Dose Response and Safety of an Oral PCSK9i, NNC0385-0434, in Patients With Established Atherosclerotic Cardiovascular Disease (ASCVD) or ASCVD Risk on Maximally Tolerated Statin Dose and Other Lipid-lowering Therapy Requiring Further LDL-C Reduction
Phase: PHASE2
Conditions: Atherosclerotic Cardiovascular Disease
Sponsor: Novo Nordisk A/S

Cover Page for Protocol 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT04992065 
Sponsor trial ID: 
NN6435-4697  
Official title of study: 
Dose response and safety of an oral PCSK9i, NNC0385-0434, 
in patients with established atherosclerotic cardiovascular 
disease (ASCVD) or ASCVD risk on maximally tolerated 
statin dose and other lipid-lowering therapy requiringfurther 
LDL-C reduction
Document date*: 
21 September 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.

Link
Link
List of contents
Protocol ...............................................................................................................................................
Protocol attachment ...........................................................................................................................
Date:
Novo Nordisk
Version:
Status:
NNC0385 0434
Trial ID: NN6435 4697
Clinical Trial Report
Appendix 16.1.1
12 September 2022
1.0
Final
16.1.1 Protocol and protocol amendments
 
 
 
Redacted protocol 
Includes redaction of personal identifiable information only. 
. 
CONFIDENTIAL

Protocol 
 
Date: 
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Trial ID: NN6435-4697 
Version: 
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Status: 
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Protocol 
 
Protocol title:  
Dose response and safety of an oral PCSK9i, NNC0385-0434, in patients with established 
atherosclerotic cardiovascular disease (ASCVD) or ASCVD risk on maximally tolerated 
statin dose and other lipid-lowering therapy requiring further LDL-C reduction  
Substance number: NNC0385-0434  
Universal Trial Number: U1111-1252-3392 
EudraCT Number: 2020-002630-32 
IND Number: 151409 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
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This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
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Date: 
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Trial ID: NN6435-4697 
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Protocol amendment summary of changes table 
 
DOCUMENT HISTORY 
Document version 
Date 
Applicable in country(-ies) and/or site(s)  
Protocol version 3.0 
28 September 2021 
United States 
Protocol version 2.0 
29 April 2021 
All 
Original protocol version 1.0 
19 March 2021 
All 
 
Protocol version 3.0 (28 September 2021), United States 
This local amendment is considered to be non-substantial based on the criteria set forth in 
Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the European 
Union, because it neither significantly impacts the safety nor physical/mental integrity of 
participants nor the scientific value of the study. 
Overall rationale for preparing protocol, version 3.0: 
Section # and name 
Description of change 
Brief rationale 
Section 10.9, Appendix 9: Country 
specific requirements 
US specific contraceptive guidance 
for male patients in the trial have been 
updated 
To align with the recommendation in 
comment 2 of the questions received 
from US FDA on 10 June 2021 
(IND151409) 
Section 10.4, Appendix 4: 
Contraceptive guidance and collection 
of pregnancy information 
Appendix 9 has been cross-referred 
for US specific contraceptive 
requirements 
To align with the recommendation in 
comment 2 of the questions received 
from US FDA on 10 June 2021 
(IND151409) 
 
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Table of Contents    
 
Page 
Protocol amendment summary of changes table ........................................................................................... 2 
Table of Contents.............................................................................................................................................. 3 
1 Protocol summary ....................................................................................................................................... 7 
1.1 
Synopsis .............................................................................................................................................. 7 
1.2 
Flowchart .......................................................................................................................................... 11 
2 Introduction ............................................................................................................................................... 15 
2.1 
Trial rationale .................................................................................................................................... 15 
2.2 
Background ....................................................................................................................................... 15 
2.3 
Benefit-risk assessment ..................................................................................................................... 17 
2.3.1 
Risk assessment ................................................................................................................. 17 
2.3.2 
Benefit assessment ............................................................................................................. 18 
2.3.3 
Overall benefit-risk conclusion ......................................................................................... 18 
3 Objectives and endpoints .......................................................................................................................... 20 
3.1 
Primary, secondary and exploratory objectives and estimands......................................................... 20 
3.1.1 
Primary objective ............................................................................................................... 20 
3.1.2 
Secondary objectives ......................................................................................................... 20 
3.1.3 
Exploratory objectives ....................................................................................................... 20 
3.1.4 
Estimands .......................................................................................................................... 20 
3.2 
Primary, secondary and exploratory endpoints ................................................................................. 23 
3.2.1 
Primary endpoint ............................................................................................................... 23 
3.2.2 
Secondary endpoints .......................................................................................................... 23 
3.2.2.1 
Confirmatory secondary endpoints ................................................................ 23 
3.2.2.2 
Supportive secondary endpoints .................................................................... 23 
3.2.3 
Exploratory endpoints........................................................................................................ 23 
4 Trial design ................................................................................................................................................ 25 
4.1 
Overall design ................................................................................................................................... 25 
4.1.1 
PK sub-study ..................................................................................................................... 26 
4.2 
Scientific rationale for trial design .................................................................................................... 27 
4.3 
Justification for dose ......................................................................................................................... 28 
4.4 
End of trial definition ........................................................................................................................ 28 
5 Trial population ......................................................................................................................................... 29 
5.1 
Inclusion criteria ............................................................................................................................... 29 
5.2 
Exclusion criteria .............................................................................................................................. 32 
5.3 
Lifestyle considerations .................................................................................................................... 32 
5.3.1 
Meals and dietary restrictions ............................................................................................ 33 
5.3.2 
Caffeine and tobacco ......................................................................................................... 33 
5.3.3 
Physical activity ................................................................................................................. 33 
5.4 
Screen failures ................................................................................................................................... 33 
5.5 
Run-in criteria, randomisation criteria and dosing day criteria ......................................................... 34 
6 Treatments ................................................................................................................................................. 35 
6.1 
Treatments administered ................................................................................................................... 35 
6.1.1 
Medical devices ................................................................................................................. 36 
6.1.1.1 
Investigational medical device(s) ................................................................... 36 
6.1.1.2 
Non-investigational medical device(s) ........................................................... 36 
6.2 
Preparation/handling/storage/accountability ..................................................................................... 36 
6.3 
Measures to minimise bias: Randomisation and blinding................................................................. 37 
6.3.1 
Randomisation ................................................................................................................... 37 
6.3.2 
Blinding ............................................................................................................................. 37 
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6.3.3 
Blind break ........................................................................................................................ 38 
6.4 
Treatment compliance ....................................................................................................................... 38 
6.4.1 
Drug treatment compliance ............................................................................................... 38 
6.5 
Concomitant medication ................................................................................................................... 39 
6.6 
Dose modification ............................................................................................................................. 40 
6.7 
Treatment after end of trial ............................................................................................................... 40 
7 Discontinuation of trial treatment and subject discontinuation/withdrawal ....................................... 41 
7.1 
Discontinuation of trial treatment ..................................................................................................... 41 
7.1.1 
Temporary discontinuation of trial treatment .................................................................... 42 
7.2 
Subject discontinuation/withdrawal from the trial ............................................................................ 42 
7.2.1 
Replacement of subjects .................................................................................................... 43 
7.3 
Lost to follow-up............................................................................................................................... 43 
8 Trial assessments and procedures............................................................................................................ 44 
8.1 
Information visit and screening......................................................................................................... 44 
8.2 
Efficacy assessments ......................................................................................................................... 45 
8.2.1 
Clinical efficacy laboratory assessments ........................................................................... 45 
8.3 
Safety assessments ............................................................................................................................ 45 
8.3.1 
Physical examinations ....................................................................................................... 46 
8.3.2 
Body measurements ........................................................................................................... 46 
8.3.3 
Vital signs .......................................................................................................................... 47 
8.3.4 
Electrocardiograms ............................................................................................................ 47 
8.3.5 
Clinical safety laboratory assessments .............................................................................. 47 
8.4 
Adverse events and serious adverse events ....................................................................................... 48 
8.4.1 
Time period and frequency for collecting AE and SAE information ................................ 48 
8.4.2 
Method of detecting AEs and SAEs .................................................................................. 48 
8.4.3 
Follow-up of AEs and SAEs ............................................................................................. 48 
8.4.4 
Regulatory reporting requirements for SAEs .................................................................... 49 
8.4.5 
Pregnancy .......................................................................................................................... 49 
8.4.6 
Cardiovascular and death events ....................................................................................... 49 
8.4.7 
Technical complaints ......................................................................................................... 49 
8.5 
Treatment of overdose ...................................................................................................................... 49 
8.6 
Pharmacokinetics .............................................................................................................................. 50 
8.6.1 
PK sub-study ..................................................................................................................... 50 
8.7 
Pharmacodynamics ........................................................................................................................... 51 
8.8 
Genetics ............................................................................................................................................ 51 
8.9 
Biomarkers ........................................................................................................................................ 51 
8.9.1 
PCSK9 levels ..................................................................................................................... 51 
8.10 Biosamples for future analysis .......................................................................................................... 51 
8.11 Immunogenicity assessments ............................................................................................................ 52 
8.11.1 
Assessments in case of suspicion of hypersensitivity to trial product ............................... 53 
8.11.2 
Digital pictures .................................................................................................................. 54 
8.12 Health economics .............................................................................................................................. 54 
9 Statistical considerations .......................................................................................................................... 55 
9.1 
Statistical hypotheses ........................................................................................................................ 55 
9.2 
Sample size determination ................................................................................................................ 55 
9.3 
Populations for analyses ................................................................................................................... 56 
9.4 
Statistical analyses ............................................................................................................................ 57 
9.4.1 
General considerations ...................................................................................................... 57 
9.4.2 
Primary endpoint ............................................................................................................... 57 
9.4.3 
Secondary endpoints .......................................................................................................... 59 
9.4.3.1 
Confirmatory secondary endpoint .................................................................. 59 
9.4.3.2 
Supportive secondary endpoints .................................................................... 59 
9.4.4 
Exploratory endpoints........................................................................................................ 59 
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9.4.5 
Other safety analyses ......................................................................................................... 59 
9.4.6 
Other analyses ................................................................................................................... 59 
9.4.6.1 
Pharmacokinetic and/or pharmacodynamic modelling .................................. 59 
9.5 
Interim analyses ................................................................................................................................ 60 
9.6 
Data monitoring committee .............................................................................................................. 60 
9.7 
Reporting of the main part of the trial ............................................................................................... 60 
10 Supporting documentation and operational considerations.................................................................. 61 
10.1 Appendix 1: Regulatory, ethical, and trial oversight considerations ................................................ 61 
10.1.1 
Regulatory and ethical considerations ............................................................................... 61 
10.1.2 
Financial disclosure ........................................................................................................... 61 
10.1.3 
Informed consent process .................................................................................................. 61 
10.1.4 
Information to patients during trial .................................................................................... 62 
10.1.5 
Data protection .................................................................................................................. 62 
10.1.6 
Committees structure ......................................................................................................... 63 
10.1.6.1 
Novo Nordisk safety committee..................................................................... 63 
10.1.7 
Dissemination of clinical trial data .................................................................................... 63 
10.1.8 
Data quality assurance ....................................................................................................... 63 
10.1.8.1 
Case report forms ........................................................................................... 63 
10.1.8.2 
Monitoring ..................................................................................................... 64 
10.1.8.3 
Protocol compliance ....................................................................................... 65 
10.1.9 
Source documents .............................................................................................................. 66 
10.1.10 Retention of clinical trial documentation .......................................................................... 66 
10.1.11 Trial and site closure.......................................................................................................... 66 
10.1.12 Responsibilities .................................................................................................................. 67 
10.1.13 Indemnity statement .......................................................................................................... 68 
10.1.14 Publication policy .............................................................................................................. 68 
10.1.14.1 
Communication of results .............................................................................. 68 
10.1.14.2 
Authorship ...................................................................................................... 69 
10.1.14.3 
Site-specific publication(s) by investigator(s)................................................ 69 
10.1.14.4 
Investigator access to data and review of results ........................................... 69 
10.2 Appendix 2: Clinical laboratory tests................................................................................................ 70 
10.3 Appendix 3: Adverse events: Definitions and procedures for recording, evaluation, follow-up, 
and reporting ..................................................................................................................................... 73 
10.3.1 
Definition of AE ................................................................................................................ 73 
10.3.2 
Definition of an SAE ......................................................................................................... 73 
10.3.3 
Description of AEs requiring additional data collection ................................................... 74 
10.3.4 
Recording and follow-up of AE and/or SAE ..................................................................... 75 
10.3.5 
Reporting of SAEs ............................................................................................................. 77 
10.4 Appendix 4: Contraceptive guidance and collection of pregnancy information ............................... 79 
10.5 Appendix 5: Technical complaints: Definition and procedures for recording, evaluation, 
follow-up and reporting .................................................................................................................... 82 
10.5.1 
Definition of technical complaint ...................................................................................... 82 
10.5.2 
Recording and follow-up of technical complaints ............................................................. 82 
10.6 Appendix 6: Retention of human biosamples ................................................................................... 84 
10.6.1 
Biosamples for future research .......................................................................................... 84 
10.6.2 
Immunogenicity samples ................................................................................................... 84 
10.7 Appendix 7: Requirements for maximally tolerated dose of statins and documented evidence 
of intolerance to statins ..................................................................................................................... 86 
10.8 Appendix 8:  Mitigations to ensure patient safety and data integrity during an emergency 
situation ............................................................................................................................................. 87 
10.8.1 
Definition and scope of appendix ...................................................................................... 87 
10.8.2 
Visits .................................................................................................................................. 87 
10.8.3 
Assessments ....................................................................................................................... 87 
10.8.4 
Study intervention ............................................................................................................. 88 
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1 
Protocol summary 
1.1 
Synopsis 
Rationale: 
PCSK9 inhibition is a new therapy indicated for treatment of hypercholesterolaemia by lowering 
LDL-C and reduction of cardiovascular risk in patients with established atherosclerotic 
cardiovascular disease (ASCVD).   
NNC0385-0434 is a new PCSK9 inhibitor in development for lowering LDL-C and offers oral 
administration. The rationale for conducting this trial is to acquire a robust dose-response 
understanding of oral NNC0385-0434 to allow for dose selection in a phase 3 programme. The trial 
includes a dose-range expected to cover the relevant therapeutic levels. The target population 
consists of patients with established ASCVD or ASCVD risk on maximally tolerated statin dose and 
other lipid-lowering therapy requiring further LDL-C lowering according to current global 
treatment guidelines. The purpose of this trial is also to examine the steady state PK, safety and 
tolerability of oral NNC0385-0434.  
Objectives and endpoints: 
Primary objective 
To demonstrate superiority of three dose levels of oral NNC0385-0434 versus placebo on percent 
change in LDL-C from baseline to week 12 in patients with established ASCVD or ASCVD risk on 
maximally tolerated statin dose and other lipid-lowering therapy requiring further LDL-C reduction.  
Secondary objectives 
To compare the effect on lipid/lipoprotein parameters excluding LDL-C of three dose levels of oral 
NNC0385-0434 versus placebo in patients with established ASCVD or ASCVD risk on maximally 
tolerated statin dose and other lipid-lowering therapy requiring further LDL-C reduction.  
To compare the effect on lipid/lipoprotein parameters of three dose levels of oral NNC0385-0434 
versus s.c. evolocumab in patients with established ASCVD or ASCVD risk on maximally tolerated 
statin dose and other lipid-lowering therapy requiring further LDL-C reduction.  
To compare the safety and tolerability of three dose levels of oral NNC0385-0434 versus placebo in 
patients with established ASCVD or ASCVD risk on maximally tolerated statin dose and other 
lipid-lowering therapy requiring further LDL-C reduction. 
Estimands 
To address the primary objective, two estimands will be used: 
• Primary estimand: Addresses the main question of interest: What is the efficacy of three dose 
levels of oral NNC0385-0434 versus placebo on percent change in LDL-C from baseline to 
week 12 in patients with established ASCVD or ASCVD risk on maximally tolerated statin dose 
and other lipid-lowering therapy if all patients had remained on trial treatment. A hypothetical 
strategy is applied for the intercurrent event premature trial treatment discontinuation. 
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• Additional estimand: Addresses an additional question of interest: What is the efficacy of three 
dose levels of oral NNC0385-0434 versus placebo on percent change in LDL-C from baseline to 
week 12 in patients with established ASCVD or ASCVD risk on maximally tolerated statin dose 
and other lipid-lowering therapy regardless of premature treatment discontinuation. A treatment 
policy strategy is applied for the intercurrent event premature trial treatment discontinuation. 
Primary endpoint 
Endpoint title 
Time frame 
Unit 
Change in LDL-cholesterol  
From baseline (week 0) to visit 9 
(week 12) 
% 
Supportive secondary endpoints 
Endpoint title 
Time frame 
Unit 
Change in total cholesterol  
From baseline (week 0) to visit 9 
(week 12) 
% 
Change in HDL-cholesterol 
From baseline (week 0) to visit 9 
(week 12) 
%  
Change in VLDL-cholesterol 
From baseline (week 0) to visit 9 
(week 12) 
% 
Change in triglycerides 
From baseline (week 0) to visit 9 
(week 12) 
%  
Change in total Apo B 
From baseline (week 0) to visit 9 
(week 12) 
% 
Change in total Apo CIII 
From baseline (week 0) to visit 9 
(week 12) 
% 
Change in total Lp(a) 
From baseline (week 0) to visit 9 
(week 12) 
Ratio  
Treatment-emergent adverse events 
From baseline (week 0) to visit 10 
(19 weeks + 4 days) 
Number of events 
 
Overall design: 
Trial design 
This is a randomised, multicentre, multinational, seven-armed, parallel group, dose finding trial. 
The trial will be double-blinded within dose level of oral NNC0385-0434 and size-matched placebo 
arm. The s.c. evolocumab arm will be open label. The trial population includes patients with 
established ASCVD or ASCVD risk on maximally tolerated statin dose and other lipid-lowering 
therapy requiring further LDL-C reduction. A PK sub-study in Japanese and non-Japanese patients 
will be performed following the 12 weeks of treatment.  
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Patients will be randomised 3:1:3:1:3:1:3 according to the following treatment arms: 
• Oral NNC0385-0434 15 mg 
• Oral placebo (size-matched to oral NNC0385-0434 15 mg) 
• Oral NNC0385-0434 40 mg 
• Oral placebo (size-matched to oral NNC0385-0434 40 mg) 
• Oral NNC0385-0434 100 mg 
• Oral placebo (size-matched to oral NNC0385-0434 100 mg) 
• S.c. evolocumab  
Randomisation will be stratified according to participation in the PK sub-study, country and 
population (inclusion criteria a/b). Within each stratum, each patient will be randomly allocated to 
one of the treatment arms. For the main statistical analyses, the 3 placebo arms will be pooled into 
one placebo group. 
Key inclusion criteria 
• Male patient or female patient of non-childbearing potential. 
• Established atherosclerotic cardiovascular disease (ASCVD) (criteria a) or ASCVD risk 
(criteria b): 
a) Age ≥40 years at the time of signing informed consent and history of ASCVD 
b) Age >50 years at the time of signing informed consent and with ASCVD risk  
• Serum LDL-C ≥1.8 mmol/L (≥70 mg/dL) as measured by the central laboratory at screening. 
o Japanese patients: Serum LDL-C ≥2.6 mmol/L (≥100 mg/dL) for patients of 
≥40 years of age and with a history of coronary heart disease, and serum LDL-C 
≥3.1 mmol/L (≥120 mg/dL) for all other Japanese patients 
• Patients must be on maximally tolerated dose of statins. 
• Patients not receiving statin must have documented evidence of intolerance to all doses of at 
least two different statins. 
Key exclusion criteria 
• Treatment with PCSK9i therapy (alirocumab or evolocumab within 90 days prior to screening) 
or PCSK9 siRNA therapy (inclisiran within 12 months prior to screening). 
• Fasting triglyceride >4.52 mmol/L (>400 mg/dL) as measured by the central laboratory at 
screening. 
• Myocardial infarction, stroke, hospitalization for unstable angina pectoris or transient ischaemic 
attack within 180 days prior to the day of screening. 
• Renal impairment with eGFR <30 ml/min/1.73 m2 as measured by the central laboratory at 
screening. 
Number of patients: 
Approximately 255 patients will be randomly assigned to trial product. Out of the 255 patients, 
30 Japanese and 30 non-Japanese patients will be randomised to the PK-sub-study.  
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Treatment groups and duration: 
The total trial duration for an individual patient will be approximately 22 weeks divided into the 
following periods: 
• Screening: up to 2 weeks 
• Treatment period: 12 weeks 
• Follow-up period: 7 weeks and 4 days 
 
The following trial products will be supplied by Novo Nordisk for the duration of the trial: 
• NNC0385-0434 A 15 mg, oral, once daily 
• NNC0385-0434 A 40 mg, oral, once daily 
• NNC0385-0434 A 100 mg, oral, once daily 
• Placebo I A (for NNC0385-0434 A 15 and 40 mg), oral, once daily 
• Placebo II A (for NNC0385-0434 A 100 mg), oral, once daily 
• Evolocumab 140 mg/mL, Repatha®, subcutaneous, solution for injection, 1 mL pre-filled 
SureClick® autoinjector (single-use) 
After end of trial, patients will continue suitable standard of care at the discretion of the 
investigator. The trial product will not be available to patients after end of treatment.  
Data monitoring committee: No 
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c Fasting for blood sampling is defined as no food or liquid within the last 8 hours prior to blood sampling, however water is allowed up until 2 hours prior to blood sampling. 
d Pre-dosing 
e Only applicable for patients in the PK sub-study to cover one dose given at site. Sampling scheme for PK sub-study is outlined in Table 1-2.  
f V9X is only applicable for patients in the PK sub-study who have discontinued trial product prematurely. Visit 9X has to be performed as soon as site has been informed of prematurely 
  trial product discontinuation by the patient. 
g Patients part of the PK sub-study who discontinue treatment will be requested to take their last trial product dose at site and attend visit 9X followed by visit 9A, 9B, 9C and 9D.  
h Visit 9 + 1 day (24 hours) 
Abbreviations: ECG: Electrocardiogram; IWRS: Interactive web response system; P: Phone visit; PCSK9: proprotein convertase subtilisin/kexin type 9; PK: pharmacokinetics; V: Clinic 
visit 
 
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Table 1-2 
Sampling scheme for PK sub-studya 
Visit 
Week no. 
Nominal timec 
Time window 
allowance 
Dosing of IMP 
NNC0385-0434 PK  
V9 
Week 12 
-15 min 
- 
 
Xe 
0 hour 
- 
Xd 
 
1 hour 
0 to 30 min 
 
X 
2 hours 
±15 min 
 
X 
4 hours 
±1 hour 
 
X 
8 hours 
±2 hours 
 
X 
V9Xb 
 
-15 min 
- 
 
Xe 
0 hour 
- 
Xd 
 
1 hour 
0 to 30 min 
 
X 
2 hours 
±15 min 
 
X 
4 hours 
±1 hour 
 
X 
8 hours 
±2 hours 
 
X 
V9A 
V9/V9X + 1 Day  
24 hours 
±4 hours 
 
X 
V9B 
V9/V9X + 1 Week 
7 days 
±3 days 
 
X 
V9C 
V9/V9X + 2 Weeks 
14 days 
±3 days 
 
X 
V9D 
V9/V9X + 3 Weeks 
21 days 
±3 days 
 
X 
a In addition to visit 9 assessments according to Table 1-1 for patients taking part in the PK sub-study. 
b V9X is only applicable for patients in the PK sub-study who have discontinued trial product prematurely. Visit 9X has to be performed as soon as site has been informed of prematurely 
trial product discontinuation by the patient.    
c From last dose. 
d Patients will receive a meal 30-60 min post dosing, and post dosing PK sampling will be performed according to sampling scheme. Date and exact time point for trial product ingestion at 
site, including start of meal must be collected in the laboratory requisition form. 
e Performed in the fasting state. Visit 9 assessments requiring fasting (lipids, fasting glucose and biosamples for future research) must also be taken pre-dosing. 
Abbreviations: IMP: investigational medicinal products; PK: pharmacokinetic 
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2 
Introduction 
Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of death globally1. Increased 
levels of LDL-C have been identified as a causal risk factor for ASCVD2. Furthermore, lowering 
LDL-C results in reduced risk of adverse cardiovascular outcomes3. In 2008, the global prevalence 
of hypercholesterolaemia among adults (total cholesterol ≥ 5.0 mmol/l) was 39% (37% for males 
and 40% for females)1.  
Reducing LDL-C levels is an important strategy for global cardiovascular risk reduction, which is 
reflected in US4, European5 and Japanese lipid lowering guidelines6 with statins as recommended 
first line standard of care. Despite the widespread availability and use of statins many patients do 
not reach their target LDL-C levels7, 8 giving rise to the need for additional effective 
pharmacotherapies. 
PCSK9 inhibition is a new therapy indicated for treatment of hypercholesterolaemia by lowering 
LDL-C and reduction of cardiovascular risk in patients with established atherosclerotic 
cardiovascular disease (ASCVD)9-12. NNC0385-0434 is a new PCSK9 inhibitor in development for 
lowering LDL-C and offers oral administration. 
2.1 
Trial rationale 
The rationale for conducting this trial is to acquire a robust dose-response understanding of 
oral NNC0385-0434 to allow for dose selection in a phase 3 programme. The trial includes a 
dose-range expected to cover the relevant therapeutic levels. The target population consists of 
patients with established ASCVD or ASCVD risk on maximally tolerated statin dose and other 
lipid-lowering therapy requiring further LDL-C lowering according to current global treatment 
guidelines. The purpose of this trial is also to examine the steady state PK, safety and tolerability of 
oral NNC0385-0434.  
2.2 
Background 
PCSK9 inhibition 
The LDL-receptor is located on liver cells and involved in the removal of LDL-C from the 
circulation. When LDL-C binds to the LDL-receptor, this complex moves into the cell. The LDL-
receptor releases LDL-C in the endosome for degradation whilst the LDL-receptor is recycled back 
to the cell surface13. If PCSK9 binds to the LDL-receptor on its epidermal growth factor-like repeat 
A (EGF-A) domain14, the LDL-receptor is no longer recycled back to the cell surface but degraded 
along with the bound LDL-C15. Therefore, when inhibiting PCSK9, more LDL-receptors will be 
recycled to the cell surface and more LDL-C can be taken up by the liver cells, reducing LDL-C in 
the circulation. 
There are currently two approved PCSK9 inhibitors on the market, evolocumab9 and alirocumab10. 
Both are s.c. administered monoclonal antibodies that have been shown to be safe, reduce risk of 
recurrent CV event and lower LDL-C levels by approximately 60% from baseline16. 
Recently, also inclisiran, a small interfering RNA therapeutic agent was approved in EU17. 
Inclisiran reduces the level of LDL-C by reducing PCSK9 hepatic production.  
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Oral NNC0385-0434 – a new PCSK9 inhibitor peptide 
NNC0385-0434 is a new medicinal product in development for lowering LDL-C. It is a peptide that 
binds to circulating PCSK9 and inhibits its interaction with the LDL-receptor by resembling the 
EGF-A domain of the human LDL-receptor. The molecule contains amino acid substitutions to 
increase PCSK9 affinity, peptide stability and allow for introduction of fatty acid moieties 
providing increased half-life.  
Preclinical data following s.c. and oral administration of NNC0385-0434 have demonstrated a 
robust dose-dependent reduction in LDL-C plasma levels (rat, cynomolgus monkey). In addition, 
NNC0385-0434 has shown a long systemic half-life across preclinical species (cynomolgus 
monkey, mini-pig and rat).  
No safety or toxicity findings were found in the nonclinical studies after two-weeks repeated daily 
s.c. dosing in rats, and s.c. and oral dosing in cynomolgus monkeys. No adverse findings were 
found in toxicity studies of up to 13-week duration in rats and the NOAEL was established as the 
highest dose administered (12 mg/kg/day s.c. + 50 mg/kg/day orally) at an exposure >100 fold 
higher than the expected human exposure at 15-100 mg daily oral dose.  
NNC0385-0434 administered s.c. has been investigated in a FHD trial (NN6434-4493) with single 
ascending doses up to 250 mg in 3 cohorts of healthy male subjects and 1 cohort of patients with 
hypercholesterolaemia treated with statins. High doses were explored in the FHD trial and 
NNC0385-0434 was found to be safe with no tolerability issues and resulted in clinically relevant 
lowering of LDL-C. The terminal half-life was approximately 10.5 days following single doses of 
10-250 mg s.c. NNC0385-0434 in healthy male subjects and patients with hypercholesterolaemia. 
Mean Cmax was 11,133.3 nmol/L following single dose of the highest dose of 250 mg 
NNC0385-0434. 
NNC0385-0434 is currently being developed as an oral treatment. Formulation with an absorption 
enhancing excipient is needed since NNC0385-0434 otherwise would have a very low 
bioavailability. Thus, NNC0385-0434 is co-formulated with SNAC, a fatty acid derivative 
protecting the peptide from enzyme degradation by local pH buffering and working as a absorption 
enhancer. In order to obtain best possible absorption from oral NNC0385-0434 tablets, a fasting 
condition is required. SNAC was fully qualified in the nonclinical and clinical development 
programme for oral semaglutide. Preclinical dog studies with NNC0385-0434 co-formulated with 
SNAC indicated a bioavailability in the same range as oral semaglutide. Based on the 
bioavailability estimate and data from the FHD trial, the treatment arm with the highest planned oral 
dose (100 mg) is predicted to have a lower exposure than the observed exposure reached with the 
s.c. 250 mg dose arm in the FHD trial (NN6434-4493) for up to 6 weeks. Furthermore, the steady 
state exposure (Cmax) in a dosing interval is expected to be 32 times lower than what was achieved 
in the s.c. 250 mg dose arm in the FHD trial (Figure 2-1). Modelling data based on the FHD trial 
data indicate that a 28-60 % LDL-C reduction can be achieved with a once daily oral dosing of 
15-100 mg NNC0385-0434 co-formulated with 500 mg SNAC. Thereby, the FHD trial data support 
proceeding to phase 2 and the further investigation of NNC0385-0434 as a once daily oral therapy 
for lowering LDL-C. 
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Figure 2-1 
Simulation of NNC0385-0434 exposure in the planned phase 2 trial vs. observed 
exposure in FHD trial (NN6434-4493) 
 
Note: Lines for NN6435-4697 treatment arms (15, 40, and 100 mg oral daily) represents geometric mean of 10,000 
simulations for each treatment arm. The line for the 250 mg s.c. observations from NN6434-4493 represents the 
observed geometric mean concentration. 
Abbreviations: FHD: first human dose 
Throughout this protocol, the compound, NNC0385-0434 co-formulated with 500 mg SNAC 
administered once daily, will be named oral NNC0385-0434. 
Trial population 
The trial population will consist of patients with established ASCVD or ASCVD risk on maximally 
tolerated statin dose and other lipid-lowering therapy requiring further LDL-C lowering. According 
to the European ESC/EAS treatment guidelines5 this trial population will benefit of obtaining LDL-
C < 1.8 mmol/L (<70 mg/dL) in order to reduce their CV risk. Only women of non-childbearing 
potential are included since embryo-foetal development studies remain to be conducted. 
2.3 
Benefit-risk assessment 
Main benefits and risks are described in the below sections. More detailed information about the 
known and expected benefits and risks and reasonably expected adverse events of oral NNC0385-
0434 may be found in the investigator’s brochure18 and in the SmPC or US PI for evolocumab19, 20.  
2.3.1 
Risk assessment 
Potential risks describe undesirable clinical outcomes for which there is scientific evidence to 
suspect the possibility of a causal relationship with oral NNC0385-0434, but where there is 
currently insufficient evidence to conclude that this association is causal. Currently, there are no 
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identified risk with evidence of a causal association with oral NNC0385-0434. The risk assessment 
for oral NNC0385-0434 and s.c. evolocumab is presented in Table 2-1. 
2.3.2 
Benefit assessment 
In this trial, patients with established ASCVD or ASCVD risk will continue their current treatment 
of maximally tolerated statin dose and other lipid-lowering therapy and be randomised to a 12-week 
LDL-C lowering treatment as an add-on therapy to statins and other lipid-lowering therapy or 
placebo. The 12-week LDL-C lowering treatment of oral NNC0385-0434 or s.c. evolocumab is 
expected to be efficacious on top of the background statin treatment. 
All patients, including patients randomised to placebo, are expected to benefit from the frequent 
medical evaluations/examinations. 
Furthermore, the data obtained from the present trial will form the basis for future development of 
oral NNC0385-0434 in patients with high ASCVD risk and dyslipidaemia. 
2.3.3 
Overall benefit-risk conclusion 
Considering the measures taken to minimise risk to patients participating in this trial, the potential 
risks identified in association with oral NNC0385-0434 are justified by the anticipated benefits that 
may be afforded to patients with established ASCVD or ASCVD risk. 
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3 
Objectives and endpoints 
3.1 
Primary, secondary and exploratory objectives and estimands 
3.1.1 
Primary objective 
To demonstrate superiority of three dose levels of oral NNC0385-0434 versus placebo on percent 
change in LDL-C from baseline to week 12 in patients with established ASCVD or ASCVD risk on 
maximally tolerated statin dose and other lipid-lowering therapy requiring further LDL-C reduction.  
3.1.2 
Secondary objectives 
To compare the effect on lipid/lipoprotein parameters excluding LDL-C of three dose levels of oral 
NNC0385-0434 versus placebo in patients with established ASCVD or ASCVD risk on maximally 
tolerated statin dose and other lipid-lowering therapy requiring further LDL-C reduction.  
To compare the effect on lipid/lipoprotein parameters of three dose levels of oral NNC0385-0434 
versus s.c. evolocumab in patients with established ASCVD or ASCVD risk on maximally tolerated 
statin dose and other lipid-lowering therapy requiring further LDL-C reduction.  
To compare the safety and tolerability of three dose levels of oral NNC0385-0434 versus placebo in 
patients with established ASCVD or ASCVD risk on maximally tolerated statin dose and other 
lipid-lowering therapy requiring further LDL-C reduction. 
3.1.3 
Exploratory objectives 
To examine the population pharmacokinetic and immunogenic properties of three dose levels of 
oral NNC0385-0434 in patients with established ASCVD or ASCVD risk on maximally tolerated 
statin dose and other lipid-lowering therapy requiring further LDL-C reduction.  
PK sub-study 
To assess and compare the pharmacokinetic properties of three dose levels of oral NNC0385-0434 
at steady-state between Japanese and non-Japanese patients with established ASCVD or ASCVD 
risk on maximally tolerated statin dose and other lipid-lowering therapy requiring further LDL-C 
reduction. 
3.1.4 
Estimands 
For the primary objective, an estimand of primary interest and an additional estimand is defined. 
The estimands are used to address the trial objectives in terms of two different aspects of the 
treatment effect of three dose levels of oral NNC0385-0434. A single intercurrent event is 
considered: Premature treatment discontinuation. Intercurrent events are events occurring after 
treatment initiation that affect the interpretation, or the existence of the measurements associated 
with the question of interest. 
The primary estimand will be used to address the primary objective and similar estimands will be 
used to address the secondary objectives for the corresponding supportive secondary endpoints. The 
additional estimand will be used to address the primary objective for the primary endpoint. The 
estimands are described below and the attributes of the estimands are presented in Table 3-1. 
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Primary estimand 
The primary estimand addresses the main question of interest: What is the efficacy of three dose 
levels of oral NNC0385-0434 versus placebo on percent change in LDL-C from baseline to week 
12 in patients with established ASCVD or ASCVD risk on maximally tolerated statin dose and 
other lipid-lowering therapy if all patients had remained on trial treatment? A hypothetical strategy 
is applied for the intercurrent event premature trial treatment discontinuation. The population-level 
summary is difference in means. 
Results based on the primary estimand quantifies the achievable treatment effect if all patients 
remain on the trial treatment. 
Additional estimand 
The additional estimand addresses an additional question of interest: What is the efficacy of three 
dose levels of oral NNC0385-0434 versus placebo on percent change in LDL-C from baseline to 
week 12 in patients with established ASCVD or ASCVD risk on maximally tolerated statin dose 
and other lipid-lowering therapy regardless of premature treatment discontinuation? For this 
estimand, the treatment policy strategy is applied for the intercurrent event premature trial treatment 
discontinuation. The population-level summary is difference in means. 
Results based on the additional estimand are expected to mirror the clinical practice scenario 
because the estimand considers both the efficacy and tolerability of oral NNC0385-0434. 
 
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Table 3-1 
Estimand attributes 
Estimand 
category 
Treatment condition 
Variable / endpoint 
Population of interest 
Intercurrent events and 
strategy 
Population-level 
summary measure 
Primary 
The effect of three dose levels of oral NNC0385-0434 
versus placebo, both in combination with maximally 
tolerated statin dose and other lipid-lowering therapy. 
Change in LDL-
cholesterol (%) from 
baseline to week 12 
Patients with established 
ASCVD or ASCVD risk. 
Further details can be 
found in Section 5. 
Hypothetical strategy is 
applied for the intercurrent 
event ‘premature trial 
treatment discontinuation’ 
Difference in 
means 
Additional 
The effect of three dose levels of NNC0385-0434 
versus placebo, both in combination with maximally 
tolerated statin dose and other lipid-lowering therapy. 
Treatment policy strategy is 
applied for the intercurrent 
event ‘premature trial 
treatment discontinuation’ 
 
 
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3.2 
Primary, secondary and exploratory endpoints 
3.2.1 
Primary endpoint 
Endpoint title 
Time frame 
Unit 
Change in LDL-cholesterol  
From baseline (week 0) to visit 9 
(week 12) 
% 
3.2.2 
Secondary endpoints 
3.2.2.1 
Confirmatory secondary endpoints 
Not applicable. 
3.2.2.2 
Supportive secondary endpoints 
Endpoint title 
Time frame 
Unit 
Change in total cholesterol  
From baseline (week 0) to visit 9 
(week 12) 
% 
Change in HDL-cholesterol 
From baseline (week 0) to visit 9 
(week 12) 
%  
Change in VLDL-cholesterol 
From baseline (week 0) to visit 9 
(week 12) 
% 
Change in triglycerides 
From baseline (week 0) to visit 9 
(week 12) 
%  
Change in total Apo B 
From baseline (week 0) to visit 9 
(week 12) 
% 
Change in total Apo CIII 
From baseline (week 0) to visit 9 
(week 12) 
% 
Change in total Lp(a) 
From baseline (week 0) to visit 9 
(week 12) 
Ratio  
Treatment-emergent adverse events 
From baseline (week 0) to visit 10 
(19 weeks + 4 days) 
Number of events 
 
3.2.3 
Exploratory endpoints 
Endpoint title 
Time frame 
Unit 
Concentration of NNC0385-0434 
at steady state 
From visit 7 (week 6) to visit 9 
(week 12) 
nmol/L 
Occurrence of NNC0385-0434 
binding antibodies  
From baseline (week 0) to visit 10 
(19 weeks + 4 days) 
Yes/no 
Occurrence of NNC0385-0434 
binding antibodies cross reacting 
with endogenous counterpart 
(EGF-A)  
From baseline (week 0) to visit 10 
(19 weeks + 4 days) 
Yes/no 
Titre of NNC0385-0434 binding 
antibodies  
From baseline (week 0) to visit 10 
(19 weeks + 4 days) 
 
No unit 
 
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PK sub-study 
 
Endpoint title 
Time frame 
Unit 
AUC0-24h,SS (area under the steady 
state plasma NNC0385-0434 
concentration−time curve) 
From 0 to 24 hours after end of 
treatment at visit 9 (week 12) 
h*nmol/L 
AUC0-∞,SS (area under the steady 
state plasma NNC0385-0434 
concentration−time curve) 
From 0 hours to infinity after end 
of treatment at visit 9 (week 12) 
h*nmol/L 
Cmax,SS (maximum observed plasma 
NNC0385-0434 concentration at 
steady state) 
From 0 to 24 hours after end of 
treatment at visit 9 (week 12) 
nmol/L 
tmax,SS (time to maximum observed 
plasma NNC0385-0434 
concentration at steady state) 
From 0 to 24 hours after end of 
treatment at visit 9 (week 12) 
Hours 
t½,SS (terminal phase elimination 
half-life of NNC0385-0434 at 
steady state) 
After end of treatment at visit 9 
(week 12) 
Hours 
 
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4 
 Trial design 
4.1 
Overall design 
This is a randomised, multicentre, multinational, seven-armed, parallel group, dose finding trial 
(Figure 4-1). The trial will be double-blinded within dose level of oral NNC0385-0434 and size-
matched placebo arm. The s.c. evolocumab arm will be open label. The trial population includes 
patients with established ASCVD or ASCVD risk on maximally tolerated statin dose and other 
lipid-lowering therapy requiring further LDL-C reduction.  
Figure 4-1 
Schematic overview of the trial design 
 
Notes: *placebo tablets are sized match to the active arm within dose level. Placebo arms will be pooled in the 
statistical analyses. 
Abbreviations: N: number of patients; OD: Once daily; Q2W: every 2 weeks; s.c. subcutaneous. 
The trial includes a 2-week screening period followed by a 12-week treatment period. Additional 
PK sampling will be performed for 60 patients following the 12 weeks of treatment (referred as ‘PK 
sub-study’, see Section 4.1.1). The follow-up period for all patients is 7 weeks and 4 days. The total 
duration for each patient will be approximately 22 weeks. Throughout this protocol, the ‘main trial’ 
refers to the trial part without PK sub-study sampling. 
Oral treatment arms (NNC0385-0434 or placebo) will be administered once daily. Each oral 
NNC0385-0434 treatment arm will be administered as tablets with varying sizes, but is blinded 
towards placebo with matching tablet sizes. The s.c. evolocumab treatment arm will be 
administered every 2 weeks.  
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The 7 treatment arms consist of 4 active treatment arms and 3 placebo arms, as follows: 
• 15 mg NNC0385-0434 co-formulated with 500 mg SNAC tablet once daily (51 patients) 
• 40 mg NNC0385-0434 co-formulated with 500 mg SNAC tablet once daily (51 patients) 
• 100 mg NNC0385-0434 co-formulated with 500 mg SNAC tablet once daily (51 patients) 
• 140 mg evolocumab s.c. injections every 2 weeks (51 patients) 
• 3 placebo arms: placebo administered as tablets (without SNAC) once daily (17 patients in each 
placebo arm, 51 patients in total) 
Patients will be randomised 3:1:3:1:3:1:3 according to Figure 4-1. Randomisation will be stratified 
according to participation in the PK sub-study (yes/no), country (Japan/non-Japan) and population 
(inclusion criteria 3a/3b). Within each stratum, each patient will be randomly allocated to one of the 
treatment arms (Section 6.3.1). For the main statistical analyses, the 3 placebo arms will be pooled 
into one placebo group.   
The initial 15 patients (3 patients in each active treatment arm and 1 patient in each of the placebo 
arms) will be recruited from few pre-selected sites and treated for minimum 4 weeks before 
recruitment of the remaining 240 patients. Randomisation of the remaining patients will be initiated 
following medical monitoring of 4 week data of these 15 patients without identification of safety 
concerns, in addition to review of PK data from the 15 patients 2 weeks after dosing. Specifically, 
for Japanese patients, an evaluation of the safety and PK from the Japanese PK trial (NN6435-4748) 
will be performed before randomisation of Japanese patients into the current trial. The safety 
evaluation will include 12 healthy male Japanese subjects on a 10-day treatment with 15 mg, 40 mg 
or 100 mg oral NNC0385-0434, or placebo (3 subjects on each). The PK review will include data of 
the 15 mg and 40 mg cohorts.  
Details on risk-based monitoring including medical monitoring and early PK evaluation is provided 
in Section 10.1.8.2.  
4.1.1 
PK sub-study 
A PK sub-study in Japanese and non-Japanese patients will be performed following the 12 weeks of 
treatment. For PK sampling details, refer to Table 1-2.   
For the PK sub-study, 30 Japanese and 30 non-Japanese patients will be randomised with ratio 
3:1:3:1:3:1:3 as randomised in the main trial (for details on randomisation ratio, refer to Figure 4-1). 
For further details on randomisation, see Section 6.3.1. 
The aim of the PK sub-study is to assess and compare the PK properties of three doses of oral 
NNC0385-0434 at steady-state between Japanese and non-Japanese patients (18 Japanese and 
18 non-Japanese patients exposed to NNC0385-0434). The evolocumab arm is not part of the PK 
sub-study. Therefore, patients randomised to the evolocumab arm will not have additional visits or 
sub-study PK samples taken. 
 
 
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4.2 
Scientific rationale for trial design 
To allow evaluation of dose-response relationship of oral NNC0385-0434, a parallel randomised, 
double-blinded within dose level, controlled design has been chosen. To minimize bias in the 
assessment, the oral NNC0385-0434 treatment arms are double-blinded for each dose level of oral 
NNC0385-0434 with size-matched placebo arm. Three dose levels of NNC0385-0434, covering the 
expected range for clinically adequate LDL-C lowering, have been chosen to evaluate the dose-
response relationship. 
The rationale for including a s.c. evolocumab arm is to compare the efficacy of oral NNC0385-0434 
against one of the already marketed PCSK9 inhibitors. The s.c. evolocumab arm is open-label to 
limit unnecessary injections (e.g., by use of double-dummy) as the primary aim of the trial is to 
investigate the effects of oral NNC0385-0434. 
The trial population will consist of patients with established ASCVD or ASCVD risk on maximally 
tolerated statin dose and other lipid-lowering therapy requiring further LDL-C lowering. In 
alignment with the European ESC/EAS treatment guideline4, 5, this is the target population that will 
benefit of obtaining LDL-C < 1.8 mmol/L (<70 mg/dL) in order to reduce their ASCVD risk. 
Specific LDL-C inclusion criteria have been defined for Japanese patients according to the Japanese 
guidelines for prevention of ASCVD (JAS guidelines)6. 
The treatment period is set to 12 weeks. The steady state exposure is expected to be reached at 
approximately 6 weeks into the trial and therefore the complete LDL-C lowering response should 
be observed within 12 weeks of treatment. 
As a precautionary measure, 15 patients will be recruited initially before recruitment of the 
remaining 240 patients. Medical monitoring of minimum 4 week safety data for these 15 patients 
will be completed before dosing of the remaining 240 patients in the trial (see Section 10.1.8.2). 
PK sub-study 
The rationale for including the PK sub-study is to assess and compare the steady state PK profiles 
of multiple doses of oral NNC0385-0434 in Japanese and non-Japanese patients. Therefore, PK 
assessments from the evolocumab arm are not relevant and this arm is not included in the PK sub-
study.  
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4.3 
Justification for dose 
The dose range of oral NNC0385-0434 to be investigated in this trial has been selected based on the 
results from the FHD trial (NN6434-4493) and on modelling data for the expected exposure 
response and dose response. 
Based on modelling analyses of the preliminary data from the FHD trial, the oral NNC0385-0434 
dose of 100 mg/day is expected to have an exposure level lower than the exposure seen in the FHD 
trial s.c. 250 mg single dose arm for up to 6 weeks. The steady state exposure (Cmax) in a dosing 
interval of the 100 mg/day dose is predicted to be 32 times lower than the exposure achieved in the 
s.c. 250 mg dose arm in the FHD trial. This is due to the relatively high s.c. dose investigated in the 
FHD trial (250 mg), the long half-life of NNC0385-0434 (10.5 days) and the predicted 
bioavailability of the oral dose (approximately 1% relative to s.c. dosing).  
Moreover, no adverse findings were found in toxicity studies of up to 13-week duration in rats and 
the NOAEL was established as the highest dose administered (12 mg/kg/day s.c. + 50 mg/kg/day 
orally) at an exposure > 100 fold higher than the expected human exposure at 15-100 mg daily oral 
dose. Also, no adverse findings were found in local tolerance study after daily oral dosing of 
100 mg NNC0385-0434 for 14 weeks in cynomolgus monkeys. 
Oral NNC0385-0434 administered as once daily doses of 15, 40 and 100 mg are expected to be 
within the therapeutically relevant range. This dose range is expected to provide exposures to cover 
the exposure-response profile with mean LDL-C responses ranging from -28 to -60% change from 
baseline.  
In summary, the exposure expected from simulated data for the oral NNC0385-0434 100 mg once-
daily arm is lower than the exposure reached in the FHD trial. Oral doses of 15, 40 and 100 mg 
NNC0385-0434 are expected to be within the therapeutically relevant range and modelling 
predictions suggest corresponding LDL-C reductions of approximately 28, 46 and 60% from 
baseline, respectively. 
4.4 
End of trial definition 
A patient is considered to have completed the trial if he/she has completed all phases of the trial 
including the last visit (Visit 10) according to the flowchart (Table 1-1).   
The end of the trial is defined as the date of the last visit of the last patient in the trial globally. 
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5 
Trial population 
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1 
Inclusion criteria 
Patients are eligible to be included in the trial only if all of the following criteria apply: 
1. Informed consent obtained before any trial-related activities. Trial-related activities are any 
procedures that are carried out as part of the trial, including activities to determine suitability for 
the trial. 
2. Male patient or female patient of non-childbearing potential. See Appendix 4 (Section 10.4), for 
the definition of a woman of non-childbearing potential. 
3. Established atherosclerotic cardiovascular disease (ASCVD) (criteria a) or ASCVD risk 
(criteria b): 
a. Age ≥40 years at the time of signing informed consent and history of ASCVD 
defined as at least one of the following (i-iii): 
i. Coronary heart disease defined as at least one of the following: 
1. Prior myocardial infarction. 
2. Prior coronary revascularization (percutaneous coronary intervention 
(PCI), coronary artery bypass graft (CABG)). 
3. ≥50% stenosis in a major epicardial coronary artery documented by   
cardiac catheterisation or computed tomography (CT) coronary 
angiography. 
4. Coronary heart disease with ischaemia documented by stress test with 
any imaging modality. 
ii. Cerebrovascular disease defined as at least one of the following: 
1. Ischemic Stroke. 
2. Prior carotid artery revascularisation procedure (surgical or 
endovascular). 
3. ≥50% stenosis in carotid artery documented by X-ray angiography, 
Magnetic resonance (MR) angiography, CT angiography or Doppler 
ultrasound. 
iii. Peripheral artery disease in the lower extremities defined as at least one of 
the following: 
1. Current symptoms of intermittent claudication and an ankle-brachial 
index (ABI) < 0.85 or toe-brachial index (TBI) < 0.7, both at rest. 
2. Current symptoms of intermittent claudication and ≥ 50% stenosis in 
lower extremity artery documented by X-ray angiography, MR 
angiography, CT angiography or Duplex ultrasound. 
3. Lower extremity artery revascularization procedure. 
4. Lower extremity amputation at or above ankle due to atherosclerotic 
disease (excluding e.g. trauma or osteomyelitis). 
b. Age >50 years at the time of signing informed consent and with ASCVD risk 
defined by at least one of the following (i-ii): 
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i. Moderate chronic kidney disease (CKD) measured as estimated Glomerular 
Filtration Rate (eGFR) values of 30-59 mL/min/1.73 m2 (both inclusive) as 
measured by central laboratory at screening 
ii. Diagnosed with type 2 diabetes mellitus  
4. Serum LDL-C ≥1.8 mmol/L (≥70 mg/dL) as measured by the central laboratory at screening. 
For Japan only: See Table 5-1 for serum LDL-C inclusion criteria for Japanese patients. 
5. Patients must be on maximally tolerated dose of statins (see Appendix 7 (Section 10.7)). 
6. Patients not receiving statin must have documented evidence of intolerance to all doses of at 
least two different statins (see Appendix 7 (Section 10.7)). 
7. Patients on any lipid-lowering therapies must be on a stable dose for ≥30 days before screening 
with no planned medication or dose change during study participation (for maximally tolerated 
statin dose, see Appendix 7 (Section 10.7); for other lipid-lowering therapies, see Section 6.5). 
Inclusion criteria for PK sub-study (in addition to inclusion criteria 1-7) 
8. For Japanese patients only: Both parents of Japanese descent and from Japanese site 
9. For non-Japanese patients only: Both parents of non-Japanese descent and from non-Japanese 
site 
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5.2 
Exclusion criteria  
Patients are excluded from the trial if any of the following criteria apply: 
1. Known or suspected hypersensitivity to trial product(s) or related products. 
2. Previous participation in this trial. Participation is defined as signed informed consent. 
3. Participation in any clinical trial of an approved or non-approved investigational medicinal 
product within 30 days before screening.  
4. Any disorder, which in the investigator’s opinion might jeopardise a patient’s safety or 
compliance with the protocol. 
5. Treatment with PCSK9i therapy (alirocumab or evolocumab within 90 days prior to screening) 
or PCSK9 siRNA therapy (inclisiran within 12 months prior to screening). 
6. Treatment with oral semaglutide therapy within 30 days prior to screening  
7. Fasting triglyceride >4.52 mmol/L (>400 mg/dL) as measured by the central laboratory at 
screening. 
8. Myocardial infarction, stroke, hospitalization for unstable angina pectoris or transient ischaemic 
attack within 180 days prior to the day of screening. 
9. Planned coronary, carotid or peripheral artery revascularisation. 
10. History of major surgical procedures involving the stomach potentially affecting absorption of 
trial product (e.g. subtotal and total gastrectomy, sleeve gastrectomy, gastric bypass surgery) 
11. Chronic heart failure classified as being in New York Heart Association (NYHA) Class IV at 
screening. 
12. Impaired liver function, defined as Alanine Aminotransferase (ALT) ≥ 2.5 times or 
Bilirubin >1.5 times upper normal limit as measured by the central laboratory at screening. 
13. Renal impairment with eGFR <30 ml/min/1.73 m2 as measured by the central laboratory at 
screening. 
14. Clinically significant arrhythmia or clinically significant conduction disorder as judged by the 
investigator at screening. 
15. Inadequately treated blood pressure defined as Systolic ≥180 mmHg or diastolic ≥110 mmHg 
at screening. 
16. Presence or history of malignant neoplasm (other than basal or squamous cell skin cancer, 
in-situ carcinomas of the cervix, or in situ prostate cancer) within 5 years before screening. 
Exclusion criteria for PK sub-study (in addition to exclusion criteria 1-12) 
There are no additional exclusion criteria for the PK sub-study. 
5.3 
Lifestyle considerations 
To ensure alignment with regards to performance of assessments across patients and trial sites, the 
below restrictions apply. 
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5.3.1 
Meals and dietary restrictions 
Visits attended fasting 
• Patients must attend the relevant visits fasting according to the flowchart (Table 1-1). 
• Fasting for blood sampling is defined as no food, liquid or any oral medication within the last 
8 hours prior to blood sampling, however water is allowed up until 2 hours prior to blood 
sampling. 
• If the patient is not fasting as required, the patient should be called in for a new visit preferably 
the following morning or within the visit window to have the fasting procedures done.  
• Assessments requiring patient to fast include blood sampling of lipids, fasting glucose and 
NNC0385-0434 PK (only pre-dose samples), and biosamples for future research.   
• PK sub-study (Table 1-2): 
• Visit 9: PK blood sampling must be performed in a fasting state 
• Visit 9A-9D: PK blood sampling is not required to be performed in a fasting state 
• A meal will be served 30-60 min post dosing at site visits for PK sampling (Table 1-1) and at 
visit 9 for patients in the PK sub-study (Table 1-2). Date and exact time point for start of meal 
must be collected in the laboratory requisition form. 
5.3.2 
Caffeine and tobacco 
Patients should avoid caffeine and smoking for at least 30 minutes prior to measuring the blood 
pressure at site visits according to the flowchart (Table 1-1). Smoking is defined as smoking at least 
one cigarette or equivalent daily. 
5.3.3 
Physical activity 
Patients should avoid unaccustomed strenuous physical exercise for 48 hours prior to blood 
sampling at site visits (including the screening visit) according to the flowchart (Table 1-1).  
Patients should avoid physical activity for at least 30 minutes prior to measuring the blood pressure 
at site visits according to the flowchart (Table 1-1).   
5.4 
Screen failures 
Screen failures are defined as patients who consent to participate in the clinical trial but are not 
eligible for participation according to inclusion/exclusion criteria. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure patients to meet 
requirements from regulatory authorities. Minimal information includes informed consent date, 
demography, screen failure details, eligibility criteria. 
For Japanese sites: For Japanese patients screened for the PK sub-study, a screen failure is also 
defined as eligible patients who cannot be randomised due to closure of randomisation into the PK 
sub-study.   
A screen failure session must be made in the interactive web response system (IWRS). The reason 
for failure will be captured in the eCRF. 
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Individuals who do not meet the criteria for participation in this trial may not be rescreened. If the 
patient has failed one of the inclusion criteria or fulfilled one of the exclusion criteria related to 
laboratory parameters, re-sampling is not allowed. However, in case of technical issues (e.g. 
haemolysed or lost), re-sampling is allowed for the affected parameters. 
5.5 
Run-in criteria, randomisation criteria and dosing day criteria 
Not applicable for this trial. 
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6 
Treatments 
6.1 
Treatments administered 
Investigational medicinal products (IMP) 
The investigational medicinal products (trial products) provided are listed in Table 6-1. 
Table 6-1 
Investigational medicinal product provided by Novo Nordisk A/S 
Trial product name 
Dosage 
form 
Route of 
administration 
Dose levels Dosing instructions 
Packaging 
NNC0385-0434 A 15 mg 
(IMP, test product) 
Tablet 
Oral 
15 mg 
Once daily 
1 tablet in the morning in 
a fasting statea 
HDPE bottle of 
10 tablets  
NNC0385-0434 A 40 mg  
(IMP, test product) 
Tablet 
Oral 
40 mg 
Once daily 
1 tablet in the morning in 
a fasting statea 
HDPE bottle of 
10 tablets  
NNC0385-0434 A 100 mg  
(IMP, test product) 
Tablet 
Oral 
100 mg 
Once daily 
1 tablet in the morning in 
a fasting statea 
HDPE bottle of 
10 tablets  
Placebo I A 
(for NNC0385-0434 A 15 and 
40 mg) 
(IMP, reference therapy) 
Tablet 
Oral 
- 
Once daily 
1 tablet in the morning in 
a fasting statea 
HDPE bottle of 
10 tablets  
Placebo II A 
(for NNC0385-0434 A 
100 mg) 
(IMP, reference therapy) 
Tablet 
Oral 
- 
Once daily 
1 tablet in the morning in 
a fasting statea 
HDPE bottle of 
10 tablets  
Evolocumab 140 mg/mL, 
Repatha® 
(IMP, reference therapy) 
Solution 
for 
injection 
Subcutaneous 
140 mg 
Every 2 weeks 
S.c. injection into areas of 
the abdomen, thigh, or 
upper arm that are not 
tender, bruised, red, or 
indurated 
 
Dose volume: 1 mL 
1 mL pre-filled 
SureClick® 
autoinjector 
(single-use) 
Note: a The tablet should be taken at least 30 min before the first food, beverage or other oral medications of the day. 
The tablet can be taken with up to half a glass of water (approximately 120 mL/ 4 fluid ounces). 
Abbreviations: HDPE: high density polyethylene, IMP: investigation medicinal product 
Directions for use 
The investigator must document that directions for use are given to the patient verbally and in 
writing as a directions for use (DFU) for s.c. evolocumab is to be handed to the patient, at the first 
dispensing visit and at visit 4 (as specified in the flowchart, Table 1-1). The investigator should 
remind patients of dosing instructions throughout the trial, as applicable. 
Dosing instructions for tablets 
Absorption of oral NNC0385-0434 could be affected by food, fluid (other than plain water) and 
other oral medications in the stomach. Therefore, patients must be instructed to take the tablet 
(either NNC0385-0434 or placebo) in the morning in a fasting state and at least 30 minutes before 
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the first food, beverage or other oral medications of the day. The tablet can be taken with up to half 
a glass of water (approximately 120 mL/4 fluid. The tablet must be swallowed whole. The tablet 
must not be cut, crushed or chewed.  
Training in pre-filled SureClick® autoinjector  
Patients will be instructed to inject every second week on the same day of the week (to the extent 
possible) throughout the trial. The patients must be trained according to the DFU in how to handle 
the pre-filled SureClick® autoinjector, when handed out the first time. Training must be repeated 
during the trial at regular intervals in order to ensure correct use of the pre-filled SureClick® 
autoinjector. The investigator must document that the DFU is given to the patient orally and in 
writing at the first dispensing visit and at visit 4 (documented in patient source notes). 
Auxiliary supplies 
Auxiliary supplies will be provided by Novo Nordisk A/S in accordance with the TMM (Table 6-2). 
Table 6-2 
Auxiliary supplies provided by Novo Nordisk A/S 
Auxiliary supply 
Details 
Directions for use 
DFU for evolocumab (Repatha®) pre-filled SureClick® autoinjector 
Not included in the dispensing unit and to be  
handed out separately.  
Abbreviations: DFU: directions for use, s.c. subcutaneous 
6.1.1 
Medical devices 
6.1.1.1 
Investigational medical device(s) 
Not applicable for this trial.  
6.1.1.2 
Non-investigational medical device(s) 
Non-investigational medical devices are listed in Section 6.1 as auxiliary supplies. 
6.2 
Preparation/handling/storage/accountability 
Only patients randomised to treatment may use trial product and only delegated site staff may 
supply trial product. 
• Acceptable temperature ranges and conditions for storage and handling of each trial product 
when not in use and when in use are described in the TMM and on the trial product label. 
• Each site will be supplied with sufficient trial products for the trial on an ongoing basis. Trial 
product will be distributed to the sites according to screening and randomisation. 
• The investigator or designee must confirm that appropriate temperature conditions have been 
maintained during transit for all trial products received, and that any discrepancies are reported 
and resolved before use of the trial products. 
• All trial products must be stored in a secure, controlled, and monitored (manual or automated) 
area in accordance with the labelled storage conditions with access limited to the investigator 
and delegated site staff. 
• The investigator must inform Novo Nordisk immediately if any trial product has been stored 
outside specified conditions. The trial product must not be dispensed to any patient before it has 
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been evaluated and approved for further use by Novo Nordisk. Additional details regarding 
handling of temperature deviations can be found in the trial materials manual (TMM). 
• The investigator or designee is responsible for drug accountability and record maintenance (i.e. 
receipt, accountability and final disposition records). 
• The investigator or designee must instruct the patient in what to return at next visit. 
• Drug accountability must be done on tablet/pen level. 
• Destruction of trial products can be performed on an ongoing basis and will be done according 
to local procedures after accountability is finalised by the site and reconciled by the monitor. 
• All returned, expired or damaged trial products (for technical complaint samples, see Section 
10.5) must be stored separately from non-allocated trial products. No temperature monitoring is 
required. 
• Non-allocated trial products including expired or damaged products must be accounted as 
unused, at the latest at closure of the site. 
Japan: For country-specific requirements, please refer to Appendix 9 (Section 10.9). 
6.3 
Measures to minimise bias: Randomisation and blinding 
6.3.1 
Randomisation 
• This is a randomised, placebo-controlled trial. 
• Patients will be randomised 3:1:3:1:3:1:3 according to Figure 4-1 
• For the PK sub-study: 
• All Japanese patients will be included in the PK sub-study. Once 30 Japanese patients have 
been included in the PK sub-study and randomised to treatment, any Japanese patient 
ongoing screening procedures should be considered a screen failure (Section 5.4). 
• Selected non-Japanese sites will include 30 non-Japanese patients for the PK sub-study. 
Once 30 non-Japanese patients have been randomised to the PK sub-study, eligible non-
Japanese patients will be randomised to the main study. 
• Randomisation will be stratified according to participation in the PK sub-study (yes/no), country 
(Japan/non-Japan) and population (inclusion criteria 3a/3b). Within each stratum, each patient 
will be randomly allocated to one of the treatment arms. 
• All patients will be screened and randomised centrally using an IWRS and assigned to the next 
available treatment according to randomisation schedule. Trial product will be 
dispensed/allocated at the trial visits summarised in the flowchart (Table 1-1). 
• At screening, each patient will be assigned a unique 6-digit number which will remain the same 
throughout the trial. Each site is assigned a 3-digit number and all patient numbers will start 
with the site number. 
6.3.2 
Blinding 
• This trial is double-blinded within dose level of oral NNC0385-0434 and size-matched placebo 
arm. Within dose level, oral NNC0385-0434 and placebo tablets are identical in appearance and 
will be packed in a manner that maintains blinding. 
• The s.c. evolocumab arm is open label and treatment for a patient will be assigned using IWRS.  
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6.3.3 
Blind break 
The IWRS will be used for blind-breaking. In case of an emergency, the investigator has the sole 
responsibility for determining if unblinding of a patient’s treatment is warranted. Patient safety must 
always be the first consideration in making such a determination. If the investigator decides that 
unblinding is warranted, the investigator should make every effort to contact Novo Nordisk prior to 
unblinding a patient’s treatment unless this could delay emergency treatment of the patient. If a 
patient’s treatment is unblinded, Novo Nordisk (Global Safety department) must be notified within 
24 hours after breaking the blind. The date and reason that the blind was broken must be recorded in 
the source documentation. The person breaking the blind must print the "code break confirmation" 
notification generated by the IWRS, sign and date the document. If IWRS is not accessible at the 
time of blind break, the IWRS helpdesk should be contacted. Contact details are listed in 
Attachment I.  
Treatment with trial product can be resumed if there are no safety concerns at the discretion of the 
investigator. 
For the early PK monitoring the laboratory will also have access to the treatment allocation. The 
laboratory responsible for analysis of  NNC0385-0434 (LC-MS/MS analysis) and the responsible 
bioanalytical scientist at special lab will have access to the treatment allocation. The Novo Nordisk 
scientific monitor for bioanalysis will have access to treatment allocation according to PK sample 
but will be blinded to subject level. Also, treatment allocation will be accessible to the laboratory 
responsible for analysis of anti-drug antibodies and the responsible immunogenicity scientist at 
Novo Nordisk. 
6.4 
Treatment compliance 
6.4.1 
Drug treatment compliance 
Throughout the trial, the investigator will remind the patients to follow the trial procedures and 
requirements to encourage patient compliance. 
When patients are dosed at the site in the main trial and in the PK sub-study (Table 1-1 and 
Table 1-2, respectively), they will receive trial product directly from the investigator or designee, 
under medical supervision. The date and time of each dose administered at the site will be recorded 
in the source documents. Site staff will observe ingestion of the tablet. If in doubt whether the tablet 
has been swallowed, site staff will enter into a dialogue with the patients, acknowledging non-
compliance can happen and addressing barriers to compliance. 
When patients self-administer trial product at home, compliance with trial product administration 
will be assessed and the assessment documented in source documents at each visit where 
information is available. 
Treatment compliance will be assessed by monitoring of drug accountability and by discussing 
treatment compliance and dosing conditions with the patient. Treatment compliance is defined as 
taking between 80-120% of the dose as prescribed between visits. The investigator must assess the 
amount of trial products returned compared to what was dispensed at the previous visit. 
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If any suspicion of non-compliance arises, apart from occasional missed doses, the site must enter 
into a dialogue with the patient, re-emphasising the importance of compliance and uncovering 
barriers to compliance. This dialogue must be documented. Compliance will be assessed by cross 
checking the following sources and comparing these to the expected use: 
• Drug accountability information; counting returned tablets 
• Questioning of patients: Discussing treatment compliance and dosing conditions with the patient 
Treatment start and stop dates will be recorded in the eCRF. 
6.5 
Concomitant medication 
During the treatment period, all oral background medication must first be ingested 30 minutes after 
oral trial product has been taken in the morning. 
Lipid-lowering therapies 
Patients must be on maximally tolerated dose of statins for at least 30 days before screening or have 
documented evidence of intolerance to all doses of at least 2 different statins 
(see Appendix 7 (Section 10.7)).  
Other lipid lowering therapies are allowed as background therapy (except PCSK9i therapy, see 
below section on Prohibited concomitant medication) if patients are on a stable dose for ≥30 days 
before screening (see Section 5.1).  
Patients must continue their background medication (maximally tolerated dose of statins and other 
lipid-lowering therapies) throughout the entire trial. The background medication must be 
maintained at the same dose level as given at screening (visit 1) and with the same frequency during 
the entire treatment period unless any safety concerns related to the background medication arise. . 
Prohibited concomitant medication 
The following medications must not be used prior to the screening visit and during the trial:  
• PCSK9i therapy: Alirocumab or evolocumab 90 days prior to screening 
• PCSK9 siRNA therapy: Inclisiran 12 months prior to screening 
• Oral semaglutide therapy within 30 days prior to screening 
Recording the use of concomitant medication 
Any medication or vaccine (including over-the-counter and prescription medicines) other than the 
trial product that the patient is receiving at the time of the first visit (screening visit) or receives 
during the trial must be recorded along with: 
• Trade name or generic name 
• Indication 
• Dates of administration including start and stop dates 
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For lipid-lowering and CV medication, the following should be also collected: 
• Dose and unit 
• Frequency 
• Route of administration 
 
Information on concomitant medication must be recorded in the concomitant medication form in 
eCRF. 
Changes in concomitant medication must be recorded at each visit. If a change is due to an AE, then 
this must be reported according to Section 8.4.  
6.6 
Dose modification 
Deviations from the planned doses are not allowed.  
6.7 
Treatment after end of trial 
After the end of trial (visit 10) the patient will continue suitable standard of care at the discretion of 
the investigator. The patients will not receive treatment after the end of treatment.  
 
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7 
Discontinuation of trial treatment and subject 
discontinuation/withdrawal 
Treatment of a patient may be discontinued at any time during the trial at the discretion of the 
investigator for safety, behavioural, compliance or administrative reasons. 
Efforts must be made to have the patients attend and complete all scheduled visit procedures. Only 
patients who withdraw consent will be considered as withdrawn from the trial. Patients must be 
educated about the continued scientific importance of their data, even if they discontinue trial 
product. 
7.1 
Discontinuation of trial treatment 
Discontinuation of trial product can be decided by either the patient or the investigator. 
The trial product must be discontinued, if any of the following applies for the patient: 
1. Pregnancy 
2. Simultaneous use of an approved or non-approved investigational medicinal product in another 
clinical trial 
3. Safety concern at the investigator´s discretion  
4. Initiation of treatment with PCSK9i therapy (alirocumab, evolocumab), PCSK9 siRNA therapy 
(inclisiran) or oral semaglutide 
See the flowchart (Table 1-1) for data to be collected at the time of treatment discontinuation (early 
discontinuation visit) and follow-up and for any further evaluations that need to be completed. 
The primary reason for discontinuation of trial product must be specified in the end-of-treatment-
form as the last treatment intake (time and date) in the eCRF, and final drug accountability must be 
performed. A treatment discontinuation session must be made in the IWRS. 
Main trial 
Patients who discontinue trial product should continue with the remaining scheduled site visits and 
assessments until the time of the originally scheduled end of trial visit (visit 10) to ensure continued 
monitoring and data collection. See the flowchart (Table 1-1). 
If the patient does not wish to attend the scheduled site visits, efforts should be made to have the 
remaining visits converted to phone contacts. However, as a minimum, these patients must be asked 
to attend visit 9 to ensure final data collection related to the primary endpoint. Also, all efforts 
should be made to have patients attend visit 10 (end of trial). The information about the attempts to 
follow up with the patient must be documented in the patient’s medical record 
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PK sub-study 
For patients who have been randomised to the PK sub-study and who discontinue trial product prior 
to visit 9 (e.g. due to challenges with dosing conditions), efforts should be made to have the patient 
to take their last trial product dose at site.  
• If a patient accepts to take the last trial product dose at site, the patient should attend visit 
9X as soon as possible followed by the PK sub-study specific visits 9A, 9B, 9C and 9D (see 
flowchart, Table 1-1 and PK sub-study sampling scheme Table 1-2). Visit 9X should be 
performed before patients may initiate new lipid-lowering treatment. After completion of the 
sub-study specific visits, patients should continue with the remaining scheduled site visits and 
assessments until the time of the originally scheduled end of trial visit (visit 10). 
• If a patient does not wish to take the last trial product dose at site, the patient should 
continue with the remaining scheduled site visits and assessments (except visit 9A, 9B, 9C and 
9D) until the time of the originally scheduled end of trial visit (visit 10). 
• If premature discontinuation of trial product is decided during a scheduled visit, the visit 
will be converted into a visit 9X and trial procedures must be performed accordingly. All efforts 
should be made to have patients attend the PK sub-study specific visits 9A, 9B, 9C and 9D (see 
flowchart, Table 1-1 and PK sub-study sampling scheme Table 1-2). After completion of the 
sub- study specific visits, patients should continue with the remaining scheduled site visits and 
assessments until the time of the originally scheduled end of trial visit (visit 10). 
7.1.1 
Temporary discontinuation of trial treatment 
If a patient has discontinued trial treatment temporarily, continuation of trial product is allowed. In 
such cases a treatment discontinuation session should not be made in the IWRS. Temporarily trial 
product treatment discontinuation must be specified in eCRF. 
7.2 
Subject discontinuation/withdrawal from the trial 
A patient may withdraw consent at any time at his/her own request or the patient's LAR. 
If a patient withdraws consent, the investigator must ask the patient if he/she is willing, as soon as 
possible, to have assessment performed according to visit 9. See the flowchart for data to be 
collected. 
Final drug accountability must be performed even if the patient is not able to come to the site. A 
treatment discontinuation session must be made in the IWRS. 
If the patient withdraws consent, Novo Nordisk may retain and continue to use any data collected 
before such a withdrawal of consent. 
If a patient withdraws from the trial, he/she may request destruction of any samples taken and not 
tested, and the investigator must document this in the medical record. 
Although a patient is not obliged to give his/her reason(s) for withdrawing, the investigator must 
make a reasonable effort to ascertain the reason(s), while fully respecting the patient's rights. Where 
the reasons are obtained, the primary reason for withdrawal must be specified in the end of trial 
form in the eCRF. 
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7.2.1 
Replacement of subjects 
Patients who discontinue trial product or withdraw from trial will not be replaced. 
7.3 
Lost to follow-up 
A patient will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the site. 
The following actions must be taken if a patient fails to return to the site for a required visit: 
• The site must attempt to contact the patient and reschedule the missed visit as soon as possible 
and counsel the patient on the importance of maintaining the assigned visit schedule and 
ascertain whether or not the patient wishes to and/or should continue in the trial. 
• Before a patient is deemed lost to follow-up, the investigator or designee must make every effort 
to regain contact with the patient (where possible, at least three telephone calls and, if necessary, 
a certified letter to the patient's last known mailing address or local equivalent methods). These 
contact attempts should be documented in the patient's source document. 
• Should the patient continue to be unreachable, he/she will be considered to have withdrawn 
from the trial with a primary reason of `lost to follow-up'. 
 
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8 
Trial assessments and procedures 
• The following sections describe the assessments and procedures, while their timing is 
summarised in the flowchart. 
• Informed consent must be obtained before any trial related activity, see Section 10.1.3. 
• All screening evaluations must be completed and reviewed to confirm that potential patients 
meet all inclusion criteria and none of the exclusion criteria. 
• The investigator will maintain a screening log to record details of all patients screened and to 
confirm eligibility or record reason for screen failure, as applicable. 
• At screening, patients will be provided with a card stating that they are participating in a trial 
and giving contact details of relevant site staff that can be contacted in case of emergency.  
• Adherence to the trial design requirements, including those specified in the flowchart, is 
essential and required for trial conduct.  
• Assessments should be carried out according to the clinic’s standard of practice unless 
otherwise specified in the current section. Efforts should be made to limit bias between 
assessments. The suggested order of the assessments: 
• Electrocardiogram (ECG) and vital signs 
• Blood sampling 
• Other assessments 
• Review of ECG, laboratory reports etc. must be documented either on the documents or in the 
patient's source documents.  
• Repeat samples may be taken for technical issues and unscheduled samples or assessments may 
be taken for safety reasons. Please refer to Appendix 2 (Section 10.2) for further details on 
laboratory samples. 
8.1 
Information visit and screening 
Demography 
The following information has to be recorded after informed consent at the information visit 
(visit 0):  
• Date of birth, unless not permitted by local regulations 
• Year of birth 
• Sex 
• Race, unless not permitted by local regulations 
• Ethnicity, unless not permitted by local regulations 
For countries participating in the PK sub-study, randomisation will be stratified by being of 
Japanese descent. The following has to be assessed at screening (visit 1): 
• Japanese descent and living in Japan (yes/no), assessed at screening visit (visit 1). 
Germany, The Netherlands: For country-specific requirements, please refer to Appendix 9 
(Section 10.9) 
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Tobacco use  
Details of tobacco use must be recorded at screening (visit 1). Smoking is defined as smoking at 
least one cigarette or equivalent daily. The collected information should include whether or not the 
patient smokes or has smoked. 
Smoking status information to be collected: 
• Never smoked 
• Previous smoker (smoking stop date)  
• Current smoker  
Woman of non-childbearing potential 
The assessment of a woman of non-childbearing potential should be performed at the screening visit 
(visit 1) and recorded as specified in the flowchart and Appendix 4 (Section  10.4). 
8.2 
Efficacy assessments  
Planned time points for all efficacy assessments are provided in the flowchart (Table 1-1).  
8.2.1 
Clinical efficacy laboratory assessments 
All protocol-required laboratory assessments, as defined in Appendix 2 (Section 10.2), must be 
conducted in accordance with the flowchart (Table 1-1) and the laboratory manual. 
8.3 
Safety assessments  
Planned time points for all safety assessments are provided in the flowchart (Table 1-1).  
Concomitant illness and medical history 
A concomitant illness is any illness that is already present at the time point from which AEs are 
collected or found as a result of a screening procedure or other trial procedures performed before 
exposure to trial product.  
Medical history is a medical event that the patient experienced. Only relevant medical history 
should be reported prior to the time point from which AEs are collected.  
In case of an abnormal and clinically significant finding fulfilling the definition of a concomitant 
illness or medical history, the investigator must record the finding on the Medical History/ 
Concomitant Illness form. The information collected for concomitant illness and medical history 
should include diagnosis, date of onset and date of resolution or continuation, as applicable. 
The following Medical History/Concomitant Illness should be reported in the eCRF:  
• History of cardiovascular disease   
• History of moderate chronic kidney disease 
• History of type 2 diabetes mellitus 
• History of dyslipidaemia 
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. 
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8.3.1 
Physical examinations 
A physical examination will include assessments of the:  
• General appearance 
• Head, ears, eyes, nose, throat, neck 
• Respiratory system 
• Cardiovascular system 
• Gastrointestinal system incl. mouth 
• Musculoskeletal system 
• Central and peripheral nervous system 
• Skin 
• Lymph node palpation 
Investigators should pay special attention to clinical signs related to previous serious illnesses.  
Any abnormal, clinically significant findings at visit 2 must be recorded as concomitant illness. Any 
clinically significant worsening from visit 2 must be reported as an AE (see Section 8.4). 
8.3.2 
Body measurements  
Body measurements (e.g. height and weight) will be measured and recorded as specified in the 
flowchart (Table 1-1). 
Body weight 
Body weight should be measured with an empty bladder, without shoes and only wearing light 
clothing on a calibrated (digital) scale. Body weight is recorded in kilograms (kg) or pounds (lb) 
with a precision of one decimal. The body weight should be assessed on the same calibrated 
weighing scale throughout the trial. The scale must be calibrated yearly as a minimum, unless the 
manufacturer certifies that calibration of the weighing scale is valid for the lifetime of the scale. 
Height 
Height is measured without shoes in centimetres (cm) or inches (in) and recorded with a precision 
of one decimal. 
Waist circumference 
Waist circumference is defined as the minimal abdominal circumference located midway between 
the lower rib margin and the iliac crest and will be measured using a non-stretchable measuring 
tape. The waist circumference should be measured to the nearest half cm or quarter inch when the 
patient is in a standing position, with an empty bladder, and wearing light clothing. The patient 
should be standing feet together, with arms down their sides and waist accessible. The tape should 
touch the skin but not compress the soft tissue, and twists in the tape should be avoided. The patient 
should be asked to breathe normally, and the measurement should be taken when the patient is 
breathing out gently. 
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8.3.3 
Vital signs 
Pulse rate, as well as systolic and diastolic blood pressure will be assessed: 
• Blood pressure and pulse rate measurements should be preceded by at least 5 minutes of rest for 
the patient in a quiet setting without distractions (e.g. no use of television, cell phones). 
• Blood pressure and pulse rate measurements will be assessed sitting with a completely 
automated device. Manual techniques must be used only if an automated device is not available. 
Any clinically significant worsening from visit 1 must be reported as an AE (see Section 8.4). 
Blood pressure  
Blood pressure will consist of 3 systolic and diastolic blood pressure measurements with intervals 
of at least 1-2 minutes. An additional fourth blood pressure measurement must be performed if the 
first two readings on systolic or diastolic blood pressure differ by >10 mmHg. Systolic blood 
pressure is to be documented as the mean of the last 2 systolic blood pressure readings, and diastolic 
blood pressure as the mean of the last 2 diastolic blood pressure readings. Only the last 2 systolic 
and last 2 diastolic blood pressure readings must be recorded in the eCRF.  
Pulse rate  
Pulse rate will be measured in connection to the blood pressure measurements. Record the pulse 
rate for the last 2 blood pressure measurements in the eCRF. The pulse rate is to be documented as 
the mean of the last 2 measurements. 
8.3.4 
Electrocardiograms 
12-lead ECG will be obtained as outlined in the flowchart (Table 1-1) using an ECG machine that 
automatically calculates the heart rate and measures PR, QRS, QT and QTcF intervals. 
The ECG should preferably be performed as the first trial assessment, prior to blood sampling and 
other assessments. At each site, ECG assessments should be performed on the same ECG machine 
throughout the trial. 
The ECG should be recorded after at least 5 minutes resting in supine position. The ECG will be 
evaluated by the investigator or designee and the outcome must be specified in the eCRF as either 
“normal” or “abnormal”.  
If “abnormal”, a comment must be given together with an assessment of clinical significance 
(yes/no). The investigator or designee must sign and date the ECG on the day of evaluation. The 
data will be transferred to the eCRF. 
Abnormal clinically significant findings at visit 2 should be recorded as concomitant illness in the 
eCRF. At the following visits, any new abnormal clinically significant findings or clinically 
significant deterioration from baseline should be reported as an AE. 
8.3.5 
Clinical safety laboratory assessments 
All protocol-required laboratory assessments, as defined in Appendix 2, must be conducted in 
accordance with the laboratory manual and the protocol flowchart. 
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8.4 
Adverse events and serious adverse events 
The investigator is responsible for detecting, documenting, recording and following up on events 
that meet the definition of an AE or SAE.  
 
The definition of AEs and SAEs can be found in Appendix 3, along with a description of AEs 
requiring additional data collection. 
 
Some AEs require additional data collection on a specific event form. This always includes 
medication error, misuse and abuse of IMP. The relevant events are listed below in Table 8-1. 
Table 8-1 
AEs requiring additional data collection (serious and non-serious AEs)  
Event type  
AE requiring additional data collection 
Medication error 
X 
Misuse and abuse 
X 
Hypersensitivity reactions 
X 
A detailed description of the events mentioned in the above table can be found in Appendix 3. 
8.4.1 
Time period and frequency for collecting AE and SAE information 
All AEs and SAEs must be collected from the randomisation visit and until the end of trial visit at 
the time points specified in the flowchart.  
Medical occurrences that take place or have onset prior to the time point from which AEs are 
collected will be recorded as concomitant illness/medical history. AE and SAE reporting timelines 
can be found in Appendix 3. All SAEs must be recorded and reported to Novo Nordisk within 
24 hours, and the investigator must submit any updated SAE data to Novo Nordisk within 24 hours 
of it being available. 
Investigators are not obligated to actively seek for AE or SAE in former trial patients. However, if 
the investigator learns of any SAE, including a death, at any time after a patient has been 
discontinued from/completed the trial, and the investigator considers the event to be 
possibly/probably related to the trial product or related to trial participation, the investigator must 
promptly notify Novo Nordisk. 
8.4.2 
Method of detecting AEs and SAEs 
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures for 
completing and transmitting SAE reports are provided in Appendix 3. 
Care should be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and non-
leading verbal questioning of the patient is the preferred method to inquire about events. 
8.4.3 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each patient at 
subsequent visits/contacts. All SAEs should be followed until final outcome of the event or the 
patient is lost to follow-up as described in Section 7.3. Further information on follow-up and final 
outcome of events is given in Appendix 3.  
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8.4.4 
Regulatory reporting requirements for SAEs 
Prompt notification by the investigator to Novo Nordisk or designee of a SAE is essential so that 
legal obligations and ethical responsibilities towards the safety of patients and the safety of a trial 
product under clinical investigation are met.  
Novo Nordisk has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a trial product under clinical investigation. Novo Nordisk 
will comply with country-specific regulatory requirements relating to safety reporting to the 
regulatory authority, IRB/IEC, and investigators. This also includes suspected unexpected serious 
adverse reactions (SUSAR). 
An investigator who receives an investigator safety report describing a SAE or other specific safety 
information (e.g. summary or listing of SAEs) from Novo Nordisk will review and then file it along 
with the investigator's brochure and will notify the IRB/IEC, if appropriate according to local 
requirements. 
8.4.5 
Pregnancy  
Only female patients of non-childbearing potential are eligible for inclusion in the trial (see 
Section 5.1 for inclusion criteria). The definition of a woman of non-childbearing potential is 
provided in Appendix 4 (Section 10.4). 
Should a pregnancy occur, details of pregnancies in female patients will be collected after first 
exposure to trial product and until the end of trial visit. 
If a female patient becomes pregnant, the investigator should inform Novo Nordisk within 
14 calendar days of learning of the pregnancy and should follow the procedures outlined in 
Appendix 4 (Section 10.4). 
No data collection of pregnancy information will be performed for female partners of male patient 
as the risk of seminal transfer of NNC0385-0434 in a magnitude that could impact a foetus in a 
female partner is highly unlikely18.  
8.4.6 
Cardiovascular and death events 
Cardiovascular and death events will be handled and reported according to Section 8.4. 
8.4.7 
Technical complaints  
Technical complaints will be collected for all products listed on the technical complaint form. 
Instructions for reporting technical complaints can be found in Appendix 5. 
In order for Novo Nordisk to perform a complete investigation of reported SAEs, Novo Nordisk 
might ask the investigator to complete a technical complaint form.  
8.5 
Treatment of overdose 
Decisions regarding dose interruptions will be made by the investigator based on the clinical 
evaluation of the patient. 
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There is no previous experience of an overdose with oral NNC0385-0434 in humans and no known 
antidote. NNC0385-0434 administered s.c. with single ascending doses up to 250 mg, and at 
maximum concentrations more than 32 fold higher than expected in this trial, have been found safe 
and well tolerated (see Section 2.2 and Figure 2-1 for details). In the event of an overdose, 
appropriate supportive treatment should be initiated according to the patient’s clinical signs and 
symptoms.  
Accidental overdose must be reported as a medication error. Intentional overdose must be reported 
as misuse and abuse, please refer to Section 8.4 and Appendix 3 (Section 10.3.3) for further details. 
In the event of an overdose, the investigator should closely monitor the patient for overdose-related 
AE/SAE and laboratory abnormalities until clinically safe, taking into account the long half-life of 
NNC0385-0434.  
For more information on overdose, please refer to the current version of the NNC0385-0434 
investigator's brochure18 and in the SmPC or US PI for evolocumab19, 20. 
8.6 
Pharmacokinetics 
Blood samples will be used to evaluate the PK of NNC0385-0434. Samples will be collected in 
accordance with the flowchart Table 1-1. 
For visits with pre-dosing PK sampling (Table 1-1): 
• Patients must be instructed to withhold their trial product dose in the morning of the clinic visit 
until blood sampling has been performed. 
• The date, exact time and dose of the latest trial product administration prior to pre-dose PK 
sampling will be obtained by patient interview at site and must be collected in the laboratory 
requisition form 
Procedures for sampling, handling, storage, labelling, and shipments of samples must be performed 
in accordance with the laboratory manual. 
Bioanalysis of NNC0385-0434 plasma samples will be performed at a special lab using a validated 
Liquid Chromatography Tandem Mass Spectrometry (LC-MS/MS) assay. The exact method will be 
described in a bioanalytical report, and the bioanalytical report must be provided before finalisation 
of the CTR. 
Residual plasma PK samples may be used for exploratory metabolite analysis. 
Potential metabolite analysis will be carried out by department of Development ADME, Novo 
Nordisk, and will be reported separately from the CTR. 
Residual PK samples will be discarded after performance of the experimental work. All samples 
will be destroyed at latest 15 years from end of trial (last patient last visit, LPLV) 
8.6.1 
PK sub-study 
For the PK sub-study, samples will be used to evaluate the PK of NNC0385-0434. Samples will be 
collected in accordance with the flowchart (Table 1-1) and the sample scheme for the PK sub-study 
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provided in Table 1-2. Window allowance for nominal times specified in Table 1-2 should be 
followed. 
• Visit 9: 
• Trial product must be taken at site and the PK blood sampling must be performed in a 
fasting state (as defined in Section 5.3.1)   
• The exact time of trial product administration, start of meal and blood sampling must be 
collected in the laboratory requisition form 
• The date, exact time and dose of the latest trial product administration prior to pre-dose PK 
sampling will be obtained by patient interview at site and must be collected in the laboratory 
requisition form 
• Visits 9A-9D:  
• PK blood sampling is not required to be performed in a fasting state 
• The exact time of blood sampling must be collected in the laboratory requisition form 
Bioanalysis of NNC0385-0434 plasma samples will be performed as described in Section 8.6 
8.7 
Pharmacodynamics 
Not applicable. 
8.8 
Genetics 
Not applicable. 
8.9 
Biomarkers 
8.9.1 
PCSK9 levels 
Blood samples will be collected for exploratory analysis of the endogenous levels of PCSK9 
(pending on assay development) as specified in the flowchart (Table 1-1) and Appendix 2 
(Table 10-1). The analyses will be performed by special laboratory contracted by Novo Nordisk. 
The samples will be processed as detailed in the laboratory manual.   
8.10 
Biosamples for future analysis 
Collection of additional blood samples for future research (stored in a biobank) is also a component 
of this trial. Participation in the biobank component is optional, and patients must sign a separate 
informed consent form to indicate their participation in each biobank component of the trial: 
• Biobank, genetic analysis 
• Biobank, circulating biomarkers 
Patients who do not wish to participate in the optional biobank component may still participate in 
the trial. For the biobank, blood samples for each biobank component will be collected according to 
the flowchart (Table 1-1) and stored for future use. 
The biobank samples are collected for the purpose of allowing future analyses of biomarkers, both 
genetic and circulating biomarkers, at a later point in time when new knowledge or improved 
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measurement techniques may have become available. The analysis may include biomarkers 
currently known or discovered in the future. 
Genetic analyses may include analysis of candidate genes or genetic markers throughout the 
genome. 
Potential biomarker and genetic analyses (for both DNA and mRNA extractions) will be performed 
with the purpose of understanding and predicting response to NNC0385-0434 as well as 
understanding cardiometabolic disease or other related diseases. The patient will not be informed 
about potential results as the analyses are intended for finding trends in the population and not in 
the individual patient.  
The analyses will be performed after the trial has come to an end, and results will, therefore, not be 
part of the CTR.  
The biobank samples will be processed as detailed in the laboratory manual. The biobank samples 
will be stored up to 15 years after end of trial at a central laboratory. Refer to Appendix 6 
(Section 10.6) for further details on the storage and intended use of these samples. 
8.11 
Immunogenicity assessments 
Anti-drug antibody samples will be collected according to the flowchart (Table 1-1). All samples 
must be drawn prior to trial product administration if trial product administration is planned on the 
sampling day. 
Assessment of antibodies against NNC0385-0434 (anti-drug antibodies) in serum will be performed 
at Novo Nordisk A/S. 
For details on blood sampling, serum preparation and storage, please refer to the laboratory manual. 
Analysis for anti-drug antibodies in patients treated with NNC0385-0434 will be done as listed in 
the flowchart (Table 1-1) with a binding anti-drug antibody assay. Positive samples will be further 
characterised for neutralising activity by correlation to PK and PD (with a validated LDL-C assay) 
i.e. the highly sensitive PD marker LDL-C. Any potential clinical effect of ADAs will be evaluated 
by correlation to PK, efficacy and safety parameters. Detailed description of the anti-drug antibody 
assay methods will be included in an analytical report. Antibody assays will be validated according 
to international guidelines and recommendations. Furthermore, samples will be banked for possible 
future analysis in a dedicated neutralising anti-drug antibody analysis if this assay would be deemed 
necessary (for further details, see Section 10.6.2). 
Results from the binding anti-drug antibody analyses from visit 2, 4, 6, 8, 9 and 10 will be available 
at the end of trial. 
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At the end of the trial, the following data will be electronically transferred to the Novo Nordisk 
database:  
• Anti-NNC0385-0434 binding antibodies (positive/negative)  
• Anti-NNC0385-0434 binding antibodies cross-reacting with endogenous EGF-A 
(positive/negative) 
• Anti-NNC0385-0434 binding antibody titre (no unit) 
Patients who have tested positive for antibodies against NNC0385-0434 (high titre of antibodies) at 
visit 10 (end-of-trial visit) will be requested to have a follow-up analysis performed 12 months after 
visit 10. If the anti-NNC0385-0434 antibody titre has not declined at the follow-up analysis, the 
patient may be requested to have an additional follow-up analysis performed. The result from 
additional follow-up analyses will be reported in a separate analytical report. Thus, the results will 
not be part of the CTR. 
The investigator will not be able to review the results of antibody measurements in relation to AEs 
as these will be analysed after LPLV. 
Refer to Section 10.6.2 for further details. 
8.11.1 
Assessments in case of suspicion of hypersensitivity to trial product 
Patients and investigators will be instructed to detect signs and symptoms of hypersensitivity 
reactions:  
•  Local reactions 
•  Systemic reactions, including anaphylaxis. 
 In the event of a hypersensitivity reaction:  
• The patient should contact the site for advice on further action as soon as possible. 
• Additional data collection will be performed on the event 
• Treatment should be provided by the investigator according to local clinical practice. 
Additional blood samples and other tests 
In the event of a systemic hypersensitivity reaction (i.e. not local reactions), as judged by the 
investigator, the patient should be called in as soon as possible to have additional blood samples 
taken in order to analyse the following parameters: 
• Tryptase (optimal 0.5 – 2 hours post the hypersensitivity reaction) 
• Anti-NNC0385-0434 binding antibodies 
• Anti-NNC0385-0434 IgE antibodies 
• Anti-EGF-A IgE antibodies 
• Total IgE  
The following additional exploratory tests may be performed on the already taken blood samples, if 
deemed relevant: 
• Histamine release assay (basophil activation test) 
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The blood sampling should if possible be repeated 1, 2 and 4 weeks following the systemic 
hypersensitivity reaction. In addition, the test should also be performed on samples drawn prior to 
first administration of trial drug.  
Prick test/intra-dermal test may be performed if deemed relevant. Complement may be measured in 
case of suspicion of immune complex mediated hypersensitivity reactions. 
Analysis of anti-NNC0385-0434 IgE, anti-EGF-A IgE, total IgE and tryptase will be performed at 
Novo Nordisk A/S. If deemed relevant, histamine release (basophil) assay will be performed at 
, as an exploratory analysis. Prick test/intra-dermal test should be performed at 
the hospital allergy unit. 
Data from the additional blood samples and tests will be reported in a separate report and attached 
to the clinical trial report. Furthermore, the results will be included in the narratives of the clinical 
trial report. 
8.11.2 
Digital pictures 
The investigator or the patient should take digital pictures of the hypersensitivity reaction as 
applicable (for example rash, urticaria, swelling of face) for reactions possibly related to the 
administration of NNC0385-0434 at time of identification and thereafter as often as judged 
necessary by the investigator.  
The pictures should include patient identification number, date and time, time after dosing and a 
ruler for scaling. All pictures should be stored as part of source documentation at site. 
8.12 
Health economics  
Not applicable. 
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9 
Statistical considerations  
9.1 
Statistical hypotheses 
Confirmation of superiority for each oral NNC0385-0434 dose vs. placebo (pooled from all 3 
placebo arms) will be evaluated using a hierarchical testing procedure starting with the treatment 
difference between the highest oral NNC0385-0434 dose (100 mg) and placebo and ending with the 
lowest dose (15 mg). In case of a non-significant treatment difference the testing procedure will 
stop. This will protect the family-wise type 1 error in the strong sense on a 5% level of significance. 
The superiority test for oral NNC0385-0434 vs. placebo will be carried out as follows. Let μNNC0385-
0434 ,x and μplacebo denote the true mean of percent change in LDL-C from baseline for dose level x of 
oral NNC0385-0434 and placebo, respectively. The null and alternative hypotheses tested are 
𝐻0: 𝜇NNC0385−0434 ,𝑥≥𝜇𝑝𝑙𝑎𝑐𝑒𝑏𝑜 vs. 𝐻𝐴: 𝜇NNC0385−0434 ,𝑥< 𝜇𝑝𝑙𝑎𝑐𝑒𝑏𝑜 
The null hypothesis will be rejected if the upper limit of the estimated two-sided 95% CI for the 
treatment difference is below 0.  
9.2 
Sample size determination  
To characterise the shape of the curve for the dose-response relationship it is considered adequate to 
test 3 doses of oral NNC0385-0434 and the sample size for each dose is determined in order to 
achieve a sufficient precision on this relationship. Furthermore, sample size calculation is done for 
analyses addressing the primary estimand. Here, measurements of the primary endpoint from 
patients that have discontinued treatment prematurely but continuing in the trial (retrieved dropouts) 
are treated as missing. 
In the sample size calculations addressing the primary estimand, missing values and assessments 
from retrieved dropouts are assumed to be similar to treatment completers within the same 
treatment group.  
The sample size calculation assumes at least 45 eligible measurements of the primary endpoint in 
each treatment arm (eligible assessment defined as non-missing and obtained during the on-
treatment observation periods, see Section 9.3 for definition of the on-treatment observation 
period). The sample size calculation assumes an SD of 30%-points for the percent change in LDL-C 
from baseline to week 12.  
Data from the currently approved PCSK9 inhibitors are as follows: 
• Alirocumab: lowering percentage LDL-C after 24 weeks by 61 percent with SE=0.7 for n=1530, 
corresponding to an SD of 27%-points21 
• Evolocumab: lowering percentage LDL-C after 52 weeks by 46.8 percent with SE=3.0 for 
n=126, corresponding to an SD of 34%-points22 
Table 9-1 includes different scenarios for the probability of the 95% confidence interval for the 
treatment difference to have the given halfwidth for different scenarios of number of patients per 
treatment arm. 
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A standard deviation of 30%-points and at least 45 eligible measurements in each treatment arm 
will allow the 95% confidence interval for the estimated difference between an oral NNC0385-0434 
dose and the placebo group, with 94% probability, to be contained within ±14%-points of the 
estimate. This is considered to be a sufficient precision for determining which doses to use for the 
continued development of oral NNC0385-0434.  
The calculations in Table 9-1 also apply for the comparison between oral doses of NNC0385-0434 
and s.c. evolocumab. 
In total this requires a sample size of 255 patients. 
Table 9-1 
Probability of desired CI half-width 
N per active arm/N for placebo group 
(Eligible) 
SD  
(%-points) 
CI half-width  
(%-points) 
Probability 
51 (45) 
30 
14 
94% 
60 (54) 
30 
14 
>99% 
51 (45) 
30 
13 
69% 
60 (54) 
30 
13 
98% 
51 (45) 
34 
14 
42% 
60 (54) 
34 
14 
88% 
51 (45) 
34 
13 
13% 
60 (54) 
34 
13 
52% 
PK sub-study 
Based on the PK endpoint AUC0-24h, a common race ratio across doses will be estimated including 
the 18 Japanese and 18 non-Japanese patients exposed to oral NNC0385-0434. Assuming that the 
true common race ratio is 1, and that the SD of log(AUC0-24h) is 0.5, and accounting for a 10% 
withdrawal rate, the 95% confidence interval of the common race ratio of AUC0-24h will, with a 
probability of 80%, be within the range from 0.67 to 1.5 times the estimated ratio. 
9.3 
Populations for analyses 
The following populations are defined: 
Population 
Description 
Full analysis set 
Full analysis set (FAS): All patients randomised. Patients will be analysed 
according to the randomised treatment. 
Safety analysis set 
Safety analysis set (SAS): All patients randomly assigned to trial treatment and 
who take at least 1 dose of trial product. Patients are analysed according to the 
treatment they actually received. 
 
The patients or observations to be excluded, and the reasons for their exclusion must be documented 
before unblinding. The patients and observations excluded from analysis sets, and the reason for 
this, will be described in the CTR.  
 
Efficacy endpoints will be analysed using the FAS; safety endpoints will be analysed using the 
SAS.  
 
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For both the primary estimand and the additional estimand, patients are analysed according to the 
randomised treatment. 
 
Two observation periods are defined for each patient: 
• The in-trial period is defined as the uninterrupted time interval from date of randomisation to 
date of last contact with trial site. Follow-up time for antibody positive patients is not included 
in the in-trial period. 
• The on-treatment period is a subset of the ‘in-trial’ observation period and represents the time 
period where patients are considered exposed to trial product. The observation period starts at 
the date of first dose of trial product and ends at the first date of any of the following: 
• The follow-up visit  
• The last date on randomised treatment regimen + 58 days 
• The end-date for the ‘in-trial’ observation period 
The in-trial and on-treatment periods define the patient years of observation (PYO) and patient 
years of exposure (PYE), respectively, as the total time duration in the periods. 
9.4 
Statistical analyses 
The statistical analysis plan will be finalised prior to first patient first visit and will include a more 
technical and detailed description of the statistical analyses described in this section. This section is 
a summary of the planned statistical analyses of the most important endpoints including primary 
and confirmatory secondary endpoints. 
9.4.1 
General considerations 
Handling of missing baseline data 
The last available and eligible observation at or before randomisation is used as the baseline value. 
If no assessments are available, the mean value at randomisation across all patients is used as the 
baseline value. 
9.4.2 
Primary endpoint 
Definition of primary endpoint: Percent change in LDL-C 
Change from randomisation at week 0 to week 12 in LDL-C (%) is defined as: 
% LDL-c change =  (LDL-C at week 12 – LDL-C at baseline)
LDL-C at baseline
 ×100% 
The primary estimand for percent change in LDL-C addresses the efficacy of oral NNC0385-0434 
and will be estimated based on the FAS using the on-treatment observation period.  
The primary analysis for the primary estimand for percent change in LDL-C is an analysis of 
covariance (ANCOVA) with randomised treatment (each oral NNC0385-0434 dose, pooled placebo 
group, and s.c. evolocumab) and strata as factors (population strata (inclusion criteria 3a/3b),  
country (Japan/non-Japan)) and baseline LDL-C as a covariate. 
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The estimated treatment difference between individual oral NNC0385-0434 doses and placebo will 
be reported together with the associated two-sided 95% CI and corresponding two-sided p-value.   
Handling of missing week 12 values for the primary estimand 
The primary estimand will be estimated based on the FAS using post-baseline measurements up to 
and including week 12 from the on-treatment observation period. Missing data and observations 
outside the on-treatment observation period such as week 12 assessments for retrieved dropouts will 
be imputed using multiple imputation assuming missing at random (MAR). Missing post-baseline 
data will be imputed sequentially within each treatment using the observed post-randomisation 
assessments for visits prior to the one in question obtained during the on-treatment observation 
period. The imputation model will include strata as factors (population strata (inclusion 
criteria 3a/3b), country (Japan/non-Japan)) and baseline and post-baseline LDL-C values prior to 
the visit in question as covariates. The proportion of missing LDL-C change data at week 12 is 
assumed to be no more than 10% and is expected to be similar in all treatment arms. 
Analysis addressing the effect of oral NNC0385-0434 vs. s.c. evolocumab 
This analysis will evaluate the treatment difference between oral NNC0385-0434 and s.c. 
evolocumab using the same analysis as the primary analysis for the primary estimand described 
above. However, the treatment differences between oral NNC0385-0434 doses and s.c. evolocumab 
will be estimated but no confirmatory testing will be carried out. 
Analyses addressing the additional estimand 
The analysis model for percent change in LDL-C is an ANCOVA with randomised treatment and 
strata as factors (population strata (inclusion criteria 3a/b), country (Japan/non-Japan)) and baseline 
LDL-C as a covariate.  
Handling of missing week 12 values for the additional estimand 
The additional estimand will be estimated based on the FAS using week 12 measurements from the 
in-trial observation period. Missing week 12 data will be imputed using multiple imputation 
assuming missing at random (MAR). Imputation will be done within groups defined by randomised 
treatment and treatment status at week 12. The imputation model will include strata as factors 
(population strata (inclusion criteria 3a/3b), country (Japan/non-Japan)) and baseline LDL-C as a 
covariate. In case of sparse data in some of the groups, a common treatment discontinuation group 
across treatments will be created and randomised treatment will be added to the model as factor. If 
this is still not sufficient, the model will be thinned in the following order, starting with the one that 
will be removed first; strata, randomised treatment, and baseline value. 
Dose-response modelling 
In order to evaluate the effect of oral NNC0385-0434 dose vs. placebo on percent change in LDL-C 
and to characterise the dose-response relationship the mean percent LDL-C change will be 
estimated using dose as a continuous variable. 
The dose-response candidate models in Table 9-2 will be fit. 
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Table 9-2 
Dose-response candidate models 
Model 
Functional form f(d,θ) 
Emax 
𝐸0 + 𝐸𝑚𝑎𝑥
𝑑
𝐸𝐷50 + 𝑑 
Linear 
𝐸0 + 𝛽𝑑 
 
The candidate models will be fit to the estimated percent change in LDL-C means at week 12 for 
the employed oral NNC0385-0434 doses and placebo from the primary analysis model described 
above. Thus, all patients in the FAS will be included and the same assumptions regarding missing 
values and the impact of explanatory variables will be applied.  
The model used to evaluate dose-response will be selected among the candidate models based on 
the best fit to data. The best fit will be evaluated based on convergence, model complexity, Akaike 
information criterion (AIC) value and visual evaluation.  
9.4.3 
Secondary endpoints 
9.4.3.1 
Confirmatory secondary endpoint 
Not applicable  
9.4.3.2 
Supportive secondary endpoints 
For details on analyses of additional supportive secondary endpoints, please refer to the SAP. 
9.4.4 
Exploratory endpoints 
For details on analyses of the exploratory endpoints, please refer to the SAP. 
9.4.5 
Other safety analyses 
All safety analyses will be made on the safety analysis set. The standard safety assessments (AEs, 
safety laboratory parameters, vital signs, etc.) will be reported descriptively; including any notable 
changes of clinical interest in laboratory parameters. 
9.4.6 
Other analyses  
For other analyses, please refer to the SAP.  
9.4.6.1 
Pharmacokinetic and/or pharmacodynamic modelling 
Population PK and exposure-response analyses will be used as supportive evidence for the 
evaluation of efficacy and safety as well as to support the dose selection of oral NNC0385-0434 for 
future clinical development in patients with established ASCVD or ASCVD risk. Firstly, plasma 
NNC0385-0434 concentrations will be analysed using a population PK model, quantifying 
covariate (such as baseline body weight, age, sex, race, ethnicity) effects on oral NNC0385-0434 
exposure. Secondly, model-based estimates of steady-state average concentrations will be derived 
for each patient, to facilitate subsequent exposure-response analyses. Relevant efficacy and safety 
endpoints will be related to steady-state average concentrations and subjected to model-based 
analysis. 
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A modelling analysis plan will be prepared before data base lock, outlining details of the analyses. 
The modelling will be performed by Quantitative Clinical Pharmacology at Novo Nordisk and will 
be reported separately from the CTR. 
9.5 
Interim analyses  
Not applicable for this trial. 
9.6 
Data monitoring committee  
Not applicable for this trial. 
9.7 
Reporting of the main part of the trial 
Not applicable for this trial. 
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10 Supporting documentation and operational considerations 
10.1 
Appendix 1: Regulatory, ethical, and trial oversight considerations 
10.1.1 
Regulatory and ethical considerations 
• This trial will be conducted in accordance with the protocol and with the following: 
• Consensus ethical principles derived from international guidelines including the Declaration of 
Helsinki23 and applicable ICH Good Clinical Practice (GCP) Guideline24 
• Applicable laws and regulations 
• The protocol, informed consent form, investigator’s brochure (as applicable) and other relevant 
documents (e.g. advertisements) must be submitted to an IRB/IEC and reviewed and approved 
by the IRB/IEC before the trial is initiated. 
• Regulatory authorities will receive the clinical trial application, protocol amendments, reports 
on SAEs, and the CTR according to national requirements. 
• Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the trial design, except for changes necessary to eliminate an immediate safety 
hazard to trial patients. 
• Before a site is allowed to start screening patients, written notification from Novo Nordisk must 
be received. 
• The investigator will be responsible for: 
• providing written summaries of the status of the trial annually or more frequently in accordance 
with the requirements, policies, and procedures established by the IRB/IEC and/or regulatory 
authorities 
• notifying the IRB/IEC of SAEs or other significant safety findings as required by IRB/IEC 
procedures 
• providing oversight of the conduct of the trial at the site and adherence to requirements of ICH 
guidelines, the IRB/IEC, and all other applicable local regulations 
• ensuring submission of the CTR synopsis to the IRB/IEC 
• reporting any potential serious breaches to the sponsor immediately after discovery 
 
Japan: For country-specific requirements, please refer to Appendix 9 (Section 10.9). 
10.1.2 
Financial disclosure 
Investigators and sub-investigators will provide Novo Nordisk with sufficient, accurate financial 
information as requested to allow Novo Nordisk to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the trial and one 
year after completion of the trial. 
For US sites: Verification under disclosures per Code of Federal Regulations (CFR) of Financial 
Conflict of Interest. 
10.1.3 
Informed consent process 
• The investigator or his/her representative will explain the nature of the trial to the patient or the 
patient’s LAR and answer all questions regarding the trial.  
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• The investigator must ensure the patient ample time to come to a decision whether or not to 
participate in the trial.  
• Patients must be informed that their participation is voluntary. 
• Patients must be informed about their privacy rights.  
• Patients or their LAR will be required to sign and date a statement of informed consent that 
meets the requirements of local regulations, ICH guidelines24, Declaration of Helsinki23 and the 
IRB/IEC or site. 
• The medical record must include a statement that written informed consent was obtained before 
any trial related activity and the date when the written consent was obtained. The authorised 
person obtaining the informed consent must also sign and date the informed consent form before 
any trial related activity. 
• The responsibility of seeking informed consent must remain with the investigator, but the 
investigator may delegate the task to a medically qualified person, in accordance with local 
requirements. 
• Patients or their LAR must be re-consented to the most current version of the informed consent 
form(s) during their participation in the trial. 
• A copy of the informed consent form(s) must be provided to the patient or the patient’s LAR. 
• A separate informed consent form intended for collection of additional blood samples for future 
research (circulating biomarkers) is available for this trial (see Section 8.10) 
• A separate informed consent form intended for collection of additional blood samples for future 
research (genetic analysis) is available for this trial (see Section 8.10) 
• A separate informed consent form intended for a male partner of a female patient in case of an 
abnormal pregnancy is available for this trial (Appendix 4 (Section 10.4)) 
10.1.4 
Information to patients during trial 
The site will be offered a communication package for the patient during the conduct of the trial. The 
package content is issued by Novo Nordisk. The communication package will contain written 
information intended for distribution to the patients. The written information will be translated and 
adjusted to local requirements and distributed to the patient at the discretion of the investigator. The 
patient may receive a “welcome to the trial letter” and a “thank you for your participation letter” 
after completion of the trial. Further, the patient may receive other written information during the 
trial.  
All written information to patients must be sent to IRB/IEC for approval/favourable opinion and to 
regulatory authorities for approval or notification according to local regulations. 
10.1.5 
 Data protection 
• Patients will be assigned a 6-digit unique identifier, a patient number. Any patient records or 
datasets that are transferred to Novo Nordisk will contain the identifier only. No direct 
identifiers from the patient are transferred to Novo Nordisk. 
• The patient and any biological material obtained from the patient will be identified by patient 
number, visit number and trial ID. Appropriate measures such as encryption or leaving out 
certain identifiers will be enforced to protect the identity of patients as required by local, 
regional and national requirements.  
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• The patient must be informed about his/her privacy rights, including that his/her personal trial 
related data will be used by Novo Nordisk in accordance with local data protection law. The 
disclosure of the data must also be explained to the patient.  
• The patient must be informed that his/her medical records may be examined by auditors or other 
authorised personnel appointed by Novo Nordisk, by appropriate IRB/IEC members, and by 
inspectors from regulatory authorities. 
10.1.6 
Committees structure 
10.1.6.1 
Novo Nordisk safety committee 
Novo Nordisk will perform ongoing safety surveillance. If new safety signals are identified, these 
will be evaluated by an internal NNC0385-0434 safety committee. The safety committee may 
recommend unblinding of any data for further analysis, and in this case an internal trial independent 
ad hoc group will be established in order to maintain the blinding of the trial personnel. 
10.1.7 
Dissemination of clinical trial data 
Information of the trial will be disclosed at clinicaltrials.gov and novonordisk-trials.com. It will also 
be disclosed according to other applicable requirements, such as those of the International 
Committee of Medical Journal Editors (ICMJE)25, the Food and Drug Administration Amendment 
Act (FDAAA)26, European Commission Requirements27-29 and other relevant recommendations or 
regulations. If a patient requests to be included in the trial via the Novo Nordisk e-mail contact at 
these web sites, Novo Nordisk may disclose the investigator’s contact details to the patient. As a 
result of increasing requirements for transparency, some countries require public disclosure of 
investigator names and their affiliations. 
The primary completion date (PCD) is the last assessment of the primary endpoint and is for this 
trial last patient first treatment (LPFT) + 12 weeks + 3 days visit window corresponding to visit 9. If 
the last patient is withdrawn early, the PCD is considered the date when the last patient would have 
completed visit 9. The PCD determines the deadline for results disclosure at clinicaltrials.gov 
according to FDAAA. 
10.1.8 
Data quality assurance 
10.1.8.1 
Case report forms 
• Novo Nordisk or designee is responsible for the data management of this trial including quality 
checking of the data. 
• All patient data relating to the trial will be recorded on electronic CRFs unless transmitted 
electronically to Novo Nordisk or designee (e.g. laboratory data). The investigator is responsible 
for verifying that data entries are accurate and correct by physically or electronically signing the 
CRF.  
• The following will be provided as paper CRFs:  
• Pregnancy forms 
• The following will be provided as paper CRFs to be used when access to the CRF is revoked or 
the CRF is temporarily unavailable:  
• AE forms  
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• Safety information forms  
• Technical complaint forms (also to be used to report complaints on trial product not yet 
allocated to a patient)  
• Corrections to the CRF data may be made by the investigator or the investigator’s delegated 
staff. An audit trail will be maintained in the CRF application containing as a minimum: the old 
and the new data, identification of the person entering the data, date and time of the entry and 
reason for the correction. If corrections are made by the investigator’s delegated staff after the 
date when the investigator signed the CRF, the CRF must be signed and dated again by the 
investigator. 
• The investigator must ensure that data is recorded in the CRF as soon as possible, preferably 
within 5 working days after the visit. Once data has been entered, it will be available to Novo 
Nordisk for data verification and validation purposes.  
10.1.8.2 
Monitoring 
• The investigator must permit trial-related monitoring, audits, IRB/IEC review, and regulatory 
agency inspections and provide direct access to source data documents (original documents, 
data and records). Direct access includes permission to examine, analyse, verify and reproduce 
any record(s) and report(s) that are important to the evaluation of the trial. If the electronic 
medical record does not have a visible audit trail, the investigator must provide the monitor with 
signed and dated printouts. In addition, the relevant site staff should be available for discussions 
at monitoring visits and between monitoring visits (e.g. by telephone).  
• Trial monitors will perform ongoing source data verification to confirm that data entered into 
the CRF by authorised site personnel are accurate, complete and verifiable from source 
documents; that the safety and rights of patients are being protected, to monitor drug 
accountability and collect completed paper CRF pages, if applicable, and that the trial is being 
conducted in accordance with the currently approved protocol and any other trial agreements, 
ICH GCP, and all applicable regulatory requirements. 
• Monitoring will be conducted using a risk-based approach including risk assessment, 
monitoring plans, centralised monitoring (remote assessment of data by Novo Nordisk) and 
visits to sites.  
• Monitors will review the patient’s medical records and other source data to ensure consistency 
and/or identify omissions compared to the CRF.  
Medical monitoring and early PK evaluation 
Bi-weekly medical monitoring of safety data including AEs, vital signs, ECG, and laboratory safety 
parameters will be performed according to the medical monitoring plan.  
The centralised monitoring will include early PK evaluation to ensure that the PK parameters after 
oral dosing are in the expected range. The early PK evaluation will be performed at 3 early 
timepoints during the trial and will include all available blinded accumulated plasma concentration 
data from patients that have initiated treatment. PK data will be related to treatment arm. The early 
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PK evaluation will be based on nominal time points for the dose administration and PK sampling. 
Additional PK evaluations may be added if deemed necessary. 
• Timepoint 1: After PK data is available from visit 4 (2 weeks of dosing) for the initial 
15 patients. 
• Timepoint 2: After PK data is available from visit 7 (6 weeks after dosing) for the initial 
15 patients  
• Timepoint 3: After PK data is available from visit 8 (9 weeks after dosing) for the initial 
15 patients and from visit 4 (2 weeks of dosing) for the following 20 patients.   
 
Further details are described in the interim modelling analysis plan.  
 
The Novo Nordisk NN6435 Safety Committee will be informed immediately in case any of the 
following criteria are met: 
• if the exposure of NNC0385-0434 exceeds the NOAEL exposure observed in the 13-week 
non-clinical toxicity study (12 mg/kg/day s.c. + 50 mg/kg/day orally) 
• if the geometric mean Cmax of NNC0385-0434 for patients treated with any dose arm of 
NNC0385-0434 is numerically higher than the geometric mean Cmax observed in the FHD trial 
NN64334-4493 (11,015.5 nmol/L). 
 
The initial 15 patients (3 patients in each active treatment arm and 1 patient in each of the placebo 
arms) will be recruited and treated for minimum 4 weeks before recruitment of the remaining 
240 patients. Recruitment of the remaining patients will be initiated following medical monitoring 
of 4 week data of these 15 patients without identification of safety concerns, in addition to review of 
PK data from the 15 patients 2 weeks after dosing 
 
If unexpected safety findings occur, a Novo Nordisk Safety Committee will be informed 
immediately and will take appropriate actions to the information received.    
10.1.8.3 
Protocol compliance 
Deviations from the protocol should be avoided. If deviations do occur, the investigator must 
inform the monitor without delay and the implications of the deviation must be reviewed and 
discussed. 
Deviations must be documented and explained in a protocol deviation by stating the reason, date, 
and the action(s) taken. Some deviations, for which corrections are not possible, can be 
acknowledged and confirmed via edit checks in the CRF or via listings from the trial database.  
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10.1.9 
Source documents 
• All data entered in the CRF must be verifiable in source documentation other than the CRF. 
• If source data is entered directly in a paper CRF, each data entry or clear series of data entries 
must be signed and dated separately by the trial staff making the entry.  
• Source documents provide evidence for the existence of the patient and substantiate the integrity 
of the data collected. Source documents are filed at the site. 
• Data reported on the paper CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents, or the discrepancies must be 
explained. The investigator may need to request previous medical records or transfer records. 
Also, current medical records must be available.  
• It must be possible to verify patient’s medical history in source documents, such as patient’s 
medical record  
• The investigator must document any attempt to obtain external medical information by noting 
the date(s) when information was requested, and who was contacted. 
• Definition of what constitutes source data can be found in a source document agreement at each 
site. There will only be one source document defined at any time for any data element. 
10.1.10 Retention of clinical trial documentation 
• Records and documents, including signed informed consent forms, pertaining to the conduct of 
this trial must be retained by the investigator for 15 years after end of trial unless local 
regulations or institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of Novo Nordisk. No records 
may be transferred to another location or party without written notification to Novo Nordisk.  
• The investigator must be able to access his/her trial documents without involving Novo Nordisk 
in any way. If applicable, electronic CRF (eCRF) and other patient data will be provided in an 
electronic readable format to the investigator before access is revoked to the systems supplied 
by Novo Nordisk. Site-specific CRFs and other patient data (in an electronic readable format or 
as paper copies or prints) must be retained by the site. A copy of all data will be stored by Novo 
Nordisk. 
• Patient’s medical records must be kept for the maximum period permitted by the hospital, 
institution or private practice. 
United States of America: For country-specific requirements, please refer to Appendix 9 (Section 
10.9). 
10.1.11 Trial and site closure 
Novo Nordisk reserves the right to close the site or terminate the trial at any time for any reason at 
the sole discretion of Novo Nordisk. If the trial is suspended or terminated, the investigator must 
inform the patients 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. 
Sites will be closed upon trial completion. A site is considered closed when all required documents 
and trial supplies have been collected and a site closure visit has been performed. 
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The investigator may initiate site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a site by Novo Nordisk or investigator may include but are not 
limited to: 
• failure of the investigator to comply with the protocol, the requirements of the IRB/IEC or local 
health authorities, Novo Nordisk procedures or GCP guidelines 
• inadequate recruitment of patients by the investigator 
• discontinuation of further trial product development. 
10.1.12 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 site. If any tasks are delegated, the investigator must 
maintain a log of appropriately qualified persons to whom he/she has delegated specified trial-
related duties. The investigator must ensure that there is adequate and documented training for all 
staff participating in the conduct of the trial. It is the investigator’s responsibility to supervise the 
conduct of the trial and to protect the rights, safety, and well-being of the patients.  
A qualified physician, who is an investigator or a sub investigator for the trial, must be responsible 
for all trial-related medical decisions.  
The investigator is responsible for filing essential documents (i.e. those documents which 
individually and collectively permit evaluation of the conduct of a trial and the quality of the data 
produced) in the investigator trial master file. The documents, including the patient identification 
code list must be kept in a secure locked facility so that no unauthorized persons can get access to 
the data.  
The investigator will take all necessary technical and organisational safety measures to prevent 
accidental or wrongful destruction, loss or deterioration of data. The investigator will prevent any 
unauthorised access to data or any other processing of data against applicable law. This also 
includes ensuring that no indirect sharing of user credentials for IT systems used in this study takes 
place (e.g., by not sharing IT equipment with others in a way where user credentials have the 
possibility of being shared). The investigator must be able to provide the necessary information or 
otherwise demonstrate to Novo Nordisk that such technical and organisational safety measures have 
been taken. 
During any period of unavailability, the investigator must delegate responsibility for medical care of 
patients to a specific qualified physician who will be readily available to patients 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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10.1.13 Indemnity statement  
Novo Nordisk carries product liability for its products, and liability as assumed under the special 
laws, acts and/or guidelines for conducting clinical trials in any country, unless others have shown 
negligence.  
Novo Nordisk assumes no liability in the event of negligence or any other liability of the sites or 
investigators conducting the trial or by persons for whom the said site or investigator are 
responsible.  
Novo Nordisk accepts liability in accordance with:  
Belgium: For country specific indemnity statement, see Appendix 9 (Section 10.9) 
10.1.14 Publication policy 
The information obtained during the conduct of this trial is considered confidential and may be used 
by or on behalf of Novo Nordisk for regulatory purposes as well as for the general development of 
the trial product. All information supplied by Novo Nordisk in connection with this trial shall 
remain the sole property of Novo Nordisk and is to be considered confidential information. 
No confidential information shall be disclosed to others without prior written consent from Novo 
Nordisk. Such information shall not be used except in the performance of this trial. 
The information obtained during this trial may be made available to other investigators who are 
conducting other clinical trials with the trial product, if deemed necessary by Novo Nordisk. 
Provided that certain conditions are fulfilled, Novo Nordisk may grant access to information 
obtained during this trial to researchers who require access for research projects studying the same 
disease and/or trial product studied in this trial. 
Novo Nordisk may publish on its clinical trials website a redacted CTR 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.  
10.1.14.1 
Communication of results 
Novo Nordisk commits to communicate and disclose results of trials regardless of outcome. 
Disclosure includes publication of a manuscript in a peer-reviewed scientific journal, abstract 
submission with a poster or oral presentation at a scientific meeting or disclosure by other means.  
The results of this trial will be subject to public disclosure on external web sites according to 
international and national regulations. Novo Nordisk reserves the right to defer the release of data 
until specified milestones are reached, for example when the CTR is available. This includes the 
right not to release the results of interim analyses, because the release of such information may 
influence the results of the entire trial. 
At the end of the trial, one or more scientific publications may be prepared collaboratively by the 
investigator(s) and Novo Nordisk. Novo Nordisk reserves the right to postpone publication and/or 
communication for up to 60 days to protect intellectual property. 
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In all cases, the trial results will be reported in an objective, accurate, balanced and complete 
manner, with a discussion of the strengths and limitations. 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. 
10.1.14.2 
Authorship 
Novo Nordisk will work with one or more investigator(s) and other experts who have contributed to 
the trial concept or design, acquisition, analysis or interpretation of data to report the results in one 
or more publications. 
Authorship of publications should be in accordance with the Recommendations for the Conduct, 
Reporting, Editing and Publication of Scholarly Work in Medical Journals by the International 
Committee of Medical Journal Editors.30 
All authors will be provided with the relevant statistical tables, figures, and reports needed to 
evaluate the planned publication.  
Where required by the journal, the investigator from each site will be named in an 
acknowledgement or in the supplementary material, as specified by the journal.  
10.1.14.3 
Site-specific publication(s) by investigator(s) 
For a multicentre clinical trial, analyses based on single-site data usually have significant statistical 
limitations and frequently do not provide meaningful information for healthcare professionals or 
patients, and therefore may not be supported by Novo Nordisk. Thus, Novo Nordisk may deny a 
request or ask for deferment of the publication of individual site results until the primary manuscript 
is accepted for publication. In line with Good Publication Practice, such individual reports should 
not precede the primary manuscript and should always reference the primary manuscript of the trial. 
10.1.14.4 
Investigator access to data and review of results 
As owner of the trial database, Novo Nordisk has the discretion to determine who will have access 
to the database. 
Individual investigators will have their own research patients' data and will be provided with the 
randomisation code after results are available. 
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10.2 
Appendix 2: Clinical laboratory tests 
• The tests detailed in Table 10-1, Table 10-2 and Table 10-3 will be performed by the central 
laboratory unless otherwise noted.  
• Additional tests may be performed at any time during the trial as determined necessary by the 
investigator or required by local regulations. Only laboratory samples specified in the protocol 
should be sent to the central laboratory for analysis; if additional laboratory sampling is needed, 
e.g. to follow up on AEs, this must be done at a local laboratory. 
• The central lab will communicate to the investigator abnormal values of parameters not 
requested in the protocol but identified by the laboratory equipment and/or their processes 
according to their lab SOPs. These data will not be transferred to the trial database. The 
investigator should review such values for AEs and report these according to this protocol. 
• The investigator must review all laboratory results for concomitant illnesses and AEs. 
• Laboratory samples will be destroyed no later than at finalisation of the CTR, except for the 
following: 
• Human biosamples for retention will be stored as described in Appendix 6 (Section 10.6). 
• For haematology samples (differential count) where the test result is not normal, then a part of 
the sample may be kept for up to two years or according to local regulations.  
 
Table 10-1 
Protocol-required efficacy laboratory assessments 
Laboratory 
assessments 
Parameters 
Lipids 
• Lipoprotein a (Lp(a)) 
• Apolipoprotein B (ApoB) 
• Apolipoprotein C III (ApoCIII) 
• Total cholesterol 
• High density lipoprotein (HDL) cholesterol 
• Low density lipoprotein (LDL) cholesterol 
• Very low density lipoprotein (VLDL) cholesterol 
• Triglycerides 
Target engagement 
• PCSK9 levelsa 
 
NOTES: 
a Analysis performed by special laboratory contracted by Novo Nordisk 
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Table 10-2 
Protocol-required safety laboratory assessments 
Laboratory 
 assessments 
Parameters 
Haematology 
• Lymphocytes 
• Eosinophils 
• Basophils 
• Monocytes 
• Neutrophils 
• Haematocrit 
• Mean corpuscular haemoglobin, concentration 
• Mean corpuscular volume 
• Reticolyctes 
• Haemoglobin 
• Erythrocytes 
• Leukocytes 
• Thrombocytes 
Biochemistrya 
• Bicarbonate Serum 
• High Sensitive C-Reactive Protein 
• eGFR Using CKD-EPI Formula (Chronic Kidney Disease Epidemiology Collaboration) 
• Aspartate Aminotransferase 
• Albumin 
• Urea 
• Calcium 
• Sodium 
• Potassium 
• Creatinine 
• Alkaline Phosphatase 
• Alanine Aminotransferase 
• Gamma-glutamyl transferase (GGT) 
• Bilirubin 
• Creatine Kinase 
• Lactate plasma 
Coagulation 
parameters 
• Prothrombin Time 
• INR 
Pregnancy Testing 
• Highly sensitive serum human chorionic gonadotropin (hCG) pregnancy testb 
Glucose metabolism  
• Fasting plasma glucose 
• HbA1c 
Antibodies 
• Anti NNC0385-0434 Antibodiesc 
Notes: 
a Details of required actions and follow-up assessments for increased liver parameters including any discontinuation 
criteria are given in Section 10.3 (Hy’s Law) and Section 7.1. 
b Only applicable for female patients who have stopped menstruating within the last 5 years 
(Appendix 4 (Section 10.4)) 
c Analysis performed at Novo Nordisk A/S 
 
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Table 10-3 
Protocol-required PK assessments 
Laboratory 
assessments 
Parameters 
Pharmacokinetics 
• NNC0385-0434 plasma concentrationsa 
Notes: 
a Analysis performed by special laboratory contracted by Novo Nordisk 
 
Laboratory results that could unblind the trial (e.g. antibodies and PK) will not be reported to the 
sites until the trial has been unblinded. 
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Figure 10-1 Decision tree for determining the event type and  the respective forms to 
complete with associated timelines
Contact details for SAE reporting can be found in the investigator trial master file.
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10.4 
Appendix 4: Contraceptive guidance and collection of pregnancy information 
Documentation of non-child-bearing potential must be recorded in the eCRF. 
Definitions 
Female patients in the following categories are considered women of non-childbearing 
potential 
• Premenopausal woman with one or more of the following: 
• Documented total hysterectomy 
• Documented bilateral salpingectomy 
• Documented bilateral oophorectomy 
Note: Documentation can come from the site staff’s review of patient’s medical records, medical 
examination or medical history interview. 
• Postmenopausal woman: 
• A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high FSH level in the postmenopausal range must be used to confirm a 
postmenopausal state in women not using hormonal contraception or hormone replacement 
therapy (HRT). However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient.  
• Females ≥ 60 years of age can be considered postmenopausal. 
Female patients on HRT and whose menopausal status is in doubt are considered of childbearing 
potential.  
Contraception guidance 
There are no contraception requirements in this trial. 
US: For country-specific requirements, please refer to Appendix 9 (Section 10.9). 
Pregnancy testing 
Only women of non-childbearing potential are eligible for inclusion in this trial. 
• Serum hCG pregnancy tests must be performed at the following five site visits for female 
patients who have stopped menstruating within the last 5 years. Criteria applies also if patient 
has prematurely discontinued trial product treatment:  
• Visit 1 (screening) 
• Visit 2 (week 0/randomisation) 
• Visit 7 (week 6) 
• Visit 9 (week 12) 
• Visit 10 (week 19+4 day/end of trial)  
• Serum hCG pregnancy test must be repeated at any time during the trial if pregnancy is 
suspected. 
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• Additional pregnancy testing should be performed during the treatment period, if required 
locally (Germany: For country-specific requirements, please refer to Appendix 9 (Section 10.9). 
Collection of pregnancy information  
Female patients who become pregnant  
Only women of non-childbearing potential are eligible for inclusion in this trial. In the unlikely 
event of a female patient becoming pregnant while participating in the trial, the female patient will 
discontinue IMP and pregnancy information will be collected. 
• Investigator will collect pregnancy information on any female patient who becomes pregnant 
while participating in this trial. 
• Information will be recorded on the appropriate form and submitted to Novo Nordisk within 14 
calendar days of learning of a patient's pregnancy (see Figure 10-2). 
• Patient will be followed to determine the outcome of the pregnancy. The investigator will 
collect follow-up information on patient and neonate which will be forwarded to Novo Nordisk 
within 14 calendar days. Generally, follow-up will not be required for longer than 1 month 
beyond the delivery date. 
• Any termination of pregnancy will be reported, regardless of foetal status (presence or absence 
of anomalies) or indication for procedure. 
• While pregnancy itself is not considered to be an AE or SAE, any adverse event in connection 
with pregnancy or elective termination of a pregnancy for medical reasons will be reported as an 
AE or SAE. If relevant, consider adding ‘gestational’, ‘pregnancy related’ or a similar term 
when reporting the AE/SAE. 
• Pregnancy outcome should be documented in the patient's medical record. Abnormal pregnancy 
outcome (e.g. spontaneous abortion, foetal death, stillbirth, congenital anomalies and ectopic 
pregnancy) is considered an SAE. 
• For abnormal pregnancy outcomes collection of information on the paternal form for male 
partners of female patients require signing of specific informed consent (see Section 10.1.3). 
• Any SAE occurring as a result of a post-trial pregnancy which is considered possibly/probably 
related to the IMP by the investigator will be reported to Novo Nordisk as described in Section 
10.3. While the investigator is not obligated to actively seek this information in former patients, 
he or she may learn of an SAE through spontaneous reporting.  
 
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Figure 10-2 Decision tree for determining the forms to complete with associated timelines for 
pregnancy. 
Maternal form 1b 
  14 calendar days after birth
Maternal form 1a
  14 calendar days
After birth/
termination 
of pregnancy
No additional 
action
Normal outcome 
Maternal form 2   14 calendar days
Paternal form*1   14 calendar days
Abnormal outcome 
Pregnancy 
verified
*1 Further information collected on Paternal form for male partners of 
female subjects requires signing of specific informed consent.
AE/SAEs in connection with the pregnancy and in the foetus/newborn 
should follow the timelines in Figure 10.1.
Prior to 
birth or 
pregnancy 
termination 
For female subjects
 
 
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10.6 
Appendix 6: Retention of human biosamples 
In countries where allowed, the trial will involve collection of human biosamples to be stored in a 
central laboratory facility for future use.  
10.6.1 
Biosamples for future research 
• Patients who do not wish to contribute with biosamples for storage may still participate in 
the trial. 
• Patients must sign and date a separate informed consent form before biosamples are 
collected to be stored for future analysis. 
• The material to be collected is: 
o Genetic analysis (whole blood): visit 2 
o Circulating biomarkers (serum and plasma): visits 2 (two samples), 6, 9 and 10  
• Biosamples will be used to improve the understanding of cardiometabolic disease or related 
diseases, mechanism of action and disease aetiology. Biosamples may also be used to 
identify responders and non-responders to oral NNC0385-0434. The analysis of biosamples 
may include DNA sequencing, epigenetic analysis and other methods in ‘omics’ used to 
characterise the disease. As new knowledge may arise related to cardiometabolic disease 
and/or safety, efficacy or mechanism of action of oral NNC0385-0434 may evolve during or 
after the conduct of the trial, the analyses of the stored biosamples may include biomarkers 
presently not known, which have not been included up-front in the scientific hypotheses of 
this trial. 
• The biosamples will be stored at a central laboratory for up to 15 years after end of trial. 
Only relevant Novo Nordisk staff and consultants, auditors, research organisations or 
laboratories working for Novo Nordisk and biorepository personnel will have access to the 
stored samples and associated data. 
• The biosamples may be transferred to other countries for analysis, if not prohibited by local 
regulations, and will be destroyed at the latest 15 years after end of trial. 
• The patient may request the stored biosamples to be destroyed by withdrawing the 
designated informed consent. The results obtained from any already-performed analyses of 
the samples will still be used. 
• In case the patient withdraws his/her informed consent for the biobank components of the 
trial, the monitor must contact the trial manager at Novo Nordisk as soon as possible in 
order to have the biosamples withdrawn from storage. 
• The patient’s identity will remain confidential and the samples will be identified only by 
subject number, visit number and trial identification number. No direct identification of the 
patient will be stored together with the samples. 
10.6.2 
Immunogenicity samples 
Antibody samples may be retained for later analysis for further characterisation of antibody 
responses towards drug, if required by health authorities or for safety reasons. 
The samples will be stored at Novo Nordisk (or a Novo Nordisk designated referral bio-repository 
with access to the samples). The samples might be transferred to other countries, if not prohibited 
by local regulations. Only Novo Nordisk staff and biorepository personnel (if applicable) will have 
access to the stored samples.  
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Samples will be anonymised (marked and identified only by a unique sample ID, visit number and 
sampling date). Confidentiality and personal data protection will be ensured during storage after the 
end of trial and no direct identification of the patient will be stored together with the samples.  
The potential future assessments may address issues such as unexpected safety events, refinement 
of the PK or anti-drug antibody assessments and to improve the understanding of the mechanism of 
action of NNC0385-0434. As new biomarkers related to the disease and/or safety, efficacy, or 
mechanism of action of NNC0385-0434 may evolve during the conduct of the trial, the analyses of 
the stored biospecimens may also include biomarkers that are unknown at present or have not been 
included in the scientific hypotheses at initiation of the trial. 
In the event that the collected biospecimens (specific whole blood, plasma and serum samples) will 
be used in the future, the investigator will be informed directly by Novo Nordisk about the results if 
the findings are deemed clinically relevant and analytically valid and quantifiable. In such case, a 
written summary of the findings, including listings of patient specific values, will be provided once 
a firm conclusion from the results has been drawn by Novo Nordisk. 
Potential further analyses of the samples will not have any medical consequences for patient and 
their relatives. Patients can contact the investigator if they wish to be informed about results derived 
from stored biosamples obtained from their own body.  
The samples might be transferred to other countries, if not prohibited by local regulations. Only 
Novo Nordisk staff and biorepository personnel will have access to the stored biospecimens. The 
samples will be stored after end of trial and until marketing authorisation approval or until the 
research project terminates, but no longer than 15 years from end of trial after which they will be 
destroyed.  
Remaining blood from the samples already collected may be used for further development of Anti-
NNC0385-0434 antibody assays, and will not be reported in this study. Residual samples may also 
be used to generate reagents for in study validation or control of future assay performance inside or 
outside this study. Selected samples would be pooled, and not be traceable to any individual. 
Pooling would not be done if it prevented retention of sufficient sample material for possible further 
characterisation of antibody responses in this trial. 
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10.7 
Appendix 7: Requirements for maximally tolerated dose of statins and documented 
evidence of intolerance to statins 
There should be no plans at the time of screening and randomization to modify the dose of statin or 
other lipid lowering medication for the duration of the trial. 
Maximally tolerated dose of statins 
Patients must be treated with one of the following highly effective statins at the specified daily 
doses and at a stable dose for at least 30 days prior to screening for the trial: 
• atorvastatin, 40 or 80 milligrams (mg) once a day; 
• rosuvastatin, 20 or 40 mg, once a day; 
• simvastatin 40 mg, once a day or, if a patient has been on that dose for >1 year, 80 mg, once a 
day. 
Combination medications that contain atorvastatin, rosuvastatin, or simvastatin components 
described at the aforementioned doses will be permitted. 
Exceptions to maximally tolerated dose of statins are described below.  
Documented evidence of intolerance to statins (exceptions to background statin treatment) 
The following background statin treatment exceptions are permitted: 
• Lower doses of statins due to partial statin intolerance: Patients may be on a lower dose of 
one of the highly effective statins described above if there is documented intolerance to any one 
of them (atorvastatin, rosuvastatin, or simvastatin) at the aforementioned doses. Intolerance to 
any dose of any statin must be documented as medical history linked to the statin in question as 
documented/reported by the patient in the source documentation and eCRF. 
• Regulatory limitations: Patients may be on a lower dose of one of the highly effective statins 
described above if the highest locally approved dose for one of the stated statins is lower than 
those doses shown above (e.g. in some countries, atorvastatin 20 mg, once a day, is the highest 
locally approved dose). 
• Alternative statins: Patients may be treated with other statins (pravastatin, fluvastatin, 
pitavastatin, or lovastatin), different from the highly effective statins listed above, if there is 
documented intolerance to any two different highly effective statins (atorvastatin, rosuvastatin, 
simvastatin) at the lowest available daily dose for at least one of those highly effective statins. 
Intolerance to any statin must be documented as medical history linked to the statin in question 
as documented/reported by the patient, in the source documentation and eCRF. 
• No background statin therapy: Patients may be enrolled who are only on non-statin lipid 
lowering therapy, if complete statin intolerance has been documented. Patients with complete 
statin intolerance must be unable to tolerate at least two statins: one statin at the lowest available 
daily dose AND another statin at any dose. Intolerance to any statin must be documented as 
medical history linked to the statin in question as documented/reported by the patient, in the 
source documentation and eCRF. The sole exception, for which a patient may participate in the 
study with documentation of intolerance to only one statin, is a documented history of 
rhabdomyolysis attributed to that statin. 
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10.8 
Appendix 8:  Mitigations to ensure patient safety and data integrity during an 
emergency situation  
10.8.1 
Definition and scope of appendix 
A major emergency is defined as a situation that causes substantial restrictions to study site access 
for patients and/or sponsor representatives – i.e. pandemics (COVID-19) or natural disasters such as 
hurricanes, floods and large-scale fires.  
In case local restrictions due to a major emergency as described above leading to lock-down of a 
site, the site must contact Novo Nordisk to allow for implementation of mitigations mentioned in 
this appendix based on mutual agreement. 
According to local regulation, health authorities and independent ethics committees should be 
notified in case elements of the emergency appendix are activated. 
Table 10-4 indicates the minimum requirements for assessments that should be performed during a 
lock-down, but sites should always try to follow the assessments outlined in the original flowchart 
(Table 1-1) to the extent possible. Implementation of specific mitigations should be based on 
assessment of feasibility at the individual site. 
Sites should comply with local regulations, requirements and/or guidelines if they are issued. 
10.8.2 
Visits 
• Screening (Visit 1) and randomisation/baseline (Visit 2) should always be performed as on-site 
visits. If a site is unable to perform these visits on-site, screening and randomisation of new 
patients at that site should be on hold until on-site visits are possible. 
• Visits (V4, V6, V7, V8, V9, V9A-D, V10) should be performed as on-site visits, if in any way 
possible. If not, assessments can be conducted remotely as home visits and if not possible then 
as video or phone visit to follow up on patient safety. Video or phone visits are not required for 
V9A-D in case these visits cannot be performed as on-site or home visits.  
• If permitted by local regulations, the investigator may engage with a Health Care Professional 
from a third party home health care service provider to perform the home visits. Prior to the 
arrangement, the investigator must obtain the patient’s consent by means of separate and locally 
approved consent form. The third party Health Care Professional must have a licence to practice 
and have received adequate protocol training. 
• If the end of treatment visit (V9) cannot be performed on-site or as home visit within the given 
visit window, the visit window for the assessment can be extended for +/- 1 week.  
• At each visit, the investigator must indicate in the eCRF how the visit was performed and 
specify the reason for the preferred assessment method. 
10.8.3 
Assessments 
• Assessments used for safety or the confirmatory endpoints (i.e., [Lipids, PK samples, blood 
sample for antibody testing, biochemistry and haematology, reporting of adverse events]) 
should be prioritised.  
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• The preferred order for the method of assessment is: on-site, home visit, video, phone. Video or 
phone visits can only be used to assess safety by AE reporting. Specifications regarding how to 
perform these assessments using home visits will be provided by Novo Nordisk or the vendor. 
• Assessments performed as home visits should follow the minimum requirements as shown in 
Table 10-4 if on-site visits are not possible and if deemed feasible for the patient.  
• If the assessments indicated in Table 10-4 cannot be performed as on-site visits or home visits 
they should be performed at the first possible timepoint following the originally scheduled visit 
in agreement with Novo Nordisk.  
10.8.4 
Study intervention 
Alternative dispensing methods of study intervention may be implemented, and details will be 
communicated and documented. The dispensing options will be provided by Novo Nordisk A/S and 
will be based on options and requirements at country level and if permitted by local regulations.  
 
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10.9 
Appendix 9: Country-specific requirements  
Belgium 
• Appendix 1, 10.1.13. Indemnity statement: Novo Nordisk accepts liability in accordance with: 
Law concerning experiments on the human person of 07 May 2004 - Article 29: §1. Even if 
without fault, the sponsor is liable for the damage which the subject and/or his rightful claimants 
sustain, and which shows either a direct or an indirect connection with the trial. 
Germany 
• Section 1.2 and 8.1. Patient's full Date of Birth is not allowed to be collected and must be 
shortened to Year of Birth. 
• Appendix 4, 10.4. Contraception requirements as per Clinical Trial Facilitation Group (CTFG)31  
Japan 
• Section 6.2. Preparation/Handling/Storage/Accountability: The head of the trial site or the 
• trial product storage manager assigned by the head of the trial site (a pharmacist in 
• principle) is responsible for control and accountability of the trial products. 
• Appendix 1, 10.1.1: Regulatory and ethical considerations: A name or a seal is accepted as a 
signature. 
The Netherlands 
• Section 1.2 and 8.1. Patient's full Date of Birth is not allowed to be collected and must be 
shortened to Year of Birth. 
United States of America 
• Section 10.1.10: Retention of clinical trial documentation: 21 CFR 312.62(c) and 21 CFR 
812.140(d) require 2 years following the date a marketing application is approved for the drug 
for the indication for which it is being investigated; or, if no application is to be filed or if the 
application is not approved for such indication, until 2 years after the investigation is 
discontinued and FDA is notified.  
• Section 10.4: Male patients in the trial with partners of childbearing potential should use 
condoms during treatment and until 53 days after the last dose of the trial product. 
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10.10 Appendix 10: Abbreviations  
AE 
adverse event 
AIC 
akaike information criterion 
ANCOVA 
analysis of covariance 
ASCVD 
atherosclerotic cardiovascular disease 
AUC 
area under the curve 
CI 
confidence interval 
CFR 
Code of Federal Regulations 
CKD 
moderate chronic kidney disease  
CT 
computed tomography 
CTR 
clinical trial report  
CV 
cardiovascular 
DFU 
directions for use  
DNA 
Deoxyribonucleic acid 
DUN 
dispensing unit number 
EAS 
European Atherosclerosis Society 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EGF-A 
epidermal growth factor-like repeat A 
eGFR 
estimated Glomerular Filtration Rate 
EMA 
European Medicines Agency 
ESC 
European Society of Cardiology 
EU 
European 
FAS 
full analysis set 
FDA 
U.S. Food and Drug Administration 
FDAAA 
U.S. Food and Drug Administration Amendments Act 
FHD 
first human dose  
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
HDL 
high density lipoprotein  
HDPE 
high density polyethylene 
HRT 
hormone replacement therapy 
ICH 
International Council for Harmonisation 
ICMJE 
International Committee of Medical Journal Editors  
IEC 
independent ethics committee 
IMP 
investigational medicinal product 
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IRB 
institutional review board 
IWRS 
interactive web response system 
LAR 
legally acceptable representative 
LDL-C 
low-density lipoprotein-cholesterol 
LPFT 
last patient first treatment 
LPLV 
last patient last visit 
MAR 
missing at random  
MR 
magnetic resonance 
NOAEL 
no-observed-adverse-effect level 
NYHA 
New York Heart Association  
PCD 
primary completion date  
PCSK9 
proprotein convertase subtilisin/kexin type 9  
PD 
pharmacodynamics 
PK 
pharmacokinetics 
PYE 
patient years of exposure 
PYO 
patient years of observation  
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAS 
safety analysis set 
s.c. 
subcutaneous 
SD 
standard deviation 
SNAC 
Salcaprozate sodium 
SUSAR 
suspected unexpected serious adverse reaction 
TBI 
toe-brachial index  
TMM 
trial materials manual  
UNL 
upper normal limit 
VLDL 
very low density lipoprotein  
 
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10.11 Appendix 11: Protocol amendment history 
The protocol amendment summary of changes in table for the current protocol version is located 
directly before the table of contents. 
Protocol version 2.0 (29 April 2021), global 
This amendment is considered to be non-substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union, because 
it neither significantly impacts the safety nor physical/mental integrity of participants nor the 
scientific value of the study. 
Overall rationale for preparing protocol, version 2.0: 
Section # and name 
Description of change 
Brief rationale 
Section 1.2 Flowchart 
Errors in flowchart  
(misplaced and missing assessments 
have been corrected) 
To align protocol text and flowchart 
Section 6.1 Treatments administered 
Incomplete protocol text description 
To align protocol text and flowchart 
Section 8.3.3 Vital signs 
Wording has been slightly changed 
To clarfiy text 
 
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11 References 
1. 
World Health Organization. Global atlas on cardiovascular disease prevention and control. 
2011. 
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Ference BA, Ginsberg HN, Graham I, Ray KK, Packard CJ, Bruckert E, et al. Low-density 
lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, 
epidemiologic, and clinical studies. A consensus statement from the European 
Atherosclerosis Society Consensus Panel. Eur Heart J. 2017;38(32):2459-72. 
3. 
Silverman MG, Ference BA, Im K, Wiviott SD, Giugliano RP, Grundy SM, et al. 
Association Between Lowering LDL-C and Cardiovascular Risk Reduction Among 
Different Therapeutic Interventions: A Systematic Review and Meta-analysis. JAMA. 
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4. 
Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, et al. 2018 
AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline 
on the Management of Blood Cholesterol: Executive Summary: A Report of the American 
College of Cardiology/American Heart Association Task Force on Clinical Practice 
Guidelines. J Am Coll Cardiol. 2018. 
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Mach F, Baigent C, Catapano AL, Koskinas KC, Casula M, Badimon L, et al. 2019 
ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce 
cardiovascular risk. Eur Heart J. 2019. 
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Kinoshita M, Yokote K, Arai H, Iida M, Ishigaki Y, Ishibashi S, et al. Japan Atherosclerosis 
Society (JAS) Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 2017. J 
Atheroscler Thromb. 2018;25(9):846-984. 
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Jones PH, Nair R, Thakker KM. Prevalence of dyslipidemia and lipid goal attainment in 
statin-treated subjects from 3 data sources: a retrospective analysis. J Am Heart Assoc. 
2012;1(6):e001800. 
8. 
Allahyari A, Jernberg T, Hagström E, Leosdottir M, Lundman P, Ueda P. Application of the 
2019 ESC/EAS dyslipidaemia guidelines to nationwide data of patients with a recent 
myocardial infarction: a simulation study. Eur Heart J. 2020;41(40):3900-9. 
9. 
Amgen. REPATHA® (evolocumab), US Prescribing Information (PI). Mar 2015 2015. 
10. 
Sanofi. PraluentTM (alirocumab), US Prescribing Information (PI). Jun 2015. 
11. 
Amgen Europe B.V. Repatha, Summary of Product Characteristics. 
12. 
Sanofi. Praluent (alirocumab), EU Summary of Product Characteristics (SmPC). 12 Nov 
2020 2015. 
13. 
Brown MS, Goldstein JL. A receptor-mediated pathway for cholesterol homeostasis. 
Science. 1986;232(4746):34-47. 
14. 
Kwon HJ, Lagace TA, McNutt MC, Horton JD, Deisenhofer J. Molecular basis for LDL 
receptor recognition by PCSK9. Proc Natl Acad Sci U S A. 2008;105(6):1820-5. 
15. 
Park SW, Moon YA, Horton JD. Post-transcriptional regulation of low density lipoprotein 
receptor protein by proprotein convertase subtilisin/kexin type 9a in mouse liver. J Biol 
Chem. 2004;279(48):50630-8. 
16. 
Sabatine MS. PCSK9 inhibitors: clinical evidence and implementation. Nat Rev Cardiol. 
2019;16(3):155-65. 
17. 
Novartis. Leqvio (inclisiran), EU Summary of Product Characteristics (SmPC). 2020. 
18. 
NovoNordisk A/S. Investigator's Brochure, NNC0385-0434, NN6435, (edition 1). 19 Mar 
2021. 
19. 
Amgen Europe B.V. Repatha, Summary of Product Characteristics. 18 Aug 2020. 
20. 
Amgen. REPATHA® (evolocumab), US Prescribing Information (PI). Feb 2019. 
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21. 
Robinson JG, Farnier M, Krempf M, Bergeron J, Luc G, Averna M, et al. Efficacy and 
safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med. 
2015;372(16):1489-99. 
22. 
Blom DJ, Hala T, Bolognese M, Lillestol MJ, Toth PD, Burgess L, et al. A 52-week 
placebo-controlled trial of evolocumab in hyperlipidemia. N Engl J Med. 
2014;370(19):1809-19. 
23. 
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. 
24. 
ICH Harmonised Tripartite Guideline. Guideline for Good Clinical Practice E6(R2), Step 4 
version. 09 Nov 2016. 
25. 
De Angelis C, Drazen JM, Frizelle FA, Haug C, Hoey J, Horton R, et al. Clinical trial 
registration: a statement from the International Committee of Medical Journal Editors. N 
Engl J Med. 2004;351(12):1250-1. 
26. 
U.S. Department of Health and Human Services, Food and Drug Administration. Food and 
Drug Administration Amendments Act of 2007 as amended by the Final Rule "Clinical 
Trials Registration and Results Information Submission". 21 September 2016. 
27. 
The European Parliament and the Council of the European Council. Directive 2001/20/EC 
of the European Parliament and of the Council of 4 April 2001 on the approximation of the 
laws, regulations and administrative provisions of the member states relating to the 
implementation of good clinical practice in the conduct of clinical trials on medicinal 
products for human use. 2001. 
28. 
The European Parliament and the Council of the European Council. Regulation (EC) No 
726/2004 of the European Parliament and of the Council of 31 March 2004 laying down 
Community procedures for the authorisation and supervision of medicinal products for 
human and veterinary use and establishing a European Medicines Agency, article 57. 30 
April 2004. 
29. 
The European Parliament and the Council of the European Council. Regulation (EC) No 
1901/2006 of the European Parliament and of the Council of 12 December 2006 on 
medicinal products for paediatric use and amending Regulation (EEC) No 1768/92, 
Directive 2001/20/EC, Directive 2001/83/EC and Regulation (EC) No 726/2004, article 41. 
Official Journal of the European Communities. 27 Dec 2006. 
30. 
International Committee of Medical Journal Editors. Recommendations for the Conduct, 
Reporting, Editing and Publication of Scholarly Work in Medical Journals; current version 
available at www.icmje.org. 
31. 
Clinical Trial Facilitation Group (CTFG), Heads of Medicines Agencies. Recommendations 
related to contraception and pregnancy testing in clinical trials. 15 Sep 2014. 
 
 
 
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16.1.01 
Protocol Attachment 
 
Protocol Attachment I is located in the Trial Master File. 
If applicable, Protocol Attachment II is also located in the Trial Master File. 
Content: Global key staff and Country key staff. 
Date:
Novo Nordisk
Version:
Status:
NNC0385 0434
Trial ID: NN6435 4697
Clinical Trial Report
Appendix 16.1.1
12 September 2022
1.0
Final
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