Clinical trial NCT03377699
Conditions: Diabetes Diabetes Mellitus, Type 1
Sponsor: Novo Nordisk A/S
Start date: 2017-11-22; Completion date: 2020-12-17
Enrollment: 225 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The investigators are doing this study to see the effect of insulin degludec in pregnant women with type 1 diabetes, and if it is safe to use. In this study the medicine insulin degludec is compared to another medicine called insulin detemir. Participants will either get insulin degludec or insulin detemir and take it together with a medicine called insulin aspart - which treatment participants get is decided by chance. Participants will get pre-filled insulin pens. Participants will need to take blood sugar measurements several times a day. The study will last between 10 and 25 months depending on whether participants are already pregnant when they join the study. The number of visits and the tests ( for example blood and urine samples and ultrasound scans) the participants will have also depends on whether they are pregnant at study start.

Detailed description:

Arms: arm 1: Insulin Degludec once daily and Insulin Aspart 2-4 times daily arm 2: Insulin Determir once daily or twice daily and Insulin Aspart 2-4 times daily
Interventions: intervention 1: Insulin degludec intervention 2: Insulin Aspart intervention 3: Insulin detemir
Intervention descriptions: intervention 1: Injection for subcutaneous (s.c., under the skin) use once daily. The total trial duration for subjects will be maximum 25 months intervention 2: Injection for subcutaneous (s.c., under the skin) use 2-4 times daily with meals. The total trial duration for subjects will be maximum 25 months intervention 3: Injection for subcutaneous (s.c., under the skin) use, once daily or twice daily. The total trial duration for subjects will be maximum 25 months

Protocol documents:
Prot_000.pdf: 
Cover Page for Protocol 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT03377699 
Sponsor trial ID: 
NN1250-4300 
Official title of study: 
A trial comparing the effect and safety of insulin degludec 
versus insulin detemir, both in combination with insulin 
aspait, in the treatment of pregnant women with type 1 
diabetes 
Document date* 
31 May 2021 
*Document date refers to the date on which the document was most recently updated. 
Note: The date in the header of Page 2 is the date of compilation of the documents and not of an update to content. 


Insulin degludec 
Tri~I ID: NN1250-4300 
Clinical Trial Report 
Appendix 16.1.1 
16.1.1 Protocol and protocol amendments 
List of contents 
Date: 
Version: 
Status: 
31 M~y 2021 
Novo Nord/.sJr 
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Final 
Protocol ............................................................................................................................................... Link 
Appendtx A ......................................................................................................................................... Litllc 
Appendtx B ......................................................................................................................................... Litllc 
AU-achment I and II ........................................................................................................................... Litllc 
Protocol amendment 1 IT.................................................................................................................. Link 
Protocol amendment 3 IT.................................................................................................................. Link 
Redacted protocol 
Includes redaction of personal identifiable information onf.v. 


Protocol 
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Protocol 
EXPECT 
Trial ID: NN1250-4300 
Updated protocol including: 
Protocol, final ven,ion 1.0 dated 24 May 2017 
Global Amendment no. 1, version 1.0 dated 23 Febt1111.ry 2018 
Global Amendment no. 3, ,·ersion 1.0 dated 03 May 2019 
Global Amendment no. 4, version 1.0 dated 17 December 2020 
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A trial comparing the effect and safety of insulin degludec versus 
insulin detemir, both in combination with insulin aspart, in the 
treatment of pregnant women with type 1 diabetes 
Tdal phase: 3b 
This Ql;)Qfoi@atia! document is the property of Novo Nordisk. NQ Y.ilfl!Wlishoo iefQrm-atiga QQAl~@d ~i:@al may b~ 
d~QIQ&~d YAUIQllt pt:jgr v.q:i1t@a apprn,1al foom ~IQVQ }lgf-disk. AcQtl<66 le 1.bis GGQ'lllR~l 1~"6t b@ r~&tilQl~d lQ i:@l@r:aat 
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Table of Contents 
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Page 
List of abb1·e"'"1atlons ........................................................................................................................... _ ............................................................. 7 
Glossary ......................................................................................................... -.......................................... 9 
1 
Summary ................................................................................................ -........................................ 10 
l 
Flowchart ............................................................................................... -........................................ 13 
2.1 
Tlial flowchart for site visits in the conc.-eption period of the trial ...................................... 13 
2.2 
Tlial flowchart for phone contacts in the conc-eption pe1iod of the tiial... ........................... 17 
2.3 
Trial flowchart for site visits in the pregnancy period of the trial ....................................... 18 
2.4 
Trial flowchart for phone contacts in the pregnancy period of the trial... ............................ 22 
3 
Background toformatton and rattonalt for the trtal .......................... -........................................ 23 
3.1 
Backgro1md information ...................................................................................................... 23 
3.2 
Rationale for the trial ........................................................................................................... 24 
4 
Objectives and tndpolnts ................................................................................................................ 25 
4. l 
Primary objective ................................................................................................................. 25 
4.2 
Secondary objectives ........................................................................................................... 25 
4.3 
Primary endpoint. ................................................................................................................. 25 
4.4 
Secondary endpoints ............................................................................................................ 26 
4.5 
Explorato1y endpoints .......................................................................................................... 27 
4.6 
Other assessments ................................................................................................................ 27 
5 
Trial design ...................................................................................................................................... 28 
5.1 
Type of trial ......................................................................................................................... 28 
5.2 
Rationale for trial design ...................................................................................................... 29 
5.3 
Tre.atment of subjects ........................................................................................................... 30 
5.4 
Treatment after discontinuation oftria) product ................................................................. .30 
5.5 
Rationale for treatulent ........................................................................................................ 30 
6 
Trial populatton ..................................................................................... -........................................ 31 
6.1 
NU111ber of subjects .............................................................................................................. 31 
6.2 
Inclusion criteria .................................................................................................................. 31 
6.3 
Exclusion criteria ................................................................................................................. 32 
6.4 
Criteria for premature discontinuation oftria) product ........................................................ 33 
6.5 
Withdrawal criteria .............................................................................................................. 33 
6.6 
Subject replacement ............................................................................................................. 33 
6.7 
Rationale for nial population ............................................................................................... 34 
7 
Mlltstonts ........................................................................................................................................ 34 
8 
Mt'fbods and asse.ssmt'ots ............................................................................................................... 36 
8. l 
Screening ............................................................................................................................. 36 
8.1.1 
Screening failures .............................................................................................. 3 7 
8.2 
Randomisation ..................................................................................................................... 37 
8.3 
Visit procedures for non-p1-egnant subjects ......................................................................... 38 
8.3.l 
Pregnancy in the non-pregnant/conception period ............................................ 38 
8.3.2 
End of non-pregnant/conception period ............................................................. 38 
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8.3.3 
Premanire discontinuation of trial product ........................................................ 39 
8.3.4 
\Vithdrawal from trial ....................................................................................... .40 
8.4 
Visit procedures for pregnant subjects ................................................................................ .4 l 
8.5 
8.4.1 
lJltrasound scan .................................................................................................. 4 1 
8.4.2 
Delivery visit .................................................................................................... .41 
8.4.3 
End oftreatnlent ................................................................................................ 42 
8.4.4 
Premanire discontinuation of trial product ...................................................... ..42 
8.4.5 
\Vithdrawal from trial ....................................................................................... .43 
Visit procedures and assessments for both non-pregnant and pregnant subjects ................ .44 
8.5.1 
Phone contacts ................................................................................................... 44 
8.5.2 
Fasting visits ...................................................................................................... 44 
8.5.3 
Follo,v-up period ................................................................................................ 45 
8.5.4 
Unscheduled site visits ...................................................................................... .45 
8.5.5 
Demography ..................................................................................................... .45 
8.5.6 
Concomitant illness, medical history and obstetric history .............................. .45 
8.5.7 
Diabetes history ................................................................................................. 46 
8.5.8 
Hypoglycaemia tma,va!'eness ............................................................................ .46 
8.5.9 
Baseline hypoglycaemic episode interview questionnaire ................................ .46 
8.5.10 
Concomitant medication (diabetes) ................................................................... 46 
8.5.1 l 
Concomitant medication (othe!') ....................................................................... .47 
8.5.12 
Alcohol use ....................................................................................................... .47 
8.5.13 
Tobacco use ....................................................................................................... 48 
8.5. 14 
Self-meas1ued plasma glucose and diaries ....................................................... .48 
8.5.15 
Basal insulin dose .............................................................................................. 50 
8.5.16 
Adverse events ................................................................................................... 50 
8.5.17 
8.5.18 
8.5.19 
8.5.20 
8.5.21 
8.5.22 
8.5.23 
8.5.24 
8.5.25 
8.5.16.1 
Medication en·or .......................................................................... 50 
8.5.16.2 
Adverse events requiring additional data collection ................... 50 
8.5.16.3 
Hypoglycaemic episodes ............................................................ .51 
8.5.16.4 
Neonatal hypoglycaemic episodes .............................................. 54 
Laboratory assessments ..................................................................................... 54 
Body weigltt and heigltt ..................................................................................... 56 
Eye examination ................................................................................................ 56 
Vital signs .......................................................................................................... 57 
Physical exatnination ......................................................................................... 57 
Electrocardiogram .............................................................................................. 57 
Training in pen haud]ing .................................................................................... 58 
Subject compliance ............................................................................................ 58 
Discontinuation ofMyGlucoHealth BG-meter and eDiary ............................... 58 
9 
Trial supplirs .................................................................................................................................................................. 59 
9.1 
Trial products ....................................................................................................................... 59 
9.2 
Labelling .............................................................................................................................. 59 
9.3 
Storage ................................................................................................................................. 60 
9.4 
Dnig accountability and destnJCtion .................................................................................... 60 
9.5 
Auxiliary supplies ................................................................................................................ 61 
10 Interactive web response system ........................................... ._ ...................................................... 61 
11 Randomlsatton prot'edure .............................................................................................................. 61 
12 Adverse events, tecbnlclll complalnts and pregnandes ............................................................... 62 
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12. l 
Definitions ........................................................................................................................... 62 
12.l .l 
Adverse event .................................................................................................... 62 
12. l . 2 
Selious adverse event. ........................................................................................ 63 
12 .1 . 3 
Non-serious adverse event ................................................................................. 64 
12.1.4 
Medication en-ors ............................................................................................... 65 
12.1.5 
Adverse events requiring additional data collection .......................................... 65 
12.l.6 
Technical cotnplaints ......................................................................................... 66 
12.2 
Reporting of adverse events ................................................................................................. 66 
12.3 
Follow-up of adverse events ................................................................................................ 68 
12.4 
Technical complaints and technical complaint samples ...................................................... 69 
12.4. l 
Reporting of technical complaints ..................................................................... 69 
12.4.2 
Collection. storage and shipment of technical complaint samples .................... 69 
12.5 
Adverse events related to pregnancies ................................................................................. 70 
12.5. l 
Reporting adverse events in com1ection with the pregnancy ............................. 71 
12.5 ,2 
Reporting adverse events on foetus and/or infant(s) .......................................... 71 
12.5.3 
Congenital anomaly ........................................................................................... 73 
12.6 
Precautions andlor overdose ................................................................................................ 73 
12.7 
Committees related to safety ................................................................................................ 73 
12.7. l 
Novo Nordisk safety committee ........................................................................ 73 
12.7 .2 
Data monitoring committee ............................................................................... 74 
12.7.3 
Event adjudication comminee ............................................................................ 74 
13 Case report rorms ............................................................................................................................ 76 
13.1 
Conections to case report fonns .......................................................................................... 77 
13.2 
Case report form flow .......................................................................................................... 77 
14 Monito1iog proct'dort'.s ····················································
····················-····································· 78 
15 Data maoagemeot ....................................................... m ....................... ·-·································
······· 79 
16 Computerised systems ............................................... m••····••m--••······ .. -· ...................................... 79 
17 Statistical considerations ...................................................................... -........................................ 80 
1 7 .1 
Sainple size calculation ........................................................................................................ 83 
17.2 
Definition of analysis sets .................................................................................................... 84 
17.3 
Primary endpoint. ................................................................................................................. 86 
17 .3. l 
Primary analysis for the primary estimand ........................................................ 86 
17 .3 .2 
Primary analysis for the secondary estimand ..................................................... 88 
17 .3 .3 
Sensirivity analyses ............................................................................................ 89 
17 .4 
Secondary endpoints ............................................................................................................ 89 
17.4. l 
Efticacy endpoints ............................................................................................. 89 
17.4.2 
Safety endpoints ................................................................................................. 90 
17.4.2.1 
Classification of Hypoglycaemia in subjects .............................. 90 
17.4.2.2 
Maternal safety endpoints ........................................................... 93 
17.4.2.3 
Pregnancy outcome endpoints .................................................... 95 
17.5 
Exploratory endpoints and other assessments ...................................................................... 96 
18 Ethics ·······························································································- ····································97 
18.1 
Benefit-risk assessment of the trial ...................................................................................... 97 
18.2 
Infonned consent ................................................................................................................. 98 
18.2. l 
Paternal info11ned consent ................................................................................. 99 
18.3 
Data handling ....................................................................................................................... 99 
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18.4 
Information to subjects dluing triaL ................................................................................... 99 
18.5 
Premamre termination of the trial ancVor trial sire ............................................................... 99 
19 Protocol compliance ...................................................................................................................... 100 
19.1 
Protocol deviations ............................................................................................................ 100 
19.2 
Prevention of missing data ................................................................................................. 100 
20 Audits and inspections ····································································-·
····································101 
21 Critical documents ··············································································- ···································101 
22 Responsibilities ..................................................................................... ·- ······························ ..... 102 
23 Reports and pubHcattons ... m••··················· .......................................... _ ...................................... 103 
23.1 
Conuuunication of results .................................................................................................. 103 
23.1. l 
Authorship ....................................................................................................... 104 
23.1.2 
Site-specific publi.cation(s) by investigator(s) ................................................. 104 
23.2 
Investigator access to data and review ofresults ............................................................... 104 
24 Retention of clinical hial documentation and human biosamples .... -...................................... 104 
24.1 
Retention of clinical trial documentation ........................................................................... 104 
24.2 
Retenrion of human biosamples ......................................................................................... 105 
25 InstHutlonlll Rt-view Boards/lndt-pendent Ethics Commlttet-S and regulatory autho11ttes .... 105 
26 Indemnity statt-ment ..................................................................................................................... 106 
27 References ...................................................................................................................................... 107 
Appendix. A 
Appendix B 
Attachment I 
Attachment II 
Insulin Titration Guideline 
Baseline hypoglycaemic episode interview questionnaire 
Global Jist of key staff and relevant depa1iments and suppliers 
Country list of key staff and relevant departments 
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Table of Figures 
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Page 
Figure 5- l Trial design for subjects who are non-pregnaut at randomisation ....................................... 29 
Figure 5- 2 Trial design for subjects who are pregnant at randomisation . ............................................. 29 
Figure 8- l Overview of key visits for subjects discontinuing trial product prematurely in the non-
pregnant/conception period of the trial. ............................................................................... 40 
Figure 8-2 Ove1view of key visits for subjects discontinuing treatment premanuely in the pregnancy 
period of the trial ................................................................................................................. .43 
Figure 12-1 Reporting of AEs ................................................................................................................. 67 
Figure 17-1 Novo Nordisk classification of hypoglycaemia ................................................................... 9 1 
Figure 17-2 ADA classification of hypoglycaemia ................................................................................. 92 
Table of Tables 
Page 
Table 5-1 
Trial duration for subjects .................................................................................................... 28 
Table 8-1 
Time points for the 9-poiut profile collected 2 days before selected visits ........................ .49 
Table 8-2 
Laboratory parameters included in the trial ........................................................................ .55 
Table 9-1 
Trial products ...................................................................................................................... .59 
Table 9-2 
Storage conditions ................................................................................................................ 60 
Table 12-1 Adverse events requiring completion of specific event fonns and/or are subject to event 
a.djudication .......................................................................................................................... 65 
Table 12- 2 Events for adjudication ........................................................................................................ 75 
Table 17- 1 Sample size for evaluation of non-inferiority based on F ASprq;w,1 with 80% power-
nlltllber of pregnanr women ................................................................................................. 84 
Table 17- 2 Sample size for evaluation of non-inferiotity based on PPpregn.ui with 80% power - number 
of pregnant women .............................................................................................................. 84 
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List of abbreviations 
ADA 
AE 
ALT 
AP 
APGAR 
AST 
BG 
BID 
BP 
CCDS 
CGM 
CI 
CLAE 
CTR 
DFU 
DMC 
DUN 
EAC 
ECG 
eCRF 
EMA 
EudraCT 
EUROCAT 
FAS 
FDA 
FPG 
FSFV 
GCP 
GW 
hCG 
HDL 
HELLP 
IAsp 
American Diabetes Association 
adverse event 
alanine aminotransferase 
alkaline phosphatase 
appearance, pulse, grimace. activity. respiration 
aspartate aminotransferase 
blood glucose 
bis in di€ (twice daily) 
blood pressure 
company core data sh~I 
continuous glucose monitoring (including flash glucose monitoring) 
confidence inteJVa] 
clinical labmatory adverse event 
clinica I trial report 
direction for use 
data monitoring committee 
dispensing unit number 
event adjudication committee 
electrocardiogram 
electronic case repo11 fonn 
European Medicines Agency 
European Clinical Trials Database 
European Concened Action on Congenital Anomalies and T\vins 
full analysis set 
U.S. Food and Drug Administration 
fa.sting plasma glucose 
first subject first visit 
Good Clinical Practice 
gestational week 
glycosylllled haemoglobin 
human chorionic gonadotropin 
high-demity lipoproleu1 
haemolysis, elevated liver enzymes, low platelet count 
insulin aspart 
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investigator's brochw·e 
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m 
ICH 
International Conference on Hannonisation of Technical Reqruremems for 
Registration of Phannaceuticals for Human Use 
ICMJE 
IDeg 
IDet 
IEC 
IMP 
IRB 
IWRS 
LSFV 
LSLV 
MedDRA 
NYHA 
OD 
PCD 
PE 
PG 
pp 
PPG 
SAE 
SAP 
SD 
SIF 
SmPC 
SiMPG 
SUSAR. 
TlDM 
TMlv[ 
TIT 
us 
UTN 
llltematioual Conunittee of Medical Jountal Editors 
insulin deglDdec 
msulin detemir 
independent ethics committee 
investigational medicinal product 
i.nsti.tutio11al review board 
inleractiYe web response system 
last subject first visit 
last subject Last visit 
Medical Dictionary for Regulatory Activities 
New Yo1k Heart Association 
once daily 
primary completion date 
pre-eclampsia 
plasma glucose 
per protocol 
post-prandial glucose 
serious adverse event 
statistical analysis plan 
subcutaneous 
standard deviation 
safety infomu1tiou fo,m 
summlll)· of product characteristics 
self-me-asured plasma glucose 
suspected unexpected serious adverse reaction 
type l diabetes mellitus 
trial materials manual 
treat-to-target 
ultrasound 
Universal Trial Number 
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Glossary 
Coagenital anomaly 
Date of conception 
Delivery 
Early foetal death 
Ectopic pregnancy 
Foetus 
HELLP syndrome 
lnfiml 
Macrosomia 
Major abnonualities 
Minor anomalies 
Neonatal mortality 
Perinatal mortality 
Planned caesarean section 
Postpartum 
Pregnancy outcome 
Pre-term deliYery 
Te11nina1ion of pregnancy 
(inducecVeledive abortion) 
Uuplanned c<1esarean section 
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A morphological, functional aml/or biochemical developmental disturbance in the 
embryo or foenis whether detected at birth or not The te1111 congenital anomaly is 
broad and includes congeoiral abnonnalities. foetopatlties, genetic diseases with 
e.arly onset, developmental delay, etc. 
Fonnation of a viable zygote by the union of the male spem1 and female ovum: 
fertilization. Typically occurs about 11-21 days after the fast day of the last period. 
The visit in which the end of the pregnaacy tak,es place. including live birth. foetal 
dead1 or lennination of p1·egn.ancy. 
The death of a foetus < 20 comp le led gestational weeks. 
Extrauteri.ne pregnancy, early foetal death. most often in d1e fallopian nibe. 
Unborn offspring from the embryo stage (> 8 completed gestational weeks) until 
delive1y. 
Obstelric complication usually considered a vanant or colIIJ)lication of pre-
eclampsia (abbreviation for: Haemolysis. E levated Liver enzymes. Low Platelet 
COUllt). 
Infunt from delivery until the end of the first year ofHfe. 
Birth weight above a defined Limit al llllY gestational age. 
A life threatening strnctural aaomaly or one likdy lo cause significant impainnent 
of health or functional capacity and which needs medical or s1.11"gical treatment. 
Relatively frequeat structural anomaly aot Hkely to cause any medicaJ or cosmetic 
problems. 
Death of an infant between 7 days and 28 completed days after delivery. 
Death of a foetus/infant betweea 
20 completed gestatioaal weeks and < 7 
completed days after delive1y. 
A caesare.an section which has be-en pla.nned > 8 hours prior to delivery. 
The period beginning immediately after delivery and ex rending for about six 
weeks. 
The outcome of the pregnancy which includes three maia categories: foetal death, 
tenuination of pregnancy, and live birth. 
Delivery< 37 completed gestatioaal weeks. 
Artificial intenuption of pregnancy. 
A caesarean section whid1 has not been planned or plaiu1ed 8 hours prior to 
delivery. 
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Summary 
ObjectJve(s) and enclpolnt(s) 
Pl'imary objective 
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To compare the effect OD glycaemic control of insulin degludec once daily plus insul.in aspart 2-4 
times daily with meals and insulin detemir once daily or twice daily plus insulin aspart 2-4 times 
daily with meaJs in a population of pregnant women with type l diabetes mellitus. 
Secondary objedlves 
To compare the effect OD maternal safety of insulin degludec once daHy plus insulin aspart 2-4 
times daily with meals and insulin detemir once daily or twice daily plus insulin aspa1t 2-4 times 
daily with meals in a population of pregnant women with type l diabetes mellitus. 
To compare the effect OD pregnancy outcome of insulin degludec once daily plus insulin aspart 2-4 
times daily with meals and insulin detemir once daily or twice daily plus insulin aspa1t 2-4 ti.mes 
daily with meals in a population of pregnant women with type l diabetes mellitus. 
Primary end[)Olnt 
Last planned glycosylated haemoglobin (HbA1c) prior to delivery after gestational ·week 16. 
Key secondary endpoints 
Supportive matemal efficacy endpoints 
• 
HbA1c 6.0% (42 mmol/mol) from last planned HbA1c prior to delivetT aft.er gestational 
week 16 (yes/no). 
• 
Last plam1ed average post-prandial glucose prior to delivery after gestational week 16. 
• Average of three main meals. 
• Last planned fasting plasma glucose prior to delivery after gestational week 16. 
Supportive maternal safety e11dpoi11ts 
• Number of hypoglycaemic episodes during the pregnancy period (from first day of pregnancy 
(date of conception) or randomisation (whichever comes last) to delivery). 
• 
Development of sight-threatening retinopathy defined as proliferative retinopathy or 
maculopatl1y from treatment baseline as well as from pregnancy baseline to the end of treatment 
visit (yes/no). 
• 
Number of adverse events dming the pregnancy period (from first day of pregnancy ( date of 
conception) or randomisation (whichever comes last) to delivery). 
• 
Pre-eclampsia defined as new-onset hypertension (blood pressure ~ 140 mrnHg systolic or 
90 mmHg diastolic, based on at least 2 measurements taken at le.ast 4 hours apart) occuning 
from gestational week 20 to delive1y and simultaneous proteinuria (defined as ~ 300 mg protein 
in a 24 bours urine sample, a protein-to-creatinine ratio of~ 300 mg/g in a urine sample or a 
urine dipstick protein of I+) or presence of eclampsia, HELLP syndrome, or other severe organ 
involvement (yes/no). 
lOofllO 


Protocol Protocol-version-4 I 
Protocol 
Tria1ID:NN125o-4300 
U1N: Ul 11 1-1191-301S 
EudraCT no.: 2017-000048-1 7 
NN 1250 -4300 
CONFIDm>m 1\1. 
Supportive pl'egnancy outcome endpoinrs 
• Birth weight (kg). 
Date: 
Vet!,ion: 
Smtus: 
Page: 
• 
P:re-tenn delivery (delivery < 37 c-ompleted gestational weeks) (yes/no). 
17 December 2020 
Novo Nordisk 
4.0 
Final 
11 of l!O 
• 
Presence of major abu.onnaJities ( classified according to EUROCA n (yes/uo ). 
• 
Live bom infants (yes/no). 
• 
Number of adverse events in the infant from delivery to final follow-up. 
• 
Neonatal hypoglycaemic episodes defined as plasma glucose :5 l .7 mmol/L (31 mg/dL) during 
the first 24 hours after birth or.'.:: 2 .5 mmol/L ( 45 mgldL) between 24 hours and 48 hours after 
birth (yes/no). 
Trial design 
This is a randomised (1: l), open-label, parallel, multi-centre, multi-national, treat-to-target, active 
controlled hi al comparing the effect and safety of insulin degludec once daily with insulin detemir 
once daily or twice daily both in combination with insulin aspart 2-4 times daily with meals in 
pregnant women with type I diabetes meUitus . 
Eligible subjects will be randomised either non-pregnant with the intention to become pregnant or 
pregnant from gestational week 8-13 (+ 6 days). The total 1:lial duration for subjects will depend on 
whether subject is randomised non-pregnant or pregnant and be maximum 25 months. 
Trial population 
It is planned to randomise a total of 214 subjects. 
Key inclusion criteria 
• Female, age~ 18 years at the time of signing infom1ed consent. 
• 
Diagnosed with type I diabetes mellitus 
I year prior to the day of screening. 
• 
Treated with multip]e daily subcutaneous insulin injections or continuous subcutaneous u1sulin 
infusion (CSil) or inhaled insulin~ 90 days prior to the day of screening. 
• The subject is plamling to become pregnant within 12 months from randonlisation and willing to 
undertake pre-pregnancy counselling or the subject is pregnant with an intraute1ine singleton 
living foetus (gestational week 8 to 13 (+6 days)) without any observed anomalies at 
randomisation, confirmed by an rultrasotmd scan. 
• 
HbA1c at screening :5 8.0% (64 mmol/mol) by central laboratory. 
K ey exclusion crileria 
• Treatment with any medication for the indication of diabetes or obesity other than stated in the 
inclusion criteria within the past 90 days prior to the day of screening. 
• 
Pregnant and having proteinuria as evaluated by mine protein-to-creatinine ratio 
300 mg/g in 
urine sample measured at screening. 
• 
Subject being treated or became pregnant with assistance of in vih·o fe1tilisation or other 
medical infertility treatm ent. 
11 of 110 


Protocol Protocol-version-4 I 
Protocol 
Tria1ID:NN125o-4300 
U1N: Ul 11 1-1191-301S 
EudraCT no.: 2017-000048- 17 
NN 1250 -4300 
CONFIDm>m 1\1. 
Date: 
Vet!,ion: 
Smtus: 
Page: 
17 December 2020 
Novo Nordisk 
4.0 
Final 
12 of 110 
• 
Receipt of any concomi.ta11t medication contraindicated in pregnancy according to local label 
within 28 days before screening and between screening and randomisation for non-pregnant 
subjects and 28 days before conception and between conception and ra11domisation for pregnant 
subjects. 
• Proliferative retinopathy or maculopathy requiring acute treatment. Verified by fimdus 
photography or phannacoiogically dilated fundoscopy perfonned within the past 90 days prior 
to randomisation for non-pregnant subjects or within 28 days prior to randomisation for 
pregnant subjects. 
• History of severe hyperemesis gravidamm (requiring hospitalisation). 
Key assessments 
• 
HbA1c (central laboratory) 
• Hypoglycaemic episodes 
• 
Adverse events duri11g the pregnancy period 
• 
Adverse events in the foetus alld infant 
Trial products 
Investigational medicinal products: 
• Test product: insulin degludec 100 U/m.L (Tresiba® [Tregludec® in Israel]), 3 mL PDS290 pen 
injector (FlexToucb«') for subcutaneous injection. 
• 
Reference therapy: insulin detemir 100 U/mL (Levem..ir®), 3 mL pre-filled pen (FlexPen«) for 
subcutaneous injection. 
• 
Other medicinal products: insulin aspa11 100 U/mL (NovoRapid®), 3 mL pre-filled pen 
(FlexPen®_) for subcutaneous injection. 
12of ll0 


Protocol 
Trial JD: N°NI 250-4300 
2 
Flowchart 
Protocol Protocol-version-4 I 
NN1250-4300 
I 
lJIN:Ul l ll-1 191·3018 
EodraCT no.: 2017-000048- 17 
I 
Date: 
Version: 
2.1 
Trial flowchart for site visits In the conception period of the trial 
J 7 December 2020 I 
Stan,s: 
4.0 
Page: 
I 
F£ D 7 , a 77&"11 
-
'Ill ---- --- --
I._ 
- -
- --
--
I 
~zT 
7 
: : = 
1: I= 
I~ '~ =·= = = I= 1: 
-
,- ,-
---
I- 1 .. 
--
:.. .. I• 
·- ... 
• • • • • • • 
• 
• • • • • --• .. • • • • 
SUBJECT RELATED INFORMATION AND ASSESSMENTS 
Infomied consent 
X 
Inclusion/exclusion criterill 
X 
X 
Randomisation 
X 
Premarure discootinuation criteriac 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Withdrawal criteria 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Demogn,pby 
X 
Medical histo.-y/concomitant illness 
X 
Obstetric history 
X 
Diabetes history 
X 
Hypoglycaemia Unawareness 
X 
Baseline hypoglycaemia questionnaire 
X 
Concomitant medic3!ion (diabetes) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant oiedic3!ion (Oilier) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
13 of 110 
WE 
-:r • -
- -
• 'iiiliiii 
• .. .. 
X 
X 
X 
X 
X 
X 
X 
Final I 
Novo Nordl&k 
13 of 110 
-
1 :~ :ii 
dixonllllllalim 
:a > 
< 
V90A 
V92A VS4D" 
·A FUl·A• l'Ul·A 
P54A 
P9JA 
-
PS-IO 
EOT•A ~OT•A 
.. 
+7d 
+30d 
-
+, 
+5 
±7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


Protocol 
Trial JD: N°NI 250-4300 
..... 
- -
- -
- -
- - .. ---... 
Height 
Alcohol use/tobacco use 
Preguaocy test (Serum hCG)" 
Home pre!!Jlllll<:y test (Urine stick)' 
EFFICACY 
2-poinr pmfite 
9-point profile 
HbAtc 
Fasting pla5wa glucose 
SAFElY 
Adverse e,·ents 
Hypoglycaemic episodes 
Technical complaints 
Haellllltolol!)' and biochemistry 
Urinalysis 
Bodyweight 
Eye examination 
Vital si!!II" 
Physical el<8Jllination 
Protocol Protocol-version-4 I 
NN1250 -4300 
I 
lJIN: Ul l ll-1191·3018 
EodraCT no.: 2017-000048- 17 
I 
Date: 
Version: 
J 7 December 2020 I 
Stan,s: 
4.0 
Page: 
I 
a 
5 
5 
77 TL"II 
WI --
,_ 
- - ,_ - -
- - - -
I 
; ii iii 1iii 1iii Ii. 1.i :I: --I• 
Ii. 
-----
I- - -.. -
1-
... 
• • -• • • • -
-------• ---• -
X 
X 
X 
(X) (X) 
(X) (X) (X) (X) (X) 
(X) (X) (X) (X) (X) (X) 
X 
X 
(X) (X) (X) (X) (X) 
(X) (X) (X) (X) (X) (X) (X) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
14 of I IO 
... , ... • -
--
• --
-.. .. 
X' 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Final I 
Novo Nordl&k 
l4of 110 
-
! 
0 ,":: 
. ., ., 
cbscontmultioo 
:a ·,: 
< 
VOOA 
V92A VS4o" 
·A FUl•A• FU2·A 
PS4A 
P91A 
-
PS4G 
EOT•A IEOT•A 
.. 
+7d 
+30d 
-
+s 
+s 
±7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
JI. 
X 
X 
X 
X 


Protocol 
Trial JD: N°NI 250-4300 
..... 
- -
- -
- -
- - .. ---... 
ECO 
OTiiER ASSESSMENTS 
BG-meter start date' 
TRIAL MATERIAL 
IWRS session 
Di.!.pensing ";sit 
First date on trial product 
New dose of trial insulin 
Dose of trial insulin 
La5t dose of trial product 
Drug acco,wtability 
REMJNDERS 
End oftreallllenl 
tnd of trial 
Sign-<>ff case-book 
Attend visit fa.sting 
Hand out and instruct i.n BG-meter 
Hand out and instrud in diwy 
Collect diwy 
Protocol Protocol-version-4 I 
NN1250 -4300 
I 
lJIN: Ul l ll-1191·3018 
EodraCT no.: 2017-000048- 17 
I 
Date: 
Version: 
J 7 December 2020 I 
Stan,s: 
4.0 
Page: 
I 
a 
5 
5 
77 TL"II 
WI --
,_ 
- - ,_ - -
- - - -
I 
; ii iii 1iii 1iii Ii. 1.i :I: --I• 
Ii. 
-----
I- - -.. -
1-
... 
• • -• • • • -
-------• ---• -
X 
(X) (X) (X) 
(X) (X) (X) (X) (X) (X) (X) (X) (X) (X) (X) (X) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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15 of 110 
... , ... • -
--
• --
-.. .. 
(X) 
(X) 
(X) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Final I 
Novo Nordl&k 
IS of 110 
-
! 
0 ,":: 
. ., ., 
cbscontmultioo 
:a ·,: 
< 
VOOA 
V92A VS4o" 
·A FUl•A• FU2·A 
PS4A 
P91A 
-
PS4G 
EOT•A IEOT•A 
.. 
+7d 
+30d 
-
+s 
+s 
±7 
(X) 
(X) 
(X) 
(X) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


Protocol 
Trial JD: N°NI 250-4300 
Protocol Protocol-version-4 I 
NN1250 -4300 
I 
lJIN:Ul l ll-1191·3018 
EodraCT no.: 2017-000048- 17 
I 
Date: 
Version: 
J 7 December 2020 I Stan,s: 
4.0 
Page: 
I 
a 
5 
5 
77 TL"II 
..... 
WI --
,_ 
- - ,_ - -
- - - -
I 
; ii iii 1iii 1iii Ii. 1.i :I: --I• 
Ii. 
- -
-----
I- - -.. -
1-
- -
--
- - .. ---... ... 
• • -• • • • -
-------• ---• -
Hand Olli directions for use' 
X 
Training in trial product. pen-baodling 
X 
Make appointment for eye 
(X) 
(X) 
(X) 
(X) (X) (X) 
(X) 
(X) 
(X) (X) 
(X) 
(X) 
(X) 
(X) 
e.u.minationd 
Check if ptt~nancy rest has been done• 
(X) 
(X) 
(X) 
(X) (X) 
(X) 
(X) 
(X) 
(X) (X) 
(X) 
(X) 
(X) 
Dispensing of pregnancy tests• 
X 
X 
(X) 
(X) 
(X) (X) (X) 
(X) 
(X) 
(X) (X) 
(X) 
(X) 
(X) 
• The first follow-up contacts P91 and P91A are phone contacts. 
... , ... • -
--
• --
-.. .. 
Final I 
Novo Nordl&k 
l6of 110 
-
! 
0 ,":: 
. ., ., 
cbscontmultioo 
:a ·,: 
< 
VOOA 
V92A VS4o" 
·A FUl•A• FU2·A 
PS4A 
P91A 
-
PS4G 
EOT•A IEOT•A 
.. 
+7d 
+30d 
-
+s 
+s 
±7 
X 
• The additional site ,isit (V54D) is applicable for subjects \\ith a positive pregnancy test and if there are more than 4 weeks between the last site '.-isit and the scheduled 
ultraso1wd visit (V55). 
' Subjects discontinuing treatment prematurely must complete the additional premarure discontinuation visits (V90A. P91A and V92A). Hereafter. all remaining planned 
,isits in the conception period of the trial should be completed. except for the V90 2-point profile. Effons should be made to ensure anendance at V54 for collection of 
a sermu pregmncy test. 
• Dispeusing of home pregnancy test kits (wine stick) is applicable for subjects in the conception period of the trial. As soon as the subject has a positiYe wine pregnancy 
test, a confmmtory senun pregnancy test. au appointmem for the V55 eye examination, and an ulu·asmmd scan must be made_ 
• Before the subject prematurely discontinues uial product the investigator should ensure that a pregnancy test (urine stick) is perfomled before s"~tching tlie subject to a 
suitable marketed insulin regimen. 
1 TI1e investigator must ensure that tl1e direction for use for the individual uial products (I.Deg and lAsp or IOet and !Asp) are handed out to tl1e subject 
• See Section 8.5.25 for details. 
16ofl!O 


Protocol Protocol-version-4 I 
Protocol 
Trial ID: 
125()-4300 
UlN: Ull I H 19J-30JS 
EudraCT n.o.: 2017-000048-17 
NN 1250 -4300 
CONFIDm>m 1\1. 
Date: 
Vet!,ion: 
Smtus: 
Page: 
17 Dec,ember 2020 
Novo Nordisk 
4.0 
Final 
17of l l0 
2.2 
Tt·ial flowchart for phone contac,ts in the conception period of the Mal 
Additional Phone 
Premature 
Ci.''' 
Contacts in case of 
Follow-up 
discontinuation 
pttgnallC)"' 
-
- -
vs 
P54 
PS4 
P91 
P91A 
------ --
--
ABC 
EFG 
(FUI) 
(FUI-A) 
·- .... 
-
-
EOT +7d 
EOT-A +7d 
- -
-
-
±3 
±3 
+s 
+5 
Premature di.continuation criteria 
X 
X 
X 
Withdrawal criteria 
X 
X 
X 
X 
X 
Concomitanl medication (diabetes) 
X 
X 
X 
X 
X 
Concomitanr medic.ation (other) 
X 
X 
X 
Howe pregwmcy test (Urine stick) 
(X) 
2-point pmfile 
X 
X 
X 
Adveffie events 
X 
X 
X 
X 
X 
Hypoglycaemic episodes 
X 
X 
X 
X 
X 
Technical complaints 
X 
X 
X 
X 
X 
New dose onl'ial insulin 
X 
X 
X 
Dose of trial insulin 
X 
X 
X 
Make appointment for eye e:wlllllation 
(X) 
(X) 
(X) 
Check if pr,egnaocy test has been done 
(X) 
• The additional phone contacts PS4A-P54G are applicable for subjects becoming pregnant in the conception period 
of the trial to ensure weekly contacts ben1;een the last site visit and the scheduled ultrasound scan visit (V55). 
17 of 110 


Protocol 
Trial JD: N°NI 250-4300 
Protocol Protocol-version-4 I 
NN1250 -4300 
I 
lJIN:Ul l ll-1191·3018 
EodraCT no.: 2017-000048- 17 
I 
Date: 
Version: 
2.3 
Trial flowcha1·t fol' site visits in the pregnancy period of the trial 
I 
' ' 
Additional \"1Slts 
I 
'II 
V55' 
V55D" 
-- -
- .. 
PSSA 
PS6 - --
--
-
--
PSSB 
PS7 --
PS5C 
PSS --.. 
OWS-13 OWl2 --.. 
- -
a -- _. __ ..... --
+6d 
,.7 - - -
SUBJECT RELATED INFORMATION AND ASSESSMENTS 
Informed consent' 
X 
Inclusion/exclusion criteria 
X 
X 
Randomisation 
X 
Prew.1ture discontinuation criteria' 
X 
X 
X 
X 
X 
X 
Withdrawal criteria 
X 
X 
X 
X 
X 
X 
Demography 
X 
Medical history/concomitant illness 
X 
Obsletric history 
X 
Diabele:s hislory 
X 
Hypo![lycaemia Unawareness 
X 
Bas..line hypogly,;aewia questionnaire 
X 
Concomilant uiedication (diabeles) 
X 
X 
X 
X 
X 
X 
X 
Concomilanl medication (olher) 
X 
X 
X 
X 
X 
X 
X 
Hei![bt 
X 
Alcohol use/tobacco use 
X 
X 
Pregnancy lest (Ser\nn bCO) 
X 
l8ofll0 
J 7 December 2020 I 
Stan,s: 
4.0 
Page: 
I 
a 
I ... 
- ----
Ill .. --
---
- - -
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
= -
--
.... -
- .. 
X 
X 
X 
X 
X 
Final I 
Novo Nordl&k 
l8of 110 
Prcmatun: 
discootiouation 
= 
V90A FUl·A• V92A 
EOT•A 
FU2•A 
P91A 
-
EOT-A EOT-A 
-
-
+7d 
+30d 
-
,.3 
-s 
-s 
X 
X 
X 
X 
X 
X 
X 
X 
X 


Protocol 
Trial JD: N°NI 250-4300 
-
--
-- 1111' 
-
-
-
- - ---- --
Eslin>1ted date of conception 
Pregnancy ultrasolllld scan 
EPFICACY 
2-poinl profile 
9-point p,oftle 
HbAt, 
Fasting plasma glucose 
SAFETY 
Adverse events 
Pre-ecla,)1)Sia 
Hypogly<:aemic episodes 
Teclmical complaints 
Haematology and biochemistry 
UrinHl)'hiS 
Body WeiJl)lt 
Eye examination 
Vital signs 
Physical examination 
ECG 
Protocol Protocol-version-4 I 
NN1250 -4300 
I 
lJIN:Ul l ll-1 191·3018 
EodraCT no.: 2017-000048- 17 
I 
Additional visits 
'II 
vss• vsm• 
P5SA 
P56 
P55B 
P57 
PSSC 
PSS 
.. 
-
OWS-13 OWJ2 
-
+6d 
:7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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I 
Date: 
Version: 
----
---
---
X 
X 
X 
X 
X 
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l9ofll0 
J 7 December 2020 I 
Stan,s: 
4.0 
Page: 
II II 
I 
.... 
RI .. ---
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X 
NS 
-.. 
-
-= = 
-
111 
X' 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Final I 
Novo Nordl&k 
l9 of 110 
.. 
Pttman1tt 
discootiuuation 
-
V90A FUt-A• V92A 
-
EOT-A 
FU2-A 
P9IA 
= 
.EOT-A EOT-A 
+7d 
• 30d 
-
:3 
-5 
-s 
X 
X 
X 
X 
X 
X 
X 
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X 
X 
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X 
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X 
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X 


Protocol 
Trial JD: N°NI 250-4300 
-
--
-- 1111' 
-
-
-
- - ---- --
Protocol Protocol-version-4 I 
NN1250 -4300 
I 
lJIN:Ull ll-1 191·3018 
EodraCT no.: 2017-000048-17 
I 
Additional visits 
'II 
vss• vsm• 
P5SA 
P56 
P55B 
P57 
PSSC 
PSS 
.. 
-
OWS-13 OWJ2 
-
+6d 
:7 
I 
Date: 
Version: 
----
---
---
01HER ASSESSMENTS / PREGNANCY AND DELIVERY 
BG-meter start date" 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
Insulin degludec cord blood 
Pregnancy outcome 
Delivery iufonnation 
lnlilllt bea!U1 status 
TRIAL MA TE.RIAL 
IWRS session 
X 
X 
X 
X 
X 
X 
X 
Di;-pensing visit 
X 
X 
X 
X 
X 
X 
First date on trial product 
X 
New dose oflrial insulin 
X 
X 
X 
X 
X 
X 
Dose of trial ins1~in 
X 
X 
X 
X 
X 
X 
Last dose ofuial product 
Dru~ HL"i.:OUUtabilily 
X 
X 
X 
X 
X 
X 
REMINDERS 
End of trcaunent 
Endoflrial 
Sign-off case-book 
AUend visit fasting 
X 
X 
X 
X 
20 of I IO 
J 7 December 2020 I 
Stan,s: 
4.0 
Page: 
II II 
I 
.... 
RI .. ---
----
---
(X) 
(X) 
(X) 
(X) 
X 
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X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
NS 
-.. 
-
-= = 
-
111 
(X) 
(X) 
X 
X 
X 
X 
X 
X 
X 
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Pttman1tt 
discootiuuation 
-
V90A FUt-A• V92A 
-
EOT-A 
FU2-A 
P9IA 
= 
.EOT-A EOT-A 
+7d 
•30d 
-
:3 
-5 
-s 
(X) 
(X) 
(X) 
(X) 
X 
X 
X 
X 
X 
X 
X 
X 


Protocol 
Trial JD: N°NI 250-4300 
-
--
-- 1111' 
-
-
-
- - ---- --
HIUld out and instmct in BO-meter 
Hand out and illstntet ill diary 
Collect diary 
Hand out directions for use< 
TraiJlillg in trial produc~ J)Cll·handling 
Make appoinllllellt for eye examination 
Protocol Protocol-version-4 I 
NN1250 -4300 
I 
lJIN:Ul l ll-1 191·3018 
EodraCT no.: 2017-000048-17 
I 
Additional visits 
'II 
vss• vsm• 
P5SA 
P56 
P55B 
P57 
PSSC 
PSS 
.. 
-
OWS-13 OWJ2 
-
+6d 
:7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
I 
Date: 
Version: 
----
---
---
X 
X 
X 
X 
X 
X 
X 
X 
J 7 December 2020 I 
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II II 
I 
.... 
RI .. ---
----
---
X 
X 
X 
X 
X 
X 
X 
NS 
-.. 
-
-= = 
-
111 
X 
X 
Final I 
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.. 
Pttman1tt 
discootiuuation 
-
V90A FUt-A• V92A 
-
EOT-A 
FU2-A 
P9IA 
= 
.EOT-A EOT-A 
+7d 
•30d 
-
:3 
-5 
-s 
X 
X 
X 
X 
. . 
... 
• The VI and V2 s1Le vmts are only applicable for subJects randollllsed pregnant l11e V55 s1le visit is only appbcable for subJecls randollllsed wn-pregnant and 
becoming pregnant in the conception period of the trial. 
• The additional site ,isit V55D is only applicable for subjects randomised pregnant before G\V 12 or for subjects that were randomised non-pregnant and become 
prcgJJant in tlJC conception period of tl1e trial and have an ultrasound scan completed before GW 12. 
' The deliwry visit (V86) is not considered a site visit, but relevant informalion liom tlie delivery will be collected. 
• The first follow-up contacts P9 l and P91A are phone contacts. 
• lf required by local legislation. the father of the foerus (if known) mu.s1 be asked to sign an agreement form for collection of blood sample5 and health information at 
and after delivery. 
' Subjects discoutiuuiug treatmcut prematurely must c.:omplctc tl,c additional prcmalim: disco11ti11ualiuu visils (V90A., P9IA aud V92A). Hcrcalkr. all n:ulllining pla,mcd 
visits in the pregnancy period of the trial should be completed, exce1>t for U1e V90 2-poilll profile. Efforls should be made to ensw-e attendance at V79 (OW 36) for 
collection of an HbA,, sample before delivery. 
1 The investigator must ensure that the direction for use for the individual trial products (!Deg and !Asp or IDet and !Asp) are handed out to the s,tbject. 
• See Section llll for details. 
2 l ofll0 


Protocol 
Trial JD: N°NI 250-4300 
Protocol Protocol-version-4 I 
NN1250 -4300 
I 
lJIN: Ul l ll-1191·3018 
EodraCT no.: 2017-000048-17 
I 
Date: 
Version: 
J 7 December 2020 I Stan,s: 
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2.4 
Trial Oowcha1·t for phone conlacts in the pregnancy pe1·iod of Che trial 
77 
7 
:::::t=i. ........ 
- - A 
·~ 
• 
.... __, 
- - - - - • 
Premature discontinuation criteria 
X 
X 
X 
X 
X 
X 
~ ithdrawal criteria 
X 
X 
X 
X 
X 
X 
;:oncomitant medication (diabetes) 
X 
X 
X 
X 
X 
X 
~oncomitaut 1ncdicntion (other) 
X 
X 
X 
X 
X 
X 
~-point profile 
X 
X 
X 
X 
X 
X 
1-\dverse events 
X 
X 
X 
X 
X 
X 
~ypoglycaemic episodes 
X 
X 
X 
X 
X 
X 
lfeclmical complaints 
X 
X 
X 
X 
X 
X 
.,rep,aDcy outcome 
X 
X 
"1fu,tr health srarus 
X 
X 
New dose of trial insulin 
X 
X 
X 
X 
X 
X 
Pose oflrial insulin 
X 
X 
X 
X 
X 
X 
as 
,-~ 
I--
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Final I 
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Fotlo9.·-up 
Premature 
discontinua1ion 
P9I 
P91A 
(Ft.JI) 
(Ft.JI-A) 
EOT 
+7d 
EOT•A+7d 
+s 
+s 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
• Tl,e additional phone contacts P55A-P55C are applicable for subjects randomised pregnant before GW 12 or for subjects that were randomised non-pregnant 
and become pregnant in the conception period oflhe rrial and have an ultrasound scan completed before GW 12. The additional phone contacts P56-P58 are 
robe completed as needed mitil visit 59 can be completed in GW 16. 
• The phone contacts P83-P85 are only applicable for subjects wilh delivery after GW 40. 
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Protocol Protocol-version-4 I 
Protocol 
Trial ID: 
125()-4300 
UlN: Ull I H 19J-30JS 
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NN 1250 -4300 
CONFIDm>m 1\1. 
Date: 
Vet!,ion: 
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Background information and rationale for the trial 
17 Dec,ember 2020 
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The uia1 will be conducted in complianc.e with this protocol, ICH GCPl and applicable regulatory 
requirements, and in accordance with the Declaration of Helsinki'.?-. 
In this document, the tenn investigator refers to the individual responsible for the overall conduct of 
the clinical uial at a nial site. 
3.1 
Background inlormat1on 
The use of insulin analogues has increased significantly in the treatment of type I diabetes mellih1s 
(TlDM). Insulin analogues are used in pregnant women with diabetes, as this group has a pa1ticular 
requirement for the safe and efficacious treatment that insulin analogue.s can deliver. Pregnancy in 
women with TlDM is associated with an increased risk of complications for both the mother and 
the foetus/infant. It is co11Sidered a medical challenge to ensure that these women recei.ve the most 
optimal glycaemic control without inducing hypoglycaemia especially if glycaemic control is 
outside the target and as the u·eatment needs to be adjusted during pregnancy. If pregnant women 
receive optimal treatment, it will both increase their own well-being and reduce the overall risk of 
diabetes complications and pregnancy complications both for the mother and the infant. During 
recent decades, pregnancy outcomes in women with TlDM have improved considernbiy. 
Hypoglycaemia and hyperglycaemia remafo major challenges in the treatment of pregnant women 
with TlDM. In a prospective observational study of pregnant women with Tl DM 45% of the 
women experienced severe hypoglycaemia during pregnancy. A history of severe hypoglycaemia 
the ye.ar preceding pregnancy was shown to be a significant risk factor for severe hypoglycaemia 
during pregnancy.I 
Information on the safety profile of insulin products is considered an imp01tant part of the 
foundation of information for health care professionals in consideting individualised treatment for 
pregnant women with TJDM. Thus it is important to compai-e different insulin analogues in terms 
of efficacy and safety to be able to offer pregnant women with T lDM the best possible option for 
insulin treatment. 
Insulin degludec 
Insulin degludec (IDeg) is an insulin analogue with unique pharn1acological properties and a long 
duration of action.i Insulin degludec has been approved in more than 70 countries as Tresiba® 
(Tregludec® in Israel) and is indicated for treatment of diabetes mellitus in adults and children from 
the age of 1 year. 
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Trial ID: 
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Insulin degludec has not been tested in a clinical trial with pregnant subjects, but has been 
investigated in animal studies covering fertility, embtyo-foetal development and pre-and post-natal 
development in rats and during the period of embryo-foetal development in rabbits. Human insulin 
(Neutral Protamine Hagedorn insulin) was included as comparator aud overall, the effects ofIDeg 
were similar to those observed ·with human insulin)- In these studies both human insulin and IDeg 
caused pre-and post-implantation losses and visceral/skeletal abnonnalities when given 
subcutaneously at a dose of 21 U/kg/day in rats and 3.3 U/kg/day in rabbits, resulting in 5 times 
(rat) and 10 times (rabbit) the human exposure (AUC, area under the curve) at a human 
subcutaneous dose of 0. 75 U/kg/day. There is no clinical experience with !Deg during lactation. In 
rats, IDeg was secreted in the milk; however the concentration in the milk was lower than in 
plasma. It is unknown whether IDeg is secreted in human milk. No metabolic effects are anticipated 
in the brem,tJed uewbom/.infaul.~ 
For further details, refer to the cun-ent version of the IDeg Investigator's Brochure (IB)~, the 
Tresiba® Smnmary of Product Characteristics (SmPC1 , and/or the local approved product 
information and any update.s thereof. 
Insulin detemir 
Insulin detemir (IDet) is a long-acting insulin analogue approved as LevemiJ'® and rndicated for 
treatment of diabetes mellitus in adults, adolescents and children aged 1 year and above (in Russia 
children aged 2 years and above) Insulin detemir is fiuthennore approved for treatment of pregnant 
women with TlDM based on a completed randomised clinical tJ.ial (NN304-l 687).l 
For further details, refer to the ClUTent version of the LevemiroJ> SmPC, and/or the local approved 
product information and any updates thereof. 
lnsulln aspat·t 
Insulin aspart (!Asp) is marketed as NovoRapid® and is a fast-acting insulin analogue indicated for 
treatment of diabetes me!Utus in adults, adolescents and children aged 1 year and above (in Russia 
children aged 2 years and above). Insulin aspart is furthe1more approved for treatment of pregnant 
women with TlDM based on a completed randomised cliuicaJ trial (Al'fA-1474).~ 
For fmther details, refer to the clm-ent version of the NovoRapid® SmPC.12 and/or the local 
approved product infmmation and any updates thereof. 
For an overall assessment of benefits and risks of the trial, see Section 18.1 
3.2 
Rationale for the trial 
Large prospective trials in women with TlDM have consistently sbown that poor glycaemic control 
leads to poor pregnancy outcomes with increased risk of spontaneous abortion (rates of 17-24%) 
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with 3-4 (and up to 10) times higher risk of malformation and 2-3 times higher risk of foetal 
mo11ality compared to risks in healthy women.,ll,;l.:i 
Macrosomia is repo11ed to occur in approximately 25-40% of infants in mothers with diabetes.lUZ 
Accordingly, keeping blood glucose in the target range both immediately before conception and 
during pregnancy is essential to reduce the above risks for the mother and the infant.~ 
Fruthe1more, hypoglycaemia is known to have a deleterious effect on outcome of pregnancies in 
women with diabetes both for tl1e motlier and tl1e infant.ll Accordingly, treatment of pregnant 
women affected by diabetes mellitus is a delicate balance bet\veen the need for intensive glucose 
control and reducing the risk of hypoglycaemia. 
The current tiial aims to evaluate effect and safety outcomes for !Deg in pregnant women ·with 
TIDM. 
4 
Objectives and endpoints 
4.1 
P1·imary objective 
To compare the effect on glycaemic control of !Deg once daily (OD) plus IAsp 2-4 times daily with 
meals and IDet OD or twice daily (BID) plus !Asp 2-4 times daily with meals in a population of 
pregnant women with TJDM. 
4.2 
Secon<lary objecth•es 
To compare the effect on maternal safety of !Deg OD plus L\sp 2-4 times daily with meals and IDet 
OD/BID plus IAsp 2-4 times daily with meals in a population of pregnant women with Tl DM. 
To compare the effect on pregnancy outcome of !Deg OD plus !Asp 2-4 times daily with meals and 
IDet OD/BID plus IAsp 2-4 times daily with meals in a population of pregnant women with TlDM. 
4.3 
Pl'imary endpoint 
Last planned HbA1c prior to delive1y after gestational week (GW) 16. 
This p1imary endpoint was chosen as it was not considered feasible to collect an HbA1c sample at 
delivery. Therefore, the primary endpoint is evaluated at last planned visit prior to delivery after 
GW 16. Gestational week 16 has been chosen as the earliest assessment of the primary endpoint, as 
some subjects, e.g. those randomised as pregnant, may not attend a site visit prior to GW 16. 
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4.4 
Secondary endpoints 
Supportive secondary endpoints 
Supportive maternal effi.cacv endpoints 
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26of l l0 
• 
HbA1c 6.0% (42 mmol/mol) from last planned HbA1c prior to delivery after GW 16 (yes/no)li 
• 
HbA1c, :5 6.5% (48 mmol/moi) from last planned HbA1c prior to delivery after GW 16 (yes/no}ll 
• 
Last planned average post-prandial glucose (PPG) prior to delive1y after GW 16 
• 
Average of three main meals 
• 
Last planned fasting plasma glucose (FPG) p1ior to delivery after GW 16 
Supportive malernal safetv endpoints 
The pregnancy period is defined as the period from the first day of pregnancy (date of conception) 
or randomisation (whichever comes last) to the date of delivery. Tue first day of pregnancy is 
calculated from the estunated gestational age from the ultrasound scan made before or at 
randomisation (visit 2) for subjects randomised pregnant and before or at visit 55 for subjects 
randomised non-pregnant and becoming pregnant in the conception period of the trial. For subjects 
with de]ivery prior to the ultrasound scan, tl1e first day of pregnancy is detennined by the 
investigator based on the estimated gestational age at time of delivery. 
Two different baselines will be applied; a treatment baseline and a pregnancy baseline. For all 
subjects the treatment baseline is defmed as the latest available measurement at or before 
randomisation (visit 2). For subjects randomised pregnant the pregnancy baseline is de1ived from 
the treatment baseline, and the two baseline values will be identical. For subjects randomised non-
pregnant and becoming pregnant in the conception period of the 1:Ii al. the pregnancy baseline 
con-esponds to data from visit 55. 
• 
Number of hypoglycaemic episodes during the pregnancy period (from first day of pregnancy 
(date of conception) or random.isatiou (whichever comes last) to delivery) 
• 
Development of sight-threatening retinopathy defined as proliferative retinopathy or 
maculopathy from treatment baseline as well as from pl'egnancy baseline to the end of treatment 
visit (yes/no) 
• 
Number of adverse events dmiug the pregnancy period (from first day of pregnancy (date of 
conception) or randomisation (wb.i.chever comes last) to de]ivery) 
• 
Pre-eclampsia defined as new~onset hypertension (blood pressure ~ 140 mmHg systolic or 
90 mm.Hg diastolic, based on at least 2 measurements taken at le:ast 4 hours apart) occmring 
from GW 20 to delive1y and simultaneous proteinuria (defined as ~ 300 mg protein in a 24 
hours urine sample, a protein-to-creatinine ratio of~ 300 mg/gin a mine sample or a urine 
dipstick protein of l +) or presence of eclampsia, HELLP syndrome, or other sever-e organ 
involvement (yes/no) 
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Trial ID: 
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UlN: Ull I H 19J-30JS 
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27of l l0 
• 
Mode of delivery, e.g. vaginaJ, operative vaginal, planned caesarean section or unplanned 
caesarean section, induced or spontaneous delivery 
• Change in body weight from pregnancy baseline to last planned visit before delivery (kg) 
Supportive pregnancv outcome endpoints 
• Birth weight (kg) 
• 
Pre-tenn delivery (delive1y < 3 7 completed GWs) (yes/no) 
• 
Early foetal death (delivery < 20 completed GWs) (yes/no) 
• 
Perinatal moliality (death of foetus/infant between ~ 20 completed GWs before delivery and < 7 
completed days after de1ive1y) (yes/no) 
• 
Neonatal mo11ality (death of infant betweeJ1 > 7 completed days after delivery and < 28 
completed days after delivery) (yes/no) 
• Presence of major abnormalities (classified according to EUROCA~ 
(yes/no) 
• 
Live bom infants (yes/no) 
• 
Number of adverse events iu the infant from delive1y to final follow-up 
• 
Neonatal hypoglycaemic episodes defined as plasma glucose ~ l 7 mmol/L (31 mg/dL) during 
the first 24 hours after bi.J.th or ::; 2.5 mmol/L (45 mgldL) betwee-n 24 hours and 48 hours after 
birth (yes/no) 
4.5 
Exploratory endpoints 
Cord blood !Deg levels in live bom infants. 
4.6 
Other assessments 
• 
Change in clinical evaluations from treatment baseline as well as from pregnancy baseline to the 
end of treatment visi1 in tem1S of: 
• Vital signs (including blood pressure and pulse) 
• Physical examinations 
• Change in central laborato1y assessments from treatment baseline as well as from pregnancy 
baseline to the end of treatment in terms of: 
• 
Haematology (haemoglobin, haematocrit, erythrocytes, thrombocytes, leucocytes) 
• Biochemistry (creatinine, alanine aminotransferase (ALn, aspartate aminotransferase 
(AST), alkaline phosphatase (AP), sodiwu, potassiwu, albumin, totaJ bilirubin) 
• 
Basal insulin dose from pregnancy baseline to the end of treatment visit 
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Trial ID: 
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Date: 
Vet!,ion: 
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UlN: Ull I H 19J-30JS 
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Page: 
2S of l l0 
5 
Trial design 
5.1 
Type of trial 
This is a randomised (1: 1), open-label, parallel, multi-centre. multi-national, treat-to-target (TIT) 
active controlled trial comparing the effect and safety of IDeg OD plus !Asp 2-4 times daily with 
meals with IDet OD/BID plus IA.sp 2-4 times daily with meals in pregnant women with TlDM. 
Subjects will be randomised either non-pregnant with the intention to become pregnaut or pregnant 
from GW 8-13 + 6 days.111e gestational age of the foetus will be based on the ultrasound scan 
performed in the screening period before or at the randomisation visit (visit 2) for subjects 
randomised pregnant and before or at visit 55 for subjects randomised non-pregnant. Randomisation 
will be stratified according to the pregnancy status at time of randomisation as well as planned 
continued use of the subject's own continuous glucose monitoring (CGM) device. 
The duration of the trial depends on the time of conception relative to the time of enrolment and 
delivery as summarised schematically in Figure S-1 and Figure 5-2. The total trial duration for the 
subject will depend on whether the subject is randomised non-pregnant or pregnant and wiU be 
maximum 25 months as summa1ised in Table 5- 1. 
Table 5-l Trial duration for subjects 
Period 
~on-pregoanf subjects 
Pregnant subjects 
Screening 
V 1, up to three ,,·eeks before randomisation 
Randomisation 
V2 
Up to 53 \Veeks for conception. 
If the subject becomes pregnant, ttial 
treatment furthennore continues tlU'oughout 
TIU'ougl1out the pregnancy period. 
Treauuent 
the pregnancy w1til end of treatment 28 days 
Trial rreatment cont.inues w1til end of 
after delivery. 
u·eatment 28 days after delivery. 
lftbe subject does not become pregnant end 
of rreatmem will be 7 days after V54. 
Follow-up period 
The trial will end with two follow-up comaccs (P91 and V92) 
7 and 30 days after end of treatmau respec.tiveJy. 
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Fm P"'!PL'""Y 
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{ 
IDeg OD + lAsp 2-4 ti.mes daily 
: 
: 
Final 
29 of l l0 
Rand~sed -----------:- - -----------1,1--...,, 
{ 
IDet OD/BID+ IAsp 2-4 times daily : 
: 
} 
f tn 
VI 
V2 
I V540 
1 
(I ilay8) 
1.' .... ' .. ', ....... ' ....... ' ....... ' ....... ' ................. 1-+--------• .... ' .. ' 1-..... '1-.. ........ ..i 
Cotu,eptioo~.iodo! ll><tcialaplo,2 w..b 
I V 55 
P>.g,,an.cypa:uxlol"tbe1n.i 
(2~ 
('.l~) 
aftttdeli=y) 
If the subject becomes pregnant at any time during the 52 \Veeks conception period of the trial tlleir next visit --.vill be 
tile V54D visit (if applicable) or V55 visit If the subject does not become pregnant in the conception period of the trial, 
the EOT vis.it v.eiJJ be completed I week after V54. Abbreviations: IDeg = insulin degludec, IDet = insulin detemir. 
IAsp = insulin aspait. OD = ouce daily, BID = twice daily, FDP = first day of pregnancy, V55 = pregnancy baseline 
visit~ EOT = end of treatment (V90), FUIIFU2 = follow-up conmcts 1 (P9l) and 2 (V92). 
FJgure 5--1 Trial deslgn for subjects who are non-pregnant at ranclomJsatJon. 
IDeg OD + IAsp 2-4 times daily 
Randomised 
u 
IDet OD/BID + !Asp 2-4 times daily 
VI 
V2 
JJdin,:y 
I 
I 
I 
I 
I 
I 
I 
I 
I 
I 
,-
... 
1 ·; ~;,.;~ • • ~•1~-------~- .-y_p,r_iod_of_1_t,.,_1n _ 
;i1---------ia ...... ;!~ 
aftc- ddi,-..y) 
FU1 
f lJ2 
(}I) da)") 
Abbreviations: IDeg = insulin degludec. IDet = insulin detemir, IAsp = insulin aspart, OD = once daily. BID = twice 
daily. V2 = pregnancy baseline visit. EOT = end of treatment (V90). FU11FU2 = foUow-up contacts 1 (P9l) and 2 
(V92). 
FJgu1·e 5--2 Trial design fo1· subjects who are pregnant at randomisation. 
5.2 
Rationale for tl'lal design 
The open-label trial design has been chosen as the tinling of dosing might not be the same between 
both treatment groups, sine~ !Deg is administered OD and IDet is administered either OD or BID. 
A blinded trial would require a double dummy approach which is considered not ethically feasible 
and unnecessary burdensome for the subject. 
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Trial ID: 
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Stratification with respect to the subject's pregnancy status at time ofrandomisation (pregnant/non-
pregnant) as well as planned continued use of the subject's own CGM (yes/no) is applied i.n order to 
avoid any potential confounding introduced by these factors. 
The TIT principle is applied to adjust the insulin dose for each individual subject with the aim of 
achieving similar glycaemic targets for !Deg and IDet. This allows for a valid comparison of the 
safety endpoints. 
5.3 
Treatment of subjects 
Eligjble subjects will be randomjsed 1:1 in an open-label manner to one of the below treatment 
regunens: 
• 
IDeg OD + IAsp 2-4 ti.Illes daily willl meals, or 
• 
IDet OD/BID + IAsp 2-4 times daily with meals 
Following randomisation, pre-trial insulin treatment must be discontinued and the subject will be 
switched to randomised treatment. Initiation and doses of trial basal insulin is based on plasma 
glucose values and are adjusted according to the Insulin Titration Guideline in Appendix A. There 
is no minimum or maximum daily insulin dose specified. Sw-veillance of insulin titration will be 
performed by Novo Nordisk. 
End of treatment will be 28 days after delivery for pregnant subjects. For subjects who do not 
become pregnant in the conception period of the tria], the end of treatment visit (visit 90) will be 7 
days after visit 54. 
After end of treatment each subject will have a 30 days safety follow-up period consisting of two 
follow-up contacts (P9I and V92), see Section 8.5.3. 
The maximum dmation of treatment of a single subject wiU depend 011 whether the subject is 
randomised non-pregnant or pregnant as summa1ised in Table 5- 1. 
5.4 
Treatment after discontinuation of trial product 
·when discontinuing trial products, eitl1er at the scheduled end of treatment visit or if trial product is 
discontinued prematmely, the subject should be switched to a suitable marketed product at the 
discretion of the investigator or it will be made available according to local regulations. 
5.5 
Rationale for treatment 
Subjects becoming pregnant in the conception period of the trial will be exposed to IDeg or IDet, 
both in combination with !Asp during organogenesis. The TIT design and consequent visit 
schedule is used in order to ensure optimal insulin titration based on self-measured plasma glucose 
(SMPG) values and to ensure improvement in glycaernic control. 
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The basal-bolus treatment regimen has been chosen for this trial since this is considered the 
standard of care for pregnant women with TlDM. 
Insulin detemir has been chosen as comparator, since IDet is approved for use during pregnancy. 
Since IDet is used botl1 OD and BID in clinical practice, this is also allowed in this trial. 
Insulin aspart has been chosen as the bolus treatment since !Asp is approved for use during 
pregnancy. 
All trial products are administered subcutirneously and should be injected in the thigh, upper anu or 
abdomen. The injection area should be consistent throughout the t1ial, however rotation of injection 
sites within the area is recommended to prevent lipohypertropby. 
Detailed information about trial products is available in the cUirent edition and any updates of the 
!Deg 
and/or SmPC~, the SmPC for IDeti and IAspl2 and/or local approved product information, 
if applicable. 
6 
Trial population 
6.1 Number of subjects 
Number of subjects planned to be screened: 306 
Number of subjects planned to be randomised: 214 
It is expected that approximately½ of the subjects are to be randomised as non-pregnant and % of 
the subjects are to be randomised as pregnant. 
6.2 
Inclusion criteria 
For an eligible subject, all inclusion criteria must be answered "yes". 
1. Informed consent obtained before any hial-related activities. Trial•related activities are any 
procedmes that are caJTied out as pa1t of the trial, including activities to detenuu1e suitability for 
the t1ial. 
2. Female, age ~ 18 years at the time of signing informed consent 
3. Diagnosed with type l diabetes mellitus 
I year prior to the day of screening. 
4. Treated with multiple daily subcutaneous insulin injections or continuous subcutaneous u1sttlin 
in.fusion (csm or inhaled insulin~ 90 days p1ior to the day of screening. 
5. The subject is planning to become pregnant within 12 months from randomisation and willing to 
undertake pre-pregnancy counselling or the subject is pregnant with an intraute1ine singleton 
living foeh1S (gestational week 8 to 13 (+6 days)) without any observed anomalies at 
randomisation, continued by an ultrasound scan. 
6. HbA1c at screening :5 8.0% (64 mmol/mol) by central laboratory. 
7. Willingness and ability to take folic acid according to local guidelines. 
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2. Previous participation in this trial. Participation is defined as signed infonned consent. 
3. Receipt of any investigational medicinal product within 28 days before scre.ening and between 
screening and randomisation for non-preg11a.t1t subjects and 28 days before conception and 
bet\veen conception and randomisation for pregnant subjects. 
For Brazil: Participation in other trials within 1 year prior to the day of screening unless there is 
a direct benefit to the research subject at the investigator's discretion. 
4. Receipt of any concomitant medication contraindicated in pregnancy according to local label 
within 28 days before screening and benveen screening and randomisation for non-pregnant 
subjects and 28 days befme conception and between conception and randomisation for pregnant 
subjects. 
5. Treatment with any medication for the indication of diabetes or obesity other than stated in the 
inclusion criteria within the past 90 days prior to the day of screening. 
6. Untreated hyperthyroidism or hypothyroidism. 
7. Any disorder, except for conditions associated with Type I Diabetes Mellitlts which in the 
investigator's opinion rnightjeopardise subject's safety or compliance with the protocol. 
8. Presence or history of malignant neoplasms within the past 5 years prior to the day of screening. 
Basal and squamous cell skin cancer and any carcinoma in situ are allowed. 
9. A.ny of the following: myocardial infarction, stroke, hospitalisation for unstable angina or 
transient ischaemic attack within the past 180 clays prior to the day of screening and between 
screening and randomisation. 
10. Subjects presently classtfied as being in New York Heart Association (NYHA) Class ill and IV. 
11. Planned coronary, carotid or peripheral revascularisation known on the day of screening. 
12. Renal impainnent measured as estimated Glomernlar Filtration Rate (eGFR) value of 
eGFR < 60 mVmin/1.73 m2 as defined by KDIGO 2012 classification using isotope dilution 
mass spectrometly (IDMS) for serum creatinine measured at screening.27 
13. Pregnant and having proteinuria as evaluated by urine protein-to-creatinine ratio 
300 mg/gin 
urine sample measured at screening. 
14. Impaired liver function, defined as alanine aminotransferase ~ 2.5 times upper normal limit or 
bilirubin > 1.5 times upper normal limit at screening. 
15. Inadequately treated blood pressure (systolic blood pressure 
140 mmHg or diastolic blood 
pressure 2: 90 mm.Hg) at screening. 
16. Known to be HIV positive. 
17. Known to be Hepatitis B or Hepatitis C positive. 
18. Proliferative retinopathy or maculopathy requiring acute treatmem. Verified by fundus 
photography or phannacologic-ally dilated fundoscopy performed within the past 90 days prior 
to randomisation for non~pregnant subjects or within 28 days prior to randomisation for 
pregnant subjects. 
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20. Subject being treated or became pregnant with assistance of in vitro fe11ilisation or other 
medical infertility treatment. 
6.4 
Criteria fot· p1·ematw·e discontinuation of trial p1•ocluct 
Efforts must be made so that subjects attend and complete aJl scheduled visit procedures. Subjects 
should stay in the trial irrespective of lack of adherence to randomised treatment, lack of adherence 
to visit schedule or missing assessments. Only subjects who decline any futther contact with the site 
in relation to the trial or do not become pregnant within the conception period of the trial will be 
considered as withdrawn from the trial (see Section 6.5). 
The subject may be premarurely discontinued from trial product at the discretion of the investigator 
due to a safety concern. 
The subJect must be prematurdy discontinued from trial product if the following applies: 
I. Included in the trial in violation of the inclusion and/or exclusion cd teri.a. 
2. Simultaneous pa.1iicipation in another clinical trial of an approved or non-approved 
investigational medicinal product. 
See Section 8.3.3 (non-pregnant subjects) and Section 8.4.4 (pregnant subjects) for procedures to be 
performed for subjects discontinuing tiial product prematurely. 
6.5 
Withdrawal criferia 
The subject may withdraw consent at will at any time. The subject's request to withdraw from the 
trial must always be respected. 
After randomisation the subject must be withdrawn from the trial if one of the following applies: 
I . If subject before having become pregnant initiates any medication that is contraindicated during 
pregnancy according to local labelling. (If subject lras already become pregnant wben initiating 
medication that is contraindicated during pregnancy according to local labelling, the subject 
should not be withdrawn, but should stop the contraindicated medicine if judged safe for the 
subj ect by the investigator and stay in the trial 011 trial medication). 
2. Commencement of medic-al infertility treatment during the course of the trial since medical 
infertility treatment can increase the risk of malfonnations. 
3. Randomised non-pregnant and still non-pregnant 12 months after randomisation. 
See Sections 8.3 A or 8.4.5 for procedures to be performed for subjects withdrawing c-0nsent. 
6.6 
Subjecf 1·eplacement 
Subjects who discontinue trial product prematurely or are withdravm will not be replaced. 
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Subjects w ith TlDM have been chosen for this trial due to previous experience from NN304-16871 
andANA-1474.2.. Furthennore, women with TlDM areprefeffedover women with type 2 diabetes 
mellitus, since the latter may have been treated with oral antidiabetic drugs from before they 
became pregnant and until randomi.sation and the safety of cun-ently available oral antidi.abetic 
dmgs is not assmed during early pregnancy. 
Gestational diabetes mellitus has been excluded because the women may only develop the disease 
late in pregnancy. Fllrthennore, at least a fraction of these may become well-controlled on di.et 
alone. 
Both from an obstetric and a methodological viewpoint it would have been optimal to recrnit the 
subjects p1ior to pregnancy to facilitate the best glycaemi.c control before conception. This would 
reduce the risk of maternal and foetal complications and provide a common baseline. However, 
even though diabetic patients are carefully instructed to plan their pregnancy, a high propo1tion of 
the women come to the clinic wtth au unplanned pregnaucy.28 In addition, most women who wish to 
become pregnant are not refened to obstet1ic clinics with specialised diabetes knowledge before 
they actually become pregnant. Therefore both pregnant and non-pregnant subjects can enter the 
trial. 
Organogenesis is the period of time where the imp01tant organs are developing in the foenas and is 
completed by GW 8. It is during this pe1iod that the foetus is most at risk of complications. IT 
pregnant subjects change insulin therapy dming organogenesis it is likely that the g]ycaemic control 
will deteriorate transiently. Due to this potential dete1ioration a change in insulin therapy during 
organogenesis may tisk bruming the foetus. Therefore, subjects emolled being pregnant will be 
randomised after completion of GW 8 and before completion ofGW 13 (+ 6 days). 
7 
l\tlilestones 
Planned duration of recrnitment pe1i od (i.e. first subject first visit (FSFV) to last subject first visit 
(LSFV)): 102 weeks. 
End of trial is defined as LSLV. 
Recmitment 
The screening and randomisation rate will be followed closely via the interactive web response 
system (IWRS) in order to estimate \.Vhen to stop screening. All investigators will be notified 
immediately when the recmitment period ends, after which no further subjects may be screened and 
the IWRS will be closed for further screening. All subjects screened during the recrnitment period 
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and folllld eligible for randomisation can be randomised within the timelines specified in the 
flowchart (see Section £). 
Trial registration 
Infon:nation of the trial will be disclosed at clinicaltrials.gov and novonordisk-trials.com. According 
to the Novo Nordisk Code of Conduct for Clinical Trial Disclosur~ it wiU also be disclosed 
according to other applicable requirements such as those of the Intemational Committee of Medical 
Journal Editors (ICMJE)Ml, the Food and Dmg Administration Amendment Act (FDAAA)ll, 
European Commission Requirement~ 
and other relevant recommendations or regulations. If a 
s11bject requests to be included in the trial via the Novo Nordisk email contact at these web sites, 
Novo Nordisk may disclose the investigator's contact details to the subject. As a result of increasing 
recquirements for transpar,ency, some countries require public disclosure of investigator names and 
their affiliations. 
The Primary Completio11 Date (PCD) is the Jast plam1ed assessment of the primary endpoint 
For subjects randomised as pregnant, the latest the primary endpoint may be assessed is 28 weeks 
after the last pregnant subject is randomised. 
For subjects randomised as non-pregnant, the Jatest the primary endpoint may be assessed is 86 
(52+34) weeks after the last non-pregnant subject is randomised. This would conespond to a 
situation where the last uon-pregnant subject randomised conceives (is in gestational week 2) 
52 weeks after randomisation and then bas delivery after the gestatioual week 36 visit, at which tl1e 
primary endpoint is assessed. Hence, for this group the last assessment of the prima1y endpoint is 
defined to be 86 weeks after the last non-pregnant subject is randomised. 
Based on the above, the estimated PCD is in this trial defined as the latest of the two dates: 
• 28 weeks after the last pregnant subject is randomised 
• 86 weeks after the last non-pregnant subject is randomised 
However, the estimated PCD will not be later than planned LSLV. For registration purposes the 
estimated PCD wiU be registered to be equal to the planned LSLV on clinicaJtrials.gov. 
The PCD detennines the deadline for results disclosure at clinicaltrials.gov according to FDA.AA. 
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The following sections describe the assessments and procedures conducted during the trial in 
relation to subject related information/assessments as well as efficacy, safety and Laboratory 
assessments. Tinling of tb.ese is specified in the flowcha1ts in Sections lJ. and 2.2 for subjects 
randomised non-pregnant as well as Sections 2.3 and 2.4 for subjects randomised pregnant. 
The timing of visits for the conception period of the tiial is based on the randomisation date 
whereas the timing of visits for the pregnancy pe1iod of the trial is based on gestational weeks. 
The trial-related assessments and procedures are considered to be an addition to the local standard 
pregnancy care. 
8.1 
Screening 
Informed consent must be obtained before any llial felated activity, see Section 18.2. The date of 
informed consent must be entered in the electJnnic case report form ( eCRF). 
At screening, subjects will be provided with a card stating that they are participating in a trial and 
given contact address( ·es) and telephone number(s) of rekvant tiial site staff. Subjects should be 
instmcted to return the card to the investigator at the last triaJ visit or to destroy the ,card after the 
last visit. 
A screening session must be perfo1med in the IWRS. Each subject will be assigned a unique 6-digit 
subject nwnber which will remain the same throughout the trial The investigator must keep a 
subject screening log, a subject identification code list and a subject enrolment log. Only subjects 
who have signed the informed consent form should be included on the logs. The subject screening 
log a.nd subject enrolment log may be combined in one log. 
A blood glucose (BG) meter and a dia1y will be provided to the subject. The subject will be 
inst:tucted that entries must be made in the diary according to Section ~ 
and the instructions 
provided. 
Eligibility assessments with regards to the inclusion and exclusion criteria must be performed. If 
any .inclusion criterion is answered "no" or any exclusion criterion answered "yes" the subject is a 
screening failure and no futther assessments should be done. 
Answers to inclusion or exclusion c1iteria cannot be ticked "yes'' or "no" in the eCRF before source 
data is available. In th.is case "result pending" should be ticked. nus is particularly relevant for 
exclusion criterion 3, the central laboratory results and in some cases the ECG and eye examination 
evaluations. Answers to these criteria must be changed to "Yes" or "No" when information, results 
and/or evaluations become available. The subject cannot be Iandomised until all resuHs are 
available. 
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For screening failmes the screening failure fonn in the eCRF must be completed with the reason for 
not continuing in the trial. Serious adverse events (SAEs) from scree11ing failures must be 
transcribed by the investigator into the eCRF. Follow-up on SAEs must be canied out according to 
Section .U.. A screening failme session must be made in the IWRS and the casebook must be 
signed. 
Re-screening is NOT alJowed if the subject has failed one of the inclusion or exclusion criteria. TI1is 
includes re-sampling if t1le subject has failed one of the inclusion or exclusion criteria related to 
laboratory parameters. 
8.2 
Randomisation 
Randomisation should take place no later than 21 days after the screening visit, but must not take 
place before all screening assessment results are available and reviewed and the subject con.finned 
eligible. For an eligible subject a randomisation session must be perfonned in the IWRS where 
subject will be randomised into one of the two t:reabnent regimens and trial product will be 
dispensed. 
The subject must attend the randomisation visit fasting as defmed in Section 8.5.2. 
Non-pt'egnant subjects 
Subjects w ith a negative screening senun pregnancy test will be randomised in the non-
pregnant/conception period of the ttia] and must follow procedures in Section 8.3 until a positive 
res.ult of the home pregnancy test. Before randomisation a urine pregnancy test should be taken in 
order to confinn the subject is still non-pregnant. In case of a positive urine pregnancy test a 
confnmatory semm pregnancy must be taken and if pregnant. the subject may not be randomised 
m1til GW 8-13 (+6 days). 
The subject and their pa1tner, if appropriate, will undergo pre-pregnancy counselling and education 
on diabetes control accordtng to standard practice at site. The subject sbould be recommended to 
use contraception during a sho1t period of time after randomisation until reasonable glycaemic 
control is achieved as judged by the investigator. 
The subject will receive the following home testing kit: 
• 
Home pregnancy testing kit (urine stick) 
• 
The subject should be instm cted to take a pregnancy test as soon as a period is missed. In 
case of a negative test, but symptoms of pregnancy remain, the subject should contact 
site. In case of a positive test the subject will follow procedures in Section 8.3.1. 
• 
For Argentina and Austria; As per local requirements a home pregnancy test must be 
taken monthly and as soon as a period is missed. This should be documented in the 
subject's medical records. 
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In addition., the site can provide a home ovulation kit to the subject. This can be used to perfonn 
tests in the middle of the menstnia1 cycle to detect the time for increase in luteinising hom1one (LH) 
indicating ovulation and optimal timing for conception. 
Pl'egnant subjects 
Subjects w ith a positive screening serum pregnancy test will be randomised in the pregnancy period 
of the trial and must follow procedures in Section 8.4. For subjects randomised pregnant visi.t 2 will 
be considered the pregnancy baseline visit. TI1e randomisation visit must take place when the 
subject is in GW 8-13 (+6 days). 
8.3 
Visit procedures for non-pregnant subjeds 
8.3.1 
Pregnancy in the non-pregnant/conception period 
In case of a positive home p regnancy test (urine stick) the subject should contact the si.te 
immediately and an unscheduled confnmatory sernm pregnancy test must be collected as soon as 
possible for analysis by the central laboratory 
If the confinnatory serum pregnancy test is positive the site must schedule an ultrasmmd (US) scan 
as per Section 8.4.1 and an eye examination as per Section 8.5.19. In case there are more than 
4 weeks between the last site visit and the scheduled US scan the subject must attend the additional 
site visit 54D to ensure sufficient supplies of trial products and optimal glycaemic control in the 
frrst period of the pregnancy. TI1e additional site visit must be scheduled midway between the last 
site visit and the scheduled US visit 55. hi-between the subject must attend the additional weekly 
phone contacts 54A to 54G, as needed. 
The subject will follow remaining vi.sit procedures for pregnant subjects in Section 8.4. 
8.3.2 
End of non-p1·egnant/conception period 
At the end of non-pregnant/conception period of the trial (visit 54) a sernm pregnancy test must be 
taken. 
In case of a positive semm pregnancy test the subject will follow remaining visit procedures for 
pregnant subjects (Section 8.4) starting with the additional weekly phone contacts 54A to 54G, as 
needed. In case there are more than 4 weeks between the last site visit and the scheduled US scan 
the subject must attend the additional site visit 54D to ensure sufficient supplies of trial products 
and optimal glycaemic control m the first period of the pregnancy. The additional site visi.t must be 
schedufod midway between the last site visit and the scheduled ultrasound visit 55. 
In case of a :negative sernm pregnancy test the subject is withdrawn from the trial. '111e investigator 
must pe1fonn a b·eatment discontinuation session in the IWRS and treatment with trial product must 
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be stopped. The end of treatment visit must be completed and the subject should be switched to a 
suitable marketed insulin regimen at the discretion of the investigator. Toe P9 l and V92 follow-up 
contacts must be performed 7 and 30 days after the end of treatment visit V90 respectively. 
If the subject has already prematurely discontinued treatment and the additional end of treatment 
visit V90A and additional follow-up contacts P91A and V92A have been performed, assessments 
con-esponding to the V92 follow-up visit (except infant health) must be pe1formed and is considered 
the end of trial visit. 
8.3.3 
Prematu1·e dlscontlnuation of trial product 
If a non-pregnant subject prematurely discontinues trial product. the investigator must perfonn the 
additional end of treatment visit V90A as soon as possible, Section 8.3.2. The additional follow-up 
contacts P91A and V92A must be pe1fonned 7 and 30 days after discontinuation of tiial product 
respectively, Section ill-
Before the subject prematurely discontinues trial product the investigator should ensure that a 
pregnancy test (urine stick) is perfonned. fa case of a positive pregnancy test, the investigator 
should discuss the pote11tia1 risks to the foetus by changing insulin treatment during early pregnancy 
before the subject is switched to a suitable maiketed insulin regimen. 
The p1imary reason for premature discontinuation oft:Iial product must be specified in the 
additional end of treatment fon11 in the eCRF and final drng accountability must be petfonned. A 
treatment discontinuation session must be made in the IWRS. 
Hereafter the subject should attend all remaining planned visits in the non-pregnant/conception 
period of the trial If applicable, the phone contacts should preferably be completed weekly in the 
eCRF and documented in the subj ect's medical records in order to optimise glycaemic control. In 
case the subject becomes pregnant in this period, follow instrnctions in Section ~
-
For subjects not able or willing to attend all planned site visits, these can be conve1t ed to phone 
contacts, except visit 54. Efforts should be made to ensure attendance at this visit for collection of a 
serum pregnancy sample. 
In case of a negative visit 54 pregnancy test, the subject is withdrawn from the trial, Section 8.3.4. 
In case of a positive visit 54 sernm pregnancy test the subject should attend all remaining planned 
visits dming pregnancy according to Section 2.3. For subjects not able or willing to attend all 
planned site visits. tllese can be convetted to phone contacts. Effo1ts should be made to ensure 
attendance at the most important key visits, i.e. visit 55, visit 79 and the delivery visi.t (visit 86). 
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• 
28 days after delivery (end of treatment visit V90). This visit can be converted to a phone 
contact. 
• 
58 days after delivery (\192 follow-visit). This visit should be a site visit 
The key visits to be completed for subjects cliscontinuing treatment prematurely are summarised in 
Figure 8- 1. 
Treatment Ill the 110t1--pri,g,,,wll=iceptioo period of the tl'ial 
Subjecl 
di!:cootrnua 
lrial producl 
prematurely 
Not Fglanf 
No funbe.- asscs""1cn1> 
Abbreviations: V2 = rnndomisation visil, EOT = end oftreabnent (V90), FU2 = follow-up visil 2 (V92), 
EOT-A = additional end of treatment (V90A), FUl-A/FU2-A= additional follow-up contacts l (P91A) and 2 (V92A), 
V54 = last visit in the concep1io11 period of the trial. VS5 = pregnancy baseline visit (ultrasound scan), 
V79 = gestational week 36, D = delivery (V86). 
Figure 8-1 Overview of key visits for subjects discontinuing trial product p1·ematuJ'ely in the 
non-pregnant/conception period of the tdal. 
8.3.4 
Withdrawal from trial 
If a subject withdraws consent, the investigator must aim to undertake procedures similar to those 
for the end of treatment visit as soon as possible. If the subject agrees. the P91 and V92 follow-up 
contacts must be perfom1ed 7 and 30 days after discontinuation of trial product respectively. 
The end of trial fonn must be completed and final drug accountability must be performed even if 
the subject is not able to come to the trial site. A treatment discontinuation session must be made in 
the rwRS (if applicable) and the casebook must be signed. 
If the subject has already discontinued treatment prematurely and attended the additional end of 
treatment visit 90A as well as the additional follow-up contacts P91A and V92A prior to 
withdrawal, the end of treatment visit V90 and follow-up contacts P91 and V92 should not be 
completed. 
Before the subject discontinues trial product and is s\vitched to a suitable marketed insulin regimen, 
the investigator should ensure tbe subject has a negative pregnancy test (urine stick). If the subject 
is confirmed non-pregnant no further assessments should be done. If the subject is confirmed 
pregnant the investigator should collect u1.fom1ation about the pregnancy, pregnancy outcome and 
infant health on the paper pregnancy fonns as per Section 12.5. 
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Although a subject is not obliged to give her reason(s) for withdrawing consent, 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 p1imary reason for withdrawing consent must be specified in 
the end of trial form in tl1e eCRF. 
8.4 
VisU procedures fot· pregnant subjects 
8.4.1 
Ultrasound scan 
Using standard equipment at the site an ultrasound (US) scan must be perfo1med either at the 
screening visit or before randomisation occurs at visit 2. For subjects randomised pregnant the 
randomisation visit must take place when the subject is in GW 8-13 (+6 days). 
Subjects randomised non-pregnant and becoming pregnant in tl1e conception period oftbe trial must 
have an US scanperfo1med in connection with visit 55 when the subject is in GW 8-13 (+6 days). 
The US scan will be used to determine the following infonnation and must be entered in the eCRF: 
• If the pregnancy is in alignment with inclusion CJiterion 5 
• 
For subjects randomised non-pregnant multiple pregnancies are accepted 
• 
Gestational age (completed gestational weeks and days), estimated conception date and 
estimated delivery date 
• 
Foetal Crown-Rump Length (CRL) 
For subjects where the ultrasound scan is completed before GW 12 the additional site visit 55D 
must be completed. TI1e additional phone contacts P55A-P55C and P56-P58 should be completed as 
needed to ensure weekl.y contacts until visit 59. 
8.4.2 
Delinry visit 
The delive1yvisit (visit 86) is not considered a site visit, but relevant: infonnat:ion concerning 
labour, delivery and neonatal assessment/infant health must be entered in the specific fo1ms in tl1e 
eCRF, if available. If required by locaJ legislation, the father of t:he foetus (if known) must be asked 
to sign an agreement fonn before delivety, see Section 18.2. 
Information collected for the mother 
The foJlowing information wm be collected for the mother: 
• 
Type and dose of insulin (if not trial products) as well as reJevaut concomitant medication 
inch1ding administration of glucose du1ing management of labour and delivery. The use of 
insulin and glucose should be according to local practice. 
• 
Mode of delivery, e.g. vagina.I., operative vaginal, planned or unplanned caesarean section, 
induced or spontaneous delivery. 
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Infant health inf 01·mation collected 
The following iof ormation will be collected for the infant: 
• 
Details on the pregnancy outcome including: 
• 
Biltb date 
• 
Gender 
• 
Gestational age (completed gestational 
weeks and days) 
• Measured in cenJimetres (cm) to one decimal place 
• 
Head circrunf erence of the newbom8 
• 
Length of the newborn3 
• 
APGAR scores assessed at 1 minute and 
5 minutes after birth 
• 
Standard Deviation (SD) score for bi11h weight (measured in grams (g) according to local 
nonnal cwves for gestational age and sex) including the birth weight percentile. 
• 
Details on the infant health status, including if the infant has any congenital anomaly or birth 
injury observed at gross examination or events such as induced abortion, resuscitation, 
respiratory distress syndrome (RDS), moderate or severe neonatal asphyxia eady foetal death 
or neonatal or perinatal death must be reported in the eCRF and as an SAE as per 
Section 12.5.2. 
• 
To measure umbilical cord !Deg levels a cord blood sample should be drawn from the umbilical 
cord (applicable for subjects randomised to IDeg only). The sample should be collected at bitth 
immediately after the umbilical cord has be.en cut. 
• Umbilical cord pH (as pa1t of standard of care). 
• 
Postpa11tm1 neonatal plasma glucose and neonatal hypoglycaemia as defined in Section 8.5.16.4. 
• 
Treatment given to the infant, e.g. ·with smfactant, ventilator or continuous positive airway 
pressure (CPAP). 
8.4.3 
End of treatment 
The end of treatment visit should take place 28 days after delivery. A treatment completion session 
must be perfom1ed i11 tbe IWRS, treatment witl1 trial product must be stopped, aod the subject 
should be switched to a suitable marketed insulin regimen at the discretion of the investigator. 
Both the mother and the infant will undergo a physical examination and infant health will be 
assessed (not applicable in case of fatal outcome) as outlined in Section _u. 
8.4.4 
Prematul'e dlscontlnua tton of trial product 
If a pregnant subject prematurely discontinues tiial product, the investigator must perfonn the 
additional end of treatment visit 90A as soon as possible, Section 8.4.3. The additional follow-up 
contacts P91A and V92A must be performed 7 and 30 days after discontinuation of trial product 
respectively, Section 8.5.3. 
The primary reason for premamre discontinuation of t1ial product must be specified in the end of 
treatment form in the eCRF, and final drng accountability must be perfonned. A ti·eatment 
discontinuation session must be made in the IWRS. 
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Pregnant subjects discontinuing treatment prematurely should hereafter attend all remaining 
planned visits of the trial. If applicable, the phone contacts should preferably be completed weekly 
in order to maintain glycaemic controL 
For subjects not able or willing to attend all planned site visits these can be conve11ed to phone 
contacts. Efforts should be made to ensure collection of tlle scheduled 9-point profiles as per 
flowchart Section 2.3 and attendance at the most impo11ant key visits, i.e. visit 79 for collection of 
an HbA1c sample prior to delivery, the delivery visit, the end of treatment visit V90 (except 2-point 
profile), and the originaJly scheduled V92 folJow-up visit. The key visits to be completed for 
subjects discontinuing treatment prematurely are summarised in Figure 8- 2. 
V2 
Treatment in the pregnancy period of the trial 
Subject 
discontinues 
trial product 
p rematurely 
EOT-A 
FUI-A 
FU2-A 
V79 
D 
EOT 
FU2 
(infWlt health) 
Abbreviations: V2 = pregmmcy baseline visit (ultrasound scan), EOT = end of treatment (V90), RJ2 = follow-up visit 2 
(V92), EOT-A = addilional end oftreatuienl (V90A), FU1-A/FU2-A = additional follow-up contacts l (P9JA) and 2 
(V92A), V79 = gestational week 36, D = delivery (V86}. 
Figure 8-2 Overview of key visits fot• subjects discontinuing treatment prematurely in the 
pregnancy pel'iod of the trial. 
8.4.5 
Withdrawal from trial 
If a subject withdraws consent, the investigator must aim to undertake procedures similar to those 
for the end of treatment visit as soon as possible. If the subject agrees, the P9 l and V92 follow-up 
contacts must be perfom1ed 7 and 30 days after disc-0ntinuation of trial product respectively. 
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 treatment discontinuation session must be made in 
the IWRS and the casebook must be signed. 
If the subject has already discontinued treatment prematurely and attended the additional end of 
treatment visit 90A as well as the additional follow-up contacts P9 IA and V92A prior to 
withdrawal, the end of treatment visit V90 and follow-up contacts P91 and V92 should not be 
completed. 
The investigator should collect infonuation about the pregnancy, pregnancy outcome and infant 
health on the paper pregnancy forms as per Section 12.5. 
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Although a subj ect is not obliged to give her reason(s) for withdrawing consent, the investigator 
must make a reasonable effo11 to ascertain the reason(s), while fully respecting the subject's rights. 
Where the reasons are obtained, the p1imary reason for withdrawing consent must be specified in 
the end of trial form in tl1e eCRF. 
8.5 
VisU procedures and assessments for both non-pregnant and p1·e-gnant subjects 
8.5.1 
Phone contacts 
Throughout the trial (borh in the conception and the pregnancy periods of the trial) weekly phone 
contacts are scheduled according to Sections 2.2 and 2.4. Phone contacts must be completed ln the 
eCRF and documented in the subject's medical records. A phone contact may be converted to a site 
visit if prefen ed. 
It must be clearly agreed how each contact is conducted. Even if it is agreed tliat the subject calls 
the investigator, it is the responsibility of the investigator that the contact takes place. 
Additional phone contacts in the conception pel"iod of the trial 
The additional p hone contacts P54A-P54G are flexible phone contacts applicable for non-pregnant 
subjects becoming pregnant in the conception period of the trial only. These phone contacts should 
be completed as needed to ensure weekly contacts between the last site visit and the scheduled 
ultrasound scan at visit 55. 
Additional phone contacts in the pregnancy period of the trial 
The additional phone contacts P55A-P55C and P56-P58 are .flexible phone contacts that should be 
completed as needed to ensure weekly contacts until visit 59. 
The additional phone contacts P83-P85 are flexible phone contacts applicable for pregnant subjects 
with delivery after GW 40. 
8.5.2 
Fasting visits 
Subject must attend specific visits in a fasting condition as outlined it1 the flowchart Sections ll 
and 2.3 for collection of an FPG blood sample. Fasting is defmed as having consumed only water 
and taken no insulin at least eight hours prior to the visit. Non-antidiabetic medication(s) are to be 
taken. 
If a subject attends a fasting visit i.n a non-fasting condition, blood sampling should be re-scheduled 
preferably within the visit window. If blood sampling has ah·eady been done before realising the 
subject was not fasting, only the FPG sample needs to be re-drawn. 
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Follow-up period 
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The first follow-up contact (P91) is a phone contact and must take place 7 days after end of 
treatment. At this visit information about antidiabetic medication and all AEs including 
hypoglycaemic episodes in the period from end of treatment visit V90 to P9 l is collected. 
The second follow-up contact (V92) is a site visit and is considered t11e end of trial visit This site 
visit must take place 30 days after end of treatment visit V90. hiformation about antidiabetic 
medication and all AEs including hypoglycaemic episodes in the period between tl1e two folJow-up 
contacts is collected. Status on infant health (if applicable) will be c-01lected for the period from end 
of treatment visit V90 until V92. 
8.5.4 
Unscheduled site visits 
If the subject attends the site outside the visit schedule, the unscheduled visit fom1 in the eCRF must 
be completed. The unscbeduled visit fonn must not be completed if the subject attends the s1te only 
to obtain trial products or for re-scheduled visits. Unscheduled visits can be pe1fo1med at any time 
at the discretion of the investigator e.g. in relation to follow-up on an AE. 
If additional trial product is needed an additional dispensing session must be perfonned in the 
IWRS. If blood sampling is needed the requisition fonn should refer to the visit number to which 
the samp]e be]ongs. 
8.5.5 
Demography 
Demography will be recorded at screening and consists of: 
• 
Date of bitth (according to local rngulation) 
• 
Sex (pre-defi11ed based on iuclusion criteria, Section §.1) 
• 
Ethnicity (according to local regulation) 
• 
Race (according to local regulation) 
8.5.6 
Concomitant illness, medical history and obstet1·ic history 
A concomitant illness is any Hlness including diabetes complicatious that is present at the sta11 of 
the trial (i.e. at the screening visit) or found as a result of a screening procedure or other trial 
procedures perfonned before exposure to trial product. 
Medical history is a relevant medical event including diabetes complications (as judged by the 
investigator) that the subject has experienced in the past. 
Obstett"ic history is information about previous pregnancies. The info1mation collected includes 
tile number of previous pregnancies, the number of live births as well as previous maternal/foetal 
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pregnancy complications and congenital anomaly(-ies). Obstetric history should also include 
relevant pregnancy related medical events. 
The infonnation collected for co11c-01nitant illness and medical history should include diagnosis, 
date of onset and date ofresolution 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. 
It must be possible to verify the subject's medical history in source documents such as subject's 
medical record. If a subj ect is not from the investigator's own practice, the investigator must make 
reasonable effo1t to obtain a copy of subject's medical record from relevant party e.g. primary 
physician. l11e investigator must document any attempt to obtain extema1 medical information by 
noting the date(s) when info1mation was requested and who has been contacted. 
8.5. 7 
Diabetes history 
Diabetes history consisting of date of diagnosis ofT lDM will be recorded in the eCRF at screening. 
8.S.8 
Hypoglycaemia unawareness 
Infonnation on hypoglycaemia unawareness will be recorded at screening according to Clarke's 
questionnaire. question 8 . .li 
The investigator must ask the subject in the following way: "To what extent can you teH by your 
symptoms that your blood glucose is low?" The subject can answer never, rarely, sometimes, often 
or always. 
Subjects answe1ing ' never, rarely or sometimes' are considered as having impaired awareness of 
hypoglycaemia. 
8.5.9 
Baselloe hypoglycaemic episode interview questJoona1re 
The baseline hypoglycaemic episode interview questionnaire in Appendix B must be pe1formed at 
the screening visit and can be recorded directly in the eCRF. The questionnaire wiU be performed in 
an interview by the investigator or delegated site staff and will be used to investigate the subject's 
experience with hypoglycaemic episodes. 
8.S.10 
Concomitant medication (diabetes) 
A concomitant antl<.tiabetlc medkadon is any diabetes medication other than the trial product(s). 
At the randomisation visit any pre-trial insuJin(s) must be discontinued and stop date(s) recorded in 
tile eCRF. 
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For subjects randomised non-pregnant this includes diabetes medication taken up to 28 days before 
screening as well as during the trial, including the screening, conception and/or pregnancy period(s) 
of the trial and until the end of trial. The info1mation must be recorded in the concomitant 
antidiabetic medication fonn in the eCRF. 
For subjects randomised pregnant this includes diabetes medic.at.ion taken at least 28 days before 
conception as well as during the trial, including the screening and pregnancy periods of the trial and 
until the end of trial. The information must be recorded in the concomitant antidiabetic medication 
form in the eCRF. 
The infonnation collected for each antidiabetic medication must be recorded in the concomitant 
antidiabetic medication fmm in the eCRF. Details include trade name or gene1ic name. indication, 
route of administration, total daily dose, strut date and stop date. 
8.5.11 
Concomitant medication (other) 
A concomitant medication is any medkation, including folic acid, other than the trial product(s). 
For subjects randomised non-pregnant this includes medication taken up to 28 days before 
screening as well as during the trial. including the screening, conception and/or pregnancy per!iod(s) 
of the trial and until end of treatment. 
For subjects randomised pregnant this includes medication taken up to 28 days before conception, 
as well as during the tri.al, including the screening and pregnancy pe1iods of the trial and until end 
of treatment. 
For the infant this includes medication administered in the period after bilth tmtil end of the follow-
up periods. 
Details of any concomitant medication for the subject must be recorded at the screening visit in the 
eCRF. Change.sin concomitant medication must be recorded at each visit as they occur. Details of 
any concomitant medication for the infant must be recorded in the eCRF after delivery. 
The information collected for each concomitant medication includes trade name or generic name, 
indication, start date and stop date or continuation. 
If a change is due to an AE, then this must be rep01ted according to Section 11-If the change 
influences the subject's eligibility to continue in the trial, the monitor must be in.fonned. 
8.5.12 
Alcohol use 
For subjects randomised non-pregnant, inf01matio11 about the average consumption of alcohol 
within the last 8 weeks before randomisation must be recorded in the eCRF at the randomisation 
visit 2. For non-pregnant subjects becoming pregnant in tl1e conception pe1iod of the trial, 
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infonnation about the average consumption of alcohol within the first 8 weeks of pregnancy must 
be recorded in the eCRF at visit 55. 
For subjects randomised pregnant, infom1ation about the average consumption alcohol within the 
first 8 weeks of pregnancy must be recorded in the eCRF at the randomisation visit 2. 
8.5.13 
Tobacco use 
For subjects randomised non-pregnant, info1mation about tobacco use within the last 8 ·weeks 
before randomisation must be recorded in the eCRF at the randomisation visit 2. For non-pregnant 
subjects becoming pregnant in the conception period of the trial, infoanation about tobacco use 
within the first 8 weeks of pregnancy must be recorded in tbe eCRF at visit 55. 
For subjects randomised pregnant. infom1ation about tobacco use within the first 8 weeks of 
pregnancy must be recorded in the eCRF at the randomisation visit 2. 
Smoking is defined as smoking at ]east one cigarette or equivalent daily in average. Details of 
smoking status to be recorded cover if the subject never smoked, is a previous smoker (includi.ng 
smoking stop date) or is a cutTent smoker. 
8.5.14 
SeH-measured plasma glucose and diaries 
The subject will be provided with a BG-meter including auxilia1ies as well as instmctions for use. 
The subject will be instructed i.n how to use the device including regular calibration according to the 
manufacnrrer's instmction. The instmction should be repeated if deemed required by the site staff. 
At e<1ch site visit the subject will be provided with a new dia1y. The diary must be collected at the 
next site visit and retained at the site as source data in accordance with Section 14. 
The subject must be instructed how to record the results of the SMPG values including a 9-potnt 
profile in the diary. The record should include date, time and value. All data from the diary must be 
transcribed into the eCRF during or following the contact. If obtained via phone and a discrepancy 
is later detected, the values in the eCRF must be co1TeCted. 
Occasional review by the investigator of the values stored in the memory of the BG-meter and 
con-ect reporting of tl.1ese in the diary is advised in order to ensure adequacy oftl1e data rep01ted in 
the trial database. 
If clarification of entlies or discrepancies in the diary is needed., the subject must be questioned and 
a conclusion made in tl1e subject' s medical record. Care must be taken not to bias the subject. 
The BG-meter uses. test strips. calibrated to plasma values. Therefore, all measurements pe1fonned 
with capillary blood are automatically calibrated to plasma equivalent glucose values which will be 
shown on the display. 
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Only the BG-meter provided by Novo Nordisk should be used for the measurements required m the 
protocol. Measurements done by the subject's own CGM must not be used for trial-related 
assessments. 
2-point and 9-point SMPG pt·ofiles 
The subject will be asked to pe1fom1 daily SMPG measurements for a 2-point profi]e throughout the 
trial until end of treatment at the following time points: 
• Before breakfast 
• Before main evening meal 
For details refer to the Insulin Titration Guideline in Appendix A. 
In addition, SMPG measLu·ements for a 9-point profile must be completed in the pe1iod between 
screening and randomisation and at specific visits in the pregnancy period of the trial as per 
flowchart in Section 2.3. The SMPG measurements should be me.tsured and recorded m the diary at 
the time points listed in Table 8-1. 
The SMPG measurements before breakfast should preferab]y be petfonned after having consumed 
only water since midnight and before insulin injection. The SMPG measurements before lunch, 
main evening meal and bedtime should be perfonned before insulin injection. Al] measurements 
will be recorded in the diary by the subject. 
Table 8-1 Time points for the 9-point proffie collected 2 days before selected visits 
Time point 
Two days 
Oueday 
before visit 
before visit 
Before breakfust 
90 minutes after lhe start .of breakfast 
Before hmch 
90 minutes after t11e slarr of lunch 
Before main evening meaJ 
90 minutes after the start ofm.ain evening meal 
Before bedtime 
At4 am 
• Measurements included in the 2-poiut profile 
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Starting after randomisation the subject should be instrncted to repott date, dose and time point of 
administration of basal insulin (IDeg/IDet) in the diaiy throughout the trial on three days prior to a 
visit and/or phone contact. 
The recommended basal insulin doses will be calculated in the eCRF based on recommendation 
from the Insulin Titration Guideline in Appendix A. At each site visit or phone contact the 
investigator must review and adjust the basal insulin doses based on the reconunendation in the 
eCRF and inf01m subject about the adjusted doses. 
In the eCRF investigator must record the first date and the last date of trial product (IDeg/lDet). 
8.5.16 
Adverse events 
Adverse events (AEs) must be repo1t ed at each visit in accordance with the procedures outlined in 
Section.ll. 
8.5.16.1 
Medication error 
If a medication enor is observed during the trial, the following .information is required and a 
specific event fo1m must be completed in the eCRF in addition to the AE f01m: 
• 
Trial product(s) involved 
• 
Classtficatiou of medication etTor 
• 
Whether the subject experienced any hypoglycaemic episode and/or adverse event(s) as a result 
of the medication eiror 
• 
Suspected primary reason for the medication enor 
For definition of medication errors, see Section 12.1.4. 
8.5.16.2 
Adverse events requiring additional data c.ollectlon 
For the following AEs additional data collection is required and specific event fmms must be 
completed in the eCRF in addition to the AE fonu. 
In case any of these eve11ts fulfil the criteria for an SAE, these must be repo1ted accordingly, see 
Section 12.2. For events reqrnirmg adjudication, see Section 12.7.3. 
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All events of benign, pre-maHgnaut/carcinoma in situ aud malignant neoplasms must be rep01ted 
during the trial and the following additional information should be obtained as part of standard of 
care aud be rep01ted in the neoplasm eCRF, if available: 
• 
Type of neoplasm 
• 
Treatment given for the event 
• 
Diagnostic imaging 
• 
Pathological examination (outcome and 
staging) 
• 
Participation in screening programs 
• 
Relevant risk factors associated with the event 
• 
Symptoms and laboratory results leading 
to identification of.event 
Pre-eclampsia 
If pre-eclampsia (PE) is observed during the trial, the following additional info1mation must be 
reported in the PE eCRF, if relevant and available: 
• 
New-onset hype1tension 
• 
HELLP syndrome 
• 
Proteinuria 
• 
Other severe organ involvement 
• 
Presence of eclampsia 
• 
Relevant risk factors associated with the event 
• Treatment given for the event 
New-onset hype1tension is defined as BP ~ 140 mmHg systolic or~ 90 mmHg diastolic, based on at 
least 2 measurements taken at least 4 hours apal1) occurring after GW 20. 
Proteinuria is defined as ~ 300 mg protein in a 24 hours urine sample, a protein-to-crea6nine ratio 
of~ 300 mg/gin a urine sample or a urine dipstick protein of 1 +. 
Congenital anomaly(-ies) 
All events of congenital anomaly(-ies) obse1ved for the infant will be collected in the specific 
eCRFs for pregnancy outcome after delivery. Cases of abnonnal pregnancy outcome must be 
reported as an AE and will be subject for event adjudication. 
8.5.16.3 
Hypoglycaemic episodes 
Plasma glucose should always be measured and recorded wben 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 in the diaiy according to the instrnctions below throughout the trial from 
random.isa6on to the end of trial. 
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Upon onset of a hypoglycaemic episode the subject is recommended to measure plasma glucose 
eve1y 15 minutes until tl1e SMPG value is > 3.9 mmol/L (70 mg/dL) and/or symptoms have been 
resolved in accordance to current guidelinesll. 
An SMPG value ~ 3.9 mmol/L (70 mg/dL) or hypoglycaemic symptoms must trigger a 
hypoglycaemic episode fonn to be completed by the subject. Repeated SMPG measurements and/or 
symptoms, occurring within a period of 60 min after onset on a hypoglycaemic episode, ,...,-ill by 
default be considered as one hypoglycaemic episode until a succeeding SMPG value is 
> 3 .9 mmol/L (70 mg/dL) and/or symptoms have been resolved and should be reported on one 
hypoglycaemic episode form SMPG measurements S 3.9 nunol/L (70 mg/dL) or hypoglycaenlic 
symptoms after the 60 min period shall trigger the repo11ing of a new hypoglycaemia episode and 
prompt the subject to fill out a new hypoglycaemic episode fon11 until a succeeding measurement is 
> 3 .9 mmol/L (70 mg/dL) and/or symptoms have been resolved. 
In case of several low SMPG values ·within the 60 minutes mterval, the lowest value is the one that 
will be rep01ted as the SMPG value for the hypoglycaemic episode but the sta1t time of the episode 
will remain as the time for the first SlvfPG value and/or symptom. 
The record should include the following infonnation: 
• 
Sta1t date and time of the hypoglycaemic episode 
• 
The plasma glucose level before treating the episode (if available) and any follow up 
measm-ements. 
The lowest value measured during the hypoglycaemic episode will be repo11e<l as the plasma 
glucose value for the episode, the remaining values will be kept as source data in the diary. 
• 
Whether the episode was symptomatic (Yes/No) 
• 
A hypoglycaemic episode sta11ing without symptoms should be updated to symptomatic if the 
subject experiences symptoms later during the episode. 
• 
Whether the subject was able to treat herself 
• 
If the seve1ity of a hypoglycaemic episode aggravates, only one hypoglycaemic episode should 
be repo11ed reflecting the most severe degree of hypoglycaemia. 
• 
Date, time and dose oflast trial product ad1ni11istration prior to the episode 
• 
Date and time of last main meal (not including snacks) prior to the episode 
• 
Whether the episode occurred in relation to physical activity 
• 
Whether the episode related to a change in any concomitant illness 
• 
Any sign of fever and/or other acute disease 
• 
Whether the subject was asleep when the episode occuITed 
• 
If yes, whether the symptoms of the episode woke up the subject 
The answer to the question: "Was the subject able to treat herself?" must be answered "No" for an 
episode requiring assistance of another person to actively administer carbohydrate, glucagon, or 
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take other corrective actions. Plasma glucose concentrations may not be available during an event, 
but neurological rec.overy following the return of plasma gltwose to normal is considered sufficient 
evidence that the event was i..nduced by a low plasma glucose concentrationll. 
Oral carbohydrates must not be given if the subject is unconscious. 
If the question "Was the subject able to treat herself?" is answered "No", the folJowing information 
should be recorded by the subject 
• 
Who assisted in the treatment of the hypoglycaemic episode (i.e. medical person or non-medical 
person)? 
• Where the treatment was administered (in clinic/emergency rooilllhospital or other. If the 
s11bject WllS treated 111 clinic/emergency room./hospitlll, whether they were tmnspot1ed in lltl 
ambulance or not) 
• Type of treatment provided by another person (i.e. oral carbohydrates, glucagon, i.v. glucose or 
other) 
• 
Were symptoms alleviated after administration of treatment? 
• Factors contributing to the episode (i.e. physical activity, missed meal, diet change, medication 
error (i e. overdose, mix-up between products, incorrect use of device), miscalculation of insulin 
dose, other factors not listed or unknown) 
• Did the subject experience seizure? 
• 
Was the subject unconscious/comatose? 
• 
Did the subject experience any of the following symptoms36 (layman te1m used in the diary is 
specified in brackets if different from the protocol term)? 
• Autonomic: sweating, trembling, hunger or palpitations (rapid or irregular heart beat) 
• 
Neuroglycopenic: confusion, drowsiness, speech difficulty, visual disturbances, odd 
behaviour, impaired balance or incoordination (reduced ability to coordinate movement) 
• General malaise: headache or malaise (feeling discomfort/unease) 
• Other symptoms 
The investigator must review the dia1}1 for ]ow SMPG values not reported as hypoglycaemic 
episodes. TI1e subject must be questioned whetber any of the low values were severe, i.e. whether 
the subject was able to self-treat or not. If the subject was not able to self-treat, it has to be reported 
as a severe hypoglycaemic episode. 
Low SMPG values for non-severe hypoglycaemic episodes not having a hypoglycaemic episode 
fonn completed within 7 days since the SMPG measurement should be repot1ed on a 
hypoglycaemic episode form with as much infom1ation as possible. Novo Nordisk wilJ not query 
for additional data except for the stat1 date, SMPG value and whether the subject was able to self-
treat due to decreased validity of such data.37• 38 
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The subject must be re-trained in how to report hypoglycaemic episodes if the investigator identifies 
low SMPG values not reported as hypoglycaemic episodes. 
If the hypoglycaemic episode fulfils the criteria for an SAE then an AE form, a safety infonuation 
form (SIF) and an event adjudication form must also be filled in, see Section 11. 
8.5.16.4 
Neonatal hypoglycaemic episodes 
A neonatal plasma glucose assessment should be taken preferably within the first 1-2 hours 
postpartum and documented in the subject's medical record as per local procedure. If deemed 
necessary the neonatal plasma glucose assessment should be repeated 
1l1e definition of neonatal hypoglycaemia is plasma glucose values: 
• 
I. 7 mmo]/L (3 l mg/dL) within the first 24 hours after birth or 
• 
2 .5 mmol/L (4 5 mg/dL} between 24 hours and 48 hours after birth 
In case a neonatal hypoglycaemic episode is measured, the episode must be recorded in the eCRF at 
the delivery visit. If the neonatal hypoglycaemic episode fulfils the c1iteria for an SAE, this must be 
reported according to Section ill-
8.5.17 
Laboratot-y assessments 
Laboratory analyses will be perfonned by both a central and special laboratory. The central 
laboratory wilJ provtde all laboratory supplies for the sampling of all blood and urine samples 
collected during the trial (Table 8- 2) as welJ as a manual with detailed desc1iption of procedures 
and fmther information regarding e.g. tubes and labels to the sites. 
Fasting plasma glucose (FPG) is measw·ed in order to evaluate metabolic control. The subject must 
attend these visits fasting as outlined in Section 8.5.2. 
An FPG result ~3 .9 mmol/L (70 mg/dL) should not be reported as a hypoglycaemic episode but as a 
clinical laboratory adverse event (CLAE) at the discretion of the investigator according to 
Section 12. L 1). 
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Table S--2 Laborato1·y panmeters included in the trial 
Haematology 
Glucose metabolism 
• 
Haemoglobin 
• 
Glycosylated haemoglobin (HbA1,) 
• Haematocrit 
• Fasting Plasma Glucose (FPG) 
• 
Erythrocytes 
• nu·ombocytes 
Urlnalysls 
• 
Leucocytes 
• 
Protein-lo<reatinine ratio"" 
Pregnancy• 
Insulin degludec cord btooct• 
• 
Hlllnan chorionic gonadotropi:n (hCG) 
• 
Umbilical cord blood !Deg del'ivate levels 
Biochemistry 
• Creatinine 
• Alanine aminotransferase (ALT) 
• 
Alblll)llll 
• 
AspaJ'lale aminotransferase (AST) 
• Bilirubin (total) 
• Alkaline phosphatase (AP) 
• Sodium 
• Estimated Glomemlar filtration rate (eGFR)b 
• Potassium 
• Sennn pr,egnancy analyses performed by ceuu-al laboratory at screening, in case of a positive home 
pregnancy lest during the conception pe1iod of the trial and al visit 54. 
& Calculated by the c-enlral Laboratory at screening lo detemnne eligibility according to exclusion 
criteria. 
' Calculated by the central laboratory dming the pregnancy period to screen for proteinuria wtthout 
coUe<:ting 24-homs urine. 
d Analysis performed by the special laboratory aud results provided to the central laboralory. 
Collection ofmnbilical cord blood sample is only applicable for subjects randomised to IDeg. 
The central laboratory provides results to the trial sites in the units preferred by the trial sites while 
the results that are transferred to the trial database will always be in SI units. Results from the 
exploratory IDeg cord blood analyses will not be provided to the trial sites (unless required by the 
com1try•s Healtb Authority or IEC/CRB) as these results wiU not be used for any clinical evaluation 
by the investigator during the trial, Section 24.2 . The exploratory levels of IDeg cord blood will be 
analysed using the analytical method used for phannacok:inetic measurements by the special 
laboratory. 
Review of laboratory repo1ts must be documented either on the laboratory repo1t or in the subject's 
medical record. All laboratory reports must be retained at the site as source data. 
Only laboratory samples specified in the protocol must be sent to the central laboratory for analysis. 
If additional laboratory sampling is needed, e.g. to follow up on AEs, this must be done at a local 
laboratory. 
The laboratory equipment may provide analyses not requested in the protocol but produced 
automatically in connection with the requested analyses according to specifications in the laboratory 
standard operating procedures. Such data will not be transfeired to the trial database, but abnormal 
values will be repo1ted to the investigator. The investigator must review all Jaboratory results for 
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concomitant illnesses and AEs and repo11 these according to Section 8.5.6 and Section 12 
respectively. 
Laboratory samples will be destroyed no later than at finalisation of the clinical trial repo11 (CTR). 
8.5.18 
Body weight ancl height 
Body weight should be assessed in light clothes without shoes. Body weight should be measm-ed in 
pounds (lb) or kilograms (kg) and recorded in tl1e eCRF to one decimal place. 
Height should be assessed without shoes. Height should be measured in inches (in) or meter (m) 
and recorded in the eCRF to two decimal places. 
Body weight and height wiU be used for calculation of the BMI in the eCRF. 
8.5.19 
Eye examination 
A fundus photography or phannacologically dilated fimdoscopy must be perfo1med as a subject 
must not be randomised without results co1ifinning absence of proliferative retinopathy or 
maculopathy requiring acute treatment. TI1e procedure may be perfonned by the investigator or 
local ophthalmologist/optometiist according to local practice. 
For subjects screened non-pregnant the pha1macologically dilated fundoscopy/fundus 
photography can be pe1fonned within 90 days before randomisation if the results are available 
before randomisation. In case the subject becomes pregnant in the conception pe1i od of the t:Ji al, an 
additional eye examination must be completed as soon as possible, but no later than 7 days after 
visit 55. 
For subjects screened pregnant the phannacologically dilated fundoscopy/fundus photogrnphy 
can be perfo1med within 28 days before randomisation if the results are available before 
randomisation. 
The eye examination at visit 71 can be performed within 28 days before or after the visit. 
The eye examination at end of treatment cau be perfom1ed within 28 days before end of treatment 
as long as the result is available at the end of treatment visit. 
The evaluation of the eye examination results by the investigator must be documented in the 
subject's medical records and recorded in the eCRF in accordance with the following categories: 
Nonnal, abnormal and if the abnonnal result was clinically significant (Yes/No) and if considered 
as sight-threaten.iug retinopathy. 
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In case of "abnormal, clinically significant" the investigator must record the finding on the medical 
history/concomitant illness fo1m if present at screening. Any new abnonnal, clinically significant 
finding during the trial and any clinically significant worsening from baseline must be recorded as 
anAE. 
8.5.20 
VUal signs 
Diastolic BP, systolic BP and pulse will be measm-ed following standard clinical practice preferably 
in the sitting position during the t1ial, aud must be recorded in the eCRF. The evaluation by the 
investigator must be in accordance with the following categories: No1mal, abnonnal and if the 
abnonnal result was clinically significant (Yes/No). 
In case of "abno1mal, clinically significant" the investigator must record the finding on the medical 
history/concomitant illness fom1 if present at screening. Any new abnormal, clinically significant 
finding during the trial and any clinically significant worsening from baseline must be recorded as 
anAE. 
8.5.21 
Physical examination 
A general physical examination will be done at the screening visit and selected visits during the 
pregnancy period of the trial. The examination must be recorded in the eCRF and includes: 
• Head, ears, eyes, nose, tlu·oat, neck 
• Gastrointestinal system including mouth 
• 
Respirntoty system 
• 
Musculoskeletal system 
• 
Cardiovascular system 
• 
Central and periplieral nervous system 
• 
Skin 
The evaluation by the investigator must be in accordance with the following catego1ies: Notmal, 
abnonnal and if the abnonnal result was clinically significant (Yes/No). 
In case of "abnonnaJ, clinically significant" the investigator must record the finding on the mectical 
histo1y/concomitant illness fotm if present at screening. Any new abno11nal, clinically significant 
fmding during the trial and any cHnically significant worsening from baseline must be recorded as 
anAE. 
8.5.22 
Electrncardiogram 
A 12-lead ECG will be perfonned according to local practice at screening or in the period between 
screening and randomisation if the result is available before randomisation. 
The evaluation of the ECG must be documented either on the printout or in the subject's medical 
record. The evaluation by the investigator must be recorded in the eCRF in accordance with the 
following categories: Normal, abnonnal and if the abnormal result was clinically significant 
(Yes/No)_ 
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In case of "abnormal, clinically significant" the investigator must record the finding on the medical 
history/concomitant illness fo1m if present at screening. Any new abnonnal, clinically significant 
finding during the trial and any clinically significant worsening from baseline must be recorded as 
anAE. 
8.5.2-3 
Tralnlng in pen handling 
The subject must be trained in how to handle the pen devices when handed out the first time. 
Training must be repeated during the trial as specified in the flowcha1ts in Section ll and 
Section 2.3 in order to ensure coITect use of the device. The following should be emphasised: 
• Always use a new needle for each injection as this will prevent contamination and blocked 
needles 
• 
Priming the pen to ,ensure product flow 
• Injection technique as per Direction for Use (DFlJ) for the individual trial products (!Deg and 
[Asp or IDet and IAsp) 
• 
Always check that the coned insulin pen is used (basal or bolus), e.g. by colour coding and 
label. Use the pen differentiation guide as a reference. 
8.5.24 
Subject compliance 
TI:u-oughout the trial, the investigator ·will remind the subject to foHow the trial procedures and 
requirements to ensure subject compliance. lf a subject is found to be non-compliant, the 
investigator will remind the subject of the impo1iance of following the instructions given induding 
taking the trial products as prescribed. 
It is important to ensure subject treatment compliance. Duting treatment with trial products, the 
investigator should evaluate adherence to trial treatment at each weekly contact (site visit or phone 
contact). 
8.5.25 
Dlscontlnuation ofl\1yGiucoHealth BG-meter and eDlary 
This section applies to subjects em-oiled prior to implementation of Protocol Amendment no. 1. 
Subjects who have used the glycaemic data collection system (the combination of the 
MyGlucoHealth Wireless BG-meter and an electronic diary) have been instructed to discontinue 
this system and use an alternative BG-meter until a new trial BG-meter and paper diary is provided 
by Novo Nordisk. 
The foJlowing must be recorded by the investigator in the eCRF: 
• 
Start date of new trial BG-meter 
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Trial supplies comprise trial products and auxiliary supplies. Additional details regarding trial 
supplies can be foUJld in the Trial Materials Manual (TMM). 
Trial products must not be dispensed to any person not included in the trial Trial products must not 
be used, if they do not appear dear and colourless. 
9.1 
Trial products 
The trial products summarised in Table 9-1 will be provided by Novo Nordisk A/S, Denmark. 
Folic acid will not be supplied by Novo Nordisk. However, folic acid will be reimbmsed if required 
by the country's regulatory authority or IRB/IEC. 
Table 9-1 Trial products 
Trial produrt 
Strength 
Dosage rorm 
Route or 
Dellnry devke 
admJnlstralion 
Insulin deg]udec 
(Tresiba•rrreg]udec• 
l OO U/wL Solution for injection 
Subcutaneous 
3 mL PDS290 pen injector 
[Israel]) 
(FlexTouch12) 
(IMP, test product) 
Insulin detemir (Levemil4 
l OO U/wL Solution for injection 
Subcutaneous 
3 mL pre-filled pen 
(IMP, r,eference therapy) 
(FlexPen• ) 
Insulin aspart (NovoRapid~ 
l OO U/mL Solution for injection 
Subcutaneous 
3 mL pre-filled pen 
(IMP, bolus .insulin) 
(FlexPen• ) 
IMP: iuYestigational medicinal product 
9.2 
LabeUing 
The trial products will be labelled in accordance with Annex 1339, local regulations and tti al 
requiI·ements. 
Each trial site will be supplied with sufficient amounts of trial products for the trial on an Oll-going 
basis controlled by the IWRS. Trial product will be distributed to the uial sites according to 
enrolment and randomisation. 
The investigator must document that the direction for use (DFU) for the individual trial products 
(!Deg and !Asp or IDet and !Asp) is given to the subject orally and in writing at the first dispensing 
visit (visit 2). Also, tl1e pen differentiation guide must be provided to the subject at the first 
dispensing visit (visit 2). Additional DFUs and pen differentiation guides can be provided as needed 
at the following dispensiL1g visits. 
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The investigator must ensure that trial product is kept under proper storage conditions (Table 9-2) 
and record and evaluate the temperature. Toe investigator must inform Novo Nordisk Immediately 
if any trial product has been stored outside specified conditions (e.g. outside temperature range). 
Additional details regarding handling of temperamre deviations can be found in tile TM1vL 
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 
approp1iate action to ensure correct storage. 
Table 9-2 Storage conditions 
Trial product 
Storage conditions 
In-use conditions 
Io-use tillK'" 
(not in-use) 
lusulin degludec • 
Store in refrigerator 
• 
Do not store above 30"C 
• 
Use ,vi.th.in 
(2"C lo 8°C) 
• Protect from light 
8 \,,reeks 
• 
Protec! from light 
• 
Can be stored in refiigerator (2°C lo 8°C) 
• 
Do not freeze 
• Do not freeze 
Insulin detemir • 
Store in l'efrigerator 
• Store below 30°C 
• Use within 
(2°C lo 8°C) 
• 
Protect from light 
6 weeks 
• 
Protect from light 
• 
Can be stored in refiigerator (2°C lo 8°C) 
• 
Do not freeze 
• Do not freeze 
Insulin aSJ)<lrt 
• 
Store in refrigerator 
• Store below 30°C 
• Use with.in 
(2°C lo 8°C) 
• 
Protect from light 
4 \veeks 
• 
Protect from light 
• Do not refrigerate 
• 
Do not freeze 
• 
Do not freeze 
• In-ru.e time stru.ts when first dose is taken. 
9.4 
Drug accountabUlty and clestructlon 
Dn1g accountability of all trial products received at site is the responsibility of the investigator. 
Dn1g accow1tability must be documeuted in the IWRS by confirming dispensing of allocated trial 
products and confirrning trial products returned by the subject or lost 
Returned trial product (used/partly used and/or unused), expired or damaged trial product can be 
stored at room temperature and must be stored separately from non-allocated trial product 
Nou~ llocated trial products including expired or damaged products must be accounted as unused at 
the latest at closure of the trial site. 
Destrnction of trial products can be performed on an on-going basis and will be done according to 
Jocal proced1ues after accountability is finalised and reconciled by the monitor. Destruction of 
products must be documented in the IWRS. 
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The following wiJI be provided by Novo Nordisk: 
• 
DFU for the pen devices 
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• 
Novo Nordisk needles for the pen devices (Only needles provided by Novo Nordisk must be 
used for administration of uial product.) 
• 
BG-meter including strips, lancets and control solution for BG-meter 
For further auxiliary supplies info1mation, refer to the Th1M. 
10 Interactive web response system 
A trial-specific fWRS wilJ be set up which can be accessed at any time via the intemet. Access to 
the IWRS must be restricted to and controlJed by authorised persons. 
The IWRS is used for: 
• 
Screening 
• Screening failure 
• 
Randomisation 
• Treaunent discontinuation 
• 
Medication anival 
• 
Completion of treatment 
• 
Dispensing 
• 
Dmg accountability 
• 
Dispensing verificalion (when barcode 
• 
Data change 
scanner is used) 
IWRS user manuals will be provided to each trial site. 
11 Randomisation procedure 
The IWRS is used for randomisation. Subjects complying with the inclusion and exclusion criteria 
will be randomised l: l into one of the two treatment regimens in an open-label nuumer. 
Randomisation will be stratified according to the subject's pregnancy status at time of 
randomisation (pregnant/non-pregnant) as well as planned continued tise of the subject's own CGM 
(Yes/No). 
Iu IWRS this means there will be two different treatment regime11s: 
• 
IDeg OD + IAsp 2-4 times daily 
• 
IDet OD/BID + IAsp 2-4 times daily 
Recruitment will be closed as soon as the total number of plalllled subjects to be randomised is 
achievable, talcing the number of screened, the screening failure ratio and non-pregnant randomised 
subjects into account. AJl investigators will be notified immediately when the recmitment period 
ends after which no further subjects may be screened and the IWRS will be closed for further 
screening. AJl subjects wcluded i.n the screening period and eligible for randomisation can be 
randomised. 
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12 Adverse events, technical complaints and pregnancies 
12.1 
DeOnitlons 
12.1.1 
Adverse eve11t 
An adverse event (AE) is any untoward medical occurrence in a subject administered a medicinal 
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 abnonnal laboratory 
finding), symptom or disease temporally associated with the use of a product, whether or not 
considered related to the product. 
For both the pregnant subject and foetus/infant there are specific AEs that should not be repo11ed as 
AEs un]ess they fulfil the seriousness criteria. These are outlined in Sections 12.S.l and 12.S.2. 
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 abnonnality that suggests a disease and/or organ toxicity and is of a 
seve1ity that requires active management. Active management includes active treatment or 
further investigations, for example change of medicine dose or more frequent foUow-up due to 
the abnormality. 
The following should not be rep011ed as AEs: 
• Pre-existing conditions, i.ncludi.ng those found as a result of screening or other trial procedures 
perfonued before exposure to trial product (pre-existing condttions should be r,epotied as 
medical histo1y or concomitant illness). 
• Pre-planned procedures un]ess the condition for which the procedure was planned has worsened 
from the first trial related activity after the subject has signed the infonn ed consent. 
• 
Non-serious hypoglycaemia is an AE, but is repo11ed on a hypoglycaemic episode fonn in the 
diaiy instead of on fill AE form in the eCRF, see Section 8.S.16.3 
The following three definitions are used when assessing an AE for both the subject and the 
foeh1s/infant 
• Severity 
• 
Mild - no or transient symptoms, no inte1ference with the subject's daily activities. 
• 
Mode1·ate - marked symptoms, moderate interference with the subject's daily activities. 
• 
Severe - considerable interference with the subject's daily activities; unacceptable. 
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• 
Causality 
Relationship between an AE and the relevant trial product(s): 
• 
Probable - Good reason and sufficient documentation to assume a causal relationship. 
• 
Possible - A causal relationship is conceivable and cannot be dismissed. 
• 
Unlikely - The event is most likely related to aetiology other than the trial product. 
• 
Final outcome 
12.1.2 
• 
Re<:overe(l/resolved - Toe subject has fully recovered, or by medical or surgical 
treatment the condition has retumed to the level observed at the fast triaJ-related activity 
after the subject signed the informed consent. 
• 
Re<:overing/resolvlng - 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 tlial 
or has died from another AE. 
• 
Recovered/1•esolved 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 ofthe subject has not improved and the 
symptoms are unchanged, or the outcome is not known. 
• 
Fatal - Tbis term is only applicable if the subject died from a condition related to the 
repor1ed AE. Outcomes of other repo1ted AEs in a subject before she died should be 
assessed as "recovered/resolved", "recovering/resolving", ''recovered/resoived with 
sequelae" or '·not recovered/not resolved". An AE with fatal outcome must be reported 
as an SAE. 
• 
Unknown - TI1is term is only applicable if the subject is lost to follow-up. 
Sel'ious adverse event 
A se1ious adverse event (SAE) is an experience that at any dose re-Sul ts in any of the following: 
• 
Death, including death of the foetus/infant as a L'esult of spontaneous abmtion, perinatal or 
neonatal death. 
• A life-threatening'- experience. 
• Ill-patient hospitalisatfonb or prolongation of existing hospitalisation. 
• 
A persistent or significant disability or incapacity of the subject. 
• 
A congenitaJ anomaJy or bi.tth defect of the foetus/infant. 
• 
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. 
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a. 
The term "life threatening" in the definition of SAE refers to fill 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. 
t>. 
The te1m "hospitalisation' is used when a subject 
-
Is admitted to a hospital or in-patient, inespective of the duration of physical stay, or 
-
Stays at the hospital for treatment or obse1vation for more than 24 hours. The 
hospitalisation for delivery/caesarean section is not considered as an SAE in this trial 
However. prolonged hospitalisation due to complications in relation to 
delivery/caesarean section should be repotied as an SAE. 
Medical judgement mnst a[ways be exercised and when in do11ht, 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 llial inclusion, are not 
considered AEs or SAEs. 
c. 
A substantial dismption of a subject's ability to conduct nonna1 life functions (e.g. 
following the event or clinical investigation the subject has significant, persistent or 
pennanent change, impainnent, damage or dismption in her body function or structure, 
physical activity and/or ,quality of life). 
d. For example intensive treatment in an emergency room or at bome of aJlergic 
bronchospasm, blood dyscrasia or convulsions that do not result in hospitalisation or 
development ofdmg dependency or dmg abuse. 
The following AEs must always be reported as an SAE using the important medical event c1iterion 
if no other seriousness criteria are applicable: 
• 
Suspicion of transmission of mf ectious agents via the trial product. 
• 
Risk ofliver injury defined as ALT or AST > 3 x upper normal limit (UNL) and total bilimbin 
> 2 x UNL, where no altemative aetiology exists (Hy's law). 
12.1.3 
Non-serlous adverse event 
A non-serious AE is any AE which does not fulfil the definition of an SAE. 
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12.1.4 
Medication errors 
A medication e1rnr concerning trial. products is defined as: 
• 
Administration of wrong drng. 
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Note: Use of wrong DUN is not considered a medication e1Tor un1ess it results in administration 
of wrong drng. 
• 
Wrong route of admin.istrntion, such as intramuscular instead of subcutaneous. 
• Administration of an overdose with the intention to e-ause hann (e.g. suicide attempt), misuse or 
abuse of trial product. 
• 
Accidental administration of a lower or higher dose than intended. That is a dose lower or 
higher than 20 % of the prescribed/intended dose. However, the administered dose must deviate 
from the intended dose to an extent where clinical consequences for the trial subject were likdy 
to happen as judged by the investigator, although they did not necessaiily occur. 
Medication errors must be repoited on an AE fonn and a specific. event form, see Section 8.5 .16.1. 
12.1.5 
Aclverse eveBts requiring a<ldltlonal cl.ata collection 
Adverse events requiring additional data collection are AEs where the additional data will benefit 
the evaluation of the product safety. Some events in this trial will be acijudicated by an independent 
external connnittee as described in Section 12.7.3. 
Table 12-l lists AEs that require completion of specific event forms in the eCRFs and/or are 
subject to event adjudication. 
For details about specific event fom1s, see Section 8.5.16.2. 
Table 12--1 Adverse events requiring completion of specific event forms and/or are subject ,to 
event adjudication 
Event 
Spedftc event form 
Ennt adjodtcatton 
Pre--ed ampsia (PE) 
Yes 
No 
Neoplasm 
Yes 
No 
Medication error 
Yes 
No 
Congenital anomaly 
No• 
Yes 
Severe hypoglycaemia or h)'pogl.ycaemic episodes reported as an SAE 
Nob 
Yes 
Fatal event'" 
No 
Yes 
• Infonnation about congenita1 anomaly(-ies) will be collected in the pregnancy outcome eCRF. 
b Hypoglycaemic episodes will be registered in the diary by the subject and transferred to eCRF by the investigator. 
• All fatal events in subjects "ill be adjudicated to determine if the cause of death was related to a severe 
hypoglycaemic episode. All fatal events for infants including in utero deaths will be adjudicated for cause of death. 
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A technical comp]aint is any written, electronjc, or oral c01U111u11ication that aJleges product 
(medicine or device) defects. The technical complaint may be associated with an AE, but does not 
concern tbe AE itself. 
Examples of technical complaints: 
• 
TI1e physical or chemical appearance of trial products (e.g. discoloration, particles or 
contamination) 
• 
AU packaging material includlllg labelling 
• 
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 adve.-se events 
All events meeting the definition of an AE must be collected and reported. Thjs includes events 
from the first fliaJ-related activity after the subject has signed the infonned consent until the end of 
the post-treatment follow-up period (V92). TI1e events must be recorded in the applicable eCRF 
fo1ms in a timely manner, see timelines below and Figm·e 12- 1. 
During each contact with the trial site staff, the subject must be asked about AEs and technical 
complaints, for examp]e by asking: "Have you experienced any problems since the last contact?''_ 
All AEs, observed either by the investigator or subject, must be reponed by the investigator and 
evaluated. 
All AEs must be recorded by the investigator on an AE fo1IIL The investigator should repo1t the 
diagnosis, if available. If no diagnosis is available, the investigator should record each sigu and 
symptom as individual AEs using separate AE forms. 
For SAEs, a SlF must be completed in addition to the AE form. If several symptoms or diagnoses 
occur as part of the same clinical picture, one SIF can be used to describe all the SAEs. 
For all non-serious AEs, the applicable fomis should be signed when the event is resolved or at the 
end of the trial at the latest. 
Tl.mellnes for initial reporting of AEs 
The investigator must complete the following forms in the eCRF within the specified timelines: 
• 
SAEs: The AE form ,,•iehin 24 hours and the SIF within 5 calendar days of the investigator's 
first lmowledge of the SAE. Both fonns must be signed within 7 calendar days from the date 
the inf01mation was entered m the eCRF. 
• For SAEs i-equJring i-epot,tlng on a specific event form: In addition to the above the specific 
event fonn within 14 calendar days from the investigator's first knowledge of the AE. 
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• 
Events fo1· Adjudication: TI1e adjudication fonu should be completed within 14 calenda1· 
clays of the investigator's first knowledge of the AE, see Section 12.3. The investigator should 
provide copies of the source documentation preferably within 4 weeks of event identification. 
If the eCRF is unavailable, the concerned AE info1mation must be reported on a paper AE fotm and 
sent to Novo Nordisk by fax, email or c-0urier within the same timelines as stated above. When the 
eCRF becomes available again. the investigator must enter the information on the fonn into the 
eCRF. Contact details (fax, telephone, email and address) are provided in the investigator trial 
master file. 
Ai fo,m < 24 M .. s 
Spr,clflc .,,..,nl form 
Adjudication form 
5IF < 5 <alendar days 
For SAE:s: 
< 14 calencla1 da.,s 
< 14 calendar days 
Source data < 4 
IMeii!i« 
Seious 
Yes 
Ye, 
Is theA<l"lerse Ennt 
Does the AE reql,jre 
lstheAE sullject to 
Quer ies ard folow-up 
AE identihd 
serioul or non• 
a specifictnnl 
adjudication and/or 
requests to be resol\ll!d 
1 .. 11001? 
form? 
is the outa,mefaral? 
< 14 calendar dars 
ND¥Herious 
No 
No 
No addition~! action 
No addition.ii .ictlon 
Time,lines are for the completion of forms from die time of invesilgatofs awarer.essAEs requiring sp«ificevent forms are 
d,esclbed in Section 12.LS AEs for adjlldcation are described in Section 12.7.3 
A£: Adve~eevent SIF: Safety information form 
F1gure 12-1 Reporting of AEs. 
Novo Nor<IJsk assessment of AE expectedness 
Novo Nordisk assessment of expectedness is performed according to the cunent versions and any 
update of the IBs for IDef, IDeti'Land IAspil. 
Reporting of trial p1·oduct-related SUSAR~ by ovo Nordisk 
Novo Nordisk will notify the investigator of ttial product-related suspected unexpected serious 
adverse reactions (SUSARs) in accordance witb local requirements and ICH GCPl . In addition, the 
investigator ,.vill be info1med of any trial-related SAEs that may warrant a change in any trial 
procedure. 
Io accordance with regulatory requirements, Novo Nordisk will infonn the regulatory authorities, 
including the European Medicines Agency (EMA), of trial product-related SUSARs. In addition, 
Novo Nordisk wi1l inform the IRBs/lECs of trial product-related SUSARs in accordance with local 
requirement and ICH GCP1, unless locally this is an obligation of the investigator. 
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If an AE is considered to have a causal relationship with a Novo Nordisk marketed product used as 
concomitant medication in the trial, it is important that the suspected relationship is repo1ted to 
Novo Nordisk, e.g. in the alternative aetiology section on the safety infom1ation form. Novo 
Nordisk may need to report this adverse event to relevant regulatory authorities. 
12.3 
Follow-up of adverse events 
The investigator must record follow-up .information by updating the forms in the eCRF. 
Follow-up infonnation must be repm1ed 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 tl1e outcome "recove1inglresolving" or "not recovered/not resolved". Cases 
c.an be closed with the outcome of "recovering/resolving" when the subject has completed the 
foUow-up period and is expected by the investigator to recover. 
The SAE follow-up information should only include new (e.g. co1rnctions or addi.tional.) 
infom1ation and must be reported within 24 hours of the investigator's first know]edge of tl1e 
information. This is also the case for previously non-serious AEs which subsequently become 
SAEs. 
• Non-serious A.Es: Non-se1ious AEs must be followed until the outcome of the event is 
"recoveringlreso]ving", "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 "recoveiinglresolving" when the subject has completed the follow-up pe1iod and is expected 
by the investigator to recover. 
The investigator must ensure that the recording of the worst case severity and seriousness of an 
event is kept throughout the trial. A worsening of an uw-esolved AE must be reported as foUow up 
with re-assessment of seve1ity and/or seriousness of the event. 
Queries or follow-up requests from Novo Nordisk must be responded to within 14 calenda1· days 
from the date of rec.eipt of the request, unless othenvise specified in the follow-up request. 
SAEs after end of trlal: If the investigator becomes aware of an SAE with a suspected causal 
relationship to the investigational medicinaJ product occurring to a subject after the subject has 
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ended the trial, the investigator should report this SAE within the same timelines as for SAEs 
during the trial. 
12.4 
Technical complalnts and technical complaint samples 
12.4.1 
Reporting of technical complaints 
All technical complaints on any of the following products: 
• 
Insulin degludec (!Deg), 100 U/mL, 3 111.L PDS290 pen injector (FlexTouch®) 
• Insulin detemir (IDet), 1 00U/m.L, 3 mL pre-filled pen (FlexPen®) 
• Insulin aspart (!Asp), 100 U/mL, 3 mL pre-filled pen (FlexPen®) 
• 
Novo Nordisk needles for pen devices 
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 Ieported to CustomeI Complaint CenteI, Novo No1di.sk. 
Contact details (fax, emaH and address) are provided in Attachment I to the protocol. 
l11e investigator must assess whether the technical complaint is related to any AEs and/or SAEs. 
Technical complaints must be reported on a separate technical complaint form: 
• 
One technical complaint form must be completed for each affected DUN 
• 
If DUN is not available, a technical complaint fonn for each batch 01 lot number must be 
completed 
The investigator must complete the technical complaint fonn 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 
• 
AU otheI technical complaints within 5 calendar days 
If the eCRF is unavailable or when reporting a technical complaint that is not subject related, the 
inf onnation must be provide-0 on a paper fotm by fax, email 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 infom1ation on the technical complaint fonn iii the 
eCRF. 
12.4.2 
Collection, storage and shipment of technical complaint samples 
The investigator must co11ect the technical complaiut sample and notify the monitor within 5 
calen(lar 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 
tl1at the sample is sent as soon as possible. A copy of the technical complaint fonn must be included 
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in the shipment of the sample. If several samples are returned in one shipment, the individual 
sample and the corresponding technical complaint fonn must be clearly separated. 
The investigator must ensure that the technical complaint sample c,ontains the batch or lot number 
and, if available, the DUN. All parts of the DUN should be returned. 
If the technical complaint sample is unobtainable, the investigator must specify 0 11 the technicaJ 
complaint form why it is unobtainable. 
Storage of the technical complaint sample must be done in accordance with the conditions described 
for the product. 
12.5 
Adverse events related to pregnancies 
The investigator must report infonnation about the pregnancy, pregnancy outcome, and health of 
the newborn infaot(s), as well as AEs in connection with the pregnancy and AEs in the foetus and 
newborn infant(s) until 2 months of age in the eCRF. 
Standard toe.al practlce for treatment/procedures during pregnancy 
Treatment or proc-edm·es of mother and/or foetus/infant(s) that are standard local practice and/or 
done for prophylactic purposes do not constitute AEs. Examples could be prophylactic i_v glucose 
given to a newborn infant of a diabetic mother or prophylactic aotibiotic ti-eatmeut of a newborn 
infant due to an infection in the mother. The infection should, however, be reported as AE in the 
mother. 
Terms not to be used fo1· reporting 
The diagnosis and symptoms used for reporting should always describe the condition as specific as 
possible. Unspecific diagnoses such as "diabetic foetopatby" should not be used. Instead the 
specific diagnose and/or symptom(s) under this term should be reported as individual AEs. 
Preterm deliYery 
Pretem1 delivery where the outcome of the delivery is without complications should not be reported 
as an AE in itself, neither on mother or infant. 
Pregnant subjects who wJthdraw consent 
For preguant subjects who withdraw consent, effo1ts should be made to obtain informatioo related 
to the pregnancy and pregnancy outcome. Iofmmation about the pregnancy and pregnancy 
outcome/health of the newborn infant(s) must be repm1ed on the paper pregnancy forms Maternal 
Fonn IA and l B, respectively. In case of an abnmm al pregnancy outcome, farther information 
must be reported on the Maternal Fotm 2. In additioo, infonnation from the biological father (if 
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known) must be reported on the Paternal Form, after an informed consent has been obtained, 
Section 18.2.1. 
Initial reporting and follow-up infonnation must be. reported within 14 ulendar days of the 
investigator's first knowledge of initial or follow-up information.. Reporting timelines for AEs in 
connection witl1 the pregnancy as well as in the foetus and newborn. infant(s) are defined in 
Section 12.2. 
The paper forms must be forwarded to Novo Nordisk either by fax, email or courier. Contact details 
are provided in Attachment II to the protocol. 
12.5.1 
Reporting adverse events Lo connection wUh the pregnancy 
The investigator has to report rdevant AEs in collllection with the pregnancy. The fom1s and 
timelines for repo11ing AEs are defined in Section 12.2. 
Pregnancy-related symptoms considered "nonnal" for a pregnant subject should only be reported as 
SAEs if they fulfil the se1iousness crite1ia. Examples could be: 
• 
Nausea 
• 
Back pain 
• 
Vomiting 
• 
Breast tendemess 
• 
Skin itching 
• 
Hot flushes 
• 
Vaginitis 
• 
SwolJen ankles or fingers 
12.5.2 
Reporting adverse events on foetus and/or mfant(s) 
The investigator has to report relevant AEs in the foetus and newborn infant(s). TI1e SAEs that must 
be reported include abnonnal outcome, such as foetal death (including spontaneous or induced 
abonion), and congenital anomaJy(-ies) (including those observed at gross examination or during 
autopsy of the foetus), as weU as other pregnancy complications fulfilling tl1e crite1ia of an SAE. 
Adverse events pertaining to the foetus/infant must be reported with the foetus/infant as the subject 
oftbe AE. The forms and ti.melines for reporting AEs are defined in Sections 12.2 and 12.7.3. 
Reporting of an abnormal pregnancy outcome 
In case of an abno1mal pregnancy outcome, e.g. congenital anomaly(-ies ), foetal death including 
spontaneous abortion and/or any abnormalities of the infant relevant information will be collected 
in the specific eCRF for pregnancy outcome after delivery. Cases of abnonnal pregnancy outcome 
must be reported as an SAE and wiU be subject to event adjudication. Section 12.7.3. Before 
infonuation for the paternal eCRF is collected a patemaJ infonned consent must be obtained, 
Section 18.2.1. 
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Some symptoms in the foetus and/or infant(s) are considered "normal" for a foetus/infant and 
should only be reported as SAEs if they fulfil the seriousness criteria. Examples could be: 
• 
Ini.tability 
• 
Neonatal hypoglycaemia (section 8.5 .16.4) 
• 
Breastfeeding problems 
• 
Macmsomia 
• 
Normal crying 
• 
Hyperbilirnbinaemia (not requiri.ng medical 
• 
Common neonatal skin reactions 
treatment) 
(diaper or bonnone rash) 
Repo11ing of foetal or neonatal death 
Foetal or neonatal death as a result of induced ab011ion should not be repo11ed as an AE, except in 
situations where the foetus/neonate was deceased prior to the induced abortion. 
In case of foetal or neonatal death the following applies: 
• 
In case of foetal or neonatal death e.g. due to spontaneous abo11io11, ectopic pregnancy or 
stillbirth, an SAE must be reported with the mother as the subject of the AE. 
• 
In c.ase the foetus/neonate also has a diagnosis e.g. an anomaly, an additional SAE must be 
repo11ed with the foetus/neonate as the subject of the AE. 
Induced abortions 
Induced abortion should not be reported as an AE as it is considered a procedure. Causes of induced 
abo1tions should always be reported as SAEs on either mother or foetus, as applicable. 
Repordng of caesarean section 
A caesarean section itself should not be repo11ed as an .AE as it is considered a procedure. Instead, 
the following details for the caesarean section will be recorded in the specific eCRF for the delivery 
visit: 
• Planned caesarean section (decision taken > 8 hours prior to delivery). TI1e reason for the 
planned caesarean section will be stated as e.g.: 
• 
Medic.ally indicated e.g. previous caesaiean section, narrow pelvis etc. 
• 
Non-medical reason(s) 
• AE or SAE e.g. breech presentation, failed induction. suspicion of macrosomia, 
deterioration of pre-eclampsia etc. 
• 
Unplanned caesarean section (decision taken s; 8 hours p1ior to delivery). The reason for the 
unplanned caesarean section 'Nill be stated as e.g.: 
• 
AE or SAE e.g. matemal bleeding 
• 
Foetal distress (always repmted as an SAE) 
• 
Lack of progression 
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Details about the congenital anomaly(-ies) wHl be collected in the specific eCRF for pregnancy 
outcome after delivery. All congenital anomalies must be repotted as an SAE, Section 12.5.2. 
As events of congenital anomalies are crucial for the ongoing safety monitoring, all congenital 
anomalies will be monitored closely by the Data Monitoring Committee (DMC, Section 12. 7 .2) and 
will be adjudicated by an independent adjudication committee (EAC, Section 12. 7.3). 
If a congenital anomaly is observed at ultrasound during pregnancy and reported as an SAE, but not 
confirmed after bi1th, the AE description should be updated with « 
o adverse effect'' or ''No 
adverse drug effect" in the eCRF. 
The EMA Guideline on 1he exposure to medicinal products during pregnancy classifies anomalies 
as congenital anomalies, major abnormalities or minor anomalies_il Specific definitions for each 
major abnormality are included in the European network of population-based registries for the 
epidemiologic srnveillanoe of congenital anomalies (EUROCA 1} 26 
Rates of congenital anomalies and malformations have in some studies been shown to be 4-5% in 
pregnant subjects with TlDM . .ll...li The most common anomalies affect the central ne1vous system, 
heart, ske]eton, kidneys, gastrointestinal tract or lungs. 
12.6 
Prec.autlons and/or overdose 
The administration ·of insulin, including an overdose of insulin, may result in hypoglycaemia. 
Symptoms may occur suddenly, see Section 8.5.16.3. 
Asymptomatic hypoglycaemia and mild to moderate symptoms ofhypoglycaemta should be treated 
with carbohydrates. Severe hypoglycaemia resulting in loss of consciousness should be n-eated with 
parenteral glucose, glucagon or dextrose at the discretion of the investigator. 
Detailed information is available in the cutTent edition and any updates of the IBs for IDef , IDeti2 
and IAspil and/or local approved product information, if applicable. 
12.7 
Committees related to safety 
12.7.1 
Novo Nordisk safety committee 
Novo Nordisk has an internal IDeg safety con11.nittee to perform ongoing safety surveillance ou 
blinded trial data. The !Deg 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 internal Novo Nordisk nial personnel. 
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The data monitoring conuuhtee (DMC) is an independent, exteruaJ committee composed of 
members whose expertise ,covers relevant specialties including statistics. Toe DMC is established to 
review and evaJuate ac,cwmdated data from the trial at predefined time points as weJl as ad hoc. 
This is in order to protect the safety of the subjects and to evaluate the benefit-risk balance. The 
DMC will have access to unblinded data, aud will provide recommendations on trial continuation, 
modification or termination. 
Information regarding responsibilities, procedures and workflow to be used by the DMC are 
specified in the DMC chaiter. 
12.7.3 
Event adjudication committee 
An independent extemal event adjudication committee (EAC) is established to peifonn validation 
of selected AEs listed in Table 12-2 accOiding to pre-defined diagnostic criteria. The validation is 
based on review of pre-defined clinical data related to the specific AE. 
The events are revie\.ved by the EAC in a blinded manner. The £AC will have no authorisations to 
impact on trial conduct, llial protocol or amendments. The EAC is composed of pennaneut 
members covering required medical specialities. The EAC members must disclose any potential 
conflicts of interest and must be independent of Novo Nordisk. 
Event adjudication will be perfonned for pre~defined AEs in randomised subjects including AEs 
with an onset date during the screening period and selected AEs in the infant(s). Event adjudication 
will not be petfonned for AEs in screening failures. 
For all events for adjudication, the source documentation should be 8Jlonym.ised by investigator 
according to the Event Adjudication Site Manual. Prior to submitting tl1e source documentation to 
the EAC, the Event Adjudication supplier will ensure translation into English, if applic.able. 
For each source document the investigator shouJd specify/indicate on tbe adjudication form when/if 
the required documents will be available. If a document is unobtainable this needs to be specified. If 
no source data are available, a clinical uanative should be provided. 
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Table 12-2Events for adjudication 
Event 
Description of event in scope fo1· 
adjadlcatton 
Fatal event (subject) 
All cause death 
Severe hypoglyc:aenria Ol' 
A1l episode requiring assistance of 
hypoglycaenric episodes t,epo11ed as 
another person to actively administer 
an SAE (subject) 
carbohydrate. gluc.agon 01· take other 
coll'ective actions. Plasma glucose 
concentrations may not be available 
dm'ing an episode, but neurological 
recove:iy folJowing the return of 
plasma glucose to nonnaJ is 
considered sufficient evidence lha.t the 
episode was induced by a low plasma 
glucose concentration. 
Congenital anomaly(-ies) 
A mmphological, functional and/or 
biochemical developmental 
disturbance ill the embryo or foelll'l 
whether detected at birth or not. The 
tenn congenital anomaly is broad and 
includes congenital abnonrnlities, 
foetopathies, genetic diseases with 
early onset, developmental delay, etc, 
Foetal or infant death (including 
Ail cause death 
spontaneous abortion) 
Final 
75 of 110 
Adjudication outcome 
Severe hypoglycaemia 
Severe hypoglycaemia 
Major abnonnality or 1niL1or aL1omaly 
Cause of d.eath 
The assessment made by the EAC will be included in the clinical t:Iial rep01t (CTR) as well as the 
assessments made by the investigator. However, the adjudication made by the EAC, giveu its 
independent analysis of each event, will be atttibuted with gre-ater importance of the two. 
DJrect reporting by the lnvestlga1tor 
Adverse events for adjudication must be reported according to Section 12.2 and Table 12-1. In 
addition, the specific adjudication fonn should be completed within 14 calendar days of the 
investigator's first knowledge of the AE, and all relevant pi-edefined documents provided within 4 
weeks according to instructions in the event adjudication site manual 
Hypoglycaemic episodes will be repo1ted by the subjec.t in the diary. For severe hypoglycaemic 
episodes and hypoglycaemic episodes reported as an SAE the adjudication fo1m must be completed 
in theeCRF. 
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Trial ID: 
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Screening of AEs 
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All AEs will be screened to detect potentiaJ missed events for adjudication. If needed, the 
investigator will be requested to provide additional infonnation suc.h as an alternative aetiology, 
underlying cause(s) and/or clinical details. 
Based on the infonnation provided, the Event Adjudication supplier or the EAC can decide to have 
an AE adjudicated even if not initiaUy repo1ied as an event for adjudication by the investigator. If 
so, the investigator must complete the adjudication form in the eCRF and upload source data when 
the request is received from Novo Nordisk or the Event Adjudication supplier. 
Events identified by the EAC 
During the review of source data the EAC may identify additional events relevant for adjudication 
which have not been reported by the investigator as such. hl case an additional event is identified, 
the site will be informed and asked to consider rep011ing the event. If the site does not report the 
event, it may still be adjudicated. 
For further details regarding event adjudication refer to the Event Adjudication Site Manual. 
13 Case report forms 
Novo Nordisk will provide a system for the eCRFs. U1is system and support se1vices to the system 
will be provided by an external supplier. 
The investigator must ensure that all relevant questions are answered, and that no empty data field 
exists. lf a test or an assessment has not been done and will not be available, or if the question is 
inelevant (e.g. is not apphcable), indicate this according to the data entry instructions. 
The investigator must ensure that all information is consistent with the source documentation. By 
electronically signing the casebook in the eCRF, the investigator coufinns that the information in 
the eCRF and related forms is complete and correct. 
The following will be provided as paper CRFs to be used when access to the eCRF is revoked or if 
the eCRF is unavailable: 
• 
AE fonns 
• 
SIF fonns 
• 
Pregnancy forms (for pregnant subjects who withdraw consent) 
• Technical complaint forms (also to be used to repo1t complaints tliat are not subject related (e.g. 
discovered at triaJ site before allocation) 
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On the paper C'RFs Wiite legibly, using a ballpoint pen. Ensure that all questions are answered, and 
that no empty data blocks exi.st. Ensure that no info1mation is recorded outside the data blocks. If a 
test/assessment has not been done and w ill not be available, indicate this by writing "ND" (not 
done) in the appropriate answer field in the CRF. If the question is iffelevant (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 tl1e CRF. 
13.1 
Corrections to case report forms 
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 o]d and the 
new data. identification of the person ente1ing the data~ date and time of the en tty and reason for the 
correction.. lf conect1ons are made by the investigator's delegated staff after the date the 
investigator has signed the casebook, the casebook must be signed and dated again by the 
investigator. 
CotTections to the data in the paper CRFs may only be made by drawing a straight line through the 
incon-ect data and then w1itmg the coITect entry next to the data that was crossed out. Each 
co1Tection must be initialled, dated and explained (if necessary) by the investigator or the 
investigator's delegated staff. If corrections are made by the investigator's delegated staff after the 
date of the investigator's signature on the affitmation statement, the affirmation statement must be 
signed and dated again by the investigator. 
Corrections necessary after the CRFs have been removed from the trial site must be documented on 
a data clarification form (D CF) or a monitor-initiated discrepancy form (MIDF). If the affirmation 
statement for the subject has not yet been signed. any corrections must be approved by the 
investigator or her/his delegated staff. If the affirmation statement for the subject has already been 
signed, the investigator must approve any cotTection. 
13.2 
Case report form Oow 
The investigator must ensure that data is recorded in the eCRF as soon as possible, preferably 
within 5 days after the visit. Once data bas been entered, it will be available to Novo Nordisk for 
data verification and validation purposes. Queries will be generated on an on-going basis and 
investigator must ensme that queries are resolved as soon as possible, preferably within 5 days. 
Site specific eCRF data (in au electronic readable fonn at) will be provided to the trial stte before 
access to the eCRF is revoked. This data must be retained at the trial site. 
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Trial ID: 
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UlN: Ull I H 19J-30JS 
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14 l\tlonitoring procedures 
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Monitoring will be conducted using a risk based approach mcluding risk assessment, monitoring 
plans, centralised monitoring and visits to trial sites. 
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 pe1fonn source data verification and to monitor 
dmg accolllltability. The first monitoring visit will be performed as soon as possible after FSFV at 
the trial site and no later than 4 weeks after. The monitoring visit intervals will depend on the 
outcome of the centralised monitoring of the eCRFs (remote assessment of data by Novo Nordisk), 
the t1ial site's recmiuneut rate and the compliance of the uial site to the protocol and GCP, but will 
not exceed 12 weeks Ulltil LSLV at the trial site. 
The monitor must be given direct access to all source documents (original documents, data and 
records). Direct access i.ncludes pennission to examine, analyse, ve1ify and reproduce any record(s) 
and report( s) that are important to the evaluation of the ttial If the electronic medical record does 
not have a visible audit trail, the investigator must provide the monitor with signed and dated 
p1intouts. In addition the relevant tiial site staff should be available for discussions at monitoring 
visits and between monit01ing visits (e.g. by telephone). 
All data must be verifiab]e in source documentation other than the eCRF, except for age and BMI 
which are calculated in the eCRF and information from the Baseline Hypoglycaemic Episode 
Interview Questionnaire in Appendix B which is entered directly into the eCRF and will be 
considered source data. 
For all data recorded the somce document must be defined in a source document agreement at each 
t1ial site. There must only be one source defined at any time for any data element. 
Source data generated by the trial site can be conected by another person than the person entering 
the source data if accepted by locaJ reguJations; any correction must be explained, signed and dated 
by the person making the conection. 
The miginal of the completed diaries must not be removed from the tiial site. 
The monitor will ensure that the eCRFs are completed and that paper CRFs are collected. The 
following data wiU be source data verified for screening fajJures: 
• 
Date for obtaining infom1ed consent 
• 
Screen failure reason 
Monitors will review the subject's medical records and other source data e.g. the paper diaries to 
ensure consistency and/or identify omissions compared to the eCRF. If discrepancies are found, the 
.investigator must be questioned about these. 
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A follow-up letter (paper or electronic) \.vill be sent to the investigator following each monito1ing 
visit. This should address any action to be taken. 
15 Data mana2ement 
Data management is the responsibility of Novo Nordisk 
Appropriate measures, indudiug encryption of data files containing person identifiab]e data, will be 
used to ensure confidentiality of subject data, when they are transmitted over open networks. 
Data from cenu·al laboratories will be transfeITed electronically. In cases where data is transfeired 
vio non-secure electronic networks, dnto will be encrypted during trnnsfcr. 
The subject and any bio[ogicaJ material obtained from the subject will be identified by subject 
number and trial ID. Appropriate measures such as encryption or leaving out celiain identifiers will 
be enforced to protect the identity of subjects in all presentations and publications as required by 
local, regional and national requirements. 
16 Computerised systems 
Novo Nordisk wi11 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 documentecl 
Investigators working on the triaJ may use their own electronic systems to capture source data. 
Data collected ptior to tlle discontinuation of the glycaemic data collection system (the combined 
use of the MyGlucoHealth BG-meter and an electronic diary): 
The eDiary software aud hardware implementation are compliant with the requirements of FDA 21 
CFR Pa11 l l 43 and the EU directive for personal data protection44. After trial finalisation, 
Novo Nordisk aud each site wm be supplied with long-life DVDs. These DVDs will contain site-
specific subject records including the subject's eDiary data and audit rrail as weU as any data 
additions and corrections made on each form. The eDiaiy vendor will fmt hermore retain and 
sec.urely store copies of all archived documents and data for 50 years or as required by loc.al data 
retention laws for tiial data. 
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Trial ID: 
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UlN: Ull I H 19J-30JS 
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NN 1250 -4300 
CONFIDm>m 1\1. 
17 Statistical considerations 
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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 wiU be finallsed before 
database lock. 
The internal Novo Nordisk blinding plan will describe how blinding of the randomised treatments 
for internal Novo Nordisk personnel will be maintained until the database has been released for 
statistical analysis. No inte1im analyses or other analyses of unblinded data will be perfonned 
before the database is locked. 
Data from all sites will be analysed and reported together. 
In statistical analyses where stratification is included, pregnancy status (Pregnant/Non-pregnant) 
and planned continuous use of CGM (Yes/No) will be based on the actual information. Hence, if 
subjects by mistake are aUocated to a wrong randomisation list, the correct stratification factor will 
be applied. 
In the statistical models explanatory factors will be parametenzed as follows: 
• Treatment: !Deg, IDet 
• Stratification factor: randomised as pregnant and planned continuous use of CGM, randomised 
as pregnant and no planned continuous use of CGM, randomised as non-pregnant and planned 
continuous use of CGM, randomised as non-pregnant and no planned continuous use of CGM. 
• 
Region: Emope (Austria, Denmark, Greece, Ireland, Italy, United Kingdom and Serbia), No1th 
America (Canada), South America (Argentina and Brazil) and Asia/Oceania (Australia, Israel 
and Russia). 
Two different baselines will be applied; a treatment baseline and a pregnancy baseline. The 
treatment baseline value will be used in the statistical models and is defined as the latest available 
measurement at or before randomisation. For all subjects the treatment baseline value hence 
coffesponds to the value obtained at the randomisation visit (visit 2) if available, or at the screening 
visit (visit 1 ). If neither of these measurements have been obtained the treatment baseline wiJI be 
le.ft missing. For subjects randomised pregnant the pregnancy baseline is derived from the treatment 
baseline, and the two baseline vailues wilJ be identical, con-esponding to t11e values obtained at 
visit 2 or visit 1. For subjects randomised non-pregnant and becoming pregnant in the conception 
period of the triaJ, the pregnancy baseline corresponds to data from visit 55. 
\Vhen summarising change from baseline for effect and safety variables assessed during or after the 
pregnancy period, both baseline variables will be applied. First the treatment baseline desc1ibed 
above to illustrate changes since initiation of treatment, second the pregnancy baseline to illustrate 
changes since early pregnancy. 
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Laboratory values below the lower limit of quantification (LLoQ) will be set to ½LLoQ. The 
number of values below LLoQ by treatment and visit will be summarised if deemed relevant. 
Results from a statistical analysis will at a m.i.ninmm be presented by the estimated treatment 
contrasts for the comparison between !Deg and IDet with associated two-sided 95% confidence 
inte1vals (CI) and p-values coITesponding to two-sided tests of no difference. 
Primary and secondary estlmands 
Primary estirnaud ("treatment policy' estimand): 
• Treatment difference in last planned HbA1c prior to delivery after GW 16 between !Deg OD 
plus IAsp 2-4 times daily with meals and IDet OD/BID plus IAsp 2-4 times daily with meals for 
all randomised pregnant womeu regaidless of actual lre:atmelll received. 
The primary estimaud assesses the average glycaemic difference prior to delivery after GW 16 in a 
population of pregnant women with TlDM, resulting from initiation of a treatment regimen with 
!Deg OD plus IAsp 2-4 times daily with meals including potential additional therapy as compared 
to initiation of a treatment regin1eu with IDet OD or BID plus !Asp 2-4 times daily with meals 
including potential additional therapy. Generalisation of this estimand depends among other things 
on tbe extent to wbicb the treatment adherence and the potentiaJ use of additionaJ therapy reflect 
clinical practice, and whether the trial population can be considered a representative sub-sample of 
the target population. 
Secondary estirnand ("If all subjects had adhered" estimand): 
• 
Treatment difference in last planned HbA1c prior to delivery after GW 16 between !Deg OD 
plus IAsp 2-4 times daily with meals and IDet OD/BID plus IAsp 2-4 times daily with meals for 
all randomised pregnant women if all subjects adhered to treatment 
The secondary estimand assesses the glycaemic benefit a pregnant woman with TlDM is expected 
to achieve prior to delive1y after GW 16 if adhe1ing to a treatment regimen with IDeg OD plus 
mealtime IAsp as compared to adhering to a treatment regimen with IDet OD or BID plus mealtime 
IAsp. Generalisation of this ,estimand depends among other things on the extent to which the 
compliance to trial product administration in this nial reflects clinical practice. Only data collected 
prior to discontinuation of trial product will be included in the analysis. 
Missing data conside1·at1ons 
Data assessed prior to the GW 16 visit will not be used in the analysis nor will it be considered 
missing and imputed. To predict how data would have been prior to delivery after GW 16 is 
considered hypothetical for subjects with a delivery prior to GW 16. Based on data from 
NN304~1687 it is assumed that at most 10% of the women may have delivery prior to GW 16.1 
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·when estimating the primary estimand, missing data will mainly be due to withdrawaJ from the 
tlial. hl the trials NN1250-3770, NNJ250-3583 and NN1250-3585 (all with !Deg as IMP and 
parallel triaJ design) with a duration of26-52 weeks in subjects with TIDM, the proportion of 
withdrawn subjects varied between 8% and 16%. In these trials subjects were withdrawn if they 
discontiuued trial drug and did not attend any scheduJed visits after discontinuation-
For subjects randomised as non-pregnant, the trial may potentially be of close to 2 years duration, 
suggesting higher drop-out rates than observed in the above mentioned t1ials. However, pregnant 
women and women with the intention to become pregnant are likely more adherent than subjects 
with diabetes in general It is assumed that at m.ost 15% of the women randomised as non-pregnant 
and 10% of the women randomised as pregnant will discontinue treatment. lt is expected that 
approximately 80% oftbe pregnant women will be randomised as pregnant, and that in total, the 
percentage of subjects discontinuing treatment is smaller than 12%. Provided it is possible to 
retrieve data from balf of these subjects, 6% of the subjects may have missing data due to 
withdrawaJ from the trial. 
Within each treatment arm, missing data at the last planned visit p1ior to delivery after GW 16 from 
subjects who have discontinued t:re<1tment will be imputed from the distribution of retrieved data at 
the last pJanned visit prior to delivery after GW 16 among subjects who hav,e discontinued 
treatment. Missing data at the last planned visit prior to delivery after GW 16 from subjects who 
have not discontinued treatment will be imputed based on the distli bution among subjects who have 
not discontinued treatment at the last planned visit prior to delivery after GW 16. If a simple 
intercept model is infeasible to estimate among discontinued subjects, an on-treatment factor will be 
included in the model instead of doing the in1putation separntely by on-treatment and off-treatment. 
A detailed description of the imputation procedure is desciibed in Section 17 .3 .1. 
Missing data considerations - secondary estimand 
·w hen estimating the secondruy estimand, missing data wiU mainly be due to discontinuation of 
treatment. As argued above it is expected that at most 12% of subjects will have missing data due to 
discontinuation of treabnent. 
Within each treatment ann, 1nissmg data at the last planned visit prior to delive1y after GW 16 will 
be imputed from subjects who have not discontinued treatment at the last planned visit prior to 
delivery after GW 16. A detailed description of the imputatiou procedure is described m 
Section 17 .3.2. 
To document the extent and reason for missing data, descriptive summaries and graphical 
representation of extent, reason(s) for and pattem of missing data will be presented by treatment 
arm. 
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Sample size calculation 
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The sample size is based on the primary objective, the primary endpoint and the primary estimaud. 
The difference in last planned HbA1c prior to delivery after GW 16 will be compared to a 
non-iuferiority (NI) margin of 0.4% for IDeg versus IDet. 
No placebo controLJed trials with IDet neither in pregnant women with TlDM or in subjects with 
TIDM have been conducted. Hence, it is unknown what the difference in HbAk between IDet and 
placebo would be in pregnant women with Tl DM. The N1 margin of 0.4% was applied in the 
phase 3a program for IDeg as well as the IDet pregnancy trial NN304-16871, but is larger than the 
NI of 0.3% cu1Te11tly being recommended by EMA.45 Investigations of feasibility have shown that it 
would not be possible to recmH the number of subjects needed for applying 0.3% as a NI margin. 
As the objective of the primary analysis mainly is to demonstrate that the difference in glycaemic 
control between tbe two treatment regimens is small enough for a reasonable compa1ison of safety, 
a NI margin of 0.4% is considered appropriate. 
FormaJly, let D be the mean treatment difference (IDeg-IDet) in ' Last planned HbA1cprior to 
delivery after GW 16' . The null-hypothesis of !Deg being infe1ior by 0.4% or more wil] be tested 
against the alternative hypothesis of NI (IDeg inferior by less than the NI-limit) as gi.ven by: 
HO: D :::: 0.4% against HA: D < 0.4% 
Non-inferiority will be considered confinned if the upper bound of the two-sided 95% CJ for D 
(mean treatment difference in HbA1c) is strictly below 0.4%. This is equivalent to using a one-sided 
test of size 2.5%. 
The sample size is caJcuJated using a t-statistic under the assumptions of a one-sided test of size 
2.5%, NI margin of0.4% and a mean treatment difference of0.0%. The standa1·d deviation (SD) of 
the observed HbA1c values prior to delivery was 0.7% in the NN304- l687 trial.1 To apply retrieved 
data and impute missing data may potentially increase the SD. Therefore, the sample size bas been 
calculated for values of SD equal to 0.85 and 0.90. 
The primary analysis is based on the full analysis set for pregnant women (F ASpregnant, Section 17.2) 
and missing data will be imputed. Hence, the sample size for the primary analysis is not adjusted for 
drop-outs. The muubers are however based on the assumption that LO% of the women will have 
delivery prior to GW 16, and hence not contribute with data in the analysis, Table 17- 1. 
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Table 17-1 Sample size for evaluadon of non-inferiority based on F ASpregnant with 80% power 
- number of pregnant women 
Total number otwomen 
Tot•l numbl'I" of 
Non-iofl'1iority limit 
Standard Dl',iation (SD) 
with delinry after GW 16 randomised and prepant 
women 
0.85 
144 
160 
0.4% 
0.90 
162 
180 
A sensitivity analysis will be made for the per protocol analysis set for pregnant women (PPpregnan1, 
Section 17 .2), Based on data from :NN304-l 687 it is assumed that approximately 10% of subjects 
may be excluded from t1Je per protocol analysis set.2 The sample size needed for evaluation of NI 
based on the PPpregwwt analysis set for pregnant women is summarised in Table 17- 2. 
Table 17-2 Sample size for evaluation of non-lnferlorlty based on PPpregn.an1 with 80% powei- -
number of pregnant women 
. on-illferiortty limit 
Standard De,iatton (SD) 
Total number ot randomised md pregnant women 
(as\lllDiDg 10°1. FAS,"'l: .... excluded from 
0.85 
178 
0.4% 
0.90 
200 
Based on this a sample size of 178 rnndom.ised and pregnant women has been chosen. At most ½ of 
the women are to be randomised as non-pregnant. The proportion of subjects randomised as non-
pregnant and becoming pregnant dmi.ng the trial is estimated to be approximately 50% based on 
experience from NN304-l 687.Tbis means that 214 women should be randomised, 142 should be 
randomised as pregnant and 72 should be randomised as non-pregnant. However, the percentage of 
women randomised as non-pregnant that actually become pregnant will be foUowed carefully. If 
this percentage is lower than 50% more ·women should be randomised to ensure 178 pregnant 
women. 
If a N ] margin of 0.3% was to be applied instead, 314 rather than 178 pregnant women would be 
needed to obtain a power of 80% for evaluating NI based on PPpregnaru. As described above, 
feasibility studies showed that it would not be possible to aim for this sample size. 
17 .2 
Definition of analysis sets 
The following analysis sets will be defined: 
• 
FuJl analysis set for pregnant women (FASp .. "11J101): includes all raudomtsed women who are 
pregnant during the trial. Subjects in the F ASpregnant will contribute to the evaluation "as 
randomised". 
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• 
Per pl'Otocol analysis set for pt·egnant women (PPpngoanr): includes subjects from F ASpregnant 
who: 
• 
Have not violated any inclusion criteria 
• 
Have not fulfilled any exclusion criteria 
• 
Are exposed to trial dmg at least tl1e first folll:" weeks after randomisation or, in case of 
termination of pregnancy within the fust four weeks after randomisation tmtil time of 
tennination of pregnancy. 
Subjects in the PPpregnant analysis set will contJibute to the analysis according to the treatment 
received prior to pote.ntiaJ discontinuation of randomised treatment. Titls w ill be refened to as 
contiibuting to the evaluation "as treated". 
• 
Safety analysis set for pregnant women (SASpregnaot): includes all randomised women 
exposed to at le.ast one dose of trial product and who are pregnant during the tlial. Subjects in 
the SASpregn;wr will contiibute to the evaluation "as treated". 
• 
Full analysis set for all women ,(F ASan): includes all randomised women_ Subjects i11 the 
FAS an will contribute to the evaluation "as randomised". 
• 
Safety analysis set for all women (SASa11): includes al] randomised women exposed to at least 
one dose of tr:iaJ product. Subjects in the SASan will contribute to the evaluahon "as treatedn_ 
Exclusion of data from analyses wiU be used restrictively, and nom1ally no data should be excluded 
from the FA~ and che F ASa11. The subjects or observations to be excluded, and the reasons for 
their exclusion must be documented before database lock. The subjects and obse1vations excluded 
from analysis sets, and tl1e reason for this, will be described in tl1e C1R.. 
Definition of data selections and observation petiods 
The in-trial observation peri.od represents the time period where subjects are considered to be in the 
trial, regardless of discontinuation of trial product. The in-trial obseivation period starts at 
randomisation and ends at trial completion. The date of tiial completion is the date of the final 
scheduled follow-up visit V92. For subjects not attending the follow-up visit V92, the date of trial 
completion will be the date of the last subject-investigator contact. 
A woman is defined to have completed the trial period if she is/becomes pregnant dming the tiial, 
is not withdrawn from the triai and attends the final follow-up visit V92. 
The on-treatment observation period represents the time period where subjects are considered 
treated with the trial product. It is a subset of the in-tJial obse1vation period, sta1ti.ng at the date of 
first dose of ttial product and ending at the date of the last day on ttial product. 
A woman is defined to have completed the n·eatment perJo<I if she is/becomes pregnant during 
the trial, receives the required treatment until the plam1ed end of treatment visit and also attends this 
visit. 
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The pl"egnancy period is defined as the period from first day of pregnancy ( date of conception 
coffesponding to the first day in GW 2) or randomisation (whichever comes last) to the date of 
delivery. The first day of pregnancy is based on the estimated gestational age from the US scan 
made before or at randomisatton (visit 2) for subjects randomised pregnant and before or at visit 55 
for subjects randomised non-pregnant and becoming pregnant m the conception period of the trial. 
For subjects witl1 delive1y prior to tl1e US scan the first day of pregnancy is detennined by the 
investigator based on the estimated gestational age at the time of delivery. 
The pl'e-pregnancy period is defined for subjects randomised as non-pregnant. The period staris at 
randomisation (visit 2). Two ddferent end-dates will be defined. For subjects who become pregnant 
the period ends at the day prior to first day of pregnancy. For subjects who do not become pregnant 
during the trial, the period ends at the same time as the in-trial period. 
The post-pregnancy period stai1s the day after the delivery and ends at the same time as the in-trial 
period. 
These definitions fonn the basis for combmations of periods. The on-treatment p1·egnancy period 
is e_g_ the intersection between tl1e on-treatment period and the pregnancy period 
17.3 
Primary endpoint 
The p1imary endpomt is the last pfalllled HbA1c prior to delivery after GW 16. 
17.3.1 
Primary analysis for fbe p1·imary estimand 
The primary estimand will be estimated based on the F ASprego.wt using data from the last planned 
visit prior to delivery a.fter GW 16. Hence, data assessed at the planned visit prior to delivery will be 
used in the analysis, provided the visit coffesponds to the GW 16 visit or later. If delivery is in 
GW 40, data from GW 36 wilJ be used. If data at this visit is missing, and data from an additional 
visit after GW 36 and prior to delivery is available, data from this visit will be used. Similarly, if 
delivery is in week GW 18, data from GW 16 will be applied. If data at this visit is missing, and 
data from an additional visit after GW 16 and prior to delivery is available, data from this visit will 
be applied. Available data from them-trial petiod will be included regardless of whether trial 
product was discontinued or not. 
The p1i.mary statistical analysis will be usmg multiple imputations to handle missing data assuming 
that the missing data ml¾harusm is missing at random (MAR) within the groups used for 
imputation. 
Imputation of missing data wm be done within four groups of subjects defined by randomised 
treatment ann and whether or not subjects discontinue treatment. It is hereby assumed that the likely 
values of what the missing data would have been if available, are best described by information 
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from subjects who at the last scheduled visit prior to delivery are similar in terms of randomised 
treatment ann and whether or not tre.atment has been discontinued. 
If there are 3 or less retrieved observations among discontinued subjects in a treatment group, it is 
infeasible to estimate a simple intercept model (including vruiance) and imputed separately by on-
treatment and off-tr,eatment Instead, on-treatment factors will be included in the models. Hereby, 
separate me:ans will be estimated for on-treatment and off-treatment observations, while only one 
joint variance is estimated. h1 the special case with no subjects off-treatment having HbAlc in one 
treatment group, an on-treatment factor will not be included in the this group but only in the other 
group (expecting that this group also has most missing values). 
Missing data at the last scheduled visit prior to delivery after GW 16 are for each gmup imputed in 
the following steps: 
• 
An analysis of cova1iance (ANCOV A) will be fitted to the obse1ved last values of last HbA1c 
prior to delivery after GW 16 
• 
For subjects where HbA1c at the last scheduled visit prior to time of delivery is in the 
on-treatment period, the model will include region and the stratification factor as 
categorical fixed effects, and a pregnancy status at randomisation-by-baseline HbA1c 
interaction. 
• 
For subjects where HbA1c at the last scheduled visit prior to time of delive1y is not in the 
on-treatment pedod, the model will include pregnancy status at randomisation and a 
pregnancy status at randomisation-by-baseline HbA1c interaction. If this modd cannot be 
fitted in case of very few retrieved observations among discontinued subjects, a model 
including pregnancy status at randomisation will be applied. If this model cannot be 
fitted either, a simple model including just the intercept will be fitted instead. If there are 
3 or less retrieved observations among discontinued subjects in one or both treatment 
groups, this step will be skipped. 
• 
With 3 or less retrieved observations among discontinued subjects in one of the 
treatment groups, the step below replaces the r.vo steps above. For subjects with HbA1c 
at the last scheduled visit prior to time of delivery, the model will include on-treatment 
(Yes/No), region and the stratification factor as categorical fixed effects, and a 
pregnancy status at raJ1domisation-by-baseline HbA,c interaction. In treatment groups 
having no subjects off-treatment with HbAlc, the on-tre.:atment factor will not be 
included. 
The estimated parameters from the analysis of cova1iance together with the va1iances of the 
estimates wiU be used to simulate 1000 data sets with imputed last planned HbA1c prior to deiivery 
after GW 16 data for subjects missing these. Each of the 1000 datasets use one set of estimated 
mean parameters aJ1d estimate of the residual variation. For subjects who have discontinued 
treatment and where retrieved last planned HbA1t piior to delivery after GW 16 data are not 
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available, it may not be known whether time of delivery is after GW 16. In this case time of 
delive1y will be assumed to be after GW 16 and last planned HbA1c prior to delivery after GW 16 
will hence be imputed, 
Analysis used for confirming non-infelio1·ity of IDeg versus IDet 
For each of the 1000 imputed datasets last planned HbA1cprior to delivery after GW 16 will be 
analysed using an ANCOV A with treatment, region and the stratification factor as categorical fixed 
effects and a pregnancy status at randomisation-by-baseline HbA1c interaction. In each analysis the 
treatment difference between IDeg and IDet and the associated standard e1rnr will be estimated. The 
estimates and standard errors from the l 000 datasets are pooled to one estimate and associated 
standard e1rnrs using Rubin's ml# to draw inference. From these pooled estima:tes the 95% CI for 
the treatment difforence 1s callculated. 
Non-inferiority will be considered con finned if the upper bound of the CI is strictly below 0.4%. 
The p-value co1Tespondi11g to a two-sided test of no difference will also be reported. 
Data from the in-trial pregnancy and post-pregnancy pe1iods ,.vill be summarised and plotted by 
treatment ann and visits based on F ASpregnant Swililaries and plots wilJ also be presented separately 
for subjects randomised as pregnant and subjects randomised as non-pregnant. 
17.3.2 
Primai-y analysis for fbe secondary estimand 
The secondary estimand will be estimated based on t11e F ASpregnant using data from the last planned 
visit prior to delivery after GW 16, similarly to the way in which the primary estimand was 
estimated. However, data relli.eved outside of the on-treatment period will not be used in the 
analysis. but will be considered missing. 
Imputation of missing data wHl now be done within two groups of subjects defined by randomised 
treatment rum . It is hereby assumed that the likely values of what the missing data would have been 
if available, are best desc1ibed by infonnation from subjects who at the last scheduled visit ptior to 
delivery are similar in terms of nmdomised treatment aim and who have not discontinued treatment. 
Missing data at the last scheduled visit prior to delivery after GW 16 are for each group imputed in 
the following steps: 
• 
An ANCOV A will be fitted to the obse1ved values of last HbA1c prior to delivery after GW 16 
for subjects where this assessment is in the on-n·eatment pe1iod. The model will include region 
and the stratification factor as categorical fixed effects, and a pregnancy status at randomisation-
by-baseline HbA1c interaction. 
• Similar to the description above for the primary esthnand tlle estimated parameters from the 
ANCOV A together wtth the variances of the estimates will be used to simulate 1000 data sets 
with imputed last planned HbA1c prior to delivery after GW 16 data for subjects missing these. 
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For each of the 1000 imputed datasets last planned HbA1c prior to delivery after GW 16 will be 
analysed as described for the primary estimand. 
Data from the on-treatment pregnancy and post-pregnancy periods will be summarised and plotted 
by treatment arm and visit based on F ASpregrum1- Smrumuies and plots will also be presented 
separately for subjects randomised as pregnant and subjects randomised as non-pregnant. 
17.3.3 
Sensitivlty analyses 
To investigate the sensitivity of the primary analysis results, complementary and separate analyses 
will be perfom1ed for the prima1y and secondary estimand in Line with guidelines from EMAil and 
the U.S. National Research Council~ . The evaluation of the robustness of the prima1y anaiysis 
result.swill be based on approaches using multiple imputations. Similar sensitivity analyses are 
made for the primary and secondaiy estimand: 
• A multiple imputation analysis based on the PPpregww1 
• 
The analysis is stmilar to the primary analysis for the primary/secondary estimand, but 
based on PPP"'S'umt. The analysis investigates the impact of protocol deviations on the 
primary anaJysis. 
• 
A multiple imputation tipping point analysis based on the F ASpreg11ani 
• 
In this sensitivity analysis, missing data will first be imputed according to the primary 
analysis for the primary/secondary estimand. Second, for the IDeg arm a penalty will be 
added to the imputed values oflast planned HbA1c prior to delivery after GW 16. The 
approach is to gradually increase this penalty until the confinned HbA1c conclusion from 
the primary analysis is 1eversed. The analysis :investigates how sensitive the 1esults of 
the primary analyses for the primary/seconda1y estimands are towards the assumption 
that missing data have the same mean level as available data within the groups specified 
for the imputation. 
17.4 
Seconcla1-y endpoints 
17 .4.1 
Efficacy endpoints 
Supportive secondary endpoints 
TI1e supportive seconda1y endpoints will be evaluated for: 
• 
The primary estimand based on F ASpre:gnant using the in-trial data 
• 
The secondary estimand based on F ASpregnant using the on-treatment data 
No sensitivity analyses are planned for these. 
Data from the in-trial pregnancy and post-pregnancy periods will be swnmarised and plotted by 
treatment aim ai1d visit based on F ASpte!!Mill, Data from the on-treatment period will be presented 
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similarly. In addition, summaries and plots will be presented separately for subjects randomised as 
pregnant and subjects randomised as non-pregnant. 
Supportive maternal binary efficacy endpoJnts 
• 
HbA1c 6.0% (42 mmol/mol) from last planned HbA1c prior to delivery after GW 16 (yes/no) 
• 
HbA1c, :5 6.5% (48 mmol/moi) from last planned HbA1c prior to delivery after GW 16 (yes/110) 
For both estimauds missing data for the responses of the above binary endpoints will be obtained 
from dichotomizing imputed values ofHbArc-Hence, 1000 imputed datasets simulated as for the 
primary analyses of the primary and secondary estimand for HbA1c, respectively, will be applied in 
tile conesponding analyses of the dichotomized endpoints. The imputed complete data sets will be 
analyse.cl using a logistic regression model with treatment, stratification factor and region as 
catego1ical fixed effects and a pregnancy status at randomisation-by-baseline HbArc interaction. 
fuference comparing tre<1tments will be dnn,vn using Rubin's rule. The odds ratio between !Deg and 
IDet will be estimated together with the 
two-sided 95% Cl The p-value 
con-esponding to a tvvo-sided test of no difference (odds ratio equal to 1) will be repolied. 
Supportive maternal continuous efficacy endpoints 
• 
Last planned average PPG prior to delivery after GW 16 
• 
Average of three main meals 
• 
Last planned FPG prior to delivery after GW 16 
The above continuous endpoints wiU be anaJysed using similar modelling approaches as for the 
p1imary endpoint with the associated baseline response as a covariate. 
17.4.2 
Safety endpoints 
17 .4.2.1 
Classification of Hypoglycaemia in subjects 
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 7 days 
from the last day on tr-iaJ product. 
Nocturnal h)l?o~lycaemic episodes: episodes occurring between 00:0 L and 05.59 both indusive. 
Hypoglycaemic episodes are classified according to the Novo Nordisk classi.fi.cation of 
hypoglycaemia (see Figure 17- 1) and the ADA classification of hypoglycaemia (see Figure 17- 2). 
N o,•o Nordisk classification of hypoglycaemia 
In nonnal physiology, symptoms of hypoglycaemia occur below a plasma glucose level of 
3.1 mmol/L (56 mg/dL):li. Therefore, Novo Nordisk has included hypoglycaemia with plasma 
glucose levels below this cut-off point in the definition of BG confirmed hypoglycaemia. 
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Novo Nordisk uses the following classification in addition to the ADA classification: 
• 
Severe hypoglycaemia according to the ADA classification.~ 
• Symptomatic BG confirmed hypoglycaemia: An episode that is BG confirmed by plasma 
glucose value <3.l mmol/L (S6 mg/dL) with symptoms consistent with hypoglycaemia. 
• 
Asymptomatic BG confinned hypoglycaemia: An episode that is BG confirmed by pfasma 
glucose value <3 .1 mmol/L (56 mg/dL) ~1th out symptoms consistent with hypoglycaemia. 
• 
Severe or BG confinned symptomatic hypogJycaemia: An episode that is severe according to 
the ADA classific.ationll or BG •Confim1ed by a plasma glucose value <3.l mmol/L (56 mg/dL) 
with symptoms consistent with hypoglycaemia. 
• 
BG confim1ed hypoglycaemia: An episode that is BG confirmed by a plasma glucose value 
<3. l mmol/L (56 mg1dL) with or without symptoms consistent with hypoglycaemia. 
• 
Severe or BG confinned hypogJycaemia: An episode that is severe according to the ADA 
d assificatio.n..ll or BG confirmed by a plasma glucose value <3.1 Il1Il1ol/L (56 mg/dL) with or 
without symptoms consistent with hypoglycaemia. 
Hypoglycaem,c 
"1)i•O<le 
·subject 
ab le ID 
trnat 
herself 
PG :s 3.9 mmol/L 
(70 mg/dl) 
or 
Alleviation of 
symptom,r 
Seizure, 
uncon'31iaous/ 
comatose or fatal 
PG < 3.1 mmol/l 
( 56 mg/dl) 
with symptoms 
PG < 3.1 mmol/l 
( 56 mg/dL) 
withaut 
symptoms 
5eVEf"e 
tv,,poglycaemoa 
(ADA 2013) 
Symplom..tic BG 
confirmed 
hypoglycaemia 
Asymptomatic BG 
1;.Q11finned 
hypoglycaemia 
Note: Glucose meas..-ements are ~erformed with capillary blood calibrated to plasma equivalent glucose v alues 
BG: blood glucose PG: plasma glumse SMPG: self-mea!HKed plasma gluoose 
FJgut·e-17-1 Novo Nordisk classification or hypog)ycaemla 
ADA dasslflcatio~ of bypoglycae-mla 
sevec-e or 
BG confirmed 
symptomatic 
hypogly,;a<rnia 
BG confirmed 
hypogly,;a<rnia 
s..v.,.., or 8G 
coolirmed 
hypOIJlyc.,emia 
• 
Severe hypog]ycaemia: An episode requiring assistance of another person to actively administer 
carbohydrate, glucagon, or take other conective actions. Plasma glucose concentrations may not 
be available during an event, but neurological recovery following the retum of plasma glucose 
to no1mal is considered sufficient evidence that the event was induced by a low plasma glucose 
concentration. 
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• 
Asymptomatic l1ypoglycaemia: An episode not accompanied by typical symptoms of 
hypoglycaemia, but with a measured plasma glucose concentration :5 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 S 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 mmoJ/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 dete1mination but that was presumably caused by a 
plasma glucose concentration S 3.9 mmol/L (70 mg/dL). 
Hypoglycaemic: 
episode 
Subject 
able to 
treat 
herself 
SMPG 
measurement 
PG 
3,9 mmoVL 
(70 mwdl ) 
or 
Alleviation or 
symptoms 
or 
Seizure, 
unconscious/ 
oomatose or fatal 
PG s.: 3.9 mmoVL 
(70 mg/dl ) 
without sy111>toms 
PG s.: 3.9 mmoVL 
(70 mgldl ) 
with symptans 
PG> 3.9 mmol/l 
(70 mg/dl ) 
with symptans 
No measurement 
with symptans 
Severe 
hypoglycaemia 
(ADA 2013) 
Asymptomatic 
hypoglycaemia 
Documen~ 
sylll)tomatic 
hypoglycaemia 
Pseudo-
hypoglycaemia 
Probable 
syl11)tomatfc 
hypoglycaemia 
Note: Glucose measurements are performed wilfl capillary blood ca6brated to plasma eguivalent glucose values 
PG: plasma glucose SMPG: Self-measured plasma gluoose 
FJga1·e 17-2 ADA classlflcatlon of hypoglycaemia 
Hypoglycaemia during the p1·egnancy period 
Data on treatment-emergent hypoglycaemic episodes with onset during the pregnancy period are 
presented in tenns of the number of subjects with at least one event (N), the percentage of subjects 
with at least one event(%), the number of events (E) and the event rate per 100 years of exposure 
(R). 
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NN 1250 -4300 
CONFIDm>m 1\1. 
Summaries will be based on SASpregnanL and will display: 
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• 
Number of severe or BG confirmed symptomatic hypoglycaemic episodes 
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• Number ofnoctumal, severe or BG confinned symptomatic llypoglycaem.ic episodes 
• Number of severe hypoglycaemic episodes 
• 
Number of hypoglycaemic episodes according to ADA definition 
Data on all hypoglycaemic episodes with onset during the pregnancy period will be presented 
similarly. 
Hypoglycaemia du11ng the in-trial period, the pre-pregnancy period and the post-pregnancy 
period 
Treatment emergent hypoglycaemic episodes with onset in the pre-pregnancy period, the post-
pregnancy period as well as all treatment emergent hypoglycaemic episodes dming them-trial 
period will be summarised similarly as described for the hypoglycaemic events during the 
pregnancy period. 
Data on all hypoglycaemic episodes within each of the three periods will be presented similarly. 
17.4.2.2 
Maternal safety endpoints 
Maternal safety endpoints assessed during and after the pregnancy period 
Summaries wiJI be based on SASpregDi3J)t unless othe1wise specified. Data will be presented for all 
subjects in SASl""8""ll1, as well as divided according to whether subjects were pregnant at 
randomisation or not. 
Development of sJgbt-threatenlng retloopathy from treatment baseUne as wen as from 
pregnancy baseline to the end of treatment visit 
Sight-threatening rerinopathy is defined as proliferative retinopathy or maculopathy. The propo1tion 
of subjects developing this between treatment baseline/pregnancy baseline to the end of treatment 
as welJ as to the additional end of treatment visit will be summarised by treatment ann. 
Pre-eclampsia 
Pre-eclampsia (PE) is defined as new-onset hype1iension (blood pressure ~140 nunHg systolic or 
~90 uunHg diastolic, based on at least 2 measurements taken at least 4-boms apart) occurring from 
GW 20 to delivery and sinmHaneous proteimuia (defined as ~ 300 mg protein in a 24 hours urine 
sample, a protein-to-creatinine ratio of ~ 300 mg/g in a urine sample or a urine dipstick protein of 
I+) or presence of eclampsia, HELLP syndrome, or other severe organ involvement. 
The number and percentage of subjects experiencing PE as well as the event rate per 100 years of 
exposure (R) will be displayed. 
Mode of delivery 
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The endpoint will be summarised by treatment aim based on the in trial data. The number and 
percentage of subjects in each c<ategory will be displayed. The endpoint will ftuther be summarised 
according to the following sub-groups: 
• Subjects randomised as pregnant 
• Subjects randomised as non-pregnant 
• 
Subjects randomised as non-pregnant aud exposed to trial drug at some point duri.ng the 
pregnancy period 
• Subjects randomised as non-pregnant and not exposed to trial drug dming the pregnancy pe1iod 
Change in body ,,·eight from pl'egnancy baseline to last planned visit before delivery 
Change in body wei.ght from pregnancy will be summarised by treatment arm and visit for all visits 
.including last plalllled vis.it before deli.very. 
Adve.-se events during the pregnancy period 
Adverse events will be coded using the most recent version of the Medical Dictionaiy for 
Regulatory Activities (MedDRA) database. 
A treatment emergent AE (fEAE) is defined as an event that has onset date on or after the first day 
of exposure to randomised treatment and no ]ater than 7 days after the last day of randomised 
treatment. If the event onset date is before the first day of exposure on randomised treatment and 
increases in severity at some point during the on-treatment period, then this event should also be 
considered as a TEAE. Major adverse cardiovascular events (MACEs, defined as all cardiovascular 
deaths, non-fatal myocardial infarctions and non-fatal strokes) are considered treatment-emergent 
until 30 days after the last day of randomised treatment. 
Treahnent emergent AEs are sumn.ia1i se-d descriptively. Data from TEAEs will be displayed in 
tenns of the number of subjects with at least one event (N), the percentage of subjects with at least 
one event (%), the number of events (E) and the event rate per 100 years of exposure (R). 
Adverse events with onset dming the pregnancy period are defined as corresponding to the 
pregnancy period. Number of TEAEs during the pregnancy period will be srul1ll1arised based on all 
subjects in SASpregnant-
Summaries of TEAEs and of seiious TEAEs will be presented as an ove1view including all TEAEs, 
serious TEAEs, TEAEs by severity, TEAEs by relation to treatment and TEAEs leading to 
treatment discontinuation or withdrawal 
Frnthermore, summary tables based on system organ class and prefened tenns are made for: 
• AHTEAEs 
• Serious TEAEs 
• TEAEs possibly or probably related to trial product 
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• 
Severe, moderate and mild TEAEs 
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• 
TEAEs with prefen-ed term that are experienced by at least 5% of the subjects in any treatment 
or by at least 5% of all subjects 
Summary tables of all SAEs induding non-treatment emergent SAEs will be presented including 
summary tables based on system organ class and prefet1·ed tenns. 
Adve1·se events during the in-tlial period, the p1·e-pregnancy period and the post-p1·egnancJ 
period 
Adverse events with onset in the pre-pregnancy period, the post-pregnancy period as well as all AEs 
during the in-tiial pe1iod will be summarised as described above for AEs with onset m the 
pregnancy petiod. 
17 .4.2.3 
Pregnancy outcome endpoints 
Supportlve continuous ancl binary 11regnancy outcome endpoints 
• 
Birth weight 
• 
Bittb weight (kg) 
• 
Bi1tb weight SD-score 
• 
Live born infants with birth weight < 10th percentile for gestational age and sex (local 
references) (yes/no) 
• 
Live bom infants with bittb weight > 90th percentile for gestational age and sex (local 
references) (yes/no) 
• 
Pre-tem1 delivery (delivery < 3 7 comp]eted GWs) (yes/no) 
• 
Early foetal death (delivery < 20 completed GWs) (yes/no) 
• 
Perinatal m01tality (death offoetus/infant between ~ 20 completed GWs before dehvery and < I 
completed week after delivery) (yes/no) 
• Neonatal mo11ality (death of infant between~ 7 completed days after delivery and < 28 
completed days after delivery) {yes/no) 
• 
Presence of major abnormalities (classified according to EUROCAn (yes/no) 
• Neonatal hypoglycaemic episodes defined as plasma glucose :5 l. 7 IIllllol/L (31 mg/dL) during 
tbe first 24 hoillS after birth or ~ 2.5 0111101/L (45 mgld.L) between 24 hours and 48 hours after 
birth (yes/no) 
The endpoints will be Slunma1ised by ti·eatment aim for all infants and ftniher sub-divided in the 
following groups: 
• 
Mother randomised as pregnant 
• 
Mother randomised as pregnant and exposed to triaJ drug at some point during the pregnancy 
pe1iod 
• 
Mother randomised as pregnant and not exposed to trial drug at some point durmg the 
pregnancy period 
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Trial ID: 
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UlN: Ull I H 19J-30JS 
EudraCT n.o.: 2017-000048-17 
• 
Mother randomised as non-pregnant 
NN 1250 -4300 
CONFIDm>m 1\1. 
Date: 
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• 
Mother randomised as non-pregnant and exposed to trial dmg at some point during the 
pregnancy period 
• Mother randomised as non-pregnant and not exposed to trial drng at any point during the 
pregnancy period 
The classification of congenital anomalies wilJ be listed. 
Adve1·se events in the infant from deUvery to final follow-up 
Adverse events will be coded using the most recent version of the MedDRA database. 
Adverse events are summarised descriptively for all infants and additionally sub-divided m the 
following groups: 
• 
Mother randomised as pregnant 
• 
Mother randomised as pregnant and exposed to trial drng at some point during the pregnancy 
period 
• 
Mother randomised as pregnant and not exposed to trial dmg at some point during the 
pregnancy period 
• Mother randomised as non-pregnant 
• Mother randomised as non-pregnant and exposed to trial mug at some point dming the 
pregnancy period 
• 
Mother randomised as non-pregnant and not exposed to trial drng at any point during the 
pregnancy period 
The summa1ies will display the number of infants with at least one event (N), the percentage of 
infants with at least one event (%) and the number of events (E). Summaries will be presented as an 
ove1view including all AEs, serious AEs, AEs by severity and AEs by relation to treatment. 
Furthermore, summary tables based on system organ class and preferred terms are made for: 
• 
AUAEs 
• 
SAEs 
• 
A.Es possibly or probably related to trial product 
• 
Severe, moderate and mild AEs 
• AEs with preferred tenn that are expe1ienced by at least 5% of the infants in any treatment or by 
at least 5% of all iofants 
17 .5 
Explo1·atory endpoints and other assessments 
The explorato1y endpoints listed in Section 4.5 and other assessments listed in Section 4.6 will be 
presented using summary statistics. 
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18 Ethics 
NN 1250 -4300 
CONFIDm>m 1\1. 
18.1 
Benefit-risk assessment of the trial 
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The trial population consists of pregnant subjects with Tl DM. For this population a good glycaemic 
control without experiencing hypoglycaemia is of great impottance in order to minimise the risk for 
complications dming pregnancy and for the pregnancy outcome. The same ethical principles apply 
to triaJs in pregnancy as in all other trials, however special attention must be given to the particular 
situation canying and having a child. Consideration must be given to the emotional state of the 
mother in relation to the infant or the pregnancy with regard to the trial requirements. For all 
subjects participating in this t:Ii al, the anticipated benefits include a very close follO\,v-up dwing 
their pregnancy potentiaJly resulting in improved glycaemic control. Titration algorithms specifying 
recommended adjustments of the basal insulin dose at different plasma glucose levels are used in 
order to ensure subJects receive an optimal treatment. Subjects will receive intensive medical care 
by means of close contact to the clinical sites with at least weekly coutacts. 
Tii al products will be provided by Novo Nordisk free of charge. Subjects will be provided with a 
BG-meter including lancets, plasma-calibrated test ships and control solutions as well as 
instmctions for use. Subjects wiU receive IDeg and IAsp or IDet and !Asp in prefilled pens. For a 
description of risks and benefits please refer to current versions and any updates of the !Deg IB1, the 
SmPC for !Deg§., IDe~ and IAsplQ and/or local approved product 
if applicable. 
Cuffently only IDet and !Asp are approved for use by pregnant subjects with TlDM. For many 
clinicians the use of IDeg during pregnancy seems a compelling choice as basal insulin due to its 
low variability and low risk of hypoglycaemia. There is no i.nfonnation available today indicating 
any other risks in coil.llection v.rith the use ofIDeg, neither for the pregnant women nor for the 
foetus, than those found with IDet ·ne trial products may be associated with side effects, but 
relevant precautions have been implemented in the design and planned conduct of the tiial in mder 
to minimise the risks and inconveniences of participating in the trial. These pr,ecautions lnclude 
thorough information regarding the con ect administration of the tiial product and handling of low 
BG measurements. Furthennore, subjects will be fully infon.ued about possible AEs aud 
inconveniences before i11itiation of any trial related activitie-s. 
Clinical benefits and risk considerations for the trial 
For the individual subjects, the personal health-related benefits are related to the medical 
examination and the benefit from a treatment regimen anticipated being equal to or better tllan the 
treatment they receive at the time they enter the trial. However, subjects will have to spend some 
extra time monitoring and recording data and on additional visits to the clinic and phone contacts. 
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The high frequency of contacts between the subject and the investigator and the thorough evaluation 
of SMPG values will provide the opportunity for optimising the titratfon of basal and bolus insulin 
and thereby may contribute to obtaining improved HbA1c results. 
For the individual subjects, the anticipated side effects associated \.vith the llial products are not 
different from what is seen with other insulins and include hypoglycaemia, hypersensitivity 
reactions, injection site reactions and lipodystrophy. The side effects will be mitigated by the close 
supervision of the subjects, the frequent measurements of BG levels and the review and monitoring 
of data by the DMC. Detailed information about tiial products is available in the cunent edition and 
any updates of the IDeg IW-, the SmPC for IDei , IDet.!! and IAsp-li' and/or local approved product 
infonnation, if applicable. 
Subjects in th.is trial will benefit from a basal-bolus insulin treatment in a TIT setting under close 
supervision. It is concluded that the clinical benefits from the trial outweigh the potential risks of 
pa1ticipating in this tJial. 
18.2 
Informed consent 
In seeking and documentmg infmmed consent, the investigator must comply with applicable 
regulatory requirement(s) and adhere to !CH ocp.l and the requirements in the Declaration of 
Helsinki1_ 
Before any trial-related acttvity, the investigator must give the subject verbal and written 
infonnation about the trial and the procedures involved in a fonn that the subject can read and 
understand. 
The s11bject must be folly infom1ed of their rights and responsibilities while participating in the trial 
as well as possible disadvantages of being treated with the trial products. 
If required by local legislation, the father of the foetu s (if known) must be asked to sign an 
agreement form before delivery it1 order to collect blood samples as well as health information 
about the infant aft.er delive1-y. If the father of the foetus is not known this must be documented in 
the subject's medical records. If tl1e father of the foetus refoses to give llis consent, this infomiation 
will not be collected. 
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 infon:ned consent must be obtained from the subject 
before any trial-related activity. 
The responsibility for seeking infom1ed consent must remain with the investigator, but the 
investigator may delegate the task to a medically qualified person, in accordance with local 
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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 info1mation 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 
wiitten subject information must be provided and a new infonued consent must be obtained. 
18.2.1 
Paternal Informed consent 
In case of abnormal pregnancy outcome the biological father of the foetus/infant(s) (if known) must 
be asked to sign an infonned consent in order to register relevant paternal infonnation to evaluate 
the reason for the abnormabty. 
The procedure for obtaining and documenting the paternal infonned consent follows the procedure 
in Section 18.2. 
18.3 
Data hancU.lng 
If the subject vvithdraws from the trial or is lost to follow up, then the subject's data will be handled 
as follows: 
• 
Data ah-eady collected and any data collected at the end of trial visit including follow-up visits 
will be retained by Novo Nordisk, entered into the database and used for the CTR. 
• 
Safety events will be reported to Novo Nordisk and regulatoty authorities according to 
locaVnatioual requirements 
If data is used, 1t will always be in accordance with local regulations and IRBs/IECs. 
18.4 
Information to subjects dm·ing 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 collllllunic.ation package will contain the letters 
intended for distribution to the subjects. Tbe letters will be translated and adjusted to Jocal 
requirements and distributed to the subject at the discretion of the investigator. The subject may 
receive a "welcome to the trlai letter" and a "thank you for yom pa1ticipatio11 letter" after 
completion of the t:Iial. Fmthem1ore, the subject may receive letters during the trial. 
All written information to subjects must be sent to IRB/IEC' for approvaVfavourable opinion and to 
regulato1y authorities for approval or notification according to JocaJ regulations. 
18.5 
Premature termination of the tt·tal and/or trial slte 
Novo Nordisk, the IR.BSJIECs or a regulatory authority may decide to stop the trial, pa1t of the trial 
or a triaJ site at any time, but agreement on procedures to be followed must be obtained. 
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If the trial is suspended or prematurely tenninated, the investigator must info1m 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 tennination of the trial, the benefit-risk analysis changes, the new evaluation must be 
provided to the IR.Bs/IECs in case d 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 infonu and protect the subjects 
should be described. 
19 Protocol compliance 
19.1 
Protocol deviations 
Deviations from the protocol should be avoided. If deviations do occur, the investigator must 
infonn 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 oorrections are not possible, can be 
acknowledged and confirmed via edit checks in the eCRF or via listings from the hiaJ database. 
Documentation on protocol deviations must be kept in the investigator trial master file and sponsor 
trial master file. 
19.2 
Pl'evention of missing data 
The impo11ance of subject retention will be addressed by Novo Nordisk in the training and 
conummication with tl1e trial sites. 
The s11bjects will be carefolly infonned about the trial procedures before signing infonned consent, 
so that they know the implications of participating in the trial. 
Close surveillance of subject retention will be performed tluoughout the trial by Novo Nordisk with 
focus on reasons for premature disoontinuation of trial product or withdrawal of consent to secure 
early mitigations in coUaboration with the trial sites. 
The investigator will make eve1y effort to ensure that aU assessments are perfonned and data is 
collected. If missing data does occur the reason will be collected via the protocol deviation process, 
see Section .121.-Novo Nordisk wiU monitor protocol deviations on an on-going basis throughout 
tile trial followed by appropriate actions ( e.g. re-training of site staft). 
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UlN: Ull I H 19J-30JS 
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20 Audits and inspections 
NN 1250 -4300 
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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. Titis includes giving auditors 
and inspectors direct access to au source documents and other documents at the trial site relevant to 
the clinical hial. This includes pemlission to examine, analyse. verify and reproduce any record(s) 
and report(s) that are relevant to the evaluation of the tiial. 
21 Critical documents 
Before a trial site is allowed to sta1t screening subjects, wiitten notification from Novo Nordisk 
must be received and 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 infonnation/info1med consent fonn, any 
other written information to be provided to the subject and subject recmitment 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) ( ctment, dated and signed - must include 
documented GCP training or a certificate) 
• 
Signed receipt of IB. SmPC or sinlilar labelling 
• 
Signed and dated Agreement on Protocol 
• 
Signed and dated Agreement on Protocol Amendment, if applicable 
• 
Conu--act, signed by the investigator and/or appropriate panjes on behalf of the investigator's site 
and Novo Nordisk 
• Source document agreement 
• 
Central laborat01y cettificatioo and oonual ranges 
• 
Insurance statement, if applicable 
• 
Financial disclosure fotm from investigator and sub-investigator(s) 
Novo Nordisk wiJI analyse and report data from all sites together if more than one site is involved in 
the trial. 
By signing the protocol agreement, each investigator agrees to comply fully with ICH GCPl, 
applicable regulatory requirements and the Declaration of Helsinki:Z._ 
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By signing the protocol agreement, each investigator also agrees to allow Novo Nordisk to make 
investigator's name and infom1ation about site name and address publically available if this is 
required by national or international regulations. 
22 Responsibilities 
The investigator is accountable for the conduct of the trial at his/her site and must ensure adequate 
supervision of the conduct of the trial at the tiial site. If any tasks are delegated, the investigator 
must maintain a log of appropriately qualified persons to whom he/she has delegated specified trial-
related duties. The investigator must ensure that there is adequate and documented h·aining 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 ofthe subjects. 
A qualified physician, who is an investigator or a sub-investigator for the trial, must be responsible 
for all trial-related medical decistons. 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 pennit evaluation of the condt1ct of a trial and the quality of the data 
produced) in the investigator trial master file. The documents including the subject identification 
code ]ist must be kept in a secure locked facility, so no unauthorized persons can get access to the 
data. 
The investigator will take all necessaJ)' technical and organisational safety measures to prevent 
accidental or wrongful destrnction, loss or deterioration of data. Tue 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 otbe1wise demonstrate to Novo Nordisk that 
such technical and organisational safety measures have been taken. 
During any period of tmavailability, the investigator must delegate responsibility for medical care of 
subjects to a specific quaHfied physician who will be readily availab]e 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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Trial ID: 
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UlN: Ull I H 19J-30JS 
EudraCT n.o.: 2017-000048-17 
NN 1250 -4300 
CONFIDm>m 1\1. 
23 Reports and publications 
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The infonnation obtained during the conduct ofthis trial is considered confidential, and may be 
used by or on behalf of Novo Nordjsk for regulatory purposes as weU as for the general 
development of the trial product. Al] infom1ation supplied by Novo Nordisk in connection with this 
trial shall remam the sole prope1ty of Novo Nordisk and is to be considered confidential 
infonnation. 
No confidential infonnation sha[l be disclosed to others without prior written consent from Novo 
Nordisk. Such infonnation shall not be used except in the performance of this trial. 111e infonuatiou 
obtained dming this t1ial may be made available to other physicians who are conducting other 
clinical trials with the trial. product, if deemed necessary by Novo Nordisk. Provided tlrnt certain 
conditions are fulfilled, Novo Nordisk may grant access to information obtained dming this trial to 
researchers who require access for research projects studying the same disease and/or trial product 
sntdied in this trial 
Novo Nordisk may publish on its clinical trials website a redacted clinical tiial report for this trial. 
One investigator will be appointed by Novo Nordisk to review and sign the CTR (signatory 
investigator) on behalf of all participating investigators. The signatory investigator will be 
appointed based upon the criteria defmed by the ICMJE for research publi.cations50. 
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 DisclosureZ2. 
Novo Nordisk rese1.res t1le tight to defer the release of data until specified milestones are reached, 
for example when the clinical trial report is available. Tbis includes the 1ight not to release the 
results of inteiim analyses, because the release of such information may influence the res1llts 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 tile 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. 
23.1.1 
Authorship 
Authorship of publications should be in accordance with the Uniform Requirements of the ICMJE.22 
(sometimes referred to as the Vancouver Criteria). The investigator(s) offered authorship will be 
asked to comment and approve the publication(s). 
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 infonnation for llealthcare professionals or 
subjects, and therefore may not be suppo1ied by Novo Nordisk. It is a Novo Nordisk policy that 
such individual rep01ts do not precede the p1ima1y manusc1ipt and should always reference the 
p1imary manuscript of the tiial. 
Novo Nordisk reseives the right to prior review of such publications. Further to allow for the 
p1imary manuscript to be published as the first, Novo Nordisk asks for deferment of publication of 
individual site results until the p1imary manusciipt 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. 
23.2 
Investigator access to data and review of results 
As owner of the triai database, Novo Nordisk bas 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. 
24 Retention of clinical trial documentation and human biosamples 
24.1 
Retention of clinical trial documentation 
Subj ect's medical records must be kept for the maximum period pennitted by the hospital, 
insrimtion or private practice. 
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The investigator must agree to archive the documentation (this includes both eleclToni.c and paper-
based records) pertaining to the trial in an archive after completion or discontinuation of the ttial if 
not otherwise notified. The investigator should not deslToy any documents without prior permission 
from Novo Nordisk. If the investigator cannot archive the doclllllents 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 ti.Jes. 
The investigator must be able to access his/her tria] 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 
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 pe11aining to the trial for at least 20 yea1s 
after discontinuation of the marketing authorisation, termination of tbe tria] or canceUation of the 
research project whichever is longest. 
The files from the hial site/institution must be retained for 15 years after end of trial as defined in 
Section L 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 human biosamples 
The !Deg cord blood samples colJected may be stored until after end of ttial until they have been 
analysed. The IDeg cord blood samples will be destroyed no later than at fi.oalisation of the CTR. 
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 repo11 the 
following to the IRB/IEC, in accordance with local requirements: updates to the IB, unexpected 
SAEs where a causal relationship cannot be rnled out~ protocol amendments according to local 
requirements, deviations to the protocol implemented to eliminate immediate hazards to the 
subjects, new infonnation 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 
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the subjects), annually written summa1ies of the trial status, and other documents as required by the 
local 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 ensure s11bmissiou of the clinical trial repmt synopsis to the JRB/IEC. 
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 autholities will receive the clinical tiial application, protocol amendments, reports on 
SAEs, and the clinical trial report according to national requirements. 
26 Indemnity statement 
Novo Nordisk earlies 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 witl1: 
For Australia: Medicines Australia Form of Indemnity for clinical tlials version 160104B dated 16 
January 2004. 
For Russia: Federal Law of 12 April 2010 No. 61-FZ "On Circulation ofMe<licines". 
For Austria: Arzneimittelge.setz (BGBI. Nr. 185/1983) last amended with BGBI Il Nr. 105/2015. 
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27 References 
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1. 
ICH Harmonised Tripartite Guideline. Guideline for Good Clinical Practice E6(R.2), Cunent 
Step 4 version. 09 Nov 2016. 
2. 
World Medical Association. WMA Declaration of Helsinki - Ethical Principles for Medical 
Research Involving Human Subjects. Last amended by the 64th WMA General Assembly, 
Fortaleza, Brazil. October 2013. 
3. 
Nielsen LR, Pedersen-Bjerggard U, Thorsteinsson B, Johansen M, Damm P, Mathiesen ER. 
Hypoglycemia in pregnant women with type 1 diabetes: predictors and role of metabolic 
control. Diabetes Care. 2008) 1(1):9-14. 
4. 
Jonassen I, Havelund S, Hoeg-Jensen T, Steensgaard DB, Wahlund PO, Ribel U. Design of 
the novel protraction mechanism of insulin degludec, an ultra-long-acting basal insulin. 
Phann Res. 2012;29(8):2104-14. 
5. 
Novo ordisk A/S. Investigatm~s Brochure, insulin degludec (Tresiba®), project NN1250, 
(edition 12). 14 Dec 2016. 
6. 
Novo 
ordisk A/S. Tresiba~ (insulin degludec) - EU Summary of Product Characteristics 
(SmPC). 28 April 2017. 
7. 
Mathiesen ER Hod M, lvanisevic M, Duran Garcia S, Bmndsted L, Jovanovic L, et al. 
Matemal efficacy and safety outcomes in a randomized, controlled trial compa1ing insulin 
detemir with NPH insulin in 310 pregnant women \<vi.th type 1 diabetes. Diabetes Care. 
2012;35{10):2012-7. 
8. 
Novo Nordisk A/S. Levernir® (insulin detemir), EU Summary of Product Characteristics 
(SmPC). 06 Feb 2017. 
9. 
Mathiesen ER, Kinsley B, Arniel SA, Heller S, Mccance D, Duran S, et al. Matemal 
glycemic control and hypoglycemia in type 1 diabetic pregnaucy: a randomized trial of 
insulin asprut versus human insulin in 322 pregnant women. Diabetes Care. 2007;30( 4):771 -
6. 
IO. 
Novo Nordisk A/S. NovoRapid~ (insulin aspart), EU Summaiy of Product Characteristics 
(SmPC). 15 Nov 2016. 
11. 
Casson IF, Clarke CA, Howard CV, McKendrick 0 , Pennycook S, Pharoah PO, et al. 
Outcome-S of pregnancy in insulin dependent diabetic women: results of a five ye-ar 
population cohort study. BMJ. 1997;315(7103):275-8. 
12. 
Ha,vtbome G, Robson S, Ryall EA, Sen D, Robe1ts SH, Ward Platt MP. Prospective 
population based survey of outcome of pregnancy in diabetic women: results of tbe 
Nmthern Diabetic Pregnancy Audit, 1994. BMJ. 1997;315(7103):279-81. 
13. 
Jensen DM, Dannn P, Moelsted-Pedersen L, Ovesen P, Westergaard JG, MoeUer M, et al. 
Outcomes in type 1 diabetic pregnancies: a nationwide, population-based study. Diabetes 
Care. 2004;27(12):2819-23. 
14. 
Macintosh MC, Fleming KM, Bailey JA, Doyle P, Modder J, Acolet D, et al. Perinatal 
mmtality and congenital anomalies in babies of women witb type l or type 2 diabetes in 
England, Wales, and No11hem freland: population based study. BMJ. 2006;333(7560):177. 
15. 
Nielsen GL, Sorensen HT, Nielsen PH, Sabroe S, Olsen J. Glycosylated hemoglobin as 
predictor of adverse fetal outcome in type 1 diabetic pregnancies. Acta Diabetologica, 
1997;34(3):217-22. 
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16. 
Jovanovic L. Role of diet and insulin treatment of diabetes in pregnancy. Clin Obstet 
Gynecol. 2000;43(1):46-55. 
17. 
Evers Ilv.1, Bos AM:, Aa.l.ders AL, van Ballegooie E, de Valle HW, van Doorrnaal JJ, et al. 
Pregnancy in women with diabetes mellitus type I: matemal and perinatal complications, in 
spite of good blood glucose control. Ned Tijdschr Geneeskd. 2000J 44(17):804-9. 
18. 
Boskovic R, Feig DS, Derewlany L, Knie B, Portnoi G, Koren G. Transfer of insulin lispro 
across the htunanplacenta : in vitro perfusion studies. Diabetes Care. 2003;26(5):1390-4. 
19. 
Danne T, Datz N, Endaltl L, Haahr H, Nestoris C, Westergaard L, et al. Insulin deternir is 
characterized by a more reproducible phannacokinetic profile than insulin glargine in 
children and adolescents with type 1 diabetes: results from a randomized, double-bHnd, 
controlled trial. Pediatric Diabetes. 2008;9(6):554-60. 
20. 
Pollex EK, Feig DS, Lubetsky A, Yip PM, Kmen G. Insulin Glargine Safety in Pregnancy: 
A transplaccntal transfer shidy. Diabetes Care. 2010;33(1):29-33. 
21. 
Kitzmiller JL, Block JM, Brown FM, Catalano PM, Conway DL, Coustan DR, et al 
Managing preexisting diabetes for pregnancy: summary of evidence and consensus 
recommendations for care. Diabetes Care. 2008;31(5): 1060-79 
22. 
Food and Drug Administration. Guidance for Industry. Pregnancy, Lactation and 
Reproductive Potential: Labeling for Human Prescription Drng and Biological Products -
Content and Fonnat, Draft Guidance. December 2014. 
23. 
ter Braak EW, Evers Il\1, Willem EI:kelens D, Visser GH. Maternal hypoglycemia during 
pregnancy in type 1 diabetes: maternal and fetal consequences_ Diabetes Metab Res Rev. 
2002~ 18(2):96-105. 
24. 
American Diabetes Association. Management of Diabetes in Pregnancy. Diabetes Care. 
2017A0(Suppl. 1):Sl 14-S9. 
25. 
National Institute for Health and Care Excellence (NICE). Diabetes in pregnancy: 
management from preconception to the postnatal period. 25 Febmary 2015. 
26. 
EUROCAT Central. Registry- University of Ulster. EUROCAT Guide 1.4: Instmction for 
the registration of congenitaJ anomalies. 2013. 
27. 
KDIGO 2012 Clinical Practice Guideline for the Evaluation a11d Management of Chronic 
Kidney Disease. http://vi\¥W.kidney-intemational.org. 2013 2013. 
28. 
Murphy H, Roland J, Skinner T, Simmons D, Gurnell E, Monish N, et al. Effectiveness of a 
regional prepregnancy care program in women with type 1 and type 2 diabetes: benefits 
beyond glycemiccoutrol. Diabetes Care. 2010;33(12):2514-20. 
29. 
Novo ordisk A/S. http://\ivww.novonordisk-trials.com/website/content/how-we-disclose-
tria1-infonnation.aspx. 
30. 
De Angelis C, Drazen JM, Ftizelle FA, Haug C, Hoey J, Horton R. et al. Clinical trial 
registration: a statement from the International Committee of Medical Journal Editors. N 
Engl J Med. 2004;351(12):1250-1. 
31. 
U.S. Food and Dmg Administration. Food and Drug Administration Amendments Act of 
2007 as amended by the final Rule "Clinical Trials Registration and Results Iufonnation 
Submission". 21 September 2016. 
32. 
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 
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implementation of good clini.cal practice in the conduct of clinical trials on medicinal 
products for human use, atticle 11 . Official Journal of the Emopean Couunw.1ities. 01 May 
2001. 
33. 
The European Parliament and the Council of the European Cmmcil. Regulation (EC) No 
726/2004 of the European Parliament and of the Council of 31 March 2004 laying dov.ru 
Community procedures for the authorisation and supervision of medicinal products for 
human and veterinary use and establishing a European Medicines Agency, a1ticle 57. 30 
April 2004. 
34. 
Clarke WL, Cox DJ, Gonder-Frederick LA, Julian D, ScWundt D, Polonsl.-y W. Reduced 
awareness of hypoglycemia i.n adults wi.th IDDM. A prospective study of hypoglycemic 
frequency and associated symptoms. Diabetes Care. 1995;18(4):517-22. 
35. 
Seaquist ER, Anderson J, Childs B, Cryer P, Dagogo-Jack S, Fish L, et al. Hypoglycemia 
and diabetes: a report of a 'Norkgroup of the American Diabetes Association and the 
Endocrine Society. Diabetes Care_ 2013~36(5):1384-95. 
36. 
McAulay V, Deary D, Frier BM. Symptoms of hypoglycaemia in people with di.abetes. 
Diabet Med. 2001;18(9):690-705_ 
37. 
U.S. Department ofHeaHh a.nd Human Services, Food and Dmg Administration. Guidance 
for Industry. Patient-Reported Outcome Measures: Use in Medical Product Development to 
Suppmt Labeling Clai.ms. December 2009. 
38. 
Stull DE, Leidy NK, Parasuraman B, Chassany 0 . Optimal recall periods for patient-
rep011ed outcomes: chaHenges and potential solutions. Curr Med Res Opin. 2009;25(4):929-
42. 
39. 
European Comnussion. The Rules Goveming Medicinal Products in the European Union, 
Volume 4, Anne~~ 13, Investigational Medicinal Products (ENTR/F/2/AM/an D[2010] 
3374). 03 Feb 2010. 
40_ 
Novo Nordisk NS. hlvestigat01~s Brochure, insulin detemir (Levemir ®), project NN304, 
(edition 13). 2019. 
41. 
Novo Nordisk NS. hlvestigatot~s Brochure, insulin aspati (NovoRapid ~>, project NN1218 
(edition 8). 30 Nov 2018. 
42. 
Guideline on the exposme to medicinal products during pregnancy: Need for post-
authorisation data (EMEA/CHMP/313666/2005). 2005. 
43. 
U.S. Food and Drng Admimstration. Code of Federal Regulations, 21 CFR Pait 11, 
Electronic Records, Electronic Signatures. 2009 2009. 
44. 
European Union. Regulation (EU) 2016/679 of the European Parliament and of the Council 
of 27 April 2016 on the protection of natural persons with regard to the processing of 
personal dat.a and on the free movement of s,1ch data, and repealing Directive 95/46/EC 
(General Data Protection Regulation). Official Journal L 2016;119(1). 
45. 
European Medicines Agency, Committee for Medicinal Products for Human Use (CHMP). 
Guideline on clinical investigation of medicinal products in the treatment or prevention of 
diabetes mellitus (CPMP/EWP/1080/00 Rev. l). Adoption by CHMP. 14 May 2012. 
46. 
Little RJA, Rubin DB. Statistical analysis with missing data: New York: John Wiley & 
Sons. 1987. 
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47. 
European Medicines Agency, Committee for Medicinal Products for Human Use (CHMP). 
Guideline 011 Missing Data iu Coufumatory Clinical Trials (EMA/CP::MP/EWP/1776/99 
Rev. 1). 2 Jul 2010. 
48. 
National Research Cow1cil. The Prevention aud Treatment of Missing Data w CJiaical 
Trials. Washington D.C.: The National Academies Press. 2010. 
49. 
Schwai1z NS, Clutter WE, Shah SD, Cryer PE. Glycemic thresholds for activation of 
glncose connteffegulatory systems are higher than the threshold for symptoms. J Clin Invest. 
1987~79(3):777-81. 
50. 
International Committee of Medical Joumal Editors. Recommeudations for the Couduct, 
Reporting, Editing and Publication of Scholarly Work in Medical Jotmials; cunent version 
available at www.icmje.org. 
ll0 ofllO 


Protocol protocol-version-4-appendix-a I 
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Protocol AppendL-.; A 
Trial ID: 
125()-4300 
UlN: Ull I H 191·30JS 
EudraCT n.o.: 2017-000048-17 
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Appendix A: Insulin Titration Guideline 
Trial ID: NN1250-4300 
A trial comparing the effect and safety of insulin deglndec versus 
insulin detemi1·, both in combination with insulin aspart, in the 
treatment of pregnant women with type 1 diabetes 
This ceafid@atia! docwnent is the property of Novo Nordisk. Ng Y,AfllWlish~ iamrmatiga ce1;11am@d k@i:@il:1 may bl} 
4i!icles@d yJi&J:ig1n pi:jgr ~nlt@<l appn>1,<al froe1 NQvg Ngmisk. ,t.,,cc@ss le IJ:ii.s det:iimMl nu1-S1 b@ £1;}smc11;}d lQ i:@k•.'3111 
1 of 7 


Protocol protocol-version-4-appendix-a I 
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Protocol AppendL-.; A 
Trial ID: 
125()-4300 
UlN: Ull I H 191·30JS 
EudraCT n.o.: 2017-000048-17 
Table of Contents 
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Page 
1 
Ioh·oductioo ............................................................................................................................................... 3 
2 
Treatment regimens .................................................................................................................................. 3 
2. l 
Injection area .................................................................................................................................. 4 
2.2 
Time ofinjection ............................................................................................................................ 4 
3 
Initiation and tttJ·atton ·····••m•·······•··•······························· 
.................... _ ...............................................•.. 4 
3. l 
Initiation ......................................................................................................................................... 4 
3.2 
Basal titration ................................................................................................................................. 4 
3.3 
Bolus titration ................................................................................................................................ 5 
3.4 
Deviations fi'on1 the algorithtn ....................................................................................................... 6 
4 
Data coUectton ........................................................................................................................................... 6 
5 
Review procedure ...................................................................................................................................... 6 
6 
References .................................................................................................................................................. 7 
List of in-text tables 
Table 3- 1 
Table 3-2 
Page 
IDeg or IDet dose increase ....................................................................................................... 5 
IDeg or IDet dose reduction ..................................................................................................... 5 
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Protocol protocol-version-4-appendix-a I 
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Protocol AppendL-.; A 
Trial ID: 
125()-4300 
UlN: Ull I H 191·30JS 
EudraCT n.o.: 2017-000048-17 
1 
Inti-oduction 
CONFIDm>m 1\1. 
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The goal of insulin therapy is to achieve near normoglycaemia, i.e. to reach a pre-defi11ed HbA1c 
level with a low rate of hypoglycaemic episodes and as little weight gai11 as possible. Several nials 
have shown that this is difficult to achieve, unJess plasma glucose (PG) values are intensively 
monitored and the insulin dose(s) frequently adjusted.~ 
To ensure treatment unifonnity between the sites, as well as to ensure that subjects receive au 
optimal treatment, titration algorithms have been developed specifying recommended dose 
adjustments at different PG levels. 
It is recognised that treatme-nts differ between different regions and countries. Likewise, spe.cific 
titration guide.lines may not be applicable in certain clinical situations. It is important that other 
.i.Jlfonnation, such as symptoms of hypoglycaemia and/or 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 
shouJd always use clinical judgement to avoid safety hazru·ds. The investigator is responsible for the 
treatment of the subjects and can therefore overmle the guideline. 
To optimise and maintain glycaem.i.c control the investigator should throughout the trial be in 
weekly contact with the subjects to assist the subjects in adjusting insulin doses and to ensure the 
subject's welfare. 
As this trial is perfonned in pregnant subjects with type 1 diabetes mellitus (TlDM), it is especially 
impot1ant that the investigator also considers that the insulin demand will vruy during pregnancy, 
e.g. being lower during the first 20 gestational weeks than dming the remainder of the pregnancy. 
2 
Treatment regimens 
At randomisation, pre-trial insulin treatm ent must be discontinued. Eligible subjects are randomised 
1: l into one of the r.vo t:re.atment aims: 
• 
Insulin degludec (IDeg) OD + insulin aspart (IAsp) 2-4 times daily with meals 
• 
Insulin detemir (IDet) OD/BID + insulin aspart (IAsp) 2-4 times daily with meals 
The treat-to-target (TIT) approach is applied in both treatment anus in order to optimise titration 
and glycaemic control throughout the trial 
There are no maximum or minimum doses. 
3 of7 


Protocol protocol-version-4-appendix-a I 
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Protocol AppendL-.; A 
Trial ID: 
125()-4300 
UlN: Ull I H 191·30JS 
EudraCT n.o.: 2017-000048-17 
2.1 
Injedlon area 
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The trial products !Deg, IDet and !Asp should be injected subcutaneously into the thigh, upper ann 
(deltoid area) or the abdomen. 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 
fusulin degludec should be admuustered OD any tin1e of the day, preferably at the same time every 
day. 
Subjects receiving IDet OD should administer the dose any time of the day, preferably at the same 
time each day. Subjects receiving IDet BID should administer one dose in the morning and the 
other dose in the evening or at bedtime. 
fusulin aspart should be administered 2-4 times daily with the meals. Additional bolus dosing is 
allowed at the investigator's recommendation. 
3 
Initiation and titration 
3.1 
Inltiatlon 
Subjects randomised to IDeg should reduce their previous basal insulin dose by 20% and dose OD. 
Subjects randomised to IDet should be transfen-ed unit-to-unit. If the subjects switch from an OD 
regimen, they should continue on an OD regimen. If the subjects switch from a BID regimen they 
should continue on a BID regimen. Dose reduction should be considered. 
The subjects should have their bolus insulin doses switched to IAsp unit-to-unit. 
3.2 
Basal titration 
After randomisation the basal insuJin doses should be adjusted onc,e weekly by the investigator in 
connection with the scheduled visits/phone contacts. 
The IDeg dose adjustment should be based on the mean of three pre-breakfast SMPG values 
measured on t\vo days prior to titration and on the day of tl1e visit. This also applies to subjects 
receiving IDet OD. 
For subjects receiving IDet BID, the morning dose will be adjusted accordiog to the mean pre-main 
evenmg meal SMPG values obtained on the three days prior to the day oftbe visit or contact. The 
evening dose will be adj11Sted according to the mean pre-breakfast SMPG values measured on the 
4 of7 


Protocol protocol-version-4-appendix-a I 
NN 1250 -4300 
Protocol AppendL-.; A 
Trial ID: 
125()-4300 
UlN: Ull I H 191·30JS 
EudraCT n.o.: 2017-000048-17 
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two days p1ior to the day of the visit or contact and on tl1e day of the visit or cont.act. Adjustments 
will be in accordance with Table 3-1 and Table 3- 2. 
If one or wore SMPG values are m..issing, the dose adjustment should be perfonued on the 
remaining SMPG value(s). The insulin dose adjustment should aim to reach an SMPG of 
4.0-5.0 mmol/L (71-90 mg/dL). 
The dose calcuJation will be based on the most recent dose taken within the last three days before 
the contact. 
Table 3-1 
IDeg 01· IDet dose increase 
Mun pre breald'a&t or pre maJn t'venlng Dlf'al SMPG 
DoSt' adjustment 
m1nol/L 
mg/dL 
u 
4.0-5.0 
71 -90 
No adjustment 
5.1 - 10.0 
91- 180 
+2 
10.1- 15.0 
181-270 
+4 
> 15.0 
> 270 
+6 
If one of the SMPG values is below target of 4.0 mmol/L (71 mg/dL) the insulin dose should be 
reduced according to Table 3-2. 
Table 3-2 
IDeg or IDet dose reduction 
Lowest 
or prt"-main t'vtning mral SMPG 
Dost- adjnsfmt'nt 
m.mol/L 
mg/dL 
u 
<3 1 
<56 
-4 
3.l - 3.9 
56 - 70 
-2 
3.3 
Bolus titntion 
Insulin aspart adjustments should be at the investigator's discretion and in collaboration with the 
subject. 
Dwing pregnancy it is recommended to measure SMPG values 60 minutes after main meal start. 
These values can be used for further bolus dose optimisation. The American College of 
Obstetrtctans and Gynecologists and American Diabetes Association recommend a 60 minutes post~ 
prandial SMPG $ 7.8 mmol/L ($140 mg/dL).l 
5 of7 


Protocol protocol-version-4-appendix-a I 
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Protocol AppendL-.; A 
Trial ID: 
125()-4300 
UlN: Ull I H 191·30JS 
EudraCT n.o.: 2017-000048-17 
CONFIDm>m 1\1. 
3.4 
Deviations from the algorithm 
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It is recommended that the algorithm is followed. However, it is also important that the decision to 
adjust the IDeg or IDet doses is based on all relevant iufon.uation as described in Section l -A 
reason for deviating from the algorithm should be entered into the eCRF. 
4 
Data collection 
The following data should be entered into the eCRF within 24 hours (on weekdays) after each site 
visit or phone contact: 
• 
Per protocol S:MPG values 
• Doses oflDeg/IDet taken the last tlu·ee days before the contact 
• New prescribed dose of IDeg/lDet at the contact 
• 
Reason(s) for deviation(s) from the titration algorithms, if any 
• 
Hypoglycaemic ,episode(s) 
5 
Review procedure 
SUIVeillance of titration data will be perfo1med centrally by Novo Nordisk in an tmbiased manner. It 
is important that data regarding dose titration is entered into the eCRF within 24 hours (on 
weekdays). If delays occur, action cannot be taken in due time before the subject's next site visit or 
phone contact. The aim is to reduce the time periods in which a subject may receive suboptimal 
treatment. 
The data listed in Section :l will be reviewed by Novo Nordisk within 24 hours (on weekdays). The 
reviewer may contact the investigator to get clatification regarding tl1e reason for deviation or to 
request entry of missing data. 
\Vhen 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 sutveillance 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 S:rv1PGs and HbA1c. This 
will be done in an unbiased and whenever possible in a blinded marmer. 
6 of7 


Protocol protocol-version-4-appendix-a I 
NN 1250 -4300 
Protocol AppendL-.; A 
Trial ID: 
125()-4300 
UlN: Ull I H 191·30JS 
EudraCT n.o.: 2017-000048-17 
6 
References 
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I . 
Rosenstock J, Davies M, Home PD, Larsen J, Koenen C, Schernthaner G. A randomised, 
52-week, treat-to-target hial 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):408-16. 
2. 
Hermansen K, Davies M, Derezinski T, Ravn GM, Clauson P, Home P, et al. A 26-week, 
randomized, parallel, treat-to-target uial comparing insulin decemir with NPH insulin as 
add-on therapy to oral glucose-lowering dmgs in insulin-naive people with type 2 diabetes. 
Diabetes Care. 2006;29(6): 1269-74. 
3. 
Philis-Tsimikas A, 01a1pentier 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 dmgs in poorly controlled type 2 diabetes. Clin Tuer. 2006;28(10):1569-81. 
4. 
Riddle MC, Rosenstock J, Gerich J, fusulin Glarg:ine Study I. 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):3080-6. 
S. 
Garber AJ, King AB, Del Prato S, Sreenan S, Balci MK, Munoz-T01Tes 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-inferio1ity tiia]. Lancet. 20 l 2;379(9825): 1498-
507. 
6. 
Heller S, Buse J, Fisher M, Garg S, Ma1Te M, Merker L, et al Insulin degludec, an ultra-
longacting basal insulin, versus insulin g]argine in basal-bolus treatment with mealtime 
insulin aspa1t in type I diabetes (BEGIN Basal-Bolus Type I): a phase 3, raudomised, open-
label, treat-to-target non-inferiority trial. Lancet. 2012:3 79(9825): 1489-97. 
7. 
Ame1i can Diabetes Association. Management of Diabetes in Pregnancy. Diabetes Care. 
2017;40(Suppl. l):S U4-S9. 
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Protocol 4300-proiocol-version-4-appendix-b I 
NN 1250 -4300 
Protocol AppendL-.; B 
Trial ID: 
125()-4300 
UlN: Ull I H 19J-30JS 
EudraCT n.o.: 2017-000048-17 
CONFIDm>m 1\1. 
Date: 
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Appendix B: Baseline hypoglycaemic episode interYie,v 
questionnail·e 
Trial ID: NN1250-4300 
A trial comparing the effect and safety of insulin degludec versus 
insulin detemi1·, both in combination with insulin aspart, in the 
treatment of pregnant women ,,·ith type 1 diabetes 
This Ql;)Qfoi@atia! document is the property of Novo Nordisk. NQ Y.ilfl!Wlishoo iefQrm-atiga QQAl~@d ~i:@al may b~ 
d~Qles~d YAUIQllt pt:ior v.q:i1t@a apprn,.•al foom ~IOVQ }lgf-disk. Acttl<66 le 1.bis dot:iuR~l oni.:t b@ r~&tilQl~d lQ i:@l@r:aat 
1 of 3 


Protocol 4300-proiocol-version-4-appendix-b I 
NN 1250 -4300 
Protocol AppendL-.; B 
Trial ID: 
125()-4300 
UlN: Ull I H 19J-30JS 
EudraCT n.o.: 2017-000048-17 
CONFIDm>m 1\1. 
lnte1·vlew questions for baseUne hypoglycaemic episodes 
Date: 
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Instructions to lntervle,,•er (do not read aloud to the subiect): 
17 December 2020 
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• 
Please read the questions as written. However, you may rephrase if subject needs 
cla1ification. 
• 
If the subject gives a range for a response (e.g. experienced 2 to 4 severe hypoglycaemic 
episodes), record the average of the Iespouse (3 times). If the average is a decimal 
number (3.5 times), then rmmd down to the nearest integer (3 times) and record this 
mnuber. 
• 
If a subject changes her response, record the last response given. 
• If the subject responds to a question by saying something like "I do not know, I never 
really think about it", ask the subject to take a minute and think about it. 
• If the subject still does not remember or refuses to answer, please do not complete the 
question (leave the field blank). 
lnstrucrtons to the subject (read aloud to the subject): 
• 
The following questions are about your experience with hypoglycaemic episodes (low 
blood sugar Ie,·els). 
• 
Please answer to the best of your recollection. 
• Please try to think of the last 6 months for the first question and the last 4 weeks for the 
second question. 
• Perhaps you experienced no symptoms, but noted the low blood sugar episode when 
measuring your blood sugar, possibly for another reason. 
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Protocol 4300-proiocol-version-4-appendix-b I 
NN 1250 -4300 
Protocol AppendL-.; B 
Trial ID: 
125()-4300 
UlN: Ull I H 19J-30JS 
EudraCT n.o.: 2017-000048-17 
General questions 
CONFIDm>m 1\1. 
Date: 
Vet!,i on: 
Smtus: 
Page: 
17 December 2020 
Novo Nordisk 
4.0 
Final 
3 of 3 
I . In the last 6 months have you had a hypoglycaemic event from which you couldn't recover 
yourself and you needed help from someone else to recover, i.e. a 'severe hypoglycaemic 
event'? 
No (if no, go to question 2) 
D Yes (ask the following questions) 
a) How many? 
b) How many of these events occmTed at nigbt (between midnight and 6 o'clock rn the 
morning)? 
2. In the last 4 weeks have you had a hypoglycaemic event which you have been able to manage 
yourself, i.e. a 'non-severe hypoglycaemic event'? 
0 No 
Yes (ask the following questions) 
a) Howmany? 
b) How many of these events occuned at night (between midnight and 6 o'clock in the 
morning)? 
Thank yout tbls ends the interview (stop here). 
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Insulin deg.tudec 
Trial ID: NN125O·4300 
Clinical Trial Report 
Appendi.'i: 16.l.l 
Global and country key Novo No1·dlsk staff 
Dare: 
Version: 
Status: 
31 May 2021 
Novo Nordlsl< 
J,0 
Final 
Attachments I and II (if applicable) to the protocol are located in the Ttial Master File. 
Content: Global key staff and Country key staff 


IT 301 lRB-IEC Approval of amend I v 1.0 I 
N 1250 -4300 
Ethics Committee/IRB Approval Cover page 
Trial ID: 
NNl250-4300 
Country code: 
IT 
Name of approving JEC/IRB: 
Comitato EticoFondazione IRCCS Ca' Granda Ospedale 
Maggiore Policlinico 
Date of approval: 
10 Aprile 2018 
Amendment no.: 
Emendamento 1 
Amendment version: 
1.0 
Amendment date: 
23 Feb 2018 
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IT 3() 1 IRB-IEC Approval of amend I v 1.0 I 
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IT 3() 1 IRB-IEC Approval of amend I v 1.0 I 
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IT 3()1 IRB-IEC Approval of amend I v 1.0 I 
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IT 3()1 IRB-IEC Approval of amend I v 1.0 I 
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IT 30 I IRB-IEC Approval amend 3 v 1.0 I 
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IT 30 I IRB-IEC Approval amend 3 v 1.0 I 
NN 1250 -4300 


IT 301 IRB-IEC Approval amend 3 v 1.0 I 
NN 1250 -4300 


IT 301 IRB-IEC Approval amend 3 v 1.0 
NN 1250 -4300 


IT 30 I IRB-IEC Approval amend 3 v 1.0 I 
NN 1250 -4300 

SAP_001.pdf: