
algorithm. It is left to the discretion of the investigator to decide which method the subject uses. 
Furthermore, the subjects are allowed to change the method at any time point during the trial if 
agreed with the investigator.
3.4.1
Carbohydrate counting - subjects following principles of flexible bolus insulin 
therapy
Bolus insulin should be dosed in accordance with principles of flexible dosing whereby the meal 
carbohydrate content and pre-prandial plasma glucose value are used to determine bolus insulin 
dose. 
Using this method, bolus insulin dose adjustment is conducted several times daily in accordance 
with the Insulin:Carbohydrate (I:Carb) ratio and the plasma glucose correction factor (sensitivity 
factor). Bolus insulin dose consists of meal bolus to cover for carbohydrates consumed in the meal 
and, if required, a correction dose (to supplement or reduce the dose based on the difference 
between the SMPG and the target). This method is applicable to subjects with prior hands-on 
experience using this method of determining bolus insulin doses. It is the responsibility of the 
investigator to ensure that the subject is comfortable with this method. If more training is needed 
this should be carried out according to local practice.
The I:Carb ratio expresses the amount of carbohydrate (in grams) for which 1U of bolus insulin 
would effectively minimise postprandial plasma glucose excursions. The plasma glucose correction 
CONFIDENTIAL


Protocol appendix A
CONFIDENTIAL
Date:
07 May 2015
Novo Nordisk
Trial ID: NN9828-4150
Version:
2.0
UTN: U1111-1154-7172
Status:
Final
EudraCT No.: 2014-001215-39
Page:
7 of 11
factor (sensitivity factor) expresses the expected reduction in plasma glucose per 1U of bolus 
insulin. The I:Carb ratio and the correction factor (sensitivity factor) per type of meal should be 
recorded at trial start and should, if needed, be adjusted at the discretion of the investigator during 
the weekly contacts based on the reviewed SMPGs. 
In this trial the target pre-prandial plasma glucose range is 71−108 mg/dl (4.0−6.0 mmol/l). 
In the following, an example on how to cover a subject’s prandial insulin dose is provided. In case 
of hypoglycaemic episodes, the dose will be reduced at the investigator’s discretion. 
Example 1 – Carbohydrate coverage of a meal and plasma glucose correction dose:
A subject has pre-prandial plasma glucose of 180 mg/dL (10.0 mmol/l) and intends to eat a meal 
containing 60 g of carbohydrates. The I:Carb ratio has been estimated to 1U:10g. 
The meal coverage dose is calculated as follows: 
Total carbohydrate in meal * I:Carb ratio = 60 g * (1U/10g) = 6U. 
The plasma glucose correction factor (sensitivity factor) has been estimated to be 36 mg/dl per 1U 
(2.0 mmol/l per 1U). The pre-prandial plasma glucose target range is 71-108 mg/dl 
(4.0-6.0 mmol/l). The subject was advised to correct to the target plasma glucose of 108 mg/dl 
(6.0 mmol/l) at this meal.
The correction dose can be calculated as follows: 
(Pre-prandial plasma glucose – target plasma glucose) ÷ plasma glucose correction factor = 
(180 mg/dl – 108 mg/dl) ÷ 36 mg/dl/U = 2U or (10.0 mmol/l – 6.0 mmol/l) ÷ 2.0 mmol/l/U  = 2U
Thus this subject needs 8U of rapid-acting insulin to cover for the meal and correct for 
hyperglycaemia before the meal.
3.4.2
Bolus dosing - subjects using the algorithm
Bolus titration should take place once weekly in relation to the visits/phone contacts. Bolus insulin
will be adjusted according to Table 3.
!
Breakfast dose will be adjusted according to the pre-lunch SMPG values obtained the 
previous 3-4 days
!
Lunch dose will be adjusted according to the pre-dinner SMPG values obtained the previous 
3-4 days
!
Dinner dose will be adjusted according to the bedtime SMPG values obtained the previous 
3-4 days.
CONFIDENTIAL


Protocol appendix A
CONFIDENTIAL
Date:
07 May 2015
Novo Nordisk
Trial ID: NN9828-4150
Version:
2.0
UTN: U1111-1154-7172
Status:
Final
EudraCT No.: 2014-001215-39
Page:
8 of 11
Table 3
Bolus insulin dose adjustment
Pre-prandial/bedtime SMPG
Dose adjustment
Rules for dose adjustment
mmol/l
mg/dl
U
< 4.0
< 71
- 1
≥ 1 SMPG below target
4.0 – 6.0
71 -108
0
0-1 SMPG above target
No SMPGs below target
> 6.0
> 108
+ 1
≥ 2 SMPGs above target
No SMPGs below target
Additional bolus dosing is allowed at the investigator’s recommendation. These additional doses 
will be documented in the diary.
3.5
Insulin reduction on the days of liraglutide/placebo initiation and dose escalations
When liraglutide/placebo is initiated, the total daily insulin dose should be reduced by 25% for a 
minimum of 24 hours after the initiation of liraglutide/ liraglutide placebo. Thereafter the doses 
should be adjusted according sections 3.2 and 3.3. On the dose escalation days the total daily insulin 
dose should be reduced by 10% on each occasion for a minimum of 24 hours after the escalation of 
liraglutide/ liraglutide placebo dose and thereafter adjusted according to sections 3.2 and 3.4.
3.6
Deviations from the algorithm
It is recommended that the algorithm is followed. However, it is also important that the decision to 
adjust the insulin doses are based on all relevant information as described in Section 1. A reason for 
deviating from the algorithm should be documented.
CONFIDENTIAL


Protocol appendix A
CONFIDENTIAL
Date:
07 May 2015
Novo Nordisk
Trial ID: NN9828-4150
Version:
2.0
UTN: U1111-1154-7172
Status:
Final
EudraCT No.: 2014-001215-39
Page:
9 of 11
4
Data collection
The following data should be available for Novo Nordisk’s Insulin Titration Group for all subjects 
within 24 hours (on weekdays) after a site visit/phone contact:
!
SMPG values
!
Carbohydrate intake per meal (CHO-counting subjects only)
!
Date and insulin doses taken (daily)
!
New insulin doses prescribed after titration
!
Reason for deviation between the recommended and the prescribed basal insulin dose 
!
Reason for deviation between the recommended and actual bolus insulin doses
!
Hypoglycaemic episodes
Furthermore the investigator should provide the following from the CHO-counting subjects:
!
I:CHO ratio per meal (initial and any changes)
!
Plasma glucose correction factor per meal (initial and any changes)
CONFIDENTIAL


Protocol appendix A
CONFIDENTIAL
Date:
07 May 2015
Novo Nordisk
Trial ID: NN9828-4150
Version:
2.0
UTN: U1111-1154-7172
Status:
Final
EudraCT No.: 2014-001215-39
Page:
10 of 11
5
Review procedure
Surveillance of titration data will be performed centrally by Novo Nordisk in an unbiased manner. It 
is important that data regarding hypoglycaemic episodes is entered into the respective system within 
24 hours (on weekdays). 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 data listed in section 4 will be reviewed by Novo Nordisk within 24 hours (on weekdays). The 
reviewer may contact the investigator to get clarification regarding the reason 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 weekdays). 
During the trial HbA1c will be monitored by Novo Nordisk for additional surveillance of the 
glycaemic control. Novo Nordisk may be in contact with sites (visit or phone contact) to discuss 
progress in glycaemic control and titration of individual subjects based on SMPGs and HbA1c. This 
will be done in an unbiased and whenever possible in a blinded manner.
CONFIDENTIAL


Protocol appendix A
CONFIDENTIAL
Date:
07 May 2015
Novo Nordisk
Trial ID: NN9828-4150
Version:
2.0
UTN: U1111-1154-7172
Status:
Final
EudraCT No.: 2014-001215-39
Page:
11 of 11
6
References
1 Rosenstock J, Davies M, Home PD, Larsen J, Koenen C, Schernthaner G. A randomised, 52-
week, treat-to-target trial comparing insulin detemir with insulin glargine when administered as 
add-on to glucose-lowering drugs in insulin-naive people with type 2 diabetes. Diabetologia 
2008; 51(3):408-416.
2 Hermansen K, Davies M, Derezinski T, Martinez RG, Clauson P, Home P. A 26-week, 
randomized, parallel, treat-to-target trial comparing insulin detemir with NPH insulin as add-on 
therapy to oral glucose-lowering drugs in insulin-naive people with type 2 diabetes. Diabetes 
Care 2006; 29(6):1269-1274.
3 Philis-Tsimikas A, Charpentier G, Clauson P, Ravn GM, Roberts VL, Thorsteinsson B. 
Comparison of once-daily insulin detemir with NPH insulin added to a regimen of oral 
antidiabetic drugs in poorly controlled type 2 diabetes. Clin Ther 2006; 28(10):1569-1581.
4 Riddle MC, Rosenstock J, Gerich J. The treat-to-target trial: randomized addition of glargine or 
human NPH insulin to oral therapy of type 2 diabetic patients. Diabetes Care 2003; 
26(11):3080-3086.
5 Garber AJ, King AB, Del PS, Sreenan S, Balci MK, Munoz-Torres M et al. Insulin degludec, an 
ultra-longacting basal insulin, versus insulin glargine in basal-bolus treatment with mealtime 
insulin aspart in type 2 diabetes (BEGIN Basal-Bolus Type 2): a phase 3, randomised, open-
label, treat-to-target non-inferiority trial. Lancet 2012; 379(9825):1498-1507.
6 Heller S, Buse J, Fisher M, Garg S, Marre M, Merker L et al. Insulin degludec, an ultra-
longacting basal insulin, versus insulin glargine in basal-bolus treatment with mealtime insulin 
aspart in type 1 diabetes (BEGIN Basal-Bolus Type 1): a phase 3, randomised, open-label, treat-
to-target non-inferiority trial. Lancet 2012; 379(9825):1489-1497.
CONFIDENTIAL


Protocol appendix B
CONFIDENTIAL
Date:
07 May 2015
Novo Nordisk
Trial ID: NN9828-4150
Version:
2.0
UTN: U1111-1154-7172
Status:
Final
EudraCT No.: 2014-001215-39
Page:
1 of 6
Appendix B:Monitoring of Calcitonin
A randomised, double-blind, double-dummy, placebo-
controlled, parallel-group multi-centre clinical proof-of-
principle trial in adult subjects with newly diagnosed type 1 
diabetes mellitus investigating the effect of NNC0114-0006 and 
liraglutide on preservation of beta-cell function
Trial phase: 2
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol appendix B
CONFIDENTIAL
Date:
07 May 2015
Novo Nordisk
Trial ID: NN9828-4150
Version:
2.0
UTN: U1111-1154-7172
Status:
Final
EudraCT No.: 2014-001215-39
Page:
2 of 6
Table of Contents
Page
Table of Contents..............................................................................................................................................2
1
Background................................................................................................................................................3
2
Calcitonin and C-cell abnormalities - evaluation and follow-up ..........................................................4
2.1
CT ≥ 100 ng/l.................................................................................................................................4
2.2
CT ≥ 50 and < 100 ng/l..................................................................................................................4
2.3
CT ≥ 20 and <50 ng/l.....................................................................................................................5
2.4
CT ≥ 10 and < 20 ng/l....................................................................................................................5
3
References..................................................................................................................................................6
CONFIDENTIAL


Protocol appendix B
CONFIDENTIAL
Date:
07 May 2015
Novo Nordisk
Trial ID: NN9828-4150
Version:
2.0
UTN: U1111-1154-7172
Status:
Final
EudraCT No.: 2014-001215-39
Page:
3 of 6
1
Background
Treatment with GLP-1 receptor agonists has shown to be associated with thyroid C-cell changes in 
rodents but not in non-human primates. The human relevance of this finding is unknown. However, 
based on the findings in rodents, monitoring of serum calcitonin (a sensitive biomarker for C-cell 
activation) is currently being performed in clinical trials with liraglutide.
While there is general agreement on the clinical interpretation of substantially elevated calcitonin 
levels (greater than 100 ng/l) as likely indicative of C-cell neoplasia, the interpretation of values 
between upper normal range (5.0 and 8.4 ng/l for women and men, respectively) and 100 ng/l can 
become challenging. 
There are several known confounding factors affecting calcitonin levels, namely renal dysfunction, 
smoking, autoimmune thyroiditis and several drug classes (e.g. proton pump inhibitors, beta-
blockers, H2-blockers and glucocorticoids). Physiology of C-cell activation in various clinical 
conditions and in different patient populations (i.e. with various co-morbidities) is poorly 
understood. There may be various clinical conditions not identified so far which mildly or 
moderately affect calcitonin secretion by C-cells.
CONFIDENTIAL


Protocol appendix B
CONFIDENTIAL
Date:
07 May 2015
Novo Nordisk
Trial ID: NN9828-4150
Version:
2.0
UTN: U1111-1154-7172
Status:
Final
EudraCT No.: 2014-001215-39
Page:
4 of 6
2
Calcitonin and C-cell abnormalities - evaluation and follow-up
Subjects with a personal or family history of medullar thyroid cancer (MTC) or multiple endocrine 
neoplasia syndrome type 2 (MEN 2) or with a screening calcitonin ≥ 50 ng/l will be excluded from 
the trial. 
A blood sample will be drawn at pre-specified trial visits for measurement of calcitonin. In case a 
subject has an increased calcitonin value ≥ 10 ng/l the algorithm outlined below should be followed. 
The algorithm applies for all calcitonin values including screening values.
The summary for the rationale for the use of specific calcitonin values to trigger medical evaluation 
and an overview of the algorithm is provided below:
2.1
CT ≥ 100 ng/l
The subject (even if a screen failure) should immediately be referred to a thyroid specialist for 
further evaluation and the subject must be withdrawn from the trial if the measurement is during the 
treatment period of the trial. If the calcitonin level is ≥ 100 ng/l during the observation period the 
subject should be referred to a thyroid specialist for further evaluation but can remain in the trial.
These values were found in 0.15% of a population with thyroid nodular disease published by 
Costante et al1 and in one subject (on active comparator) in the liraglutide development program. 
For a calcitonin value of ≥100 ng/l, the subject should be assumed to have significant C-cell disease 
and a high likelihood of having medullary carcinoma of the thyroid. Diagnostic evaluation should 
consist of thyroid ultrasound, fine needle aspiration of any nodules >1 cm and potentially surgery 
with neck dissection. Family history of MTC or MEN2 should be evoked and a RET proto-
oncogene analysis should be performed. 
2.2
CT ≥ 50 and < 100 ng/l
The subject (even if a screen failure) should be referred to a thyroid specialist for further evaluation 
and the subject must be withdrawn from the trial if the measurement is during the treatment period 
of the trial. If the calcitonin level is ≥50 and <100 ng/l during the observation period the subject
should be referred to a thyroid specialist for further evaluation but can remain in the trial. 
These values were found in 0.14% of the population with thyroid nodular disease published by 
Costante et al1. Diagnostic evaluation will likely include ultrasound examination and if available 
and if there is no contraindication, subjects should undergo a pentagastrin stimulation test. Subjects 
with positive pentagastrin stimulation tests will be considered to undergo surgery. In the US and 
other countries where pentagastrin is not available, thyroid ultrasound and fine needle aspiration 
biopsy may add important clinical information informing the need for surgery. 
CONFIDENTIAL


Protocol appendix B
CONFIDENTIAL
Date:
07 May 2015
Novo Nordisk
Trial ID: NN9828-4150
Version:
2.0
UTN: U1111-1154-7172
Status:
Final
EudraCT No.: 2014-001215-39
Page:
5 of 6
2.3
CT ≥ 20 and <50 ng/l
The subject can continue in the trial. Repeat testing of calcitonin at next protocol scheduled 
calcitonin visit. If the subject is a screen failure or if the value is the last one taken in the trial, the 
subject should be referred to a thyroid specialist for further evaluation.
These values are expected to be found in up to 1% of subjects. Based on data from Costante et al1, 
the predictive value of calcitonin levels ≥ 20 and < 50 ng/l for clinically significant C-cell disease 
begins to fall. However, up to 25% of these subjects had a positive pentagastrin stimulation test. 
The likelihood of having a medullary carcinoma >1 cm with calcitonin in this range is extremely 
low. 
2.4
CT ≥ 10 and < 20 ng/l
The subject can continue in the trial. Repeat testing of calcitonin at next protocol scheduled 
calcitonin visit. If the subject is a screen failure or if the value is the last one taken in the trial, the 
subject should be referred to a thyroid specialist for further evaluation. 
Costante et al 1 had 216 (3.7%) patients in this category. One patient out of the 216 had a 
subsequent basal (unstimulated) calcitonin of 33 ng/l, and had C-cell hyperplasia at surgery, a lesion 
of unknown clinical significance. Two other studies used a cut-off of CT > 10 ng/l to screen for C-
cell disease, but they do not provide sufficient information on patients with basal CT >10 and <20 
ng/l to allow conclusions 2,3.
CONFIDENTIAL


Protocol appendix B
CONFIDENTIAL
Date:
07 May 2015
Novo Nordisk
Trial ID: NN9828-4150
Version:
2.0
UTN: U1111-1154-7172
Status:
Final
EudraCT No.: 2014-001215-39
Page:
6 of 6
3
References
1 Costante G, Meringolo D, Durante C, Bianchi D, Nocera M, Tumino S et al. Predictive value of 
serum calcitonin levels for preoperative diagnosis of medullary thyroid carcinoma in a cohort of 
5817 consecutive patients with thyroid nodules. J Clin Endocrinol Metab 2007; 92(2):450-455.
2 Scheuba C, Kaserer K, Moritz A, Drosten R, Vierhapper H, Bieglmayer C et al. Sporadic 
hypercalcitoninemia: clinical and therapeutic consequences. Endocr Relat Cancer 2009; 
16(1):243-253.
3 Verga U, Ferrero S, Vicentini L, Brambilla T, Cirello V, Muzza M et al. Histopathological and 
molecular studies in patients with goiter and hypercalcitoninemia: reactive or neoplastic C-cell 
hyperplasia? Endocr Relat Cancer 2007; 14(2):393-403.
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
01 July 2015
Novo Nordisk
Trial ID: NN9828-4150
Version:
1.0
UTN:1111-1154-7172
Status:
Final
EudraCT No.: 2014-001215-39
Page:
1 of 11
Protocol Amendment
no 1.0
to Protocol, final version 2.0
dated 07 May 2015
Trial ID: NN9828-4150
A randomised, double-blind, double-dummy, placebo-controlled, parallel-group multi-centre 
clinical proof-of-principle trial in adult subjects with newly diagnosed type 1 diabetes mellitus 
investigating the effect of NNC0114-0006 and liraglutide on preservation of beta-cell function
Trial phase: 2
Applicable to all countries
Amendment originator:
Department: ClinOps 1, Insulin, GH & Devices
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol Amendment
CONFIDENTIAL
Date:
01 July 2015
Novo Nordisk
Trial ID: NN9828-4150
Version:
1.0
UTN:1111-1154-7172
Status:
Final
EudraCT No.: 2014-001215-39
Page:
2 of 11
Table of Contents   
Page
Table of Contents..............................................................................................................................................2
1
Introduction including rationale for the protocol amendment.............................................................3
1.1
Rationale for protocol updates due to requirements from VHP.....................................................3
1.2
Rational for clarification of minor inconsistencies and clarifications in the protocol and the 
subject information ........................................................................................................................3
2
Changes......................................................................................................................................................5
2.1
Changes to protocol due to requirements from VHP.....................................................................5
2.1.1
Section 2 Flowchart .....................................................................................................5
2.1.2
Section 6.3 Exclusion criteria 3 ...................................................................................5
2.1.3
Section 6.3 Exclusion criteria 4 ...................................................................................6
2.1.4
Section 8.5.2.1 Pregnancy test.....................................................................................6
2.1.5
Section 11.1 Breaking of blinded codes ......................................................................7
2.2
Changes to the protocol due to corrections of minor inconsistencies and clarifications to 
the protocol and the subject information .......................................................................................7
2.2.1
Section 1 Summary......................................................................................................7
2.2.2
Section 2 Flowchart .....................................................................................................7
2.2.3
Section 5.3.3 Insulin treatment ....................................................................................8
2.2.4
Section 6.2 Inclusion criteria .......................................................................................8
2.2.5
Section 6.3 Exclusion criteria ......................................................................................8
2.2.6
Section 6.8 Rationale for trial population....................................................................9
2.2.7
Section 8.1 Visit procedures ........................................................................................9
2.2.8
Section 8.2.6 Diagnosis of diabetes.............................................................................9
2.2.9
Section 8.3.1 Mixed meal tolerance test......................................................................9
2.2.10
Section 8.4.2.7 Hypoglycaemic episodes ....................................................................9
2.2.11
Section 8.5.1.3 Biomarkers........................................................................................10
2.2.12
Section 9.3 Storage ....................................................................................................10
2.3
Master SI/IC.................................................................................................................................11
2.3.1
Section For how long time will your data be stored..................................................11
2.3.2
Section Schematic overview of the trial ....................................................................11
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
01 July 2015
Novo Nordisk
Trial ID: NN9828-4150
Version:
1.0
UTN:1111-1154-7172
Status:
Final
EudraCT No.: 2014-001215-39
Page:
3 of 11
1
Introduction including rationale for the protocol amendment
The rationale for this protocol amendment is divided into two categories:
!
Updates due to requirement from the Voluntary Harmonisation Procedure (VHP)
!
Clarification of minor inconsistencies and clarifications in the protocol and the subject
information
1.1
Rationale for protocol updates due to requirements from VHP
6.3 Exclusion criteria 3
Exclusion criteria 3 and 4 have been updated to reflect Clinical Trial Facilitation Group (CTFG)
guideline for highly effective contraception 
8.5.2.1 Pregnancy test
Updated to reflect requirement for Ireland that female of childbearing potential must have a urinary 
pregnancy test done at each visit
11.1 Breaking of blinded codes
It has been specified that Investigators are responsible for all trial related medical decisions
1.2
Rational for clarification of minor inconsistencies and clarifications in the protocol 
and the subject information
The rationale for this part of the amendment is to correct some minor inconsistencies and 
clarifications in the protocol and subject information.
5.3.3 Insulin treatment
It has been clarified that it is preferred that subjects continue on their pre-trial insulin treatment in 
order to minimise “noise” from different insulin treatments.
6.2 Inclusion criteria
It has been clarified what is considered as the date of the diagnosis of T1DM
6.3 Exclusion criteria 
Exclusion criteria 14 has been updated due to a typing error
Exclusion criteria 39 has been updated to ensure not to exclude subjects that we do not believe have
any safety concerns by participating in this trial
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
01 July 2015
Novo Nordisk
Trial ID: NN9828-4150
Version:
1.0
UTN:1111-1154-7172
Status:
Final
EudraCT No.: 2014-001215-39
Page:
4 of 11
6.8 Rationale for the trial population
It has been clarified that the presence of islet-specific auto-antibodies should be confirmed at 
screening
8.1 Visit procedures
It has been clarified that the investigator should keep a pre-screening log so that the sponsor can
react if it is shown that some in and exclusion criteria are resulting in many subjects being unable to 
participate in the trial.
8.2.6 Diagnosis of diabetes
It has been clarified what is considered the date of the diagnosis of T1DM.
8.3.1 Mixed meal tolerance test 
It has been clarified that no special BG meter is required for the mixed meal tolerance test (MMTT) 
as all blood glucose (BG) meters are validated.
8.4.2.7 Hypoglycaemic episodes
It has been clarified that all hypoglycaemic episodes should be reported in the e-diary by the 
subject.
8.5.1.3: Biomarker
Lab sampling for Il-21 have been added for additional 3 visits in order to ensure understanding of 
the synthesis rate of IL-21 
9.3 Storage
The storage conditions for in-use conditions has been corrected as there was a minor error in this 
section
Master SI/IC
The archiving period of the data has been updated as this was incorrect. Furthermore some minor
corrections to the schematic overview of the trial have been made.
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
01 July 2015
Novo Nordisk
Trial ID: NN9828-4150
Version:
1.0
UTN:1111-1154-7172
Status:
Final
EudraCT No.: 2014-001215-39
Page:
5 of 11
2
Changes
In this protocol amendment:
Any new text is written in italics.
Any text deleted from the protocol is written using strike through.
2.1
Changes to protocol due to requirements from VHP
2.1.1
Section 2 Flowchart
Visit 1 to 37 procedures
Foot note:
2. For woman of childbearing potential only. Blood sample at V1. For all subsequent visits a urine 
stick must only be measured for females of childbearing potential if a menstrual period is missed or
as required by law. Austria: Urine-stick pregnancy test will be performed monthly at all visits to the 
clinic. Ireland: Urine-stick pregnancy test will be performed at all visits to the clinic.
Visit 38-90 procedures
Foot note:
3. Blood sample at V63. A urine stick pregnancy test must be performed throughout the trial for 
females of childbearing potential if a menstrual period is missed or as required by local law. 
Austria: Urine-stick pregnancy test will be performed monthly at all visits to the clinic. Ireland:
Urine-stick pregnancy test will be performed at all visits to the clinic
2.1.2
Section 6.3 Exclusion criteria 3
Female who is pregnant, breast-feeding or intends to become pregnant or is of child-bearing 
potential not using highly effective adequate contraceptive methods for the duration of the trial
(highly effectiveadequate contraceptive measures, as required by local regulations or practice, i.e. a 
measure that results in less than 1% per year failure rate when used consistently and correctly)
For Ireland: Highly effective Adequate contraceptive measures are defined as established use of 
combined oral contraceptives, injected or implanted hormonal methods of contraception, 
sterilisation, IUD or intrauterine system or consistent use of barrier methods together with the use of
spermicide and or true sexual abstinence.*
For Sweden: Highly effective Adequate contraceptive measures are: oral (except low-dose gestagen
(lynestrenol and norestisteron)), injectable, or implanted hormonal contraceptives, intrauterine 
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
01 July 2015
Novo Nordisk
Trial ID: NN9828-4150
Version:
1.0
UTN:1111-1154-7172
Status:
Final
EudraCT No.: 2014-001215-39
Page:
6 of 11
device, intrauterine system (for example, progestin-releasing coil), vasectomized male (with 
appropriate post vasectomy documentation of the absence of sperm in the ejaculate).
For United Kingdom: Only highly effective methods of birth control for the duration of the trial 
are accepted (i.e. one that results in less than 1% per year failure rate when used consistently and 
correctly). Highly effective Adequate contraceptive measures are defined as established use of oral, 
injected or implanted intravaginal, transdermal combined estrogen and progestogen hormonal 
methods of contraception; oral, injected or implanted progestogen only hormonal methods of 
contraception; placement of an intrauterine device or intrauterine hormone releasing system, 
bilateral tubal occlusion, female sterilisation, vasectomised partner (where partner is sole partner 
of subject), or true abstinence*(when in line with preferred and usual lifestyle).sterilisation, IUD or 
intrauterine system, or consistent use of barrier methods together with the use of spermicide,and 
sexual abstinence.
*Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods),declaration of abstinence for the duration of a trial, and withdrawal are not acceptable 
methods of  contraception
2.1.3
Section 6.3 Exclusion criteria 4
Male of reproductive age who or whose partner(s) is not using highly effective adequate 
contraceptive methods for the duration of the trial (highly effectiveadequate contraceptive 
measures, as required by local regulation or practice, i.e. a measure that results in less than 1% per 
year failure rate when used consistently and correctly)
2.1.4
Section 8.5.2.1 Pregnancy test
A human chorionic gonadotropin serum pregnancy test will be performed at Visit 1 and 63 on all 
women where childbearing potential has not been ruled out by for example measuring FSH levels. 
Urine pregnancy test will be performed for females of childbearing potential at any time during the 
trial if a menstrual period is missed or required by local law. If a subject during a phone contact 
reports missing menstrual period, an unscheduled visit should be scheduled as soon as possible to 
have a urine pregnancy test performed. Urine pregnancy kits will be supplied by the central 
laboratory. The test will be performed at site.
For Austria: A monthly urine pregnancy test is mandatory for female subjects of childbearing
potential.
For Ireland: A urine pregnancy test at each visit is mandatory for female subjects of childbearing 
potential.
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
01 July 2015
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Trial ID: NN9828-4150
Version:
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UTN:1111-1154-7172
Status:
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EudraCT No.: 2014-001215-39
Page:
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2.1.5
Section 11.1 Breaking of blinded codes
The IV/WRS will notify Novo Nordisk (monitor and the Global Safety department) immediately 
after the code is broken. 
The Investigators are responsible for all trial related medical decisions. The code for a particular 
subject may be broken in a medical emergency if knowing the actual treatment would influence the 
treatment of the subject. Whenever a code is broken the person breaking the code must print the 
Code Break Confirmation Notification generated by the IV/WRS, record the reason, and sign and 
date the document. When the code is broken, the treatment allocation will be accessible to the 
investigator and the Novo Nordisk Global Safety department. If IV/WRS is not accessible at the 
time of code break the IV/WRS helpdesk should be contacted. Contact details are listed in 
Attachment I. If the code has been broken the subject must be withdrawn from the trial and a 
withdrawal session must be completedin IV/WRS.
2.2
Changes to the protocol due to corrections of minor inconsistencies and clarifications 
to the protocol and the subject information
2.2.1
Section 1 Summary
The clinical diagnosis of T1DM is defined by the following two paragraphs:
1. One or more of the following:
!
HbA1c ≥ 6.5% or
!
fasting plasma glucose ≥ 7.0 mmol/l (126 mg/dl) or
!
a 2 hour plasma glucose ≥ 11.1 mmol/l (200 mg/dl) during an oral glucose tolerance test with a
glucose load of 75 grams anhydrous glucose in water or
!
classical symptoms of hyperglycaemia and a random plasma glucose ≥ 11.1 mmol/l (200
mg/dl)1
2. In order to:
!
ensure that the aetiology is autoimmune, the clinical diagnosis needs to be confirmed by the
presence of islet-specific auto-antibodies at screening
!
exclude T2DM and LADA the subjects should be without severe insulin resistance (i.e.
total daily insulin dose larger than 1 U/kg per day at screening).
Key exclusion criteria
9. Known impairment of the immune system, except for T1DM, coeliac disease, alopecia and
vitiligo
2.2.2
Section 2 Flowchart
Visit 1 to 37 procedures
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Protocol Amendment
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Date:
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Trial ID: NN9828-4150
Version:
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UTN:1111-1154-7172
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EudraCT No.: 2014-001215-39
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Extra X has been added to “immunology” visit 4, 5 and 6.
Visit 38 to 90 procedures
2.2.3
Section 5.3.3 Insulin treatment
Subject will continue on their current insulin treatment after they have been randomised. It is 
preferred that subjects continue on the same type of insulin treatment throughout the trial. Subjects 
will be trained in diabetes self-care including carbohydrate counting before and at randomisation 
and whenever needed during the course of the study in order to achieve the most optimal diabetes 
control. 
2.2.4
Section 6.2 Inclusion criteria
2. Type 1 diabetes mellitus (as diagnosed clinically*) ≤ 12 weeks prior to randomisation (see 
Section 8.2.6)
2.2.5
Section 6.3 Exclusion criteria
14. Evidence of or cytomegalovirus infection (CMV) resolved less than 2 months prior to screening 
(V1)
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Protocol Amendment
CONFIDENTIAL
Date:
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Trial ID: NN9828-4150
Version:
1.0
UTN:1111-1154-7172
Status:
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EudraCT No.: 2014-001215-39
Page:
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39. Known impairment of the immune system, except for T1DM, coeliac disease, alopecia and 
vitiligo
2.2.6
Section 6.8 Rationale for trial population
The clinical diagnosis of T1DM is defined by the following two paragraphs:
3. One or more of the following:
!
HbA1c ≥ 6.5% or 
!
fasting plasma glucose ≥ 7.0 mmol/l (126 mg/dl) or 
!
a 2 hour plasma glucose ≥ 11.1 mmol/l (200 mg/dl) during an oral glucose tolerance test with a 
glucose load of 75 grams anhydrous glucose in water or 
!
classical symptoms of hyperglycaemia and a random plasma glucose ≥ 11.1 mmol/l (200 
mg/dl)1
4. In order to:
!
ensure that the aetiology is autoimmune, the clinical diagnosis needs to be confirmed by the 
presence of islet-specific auto-antibodies at screening
!
exclude T2DM and LADA the subjects should be without severe insulin resistance (i.e. 
total daily insulin dose larger than 1 U/kg per day at screening). 
2.2.7
Section 8.1 Visit procedures
The investigator must keep a subject screening log, a subject identification code list and a subject 
enrolment log. The subject screening log and subject enrolment log may be combined in one list 
and may be generated from the IV/WRS. The investigator should keep a pre-screening log.
2.2.8
Section 8.2.6 Diagnosis of diabetes
The following information has to be recorded:
!
Date of diagnosis of T1DM
The date of diagnosis of T1DM is the day a doctor has confirmed the diagnosis of T1DM upon 
review of relevant laboratory results (see section 6.8.)
2.2.9
Section 8.3.1 Mixed meal tolerance test
All plasma glucose values to be measured at site must be measured with at validated BG 
instrument. The BG meter handed out to the subjects should not be used for this purpose.
2.2.10
Section 8.4.2.7 Hypoglycaemic episodes
The Investigator must review the e-diary data for correct reporting of SMPGs and hypoglycaemic 
episodes at each contact. If the investigator experiences missing data in the diary, the subject must 
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
01 July 2015
Novo Nordisk
Trial ID: NN9828-4150
Version:
1.0
UTN:1111-1154-7172
Status:
Final
EudraCT No.: 2014-001215-39
Page:
10 of 11
be questioned whether there have been any severe hypoglycaemic episodes since the last visit i.e. 
any hypoglycaemic episodes where the subject was not able to self-treat. Any severe 
hypoglycaemic episodes must be reported on a hypoglycaemic episode form in the e-diary by the 
subject.
If the hypoglycaemic episode fulfils the criteria for an SAE and/or a medical event of special 
interest (MESI) then an AE form and a safety information form must also be filled in, see section 
12.1
2.2.11
Section 8.5.1.3 Biomarkers
The following will be analysed:
T-cell profiling including islet-specific auto reactive CD8+ T-cells, except at Visit 4, 5 and 6
IL-21, excepted at Visit 2
The blood sampling for assessment of T-cell profiling including islet-specific auto reactive CD8+ 
T-cells should preferably be performed at about the same time of day for a given subject.
Blood sampling for the assessment of Il-21 should be taken pre-dose if of the NNC0114-0006 is 
given at the sampling visitsadministration. IL-21 will be analysed at a specialised laboratory only if 
a functioning assay is available in due time to ensure analyses and results are ready for data base 
lock. The investigator will receive the results of the immunology assessments at the end of the trial. 
If no functional assay is available the samples will be destroyed. 
2.2.12
Section 9.3 Storage
Trial product
Storage 
conditions
(not-in-use)
In-use 
conditions*
In-use time**
NNC0114-0006 C 100 mg/ml
Store in a 
refrigerator
(2°C to 8°C)
Protect from light
Do not freeze
Below 30°C
Protect from light
Do not freeze
For 6 hours
NNC0114-0006 C 0 mg/ml
Trial product
Storage 
In-use conditions
In-use time***
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
01 July 2015
Novo Nordisk
Trial ID: NN9828-4150
Version:
1.0
UTN:1111-1154-7172
Status:
Final
EudraCT No.: 2014-001215-39
Page:
11 of 11
conditions
(not-in-use)
Liraglutide 
6.0 mg/ml, 3 ml pre-filled 
pen 
Store in a 
refrigerator
(2°C to 8°C)
Protect from light
Do not freeze
Store below 30°C
US:
15-30° or in a 
refrigerator (2°C-
8°C)
CA:
At room 
temperature not 
above 30°C or in 
a refrigerator (2°-
8°C)
Protect from light
Do not freeze
1 month 
US:
For 30 days
CA:
For 30 days 
Liraglutide placebo
3 ml pre-filled pen 
*During in-use the trial product should not be exposed to direct sun light
**In-use time starts after removal from the refrigerator at site. The dosing should be performed 
within 6 hours after the trial product is removed from the refrigerator. 
*** In-use time starts when first dose is taken 
2.3
Master SI/IC
2.3.1
Section For how long time will your data be stored
All data from this trial will be archived for at least 25 15 years at the site, but the sponsor may store 
the data up to 20 years after the trial product has become commercially available.
2.3.2
Section Schematic overview of the trial
Extra X has been added to “bring insulin to the site” week 65 and 69.
CONFIDENTIAL


Protocol Amendment 2
CONFIDENTIAL
Date:
14 March 2016
Novo Nordisk
Trial ID: NN9828-4150
Version:
1.0
UTN: U1111-1154-7172
Status:
Final
EudraCT No.: 2014-001215-39
Page:
1 of 27
Protocol Amendment 
no 2
to Protocol, final version 3.0
dated 01 July 2015
Trial ID: NN9828-4150
A randomised, double-blind, double-dummy, placebo-controlled, parallel-group 
multi-centre clinical proof-of-principle trial in adult subjects with newly 
diagnosed type 1 diabetes mellitus investigating the effect of NNC0114-0006 and 
liraglutide on preservation of beta-cell function
Trial phase: 2
Applicable to all countries 
Amendment originator:
ClinOps 1, Insulin, GH & Devices
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol Amendment 2
CONFIDENTIAL
Date:
14 March 2016
Novo Nordisk
Trial ID: NN9828-4150
Version:
1.0
UTN: U1111-1154-7172
Status:
Final
EudraCT No.: 2014-001215-39
Page:
2 of 27
Table of Contents   
Page
Table of Contents .............................................................................................................................................2
1
Introduction including rationale for the protocol amendment.............................................................4
2
Changes......................................................................................................................................................6
2.1
Section 1 Summary........................................................................................................................6
2.2
Section 2 Flow chart ......................................................................................................................7
2.3
Section 4.1 Secondary objectives ................................................................................................18
2.4
Section 4.2.2.1 Supportive secondary efficacy endpoints ...........................................................18
2.5
Section 4.2.2.3 Supportive secondary biomarker endpoints........................................................18
2.6
Figure 2–1  Trial design...............................................................................................................18
2.7
Section 5.3.1 NNC0114-0006......................................................................................................18
2.8
Section 5.3.2 Liraglutide..............................................................................................................19
2.9
Section 5.3.3 Insulin treatment ....................................................................................................20
2.10
Section 6.1 Number of subjects...................................................................................................20
2.11
Section 6.2 Inclusion criteria .......................................................................................................20
2.12
Section 6.3 Exclusion criteria ......................................................................................................20
2.13
Section 6.4 Randomisation criteria..............................................................................................21
2.14
Section 6.8 Rationale for trial population....................................................................................21
2.15
Section 8.1.4 Re-screening/ re-sampling .....................................................................................21
2.16
Section 8.1.6 Missed visits and unscheduled visits .....................................................................21
2.17
Section 8.1.7 Withdrawn subjects................................................................................................22
2.18
Section 8.1.8 Fasting visits ..........................................................................................................22
2.19
Section 8.2.2 Concomitant medication........................................................................................22
2.20
Section 8.2.3 Smoking status.......................................................................................................22
2.21
Section 8.2.6 Diagnosis of diabetes.............................................................................................22
2.22
Section 8.2.7 Diabetes treatment history .....................................................................................23
2.23
Section 8.3.1 Mixed meal tolerance test......................................................................................23
2.24
Section 8.3.4 7-point profile ........................................................................................................24
2.25
Section 8.3.5 Insulin doses ..........................................................................................................24
2.26
Section 8.3.6 Carbohydrate intake per meal................................................................................24
2.27
Section 8.4.2.1 Pancreatitis..........................................................................................................24
2.28
Section 8.4.2.3 Neoplasm ............................................................................................................25
2.29
Section 8.4.2.5 Injection/Infusion site reactions..........................................................................25
2.30
Section 8.4.2.7 Hypoglycaemic episodes ....................................................................................25
2.31
Section 8.4.3 Technical complaints.............................................................................................25
2.32
Section 8.4.4.3 BMI.....................................................................................................................25
2.33
Section 8.4.8 Vital signs ..............................................................................................................26
2.34
Section 8.5 Laboratory assessments ............................................................................................26
2.35
Section 8.5.1.3 Biomarkers..........................................................................................................26
2.36
Section 8.5.2.2 Anti-drug antibodies ...........................................................................................26
2.37
Section 8.6.2 Liraglutide/liraglutide placebo...............................................................................27
2.38
Section 8.7 Subject compliance...................................................................................................27
CONFIDENTIAL


Protocol Amendment 2
CONFIDENTIAL
Date:
14 March 2016
Novo Nordisk
Trial ID: NN9828-4150
Version:
1.0
UTN: U1111-1154-7172
Status:
Final
EudraCT No.: 2014-001215-39
Page:
3 of 27
2.39
Section 13.3 E-diaries..................................................................................................................27
2.40
Section 17.4.1.1 Efficacy endpoints ............................................................................................27
2.41
Section 26 Indemnity statement...................................................................................................27
CONFIDENTIAL


Protocol Amendment 2
CONFIDENTIAL
Date:
14 March 2016
Novo Nordisk
Trial ID: NN9828-4150
Version:
1.0
UTN: U1111-1154-7172
Status:
Final
EudraCT No.: 2014-001215-39
Page:
4 of 27
1
Introduction including rationale for the protocol amendment
This amendment was prepared based on feedback from participating countries resulting in scientific 
re-evaluation of the need for all analyses. The feedback underlines subjects’ reluctance to 
participate in the trial due to the heavy time commitment. Further, the timing of inclusion criterion 
2 has proven to be a logistical challenge. 
As a result of this we have reduced the number of subjects included in the full PK analysis to the 
first 80 randomised subjects. The remaining subjects will attend 9 site visits less during the trial 
period of 90 weeks. It is estimated that planning for taking a full PK profile from 20 subjects per 
treatment group (80 in total) will give approximately 13 subjects per treatment group with a full PK 
profile if withdrawals are taken into consideration. This is the level of PK assessment in single dose 
and multiple dose trials found to be sufficient. This change is captured by introducing a separate 
flow chart for subjects included after 80 randomised subjects. In addition the visit schedule will be 
reduced by changing 5 site visits (V58, V59, V61, V69 and V78) into phone visits and deleting 4 
site visits (V4, V5, V56 and V57), but otherwise remain the same.
It has proven challenging to identify and randomise the subjects within the diagnosis window of 
12 weeks up to randomisation. There is no scientific data in adults, which shows that changing the 
diagnosis duration from 12 weeks to 24 weeks (including run-in period) will affect the primary 
endpoint of AUC0-4h for a mixed meal tolerance test which is a measure for the subject’s beta cell 
mass. It is hence decided to make this change to facilitate identification of subjects within the 
period given by inclusion criterion 2. Changing the cut-off day to the day of screening instead of 
randomisation will mitigate the logistical challenges in having all eligibility parameters ready for 
randomisation and reduce the risk of screen failing an eligible subject due to violation of the visit 
window. The enrolment window of 12 weeks (inclusion criterion 2) is therefore changed from
diagnosis of Type 1 diabetes mellitus ≤ 12 weeks prior to randomisation to diagnosis of Type 1 
diabetes mellitus ≤ 20 weeks prior to screening. 
Several subjects have failed to fulfil inclusion criterion 4 due to not fulfilling the requirement of 
being non-fasting, which may result in a lowering of the subjects C-peptide result. To mitigate this,
the measurement of non-fasting C-peptide will be moved to Visit 2 at which the first MMTT is 
performed. By having the stimulated C-peptide level at Visit 2 during the MMTT above or equal to 
0.2 nmol/l the eligible subjects will have the desired beta cell function, and excluding possibly 
eligible patients, who were fasting at Visit 1, will be avoided. 
Termination of bolus insulin use is a good measure of the quality of life of the participating 
subjects. In order to measure this, an additional secondary endpoint has been introduced in section
4.2.2.1 assessing the number of subjects no longer using bolus insulin. Further, section 5.3.3 has 
been updated based on this additional endpoint. This end-point should ideally have been 
CONFIDENTIAL


Protocol Amendment 2
CONFIDENTIAL
Date:
14 March 2016
Novo Nordisk
Trial ID: NN9828-4150
Version:
1.0
UTN: U1111-1154-7172
Status:
Final
EudraCT No.: 2014-001215-39
Page:
5 of 27
implemented from start trial. Data from >200 subjects, will however provide important data from a 
clinical important parameter. 
The INS DNA assay was hypothesized to identify waves of beta-cell death by measuring the ratio 
of methylated to un-methylated insulin DNA, thus providing a method of assessing beta-cell loss. 
No functioning assay for analysing differential INS DNA has been developed and it is hence 
decided to exclude this assessment from the protocol in section 4.2.2.3 and 8.5.1.3.
Treatment with liraglutide and insulin has been clarified in section 5.3.2 and section 5.3.3 with 
regards to escalation and missed doses.
Maximum number of subjects to be randomised has been deleted in section 1 and section 6.1 to 
avoid screened failing subjects due to maximum randomisation number met. The period between 
screening and randomisation is up to 4 weeks and screening in IV/WRS will be monitored very 
closely when the planned number of randomised subjects is approaching. The current screen failure 
rate will be considered when the decision of closing screening is taken.  
Exclusion criteria 16, 21 and 39 have been updated in section 6.3 for clarification based on 
questions from participating sites. These changes have no medical or scientific impact on the 
criteria. 
In section 8.1.4 it has been clarified that all screening lab samples can be re-taken if a result is 
inconclusive. 
Section 8.2.2 Concomitant medication was updated to reflect that the insulin dose which the subject 
enters the trial on has to be captured on the concomitant medication form in EDC.
There is a need to further clarify the description of the exact date of diagnosis of T1DM and section 
8.2.6 has hence been updated to clarify.
If the subject experiences a hypoglycaemic episode prior to the MMTT visit it should be assessed 
by the investigator whether the MMTT needs to be postponed or if it can be carried out as a 
treatment of the hypoglycaemic episode. Section 8.3.1 has been updated to reflect this.
Section 8.4.2 has been updated based on the SHARP (Simplified Handling of Adverse Events 
Reporting) forms to simplify/uniform safety data collection on specific event categories.
Additional editorial corrections have been made to the protocol for clarification and simplification.
In this protocol amendment:
!
Any new text is written in italics.
!
Any text deleted from the protocol is written using strike through.
CONFIDENTIAL


Protocol Amendment 2
CONFIDENTIAL
Date:
14 March 2016
Novo Nordisk
Trial ID: NN9828-4150
Version:
1.0
UTN: U1111-1154-7172
Status:
Final
EudraCT No.: 2014-001215-39
Page:
6 of 27
2
Changes
2.1
Section 1 Summary
Secondary objectives
Objectives related to treatment period (from baseline (week 0) to week 54):
Trial Design
The rRandomisation will be stratified according to the non-fasting peak C-peptide value at 
screening Visit 2. 
Trial population
304 adult subjects with newly diagnosed T1DM are required according to the sample size 
calculation. A maximum number of 314 subjects will be randomised.
Key inclusion criteria
2. T1DM (as diagnosed clinically*) ≤ 1220 weeks prior to randomisation screening
4. Non-fasting peak C-peptide ≥0.2 nmol/l during MMTT at Visit 2
Key exclusion criteria
9. Known impairment of the immune system, except for T1DM, coeliac disease, alopecia, 
autoimmune antibodies not considered clinical important (e.g. thyroid antibodies without any 
clinically important thyroid disease), and vitiligo
CONFIDENTIAL


Protocol Amendment 2
UTN: U1111-1154-7172
Date:
14 March 2016
Status:
Final
Novo Nordisk
Trial ID: NN9828-4150
EudraCT No.: 2014-001215-39
Version:
1.0
Page:
7 of 27
2.2
Section 2 Flow chart
Visit 1 to 37 procedures for the first 80 randomised subjects only
Trial periods
S
R
Treatment
Visit type:
C: Clinic, P: Phone contact
C
C
C
C
C
C
C
P
P
C
P
P
C
P
C
P
C
P
C
P
C
P
C
P
C
P
C
P
C
Visit number
1
2
3
4
5
6
7
8
9
10
11
12
13
14,15
16
17,18
19
20-22
23
24
25
26-28
29
30
31
32-34
35
36
37
Timing of visit (weeks (W), or 
days (D) if specified)
-D28 to 
–D14
-D10
0
1D
3D
W1
W2
W2 + 
1D
W3
W4
W4 + 
1D
W5
W6
W7,8
W9
W10,11
W12
W13-15
W16
W17
W18
W19-21
W22
W23
W24
W25-27
W28
W29
W30
Visit window (days)
± 
4
±
1
±
1
±
1
±
1
±
1
±
1
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
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
x
x
x
Hyperglycaemic episodes
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
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
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
x
x
x
x
x
x
x
Body measurements5
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
EFFICACY
Glucose metabolism
x
x
x
x
x
x
x
Meal test3
x
x
x
Self-measured plasma glucose:
7-point profile prior to visit
x
x
x
x
x
x
x
x
x
x
x
x
4-point profile prior to visit4
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
PRO questionnaires
x
x
Biomarkers:
Differential methylated INS DNA
x
x
x
x
Anti-IAA and –GAD isotypes
x
x


Protocol Amendment 2
UTN: U1111-1154-7172
Date:
14 March 2016
Status:
Final
Novo Nordisk
Trial ID: NN9828-4150
EudraCT No.: 2014-001215-39
Version:
1.0
Page:
8 of 27
Visit 38 to 90 procedures for the first 80 randomised subjects only
Trial period
Treatment
Follow-up
Visit type:
C: Clinic, P: Phone contact
P
C
P
C
P
C
P
C
P
C
P
C
C
C
C
P
C
P
C
P
C
P
C
P
C
P
C
C
Visit number
38-40
41
42
43
44-46
47
48
49
50-52
53
54
55
56
57
58,59
60
61
62
63
64-68
69
70-73
74
75-77
78
79-88
89
901
Timing of visit 
(weeks (wW), or days (D) if 
specified)                      
W31-33
W34
W35
W36
W37-39
W40
W41
W42
W43-45
W46
W47
W48
W48 + 
1D
W48 + 
3D
W49, 50
W51
W52
W53
W54
W55-59
W60
W61-64
W65
W66-68
W69
W70-79
W80
Visit window (days)
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
7
EFFICACY
Glucose metabolism
x
x
x
x
x
x
x
x
Meal test4
x
x
x
x
Self-measured plasma glucose:
7-point profile prior to visit
x
x
x
x
x
x
x
x
4-point profile prior to visit5
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
PRO questionnaires
x
x
Biomarkers:
Differential methylated INS
DNA
x
x
x
x
Anti-IAA and –GAD isotypes
x
x
1. Only for NNC00114-0006
2. For woman of childbearing potential only. Blood sample at V1. For all subsequent visits a urine stick must only be measured for females of childbearing potential if a 
menstrual period is missed or as required by law. 
3. The MMTT may be re-scheduled twice within 10 days. At Visit 2 the MMTT must be performed before Visit 3 and leaving sufficient time for randomisation lab results.  


Protocol Amendment 2
UTN: U1111-1154-7172
Date:
14 March 2016
Status:
Final
Novo Nordisk
Trial ID: NN9828-4150
EudraCT No.: 2014-001215-39
Version:
1.0
Page:
9 of 27
Visit 1 to 37 procedures after 80 subjects have been randomised
Trial periods
S
R
Treatment
Visit type:
C: Clinic, P: Phone contact
C
C
C
C
C
P
P
C
P
P
C
P
C
P
C
P
C
P
C
P
C
P
C
P
C
P
C
Visit number
1
2
3
6
7
8
9
10
11
12
13
14,15
16
17,18
19
20-22
23
24
25
26-28
29
30
31
32-34
35
36
37
Timing of visit (weeks (W), or days (D) if 
specified)
-D28 to 
–D14
-D10
0
W1
W2
W2 + 
1D
W3
W4
W4 + 
1D
W5
W6
W7,8
W9
W10,11
W12
W13-15
W16
W17
W18
W19-21
W22
W23
W24
W25-27
W28
W29
W30
Visit window (days)
± 
4
±
1
±
1
±
1
±
1
±
1
±
1
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
SUBJECT RELATED
INFO/ASSESSMENTS
Informed consent
x
Genotyping consent, optional
x
Long term retention consent, optional
x
In/exclusion criteria
x
x
x
Randomisation
x
Randomisation criteria
x
Withdrawal criteria
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
Dosing day exclusion criteria1
x
x
x
x
x
x
Abuse of alcohol
x
Abuse of drugs
x
Medical history
x
Concomitant illness
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
x
x
x
x
x
Demography
x
Diagnosis of diabetes
x
Diabetes treatment history
x


Protocol Amendment 2
UTN: U1111-1154-7172
Date:
14 March 2016
Status:
Final
Novo Nordisk
Trial ID: NN9828-4150
EudraCT No.: 2014-001215-39
Version:
1.0
Page:
10 of 27
Trial periods
S
R
Treatment
Visit type:
C: Clinic, P: Phone contact
C
C
C
C
C
P
P
C
P
P
C
P
C
P
C
P
C
P
C
P
C
P
C
P
C
P
C
Visit number
1
2
3
6
7
8
9
10
11
12
13
14,15
16
17,18
19
20-22
23
24
25
26-28
29
30
31
32-34
35
36
37
Timing of visit (weeks (W), or days (D) if 
specified)
-D28 to 
–D14
-D10
0
W1
W2
W2 + 
1D
W3
W4
W4 + 
1D
W5
W6
W7,8
W9
W10,11
W12
W13-15
W16
W17
W18
W19-21
W22
W23
W24
W25-27
W28
W29
W30
Visit window (days)
± 
4
±
1
±
1
±
1
±
1
±
1
±
1
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
Pregnancy test2
x
Smoking habits
x
Family history of diabetes
x
Diabetes complications
x
Blood sample for genotyping (optional)
x
EFFICACY
Glucose metabolism
x
x
x
x
x
x
x
Meal test3
x
x
x
Self-measured plasma glucose:
7-point profile prior to visit
x
x
x
x
x
x
x
x
x
x
4-point profile prior to visit4
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
PRO questionnaires
x
x
Biomarkers:
Antibodies (autoantibodies)
x
x
x
x
x
Immunology
x
x
x
x
x
x
Vitamin D (1,25 dehydroxy-calciferol
x
x
x
x
Dose of insulin administrations
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
Carbohydrate intake
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
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
x


Protocol Amendment 2
UTN: U1111-1154-7172
Date:
14 March 2016
Status:
Final
Novo Nordisk
Trial ID: NN9828-4150
EudraCT No.: 2014-001215-39
Version:
1.0
Page:
11 of 27
Trial periods
S
R
Treatment
Visit type:
C: Clinic, P: Phone contact
C
C
C
C
C
P
P
C
P
P
C
P
C
P
C
P
C
P
C
P
C
P
C
P
C
P
C
Visit number
1
2
3
6
7
8
9
10
11
12
13
14,15
16
17,18
19
20-22
23
24
25
26-28
29
30
31
32-34
35
36
37
Timing of visit (weeks (W), or days (D) if 
specified)
-D28 to 
–D14
-D10
0
W1
W2
W2 + 
1D
W3
W4
W4 + 
1D
W5
W6
W7,8
W9
W10,11
W12
W13-15
W16
W17
W18
W19-21
W22
W23
W24
W25-27
W28
W29
W30
Visit window (days)
± 
4
±
1
±
1
±
1
±
1
±
1
±
1
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
Hyperglycaemic episodes
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
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
x
x
x
x
Body measurements5
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
ECG
x6
x
x
x
x
x
Eye examination
x7
Physical examination
x
x
x
x
x
x
Vital signs
x
x
x
x
x
x
x
x
x
x
x
Antibodies:
Anti-NNC0114-0006 antibodies
x
x
x
Anti-liraglutide antibodies
x
x
x
IgE
x
x
x
x
x
Biochemistry
x
x
x
x
x
x
Coagulation parameters
x
x
x
x
x
x
Haematology
x
x
x
x
x
x
Cytokines
x
x
x
x
Urine dipsticks 
x
x
x
x
x
x
Hepatitis B
x
x
x
x
x
x
Hepatitis C
x
Tuberculosis screening test 
x


Protocol Amendment 2
UTN: U1111-1154-7172
Date:
14 March 2016
Status:
Final
Novo Nordisk
Trial ID: NN9828-4150
EudraCT No.: 2014-001215-39
Version:
1.0
Page:
12 of 27
Trial periods
S
R
Treatment
Visit type:
C: Clinic, P: Phone contact
C
C
C
C
C
P
P
C
P
P
C
P
C
P
C
P
C
P
C
P
C
P
C
P
C
P
C
Visit number
1
2
3
6
7
8
9
10
11
12
13
14,15
16
17,18
19
20-22
23
24
25
26-28
29
30
31
32-34
35
36
37
Timing of visit (weeks (W), or days (D) if 
specified)
-D28 to 
–D14
-D10
0
W1
W2
W2 + 
1D
W3
W4
W4 + 
1D
W5
W6
W7,8
W9
W10,11
W12
W13-15
W16
W17
W18
W19-21
W22
W23
W24
W25-27
W28
W29
W30
Visit window (days)
± 
4
±
1
±
1
±
1
±
1
±
1
±
1
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
(QuantiFERON)
Epstein–Barr virus
x
x
x
x
x
x
CMV8
x
x
x
x
x
x
HIV
x
Hormones
x
x
x
Lipids
x
x
x
OTHER ASSESSMENTS
PK sampling
NNC0114-0006
x9
x
x
x
x
x
x
x
x
x
PK sampling
Liraglutide10
x
x
x
x
x
x
x
x
x
x
TRIAL MATERIAL
IV/IWRS
x
x
x
x
x
x
x
Administration and dispensing of trial 
product NNC0114-0006/placebo
x
x
x
x
x
x
Dispensing of liraglutide/placebo11
x
x
x
x
x
x
Drug accountability for IMP12
x
x
x
x
x
x
REMINDERS
Handout ID cards
x
Handout direction for use13
x
Handout and instruct in e-diary
x


Protocol Amendment 2
UTN: U1111-1154-7172
Date:
14 March 2016
Status:
Final
Novo Nordisk
Trial ID: NN9828-4150
EudraCT No.: 2014-001215-39
Version:
1.0
Page:
13 of 27
Trial periods
S
R
Treatment
Visit type:
C: Clinic, P: Phone contact
C
C
C
C
C
P
P
C
P
P
C
P
C
P
C
P
C
P
C
P
C
P
C
P
C
P
C
Visit number
1
2
3
6
7
8
9
10
11
12
13
14,15
16
17,18
19
20-22
23
24
25
26-28
29
30
31
32-34
35
36
37
Timing of visit (weeks (W), or days (D) if 
specified)
-D28 to 
–D14
-D10
0
W1
W2
W2 + 
1D
W3
W4
W4 + 
1D
W5
W6
W7,8
W9
W10,11
W12
W13-15
W16
W17
W18
W19-21
W22
W23
W24
W25-27
W28
W29
W30
Visit window (days)
± 
4
±
1
±
1
±
1
±
1
±
1
±
1
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
Investigator review of e-diary
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
Handout and instruct in BG meter use
x
Attend fasting visit
x
x
x
x
x
x
x
Blood sample for long term retention 
(optional)
x
x
1. Only for NNC0114-0006
2. Blood sample at V1. For all subsequent visits a urine stick must only be measured for females of childbearing potential if a menstrual period is missed or as required 
by law. Austria: Urine-stick pregnancy test will be performed monthly. Ireland: Urine-stick pregnancy test will be performed at all visits to the clinic.
3. The MMTT may be re-scheduled twice within 10 days. At Visit 2 the MMTT must be performed before Visit 3 and leaving sufficient time for randomisation lab results.
4. 4-point profile will be used for T-T-T  
5. At V1 height and weight will be measured and BMI will be calculated via the eCRF. At the following visits only weight must be measured
6. A baseline ECG performed for any reason unrelated to the trial within 30 days prior to V1 is acceptable provided no clinical symptoms suggestive of cardiac disease 
have occurred in the meantime
7. A baseline fundoscopy/ fundus photography performed for any reason unrelated to the trial within 90 days prior to V3 is acceptable
8. Cytomegalovirus
9. PK sample for NNC0114-0006 (pre-dose and 1 hour sample after start of infusion)
10. PK sample at any time during the visit
11. Liraglutide/liraglutide placebo will be administered once daily
12. Investigational medicinal product
13. Injection of liraglutide will be trained at V3 and at following visits as needed.


Protocol Amendment 2
UTN: U1111-1154-7172
Date:
14 March 2016
Status:
Final
Novo Nordisk
Trial ID: NN9828-4150
EudraCT No.: 2014-001215-39
Version:
1.0
Page:
14 of 27
Visit 38 to 90 procedures after 80 subjects have been randomised
Trial period
Treatment
Follow-up
Visit type:
C: Clinic, P: Phone contact
P
C
P
C
P
C
P
C
P
C
P
C
P
P
P
P
C
P
P
P
C
P
P
P
C
C
Visit number
38-40
41
42
43
44-46
47
48
49
50-52
53
54
55
58,59
60
61
62
63
64-68
69
70-73
74
75-77
78
79-88
89
901
Timing of visit 
(weeks (W), or days (D) if specified)                      
W31-33
W34
W35
W36
W37-39
W40
W41
W42
W43-45
W46
W47
W48
W49, 50
W51
W52
W53
W54
W55-59
W60
W61-64
W65
W66-68
W69
W70-79
W80
Visit window (days)
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
1
±
1
±
1
±
3
±
1
±
1
±
1
±
3
±
1
±
1
±
1
±
3
±
7
SUBJECT RELATED
INFO/ASSESSMENTS
Withdrawal criteria
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Dosing day exclusion criteria2
x
x
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
x
x
x
x
Pregnancy test3
x
Diabetes complications
x
x
EFFICACY
Glucose metabolism
x
x
x
x
x
x
Meal test4
x
x
x
x
Self-measured plasma glucose:
7-point profile prior to visit
x
x
x
x
x
x
x
x
4-point profile prior to visit5
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
PRO questionnaires
x
x
Biomarkers:
Antibodies (autoantibodies)
x
x
x
x
Anti-IAA and –GAD isotypes
x
x
Immunology
x
x
x
x
Vitamin D (1,25 dehydroxy-calciferol)
x
x
x
x
Dose of insulin administrations
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


Protocol Amendment 2
UTN: U1111-1154-7172
Date:
14 March 2016
Status:
Final
Novo Nordisk
Trial ID: NN9828-4150
EudraCT No.: 2014-001215-39
Version:
1.0
Page:
15 of 27
Trial period
Treatment
Follow-up
Visit type:
C: Clinic, P: Phone contact
P
C
P
C
P
C
P
C
P
C
P
C
P
P
P
P
C
P
P
P
C
P
P
P
C
C
Visit number
38-40
41
42
43
44-46
47
48
49
50-52
53
54
55
58,59
60
61
62
63
64-68
69
70-73
74
75-77
78
79-88
89
901
Timing of visit 
(weeks (W), or days (D) if specified)                      
W31-33
W34
W35
W36
W37-39
W40
W41
W42
W43-45
W46
W47
W48
W49, 50
W51
W52
W53
W54
W55-59
W60
W61-64
W65
W66-68
W69
W70-79
W80
Visit window (days)
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
1
±
1
±
1
±
3
±
1
±
1
±
1
±
3
±
1
±
1
±
1
±
3
±
7
Carbohydrate intake
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
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
Hyperglycaemic episodes
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
x
x
x
Technical complaints
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Body measurements
x
x
x
x
x
x
x
x
x
x
ECG
x
x
x
x
x
x
Eye examination6
x
x
Physical examination
x
x
x
x
x
x
Vital signs
x
x
x
x
x
x
x
Antibodies: 
Anti-NNC0114-0006 antibodies
x
x
x
x
Anti-liraglutide antibodies
x
x
x
x
IgE
x
x
x
x
x
x
Biochemistry
x
x
x
x
x
x
Coagulation parameters
x
x
x
x
x
x
Haematology
x
x
x
x
x
x
Cytokines
x
x
x
x
x
x
Urine dipsticks 
x
x
x
x
x
x
Hepatitis B 
x
x
x
x
EBV
x
x
x
x


Protocol Amendment 2
UTN: U1111-1154-7172
Date:
14 March 2016
Status:
Final
Novo Nordisk
Trial ID: NN9828-4150
EudraCT No.: 2014-001215-39
Version:
1.0
Page:
16 of 27
Trial period
Treatment
Follow-up
Visit type:
C: Clinic, P: Phone contact
P
C
P
C
P
C
P
C
P
C
P
C
P
P
P
P
C
P
P
P
C
P
P
P
C
C
Visit number
38-40
41
42
43
44-46
47
48
49
50-52
53
54
55
58,59
60
61
62
63
64-68
69
70-73
74
75-77
78
79-88
89
901
Timing of visit 
(weeks (W), or days (D) if specified)                      
W31-33
W34
W35
W36
W37-39
W40
W41
W42
W43-45
W46
W47
W48
W49, 50
W51
W52
W53
W54
W55-59
W60
W61-64
W65
W66-68
W69
W70-79
W80
Visit window (days)
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
1
±
1
±
1
±
3
±
1
±
1
±
1
±
3
±
1
±
1
±
1
±
3
±
7
CMV
x
x
x
x
Hormones
x
x
x
x
x
x
Lipids
x
x
x
x
x
x
OTHER ASSESSMENTS
PK sampling NNC0114-0006
x
x
x7
x
x
x
x
PK sampling Liraglutide
x
x
x
x
TRIAL MATERIAL
IV/IWRS
x
x
x
x
x
Administration and dispensing of  trial product 
NNC0114-0006/placebo
x
x
x
Dispensing of liraglutide/placebo
x
x
x
Drug accountability for IMP
x
x
x
x
REMINDERS
Investigator review of e-diary
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
Attend fasting visit
x
x
x
x
x
x
x
Blood sampling for long term retention (optional)
x
x
End of dosing
x8
x9
Collection of e-diary
x
x
End of trial
x
x
Sign off Casebook
x
x
1. Safety follow-up visit. To be conducted for subjects who have been withdrawn less than 14 weeks after last dose of NNC0114-0006/placebo. The visit should be 
conducted 15 weeks ± 1 week after last dose of NNC0114-0006/placebo
2. Only for NNC0114-0006


Protocol Amendment 2
UTN: U1111-1154-7172
Date:
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Status:
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Novo Nordisk
Trial ID: NN9828-4150
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Version:
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3. Blood sample at V63. A urine stick pregnancy test must be performed throughout the trial for females of childbearing potential if a menstrual period is missed or as 
required by local law. Austria: Urine-stick pregnancy test will be performed monthly. Ireland: Urine-stick pregnancy test will be performed at all visits to the clinic.
4. The MMTT may be re-scheduled twice within 10 days
5. 4-point profile will be used for T-T-T  
6. A fundoscopy/ fundus photography may be performed up to 2 weeks before or after V63 and up to 2 weeks before V89
7. PK sample for NNC0114-0006 (pre-dose and 1 hour sample after start of infusion)
8. Last dosing of NNC0114-0006/placebo
9. Last dosing of liraglutide/liraglutide placebo is the day prior to V63


Protocol Amendment 2
CONFIDENTIAL
Date:
14 March 2016
Novo Nordisk
Trial ID: NN9828-4150
Version:
1.0
UTN: U1111-1154-7172
Status:
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EudraCT No.: 2014-001215-39
Page:
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2.3
Section 4.1 Secondary objectives
Objectives related to treatment period (from baseline (week 0) to week 54):
2.4
Section 4.2.2.1 Supportive secondary efficacy endpoints
!
Change in tTotal daily insulin dose in units per kg (three day average) at from baseline to
week 54 and week 80*
!
Change in nNumber of insulin injections per day (three day average) at from baseline to
week 54 and week 80
!
Number of weeks off bolus insulin from baseline to week 54 and week 80
2.5
Section 4.2.2.3 Supportive secondary biomarker endpoints
!
Change in differential methylated INS DNA in plasma from baseline to week 54 and week
80
!
Change in serum vitamin D (1,25 dehydroxy-calciferol) from baseline to week 54 and week
80
Differential methylated INS DNA and IL-21 will be analysed only if a functioning assay will be 
available in due time allowing to incorporate the analyses results in the database prior to database 
lock.
2.6
Figure 2–1
Trial design
New Figure 5-1
2.7
Section 5.3.1 NNC0114-0006
Dosing day exclusion criteria
CONFIDENTIAL


Protocol Amendment 2
CONFIDENTIAL
Date:
14 March 2016
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Trial ID: NN9828-4150
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EudraCT No.: 2014-001215-39
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The infusion of NNC0114-0006/NNC0114-0006 placebo must be postponed if there are symptoms 
or signs of infection, which in the opinion of the investigator are clinically significant (e.g. fever, 
pneumonia or tonsillitis or unspecific viral infection).
If NNC0114-0006/NNC0114-0006 placebo cannot be given within 2 weeks after the scheduled visit 
this should be recorded as a missed dosing in the electronic Ccase Rreport Fform (eCRF). The next 
NNC0114-0006/NNC0114-0006 placebo dose will be given as planned.
2.8
Section 5.3.2 Liraglutide
Initiation and escalation of liraglutide/liraglutide placebo
In case of intolerable liraglutide side effects related to the dose escalation it is acceptable to 
maintain current liraglutide dose and postpone escalation by reduce the dose to the previous dose 
level for up to an additional 2 weeks. 
Missed doses of liraglutide/liraglutide placebo before target dose is reached
If any dose is missed by the subject ≤ 3 consecutive days before reaching the target dose of 1.8 mg 
liraglutide or 0.3 ml liraglutide placebo (1.2 mg liraglutide or 0.2 ml liraglutide placebo, if higher 
dose is not tolerated), it must be documented in the medical record and the investigator should 
discuss the importance of treatment compliance with the subject. After having missed liraglutide/ 
liraglutide placebo doses for ≤ 3 days the subject must be re-initiated on the dose the subject was 
taking prior to the missed doses. The dose escalation should be performed as originally planned. 
If any dose is missed by the subject > 3 consecutive days at any time point it must be documented 
in the medical record and the investigator should discuss the importance of treatment compliance 
with the subject. The subject must be re-initiated on 0.6 mg liraglutide/ liraglutide placebo and dose 
escalation should be every 2 weeks. 
Missed doses of liraglutide/liraglutide placebo after target dose is reached
After reaching the target dose of 1.8 mg liraglutide or 0.3 ml liraglutide placebo (1.2 mg liraglutide
or 0.2 ml liraglutide placebo, if higher dose is not tolerated), dose and dose frequency should not be 
changed at any time during the treatment period. 
If any dose is missed by the subject ≤ 3 consecutive days it must be documented in the medical 
record and the investigator should discuss the importance of treatment compliance with the subject. 
After having missed liraglutide doses ≤ 3 days the subject must should be re-initiated on the target 
dose. 
If any dose is missed by the subject > 3 consecutive days at any time point it must be documented 
in the medical record and the investigator should discuss the importance of treatment compliance 
with the subject. The subject must should be re-initiated on 0.6 mg liraglutide/placebo and dose 
CONFIDENTIAL


Protocol Amendment 2
CONFIDENTIAL
Date:
14 March 2016
Novo Nordisk
Trial ID: NN9828-4150
Version:
1.0
UTN: U1111-1154-7172
Status:
Final
EudraCT No.: 2014-001215-39
Page:
20 of 27
escalation should be every 2 weeks. or continue on current dose of liraglutide/placebo at the 
discretion of the investigator.
2.9
Section 5.3.3 Insulin treatment
During the trial subjects will receive insulin treatment in order to achieve metabolic control 
according to the insulin titration guideline (Appendix A). This insulin treatment will be handled by 
the local trial sites in collaboration with Novo Nordisk’s Insulin Titration Group. Bolus and/or 
basal insulin can be stopped or paused at all times during the trial at the discretion of the 
investigator. The subject’s need for bolus insulin will be documented in the eCRF. It is acceptable to 
pause or stop insulin treatment if the investigator assesses that the subject is in remission.
Insulin reduction on the day of liraglutide/ liraglutide placebo initiation and escalation
As it is a blinded trial, wWhen liraglutide/ liraglutide placebo is initiated, the total daily pre-
randomisation insulin dose should be reduced by 25 % for a minimum of 24 hours after the 
initiation of liraglutide/ liraglutide placebo. 
Thereafter the insulin dose should be adjusted according to the glucose target in Table 5-2. As it is a 
blinded trial this insulin reduction applies to all treatment arms.
2.10
Section 6.1 Number of subjects
Maximum number of subjects to be randomised: 314
2.11
Section 6.2 Inclusion criteria
2. Type 1 diabetes mellitus (as diagnosed clinically*) ≤ 2012 weeks prior to randomisation
screening (see Section 8.2.6).
4. Non-fasting peak** C-peptide ≥0.2 nmol/l during MMTT at Visit 2
*See Section 6.8 for the clinical diagnosis.
**The highest C-peptide value of the 11 samples performed during the MMTT.
2.12
Section 6.3 Exclusion criteria
16. A positive QuantiFERON®-TB Gold test (test may be repeated if result is inconclusive) 
throughout the trial.
21. Positive test results for hepatitis C virus (HCV) as documented by any of the following: Aanti-
HCV antibody positivity (as assessed by an enzyme immunoassay) or Ppresence of HCV 
ribonucleic acid (RNA) in serum.
31. One or more screening (V1) laboratory values as stated:
CONFIDENTIAL


Protocol Amendment 2
CONFIDENTIAL
Date:
14 March 2016
Novo Nordisk
Trial ID: NN9828-4150
Version:
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UTN: U1111-1154-7172
Status:
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EudraCT No.: 2014-001215-39
Page:
21 of 27
!
Haemoglobin <6.2 mmol/l (10.0 g/dl / 100.0 g/l)
39: Known impairment of the immune system, except for T1DM, coeliac disease, alopecia, 
autoimmune antibodies not considered clinically important (e.g. thyroid antibodies without any 
clinical important thyroid disease), and vitiligo.
2.13
Section 6.4 Randomisation criteria
If one or more randomisation criteria are answered “no”, the subject should be offered to have the 
randomisation visit re-scheduled not later than 12 weeks after the diagnosis of T1DM.
2.14
Section 6.8 Rationale for trial population
In order to ensure that patients with a residual beta-cell mass potentially can achieve a clinically 
meaningful improvement in glucose control, the peak or mean non-fasting C-peptide level needs to 
be above or equal to 0.2 nmol/l26at Visit 2. Further, onset of T1DM must be within 12 20 weeks 
after onset of T1DM before screening (Visit 1) and that the subjects are metabolically stable 
(defined as no severe DKA, (confirmed pH below 7.2) within the last 2 weeks prior to screening
randomisation (Visit 3)).
2.15
Section 8.1.4 Re-screening/ re-sampling
However, if the tuberculosis screening test a lab test at Visit 1 or Visit 2 is inconclusive a re-tests
can be performed. The repeat test results must be available for evaluating the subject’s eligibility 
before Visit 3. 
2.16
Section 8.1.6 Missed visits and unscheduled visits
If a visit is missed every effort should be made to ensure information is collected at a telephone 
contact. Subjects will be invited for the next scheduled visit according to the visit schedule.
An unscheduled visit can be scheduled at any time at the discretion of the investigator, e.g. in case 
additional blood samples must be performed for safety reasons. If the investigator asks to subject to 
have a test described in the protocol re- done (e.g extra blood sample if some of the blood sample 
values are out of range) tThis should be recordedreported as on the an unscheduled visit and an
unscheduled visit form in the eCRF must be completedstating the reason for the visit.
If the subject attends the clinic due to re-sampling of visit-related assessments, including MMTT 
and dosing of NNC0114-0006/placebo, this is not considered an unscheduled visit. The date of the 
assessments for a specific visit must be updated in the eCRF accordingly. Likewise, coming to the 
site for additional trial products or ancillary supplies is not considered as an unscheduled visit. In 
the case of additional trial products, a dispensing session should be made in the IV/WRS selecting 
additional medication and the subject notes should be updated accordingly.and some of the tests 
have to be re-scheduled (e.g. in a non-fasting state at a fasting visit) the re-scheduled tests should 
CONFIDENTIAL


Protocol Amendment 2
CONFIDENTIAL
Date:
14 March 2016
Novo Nordisk
Trial ID: NN9828-4150
Version:
1.0
UTN: U1111-1154-7172
Status:
Final
EudraCT No.: 2014-001215-39
Page:
22 of 27
NOT be recorded as an unscheduled visit. In this case blood samples will have a different date of 
collection than the rest of the assessments. Likewise  re-scheduling of the MMTT and dosing of 
NNC0114-0006/placebo should not be recorded as an unscheduled visit.
2.17
Section 8.1.7 Withdrawn subjects
The case book must be signed by the investigator after all queries have been closed. 
If a subject is withdrawn the e-diary must be returned to site.
If subjects fails to return for these visits or is unable to do so, every effort should be made by the 
investigator to contact him/her by phone or by sending appropriate correspondence (i.e. certified 
letter). It must be documented in that will become part of the investigators’ file to record that efforts 
were made to reach the subject.
2.18
Section 8.1.8 Fasting visits
The subject should attend selected visits in a fasting state (see Section 2.2).
If the subject is not fasting, as required on days where fasting blood sampling should be drawn, all 
blood samples (both fasting and non-fasting) must be re-scheduled within the visit window. and 
Tthe date for the fasting blood samples must be recorded in the eCRF. All other assessments can be 
performed even though the subject is not fasting. Re-scheduling of fasting blood samples is not 
considered as an unscheduled visit.
2.19
Section 8.2.2 Concomitant medication
A concomitant medication is any medication, other than the NNC0114-0006 and liraglutide and 
insulin, which is taken during the trial, including the screening and follow-up periods. Information 
on the subject’s insulin treatment at screening (Visit 1) is recorded in diabetes treatment history see 
Section 2.20 aon the concomitant medication form in the eCRF and any changes to the insulin 
doses after Visit 2 are recorded in the e-diary (see Section 8.6.3)Error! Reference source not 
found.. If the brand of insulin changes during the trial the new information must be entered on the 
concomitant medication form. 
2.20
Section 8.2.3 Smoking status
2.20
Section 8.2.3 Smoking status
Details of smoking status must be recorded at the first visit Visit 1. Smoking is defined as smoking 
at least one cigarette, cigar or pipe daily.
2.21
Section 8.2.6 Diagnosis of diabetes
The date of diagnosis of T1DM is the day date a doctor has confirmed the diagnosis of T1DM in the 
subject’s medical record upon review of relevant laboratory results (see section 6.8). In case the 
CONFIDENTIAL


Protocol Amendment 2
CONFIDENTIAL
Date:
14 March 2016
Novo Nordisk
Trial ID: NN9828-4150
Version:
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UTN: U1111-1154-7172
Status:
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EudraCT No.: 2014-001215-39
Page:
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diagnosis has not been noted in the medical record the date of diagnosis of T1DM is the date a
doctor has reviewed, signed and dated the relevant laboratory results.
2.22
Section 8.2.7 Diabetes treatment history
The following information has to be recorded:
!
Start date of current diabetes treatment
!
Number of severe hypoglycaemic episodes since diagnosis
2.23
Section 8.3.1 Mixed meal tolerance test
!
Not to take their basal insulin after 22.00 the evening within 9 hours before the MMTT visit
o
Subjects who normally take basal insulin in the morning should bring their basal 
insulin to the MMTT visit
!
Remember to bring their bolus insulin to the MMTT visits (to be given after the MMTT)
!
Take liraglutide/liraglutide placebo at the same time as usual both on the day before the 
MMTT visit and as well as on the day of the MMTT
!
Remember the importance of having BG on at target
Preparation and conduct of the MMTT
The MMTT will be initiated in the morning after fasting for at least 6 hours. The NNC0114-
0006/placebo may be given during the MMTT. 
Subjects will be instructed not to take basal insulin after 22.00 the evening before the MMTT. 
Receipt of insulin boluses is allowed until 2 hours prior to the MMTT. 
The MMTT may also be re-scheduled within 1-10 days. Re-scheduling of the MMTT is not 
considered as an unscheduled visit. Two rescheduling’s are allowed per The MMTT visit can be 
rescheduled twice at a maximum. If this is still not possible the MMTT must be reported as not 
done. All other assessments at the visit should be conducted as planned including dosing of 
NNC0114-0006/placebo. 
If the plasma glucose value measured at the site before the MMTT is ≤3.9 mmol/l (70 mg/dl), the 
hypoglycaemic episode must be reported in the subject’s e-diary. The investigator should consider 
if the MMTT is appropriate treatment. If the subject needs further treatment the MMTT must will
be rescheduled within 1-10 daysRe-scheduling of the MMTT is not considered as an unscheduled 
visit. Two rescheduling’s are allowed per MMTT visit. If this is not possible the MMTT must be 
reported as not done. All other assessments at the visit should be conducted as planned including 
dosing of NNC0114-0006/placebo.
CONFIDENTIAL


Protocol Amendment 2
CONFIDENTIAL
Date:
14 March 2016
Novo Nordisk
Trial ID: NN9828-4150
Version:
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UTN: U1111-1154-7172
Status:
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EudraCT No.: 2014-001215-39
Page:
24 of 27
During the MMTT plasma glucose will be monitored on a validated plasma glucose instrument
using a BG meter. If the glucose level exceeds 16.7 mmol/l (300 mg/dl) plasma ketones
(betahydroxybutyrate) should be measured on a BG meter.
Precautions during the MMTT
In case of hypoglycaemia during the MMTT (plasma glucose value ≤ <3.9 mmol/l (70 mg/dl)), the 
MMTT can be stopped at the discretion of the investigator and rescue treatment according to local 
practice can be initiated. 
After the MMTT
It is up to theis at the discretion of the investigator to decide if subjects who normally takes basal 
insulin in the morning should take their basal insulin after the MMTT.
2.24
Section 8.3.4 7-point profile
Subjects will be instructed to perform SMPG measurements before and 90 minutes after the start of 
breakfast, lunch, and dinner and at bedtime. Measurements will be performed prior to a site or 
phone visit, preferably on the day before the visit according to the flowchart in Section 2.
The 74-point plasma glucose profile includes one before breakfast measurements will be replaced 
by the 7-point profile measurements on the specific day that the 7-point profile is performed., one 
before lunch, one before dinner and one at bedtime measurement. These measurements are the same 
needed for the 4-point profile.
2.25
Section 8.3.5 Insulin doses
Subjects will be instructed in how to record the insulin doses in the e-diaries. 
If a subjects reports an actual bolus insulin dose that deviates from the prescribed recommended in 
the e-diary bolus insulin dose the subject will be asked to report a reason for this deviation in the e-
diary. Likewise, if the investigator deviates from the titration algorithm the reason for deviation 
should be documented in Study Works. 
2.26
Section 8.3.6 Carbohydrate intake per meal
Subjects who will be titrated according to the principle of flexible insulin therapy (see Appendix A) 
will be instructed in how to record the carbohydrate intake in the e-diary.
2.27
Section 8.4.2.1 Pancreatitis
!
Complications to the event
!
Treatment for the event
!
Relevant risk factors for pancreatic disease including:
o
History of gall-stones
CONFIDENTIAL


Protocol Amendment 2
CONFIDENTIAL
Date:
14 March 2016
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Trial ID: NN9828-4150
Version:
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UTN: U1111-1154-7172
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EudraCT No.: 2014-001215-39
Page:
25 of 27
o
History of pancreatitis
o
Family history of pancreatitis
o
Trauma
o
Hyper-triglyceridemia
o
Tumour
o
Alcohol assumptions
o
Hypercalcaemia
2.28
Section 8.4.2.3 Neoplasm
!
Type of neoplasm
!
Anatomic location of the neoplasm
!
Symptoms leading to identification of event
!
Diagnostic imaging
!
Relevant laboratory test
2.29
Section 8.4.2.5 Injection/Infusion site reactions
!
Type of reaction – local or generalised
!
Symptoms associated to the event
!
Treatment for the event
!
Association with the trial product(s) and/ or needles used
2.30
Section 8.4.2.7 Hypoglycaemic episodes
Any severe hypoglycaemic episodes must be reported on a hypoglycaemic episode form in the e-
diary by the subject. If the severe hypoglycaemic episode is older than 7 days the investigator must 
report this through a Data Change Request (DCR) in Study Works.
2.31
Section 8.4.3 Technical complaints
Technical complaints must be recorded in accordance with the procedures outlined in Section 12.4. 
The following information has to be recorded:
!
Product 
!
Code no
!
DUN, if applicable
2.32
Section 8.4.4.3 BMI
BMI will be calculated at the first visitVisit 1 by in the eCRF by using the equation:
CONFIDENTIAL


Protocol Amendment 2
CONFIDENTIAL
Date:
14 March 2016
Novo Nordisk
Trial ID: NN9828-4150
Version:
1.0
UTN: U1111-1154-7172
Status:
Final
EudraCT No.: 2014-001215-39
Page:
26 of 27
2.33
Section 8.4.8 Vital signs
!
Body temperature, ear
!
Respiratory rate (breaths/minutes)
2.34
Section 8.5 Laboratory assessments
The timing of the blood samples are outlined in the flow chart (see Section 2.2). Laboratory 
assessments can be done at another day than on the day of the actual visit as long as it is within the 
visit window.
2.35
Section 8.5.1.3 Biomarkers
Differentially methylated INS DNA
Minimally invasive methods to determine episodes of beta-cell death could be a valuable tool for 
patient stratification in clinical trials, assessing clinical response to therapy, and directing patient 
care. When beta-cells die, they release insulin (INS) DNA that can be measured in serum. Though 
the INS gene can be detected in cells other than beta-cells, the methylation status of this gene is 
tissue-dependent, e.g., beta-cell-derived INS is hypomethylated. The differentially methylated INS 
DNA assay is hypothesized to identify waves of beta-cell death by measuring the ratio of 
methylated to unmethylated insulin DNA, thus providing a method of assessing beta-cell loss.
Samples will be drawn according to Section 2.2. This hypothesis-testing assay will be used by a 
specialised lab if a functioning assay is available in due time to ensure analysis and results ready for 
data base lock. If no functional assay is available the samples will be destroyed. 
Antibodies (autoantibodies) & isotypes
Additionally, isotypes for anti-IAA and –GAD will be evaluated according to Section 2excepted at 
Visit 1.
2.36
Section 8.5.2.2 Anti-drug antibodies
Anti-drug antibodies are stable for many years when stored frozen (i.e.e.g. -20 degrees Celsius), and 
further characterisation is therefore possible.
Anti-NNC0114-0006 antibodies
The screening analysis of serum samples for antibodies against NNC0114-0006 will be done in the 
two arms dosed with NNC01114-0006 at Visit 3, 19, 31, 43, 63, 89 and 90.
CONFIDENTIAL


Protocol Amendment 2
CONFIDENTIAL
Date:
14 March 2016
Novo Nordisk
Trial ID: NN9828-4150
Version:
1.0
UTN: U1111-1154-7172
Status:
Final
EudraCT No.: 2014-001215-39
Page:
27 of 27
2.37
Section 8.6.2 Liraglutide/liraglutide placebo
Subjects will be instructed to report the dose (0.6, 1.2 or 1.8 mg) as indicated on the pen in their e-
diary on a daily basis. Each record should also include date, time and injection site.
2.38
Section 8.7 Subject compliance
Treatment compliance: 
Throughout the trial the treatment compliance will be assessed by monitoring of drug accountability 
as specified in Section 9.4. The unused/used liraglutide/liraglutide placebo pens DUN code 
numbers will be assessed checked against the dispensed DUNs code numbers and in case of 
discrepancies the subject must be asked.
The target dose of liraglutide or placebo is 1.8 mg. If 1.8 mg per day is not tolerated, the subject can 
stay on 1.2 mg per day. 
Subjects are asked to report the actual daily liraglutide dose in the e-dairy. Prior to or during each 
visit/phone contact the investigator or delegated staff should review the subject’s compliance with 
regards to liraglutide/liraglutide placebo treatment.
2.39
Section 13.3 E-diaries
The e-diary device will be returned by the subjects at the EOT visit or if the subject is screen failed 
between Visit 2 and Visit 3. 
2.40
Section 17.4.1.1 Efficacy endpoints
Number of insulin injections
The number of insulin injections will be derived as the average of the reported number on the three 
days prior to the visit. The endpoints will be summarised using descriptive statistics.
Number of weeks off bolus insulin
The number of weeks the subject is off bolus insulin will be summarised using descriptive statistics.
2.41
Section 26 Indemnity statement
For Austria: Arzneimittelgesetz (BGBL Nr. 185/1983) last amended with BGBl. I Nr. 48/2013
105/2015.
CONFIDENTIAL


Protocol Amendment 3
CONFIDENTIAL
Date:
08 November 2016
Novo Nordisk
Trial ID: NN9828-4150
Version:
2.0
UTN: U1111-1154-7172
Status:
Final
EudraCT No.: 2014-001215-39
Page:
1 of 28
Protocol Amendment 
no 3
to Protocol, final version 4.0
dated 14 March 2016
Trial ID: NN9828-4150
A randomised, double-blind, double-dummy, placebo-controlled, parallel-group 
multi-centre clinical proof-of-principle trial in adult subjects with newly 
diagnosed type 1 diabetes mellitus investigating the effect of NNC0114-0006 and 
liraglutide on preservation of beta-cell function
Trial phase: 2
Applicable to all countries 
Amendment originator:
GLP-1 diabetes, NADs & Complications TrialOps 1
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol Amendment 3
CONFIDENTIAL
Date:
08 November 2016
Novo Nordisk
Trial ID: NN9828-4150
Version:
2.0
UTN: U1111-1154-7172
Status:
Final
EudraCT No.: 2014-001215-39
Page:
2 of 28
Table of Contents   
Page
Table of Contents..............................................................................................................................................2
1
Introduction including rationale for the protocol amendment.............................................................3
2
Changes......................................................................................................................................................5
2.1
Section 2 Flow chart ......................................................................................................................5
2.2
Section 4.2.2.3 Supportive secondary biomarker endpoints........................................................24
2.3
Section 5.3.1 NNC0114-0006......................................................................................................24
2.4
Section 6.3 Exclusion criteria ......................................................................................................24
2.5
Section 8.5.1.3 Biomarkers..........................................................................................................25
2.6
Section 8.5.2.1 Pregnancy test.....................................................................................................27
2.7
Section 9.1 Trial products............................................................................................................27
2.8
Section 18.2 Informed consent ....................................................................................................27
2.9
Section 26 Indemnity statement...................................................................................................27
CONFIDENTIAL


Protocol Amendment 3
CONFIDENTIAL
Date:
08 November 2016
Novo Nordisk
Trial ID: NN9828-4150
Version:
2.0
UTN: U1111-1154-7172
Status:
Final
EudraCT No.: 2014-001215-39
Page:
3 of 28
1
Introduction including rationale for the protocol amendment
This amendment was prepared to accommodate the recent results from two Novo Nordisk
biomarker studies. Based on the outcome of these two studies, the profiling of the immune
biomarkers described in the NN9828-4150 protocol will be changed as well as the sample 
frequency. 
In addition, to increase the recruitment pace two more countries have been added to this NN9828-
4150 trial (Poland and Belgium). Since Belgium has been added as country, appropriate sections 
have been updated to reflect specific Belgian requirements.
Novo Nordisk has conducted two exploratory studies where the longitudinal variation of several 
immune biomarkers over 1 to 1.5 years was evaluated in pre-diabetic and type 1 diabetic subjects. 
The result from these studies demonstrated that the frequency of islet-specific auto-reactive CD8+ 
T-cells was too low and the variation was too high to provide meaningful information. Therefore, it 
has been decided not to include this analysis (QDOT) in the trial. Immune profiling using flow 
cytometry will still be performed and the final flow panels will be decided prior to the analysis of 
the first trial sample. This change will not change the sampling or the isolation of the immune cells
from peripheral blood mononuclear subpopulations (PBMCs).
Furthermore, in the biomarker studies it was observed that the variation of the profiling of non-
antigen-specific T-cells and other immune populations was low. This will allow for the sampling 
frequency to be decreased from every 3rd months with 2 baseline samples to every ½ year with 1 
baseline samples. 
Also as part of these two biomarker studies, anti-GAD65 and anti-insulin antibody (GAD and IAA, 
respectively) isotyping was performed and evaluated. The results demonstrated that such analyses 
was not informative, particularly in subjects who are on exogenous insulin treatment as this impacts 
the IAA formation and level. Therefore, isotyping of GAD and IAA will also been removed from 
the protocol.
Including the immune phenotyping of PBMC as biomarkers will allow us to evaluate effects related 
to anti-IL-21 treatment. Several publications have demonstrated IL-21 effects these immune 
populations. The removal of the evaluation of the specific detection of auto-reactive CD8+ T-cells 
and isotyping of IAA and GAD is not expected to have implications on the scientific content or 
interpretation 
These changes will significantly lower the amount of blood samples from the subjects. The 
immunology profiling sample will be taken at the following visits; 3, 31, 63, 89.
In addition, editorial changes are introduced in this amendment.    
CONFIDENTIAL


Protocol Amendment 3
CONFIDENTIAL
Date:
08 November 2016
Novo Nordisk
Trial ID: NN9828-4150
Version:
2.0
UTN: U1111-1154-7172
Status:
Final
EudraCT No.: 2014-001215-39
Page:
4 of 28
In section 2 distinction between ‘the first 80 subjects’ and ‘once 80 subjects have been randomised’
flowcharts have been clarified and made clearer. 
In section 4.2.2.3 the supportive secondary biomarker endpoints has been changed/updated to 
account for the changes made to the immune biomarkers.
In section 5.3.1 the importance of accessing infection parameters prior of NNC0114-
0006/NNC0114-0006 placebo infusion has been emphasised. 
Section 8.5.1 has been updated to reflect the changes made to the biomarker assessment. The 
isotypes have been deleted and the future PBMC analyses have been specified in details. 
In addition, changes to section 6.3 are introduced to reflect specific requirements for Belgium and 
United Kingdom and in section 26 to reflect specific Belgian requirements in this amendment.    
In this protocol amendment:
!
Any new text is written in italics.
!
Any text deleted from the protocol is written using strike through.
CONFIDENTIAL


Protocol Amendment 3
UTN: U1111-1154-7172
Date:
08 November 2016
Status:
Final
Novo Nordisk
Trial ID: NN9828-4150
EudraCT No.: 2014-001215-39
Version:
2.0
Page:
5 of 28
2
Changes
2.1
Section 2 Flow chart
The full PK profile consisting of 25 samples is only applicable for the first minimum 80 subjects. The remaining subjects will follow a 
reduced visit scheduled outlined in the flowchart (reference section 2.2) “Visit procedures once 80 subjects have been randomised”
2.1 Flowchart for the first 80 randomised subjects only
Visit 1 to 37 procedures for the first 80 randomised subjects only
Trial periods
S
R
Treatment
Visit type:
C: Clinic, P: Phone contact
C
C
C
C
C
C
C
P
P
C
P
P
C
P
C
P
C
P
C
P
C
P
C
P
C
P
C
P
C
Visit number
1
2
3
4
5
6
7
8
9
10
11
12
13
14,15
16
17,18
19
20-22
23
24
25
26-28
29
30
31
32-34
35
36
37
Timing of visit (weeks (W), or days 
(D) if specified)
-D28 to 
–D14
-D10 
0
1D
3D
W1
W2
W2 + 
1D
W3
W4
W4 + 
1D
W5
W6
W7,8
W9
W10,11
W12
W13-15
W16
W17
W18
W19-21
W22
W23
W24
W25-27
W28
W29
W30
Visit window (days)
± 
4
±
1
±
1
±
1
±
1
±
1
±
1
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
SUBJECT RELATED
INFO/ASSESSMENTS
Informed consent
x
Genotyping consent, optional
x
Long term retention consent, optional
x
In/exclusion criteria
x
x
x
Randomisation
x
Randomisation criteria
x


Protocol Amendment 3
UTN: U1111-1154-7172
Date:
08 November 2016
Status:
Final
Novo Nordisk
Trial ID: NN9828-4150
EudraCT No.: 2014-001215-39
Version:
2.0
Page:
6 of 28
Trial periods
S
R
Treatment
Visit type:
C: Clinic, P: Phone contact
C
C
C
C
C
C
C
P
P
C
P
P
C
P
C
P
C
P
C
P
C
P
C
P
C
P
C
P
C
Visit number
1
2
3
4
5
6
7
8
9
10
11
12
13
14,15
16
17,18
19
20-22
23
24
25
26-28
29
30
31
32-34
35
36
37
Timing of visit (weeks (W), or days 
(D) if specified)
-D28 to 
–D14
-D10 
0
1D
3D
W1
W2
W2 + 
1D
W3
W4
W4 + 
1D
W5
W6
W7,8
W9
W10,11
W12
W13-15
W16
W17
W18
W19-21
W22
W23
W24
W25-27
W28
W29
W30
Visit window (days)
± 
4
±
1
±
1
±
1
±
1
±
1
±
1
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
Withdrawal criteria
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Dosing day exclusion criteria1
x
x
x
x
x
x
Abuse of alcohol
x
Abuse of drugs
x
Medical history
x
Concomitant illness
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
x
x
x
x
x
x
x
Demography
x
Diagnosis of diabetes
x
Diabetes treatment history
x
Pregnancy test2
x
Smoking habits
x
Family history of diabetes
x
Diabetes complications
x
Blood sample for genotyping 
(optional)
x
EFFICACY
Glucose metabolism
x
x
x
x
x
x
x
Meal test3
x
x
x
Self-measured plasma glucose:


Protocol Amendment 3
UTN: U1111-1154-7172
Date:
08 November 2016
Status:
Final
Novo Nordisk
Trial ID: NN9828-4150
EudraCT No.: 2014-001215-39
Version:
2.0
Page:
7 of 28
Trial periods
S
R
Treatment
Visit type:
C: Clinic, P: Phone contact
C
C
C
C
C
C
C
P
P
C
P
P
C
P
C
P
C
P
C
P
C
P
C
P
C
P
C
P
C
Visit number
1
2
3
4
5
6
7
8
9
10
11
12
13
14,15
16
17,18
19
20-22
23
24
25
26-28
29
30
31
32-34
35
36
37
Timing of visit (weeks (W), or days 
(D) if specified)
-D28 to 
–D14
-D10 
0
1D
3D
W1
W2
W2 + 
1D
W3
W4
W4 + 
1D
W5
W6
W7,8
W9
W10,11
W12
W13-15
W16
W17
W18
W19-21
W22
W23
W24
W25-27
W28
W29
W30
Visit window (days)
± 
4
±
1
±
1
±
1
±
1
±
1
±
1
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
7-point profile prior to visit
x
x
x
x
x
x
x
x
x
x
x
x
4-point profile prior to visit4
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
PRO questionnaires
x
x
Biomarkers:
Antibodies (autoantibodies)
x
x
x
x
x
Anti-IAA and –GAD isotypes
x
x
Immune phenotyping
x
x
Immunology Total IL-21
x
x
x
x
x
x
x
x
Vitamin D (1,25 dehydroxy-
calciferol
x
x
x
x
Dose of insulin administrations
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Carbohydrate intake
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
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
x
x
x
Hyperglycaemic episodes
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
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
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
x
x
x
x
x
x
Body measurements5
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
ECG
x6
x
x
x
x
x


Protocol Amendment 3
UTN: U1111-1154-7172
Date:
08 November 2016
Status:
Final
Novo Nordisk
Trial ID: NN9828-4150
EudraCT No.: 2014-001215-39
Version:
2.0
Page:
8 of 28
Trial periods
S
R
Treatment
Visit type:
C: Clinic, P: Phone contact
C
C
C
C
C
C
C
P
P
C
P
P
C
P
C
P
C
P
C
P
C
P
C
P
C
P
C
P
C
Visit number
1
2
3
4
5
6
7
8
9
10
11
12
13
14,15
16
17,18
19
20-22
23
24
25
26-28
29
30
31
32-34
35
36
37
Timing of visit (weeks (W), or days 
(D) if specified)
-D28 to 
–D14
-D10 
0
1D
3D
W1
W2
W2 + 
1D
W3
W4
W4 + 
1D
W5
W6
W7,8
W9
W10,11
W12
W13-15
W16
W17
W18
W19-21
W22
W23
W24
W25-27
W28
W29
W30
Visit window (days)
± 
4
±
1
±
1
±
1
±
1
±
1
±
1
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
Eye examination
x7
Physical examination
x
x
x
x
x
x
x
Vital signs
x
x
x
x
x
x
x
x
x
x
x
x
Antibodies:
Anti-NNC0114-0006 antibodies
x
x
x
Anti-liraglutide antibodies
x
x
x
IgE
x
x
x
x
x
Biochemistry
x
x
x
x
x
x
Coagulation parameters
x
x
x
x
x
x
Haematology
x
x
x
x
x
x
Cytokines
x
x
x
x
Urine dipsticks 
x
x
x
x
x
x
Hepatitis B
x
x
x
x
x
x
Hepatitis C
x
Tuberculosis screening test 
(QuantiFERON)
x
Epstein–Barr virus
x
x
x
x
x
x
CMV8
x
x
x
x
x
x
HIV
x
Hormones
x
x
x


Protocol Amendment 3
UTN: U1111-1154-7172
Date:
08 November 2016
Status:
Final
Novo Nordisk
Trial ID: NN9828-4150
EudraCT No.: 2014-001215-39
Version:
2.0
Page:
9 of 28
Trial periods
S
R
Treatment
Visit type:
C: Clinic, P: Phone contact
C
C
C
C
C
C
C
P
P
C
P
P
C
P
C
P
C
P
C
P
C
P
C
P
C
P
C
P
C
Visit number
1
2
3
4
5
6
7
8
9
10
11
12
13
14,15
16
17,18
19
20-22
23
24
25
26-28
29
30
31
32-34
35
36
37
Timing of visit (weeks (W), or days 
(D) if specified)
-D28 to 
–D14
-D10 
0
1D
3D
W1
W2
W2 + 
1D
W3
W4
W4 + 
1D
W5
W6
W7,8
W9
W10,11
W12
W13-15
W16
W17
W18
W19-21
W22
W23
W24
W25-27
W28
W29
W30
Visit window (days)
± 
4
±
1
±
1
±
1
±
1
±
1
±
1
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
Lipids
x
x
x
OTHER ASSESSMENTS
PK sampling
NNC0114-0006
x9
x
x
x
x
x
x
x
x
x
x
x
PK sampling
Liraglutide10
x
x
x
x
x
x
x
x
x
x
x
x
TRIAL MATERIAL
IV/IWRS
x
x
x
x
x
x
x
Administration and dispensing of 
trial product 
NNC0114-0006/placebo
x
x
x
x
x
x
Dispensing of liraglutide/placebo11
x
x
x
x
x
x
Drug accountability for IMP12
x
x
x
x
x
x
REMINDERS
Handout ID cards
x
Handout direction for use13
x
Handout and instruct in e-diary
x
Investigator review of e-diary
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Handout and instruct in BG meter 
use
x
Attend fasting visit
x
x
x
x
x
x
x
Blood sample for long term 
x
x


Protocol Amendment 3
UTN: U1111-1154-7172
Date:
08 November 2016
Status:
Final
Novo Nordisk
Trial ID: NN9828-4150
EudraCT No.: 2014-001215-39
Version:
2.0
Page:
10 of 28
Trial periods
S
R
Treatment
Visit type:
C: Clinic, P: Phone contact
C
C
C
C
C
C
C
P
P
C
P
P
C
P
C
P
C
P
C
P
C
P
C
P
C
P
C
P
C
Visit number
1
2
3
4
5
6
7
8
9
10
11
12
13
14,15
16
17,18
19
20-22
23
24
25
26-28
29
30
31
32-34
35
36
37
Timing of visit (weeks (W), or days 
(D) if specified)
-D28 to 
–D14
-D10 
0
1D
3D
W1
W2
W2 + 
1D
W3
W4
W4 + 
1D
W5
W6
W7,8
W9
W10,11
W12
W13-15
W16
W17
W18
W19-21
W22
W23
W24
W25-27
W28
W29
W30
Visit window (days)
± 
4
±
1
±
1
±
1
±
1
±
1
±
1
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
retention (optional)
1. Only for NNC0114-0006
2. Blood sample at V1. For all subsequent visits a urine stick must only be measured for females of childbearing potential if a menstrual period is missed or as required 
by law. Austria: Urine-stick pregnancy test will be performed monthly. Ireland: Urine-stick pregnancy test will be performed at all visits to the clinic.
3. The MMTT may be re-scheduled twice within 10 days. At Visit 2 the MMTT must be performed before Visit 3 and leaving sufficient time for randomisation lab 
results.
4. 4-point profile will be used for T-T-T
5. At V1 height and weight will be measured and BMI will be calculated via the eCRF. At the following visits only weight must be measured
6. A baseline ECG performed for any reason unrelated to the trial within 30 days prior to V1 is acceptable provided no clinical symptoms suggestive of cardiac disease 
have occurred in the meantime
7. A baseline fundoscopy/ fundus photography performed for any reason unrelated to the trial within 90 days prior to V3 is acceptable. Fundoscopy/ fundus photography 
can be performed at V2. 
8. Cytomegalovirus
9. PK sample for NNC0114-0006 (pre-dose and 1 hour sample after start of infusion)
10. PK sample at any time during the visit
11. Liraglutide/liraglutide placebo will be administered once daily
12. Investigational medicinal product
13. Injection of liraglutide will be trained at V3 and at following visits as needed.


Protocol Amendment 3
UTN: U1111-1154-7172
Date:
08 November 2016
Status:
Final
Novo Nordisk
Trial ID: NN9828-4150
EudraCT No.: 2014-001215-39
Version:
2.0
Page:
11 of 28
Visit 38 to 90 procedures for the first 80 randomised subjects only
Trial period
Treatment
Follow-up
Visit type:
C: Clinic, P: Phone contact
P
C
P
C
P
C
P
C
P
C
P
C
C
C
C
P
C
P
C
P
C
P
C
P
C
P
C
C
Visit number
38-40
41
42
43
44-46
47
48
49
50-52
53
54
55
56
57
58,59
60
61
62
63
64-68
69
70-73
74
75-77
78
79-88
89
901
Timing of visit 
(weeks (W), or days (D) if specified)                     
W31-33
W34
W35
W36
W37-39
W40
W41
W42
W43-45
W46
W47
W48
W48 + 1D
W48 + 3D
W49, 50
W51
W52
W53
W54
W55-59
W60
W61-64
W65
W66-68
W69
W70-79
W80
Visit window (days)
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
7
SUBJECT RELATED
INFO/ASSESSMENTS
Withdrawal criteria
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
Dosing day exclusion criteria2
x
x
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
x
x
x
x
x
x
Pregnancy test3
x
Diabetes complications
x
x
EFFICACY
Glucose metabolism
x
x
x
x
x
x
x
x
Meal test4
x
x
x
x
Self-measured plasma glucose:
7-point profile prior to visit
x
x
x
x
x
x
x
x
4-point profile prior to visit5
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
PRO questionnaires
x
x
Biomarkers:
Antibodies (autoantibodies)
x
x
x
x
Anti-IAA and –GAD isotypes
x
x


Protocol Amendment 3
UTN: U1111-1154-7172
Date:
08 November 2016
Status:
Final
Novo Nordisk
Trial ID: NN9828-4150
EudraCT No.: 2014-001215-39
Version:
2.0
Page:
12 of 28
Trial period
Treatment
Follow-up
Visit type:
C: Clinic, P: Phone contact
P
C
P
C
P
C
P
C
P
C
P
C
C
C
C
P
C
P
C
P
C
P
C
P
C
P
C
C
Visit number
38-40
41
42
43
44-46
47
48
49
50-52
53
54
55
56
57
58,59
60
61
62
63
64-68
69
70-73
74
75-77
78
79-88
89
901
Timing of visit 
(weeks (W), or days (D) if specified)                     
W31-33
W34
W35
W36
W37-39
W40
W41
W42
W43-45
W46
W47
W48
W48 + 1D
W48 + 3D
W49, 50
W51
W52
W53
W54
W55-59
W60
W61-64
W65
W66-68
W69
W70-79
W80
Visit window (days)
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
7
Immune phenotyping
x
x
Immunology Total IL-21
x
x
x
x
Vitamin D (1,25 dehydroxy-calciferol)
x
x
X
x
Dose of insulin administrations
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Carbohydrate intake
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
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
x
x
Hyperglycaemic episodes
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
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
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
Body measurements
x
x
x
x
x
x
x
x
x
x
x
x
x
x
ECG
x
x
x
x
x
x
Eye examination6
x
x
Physical examination
x
x
x
x
x
x
Vital signs
x
x
x
x
x
x
x
x
x
Antibodies: 
Anti-NNC0114-0006 antibodies
x
x
x
x
Anti-liraglutide antibodies
x
x
x
x
x
IgE
x
x
x
x
x
x
x
Biochemistry
x
x
x
x
x
x
Coagulation parameters
x
x
x
x
x
x


Protocol Amendment 3
UTN: U1111-1154-7172
Date:
08 November 2016
Status:
Final
Novo Nordisk
Trial ID: NN9828-4150
EudraCT No.: 2014-001215-39
Version:
2.0
Page:
13 of 28
Trial period
Treatment
Follow-up
Visit type:
C: Clinic, P: Phone contact
P
C
P
C
P
C
P
C
P
C
P
C
C
C
C
P
C
P
C
P
C
P
C
P
C
P
C
C
Visit number
38-40
41
42
43
44-46
47
48
49
50-52
53
54
55
56
57
58,59
60
61
62
63
64-68
69
70-73
74
75-77
78
79-88
89
901
Timing of visit 
(weeks (W), or days (D) if specified)                     
W31-33
W34
W35
W36
W37-39
W40
W41
W42
W43-45
W46
W47
W48
W48 + 1D
W48 + 3D
W49, 50
W51
W52
W53
W54
W55-59
W60
W61-64
W65
W66-68
W69
W70-79
W80
Visit window (days)
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
7
Haematology
x
x
x
x
x
x
Cytokines
x
x
x
x
x
x
Urine dipsticks 
x
x
x
x
x
x
Hepatitis B 
x
x
x
x
EBV
x
x
x
x
CMV
x
x
x
x
Hormones
x
x
x
x
x
x
Lipids
x
x
x
x
x
x
OTHER ASSESSMENTS
PK sampling NNC0114-0006
x
x
x
7
x
x
x
x
x
x
x
x
x
x
PK sampling Liraglutide
x
x
x
x
x
x
x
x
TRIAL MATERIAL
IV/IWRS
x
x
x
x
x
Administration and dispensing of  trial 
product NNC0114-0006/placebo
x
x
x
Dispensing of liraglutide/placebo
x
x
x
Drug accountability for IMP
x
x
x
x
REMINDERS
Investigator review of e-diary
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Attend fasting visit
x
x
x
x
x
x
x
x
x
Blood sampling for long term retention 
(optional)
x
x


Protocol Amendment 3
UTN: U1111-1154-7172
Date:
08 November 2016
Status:
Final
Novo Nordisk
Trial ID: NN9828-4150
EudraCT No.: 2014-001215-39
Version:
2.0
Page:
14 of 28
Trial period
Treatment
Follow-up
Visit type:
C: Clinic, P: Phone contact
P
C
P
C
P
C
P
C
P
C
P
C
C
C
C
P
C
P
C
P
C
P
C
P
C
P
C
C
Visit number
38-40
41
42
43
44-46
47
48
49
50-52
53
54
55
56
57
58,59
60
61
62
63
64-68
69
70-73
74
75-77
78
79-88
89
901
Timing of visit 
(weeks (W), or days (D) if specified)                     
W31-33
W34
W35
W36
W37-39
W40
W41
W42
W43-45
W46
W47
W48
W48 + 1D
W48 + 3D
W49, 50
W51
W52
W53
W54
W55-59
W60
W61-64
W65
W66-68
W69
W70-79
W80
Visit window (days)
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
7
End of dosing
x
8
x
9
Collection of e-diary
x
x
End of trial
x
x
Sign off Casebook
x
x
1. Safety follow-up visit. To be conducted for subjects who have been withdrawn less than 14 weeks after last dose of NNC0114-0006/placebo. The visit should be 
conducted 15 weeks ± 1 week after last dose of NNC0114-0006/placebo
2. Only for NNC0114-0006
3. Blood sample at V63. A urine stick pregnancy test must be performed throughout the trial for females of childbearing potential if a menstrual period is missed or as 
required by local law. Austria: Urine-stick pregnancy test will be performed monthly. Ireland: Urine-stick pregnancy test will be performed at all visits to the clinic.
4. The MMTT may be re-scheduled twice within 10 days
5. 4-point profile will be used for T-T-T  
6. A fundoscopy/ fundus photography may be performed up to 2 weeks before or after V63 and up to 2 weeks before V89
7. PK sample for NNC0114-0006 (pre-dose and 1 hour sample after start of infusion)
8. Last dosing of NNC0114-0006/placebo
9. Last dosing of liraglutide/liraglutide placebo is the day prior to V63
2.2 Flowchart for once 80 subjects have been randomised 
Visit 1 to 37 procedures once 80 subjects have been randomised


Protocol Amendment 3
UTN: U1111-1154-7172
Date:
08 November 2016
Status:
Final
Novo Nordisk
Trial ID: NN9828-4150
EudraCT No.: 2014-001215-39
Version:
2.0
Page:
15 of 28
Trial periods
S
R
Treatment
Visit type:
C: Clinic, P: Phone contact
C
C
C
C
C
P
P
C
P
P
C
P
C
P
C
P
C
P
C
P
C
P
C
P
C
P
C
Visit number
1
2
3
6
7
8
9
10
11
12
13
14,15
16
17,18
19
20-22
23
24
25
26-28
29
30
31
32-34
35
36
37
Timing of visit (weeks (W), or days (D) 
if specified)
-D28 to –
D14
-D10 
0
W1
W2
W2 + 1D
W3
W4
W4 + 1D
W5
W6
W7,8
W9
W10,11
W12
W13-15
W16
W17
W18
W19-21
W22
W23
W24
W25-27
W28
W29
W30
Visit window (days)
± 
4
±
1
±
1
±
1
±
1
±
1
±
1
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
SUBJECT RELATED
INFO/ASSESSMENTS
Informed consent
x
Genotyping consent, optional
x
Long term retention consent, optional
x
In/exclusion criteria
x
x
x
Randomisation
x
Randomisation criteria
x
Withdrawal criteria
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
Dosing day exclusion criteria1
x
x
x
x
x
x
Abuse of alcohol
x
Abuse of drugs
x
Medical history
x
Concomitant illness
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
x
x
x
x
x
Demography
x
Diagnosis of diabetes
x
Diabetes treatment history
x
Pregnancy test2
x
Smoking habits
x


Protocol Amendment 3
UTN: U1111-1154-7172
Date:
08 November 2016
Status:
Final
Novo Nordisk
Trial ID: NN9828-4150
EudraCT No.: 2014-001215-39
Version:
2.0
Page:
16 of 28
Trial periods
S
R
Treatment
Visit type:
C: Clinic, P: Phone contact
C
C
C
C
C
P
P
C
P
P
C
P
C
P
C
P
C
P
C
P
C
P
C
P
C
P
C
Visit number
1
2
3
6
7
8
9
10
11
12
13
14,15
16
17,18
19
20-22
23
24
25
26-28
29
30
31
32-34
35
36
37
Timing of visit (weeks (W), or days (D) 
if specified)
-D28 to –
D14
-D10 
0
W1
W2
W2 + 1D
W3
W4
W4 + 1D
W5
W6
W7,8
W9
W10,11
W12
W13-15
W16
W17
W18
W19-21
W22
W23
W24
W25-27
W28
W29
W30
Visit window (days)
± 
4
±
1
±
1
±
1
±
1
±
1
±
1
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
Family history of diabetes
x
Diabetes complications
x
Blood sample for genotyping (optional)
x
EFFICACY
Glucose metabolism
x
x
x
x
x
x
x
Meal test3
x
x
x
Self-measured plasma glucose:
7-point profile prior to visit
x
x
x
x
x
x
x
x
x
x
4-point profile prior to visit4
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
PRO questionnaires
x
x
Biomarkers:
Antibodies (autoantibodies)
x
x
x
x
x
Anti IAA and GAD Isotypes
x
x
Immune phenotyping
x
x
Immunology Total IL-21
x
x
x
x
x
x
Vitamin D (1,25 dehydroxy-calciferol
x
x
x
x
Dose of insulin administrations
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
Carbohydrate intake
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
SAFETY


Protocol Amendment 3
UTN: U1111-1154-7172
Date:
08 November 2016
Status:
Final
Novo Nordisk
Trial ID: NN9828-4150
EudraCT No.: 2014-001215-39
Version:
2.0
Page:
17 of 28
Trial periods
S
R
Treatment
Visit type:
C: Clinic, P: Phone contact
C
C
C
C
C
P
P
C
P
P
C
P
C
P
C
P
C
P
C
P
C
P
C
P
C
P
C
Visit number
1
2
3
6
7
8
9
10
11
12
13
14,15
16
17,18
19
20-22
23
24
25
26-28
29
30
31
32-34
35
36
37
Timing of visit (weeks (W), or days (D) 
if specified)
-D28 to –
D14
-D10 
0
W1
W2
W2 + 1D
W3
W4
W4 + 1D
W5
W6
W7,8
W9
W10,11
W12
W13-15
W16
W17
W18
W19-21
W22
W23
W24
W25-27
W28
W29
W30
Visit window (days)
± 
4
±
1
±
1
±
1
±
1
±
1
±
1
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
Adverse events
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Hyperglycaemic episodes
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
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
x
x
x
x
Body measurements5
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
ECG
x6
x
x
x
x
x
Eye examination
x7
Physical examination
x
x
x
x
x
x
Vital signs
x
x
x
x
x
x
x
x
x
x
x
Antibodies:
Anti-NNC0114-0006 antibodies
x
x
x
Anti-liraglutide antibodies
x
x
x
IgE
x
x
x
x
x
Biochemistry
x
x
x
x
x
x
Coagulation parameters
x
x
x
x
x
x
Haematology
x
x
x
x
x
x
Cytokines
x
x
x
x
Urine dipsticks 
x
x
x
x
x
x
Hepatitis B
x
x
x
x
x
x


Protocol Amendment 3
UTN: U1111-1154-7172
Date:
08 November 2016
Status:
Final
Novo Nordisk
Trial ID: NN9828-4150
EudraCT No.: 2014-001215-39
Version:
2.0
Page:
18 of 28
Trial periods
S
R
Treatment
Visit type:
C: Clinic, P: Phone contact
C
C
C
C
C
P
P
C
P
P
C
P
C
P
C
P
C
P
C
P
C
P
C
P
C
P
C
Visit number
1
2
3
6
7
8
9
10
11
12
13
14,15
16
17,18
19
20-22
23
24
25
26-28
29
30
31
32-34
35
36
37
Timing of visit (weeks (W), or days (D) 
if specified)
-D28 to –
D14
-D10 
0
W1
W2
W2 + 1D
W3
W4
W4 + 1D
W5
W6
W7,8
W9
W10,11
W12
W13-15
W16
W17
W18
W19-21
W22
W23
W24
W25-27
W28
W29
W30
Visit window (days)
± 
4
±
1
±
1
±
1
±
1
±
1
±
1
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
Hepatitis C
x
Tuberculosis screening test 
(QuantiFERON)
x
Epstein–Barr virus
x
x
x
x
x
x
CMV8
x
x
x
x
x
x
HIV
x
Hormones
x
x
x
Lipids
x
x
x
OTHER ASSESSMENTS
PK sampling
NNC0114-0006
x9
x
x
x
x
x
x
x
x
x
PK sampling
Liraglutide10
x
x
x
x
x
x
x
x
x
x
TRIAL MATERIAL
IV/IWRS
x
x
x
x
x
x
x
Administration and dispensing of trial 
product NNC0114-0006/placebo
x
x
x
x
x
x
Dispensing of liraglutide/placebo11
x
x
x
x
x
x
Drug accountability for IMP12
x
x
x
x
x
x
REMINDERS
Handout ID cards
x


Protocol Amendment 3
UTN: U1111-1154-7172
Date:
08 November 2016
Status:
Final
Novo Nordisk
Trial ID: NN9828-4150
EudraCT No.: 2014-001215-39
Version:
2.0
Page:
19 of 28
Trial periods
S
R
Treatment
Visit type:
C: Clinic, P: Phone contact
C
C
C
C
C
P
P
C
P
P
C
P
C
P
C
P
C
P
C
P
C
P
C
P
C
P
C
Visit number
1
2
3
6
7
8
9
10
11
12
13
14,15
16
17,18
19
20-22
23
24
25
26-28
29
30
31
32-34
35
36
37
Timing of visit (weeks (W), or days (D) 
if specified)
-D28 to –
D14
-D10 
0
W1
W2
W2 + 1D
W3
W4
W4 + 1D
W5
W6
W7,8
W9
W10,11
W12
W13-15
W16
W17
W18
W19-21
W22
W23
W24
W25-27
W28
W29
W30
Visit window (days)
± 
4
±
1
±
1
±
1
±
1
±
1
±
1
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
Handout direction for use13
x
Handout and instruct in e-diary
x
Investigator review of e-diary
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
Handout and instruct in BG meter use
x
Attend fasting visit
x
x
x
x
x
x
x
Blood sample for long term retention 
(optional)
x
x
1. Only for NNC0114-0006
2. Blood sample at V1. For all subsequent visits a urine stick must only be measured for females of childbearing potential if a menstrual period is missed or as required 
by law. Austria: Urine-stick pregnancy test will be performed monthly. For Belgium: A monthly urine pregnancy test is mandatory for female subjects of childbearing 
potential. Ireland: Urine-stick pregnancy test will be performed at all visits to the clinic.
3. The MMTT may be re-scheduled twice within 10 days. At Visit 2 the MMTT must be performed before Visit 3 and leaving sufficient time for randomisation lab 
results.  
4. 4-point profile will be used for T-T-T  
5. At V1 height and weight will be measured and BMI will be calculated via the eCRF. At the following visits only weight must be measured
6. A baseline ECG performed for any reason unrelated to the trial within 30 days prior to V1 is acceptable provided no clinical symptoms suggestive of cardiac disease 
have occurred in the meantime
7. A baseline fundoscopy/ fundus photography performed for any reason unrelated to the trial within 90 days prior to V3 is acceptable. Fundoscopy/ fundus photography 
can be performed at V2. 
8. Cytomegalovirus


Protocol Amendment 3
UTN: U1111-1154-7172
Date:
08 November 2016
Status:
Final
Novo Nordisk
Trial ID: NN9828-4150
EudraCT No.: 2014-001215-39
Version:
2.0
Page:
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9. PK sample for NNC0114-0006 (pre-dose and 1 hour sample after start of infusion)
10. PK sample at any time during the visit
11. Liraglutide/liraglutide placebo will be administered once daily
12. Investigational medicinal product
13. Injection of liraglutide will be trained at V3 and at following visits as needed.
Visit 38 to 90 procedures once after 80 subjects have been randomised
Trial period
Treatment
Follow-up
Visit type:
C: Clinic, P: Phone contact
P
C
P
C
P
C
P
C
P
C
P
C
P
P
P
P
C
P
P
P
C
P
P
P
C
C
Visit number
38-40
41
42
43
44-46
47
48
49
50-52
53
54
55
58,59
60
61
62
63
64-68
69
70-73
74
75-77
78
79-88
89
901
Timing of visit 
(weeks (W), or days (D) if specified)                      
W31-33
W34
W35
W36
W37-39
W40
W41
W42
W43-45
W46
W47
W48
W49, 50
W51
W52
W53
W54
W55-59
W60
W61-64
W65
W66-68
W69
W70-79
W80
Visit window (days)
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
1
±
1
±
1
±
3
±
1
±
1
±
1
±
3
±
1
±
1
±
1
±
3
±
7
SUBJECT RELATED
INFO/ASSESSMENTS
Withdrawal criteria
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Dosing day exclusion criteria2
x
x
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
x
x
x
x
Pregnancy test3
x
Diabetes complications
x
x
EFFICACY
Glucose metabolism
x
x
x
x
x
x
Meal test4
x
x
x
x
Self-measured plasma glucose:
7-point profile prior to visit
x
x
x
x
x
x
x
x
4-point profile prior to visit5
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


Protocol Amendment 3
UTN: U1111-1154-7172
Date:
08 November 2016
Status:
Final
Novo Nordisk
Trial ID: NN9828-4150
EudraCT No.: 2014-001215-39
Version:
2.0
Page:
21 of 28
Trial period
Treatment
Follow-up
Visit type:
C: Clinic, P: Phone contact
P
C
P
C
P
C
P
C
P
C
P
C
P
P
P
P
C
P
P
P
C
P
P
P
C
C
Visit number
38-40
41
42
43
44-46
47
48
49
50-52
53
54
55
58,59
60
61
62
63
64-68
69
70-73
74
75-77
78
79-88
89
901
Timing of visit 
(weeks (W), or days (D) if specified)                      
W31-33
W34
W35
W36
W37-39
W40
W41
W42
W43-45
W46
W47
W48
W49, 50
W51
W52
W53
W54
W55-59
W60
W61-64
W65
W66-68
W69
W70-79
W80
Visit window (days)
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
1
±
1
±
1
±
3
±
1
±
1
±
1
±
3
±
1
±
1
±
1
±
3
±
7
PRO questionnaires
x
x
Biomarkers:
Antibodies (autoantibodies)
x
x
x
x
Anti-IAA and –GAD isotypes
x
x
Immune phenotyping
x
x
Immunology Total IL-21
x
x
x
x
Vitamin D (1,25 dehydroxy-calciferol)
x
x
x
x
Dose of insulin administrations
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
Carbohydrate intake
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
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
Hyperglycaemic episodes
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
x
x
x
Technical complaints
x
x
x
x
x
x
x
x
x
x
x
x
X
x
x
x
x
Body measurements
x
x
x
x
x
x
x
x
x
x
ECG
x
x
x
x
x
x
Eye examination6
x
x
Physical examination
x
x
x
x
x
x
Vital signs
x
x
x
x
x
x
x
Antibodies: 
Anti-NNC0114-0006 antibodies
x
x
x
x
Anti-liraglutide antibodies
x
x
x
x


Protocol Amendment 3
UTN: U1111-1154-7172
Date:
08 November 2016
Status:
Final
Novo Nordisk
Trial ID: NN9828-4150
EudraCT No.: 2014-001215-39
Version:
2.0
Page:
22 of 28
Trial period
Treatment
Follow-up
Visit type:
C: Clinic, P: Phone contact
P
C
P
C
P
C
P
C
P
C
P
C
P
P
P
P
C
P
P
P
C
P
P
P
C
C
Visit number
38-40
41
42
43
44-46
47
48
49
50-52
53
54
55
58,59
60
61
62
63
64-68
69
70-73
74
75-77
78
79-88
89
901
Timing of visit 
(weeks (W), or days (D) if specified)                      
W31-33
W34
W35
W36
W37-39
W40
W41
W42
W43-45
W46
W47
W48
W49, 50
W51
W52
W53
W54
W55-59
W60
W61-64
W65
W66-68
W69
W70-79
W80
Visit window (days)
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
1
±
1
±
1
±
3
±
1
±
1
±
1
±
3
±
1
±
1
±
1
±
3
±
7
IgE
x
x
x
x
x
x
Biochemistry
x
x
x
x
x
x
Coagulation parameters
x
x
x
x
x
x
Haematology
x
x
x
x
x
x
Cytokines
x
x
x
x
x
x
Urine dipsticks 
x
x
x
x
x
x
Hepatitis B 
x
x
x
x
EBV
x
x
x
x
CMV
x
x
x
x
Hormones
x
x
x
x
x
x
Lipids
x
x
x
x
x
x
OTHER ASSESSMENTS
PK sampling NNC0114-0006
x
x
x7
x
x
x
x
PK sampling Liraglutide
x
x
x
x
TRIAL MATERIAL
IV/IWRS
x
x
x
x
x
Administration and dispensing of  trial product 
NNC0114-0006/placebo
x
x
x
Dispensing of liraglutide/placebo
x
x
x
Drug accountability for IMP
x
x
x
x
REMINDERS
Investigator review of e-diary
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
Attend fasting visit
x
x
x
x
x
x
x


Protocol Amendment 3
UTN: U1111-1154-7172
Date:
08 November 2016
Status:
Final
Novo Nordisk
Trial ID: NN9828-4150
EudraCT No.: 2014-001215-39
Version:
2.0
Page:
23 of 28
Trial period
Treatment
Follow-up
Visit type:
C: Clinic, P: Phone contact
P
C
P
C
P
C
P
C
P
C
P
C
P
P
P
P
C
P
P
P
C
P
P
P
C
C
Visit number
38-40
41
42
43
44-46
47
48
49
50-52
53
54
55
58,59
60
61
62
63
64-68
69
70-73
74
75-77
78
79-88
89
901
Timing of visit 
(weeks (W), or days (D) if specified)                      
W31-33
W34
W35
W36
W37-39
W40
W41
W42
W43-45
W46
W47
W48
W49, 50
W51
W52
W53
W54
W55-59
W60
W61-64
W65
W66-68
W69
W70-79
W80
Visit window (days)
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
1
±
1
±
1
±
3
±
1
±
1
±
1
±
3
±
1
±
1
±
1
±
3
±
7
Blood sampling for long term retention (optional)
x
x
End of dosing
x8
x9
Collection of e-diary
x
x
End of trial
x
x
Sign off Casebook
x
x
1. Safety follow-up visit. To be conducted for subjects who have been withdrawn less than 14 weeks after last dose of NNC0114-0006/placebo. The visit should be 
conducted 15 weeks ± 1 week after last dose of NNC0114-0006/placebo
2. Only for NNC0114-0006
3. Blood sample at V63. A urine stick pregnancy test must be performed throughout the trial for females of childbearing potential if a menstrual period is missed or as 
required by local law. Austria: Urine-stick pregnancy test will be performed monthly. For Belgium: A monthly urine pregnancy test is mandatory for female subjects of 
childbearing potential. Ireland: Urine-stick pregnancy test will be performed at all visits to the clinic.
4. The MMTT may be re-scheduled twice within 10 days
5. 4-point profile will be used for T-T-T  
6. A fundoscopy/ fundus photography may be performed up to 2 weeks before or after V63 and up to 2 weeks before V89
7. PK sample for NNC0114-0006 (pre-dose and 1 hour sample after start of infusion)
8. Last dosing of NNC0114-0006/placebo
9. Last dosing of liraglutide/liraglutide placebo is the day prior to V63


Protocol Amendment 3
CONFIDENTIAL
Date:
08 November 2016
Novo Nordisk
Trial ID: NN9828-4150
Version:
2.0
UTN: U1111-1154-7172
Status:
Final
EudraCT No.: 2014-001215-39
Page:
24 of 28
2.2
Section 4.2.2.3 Supportive secondary biomarker endpoints
!
Change in biomarker parameters from baseline to week 54 and week 80
o
T-cell profiling including islet-specific auto reactive CD8+ T-cells
o
Immune phenotyping of peripheral blood mononuclear cells (PBMC) (the analyses 
will include, but are not restricted to, the following populations):

NK subpopulations

Monocyte subpopulations

CD8+ & CD4+ subpopulations (e.g., anergy/exhaustion vs. activation; 
memory, effector, regulatory cells; follicular helper (Tfh) & regulatory Tfh)
o
Total IL-21
o
Islet aAutoantibodies against glutamic acid decarboxylase 65 (GAD), zinc-
transporter 8 (ZnT8), islet antigen-2 (IA2), insulin autoantibody (IAA), isotypes of 
IAA and GAD
!
Change in serum vitamin D (1,25 dehydroxy-calciferol) from baseline to week 54 and week 
80
2.3
Section 5.3.1 NNC0114-0006
NNC0114-0006 C 100 mg/ml and NNC0114-0006 C 0 mg/ml will be administered as an i.v. 
infusion every 6 weeks (first administration Week 0 and last administration Week 48) at the 
trial sites. The i.v. infusion of NNC0114-0006 C 100 mg/ml or NNC0114-0006 C 0 mg/ml 
will be administered according to instructions as detailed in the Trial Materials Manual 
(TMM). Subjects will remain at the clinical trial site for at least 2 hours after completion of 
NNC0114-0006 C 100 mg/ml or NNC0114-0006 C 0 mg/ml administration to be observed 
for AEs. On days with MMTT the administration of NNC0114-0006/placebo, may be done 
during the MMTT. 
It must be confirmed by the investigator that infection parameters for Epstein-Barr, 
cytomegalovirus and hepatitis B (i.e. IgM EBV antibodies, IgG EBV nuclear antigen, CMV 
IgM, CMV IgG, HBcAB, HBsAb, HBsAg) have been accessed prior each infusion.
2.4
Section 6.3 Exclusion criteria
3. Female who is pregnant, breast-feeding or intends to become pregnant or is of child-
bearing potential not using highly effective contraceptive methods for the duration of the trial
(highly effective contraceptive measures, as required by local regulations or practice, i.e. a 
measure that results in less than 1% per year failure rate when used consistently and correctly) 
For Belgium: Highly effective methods of birth control are defined as those, alone or in 
combination, that result in a low failure rate (i.e., less than 1% per year) when used 
CONFIDENTIAL


Protocol Amendment 3
CONFIDENTIAL
Date:
08 November 2016
Novo Nordisk
Trial ID: NN9828-4150
Version:
2.0
UTN: U1111-1154-7172
Status:
Final
EudraCT No.: 2014-001215-39
Page:
25 of 28
consistently and correctly; such as implants, injectables, combined oral contraceptives, some 
IUDs, true sexual abstinence (i.e. refraining from heterosexual intercourse during the entire 
period of risk associated with the study treatments) or vasectomised partner.
4. Male of reproductive age who or whose partner(s) is not using highly effective
contraceptive methods for the duration of the trial (highly effective contraceptive measures, as 
required by local regulation or practice, i.e. a measure that results in less than 1% per year 
failure rate when used consistently and correctly).
For United Kingdom: Male patients who are sexually active and have partners must use a 
barrier method of contraception (e.g. condom) for the duration of the study
2.5
Section 8.5.1.3 Biomarkers 
Auto-Antibodies & isotypes
The autoantibodies are used to confirm the clinical diagnosis of TD1DM at screening and 
the assessments during the trial will give information of disease development. Further 
during the trial, isotypes of anti-insulin (IAA) and of anti-GAD autoantibodies will also be 
determined. Isotypes will change over time as the diabetes-associated immune response 
progresses or is modified by therapy. Therefore, autoantibody isotypes will provide 
information regarding the immune and disease status of an individual.
Blood samples for aAutoantibodies will be drawn according to Section 2. The following 
autoantibodies will beanalysed:
o
Anti-GAD 
o
Anti-ZnT8
o
Anti-IA2
o
Anti-IAA, excepted at Visit 1
Additionally, isotypes for anti-IAA and –GAD will be evaluated according to Section 2..
Anti-IAA and –GAD isotypes will be analysed at a specialised laboratory and only if the 
sample is positive for anti-IAA or anti-GAD antibodies. These results will be reported to the 
investigator at the end of the trial.
Immunology
T1DM is mediated by immune destruction of the islets, characterised by T-cell infiltrate and 
detectable autoantibodies in the periphery. Additionally, IL-21 is an important immune-modifying 
CONFIDENTIAL


Protocol Amendment 3
CONFIDENTIAL
Date:
08 November 2016
Novo Nordisk
Trial ID: NN9828-4150
Version:
2.0
UTN: U1111-1154-7172
Status:
Final
EudraCT No.: 2014-001215-39
Page:
26 of 28
cytokine that has been demonstrated to impact B- and T-cell compartments. The assays proposed 
will assess the disease- and treatment-associated effects on the immune response mediating T1DM.
Samples will be drawn according to Section 2. The investigator must record the date and the exact 
time for sampling the blood.
The following will be analysed for exploratory reasons:
!
T-cell profiling including islet-specific auto reactive CD8+ T-cells, except at Visit 4, 5 and 6
!
IL-21, except at Visit 2
!
Immune phenotyping of PBMC populations (the analyses will include, but are not restricted 
to, the following populations):
!
NK subpopulations
!
Monocyte subpopulations
!
CD8+ & CD4+ subpopulations (e.g., anergy/exhaustion vs. activation; memory, 
effector, regulatory cells; follicular helper (Tfh) & regulatory Tfh)
!
The blood sampling for assessment of T cell profiling including islet specific auto reactive 
CD8+ T cells PBMC populations should preferably, if possible, be performed at about the 
same time of day each time for a given subject.
!
The PBMCs will be stored for up to 15 years for potential future assessments if the subject 
has consented to it (see Section 24.2). 
!
Total IL-21, except at Visit 2
The IL-21 analysis will be of exploratory reasons and analysed at a specialised laboratory. The 
assay measure IL-21 bound to NNC0114-0006. Samples taken at predose will be equal to free IL-21
should be pre-dose if the NNC0114-0006 is given at the sampling visits. All other sampling will 
measure total IL-21
The blood sampling for assessment of T-cell profiling including islet-specific auto reactive CD8+
T-cells should preferably be performed at about the same time of day for a given subject.
Blood sampling for the assessment of Il-21 should be pre-dose if the NNC0114-0006 is given at the
sampling visits. IL-21 will be analysed at a specialised laboratory only if a functioning assay is
available in due time to ensure analyses and results are ready for data base lock. The investigator
will receive the results of the immunology assessments at the end of the trial. If no functional assay
is available the samples will be destroyed.
CONFIDENTIAL


Protocol Amendment 3
CONFIDENTIAL
Date:
08 November 2016
Novo Nordisk
Trial ID: NN9828-4150
Version:
2.0
UTN: U1111-1154-7172
Status:
Final
EudraCT No.: 2014-001215-39
Page:
27 of 28
The periphery blood mononuclear cells (PBMCs) used for the analyses of the T-cell profiling 
including islet-specific auto reactive CD8+ T-cells will be stored for up to 15 years for potential 
future assessments if the subject has consented to it (see Section Error! Reference source not 
found.). 
2.6
Section 8.5.2.1 Pregnancy test
For Belgium: A monthly urine pregnancy test is mandatory for female subjects of 
childbearing potential.
2.7
Section 9.1 Trial products 
!
The following non-IMPs are used in this trial:
o
Insulin:
During the trial subjects will receive insulin treatment in order to achieve a metabolic
control according to the insulin titration guideline. Subjects will continue their pre-trial
insulin treatment. Thus treatment will be considered background treatment. Preferably
the type and/or brand of basal and bolus insulin should not be changed throughout the
trial.
Insulin will not be provided by Novo Nordisk.
o
Glucagon
Glucagon will can be used as rescue medication for the treatment of severe
hypoglycaemia.
Glucagon will not be provided by Novo Nordisk.
2.8
Section 18.2 Informed consent
Furthermore if the subject agrees to have a blood sample taken for long term storage of 
human samples (see Section 8.5.3.2) and/or to have some of the blood stored from the T-cell 
profiling islet-specific auto reactive CD8+ T-cells PBMC samples (see Section 8.5.1.3) a 
separate signed informed consent form will be obtained from the subject.
CONFIDENTIAL


Protocol Amendment 3
CONFIDENTIAL
Date:
08 November 2016
Novo Nordisk
Trial ID: NN9828-4150
Version:
2.0
UTN: U1111-1154-7172
Status:
Final
EudraCT No.: 2014-001215-39
Page:
28 of 28
2.9
Section 26 Indemnity statement 
For Belgium: Law concerning experiments on the human person of 07 May 2004 - Article 
29: §1. Even if without fault, the sponsor is liable for the damage which the subject and/or 
his rightful claimants sustain and which shows either a direct or an indirect connection with 
the trial.
CONFIDENTIAL


Protocol Amendment 4
CONFIDENTIAL
Date:
21 November 2016
Novo Nordisk
Trial ID: NN9828-4150
Version:
1.0
UTN: U1111-1154-7172
Status:
Final
EudraCT No.: 2014-001215-39
Page:
1 of 4
Protocol Amendment
no 4
to Protocol, final version 4.0
dated 14 March 2016
Trial ID: NN9828-4150
A randomised, double-blind, double-dummy, placebo-controlled, parallel-group 
multi-centre clinical proof-of-principle trial in adult subjects with newly 
diagnosed type 1 diabetes mellitus investigating the effect of NNC0114-0006 and 
liraglutide on preservation of beta-cell function
Trial phase: 2
Applicable to Poland
Amendment originator:
Clinical, Medical & Regulatory, Poland
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol Amendment 4
CONFIDENTIAL
Date:
21 November 2016
Novo Nordisk
Trial ID: NN9828-4150
Version:
1.0
UTN: U1111-1154-7172
Status:
Final
EudraCT No.: 2014-001215-39
Page:
2 of 4
Table of Contents   
Page 
Table of Contents.............................................................................................................................................. 2 
1 
Introduction including rationale for the protocol amendment ............................................................. 3 
2 
Changes ...................................................................................................................................................... 4 
2.1 
Section 6.3 Exclusion criteria (page 51) ........................................................................................ 4 
2.2 
8.5.2.1 Pregnancy test (page 82) .................................................................................................... 4 
2.3 
Section 2, table text below the table, point 2 (page 20, 25, 30, and 34) ........................................ 4 
CONFIDENTIAL


Protocol Amendment 4
CONFIDENTIAL
Date:
21 November 2016
Novo Nordisk
Trial ID: NN9828-4150
Version:
1.0
UTN: U1111-1154-7172
Status:
Final
EudraCT No.: 2014-001215-39
Page:
3 of 4
1
Introduction including rationale for the protocol amendment
This amendment has been prepared following a request for additional information from the Polish 
Health Authority - The Office for Registration of Medicinal Products, Medical Devices and 
Biocidal Products, Department for Clinical Trials of Medicinal Products – to implement in the 
protocol the following: 
x
for women of childbearing potential to use highly effective methods of contraception with 
their partners during the clinical trial; 
x
to perform a pregnancy test every month in patients enrolled in the trail.
In this protocol amendment: 
x
Any new text is written in italics.
x
Any text deleted from the protocol is written using strike through. 
CONFIDENTIAL


Protocol Amendment 4
CONFIDENTIAL
Date:
21 November 2016
Novo Nordisk
Trial ID: NN9828-4150
Version:
1.0
UTN: U1111-1154-7172
Status:
Final
EudraCT No.: 2014-001215-39
Page:
4 of 4
2
Changes
Text to be inserted; relates to protocol version 4.0: 
2.1
Section 6.3 Exclusion criteria (page 51) 
For Poland: Highly effective contraceptive measures are: oral (except low-dose gestagen 
(lynestrenol and norestisteron)), injectable, or implanted hormonal contraceptives, intrauterine 
device, intrauterine system (for example, progestin-releasing coil), vasectomized male (with 
appropriate postvasectomy documentation of the absence of sperm in the ejaculate). 
2.2
8.5.2.1 Pregnancy test (page 82) 
Poland: Urine-stick pregnancy test will be performed monthly.
2.3
Section 2, table text below the table, point 2 (page 20, 25, 30, and 34) 
Poland: Urine-stick pregnancy test will be performed monthly.
CONFIDENTIAL


Protocol Amendment 5
CONFIDENTIAL
Date:
02 May 2017
Novo Nordisk
Trial ID: NN9828-4150
Version:
1.0
UTN: U1111-1154-7172
Status:
Final
EudraCT No.: 2014-001215-39
Page:
1 of 17
Protocol Amendment 
no 5
to Protocol, final version 6.0
dated 08 November 2016
Trial ID: NN9828-4150
A randomised, double-blind, double-dummy, placebo-controlled, parallel-group 
multi-centre clinical proof-of-principle trial in adult subjects with newly 
diagnosed type 1 diabetes mellitus investigating the effect of NNC0114-0006 and 
liraglutide on preservation of beta-cell function
Trial phase: 2
Applicable to all countries 
Amendment originator:
GLP-1 diabetes, NADs & Complications TrialOps 1
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol Amendment 5
CONFIDENTIAL
Date:
02 May 2017
Novo Nordisk
Trial ID: NN9828-4150
Version:
1.0
UTN: U1111-1154-7172
Status:
Final
EudraCT No.: 2014-001215-39
Page:
2 of 17
Table of Contents   
Page
Table of Contents........................................................................................................................................2
1
Introduction including rationale for the protocol amendment...........................................................3
2
Changes ................................................................................................................................................5
2.1
List of abbreviations..................................................................................................................5
2.2
Section 2.1 Flowchart for the first 80 randomised subjects only.................................................6
2.3
Section 2.2 Flowchart for once 80 subjects have been randomised.............................................7
2.4
Section 5.3.4 Prohibited medication ........................................................................................15
2.5
Section 6.3 Exclusion criteria ..................................................................................................15
2.6
Section 6.6 Withdrawal criteria ...............................................................................................15
2.7
Section 8.3.2  Self-measured blood glucose.............................................................................16
2.8
Section 8.5.1.1 Glucose metabolism ........................................................................................16
2.9
Section 8.5.3.3 Serum concentration of NNC0114-0006 for pharmacokinetics.........................16
2.10
Section 8.7  Subject compliance ..............................................................................................17
CONFIDENTIAL


Protocol Amendment 5
CONFIDENTIAL
Date:
02 May 2017
Novo Nordisk
Trial ID: NN9828-4150
Version:
1.0
UTN: U1111-1154-7172
Status:
Final
EudraCT No.: 2014-001215-39
Page:
3 of 17
1
Introduction including rationale for the protocol amendment
This amendment was prepared to update Protocol NN9828-4150 version 6.0 dated 08 November 
2016 with the following changes:
!
To allow for the use of Continuous Glucose Monitoring (CGM) and Flash Glucose 
Monitoring devices for patients having access to these. Allowing the use of these devices 
will ease the burden for the patients during their trial participation. All end point related data 
are still to be measured using the BG meter provided by Novo Nordisk and it is hence 
assessed that neither patient safety nor data integrity is affected by introducing the two 
device options.
!
Visit 4 (V4), in the flowchart for section 2.2 Visit 1 to 37 procedures once 80 subjects have 
been randomised, was removed in Global Protocol Amendment No. 2 due to removal of PK 
sampling at this visit. As this visit also serves the purpose of monitoring the patient after 
initiation of liraglutide/ liraglutide placebo, V4 is re-instated as a phone contact and with 
safety monitoring only.
!
In section 2, the flowchart has been updated to reflect the re-introduction of V4 once 80 
patients have been randomised. Furthermore, the tick mark for IV/IWRS call for visit 89
and the drug accountability for visit 3 are removed as these are not applicable. In addition, 
monthly mandatory urine pregnancy test for female Polish subjects has been incorporated
due to a local requirement. 
!
In section 5.3.4, the period for which systemically corticosteroids, monoamine oxidase 
(MAO) inhibitors, systemic non-selective beta-blockers and growth hormone as well as 
treatment with any medication for the indication of diabetes or obesity other than insulin 
and trial medication is prohibited has been extended to include the follow-up period (week 
54 to week 80). Patients may not initiate these medications at any time during the trial 
period as secondary efficacy parameters may be influenced. 
!
In section 6.3, contraceptive requirements for Poland have been added. In addition, 
clarifying editorial changes has been made to the UK requirement for males of reproductive 
age.   
!
In section 6.6, it has been clarified that vaccines taken during the follow-up period will not 
lead to exclusion from the trial as no trial medication is administered. Vaccines are,
however, still prohibited medication during the entire trial period.
!
In section 8.3.2, the option of using CGM and Flash Glucose Monitoring devices has been 
introduced. 
CONFIDENTIAL


Protocol Amendment 5
CONFIDENTIAL
Date:
02 May 2017
Novo Nordisk
Trial ID: NN9828-4150
Version:
1.0
UTN: U1111-1154-7172
Status:
Final
EudraCT No.: 2014-001215-39
Page:
4 of 17
!
In section 8.5.1.1, measurement of non-fasting C-peptide at visit 1 (V1) is removed to 
reflect the updates in Global Amendment No. 2. 
!
In section 8.7, it has been emphasised that patients should be re-trained if they fail to 
comply with the data entry in the eDiary. 
!
In addition, minor editorial changes are introduced in this amendment.
In this protocol amendment:
!
Any new text is written in italics.
!
Any text deleted from the protocol is written using strike through.
CONFIDENTIAL


Protocol Amendment 5
CONFIDENTIAL
Date:
02 May 2017
Novo Nordisk
Trial ID: NN9828-4150
Version:
1.0
UTN: U1111-1154-7172
Status:
Final
EudraCT No.: 2014-001215-39
Page:
5 of 17
2
Changes
2.1
List of abbreviations
CGM Continuous Glucose Monitoring 
CONFIDENTIAL


Protocol Amendment 5
UTN: U1111-1154-7172
Date:
02 May 2017
Status:
Final
Novo Nordisk
Trial ID: NN9828-4150
EudraCT No.: 2014-001215-39
Version:
1.0
Page:
6 of 17
2.2
Section 2.1 Flowchart for the first 80 randomised subjects only
Visit 1 to 37 procedures for the first 80 randomised subjects only
Trial periods
S
R
Treatment
Visit type:
C: Clinic, P: Phone contact
C
C
C
P
C
C
P
P
C
P
P
C
P
C
P
C
P
C
P
C
P
C
P
C
P
C
P
C
Visit number
1
2
3
4
6
7
8
9
10
11
12
13
14,15
16
17,18
19
20-22
23
24
25
26-28
29
30
31
32-34
35
36
37
Timing of visit (weeks (W), or days (D) 
if specified)
-D28 to 
–D14
-D10 
0
1D
W1
W2
W2 + 
1D
W3
W4
W4 + 
1D
W5
W6
W7,8
W9
W10,11
W12
W13-15
W16
W17
W18
W19-21
W22
W23
W24
W25-27
W28
W29
W30
Visit window (days)
± 
4
±
1
±
1
±
1
±
1
±
1
±
1
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
TRIAL MATERIAL
Drug accountability for IMP12
x
x
x
x
x
x
2. Blood sample at V1. A urine stick pregnancy test must be performed throughout the trial for females of childbearing potential if a menstrual period is missed or as required by local law. Austria & Poland: 
Urine-stick pregnancy test will be performed monthly. For Belgium: A monthly urine pregnancy test is mandatory for female subjects of childbearing potential. Ireland: Urine-stick pregnancy test will be 
performed at all visits to the clinic.
Visit 38 to 90 procedures for the first 80 randomised subjects only
Trial period
Treatment
Follow-up
Visit type:
C: Clinic, P: Phone contact
P
C
P
C
P
C
P
C
P
C
P
C
C
C
C
P
C
P
C
P
C
P
C
P
C
P
C
C
Visit number
38-40
41
42
43
44-46
47
48
49
50-52
53
54
55
56
57
58,59
60
61
62
63
64-68
69
70-73
74
75-77
78
79-88
89
901


Protocol Amendment 5
UTN: U1111-1154-7172
Date:
02 May 2017
Status:
Final
Novo Nordisk
Trial ID: NN9828-4150
EudraCT No.: 2014-001215-39
Version:
1.0
Page:
7 of 17
Timing of visit 
(weeks (W), or days (D) if 
specified)                      
W31-33
W34
W35
W36
W37-39
W40
W41
W42
W43-45
W46
W47
W48
W48 + 1D
W48 + 3D
W49, 50
W51
W52
W53
W54
W55-59
W60
W61-64
W65
W66-68
W69
W70-79
W80
Visit window (days)
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
7
IV/IWRS
x
x
x
x
x
3. Blood sample at V63. A urine stick pregnancy test must be performed throughout the trial for females of childbearing potential if a menstrual period is missed or as required by local law. Austria & Poland: 
Urine-stick pregnancy test will be performed monthly. For Belgium: A monthly urine pregnancy test is mandatory for female subjects of childbearing potential. Ireland: Urine-stick pregnancy test will be 
performed at all visits to the clinic.
2.3
Section 2.2 Flowchart for once 80 subjects have been randomised 
Visit 1 to 37 procedures once 80 subjects have been randomised
Trial periods
S
R
Treatment
Visit type:
C: Clinic, P: Phone contact
C
C
C
P
C
C
P
P
C
P
P
C
P
C
P
C
P
C
P
C
P
C
P
C
P
C
P
C
Visit number
1
2
3
4
6
7
8
9
10
11
12
13
14,15
16
17,18
19
20-22
23
24
25
26-28
29
30
31
32-34
35
36
37
Timing of visit (weeks (W), or days (D) 
if specified)
-D28 to 
–D14
-D10 
0
1D
W1
W2
W2 + 
1D
W3
W4
W4 + 
1D
W5
W6
W7,8
W9
W10,11
W12
W13-15
W16
W17
W18
W19-21
W22
W23
W24
W25-27
W28
W29
W30
Visit window (days)
± 
4
±
1
±
1
±
1
±
1
±
1
±
1
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
SUBJECT RELATED
INFO/ASSESSMENTS
Informed consent
x
Genotyping consent, optional
x
Long term retention consent, optional
x
In/exclusion criteria
x
x
x


Protocol Amendment 5
UTN: U1111-1154-7172
Date:
02 May 2017
Status:
Final
Novo Nordisk
Trial ID: NN9828-4150
EudraCT No.: 2014-001215-39
Version:
1.0
Page:
8 of 17
Trial periods
S
R
Treatment
Visit type:
C: Clinic, P: Phone contact
C
C
C
P
C
C
P
P
C
P
P
C
P
C
P
C
P
C
P
C
P
C
P
C
P
C
P
C
Visit number
1
2
3
4
6
7
8
9
10
11
12
13
14,15
16
17,18
19
20-22
23
24
25
26-28
29
30
31
32-34
35
36
37
Timing of visit (weeks (W), or days (D) 
if specified)
-D28 to 
–D14
-D10 
0
1D
W1
W2
W2 + 
1D
W3
W4
W4 + 
1D
W5
W6
W7,8
W9
W10,11
W12
W13-15
W16
W17
W18
W19-21
W22
W23
W24
W25-27
W28
W29
W30
Visit window (days)
± 
4
±
1
±
1
±
1
±
1
±
1
±
1
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
Randomisation
x
Randomisation criteria
x
Withdrawal criteria
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
Dosing day exclusion criteria1
x
x
x
x
x
x
Abuse of alcohol
x
Abuse of drugs
x
Medical history
x
Concomitant illness
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
x
x
x
x
x
x
Demography
x
Diagnosis of diabetes
x
Diabetes treatment history
x
Pregnancy test2
x
Smoking habits
x
Family history of diabetes
x


Protocol Amendment 5
UTN: U1111-1154-7172
Date:
02 May 2017
Status:
Final
Novo Nordisk
Trial ID: NN9828-4150
EudraCT No.: 2014-001215-39
Version:
1.0
Page:
9 of 17
Trial periods
S
R
Treatment
Visit type:
C: Clinic, P: Phone contact
C
C
C
P
C
C
P
P
C
P
P
C
P
C
P
C
P
C
P
C
P
C
P
C
P
C
P
C
Visit number
1
2
3
4
6
7
8
9
10
11
12
13
14,15
16
17,18
19
20-22
23
24
25
26-28
29
30
31
32-34
35
36
37
Timing of visit (weeks (W), or days (D) 
if specified)
-D28 to 
–D14
-D10 
0
1D
W1
W2
W2 + 
1D
W3
W4
W4 + 
1D
W5
W6
W7,8
W9
W10,11
W12
W13-15
W16
W17
W18
W19-21
W22
W23
W24
W25-27
W28
W29
W30
Visit window (days)
± 
4
±
1
±
1
±
1
±
1
±
1
±
1
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
Diabetes complications
x
Blood sample for genotyping (optional)
x
EFFICACY
Glucose metabolism
x
x
x
x
x
x
x
Meal test3
x
x
x
Self-measured plasma glucose:
7-point profile prior to visit
x
x
x
x
x
x
x
x
x
x
4-point profile prior to visit4
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
PRO questionnaires
x
x
Biomarkers:
Antibodies (autoantibodies)
x
x
x
x
x
Immune phenotyping
x
x


Protocol Amendment 5
UTN: U1111-1154-7172
Date:
02 May 2017
Status:
Final
Novo Nordisk
Trial ID: NN9828-4150
EudraCT No.: 2014-001215-39
Version:
1.0
Page:
10 of 17
Trial periods
S
R
Treatment
Visit type:
C: Clinic, P: Phone contact
C
C
C
P
C
C
P
P
C
P
P
C
P
C
P
C
P
C
P
C
P
C
P
C
P
C
P
C
Visit number
1
2
3
4
6
7
8
9
10
11
12
13
14,15
16
17,18
19
20-22
23
24
25
26-28
29
30
31
32-34
35
36
37
Timing of visit (weeks (W), or days (D) 
if specified)
-D28 to 
–D14
-D10 
0
1D
W1
W2
W2 + 
1D
W3
W4
W4 + 
1D
W5
W6
W7,8
W9
W10,11
W12
W13-15
W16
W17
W18
W19-21
W22
W23
W24
W25-27
W28
W29
W30
Visit window (days)
± 
4
±
1
±
1
±
1
±
1
±
1
±
1
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
Total IL-21
x
x
x
x
Vitamin D (1,25 dehydroxy-calciferol)
x
x
x
x
Dose of insulin administrations
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Carbohydrate intake
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
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
x
x
Hyperglycaemic episodes
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
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
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
x
x
x
x
x
Body measurements5
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
ECG
x6
x
x
x
x
x
Eye examination
x7
Physical examination
x
x
x
x
x
x
Vital signs
x
x
x
x
x
x
x
x
x
x
x
Antibodies:
Anti-NNC0114-0006 antibodies
x
x
x
Anti-liraglutide antibodies
x
x
x
IgE
x
x
x
x
x
Biochemistry
x
x
x
x
x
x


Protocol Amendment 5
UTN: U1111-1154-7172
Date:
02 May 2017
Status:
Final
Novo Nordisk
Trial ID: NN9828-4150
EudraCT No.: 2014-001215-39
Version:
1.0
Page:
11 of 17
Trial periods
S
R
Treatment
Visit type:
C: Clinic, P: Phone contact
C
C
C
P
C
C
P
P
C
P
P
C
P
C
P
C
P
C
P
C
P
C
P
C
P
C
P
C
Visit number
1
2
3
4
6
7
8
9
10
11
12
13
14,15
16
17,18
19
20-22
23
24
25
26-28
29
30
31
32-34
35
36
37
Timing of visit (weeks (W), or days (D) 
if specified)
-D28 to 
–D14
-D10 
0
1D
W1
W2
W2 + 
1D
W3
W4
W4 + 
1D
W5
W6
W7,8
W9
W10,11
W12
W13-15
W16
W17
W18
W19-21
W22
W23
W24
W25-27
W28
W29
W30
Visit window (days)
± 
4
±
1
±
1
±
1
±
1
±
1
±
1
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
Coagulation parameters
x
x
x
x
x
x
Haematology
x
x
x
x
x
x
Cytokines
x
x
x
x
Urine dipsticks 
x
x
x
x
x
x
Hepatitis B
x
x
x
x
x
x
Hepatitis C
x
Tuberculosis screening test 
(QuantiFERON)
x
Epstein–Barr virus
x
x
x
x
x
x
CMV8
x
x
x
x
x
x
HIV
x
Hormones
x
x
x
Lipids
x
x
x
OTHER ASSESSMENTS
PK sampling
NNC0114-0006
x9
x
x
x
x
x
x
x
x
x
PK sampling
Liraglutide10
x
x
x
x
x
x
x
x
x
x
TRIAL MATERIAL
IV/IWRS
x
x
x
x
x
x
x
Administration and dispensing of trial 
x
x
x
x
x
x


Protocol Amendment 5
UTN: U1111-1154-7172
Date:
02 May 2017
Status:
Final
Novo Nordisk
Trial ID: NN9828-4150
EudraCT No.: 2014-001215-39
Version:
1.0
Page:
12 of 17
Trial periods
S
R
Treatment
Visit type:
C: Clinic, P: Phone contact
C
C
C
P
C
C
P
P
C
P
P
C
P
C
P
C
P
C
P
C
P
C
P
C
P
C
P
C
Visit number
1
2
3
4
6
7
8
9
10
11
12
13
14,15
16
17,18
19
20-22
23
24
25
26-28
29
30
31
32-34
35
36
37
Timing of visit (weeks (W), or days (D) 
if specified)
-D28 to 
–D14
-D10 
0
1D
W1
W2
W2 + 
1D
W3
W4
W4 + 
1D
W5
W6
W7,8
W9
W10,11
W12
W13-15
W16
W17
W18
W19-21
W22
W23
W24
W25-27
W28
W29
W30
Visit window (days)
± 
4
±
1
±
1
±
1
±
1
±
1
±
1
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
±
1
±
3
product NNC0114-0006/placebo
Dispensing of liraglutide/placebo11
x
x
x
x
x
x
Drug accountability for IMP12
x
x
x
x
x
x
REMINDERS
Handout ID cards
x
Handout direction for use13
x
Handout and instruct in e-diary
x
Investigator review of e-diary
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
Handout and instruct in BG meter use
x
Attend fasting visit
x
x
x
x
x
x
x
Blood sample for long term retention 
(optional)
x
x


Protocol Amendment 5
UTN: U1111-1154-7172
Date:
02 May 2017
Status:
Final
Novo Nordisk
Trial ID: NN9828-4150
EudraCT No.: 2014-001215-39
Version:
1.0
Page:
13 of 17
2. Blood sample at V1. A urine stick pregnancy test must be performed throughout the trial for females of childbearing potential if a menstrual period is missed or as required by local law. Austria & Poland: 
Urine-stick pregnancy test will be performed monthly. For Belgium: A monthly urine pregnancy test is mandatory for female subjects of childbearing potential. Ireland: Urine-stick pregnancy test will be 
performed at all visits to the clinic.


Protocol Amendment 5
UTN: U1111-1154-7172
Date:
02 May 2017
Status:
Final
Novo Nordisk
Trial ID: NN9828-4150
EudraCT No.: 2014-001215-39
Version:
1.0
Page:
14 of 17
Visit 38 to 90 procedures once 80 subjects have been randomised
Trial period
Treatment
Follow-up
Visit type:
C: Clinic, P: Phone contact
P
C
P
C
P
C
P
C
P
C
P
C
P
P
P
P
C
P
P
P
C
P
P
P
C
C
Visit number
38-40
41
42
43
44-46
47
48
49
50-52
53
54
55
58,59
60
61
62
63
64-68
69
70-73
74
75-77
78
79-88
89
901
Timing of visit 
(weeks (W), or days (D) if 
specified)                      
W31-33
W34
W35
W36
W37-39
W40
W41
W42
W43-45
W46
W47
W48
W49, 50
W51
W52
W53
W54
W55-59
W60
W61-64
W65
W66-68
W69
W70-79
W80
Visit window (days)
±1
±3
±1
±3
±1
±3
±1
±3
±1
±3
±1
±3
±1
±1
±1
±1
±3
±1
±1
±1
±3
±1
±1
±1
±3
±7
IV/IWRS
x
x
x
x
x
‘
3. Blood sample at V63. A urine stick pregnancy test must be performed throughout the trial for females of childbearing potential if a menstrual period is missed or as required by local law. 
Austria & Poland: Urine-stick pregnancy test will be performed monthly. For Belgium: A monthly urine pregnancy test is mandatory for female subjects of childbearing potential. Ireland: 
Urine-stick pregnancy test will be performed at all visits to the clinic.


Protocol Amendment 5
CONFIDENTIAL
Date:
02 May 2017
Novo Nordisk
Trial ID: NN9828-4150
Version:
1.0
UTN: U1111-1154-7172
Status:
Final
EudraCT No.: 2014-001215-39
Page:
15 of 17
2.4
Section 5.3.4
Prohibited medication
The following medications must not be used during the treatment period (week 0-54):
1. Systemically corticosteroids, monoamine oxidase (MAO) inhibitors, systemic non-selective beta-
blockers and growth hormone
1. 2. Medications or herbal products that can influence the glucose homeostasis (except for 
insulin) and/or the immune system. It is up to the investigator to judge which herbal 
products influence on the glucose homeostasis
1. Treatment with any medication for the indication of diabetes or obesity other than 
insulin and trial medication.
The following medications must not be used during the trial period (week 0-80):
1. Live vVaccines with the exception of influenza vaccination according to local diabetes 
treatment requirements. The influenza vaccine can be given 3 weeks after a dose of 
NNC0114-0006 and 2 weeks before next dose of NNC0114-0006. 
2. Systemically corticosteroids, monoamine oxidase (MAO) inhibitors, systemic non-
selective beta-blockers and growth hormone unless only prescribed for a short period of 
time and if determined by investigator not to have an significant extended half-life
3. Treatment with any medication for the indication of diabetes or obesity other than 
insulin and trial medication.
2.5
Section 6.3 Exclusion criteria
3. For Poland: Highly effective contraceptive measures are: oral (except low-dose 
gestagen (lynestrenol and norestisteron)), injectable, or implanted hormonal 
contraceptives, intrauterine device, intrauterine system (for example, progestin-releasing 
coil), vasectomized male (with appropriate postvasectomy documentation of the absence of 
sperm in the ejaculate).
4. For United Kingdom: Male patients who are sexually active and have partners must use 
a barrier method of contraception (e.g. condom) for the duration of the study.
2.6
Section 6.6 Withdrawal criteria
8. Initiation of any prohibited medication (see Section 5.3.4). Use of vaccines in the follow-
up period (week 54 to week 80) is prohibited but will not lead to subject withdrawal.
CONFIDENTIAL


Protocol Amendment 5
CONFIDENTIAL
Date:
02 May 2017
Novo Nordisk
Trial ID: NN9828-4150
Version:
1.0
UTN: U1111-1154-7172
Status:
Final
EudraCT No.: 2014-001215-39
Page:
16 of 17
2.7
Section 8.3.2
Self-measured blood glucose 
Subjects will be instructed in how to record the results of the self-measured blood glucose 
(SMBGs) in the e-diaries. The record of each SMPG will include date, time point (e.g. 
before breakfast, before lunch, etc.) and value. BG should always be measured when a 
hypo- or hyperglycaemic episode is suspected. Hypoglycaemic and hyperglycaemic 
episodes will be recorded by the subject in the e-diary (see Section 8.6.3). The investigator 
may ask the subject to perform additional SMPG measurements if needed for any safety 
reason. 
If subjects have their own CGM or Flash Glucose Monitoring devices they may use these 
for measuring the 4-point profiles only (i.e. before breakfast, before lunch, before dinner 
and bedtime) as per section 8.3.3  The use of these devices must be recorded in EDC.
The instruction of use of the CGM and Flash Glucose Monitoring devices is at the 
discretion of the investigator. These devices will not be supplied nor compensated by Novo 
Nordisk.
All subjects must receive and be instructed in the use of the blood glucose meter provided 
by Novo Nordisk. This Novo Nordisk supplied blood glucose meter must be used to:
!
confirm any glucose values measured  in connection with a hypoglycaemic episode
o
≤ 3.9 mmol/l (70 mg/dl) or
o
> 3.9 mmol /l (70 mg/dl) occurring in conjunction with hypoglycaemic symptoms
!
confirm any glucose values measured in connection with a hyperglycaemic episode
o
> 16.7 mmol/l (300 mg/dl)
!
measure all 7-point profiles (all 7 SMPGs from the same device)
2.8
Section 8.5.1.1 Glucose metabolism
• C-peptide (non-fasting ) will be measured at Visit 1
2.9
Section 8.5.3.3 Serum concentration of NNC0114-0006 for pharmacokinetics
PK samples will be taken according to Section 2. At Visit 3 and 55, samples will be taken 
pre-dose (up to 60 min before V55) and 1 hour after start of the infusion. At NNC0114-
0006 dosing visits, the sample should be taken pre-dose. The investigator must record the 
date and the exact time for sampling the blood.
CONFIDENTIAL


Protocol Amendment 5
CONFIDENTIAL
Date:
02 May 2017
Novo Nordisk
Trial ID: NN9828-4150
Version:
1.0
UTN: U1111-1154-7172
Status:
Final
EudraCT No.: 2014-001215-39
Page:
17 of 17
2.10
Section 8.7 
Subject compliance
Throughout the trial, the investigator will remind the subjects to follow the trial procedures 
and requirements to ensure subject compliance. If a subject is found to be non-compliant, 
the investigator will remind the subject of the importance of following the instructions 
given including taking the trial products as prescribed. Substantial failure to comply with 
the prescribed dose regimen can lead to withdrawal at the discretion of the investigator.
In case of subject non-compliance with data entry in the eDiary, re-training should be 
performed and documented. 
CONFIDENTIAL


Protocol Amendment no 6
CONFIDENTIAL
Date:
17 October 2017
Novo Nordisk
Trial ID: NN9828-4150
Version:
1.0
     
Status:
Final
     
Page:
1 of 3
Protocol Amendment
no 6
to Protocol, version 7
dated 02 May 2017
Trial ID: NN9828-4150
A randomised, double-blind, double-dummy, placebo-controlled, parallel-group
multi-centre clinical proof-of-principle trial in adult subjects with newly
diagnosed type 1 diabetes mellitus investigating the effect of NNC0114-0006 and
liraglutide on preservation of beta-cell function
Trial phase: 2
Applicable to Ireland
Amendment originator:
CMR, Ireland
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol Amendment no 6
CONFIDENTIAL
Date:
17 October 2017
Novo Nordisk
Trial ID: NN9828-4150
Version:
1.0
     
Status:
Final
     
Page:
2 of 3
Table of Contents   
1
Introduction including rationale for the protocol amendment...........................................................3
2
Changes ................................................................................................................................................3
CONFIDENTIAL


Protocol Amendment no 6
CONFIDENTIAL
Date:
17 October 2017
Novo Nordisk
Trial ID: NN9828-4150
Version:
1.0
     
Status:
Final
     
Page:
3 of 3
1
Introduction including rationale for the protocol amendment
This amendment was prepared to update protocol NN9828-4150 version 7.0 dated 02 May 2017 
with the following change:
!
To update contraceptive requirements for subjects in Ireland as per request from the Irish 
regulatory authority, the Health Products Regulatory Authority on 12 Oct 2017
In this protocol amendment:
!
Any new text is written in italics.
!
Any text deleted from the protocol is written using strike through.
2
Changes
6.3 Exclusion Criteria
3. For Ireland: Highly effective contraceptive measures are defined as established use of
combined oral contraceptives, injected or implanted hormonal methods of contraception,
sterilisation, IUD or intrauterine system or true sexual abstinence.
For United Kingdom and Ireland: Only highly effective methods of birth control for the duration of 
the trial are accepted (i.e. one that results in less than 1% per year failure rate when used
consistently and correctly). Highly effective contraceptive measures are defined as
established use of oral, intravaginal, transdermal combined estrogen and progestogen
hormonal methods of contraception; oral, injected or implanted progestogen only hormonal
methods of contraception; placement of an intrauterine device or intrauterine hormone
releasing system, bilateral tubal occlusion, female sterilisation, vasectomised partner (where
partner is sole partner of subject), or true abstinence*(when in line with preferred and usual
lifestyle).
*Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods),
declaration of abstinence for the duration of a trial, and withdrawal are not acceptable
methods of contraception.
4. For United Kingdom and Ireland: Male patients who are sexually active must use a barrier 
method of contraception (e.g. condom) for the duration of the study.
CONFIDENTIAL


Protocol Amendment no. 7
CONFIDENTIAL
Date:
23 March 2018
Novo Nordisk
Trial ID: NN9828-4150
Version:
1.0
UTN: U1111-1154-7172
Status:
Final
EudraCT no.: 2014-001215-39
Page:
1 of 4
Protocol Amendment
no 7
to Protocol, version 7.0
dated 02-May-2017
Trial ID: NN9828-4150
A randomised, double-blind, double-dummy, placebo-controlled, parallel-group multi-centre 
clinical proof-of-principle trial in adult subjects with newly diagnosed type 1 diabetes mellitus 
investigating the effect of NNC0114-0006 and liraglutide on preservation of beta-cell function
Trial phase: 2
Applicable to all countries
Amendment originator: 
GLP-1 diabetes, NADs & Complications, TrialOps 1
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol Amendment no. 7
CONFIDENTIAL
Date:
23 March 2018
Novo Nordisk
Trial ID: NN9828-4150
Version:
1.0
UTN: U1111-1154-7172
Status:
Final
EudraCT no.: 2014-001215-39
Page:
2 of 4
Table of Contents   
1
Introduction including rationale for the protocol amendment...........................................................3
2
Changes ................................................................................................................................................3
2.1
List of abbreviations..................................................................................................................3
2.2
Section 6.3  Exclusion criteria ...................................................................................................3
2.3
Section 17.5  Interim analysis....................................................................................................4
CONFIDENTIAL


Protocol Amendment no. 7
CONFIDENTIAL
Date:
23 March 2018
Novo Nordisk
Trial ID: NN9828-4150
Version:
1.0
UTN: U1111-1154-7172
Status:
Final
EudraCT no.: 2014-001215-39
Page:
3 of 4
1
Introduction including rationale for the protocol amendment
This amendment was prepared to update Protocol NN9828-4150 version 7.0, dated 02 May 2017
with the following changes:
!
NN9828-4150 is a 1 year proof of principle trial with 6 months follow-up period. As 
originally planned, the primary endpoint is at week 54 (visit 63, being last patient last 
treatment (LPLT)). In addition to the data analysis after last patient last visit (LPLV), Novo 
Nordisk will introduce an additional database lock (DBL) after visit 63 in order to perform 
an internal main phase analysis. The DBL will be performed, when all patients have 
completed the main phase of the trial (treatment period), i.e. after LPLT at visit 63. After the 
additional DBL, Novo Nordisk will become unblinded, while the trial investigators and 
patients will remain blinded throughout the entire trial. The objective of the main phase 
analysis is to inform on future clinical trials. Conduct and design of the ongoing trial will 
remain unchanged. Following the end of trial, results from the entire trial period (main and 
extension phase) will be reported.
!
To include local Irish Protocol Amendment no 6, dated 17 October 2017, to Protocol version 
7.0, dated 02 May 2017. This Amendment contains updates to contraceptive requirements 
for subjects in Ireland as per request from the Irish regulatory authority, the Health Products 
Regulatory Authority on 12 October 2017.
!
In addition, minor editorial changes are introduced in this amendment.
In this protocol amendment:
!
Any new text is written in italics.
!
Any text deleted from the protocol is written using strike through.
2
Changes
2.1
List of abbreviations
DBL
Database lock
LPLT
Last patient last treatment
SMBG
self-measured blood glucose
2.2
Section 6.3 
Exclusion criteria
3. For Ireland: Highly effective contraceptive measures are defined as established use of 
combined oral contraceptives, injected or implanted hormonal methods of contraception, 
sterilisation, IUD or intrauterine system or true sexual abstinence.
CONFIDENTIAL


Protocol Amendment no. 7
CONFIDENTIAL
Date:
23 March 2018
Novo Nordisk
Trial ID: NN9828-4150
Version:
1.0
UTN: U1111-1154-7172
Status:
Final
EudraCT no.: 2014-001215-39
Page:
4 of 4
For United Kingdom & Ireland: Only highly effective methods of birth control for the 
duration of the trial are accepted (i.e. one that results in less than 1% per year failure rate 
when used consistently and correctly). Highly effective contraceptive measures are defined 
as established use of oral, intravaginal, transdermal combined estrogen and progestogen 
hormonal methods of contraception; oral, injected or implanted progestogen only hormonal 
methods of contraception; placement of an intrauterine device or intrauterine hormone 
releasing system, bilateral tubal occlusion, female sterilisation, vasectomised partner 
(where partner is sole partner of subject), or true abstinence*(when in line with preferred 
and usual lifestyle).
*Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods), 
declaration of abstinence for the duration of a trial, and withdrawal are not acceptable 
methods of contraception.
4. Male of reproductive age who or whose partner(s) is not using highly effective
contraceptive methods for the duration of the trial (highly effective contraceptive measures, 
as required by local regulation or practice, i.e. a measure that results in less than 1% per 
year failure rate when used consistently and correctly).
For United Kingdom & Ireland: Male patients who are sexually active must use a barrier 
method of contraception (e.g. condom) for the duration of the study.
2.3
Section 17.5 
Interim analysis
No formal interim analysis has been planned. However, an internal Novo Nordisk analysis is to be 
conducted after global last patient last treatment (LPLT) (visit 63) to inform on future clinical 
trials. An additional database lock (DBL) will be performed, when all patients have completed the 
main phase of the trial, i.e. after LPLT at visit 63. After the additional DBL, Novo Nordisk will 
become unblinded, while the trial investigators and patients will remain blinded throughout the 
entire trial.
CONFIDENTIAL


Global and country key Novo Nordisk staff
Attachments I and II (if applicable) to the protocol are located in the Trial Master File.
Content: Global key staff and Country key staff
CONFIDENTIAL
Date:
Novo Nordisk
Version:
Status:
NNC0114-0006
Trial ID: NN9828-4150
Clinical Trial Report
Appendix 16.1.1
08 July 2019
1.0
Final
CONFIDENTIAL

SAP_001.pdf: 
Cover Page for Statistical Analysis Plan 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT02443155 
Sponsor trial ID: 
NN9828-4150 
Official title of study: 
A randomised, double-blind, double-dummy, placebo-
controlled, parallel-group, multi-centre clinical proof-of 
principle trial in adult subjects with newly diagnosed type 1 
diabetes mellitus investigating the effect of NNC0114-0006 
and liraglutide on preservation of beta-cell function 
Document date: 
17 September 2019 


Link
List of contents
Statistical analysis plan......................................................................................................................
CONFIDENTIAL
Date:
Novo Nordisk
Version:
Status:
NNC0114-0006
Trial ID: NN9828-4150
Clinical Trial Report
Appendix 16.1.9
 6HSWHPEHU 2019
1.0
Final
16.1.9 Documentation of statistical methods
CONFIDENTIAL
Redacted VWDWLVWLFDODQDO\VLVSODQ 
Includes redaction of personal identifiable information only. 
. 


Statistical Analysis Plan
CONFIDENTIAL
Date:
19 September 2018
Novo Nordisk
Trial ID: NN9828-4150
Version:
1.0
UTN: U1111-1154-7172 
Status:
Final
EudraCT No.: 2014-001215-39
Page:
1 of 28
Statistical Analysis Plan
Trial ID: NN9828-4150
A randomised, double-blind, double-dummy, placebo-controlled, 
parallel-group multi-centre clinical proof-of-principle trial in adult 
subjects with newly diagnosed type 1 diabetes mellitus investigating 
the effect of NNC0114-0006 and liraglutide on preservation of beta-
cell function
Author
Biostatistics Aalborg 1
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Statistical Analysis Plan
CONFIDENTIAL
Date:
19 September 2018
Novo Nordisk
Trial ID: NN9828-4150
Version:
1.0
UTN: U1111-1154-7172 
Status:
Final
EudraCT No.: 2014-001215-39
Page:
2 of 28
Table of contents   Page
Table of contents.........................................................................................................................................2
List of abbreviations ...................................................................................................................................3
1
Introduction .........................................................................................................................................5
1.1
Trial information.......................................................................................................................5
1.1.1
Objectives................................................................................................................5
1.1.2
Endpoints.................................................................................................................6
1.1.2.1
Primary endpoint................................................................................6
1.1.2.2
Supportive secondary endpoints .........................................................6
1.1.3
Type of trial.............................................................................................................8
1.2
Flow-chart.................................................................................................................................9
1.3
Scope of the statistical analysis plan..........................................................................................9
2
Statistical considerations .....................................................................................................................9
2.1
Sample size calculation ...........................................................................................................11
2.2
Definition of analysis sets........................................................................................................12
2.3
Primary endpoint.....................................................................................................................13
2.4
Secondary endpoints ...............................................................................................................16
2.4.1
Supportive secondary endpoints .............................................................................16
2.4.1.1
Efficacy endpoints............................................................................16
2.4.1.2
Safety endpoints...............................................................................19
2.4.1.3
Pharmacokinetic endpoints...............................................................24
2.4.2
Interim analysis......................................................................................................25
3
Changes to the statistical analyses planned in the protocol..............................................................25
4
References ..........................................................................................................................................28
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
19 September 2018
Novo Nordisk
Trial ID: NN9828-4150
Version:
1.0
UTN: U1111-1154-7172 
Status:
Final
EudraCT No.: 2014-001215-39
Page:
3 of 28
List of abbreviations
ADA
American Diabetes Association
AE
adverse event
AUC
area under the curve
BG
blood glucose
CI
confidence interval
Cmax
maximum concentration
CPOP
clinical proof of principle
CRF
case report form
CTR
clinical trial report
DBL
Database lock
DKA
diabetic ketoacidosis 
DTSQ
Diabetes Treatment Satisfaction Questionnaire 
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
FPG
fasting plasma glucose
GAD
glutamic acid decarboxylase
GLP-1
glucagon-like peptide-1
HbA1c
glycosylated haemoglobin
HLA
human leucocyte antigen
IA2
islet antigen-2 
IAA
insulin autoantibodies
i.v.
intravenous(ly) 
LOCF
last observation carried forward
LPLT
Last patient last treatment
LSMeans
least square mean
mAb
monoclonal antibody 
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
mixed model for repeated measurements 
MMTT
mixed meal tolerance test 
MRT
mean residence time
NK
natural killer
PBMsCs
periphery blood mononuclear cells
PG
plasma glucose
PPG
postprandial glucose
PK
pharmacokinetic
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
19 September 2018
Novo Nordisk
Trial ID: NN9828-4150
Version:
1.0
UTN: U1111-1154-7172 
Status:
Final
EudraCT No.: 2014-001215-39
Page:
4 of 28
PRO
patient reported outcome
SAE
serious adverse event
SAP
statistical analysis plan
s.c.
subcutaneous(ly)
SD
standard deviation 
SE
standard error
SF-36v2
Short Form Health Survey version 2 
SLE
systemic lupus erythematosus 
SMPG
self-measured plasma glucose
SS
steady state
T1DM
type 1 diabetes mellitus
TSH
Thyroid-stimulating hormone 
T-T-T
treat-to-target 
ZnT8
zinc-transporter 8 
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
19 September 2018
Novo Nordisk
Trial ID: NN9828-4150
Version:
1.0
UTN: U1111-1154-7172 
Status:
Final
EudraCT No.: 2014-001215-39
Page:
5 of 28
1
Introduction
1.1
Trial information
This section includes the information of objectives, endpoints and type of trial as described in the 
trial protocol.
1.1.1
Objectives
Primary objective
The primary objective is to evaluate the effect of NNC0114-0006, liraglutide, and the combination 
of NNC0114-0006 and liraglutide, compared to placebo, on preservation of beta-cell function after 
54 weeks of treatment in adult subjects with newly diagnosed type 1 diabetes mellitus (T1DM).
Secondary objectives
Objectives related to treatment period (from baseline (week 0) to week 54):
!
To assess safety and tolerability of NNC0114-0006 and liraglutide in combination and 
alone in subjects with newly diagnosed T1DM
!
To assess effect on glycaemic parameters (including insulin usage and insulin regimen) of 
NNC0114-0006 and liraglutide in combination and alone in subjects with newly diagnosed 
T1DM 
!
To assess pharmacokinetic (PK) properties of NNC0114-0006 and liraglutide in 
combination and alone in subjects with newly diagnosed T1DM
!
To explore biomarkers relevant for the effect of NNC0114-0006 and liraglutide in 
combination and alone in subjects with newly diagnosed T1DM
!
To assess disease burden and health status in subjects with newly diagnosed T1DM treated 
with NNC0114-0006 and liraglutide in combination and alone 
Objectives related to the post-treatment observation period (from week 54 to week 80):
!
To assess post-treatment safety and tolerability of NNC0114-0006 and liraglutide in 
combination and alone in subjects with newly diagnosed T1DM
!
To assess post-treatment effect on preservation of beta-cell function of NNC0114-0006 and 
liraglutide in combination and alone in subjects with newly diagnosed T1DM 
!
To assess post-treatment effect on glycaemic parameters (including insulin usage and 
insulin regimen) of NNC0114-0006 and liraglutide in combination and alone in subjects 
with newly diagnosed T1DM 
!
To explore biomarkers relevant for the post-treatment effect of NNC0114-0006 and 
liraglutide in combination and alone in subjects with newly diagnosed T1DM
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
19 September 2018
Novo Nordisk
Trial ID: NN9828-4150
Version:
1.0
UTN: U1111-1154-7172 
Status:
Final
EudraCT No.: 2014-001215-39
Page:
6 of 28
!
To assess post-treatment development of disease burden and health status in subjects with 
newly diagnosed T1DM treated with NNC0114-0006 and liraglutide in combination and 
alone
1.1.2
Endpoints
1.1.2.1
Primary endpoint
The primary endpoint is AUC0-4h for a mixed meal tolerance test (MMTT) stimulated C-peptide 
concentration-time curve at week 54 relative to baseline (defined as the MMTT performed at Visit 
2).
!
AUC0-4h, C-peptide, 54w/AUC0-4h, C-peptide, baseline
1.1.2.2
Supportive secondary endpoints 
Supportive secondary efficacy endpoints
!
AUC0-4h for MMTT stimulated C-peptide concentration time curve at week 80 relative to 
baseline* 
!
AUC0-2h for MMTT stimulated C-peptide concentration time curve at week 54 and week 80 
relative to baseline*
!
Maximum MMTT stimulated C-peptide concentration (Cmax, C-peptide) at week 54 and week 
80 relative to baseline*
!
AUC0-4h for MMTT stimulated plasma glucose concentration time curve at week 54 and 
week 80 relative to baseline
!
AUC0-2h for MMTT stimulated plasma glucose concentration time curve at week 54 and 
week 80 relative to baseline
!
Maximum MMTT stimulated plasma glucose concentration (Cmax, glucose) week 54 and week 
80 relative to baseline
!
Change in total daily insulin dose in units per kg (three day average) from baseline to week 
54 and week 80* 
!
Change in number of insulin injections per day (three day average) from baseline to week 
54 and week 80
!
Number of weeks off bolus insulin from baseline to week 54 and week 80
!
Change in HbA1c from baseline to week 54 and week 80*
!
Change in fasting plasma glucose from baseline to week 54 and week 80*
!
Change in fasting C-peptide from baseline to week 54 and week 80*
!
Change in fasting glucagon from baseline to week 54 and week 80
!
7-point self-measured plasma glucose (SMPG) profiles. The following endpoints will be 
derived:
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
19 September 2018
Novo Nordisk
Trial ID: NN9828-4150
Version:
1.0
UTN: U1111-1154-7172 
Status:
Final
EudraCT No.: 2014-001215-39
Page:
7 of 28
o
7-point profiles at week 54 and week 80
o
Change in postprandial glucose (PPG)/prandial increment (breakfast, lunch, dinner
and average over the three meals) from baseline to week 54 and week 80
o
Change in mean of 7-point profiles from baseline to week 54 and week 80
!
Before breakfast SMPG at week 54 and week 80
!
Change in patient reported outcome (PRO) scores (SF36, Experience of Treatment Benefits
and Barriers, Diabetes Treatment Satisfaction Questionnaire (DTSQ)) from baseline to
week 54 and week 80
* Key supportive secondary endpoint prospectively selected for disclosure (e.g. clinicaltrials.gov
and EudraCT)
Supportive secondary safety endpoints
!
Number of treatment emergent adverse events reported
o
from first dose of trial product to week 54
o
from week 54 to week 80
!
Number of treatment emergent hyperglycaemic episodes
o
from first dose of trial product to week 54
o
from week 54 to week 80
!
Number of treatment emergent episodes of diabetic ketoacidosis (DKA)
o
from first dose of trial product to week 54*
o
from week 54 to week 80
!
Number of subjects experiencing treatment emergent injection/infusion site reactions from
first dose of trial product and during treatment period (54 weeks) caused by:
o
NNC0114-0006/liraglutide/placebo injection/infusion
!
Number of treatment emergent hypoglycaemic episodes according to the American
Diabetes Association (ADA) and Novo Nordisk definitions
o
from first dose of trial product to week 54*
o
from week 54 to week 80
!
Change in body weight from baseline to week 54 and week 80
!
Diabetes complications (retinopathy and estimated glomeruli filtration rate) from baseline
to week 54 and week 80
!
Change in laboratory safety variables (haematology, biochemistry, coagulation, lipids, IgE,
urine dipsticks, cytokine panel, and hormones), vital signs, electrocardiograms (ECGs),
eye-examination and outcome of physical examination from baseline to week 54 and week
80
!
Change in anti-NNC0114-0006 antibodies from baseline to week 54 and week 80
!
Change in anti-liraglutide antibodies from baseline to week 54 and week 80
*Key supportive secondary endpoint prospectively selected for disclosure (e.g. clinicaltrials.gov

and EudraCT)
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
19 September 2018
Novo Nordisk
Trial ID: NN9828-4150
Version:
1.0
UTN: U1111-1154-7172 
Status:
Final
EudraCT No.: 2014-001215-39
Page:
8 of 28
Supportive secondary biomarker endpoints
!
Change in biomarker parameters from baseline to week 54 and week 80
o
Immune phenotyping of peripheral blood mononuclear cells (PBMC)  (the analyses
will include, but are not restricted to, the following populations):

NK subpopulations

Monocyte subpopulations

CD8+ & CD4+ subpopulations (e.g., anergy/exhaustion vs. activation;
memory, effector, regulatory cells; follicular helper (Tfh) & regulatory Tfh)
o
Total IL-21
o
Autoantibodies against glutamic acid decarboxylase 65 (GAD), zinc-transporter 8
(ZnT8), islet antigen-2 (IA2), insulin (IAA)
!
Change in serum vitamin D (1,25 dehydroxy-calciferol) from baseline to week 54 and week
80
Supportive secondary pharmacokinetic endpoints
NNC0114-0006:
!
AUCτ, NNC0114-0006, area under the NNC0114-0006 time-concentration curve over a dosing
interval at steady state (SS) (defined as after last dose)
!
Terminal half-life (t½) after last dose of NNC0114-0006
!
Vss, NNC0114-0006, the apparent volume of distribution of NNC0114-0006 at steady-state
!
CLss, NNC0114-0006, clearance of NNC0114-0006 at steady state
!
MRT, NNC0114-0006, the mean residence time of NNC0114-0006
!
RA,AUC, NNC0114-0006, accumulation ratio of NNC114-0006 defined as AUC48-54 weeks/AUC0-6
weeks
!
Ctrough, NNC0114-0006, observed NNC0114-0006 concentration prior to dosing of
NNC0114-0006 at steady state
!
C1h, NNC0114-0006, observed NNC0114-0006 concentration 1 hour after dosing of
NNC0114-0006 at steady state
The following pharmacokinetic endpoints for liraglutide will be derived after the last dose 
administered at week 54:
!
C liraglutide, liraglutide concentration at steady state
1.1.3
Type of trial
The trial is a randomised, multi-centre, multinational, placebo-controlled, double-dummy, double-
blind, efficacy, safety and PK CPOP trial in subjects with newly diagnosed T1DM with residual 
beta-cell function. The trial includes four parallel treatment groups, one with NNC0114-0006 12 
mg/kg i.v. every 6 weeks and liraglutide 1.8 mg s.c. daily, one with NNC0114-0006 12 mg/kg i.v. 
every 6 week, one with liraglutide 1.8 mg subcutaneously (s.c.) daily and, one placebo arm 
randomised in an even ratio. The randomisation will take place not more than 4 weeks from start of 
screening (V1). The exposure period for NNC0114-0006 and liraglutide in combination or alone is 
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
19 September 2018
Novo Nordisk
Trial ID: NN9828-4150
Version:
1.0
UTN: U1111-1154-7172 
Status:
Final
EudraCT No.: 2014-001215-39
Page:
9 of 28
54 weeks. The primary endpoint (C-peptide) is at week 54 as defined per U.S. FDA and EMA 
requirements1,2followed by a 26 weeks observation period. All groups will receive insulin 
treatment according to a treat-to-target (T-T-T) regimen throughout the entire trial. See )LJXUH±
for the schematic trial design.
Figure 1–1
Trial design
1.2
Flow-chart
Please refer to the trial protocol, Section 2.
The full PK profile consisting of 25 samples is only applicable for the first minimum 80 subjects. 
These subjects follows the flowchart listed in the protocol, sub-section 2.1 “Visit procedure for the 
first 80 randomised subjects only”. The remaining subjects will follow a reduced visit schedule. 
These subjects follows the flowchart listed in the protocol, sub-section 2.2 “Visit procedure for once 
80 subjects have been randomised”.
1.3
Scope of the statistical analysis plan
This SAP is based on the protocol “A randomised, double-blind, double-dummy, placebo-
controlled, parallel-group multi-centre clinical proof-of-principle trial in adult subjects with newly 
diagnosed type 1 diabetes mellitus investigating the effect of NNC0114-0006 and liraglutide on 
preservation of beta-cell function” version 8.0, including amendments no. 1, 2, 3, 4, 5, 6 and 7.
2
Statistical considerations
Based on the statistical model, treatment means or geometric means (LSMeans) and treatment 
comparisons (i.e. treatment differences or treatment ratios) will be presented with 95% confidence 
intervals (CI) and p-values for the two-sided test of no treatment difference. A significance level of 
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
19 September 2018
Novo Nordisk
Trial ID: NN9828-4150
Version:
1.0
UTN: U1111-1154-7172 
Status:
Final
EudraCT No.: 2014-001215-39
Page:
10 of 28
5% will be used. All pairwise treatment differences (or ratios) will be presented. No adjustment for 
multiple testing will be performed.
Some endpoints will be summarised for the treatment period, for the observation period and for the 
entire trial period (i.e. the treatment period together with the observation period)
The treatment period and the observation period will be derived for completed subjects as
!
The start of the treatment period will be the date of first trial product administration
!
The end of the treatment period will be the date of the visit at week 54 (i.e. the day of visit 
63)
!
The start of the observation period will be the day after the end of the treatment period
!
The end of the observation period will be the date of the last visit
For withdrawn subjects the date of last contact will be the maximum of the date of the last visit and 
the withdrawal date. The treatment period and the observation period will be derived for withdrawn 
subjects as
!
The start of the treatment period will be defined as described for completed subjects
!
The end of the treatment period will be as defined for competed subjects if this date is 
before or on the date of last contact. Otherwise the end of the treatment period will be the 
date of last contact
!
An observation period will only be defined if the date of last contact is after the end of the 
treatment period
o
The start of the observation period will be defined as for completed subjects
o
The end of the observation period will be the date of last contact
For endpoints evaluated as change from baseline and/or for baseline adjustment in the statistical 
analyses, baseline will be defined as the information recorded at the Visit 3 (randomisation). If no 
measurement is available at Visit 3, then the information recorded at Visit 2 will be used as the 
baseline. Furthermore, if no measurement is available at Visit 2, then the information recorded at 
Visit 1 will be used as the baseline.
In case an endpoint is assessed at visits other than baseline, week 6, 12, 18, 24, 30, 36, 42, 48, 54, 
65, and 80, values from the other visits will not be included in the mixed model for repeated 
measurements (MMRM).
As there is no previous experience with NNC0114-0006 in subjects with T1DM, the defined 
endpoints and analyses may be supplemented with additional endpoints or analyses such that a 
better evaluation of the effect and safety of NNC0114-0006 can be obtained.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
19 September 2018
Novo Nordisk
Trial ID: NN9828-4150
Version:
1.0
UTN: U1111-1154-7172 
Status:
Final
EudraCT No.: 2014-001215-39
Page:
11 of 28
2.1
Sample size calculation
This is a phase 2 trial and the first Novo Nordisk trial of NNC0114-0006 in subjects with newly 
diagnosed T1DM. Therefore the knowledge on treatment effects and on the standard deviation of 
the primary endpoint is limited. 
The statistical power calculations have been done under the following assumptions
!
The primary endpoint is AUC0-4h for a MMTT stimulated C-peptide concentration-time
curve at week 54 relative to baseline, i.e. AUC0-4h, C-peptide, 54w/AUC0-4h, C-peptide, baseline. The
primary endpoint will be log-transformed in the statistical analysis and this will be denoted
ln(AUC0-4h,C-peptide,∆54w). Thus, AUC0-4h, C-peptide,∆54w is the proportion of AUCC-peptide that is
preserved after 54 weeks relative to the level at baseline. E.g. a reduction of AUCC-peptide of
35% corresponds to a preservation of 65% and value of the ln(AUC0-4h,C -peptide,∆54w) is
ln(0.65)=-0.431.
!
The residual standard deviation of ln(AUC0-4h, C-peptide, Δ54w) in the model described above
may depend on the treatment. Based on the results of Herold et al.3 the standard deviation is
assumed to be 1 in the placebo group and 0.5 in the group treated with NNC0114-0006 in
combination with liraglutide.
!
The expected preservation in the placebo treated patients is 65%, based on the results of
Herold et al.3 who found a mean of 70% decline in AUCC-peptide over a 24-months period.
Assuming a linear decline, the mean 12-months decline would be 35%, i.e. a preservation
of 65%. The statistical power calculations have been done assuming three levels of
treatment effects for NNC0114-0006 in combination with liraglutide; a preservation of 85%
and 95% and 98%, respectively.
Table 2–1 shows the statistical power for the test of no treatment effect if the true mean 
preservation is 85%, 95% or 98% in the group treated with NNC0114-0006 in combination with 
liraglutide and 65% in the placebo group when the numbers of completers are 40, 60 or 80, 
respectively using a two-sided test and 5% level of significance. The rows corresponding to the 
chosen number of (completing) subjects are highlighted.
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Statistical Analysis Plan
CONFIDENTIAL
Date:
19 September 2018
Novo Nordisk
Trial ID: NN9828-4150
Version:
1.0
UTN: U1111-1154-7172 
Status:
Final
EudraCT No.: 2014-001215-39
Page:
12 of 28
Table 2–1
Power calculations
True treatment effect (preservation)
N (completers per group)
Statistical power
85%
40
0.320
85%
60
0.451
85%
80
0.566
95%
40
0.561
95%
60
0.740
95%
80
0.854
98%
40
0.628
98%
60
0.804
98%
80
0.903
Assuming a preservation of 98% and a SD of 0.5 for NNC0114-0006 in combination with 
liraglutide and a preservation of 65% and a SD of 1 for placebo, then the power will be 80.4% with 
60 subjects completing the trial in each of the two treatment arms.
2.2
Definition of analysis sets
The following analysis sets are defined in accordance with the ICH-E94 guidance:
!
The full analysis set (FAS) will include all randomised subjects. Only in exceptional cases 
subjects may be excluded from the FAS. In such cases the reason for exclusion 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’. 
!
The PK analysis set will include all randomised subjects following the flowchart for the 
first 80 randomised subjects only, with at least one valid PK measurement. Subjects in the 
PK analysis set will contribute to the evaluation ‘as treated’.
!
The safety analysis set will include all subjects receiving at least one dose of randomised 
treatment. Subjects in the safety analysis set will contribute to the evaluation ‘as treated’.
Analyses of efficacy and biomarker endpoints will be based on the FAS. Analyses of the PK 
endpoints will be based on the PK analysis set. Analyses of safety endpoints will be based on the 
safety analysis set.
Before the database is locked and ready for statistical analysis a review of all data will take place. 
Extreme values and outliers will be identified by the study group during programming and data 
review according to ICH-E94 using a fake randomisation. In addition, protocol deviations, which 
may potentially affect the results, will be identified and it will be evaluated if subjects and/or data 
should be excluded from analysis.
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Statistical Analysis Plan
CONFIDENTIAL
Date:
19 September 2018
Novo Nordisk
Trial ID: NN9828-4150
Version:
1.0
UTN: U1111-1154-7172 
Status:
Final
EudraCT No.: 2014-001215-39
Page:
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Obviously erroneous data points may be excluded from the analyses or re-analysed (in case of e.g. 
serum concentrations). The decision to re-analyse or exclude data points from the statistical analysis 
is the joint responsibility of the study group. Furthermore, the individual profiles for C-peptide and 
plasma glucose from the MMTT in the treatment phase will be examined prior to interim database 
lock to establish whether it is possible to calculate all endpoints. If samples that are important for 
the derivation of certain endpoints are missing, these endpoints will not be calculated and they will 
be excluded from the analysis. In these cases, the subjects, observations or endpoints to be excluded 
and the reason for their exclusion will be documented prior to interim database lock. Data that are 
not in scope for the interim database lock, including individual PK profiles, biomarkers, antibodies, 
and all data from the observation period may be examined after the interim database lock but before 
the full database lock. In cases where observations or endpoints are excluded from these data, it will 
be documented prior to the full database lock, and clearly stated if a decision was taken after 
randomisation code break. The subjects and observations excluded from analysis and the reason for 
exclusion will also be described in the clinical trial report.
The impact of protocol deviations and outliers may be investigated further in sensitivity analyses, if 
deemed relevant.
2.3
Primary endpoint
The primary endpoint is AUC0-4h for a MMTT stimulated C-peptide concentration-time curve at 
week 54 relative to baseline: AUC0-4h, C-peptide, 54w/AUC0-4h, C-peptide, baseline.
The AUC0-4h for MMTT stimulated C-peptide is derived at baseline and at 12, 24, 36, and 54 
weeks and is denoted AUC0-4h, C-peptide, t, where t is the time of the assessment. Thus, t=54 
weeks corresponds to the primary endpoint.
More specifically, AUC0-4h, C-peptide, t at time ‘t’ will be determined as the area from 0 to 4 hours 
under the C-peptide concentration profile after a MMTT using the trapezoidal method based on 
observed concentration values and actual measurement times. If the MMTT is stopped before 4 
hours due to hyperglycaemia or hypoglycaemia, the last measured C-peptide concentration will be 
carried forward for calculation of the primary endpoint. If the MMTT is stopped before 4 hours it 
will most likely be due to hyperglycaemia as hypoglycaemia is not expected when a high amount of 
carbohydrates are ingested. Using last observation carried forward (LOCF) will result in an 
overestimated AUC since the C-peptide response is expected to be at the maximum level during 
hyperglycaemia. Furthermore, the risk of hyperglycaemia during MMTT will be higher in the 
placebo group if the active treatments have an effect on beta-cell preservation. Thus, LOCF is 
considered as a conservative approach. In case the MMTT is stopped before 4 hours for reasons that 
are not due to hyperglycaemia or hypoglycaemia, the remaining C-peptide concentrations will be 
set to lloq/2.
Let yit denote the value of AUC0-4h, C-peptide,∀t evaluated relative to baseline at time t for subject i, i.e. 
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
19 September 2018
Novo Nordisk
Trial ID: NN9828-4150
Version:
1.0
UTN: U1111-1154-7172 
Status:
Final
EudraCT No.: 2014-001215-39
Page:
14 of 28
yit = AUC0-4h, C-peptide,∀t = AUC0-4h, C-peptide, t/AUC0-4h, C-peptide, baseline
log of yit will be analysed using an (MMRM) including all available assessments over time with 
treatment, stratum and sex as factors and ln(AUC0-4h, C-peptide, baseline) and age at baseline as covariates 
(see Table 2–2). The interaction between all variables and visit (week) will be included in the model
as fixed effects.
Table 2–2
Model terms for the statistical model for the primary endpoint
Model term
Description
ln(yit)
dependent variable, subject i, time t
ln(AUC0-4h, C-peptide, baseline)
fixed effect covariate with a visit dependent coefficient
Visit
fixed effect factor corresponding to time t=12w, 24w, 36w, 54w
Treatment
fixed effect interaction term between treatment and visit (i.e. the treatment effect is 
not assumed the same for all visits), with treatment as a factor with 4 levels: 
NNC0114-0006 in combination with liraglutide, NNC0114-0006, liraglutide and 
placebo 
Stratum
fixed effect interaction term between stratum and visit, with stratum as a factor with 
two levels according to non-fasting max C-peptide measurement during MMTT at 
Visit 2: 0.2-0.6 nmol/l and >0.6 nmol/l
Age
fixed effect covariate with a visit dependent coefficient
Sex
fixed effect interaction term between sex and visit
The variance-covariance matrix for the repeated measurements for each subject will be 
unstructured.
From the model, least square means (LSMeans) for each treatment group at selected time points, 
including week 54 will be estimated, and mean differences between treatment groups in log-
transformed AUC0-4h, C-peptide,∀t at these time points will be estimated. These estimates will be back-
transformed to the original scale to represent treatment (geometric) means and treatment (geometric 
mean) ratios with 95% CIs.
The primary endpoint will be summarised using descriptive statistics and presented graphically.
Sensitivity analyses of the primary endpoint
The following sensitivity analyses will be made
!
To assess the impact of the endpoints calculated from MMTT that is stopped before 4 hours 
due to hyperglycaemia or hypoglycaemia, a sensitivity analysis will be performed 
excluding these endpoints.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
19 September 2018
Novo Nordisk
Trial ID: NN9828-4150
Version:
1.0
UTN: U1111-1154-7172 
Status:
Final
EudraCT No.: 2014-001215-39
Page:
15 of 28
!
To assess the impact of the endpoints calculated from MMTT profile that includes imputed 
values, a sensitivity analysis will be performed excluding these endpoints.
!
A sensitivity analysis will be performed excluding endpoints calculated from the MMTT, 
where the date of the MMTT is more than one day after the last liraglutide dosing.
!
An analysis using last observation carried forward (LOCF) of the primary endpoint. The 
analysis will be made using a normal linear regression model for the log-transformed 
primary endpoint with treatment, stratum and sex as fixed factors and age and baseline 
value (log-transformed) as covariates.
!
An analysis based on the subjects completing the treatment period (i.e. completing the visit 
at week 54). The analysis will be made using a normal linear regression model for the log-
transformed primary endpoint with treatment, stratum and sex as fixed factors and age and 
baseline value (log-transformed) as covariates
!
In case the assumption of equal variance-covariance between the treatments turns out not to 
be reasonable a sensitivity analysis will be added where the variance-covariance matrix for 
the repeated measurements for each subject will depend on treatment.
Exploratory analyses
Effect of stratum on the primary endpoint
An exploratory analysis will be made to investigate a potential interaction between treatment and 
stratum for the primary endpoint. The analysis will be made by adding the interaction between 
stratum, treatment and visit as a factor in the mixed model for repeated measurements (MMRM) 
described for the primary endpoint. The treatment means and the treatment ratios at selected time 
points including week 54 will be presented with 95% CIs for each stratum separately. 
Effect of biomarkers on the primary endpoint
The effect of the biomarkers at baseline and high resolution HLA (class I) genotyping on the 
primary endpoint will be explored one variable at a time.
For continuous variables, the analysis will be made by adding the biomarker at baseline (log-
transformed) as a fixed effect covariate with a coefficient that depends on visit and treatment to the 
MMRM described for the primary endpoint. The estimated effect of the variable at selected time 
points including week 54 will be presented with a 95% CI for each treatment.
Effect of liraglutide concentration on the primary endpoint
An exploratory analysis will be made to investigate a potential effect of the concentration of 
liraglutide on the primary endpoint using data from the two groups of subjects treated with 
liraglutide. This analysis will be made by adding the log-transformed concentration of liraglutide 
measured on the date corresponding to the last MMTT as a covariate in the analysis using LOCF for 
the primary endpoint.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
19 September 2018
Novo Nordisk
Trial ID: NN9828-4150
Version:
1.0
UTN: U1111-1154-7172 
Status:
Final
EudraCT No.: 2014-001215-39
Page:
16 of 28
2.4
Secondary endpoints
2.4.1
Supportive secondary endpoints
2.4.1.1
Efficacy endpoints
Other endpoints derived from the mixed meal tolerance test
The other endpoints based on the mixed meal tolerance test will be derived from the individual C-
peptide concentration-time curves and from the individual plasma glucose concentration-time 
curves. The AUC endpoints will be derived using the same approach as described for the primary 
endpoint. The Cmax endpoints will be derived as the ratio between the Cmax at the relevant time 
points.
The endpoints will be analysed using a similar model as applied for the primary endpoint except 
that the corresponding value at baseline will be included as a covariate. 
The endpoints will be summarised using descriptive statistics and presented graphically. The C-
peptide concentration-time curves and the plasma glucose concentration-time curves will be 
presented graphically. 
Insulin dose
The total daily insulin dose will be derived as the average of the doses per kg body weight reported 
on the three days prior to visit 3, 63 and 89. 
The endpoints will be analysed using normal linear regression model for the endpoint with 
treatment, stratum and sex as fixed factors and age and baseline value as covariates. Treatment 
means (LSMeans) and treatment differences will be presented with 95% CIs. The analysis will not 
account for missing data.
The endpoints will be summarised using descriptive statistics and presented graphically.
Number of insulin injections
The number of insulin injections will be derived as the average of the reported number on the three 
days prior to visit 3, 63 and 89. The endpoints will be summarised using descriptive statistics.
Number of weeks off bolus insulin
The number of weeks the subject is off bolus insulin will be derived based on the question in the 
CRF “Has the subject stopped taking bolus insulin since last visit”. The endpoint will be 
summarised using descriptive statistics.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
19 September 2018
Novo Nordisk
Trial ID: NN9828-4150
Version:
1.0
UTN: U1111-1154-7172 
Status:
Final
EudraCT No.: 2014-001215-39
Page:
17 of 28
HbA1c, FPG, fasting C-peptide and fasting glucagon
The HbA1c and FPG endpoints will be analysed using a similar model as described for the primary 
endpoint except that the corresponding value at baseline will be included as a covariate and the 
analysis will be made on the original scale (i.e. without the log-transformation). Consequently, 
treatment means (LSMeans) and treatment differences will be presented with 95% CIs.
The fasting C-peptide and fasting glucagon endpoints will be analysed using a similar model as 
described for the primary endpoint except that the corresponding value at baseline will be included 
as a covariate. The values will be log-transformed prior to analysis, i.e. the change will be 
calculated for the log-transformed data and the log-transformed value at baseline will be included as 
a covariate.
In addition to the endpoints listed in Section 1.1.2.1, the following binary endpoints are derived for 
all subjects at baseline, week 54 and week 80:
!
Hba1c < 7.0 %. 
!
Hba1c <= 6.5 %. 
All the endpoints will be summarised using descriptive statistics and presented graphically.
Self-measured plasma glucose profiles
The 7-point SMPG profile will include a pre-meal measurement and a measurements 90 minutes 
after start of meal for breakfast lunch and dinner as well a measurement at bedtime.
The 4-point SMPG profile will be used for titration of the insulin dose and will include a pre-meal 
measurement for breakfast, lunch and dinner and a measurement at bedtime.
7-point SMPG profiles at week 54 and week 80
The 7-point SMPG profiles will be summarised using descriptive statistics and presented 
graphically.
Change in prandial increment and change in mean of 7-point SMPG profile
The prandial increment at a meal will be calculated as the post-meal measurement minus the pre-
meal measurement. The prandial increment will be calculated for breakfast, lunch and dinner 
separately. The average over the three meals will also be calculated. The mean of the 7-point SMPG 
profile will be calculated as the mean of all 7 points.
The endpoints will be analysed using a similar model as described for the primary endpoint except 
that the corresponding value at baseline will be included as a covariate and the analysis will be 
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
19 September 2018
Novo Nordisk
Trial ID: NN9828-4150
Version:
1.0
UTN: U1111-1154-7172 
Status:
Final
EudraCT No.: 2014-001215-39
Page:
18 of 28
made on the original scale. Consequently, treatment means (LSMeans) and treatment differences 
will be presented with 95% CIs.
The endpoints will be summarised using descriptive statistics and presented graphically.
Before breakfast SMPG
The within-subject variability will be evaluated using the before breakfast measurements from 4-
point SMPG profiles at week 54 and week 80.
A normal linear mixed effect model will be fitted to the before breakfast SMPG values at week 54. 
The model will include treatment, sex and stratum as fixed factors, age as a covariate and subject as 
a random effect. The model will assume independent within- and between-subject error variances 
depending on treatment. The within-subject variance will be presented for each treatment with the 
95% CI. The analysis will not account for missing data.
The same analysis will be made for the before breakfast SMPG values at week 80.
PRO endpoints
Data collected with the PRO questionnaires (SF-36v2, Experience of Treatment Benefits and 
Barriers, and DTSQ (status)) will be scored according to the instruments’ respective scoring 
algorithms into the following endpoints (domains)
!
For Experience of Treatment Benefits and Barriers:
o
’Perceived benefits’
o
’Perceived barriers’
!
For Diabetes Treatment Satisfaction Questionnaire (status):
o
’Treatment satisfaction’
o
‘Perceived frequency of hypoglycaemia’
o
‘Perceived frequency of hyperglycaemia’
!
For SF-36v2:
o
‘Physical Component Summary’ score
o
‘Mental Component Summary’ score
o
‘Physical functioning’
o
‘Role-physical’
o
‘Bodily pain’
o
‘General health’
o
‘Vitality’
o
‘Social functioning’
o
‘Role-emotional’
o
’Mental health’
The PRO endpoints will be summarised using descriptive statistics.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
19 September 2018
Novo Nordisk
Trial ID: NN9828-4150
Version:
1.0
UTN: U1111-1154-7172 
Status:
Final
EudraCT No.: 2014-001215-39
Page:
19 of 28
Biomarker endpoints
The biomarker endpoints will be analysed using a similar model as described for the primary 
endpoint except that the corresponding value at baseline will be included as a covariate and the 
analysis will be made on the original scale. Consequently, treatment means (LSMeans) and 
treatment differences will be presented with 95% CIs. If the model assumptions are not fulfilled 
then transformations of the data will be considered, e.g. the change will be calculated on the log-
transformed data and the log-transformed value at baseline will be included as a covariate.
The biomarker endpoints will be summarised using descriptive statistics and presented graphically.
2.4.1.2
Safety endpoints
Adverse events, DKA episodes and infusion/injection site reactions
All adverse events (including DKA episodes and infusion/injection site reactions) will be coded 
using the latest version of Medical Dictionary for Regulatory Activities (MedDRA). An adverse 
event will be defined as treatment emergent if the onset of the adverse event occurs on or after the 
first day of trial product administration.
Treatment emergent adverse events will be summarised by system organ class, preferred term, 
seriousness, severity and relation to trial product. Separate summaries will be made for treatment 
emergent DKA episodes and for treatment emergent infusion/injection site reactions. The 
summaries will be made for the treatment period, for the observation period and for the entire trial 
period. 
Additional information will be recorded on special eCRF pages for selected adverse events. This 
information will be listed.
All adverse events will be listed and separate listings will be made for DKA episodes and 
infusion/injection site reactions.
Hyperglycaemic episodes
Hyperglycaemic episodes will be defined as treatment emergent if the onset occurs on or after the 
first day of trial product administration.
The number of treatment emergent hyperglycaemic episodes will be summarised by treatment. The 
summaries will be made for the treatment period, for the observation period and for the entire trial 
period.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
19 September 2018
Novo Nordisk
Trial ID: NN9828-4150
Version:
1.0
UTN: U1111-1154-7172 
Status:
Final
EudraCT No.: 2014-001215-39
Page:
20 of 28
Hypoglycaemic episodes
Classification of Hypoglycaemia: 
Treatment emergent: hypoglycaemic episodes will be defined as treatment emergent if the onset of 
the episode occurs on or after the first day of trial product administration, and no later than 1 day 
after the date of last contact.
Nocturnal hypoglycaemic episodes: are episodes occurring between 00:01 and 05.59 both inclusive.
Hypoglycaemic episodes are classified according to the Novo Nordisk classification of 
hypoglycaemia (see Figure 2–1) and the ADA classification of hypoglycaemia (see Figure 2–2).
Novo Nordisk classification of hypoglycaemia
In normal physiology, symptoms of hypoglycaemia occur below a plasma glucose level of 3.1 
mmol/l (56 mg/dl)5.Therefore, Novo Nordisk has included hypoglycaemia with plasma glucose 
levels below this cut-off point in the definition of blood glucose (BG) confirmed hypoglycaemia.
Novo Nordisk uses the following classification (see Figure 2–1) in addition to the ADA 
classification: 
!
Severe hypoglycaemia according to the ADA classification6
!
Symptomatic BG confirmed hypoglycaemia: An episode that is BG confirmed by plasma 
glucose value <3.1 mmol/l (56 mg/dl) with symptoms consistent with hypoglycaemia.
!
Asymptomatic BG confirmed hypoglycaemia: An episode that is BG confirmed by plasma 
glucose value <3.1 mmol/l (56 mg/dl) without symptoms consistent with hypoglycaemia.
!
Severe or BG confirmed symptomatic hypoglycaemia: An episode that is severe according 
to the ADA classification6 or BG confirmed by a plasma glucose value <3.1 mmol/l (56 
mg/dl) with symptoms consistent with hypoglycaemia. 
!
BG confirmed hypoglycaemia: An episode that is BG confirmed by a plasma glucose value 
<3.1 mmol/l (56 mg/dl) with or without symptoms consistent with hypoglycaemia. 
!
Severe or BG confirmed hypoglycaemia: An episode that is severe according to the ADA 
classification6 or BG confirmed by a plasma glucose value <3.1 mmol/l (56 mg/dl) with or 
without symptoms consistent with hypoglycaemia.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
19 September 2018
Novo Nordisk
Trial ID: NN9828-4150
Version:
1.0
UTN: U1111-1154-7172 
Status:
Final
EudraCT No.: 2014-001215-39
Page:
21 of 28
Hypoglycaemic
episode
PG ≤ 3.9 mmol/l 
(70 mg/dl) 
or 
Alleviation of 
symptoms 
or
Seizure, coma or 
fatal 
SMBG
measurement
PG < 3.1 mmol/l
(56 mg/dl)
with symptoms
PG < 3.1 mmol/l
(56 mg/dl)
without
symptoms
Symptomatic BG 
confirmed 
hypoglycaemia
Asymptomatic BG 
confirmed 
hypoglycaemia
Yes
No
Severe or 
BG confirmed 
symptomatic 
hypoglycaemia
BG confirmed 
hypoglycaemia
Severe or BG 
confirmed 
hypoglycaemia
Note: Glucose measurements are performed with capillary blood calibrated to plasma equivalent glucose values
Subject 
able to 
treat him/
herself
Severe 
hypoglycaemia
(ADA 2013)
Figure 2–1
Novo Nordisk classification of hypoglycaemia
ADA classification6 of hypoglycaemia 
!
Severe hypoglycaemia: An episode requiring assistance of another person to actively 
administer carbohydrate, glucagon, or take other corrective actions. Plasma glucose 
concentrations may not be available during an event, but neurological recovery following 
the return of plasma glucose to normal is considered sufficient evidence that the event was 
induced by a low plasma glucose concentration.
!
Asymptomatic hypoglycaemia: An episode not accompanied by typical symptoms of 
hypoglycaemia, but with a measured plasma glucose concentration ≤ 3.9 mmol/l (70 
mg/dl).
!
Documented symptomatic hypoglycaemia: An episode during which typical symptoms of 
hypoglycaemia are accompanied by a measured plasma glucose concentration ≤ 3.9 mmol/l 
(70 mg/dl).
!
Pseudo-hypoglycaemia: An episode during which the person with diabetes reports any of 
the typical symptoms of hypoglycaemia with a measured plasma glucose concentration > 
3.9 mmol/l (70 mg/dl) but approaching that level.
!
Probable symptomatic hypoglycaemia: An episode during which symptoms of 
hypoglycaemia are not accompanied by a plasma glucose determination but that was 
presumably caused by a plasma glucose concentration ≤ 3.9 mmol/l (70 mg/dl).
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
19 September 2018
Novo Nordisk
Trial ID: NN9828-4150
Version:
1.0
UTN: U1111-1154-7172 
Status:
Final
EudraCT No.: 2014-001215-39
Page:
22 of 28
Hypoglycaemic 
episode 
PG ≤ 3.9 mmol/l 
(70 mg/dl) 
or 
Alleviation of 
symptoms 
or
Seizure, coma or 
fatal 
SMBG
measurement
Asymptomatic 
hypoglycaemia
Documented 
symptomatic 
hypoglycaemia
Pseudo-
hypoglycaemia
Probable 
symptomatic 
hypoglycaemia
No
Yes
No measurement 
with symptoms
PG > 3.9 mmol/l 
(70 mg/dl)
with symptoms
PG ≤3.9 mmol/l 
(70 mg/dl)
with symptoms
PG ≤3.9 mmol/l 
(70 mg/dl)
without symptoms
No
Yes
Note: Glucose measurements are performed with capillary blood calibrated to plasma equivalent glucose values
Subject 
able to 
treat him/
herself
Severe 
hypoglycaemia
(ADA 2013)
Figure 2–2
ADA classification of hypoglycaemia
Analysis of hypoglycaemic episodes
The number of treatment emergent hypoglycaemic episodes will be summarised by treatment. 
Separate summaries will be made for the Novo Nordisk and for the ADA classifications and for 
nocturnal episodes. The summaries will be made for the treatment period, for the observation period 
and for the entire trial period.
The total number of treatment emergent severe or BG confirmed symptomatic hypoglycaemic 
episodes will be analysed using a negative binominal regression model with a log link function, and 
the logarithm of the exposure time as an offset. The model will include treatment, stratum and sex 
as factors and age as a covariate. The treatment ratio will be estimated and the corresponding two-
sided 95% CI will be calculated. The analysis will be made for the treatment period, for the 
observation period and for the entire trial period.
The total number of treatment emergent nocturnal severe or BG confirmed symptomatic 
hypoglycaemic episodes will be analysed using the same model as above. The analysis will be made 
for the treatment period, for the observation period and for the entire trial period.
To the extent that data allows, additional analyses may be performed for the other classes of 
hypoglycaemic episodes using the same model as described above.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
19 September 2018
Novo Nordisk
Trial ID: NN9828-4150
Version:
1.0
UTN: U1111-1154-7172 
Status:
Final
EudraCT No.: 2014-001215-39
Page:
23 of 28
Sensitivity analyses will be made (for each analysed class of hypoglycaemia) comparing number 
and individual rates of hypoglycaemic episodes, respectively, using the Wilcoxon-Mann-Whitney 
method. This will be made for all different pairs of treatments.
Body weight
The body weight endpoints will be analysed using a similar model as described for the primary 
endpoint except that the body weight at baseline will be included as a covariate and the analysis will 
be made on the original scale. Consequently, treatment means (LSMeans) and treatment differences 
will be presented with 95% CIs.
Body weight endpoints will be summarised using descriptive statistics and presented graphically.
Diabetes complications, eye examination and physical examination
The eGFR endpoint will be log-transformed and analysed using normal linear regression model 
with treatment, stratum and sex as fixed factors and age and baseline value as covariates. Treatment 
means (LSMeans) and treatment ratio for the back-transformed results will be presented with 95% 
CIs. The analysis will not account for missing data.
All endpoints will be summarised. The endpoints for eGFR will be presented graphically.
Laboratory safety variables (haematology, biochemistry, coagulation, lipids, IgE, urine 
dipsticks, cytokine panel and hormones)
The laboratory safety variables will be flagged if outside the reference range and abnormal values 
will be listed.
All endpoints for the laboratory safety variables will be summarised and the numerical variables 
will be presented graphically.
The endpoints for amylase and lipase will be analysed using a similar model as described for the 
primary endpoint except that the corresponding value at baseline will be included as a covariate. 
The individual values will be log-transformed prior to analysis, i.e. the change will be calculated on 
the log-transformed data and the log-transformed value at baseline will be included as a covariate. 
The endpoints for TSH, IgE and cytokine panel will be analysed using a similar model as described
for the primary endpoint except that the corresponding value at baseline will be included as a 
covariate and the analysis will be made on the original scale. Consequently, treatment means 
(LSMeans) and treatment differences will be presented with 95% CIs. If the model assumptions are 
not fulfilled then transformations of the data will be considered, e.g. the change will be calculated 
on the log-transformed data and the log-transformed value at baseline will be included as a 
covariate.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
19 September 2018
Novo Nordisk
Trial ID: NN9828-4150
Version:
1.0
UTN: U1111-1154-7172 
Status:
Final
EudraCT No.: 2014-001215-39
Page:
24 of 28
Vital signs and ECG
The systolic blood pressure, diastolic blood pressure and pulse endpoints will be analysed using a 
similar model as described for the primary endpoint except that the corresponding value at baseline 
will be included as a covariate and the analysis will be made on the original scale. Consequently, 
treatment means (LSMeans) and treatment differences will be presented with 95% CIs.
All endpoints will be summarised. The numerical endpoints will be presented graphically.
Anti-NNC0114-0006 antibodies and anti-liraglutide antibodies
All endpoints will be summarised and presented graphically.
2.4.1.3
Pharmacokinetic endpoints
The PK endpoints described in Table 2–3 will be derived from the individual NNC0114-0006 
concentration-time curves after the first dose and after the last dose of NNC0114-0006. 
Furthermore, the trough concentration prior to dosing and the concentration 1 hour after dosing will 
be determined for NNC0114-0006 and the liraglutide concentration will be determined for 
liraglutide at the visits specified in the protocol, Section 2.
Table 2–3
Definition and calculation of PK endpoints
Endpoint
Description
Calculation
AUCτ, NNC0114-0006
Area under the NNC0114-0006 
concentration-time curve over a dosing 
interval at steady state (SS) (defined as 
after last dose)
AUCτ, NNC0114-0006 will be derived as the area 
under the concentration-time curve using the 
linear trapezoidal technique based on observed 
values and actual measurement times between 0 
and 6 weeks (after the last dose).
Missing values will be imputed using linear 
interpolation, possibly using measurements after 
6 weeks. If the end time of the interval (i.e. 6 
weeks) is after the time of the last quantifiable 
concentration, tz, and the terminal rate constant, 
λz, can be determined then AUCτ, NNC0114-0006 will 
be derived as the sum of AUC0-tz, NNC0114-0006 and 
AUCtz-6 weeks, NNC0114-0006, where 
AUCtz-6 weeks,NNC0114-0006 will be approximated 
using estimated values from the linear regression 
model applied for estimation of λz. If λz cannot be 
determined, then AUC0-tz, NNC0114-0006 will be used
instead of AUCτ, NNC0114-0006.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
19 September 2018
Novo Nordisk
Trial ID: NN9828-4150
Version:
1.0
UTN: U1111-1154-7172 
Status:
Final
EudraCT No.: 2014-001215-39
Page:
25 of 28
Endpoint
Description
Calculation
λz
Terminal rate constant for NNC0114-
0006 (this is not an endpoint but it is 
used for calculation of some 
endpoints)
The terminal rate constant λz will be determined 
through linear regression with the logarithm to 
concentration as the response variable and actual 
measurement time as the explanatory variable. 
Valid observations from the terminal part of the 
curve, which is approximately linear, will be used 
for the determination. 
t½
Terminal serum half-life after last dose 
of NNC0114-0006
Calculated as log(2)/λz
Vss, NNC0114-0006
The apparent volume of distribution of 
NNC0114-0006 at steady-state
Calculated as MRTNNC0114-0006 * CLSS, NNC0114-0006
CLss, NNC0114-0006
Clearance of NNC0114-0006 at steady 
state
Calculated as dose/AUCτ, NNC0114-0006
MRTNNC0114-0006
The mean residence time of 
NNC0114-0006
Calculated as
MRT
= AUMC + τ ∗AUC
AUC
where
AUC = AUC + AUC −AUC
and
AUMC = 
( −)( + )


RA,AUC, NNC0114-0006
Accumulation ratio of NNC114-0006 
defined as AUC48-54 weeks/AUC0-6 weeks
AUC48-56 weeks will be calculated as described for 
AUCτ, NNC0114-0006.
AUC0-6 weeks will be calculated using a similar 
approach except that extrapolation using λz will 
not be made
The PK endpoints will be summarised using descriptive statistics. The PK data will be presented 
graphically.
2.4.2
Interim analysis
No formal interim analysis has been planned. However, an internal Novo Nordisk analysis is to be 
conducted after global last patient last treatment (LPLT) (visit 63) to inform on future clinical trials. 
An additional database lock (DBL) will be performed, when all patients have completed the main 
phase of the trial, i.e. after LPLT at visit 63. After the additional DBL, Novo Nordisk will become 
unblinded, while the trial investigators and patients will remain blinded throughout the entire trial.
3
Changes to the statistical analyses planned in the protocol
The below changes are made prior to the randomisation code break at the interim database lock:
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
19 September 2018
Novo Nordisk
Trial ID: NN9828-4150
Version:
1.0
UTN: U1111-1154-7172 
Status:
Final
EudraCT No.: 2014-001215-39
Page:
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!
Various minor changes in wording done for clarification.
!
The end of the treatment period is changed from the day before the visit at week 54 to the 
date of the visit at week 54, to ensure that the observations at end of treatment (Visit 63) 
gets assigned to the treatment period.
!
Due to the change in assessments between the two flowcharts, it has been added that in case 
an endpoint is assessed at visits other than baseline, week 6, 12, 18, 24, 30, 36, 42, 48, 54, 
65, and 80, values from the other visits will not be included in the MMRM.
!
Subjects in the full analysis set will contribute ‘as randomised’ and not ‘as treated’ as per 
the ITT principle.
!
The definition of the PK analysis set has been updated to include randomised subjects 
following the flowchart for the first 80 randomised subjects only.
!
The following paragraph has been re-written to specify that decisions on data that are not in 
scope for the interim database lock can be taken after randomisation code break.
o
Furthermore, the individual profiles for C-peptide and plasma glucose from the 
MMTT in the treatment phase will be examined prior to interim database lock to 
establish whether it is possible to calculate all endpoints. If samples that are 
important for the derivation of certain endpoints are missing, these endpoints will not 
be calculated and they will be excluded from the analysis. In these cases, the 
subjects, observations or endpoints to be excluded and the reason for their exclusion 
will be documented prior to interim database lock. Data that are not in scope for the 
interim database lock, including individual PK profiles, biomarkers, antibodies and 
all data from the observation period may be examined after the interim database lock 
but before the full database lock. In cases where observations or endpoints are 
excluded from these data, it will be documented prior to the full database lock, and 
clearly stated if a decision was taken after randomisation code break.
!
Specification on how to derive the primary endpoint in case the MMTT is stopped before 4 
hours for reasons that are not due to hyperglycaemia or hypoglycaemia has been added:
o
In case the  MMTT is stopped before 4 hours for reasons that are not due to 
hyperglycaemia or hypoglycaemia, the remaining C-peptide concentrations will be 
set to lloq/2. 
!
The description of the stratification variable has been updated from non-fasting C-peptide 
measurement at screening to non-fasting peak C-peptide measurement during MMTT at 
Visit 2 in alignment with protocol amendment 2.
!
In the analysis of the primary endpoint, it has been deleted, that the variance-covariance 
matrix may depend on treatment, if an assumption of equal variance-covariance matrix 
between treatments turns out not to be reasonable. Instead it has been included that a 
sensitivity analysis where the variance-covariance matrix depends on treatment will be 
added if an assumption of equal variance-covariance matrix between treatments turns out 
not to be reasonable.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
19 September 2018
Novo Nordisk
Trial ID: NN9828-4150
Version:
1.0
UTN: U1111-1154-7172 
Status:
Final
EudraCT No.: 2014-001215-39
Page:
27 of 28
!
Update of the first sensitivity analysis to specify that it is the endpoints calculated from 
MMTT stopped before 4 hours due to hyperglycaemia or hypoglycaemia that are excluded 
from the analysis, and not all the data for that subject.
!
Sensitivity analysis added where endpoints calculated from MMTT profile that includes 
imputed values is excluded.
!
Sensitivity analysis added where endpoints calculated from the MMTT, where the date of 
the MMTT is more than one day after the last liraglutide dosing is excluded.
!
In the analysis exploring the effect of the different biomarkers on primary endpoint, the 
description of the analysis for categorical biomarkers has been deleted, as all biomarkers 
are continuous.
!
In the exploratory analysis that investigates a potential effect of the concentration of 
liraglutide on the primary endpoint, it has been specified that the liraglutide concentration 
should be measured at the date corresponding to the MMTT, and not just the visit 
corresponding to the MMTT. The specification is done as the MMTT can be re-scheduled
within 1-10 days. 
!
In alignment with the endpoint description in Section 1.1.2.2, it is specified that the 
endpoint for total daily insulin dose is derived per kg body weight. 
!
As only the insulin doses prior to visit 3, 63 and 89 will be transferred from the eDiary (as 
per the trial data handling plan), the description of the endpoints has been updated, and the 
statistical analysis has been changed from a MMRM to a normal regression model:
o
The total daily insulin dose will be derived as the average of the doses reported on 
the three days prior to visit 3, 63 and 89. 
o
The endpoints will be analysed using normal linear regression model for the 
endpoint with treatment, stratum and sex as fixed factors and age and baseline value 
as covariates. Treatment means (LSMeans) and treatment differences will be 
presented with 95% CIs. The analysis will not account for missing data.
The number of insulin injections will be derived as the average of the reported 
number on the three days prior to visit 3, 63 and 89.
!
As only the insulin doses prior to visit 3, 63 and 89 will be transferred from the eDiary, the 
calculation of the endpoint “The number of weeks the subject is off bolus insulin” is not 
derived based on the dose information in the eDiary as originally planned, but based on the 
question in the CRF “Has the subject stopped taking bolus insulin since last visit”.  
!
The following analysis has been deleted in alignment with standard in GLP-1 trials:
o
A normal linear mixed effect model will be fitted to the 7-point SMPG profile data at 
week 54. The model will include treatment, time-point, the interaction between 
treatment and time-point, sex and stratum as fixed factors, age as a covariate and 
subject as a random effect. The variance-covariance matrix will be unstructured and 
may depend on treatment if an assumption of equal variance-covariance matrix 
between treatments turn out not to be reasonable. From this model the treatment 
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
19 September 2018
Novo Nordisk
Trial ID: NN9828-4150
Version:
1.0
UTN: U1111-1154-7172 
Status:
Final
EudraCT No.: 2014-001215-39
Page:
28 of 28
differences at each time-point will be estimated and explored. The same analysis will 
be made using the 7-point SMPG profile data at week 80
!
For the analysis of within-subject variability of the before breakfast SMPG, it has been 
deleted that the 95% CI will be calculated using the delta method. Furthermore it has been 
clarified that the analysis will not account for missing data. 
!
As eGFR is only assessed at visit 1, 63 and 89, the statistical analysis has been changed 
from a MMRM to a normal regression model. Furthermore, it has been specified that the 
analysis will be done for the log-transformed endpoint: 
o
The eGFR endpoint will be log-transformed and analysed using normal linear 
regression model with treatment, stratum and sex as fixed factors and age and 
baseline value as covariates. Treatment means (LSMeans) and treatment ratio for the 
back-transformed results will be presented with 95% CIs. The analysis will not 
account for missing data.
!
Added:
o
In addition to the endpoints listed in Section 1.1.2.1, the following binary endpoints 
are derived for all subjects at baseline, week 54 and week 80:

HbA1c < 7.0 %. 

HbA1c <= 6.5 %. 
4
References
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Treatment and Prevention, Draft Guidance. 13 Feb 2008.
2. EMA/CPMP/EWP/1080/00 Rev.1 Guideline on clinical investigation of medicinal products in 
the treatment of diabetes mellitus. 15 Nov 2012. 
3. Herold KC, Gitelman SE, Ehlers MR, Gottlieb PA, Greenbaum CJ, Hagopian W et al. 
Teplizumab (anti-CD3 mAb) treatment preserves C-peptide responses in patients with new-
onset type 1 diabetes in a randomized controlled trial: metabolic and immunologic features at 
baseline identify a subgroup of responders. Diabetes 2013; 62(11):3766-3774.
4. ICH E9 guidelines: Statistical principles for clinical trials, step 4 version, 1998, 
CPMP/ICH/363/96.  1-35. 5 Feb 1998. 
5. Schwartz NS, Clutter WE, Shah SD, Cryer PE. Glycemic thresholds for activation of glucose 
counterregulatory systems are higher than the threshold for symptoms. J Clin Invest 1987; 
79(3):777-781.
6. 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):1384-1395.
CONFIDENTIAL