Conditions: Safety Tolerability
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 97
Healthy volunteers: yes

Brief summary:
This is a First in Human (FIH), double-blind, randomised, placebo-controlled study designed to evaluate safety, tolerability and pharmacokinetics (PK) of single and multiple ascending oral doses of AM1476 in healthy subjects.

Detailed description:
Part A (SAD); In the SAD part of the study, single oral doses of AM1476 will be administered in up to 9 sequential groups, each consisting of 8 subjects randomised to receive either AM1476 or placebo in a 3:1 ratio. The first 2 subjects in each group will be dosed in a sentinel fashion, 1 subject will receive AM1476 and the other will receive placebo as randomised.

Part B (MAD); The MAD part of the study will explore multiple ascending dosing of AM1476 for 10 days. AM1476 will be administered in up to 6 sequential groups, each consisting of 8 subjects randomised to receive either AM1476 or placebo in a 3:1 ratio.

Arms:
arm 1: Part A, Group 1: AM1476 1 mg capsule, orally once on Day 1 in fasted state arm 2: Part A, Group 2: AM1476 5 mg capsule, orally once on Days 1 in fasted state arm 3: Part A, Group 3: AM1476 25 mg capsule, orally once on Days 1 in fasted state arm 4: Part A, Group 4: AM1476 125 mg capsule, orally once on Days 1 in fasted state arm 5: Part A, Group 5: AM1476 375 mg capsule, orally once on Days 1 in fasted state arm 6: Part A, Group 6: AM1476 650 mg capsule, orally once on Days 1 in fasted state arm 7: Part A, Group 7: AM1476 950 mg capsule, orally once on Days 1 in fasted state arm 8: Part A, Group 8: AM1476 1500 mg capsule, orally once on Days 1 in fasted state arm 9: Part A, Group 9: AM1476 2400 mg capsule, orally once on Days 1 in fasted state arm 10: Part A, Groups 1 to 9: AM1476 placebo-matching capsule, orally once on Days 1 in fasted state arm 11: Part B, Group 1: AM1476 100 mg capsule, orally once on Days 1-10 in fasted state arm 12: Part B, Group 2: AM1476 375 mg capsule, orally twice on Days 1-9 and once on Days 10 in fasted state arm 13: Part B, Group 3: AM1476 500 mg capsule, orally twice on Days 1-9 and once on Days 10 in fasted state arm 14: Part B, Groups 1 to 3: AM1476 placebo-matching capsule, orally once or twice on Days 1-10 in fasted state

Interventions: intervention 1: AM1476 intervention 2: Placebo
Intervention descriptions: intervention 1: AM1476 Capsules intervention 2: Placebo Capsules

Protocol document:
Prot_000.pdf: 
 
 
 
Protocol 
AM1476 - A Phase I, Double-blind, Placebo-controlled, Single- and 
Multiple-oral Dose, Safety, Tolerability, and Pharmacokinetic Study in 
Healthy Subjects 
Protocol Status: Final 
Protocol Date: 06 January 2021 
Protocol Version: 5 
 
Investigational Medicinal Product: AM1476 
 
 
Protocol Reference Number: 1476-291-001 
Covance Study Number: 8417263 
EudraCT Number: 2019-004800-37 
 
 
Sponsor: 
AnaMar AB 
Medicon Village 
Scheeletorget 1 
SE-223 81 Lund 
Sweden 
Study Site: 
Covance Clinical Research Unit (CRU) Ltd. 
Springfield House 
Hyde Street 
Leeds, LS2 9LH 
United Kingdom 
 
 
Sponsor Signatory: 
 
Principal Investigator: 
 
 
 
Information described herein is confidential and may be disclosed only with the express 
written permission of the Sponsor. 










Protocol 
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Protocol Reference: 1476-291-001 
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SYNOPSIS 
Study Title 
AM1476 - A Phase I, Double-blind, Placebo-controlled, Single- and Multiple-oral Dose, 
Safety, Tolerability, and Pharmacokinetic Study in Healthy Subjects 
Objectives 
The primary objective of the study is: 
• to determine the safety and tolerability of single- and multiple-oral doses of 
AM1476 in healthy subjects. 
The secondary objectives of the study are: 
• to determine the single- and multiple-oral dose pharmacokinetics (PK) of 
AM1476 in healthy subjects. 
• to determine the effect of food on the single oral dose PK of AM1476 in healthy 
subjects. 
Study Design 
This will be a double-blind, randomised, placebo-controlled, single- and multiple-oral dose 
study conducted in 2 parts. 
Part A will comprise a single-ascending dose, sequential-group design incorporating a 
single-group, 2-period crossover arm incorporating a food-effect evaluation. 
Overall, 48 subjects will be studied in 6 groups (Groups A1 to A6), with each group 
consisting of 8 subjects. 
Each subject will participate in 1 treatment period only, except for Group A3, where each 
subject will participate in 2 treatment periods separated by a minimum of 6 days. Subjects 
will reside at the Clinical Research Unit (CRU) from Day -1 (the day before dosing) to Day 3 
of each treatment period, as applicable. All subjects will return for a Follow-up visit 7 to 
10 days after their final dose. 
In each of Groups A1 to A6, 6 subjects will receive AM1476 and 2 subjects will receive 
placebo. In Groups A1, A2, and A4 to A6, all doses will be administered in the fasted state in 
accordance with a randomisation schedule on the morning of Day 1. For Group A3, 
Treatment Period 1, Day 1 doses will be administered in the fasted state in accordance with a 
randomisation schedule and Treatment Period 2, Day 1 doses will be given 30 minutes after 
starting a standard high-fat breakfast. Each subject in Groups A1, A2, and A4 to A6 will 
receive only a single dose of AM1476 or placebo during the study. In Group A3, subjects will 
have the same treatment in both periods, such that each subject will receive 2 single doses of 
AM1476 or placebo during the study. Although a food-effect evaluation is planned to occur 
in Group A3, this may be subject to change depending upon ongoing review of the PK data. 


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All groups in Part A will be divided into 2 cohorts, with each cohort being dosed at least 
24 hours apart. The first cohort will comprise 2 subjects, with 1 subject receiving AM1476 
and 1 subject receiving placebo. The second cohort will comprise 6 subjects, with 5 subjects 
receiving AM1476 and 1 subject receiving placebo. For groups participating in a food-effect 
evaluation, sentinel dosing will only be utilised in Treatment Period 1 when AM1476 or 
placebo are administered in the fasted state. Dosing of subjects in the second cohort will not 
continue if any of the dose escalation stopping criteria are met by the sentinel subjects (first 
cohort). 
There will be a minimum of 6 days between dose escalations for each group. 
Part B will comprise a multiple-ascending dose, sequential-group design. Overall, 
24 subjects will be studied in 3 groups (Groups B1 to B3), with each group consisting of 
8 subjects. Part B may start following review of the safety and tolerability and PK data for 
Group A4, at a dose equal or less than given in Groups A1 to A4, but cannot be equal to a 
dose level from Part A if that dose met any of the dose escalation stopping rules. 
Each subject will participate in 1 treatment period only and reside at the CRU from Day -1 
until the morning of Day 12. All subjects will return for a Follow-up visit 7 to 10 days after 
their final dose. 
In each of Groups B1 to B3, 6 subjects will receive AM1476 and 2 subjects will receive 
placebo. The dietary state for dosing in Part B will be subject to review of the PK data from 
the fed/fasted comparison in Part A. For all subjects, dosing is planned to be once daily (QD) 
on Days 1 to 10, inclusive. However, the dietary state (including fasting requirement and 
meal compositions), dosing duration, and dosing frequency may be changed following review 
of safety, tolerability, and PK data from Part A or earlier groups in Part B. The dose regimen 
will comprise no less than once every 2 days and will not exceed twice daily (BID) dosing. 
The total daily dose administered will not exceed an exposure shown to be safe and 
well-tolerated in Part A. The dosing duration will comprise no fewer than 7 consecutive days 
and will not exceed 28 consecutive days. There will be a minimum of 6 days between dose 
escalations for each group. 
Number of Subjects 
Part A: 48 subjects will be studied in 6 groups (Groups A1 to A6). 
Part B: 24 subjects will be studied in 3 groups (Groups B1 to B3). 
Additional groups: following review of the safety, tolerability, and PK data, additional dose 
groups (where systemic exposure is not expected to exceed that stated in the dose escalation 
stopping criteria) may be added to the study. There will be no further dose escalation in these 
additional groups if dose escalation stopping criteria have been met and a dose level cannot 
be repeated if it previously met a stopping criterion. Up to 3 further groups of 8 subjects 
(6 active:2 placebo) may be included in each of Parts A and B. 
Diagnosis and Main Criteria for Inclusion 
Healthy male and female subjects aged between 18 and 60 years (inclusive) with a body mass 
index (BMI) between 18.0 and 32.0 kg/m2 (inclusive). 


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Investigational Medicinal Products, Dose, and Mode of Administration 
Proposed dose levels for Part A: 1 mg for Group A1; subsequent dose levels are to be 
determined following satisfactory review by the Sponsor and Investigator of the safety and 
tolerability data (up to 48 hours post-final dose) and plasma PK data (up to 24 hours 
post-final dose [ie, Day 1 in Part A and Day 10 in Part B]) from the lower dose levels. 
Proposed dose levels for Part B: the dose levels, dosing frequency, and dosing duration for 
Part B will be decided, in consultation with the Sponsor, on the basis of data from Part A of 
the study or earlier groups in Part B. The total daily exposure of AM1476 administered 
during this part of the study will be planned to not exceed an exposure shown to be safe and 
well-tolerated in Part A. 
Administration route: oral. 
Reference Product and Mode of Administration 
Reference product: placebo capsules. 
Administration route: oral. 
Duration of Subject Participation in the Study 
Part A 
Planned Screening duration: approximately 4 weeks (approximately 5 weeks for Group A1). 
Planned study duration (Screening to Follow-up): approximately 6 weeks for subjects not 
participating in the food-effect evaluation (approximately 7 weeks for Group A1) and 
approximately 7 weeks for those participating in the food-effect evaluation. 
Part B 
Planned Screening duration: approximately 4 weeks. 
Planned study duration (Screening to Follow-up): approximately 7 weeks. 
Endpoints 
Safety: 
Adverse events (AEs), clinical laboratory evaluations (clinical chemistry, haematology, 
coagulation, and urinalysis), vital signs measurements, 12-lead electrocardiograms (ECGs), 
telemetry, neurological examinations, Columbia-Suicide Severity Rating Scale (C-SSRS), 
and physical examinations. 
Pharmacokinetics: 
Blood and urine samples for the analysis of plasma and urinary concentrations of AM1476. 
Pharmacokinetic parameters will be derived by non-compartmental analysis. 
In Part A, the PK parameters will include area under the plasma concentration-time curve 
from time zero to infinity (AUC0-∞), area under the plasma concentration-time curve from 


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time zero to the time of the last quantifiable concentration (AUC0-tlast), maximum observed 
plasma concentration (Cmax), time of the maximum observed plasma concentration (tmax), 
apparent plasma terminal elimination half-life (t½), apparent total plasma clearance (CL/F), 
apparent volume of distribution (Vz/F), renal clearance (CLR), amount of drug excreted in the 
urine (Ae), and percentage of dose excreted unchanged in urine (Fe). 
In Part B, the PK parameters will include: area under the plasma concentration-time curve 
over a dosing interval (AUC0-τ), AUC0-∞ (Day 1 only), Cmax, minimum observed plasma 
concentration (Cmin), tmax, t½, CL/F, Vz/F, observed accumulation ratio based on AUC0-τ 
(RAAUC0-τ), and observed accumulation ratio based on Cmax (RACmax), CLR, Ae, and Fe. 
Other PK parameters may also be reported. 
Statistical Methods 
Safety: 
Safety parameters will be listed and summarised using descriptive statistics. No formal 
statistical analysis of safety data is planned. 
Pharmacokinetics: 
Individual plasma and urine concentrations of AM1476 and plasma and urine PK parameters 
will be listed and summarised using descriptive statistics. Individual and mean AM1476 
concentration-time profiles will be presented graphically. 
In Part A, where data are available, AM1476 dose proportionality will be examined across 
the dose groups. The PK parameters will be analysed for dose proportionality using a power 
model approach or analysis of variance (ANOVA) model as appropriate. Where data are 
available, the effect of food at 1 dose level in Part A will be investigated using ANOVA. 
In Part B, AUC0-τ and Cmax on Day 10 will be analysed for dose proportionality using a power 
model approach or ANOVA model as appropriate. 
To investigate the effect of food on the PK of AM1476, the log-transformed AUC0-∞, 
AUC0-tlast, and Cmax values for AM1476 administered with and without food will be analysed 
using a linear mixed-effects model with treatment as fixed effect and subject as a random 
effect. Point estimates and 90% confidence intervals (CIs) for differences between the 
treatments (fed versus fasted) on the log scale will be exponentiated to obtain estimates for 
the ratios of geometric means and respective 90% CIs on the original scale. 


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TABLE OF CONTENTS 
TITLE PAGE .............................................................................................................................1 
SPONSOR APPROVAL ...........................................................................................................2 
INVESTIGATOR AGREEMENT.............................................................................................3 
STUDY IDENTIFICATION .....................................................................................................4 
SYNOPSIS .................................................................................................................................6 
TABLE OF CONTENTS .........................................................................................................10 
LIST OF TABLES AND FIGURES........................................................................................12 
LIST OF ABBREVIATIONS ..................................................................................................13 
1. 
INTRODUCTION ...........................................................................................................16 
1.1. 
Overview ................................................................................................................16 
1.2. 
Summary of Non-clinical Pharmacology ...............................................................16 
1.3. 
Summary of Safety Pharmacology ........................................................................17 
1.4. 
Summary of Genotoxicology .................................................................................17 
1.5. 
Summary of Development and Reproductive Toxicity .........................................17 
1.6. 
Summary of Toxicology ........................................................................................18 
1.6.1. 
28-day Oral Toxicity Study with a 4- or 6-week Recovery Period in 
Mice (GLP Study) ...................................................................................18 
1.6.2. 
13-Week Oral Toxicity Study in Mice (GLP Study) ...................................19 
1.6.3. 
28-day Oral Toxicity Study with a 4-week Recovery Period in Dogs 
(GLP Study) ............................................................................................19 
1.6.4. 
13-Week Oral Toxicity Study in Dogs (GLP Study) ...................................19 
1.7. 
Summary of Non-clinical Pharmacokinetics .........................................................20 
 
 
 
 
1.8. 
Summary of Clinical Experience ...........................................................................24 
1.9. 
Study Rationale ......................................................................................................24 
1.10. 
Benefit-risk Assessment .........................................................................................24 
2. 
OBJECTIVES AND ENDPOINTS .................................................................................25 
2.1. 
Objectives ..............................................................................................................25 
2.2. 
Endpoints ...............................................................................................................25 
2.2.1. 
Primary Endpoints .......................................................................................25 
2.2.2. 
Secondary Endpoints ...................................................................................25 
3. 
INVESTIGATIONAL PLAN ..........................................................................................26 
3.1. 
Overall Study Design and Plan ..............................................................................26 
3.1.1. 
Part A ...........................................................................................................26 
3.1.2. 
Part B ...........................................................................................................28 
3.2. 
Study Start and End of Study Definitions ..............................................................30 
3.3. 
Additional Groups ..................................................................................................30 
3.4. 
Discussion of Study Design, Including the Choice of Control Groups .................30 


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3.4.1. 
Dose Interval ................................................................................................31 
3.5. 
Selection of Doses in the Study .............................................................................31 
3.5.1. 
Starting Dose of 1 mg ..................................................................................31 
3.5.2. 
Maximum Dose ............................................................................................33 
3.6. 
Dose Escalation ......................................................................................................35 
3.7. 
Dose Escalation Stopping Criteria .........................................................................36 
4. 
SELECTION OF STUDY POPULATION .....................................................................37 
4.1. 
Inclusion Criteria ...................................................................................................37 
4.2. 
Exclusion Criteria ..................................................................................................37 
4.3. 
Rescreening of Subjects .........................................................................................39 
4.4. 
Subject Number and Identification ........................................................................39 
4.5. 
Subject Withdrawal and Replacement ...................................................................40 
4.6. 
Study Termination .................................................................................................41 
5. 
STUDY TREATMENTS .................................................................................................41 
5.1. 
Description, Storage, Packaging, and Labelling ....................................................41 
5.2. 
Study Treatment Administration ............................................................................41 
5.3. 
Randomisation .......................................................................................................42 
5.4. 
Blinding..................................................................................................................42 
5.5. 
Treatment Compliance ...........................................................................................42 
5.6. 
Drug Accountability...............................................................................................43 
6. 
CONCOMITANT THERAPIES AND OTHER RESTRICTIONS ................................43 
6.1. 
Concomitant Therapies ..........................................................................................43 
6.2. 
Diet .........................................................................................................................43 
6.3. 
Smoking .................................................................................................................44 
6.4. 
Exercise ..................................................................................................................44 
6.5. 
Blood Donation ......................................................................................................44 
6.6. 
Exposure to Ultraviolet Light ................................................................................45 
7. 
STUDY ASSESSMENTS AND PROCEDURES ...........................................................45 
7.1. 
Pharmacokinetic Assessments ...............................................................................45 
7.1.1. 
Sample Collection and Processing ...............................................................45 
7.1.2. 
Analytical Methodology ..............................................................................46 
7.2. 
Safety and Tolerability Assessments .....................................................................46 
7.2.1. 
Adverse Events ............................................................................................46 
7.2.2. 
Clinical Laboratory Evaluations ..................................................................46 
7.2.3. 
Vital Signs ....................................................................................................47 
7.2.4. 
Electrocardiograms ......................................................................................47 
7.2.5. 
Physical Examination...................................................................................48 
7.2.6. 
Neurological Examination ...........................................................................48 
7.2.7. 
Columbia-Suicide Severity Rating Scale .....................................................48 
7.2.8. 
Body Weight ................................................................................................48 


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8. 
SAMPLE SIZE AND DATA ANALYSIS ......................................................................49 
8.1. 
Determination of Sample Size ...............................................................................49 
8.2. 
Analysis Populations ..............................................................................................49 
8.2.1. 
Pharmacokinetic Population ........................................................................49 
8.2.2. 
Safety Population .........................................................................................49 
8.3. 
Pharmacokinetic Analyses .....................................................................................49 
8.4. 
Safety Analysis ......................................................................................................50 
8.5. 
Interim Analysis .....................................................................................................50 
9. 
REFERENCES ................................................................................................................50 
10. APPENDICES .................................................................................................................52 
Appendix 1: Adverse Event Reporting ........................................................................53 
Appendix 2: Clinical Laboratory Evaluations .............................................................56 
Appendix 3: Total Blood Volume ................................................................................57 
Appendix 4: Contraception Guidance ..........................................................................59 
Appendix 5: Regulatory, Ethical, and Study Oversight Considerations ......................62 
Appendix 6: Schedule of Assessments – Part A (Single-dose, Incorporating a 
Food-effect Evaluation) ..........................................................................65 
Appendix 7: Schedule of Assessments – Part B (Multiple-dose) ................................68 
Appendix 8: Summary of Amended Protocol Changes ...............................................72 
 
LIST OF TABLES AND FIGURES 
Table 1: 
Pharmacokinetic Parameters of AM1476 in Mice .....................................21 
Table 2: 
Pharmacokinetic Parameters of AM1476 in Dogs .....................................23 
Table 3: 
Predicted Inhibition of the 5-HT2B Receptor at a Single Dose of 1 mg 
AM1476 ....................................................................................................32 
Table 4: 
Safety Margins for the Starting Dose of 1 mg Dose AM1476 Based on 
the Estimated Exposure for the Relevant Non-clinical Findings ..............33 
Table 5: 
Safety Margins for Maximum Permitted Exposure Based on the 
Estimated Exposure for the Relevant Non-clinical Findings ....................34 
Table 6: 
Proposed Investigational Medicinal Product Dose Levels for Parts A 
and B .........................................................................................................35 
Table 7: 
High-fat Breakfast Content ........................................................................44 
 
Figure 1: 
Study Schematic (Part A) for Groups A1, A2, and A4 to A6 ....................28 
Figure 2: 
Study Schematic (Part A) for Food-effect Evaluation(s) ...........................28 
Figure 3: 
Planned Dose Levels (Part A) ....................................................................28 
Figure 4: 
Study Schematic (Part B) ...........................................................................29 
Figure 5: 
Planned Dose Levels (Part B) ....................................................................30 
 


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LIST OF ABBREVIATIONS 
Abbreviation Definition 
5-HT 
5-hydroxytryptamine 
5-HT2B 
5-hydroxytryptamine receptor 2B 
Ae 
amount of drug excreted in the urine 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANOVA 
analysis of variance 
API 
active pharmaceutical ingredient 
AST 
aspartate aminotransferase 
AUC0-24 
area under the plasma concentration-time curve from time zero to 24 hours 
postdose 
AUC0-∞ 
area under the plasma concentration-time curve from time zero to infinity 
AUC0-tlast 
area under the plasma concentration-time curve from time zero to the time 
of the last quantifiable concentration 
AUC0-τ 
area under the plasma concentration-time curve over a dosing interval 
BID 
twice daily 
BMI 
body mass index 
bpm 
beats per minute 
CFR 
Code of Federal Regulations 
cGvHD 
chronic graft versus host disease 
CI 
confidence interval 
CIOMS 
Council for International Organizations of Medical Sciences 
CL/F 
apparent total plasma clearance 
CLR 
renal clearance 
Cmax 
maximum observed plasma concentration 
Cmin 
minimum observed plasma concentration 
CRO 
Contract Research Organisation 
CRU 
Clinical Research Unit 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
 
 
DSS 
Drug Safety Services 
EC 
Ethics Committee 
ECG 
electrocardiography/electrocardiogram 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
Fe 
percentage of drug excreted in the urine 
FSH 
follicle-stimulating hormone 


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GCP 
Good Clinical Practice 
 
 
GGT 
gamma-glutamyl transferase 
GLP 
Good Laboratory Practice 
GMP 
Good Manufacturing Practice 
HED 
human equivalent dose 
hERG 
human-ether-à-go-go-related gene 
HIV 
human immunodeficiency virus 
IB 
Investigator’s Brochure 
IC50 
half maximal inhibitory concentration 
ICF 
Informed Consent Form 
ICH 
International Council for/Conference on Harmonisation 
IMP 
investigational medicinal product 
IUD 
intrauterine device 
 
 
N 
number of subjects 
NA 
not applicable 
NC 
not calculated 
NOAEL 
no-observed-adverse-effect level 
 
 
NR 
not reported 
PBPK 
physiologically based pharmacokinetic 
 
 
PK 
pharmacokinetic(s) 
 
 
pSmad3 
phosphorylated Smad3 
QD 
once daily 
QTc 
QT interval corrected for heart rate 
QTcF 
QT interval corrected for heart rate using Fridericia’s method 
RAAUC0-τ 
observed accumulation ratio based on AUC0-τ 
RACmax 
observed accumulation ratio based on Cmax 
RBC 
red blood cell 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SMF 
Site Master File 
SSc 
systemic sclerosis 
t½ 
apparent plasma terminal elimination half-life 
TBD 
to be determined 
TGF 
transforming growth factor 
tmax 
time of the maximum observed plasma concentration 


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TMF 
Trial Master File 
TSE 
Transmissible Spongiform Encephalopathy 
Tsk-1 
tight-skin-1 
ULN 
upper limit of normal 
Vz/F 
apparent volume of distribution 
WBC 
white blood cell 
 
 


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1. INTRODUCTION 
1.1. 
Overview 
AM1476 is a 5-hydroxytryptamine receptor 2B (5-HT2B) antagonist being developed by 
AnaMar AB for the treatment of systemic sclerosis. Peripheral 5-HT2B receptors have been 
suggested to play a significant role in fibrosis, with the receptor being upregulated in fibrotic 
tissues. Activation of the 5-HT2B receptor leads to increased production of profibrotic 
mediators, modifying cell differentiation leading to excessive extracellular matrix synthesis 
and eventually fibrosis.1–3 
Due to the high number of affected individuals, incomplete knowledge of the fibrotic process 
pathogenesis, the marked heterogeneity in their aetiology and clinical manifestations, the 
absence of appropriate and fully validated biomarkers, and most importantly, the current lack 
of effective disease-modifying therapeutic agents, human fibrotic diseases represent a major 
global health problem. Despite many differences, the fibrotic diseases share the common 
feature of an uncontrolled and progressive accumulation of fibrotic tissue in affected organs 
and numerous studies have identified activated myofibroblasts as the cells ultimately 
responsible for the replacement of normal tissues with non-functional fibrotic tissue. Critical 
signalling cascades, initiated primarily by transforming growth factor (TGF)-β, but also 
involving numerous cytokines and signalling molecules, such as 5-hydroxytryptamine 
(5-HT), which stimulate pro-fibrotic reactions in myofibroblasts, offer potential therapeutic 
targets.4 
Serotonin (5-HT) is well-established scientifically as a stimulator of tissue fibrosis.5 
The 5-HT2B receptor, therefore, represents a promising target for new anti-fibrotic treatments. 
The development of new drugs targeting the 5-HT2B receptor has so far been hampered by 
non-selective compounds with unwanted side effects. New, safe, and selective 5-HT2B 
receptor antagonists are therefore needed. 
1.2. 
Summary of Non-clinical Pharmacology 
AM1476 has been evaluated for 5-HT2B receptor interactions using mouse, rat, and human 
receptors. Both binding (human only) assays and functionality assays have been employed. 
In a chronic graft versus host disease (cGvHD) model of systemic sclerosis (SSc) using minor 
histocompatibility antigen-mismatched syngeneically and allogeneically transplanted mice, 
statistically significant effects on readouts of fibrosis (dermal and pulmonary fibrosis and 
reduced number of cells positive for phosphorylated Smad3 [pSmad3]) were observed 
following oral administration of AM1476 at 1 mg/kg, 10 mg/kg, or 30 mg/kg twice daily 
(BID) or 10 mg/kg once daily (QD). Inflammation-driven manifestations such as weight loss 
or the cutaneous skin score were not significantly affected by treatment. In the tight-skin-1 
(Tsk-1) mouse model, oral administration of 1 mg/kg or 10 mg/kg BID AM1476 or 10 mg 
QD resulted in statistically significant and highly potent amelioration of skin fibrosis and a 
reduced number of cells positive for pSmad3. 


















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2. OBJECTIVES AND ENDPOINTS 
2.1. 
Objectives 
The primary objective of the study is: 
• to determine the safety and tolerability of single and multiple oral doses of 
AM1476 in healthy subjects. 
The secondary objectives of the study are: 
• to determine the single- and multiple-oral dose PK of AM1476 in healthy 
subjects. 
• to determine the effect of food on the single-oral dose PK of AM1476 in healthy 
subjects. 
2.2. 
Endpoints 
2.2.1. 
Primary Endpoints 
The primary safety endpoints for this study are as follows: 
• incidence and severity of AEs 
• incidence of laboratory abnormalities, based on haematology, clinical chemistry, 
coagulation, and urinalysis test results 
• vital signs measurements 
• 12-lead ECG parameters 
• telemetry 
• neurological examinations 
• Columbia-Suicide Severity Rating Scale (C-SSRS) 
• physical examinations. 
2.2.2. 
Secondary Endpoints 
For Part A, the single-ascending dose and food (fed versus fasted dietary status at dosing), 
PK outcome endpoints of AM1476 are as follows: 
• area under the plasma concentration-time curve from time zero to infinity 
(AUC0-∞) 
• area under the plasma concentration-time curve from time zero to the time of the 
last quantifiable concentration (AUC0-tlast) 
• maximum observed plasma concentration (Cmax) 
• time of the maximum observed plasma concentration (tmax) 
• apparent plasma terminal elimination half-life (t½) 


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• apparent total plasma clearance (CL/F) 
• apparent volume of distribution (Vz/F) 
• renal clearance (CLR) 
• amount of drug excreted in the urine (Ae) 
• percentage of drug excreted in the urine (Fe). 
For Part B, the multiple-ascending dose PK outcome endpoints of AM1476 are as follows: 
• area under the plasma concentration-time curve over a dosing interval (AUC0-τ) 
• AUC0-∞ (Day 1 only) 
• Cmax 
• minimum observed plasma concentration (Cmin) 
• tmax 
• t½ 
• CL/F 
• Vz/F 
• observed accumulation ratio based on AUC0-τ (RAAUC0-τ) 
• observed accumulation ratio based on Cmax (RACmax) 
• CLR 
• Ae 
• Fe. 
Other PK parameters may also be reported. 
3. INVESTIGATIONAL PLAN 
3.1. 
Overall Study Design and Plan 
This will be a double-blind, randomised, placebo-controlled, single- and multiple-oral dose 
study conducted in 2 parts. 
3.1.1. 
Part A 
Part A will comprise a single-ascending dose, sequential-group design incorporating a 
single-group, 2-period crossover arm incorporating a food-effect evaluation. Overall, 
48 subjects will be studied in 6 groups (Groups A1 to A6), with each group consisting of 
8 subjects. 
Potential subjects will be screened to assess their eligibility to enter the study within 28 days 
prior to the first dose administration (within 35 days for Group A1). Each subject will 
participate in 1 treatment period only, except for those participating in a food-effect 


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evaluation, where each subject will participate in 2 treatment periods separated by a 
minimum of 6 days. 
Subjects will reside at the Clinical Research Unit (CRU) from Day -1 (the day before dosing) 
to Day 3 of each treatment period, as applicable. All subjects will return for a Follow-up visit 
7 to 10 days after their final dose. 
Based on the ongoing review of the safety, tolerability, and PK results, additional 
non-residential visits may be required. The number of additional visits per subject will not 
exceed 3 per period and will not extend beyond 28 days after each final dosing occasion. 
In each of Groups A1 to A6, 6 subjects will receive AM1476 and 2 subjects will receive 
placebo. 
Groups A1, A2, and A4 to A6 
It is planned for each subject in Groups A1, A2, and A4 to A6 to receive only a single dose of 
AM1476 or placebo during the study. Doses will be administered in the fasted state in 
accordance with a randomisation schedule on the morning of Day 1. 
Group A3 
It is planned for each subject in Group A3 to have the same treatment in both treatment 
period such that each subject will receive 2 single doses of AM1476 or placebo during the 
study. On Day 1 in Treatment Period 1, doses will be administered in the fasted state in 
accordance with a randomisation schedule. On Day 1 in Treatment Period 2, doses will be 
given 30 minutes after starting a standard high-fat breakfast. Although a food-effect 
evaluation is planned to occur in Group A3, this may be subject to change depending upon 
ongoing review of the PK data. 
Additional Groups (Groups A7 to A9) 
If it is decided to enrol additional groups (Section 3.3), the effect of food on the PK of 
AM1476 may further be evaluated as described for Group A3. However, fasting 
requirements, meal compositions, and timing of doses will be determined following review of 
the available PK data. 
Sentinel Dosing 
All groups in Part A will be divided into 2 cohorts, with each cohort being dosed at least 
24 hours apart. The first cohort will comprise 2 subjects, with 1 subject receiving AM1476 
and 1 subject receiving placebo. The second cohort will comprise 6 subjects, with 5 subjects 
receiving AM1476 and 1 subject receiving placebo. For groups participating in a food-effect 
evaluation, sentinel dosing will only be utilised in Treatment Period 1 when AM1476 or 
placebo are administered in the fasted state. Dosing of subjects in the second cohort will not 
continue if any of the dose escalation stopping criteria (Section 3.7) are met by the sentinel 
subjects (first cohort). 
The total duration of study participation for each subject (from Screening through Follow-up 
visit) is anticipated to be approximately 6 weeks for subjects not participating in the 
food-effect evaluation (approximately 7 weeks for Group A1) and approximately 7 weeks for 
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An overview of the study design is shown in Figure 1 and Figure 2, and the planned dose 
levels in Figure 3. A Schedule of Assessments is presented in Appendix 6. 
Figure 1: 
Study Schematic (Part A) for Groups A1, A2, and A4 to A6 
 
Abbreviations: CRU = Clinical Research Unit; N = number of subjects. 
Note: Group A1: Screening period from Day -35 to Day -2 (approximately 5 weeks) 
Figure 2: 
Study Schematic (Part A) for Food-effect Evaluation(s) 
 
Abbreviations: CRU = Clinical Research Unit; N = number of subjects. 
Figure 3: 
Planned Dose Levels (Part A) 
 
Abbreviations: N = number of subjects; PK = pharmacokinetic(s); TBD = to be determined. 
NOTE: dose levels may be adjusted based on the ongoing review of the safety, tolerability, and PK data. Doses will be 
administered in an escalating manner following satisfactory review by the Sponsor and Investigator of the safety and 
tolerability data (up to 48 hours post-final dose) and plasma PK data (up to 24 hours post-final dose [ie, Day 1 in Part A]) 
from the lower dose levels. 
Although the food-effect evaluation is planned to occur in Group A3, this may be subject to change depending upon ongoing 
review of the PK data. 
3.1.2. 
Part B 
Part B will comprise a multiple-ascending dose, sequential-group design. Overall, it is 
planned for 24 subjects to be studied in 3 groups (Groups B1 to B3), with each group 


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consisting of 8 subjects. Part B may start following review of the safety and tolerability and 
PK data for Group A4, at a dose equal or less than given in Groups A1 to A4, provided the 
predicted exposure is not expected to exceed an exposure already shown to be safe and well 
tolerated. The dose level cannot be equal to a dose level from Part A if that dose met any of 
the dose escalation stopping rules. 
Potential subjects will be screened to assess their eligibility to enter the study within 28 days 
prior to the first dose administration. Each subject will participate in 1 treatment period only 
and reside at the CRU from Day -1 until the morning of Day 12. All subjects will return for a 
Follow-up visit 7 to 10 days after their final dose. 
Based on the ongoing review of available safety, tolerability, and PK data, up to 3 additional 
non-residential visits may be required. The number of additional visits per subject will not 
exceed 3 and will not extend beyond 28 days after each final dosing occasion. 
In each of Groups B1 to B3, 6 subjects will receive AM1476 and 2 subjects will receive 
placebo. The dietary state for dosing in Part B will be subject to review of the PK data from 
the fed/fasted comparison in Part A. For all subjects, dosing is planned to be QD on Days 1 to 
10, inclusive. However, the dietary state (including fasting requirement and meal 
compositions), dosing duration, and dosing frequency may be changed following review of 
safety, tolerability, and PK data from Part A or earlier groups in Part B (Section 3.4). The 
dose regimen will comprise no less than once every 2 days and will not exceed BID dosing. 
The predicted total daily exposure at the selected dose administered will not exceed an 
exposure shown to be safe and well-tolerated in Part A. The dosing duration will comprise no 
fewer than 7 consecutive days and will not exceed 28 consecutive days. There will be a 
minimum of 6 days between dose escalations for each group. 
The total duration of study participation for each subject (from Screening through Follow-up 
visit) is anticipated to be approximately 7 weeks. 
An overview of the study design is shown in Figure 4, and the planned dose levels in 
Figure 5. A Schedule of Assessments is presented in Appendix 7. 
Figure 4: 
Study Schematic (Part B) 
 
Abbreviations: BID = twice daily; CRU = Clinical Research Unit; N = number of subjects; QD = once daily. 
a. Dosing is planned to be QD on Days 1 to 10, inclusive. The dosing regimen in Part B may be changed following review 
of data from groups in Part A or earlier groups in Part B. The dose regimen will comprise no less than once every 2 days 
and will not exceed BID dosing. The dosing duration will comprise no fewer than 7 consecutive days and will not exceed 
28 consecutive days. 


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Figure 5: 
Planned Dose Levels (Part B) 
 
Abbreviations: BID = twice daily; N = number of subjects; QD = once daily; TBD = to be determined. 
NOTE: doses will be administered in an escalating manner following satisfactory review by the Sponsor and Investigator of 
the safety and tolerability data (up to 48 hours post-final dose) and plasma PK data (up to 24 hours post-final dose [ie, Day 1 
in Part A and Day 10 in Part B]) from Part A or earlier groups in Part B. 
a. Dosing is planned to be QD on Days 1 to 10, inclusive. The dosing regimen in Part B may be changed following review 
of data from groups in Part A or earlier groups in Part B and will not exceed BID dosing. 
3.2. 
Study Start and End of Study Definitions 
The start of the study is defined as the date the first subject signs an Informed Consent Form 
(ICF). The point of enrolment occurs at the time of subject number allocation. The end of the 
study is defined as the date of the last subject’s last assessment (scheduled or unscheduled). 
3.3. 
Additional Groups 
Following review of the safety, tolerability, and PK data, additional dose groups (where 
systemic exposure is not expected to exceed that stated in the dose escalation stopping criteria 
[Section 3.7]) may be added to the study. There will be no further dose escalation in these 
additional groups if dose escalation stopping criteria have been met and a dose level cannot 
be repeated if it previously met a stopping criterion. Up to 3 further groups of 8 subjects 
(6 active:2 placebo) may be included in each of Parts A and B. The requirement for 
additional groups will be agreed with the Sponsor and documented in the Trial Master File 
(TMF). 
3.4. 
Discussion of Study Design, Including the Choice of Control Groups 
For both parts of the study, a sequential-group, ascending-dose design has been chosen for 
safety reasons as AM1476 is in the early stages of clinical development, with Part A of the 
study being the first time it will be administered to humans. Oral doses have been chosen for 
both parts of the study, as this is the intended clinical route of administration. A 2-period 
crossover design has been chosen for the food-effect arm, as this gives a within-subject 
assessment of the influence of food on the PK of AM1476 and so increases the power of the 
study for the given number of subjects. 
It is the intent of Part B to dose subjects such that steady-state plasma levels of AM1476 are 
achieved and maintained for several days. Based on the available non-clinical data, it is 
expected that this will be achieved following 10 days of QD dosing; however, a full review of 
all the safety, tolerability, and PK data from Part A will be performed to confirm the dose 
regimen for Part B. If the t½ of AM1476 is shorter than predicted by the non-clinical data, 
BID dosing over 7 days may be appropriate. If the t½ of AM1476 is longer than predicted by 
the non-clinical data, QD dosing may be more appropriate over 28 days (as steady-state will 
take longer to achieve). The dose regimen will comprise no less than once every 2 days and 
will not exceed BID dosing. The dosing duration will comprise no fewer than 7 consecutive 
days and will not exceed 28 consecutive days of dosing. 










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Table 6: 
Proposed Investigational Medicinal Product Dose Levels for Parts A 
and B 
Study Part Group 
Subject Numbers 
Treatment Period 1 
Treatment Period 2 
Part A 
A1 
0101 – 0108 
1 mg or placebo 
NA 
A2 
0109 – 0116 
TBD mg or placebo 
NA 
A3a 
0117 – 0124 
TBD mg (fasted) or placebo TBD mg (fed) or placebo 
A4 
0125 – 0132 
TBD mg or placebo 
NA 
A5 
0133 – 0140 
TBD mg or placebo 
NA 
A6 
0141 – 0148 
TBD mg or placebo 
NA 
A7b 
0149 – 0156 
TBD 
TBD 
A8b 
0157 – 0164 
TBD 
TBD 
A9b 
0165 – 0172 
TBD 
TBD 
Part B 
B1 
0201 – 0208 
TBD mg or placebo 
NA 
B2 
0209 – 0216 
TBD mg or placebo 
NA 
B3 
0217 – 0224 
TBD mg or placebo 
NA 
B4b 
0225 – 0232 
TBD 
TBD 
B5b 
0233 – 0240 
TBD 
TBD 
B6b 
0241 – 0248 
TBD 
TBD 
Abbreviations: NA = not applicable; PK = pharmacokinetic(s); TBD = to be determined. 
a. Although a food-effect evaluation is planned to occur in Group A3, this may be subject to change depending upon 
ongoing review of the PK data. 
b. Following review of the safety, tolerability, and PK data, additional dose groups (where systemic exposure is not 
expected to exceed that stated in the dose escalation stopping criteria [Section 3.7]) may be added to the study. Up to 
3 further groups of 8 subjects (6 active:2 placebo) may be included in each of Parts A and B. 
For predicted non-pharmacologically active dose levels, dose levels should not increase such 
that the maximum exposure (as assessed by Cmax and/or AUC0-24) is predicted to increase by 
> 5-fold for any individual subject. For predicted pharmacologically active dose levels, dose 
levels should not increase such that the maximum exposure (as assessed by Cmax and/or 
AUC0-24) is predicted to increase by > 3-fold for any individual subject. Exposures will be 
planned to not exceed that stated in the dose escalation stopping criteria (Section 3.7). 
Exposure will be assumed to increase in a dose-proportional manner until there is sufficient 
PK data available to suggest PK is not linear. 
Details of all doses administered in Parts A and B of the study will be documented in the 
TMF. 
3.6. 
Dose Escalation 
Doses will be administered in an escalating manner following satisfactory review by the 
Sponsor and Investigator of the safety and tolerability data (up to 48 hours post-final dose) 
and plasma PK data (up to 24 hours post-final dose [ie, Day 1 in Part A and Day 10 in 
Part B]) from the lower dose levels. Doses may be reduced and may be lower than the 
starting dose. There will be a minimum of 6 days between dose escalations to allow sufficient 
time for an adequate safety review. 
Dose escalation in both Parts A and B will only occur if data from a minimum of 6 subjects 
have been reviewed from the previous lower dose group, such that data from a minimum of 
4 subjects who have received AM1476 will be used to make the dose escalation decision. 






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2. History of significant hypersensitivity, intolerance, or allergy to any drug compound, 
food, or other substance, unless approved by the Investigator (or designee). 
3. History of stomach or intestinal surgery or resection that would potentially alter 
absorption and/or excretion of orally administered drugs (uncomplicated 
appendectomy and hernia repair will be allowed). 
4. Any of the following observed in at least 2 of 3 ECG measurements performed: 
a. QTcF > 450 msec. 
b. QRS duration > 110 msec. 
c. PR interval > 220 msec. 
d. findings which would make QTc measurements difficult or QTc data 
uninterpretable. 
5. Any history of additional risk factors for torsades de pointes (eg, heart failure, 
hypokalaemia, family history of long QT syndrome). 
6. Any history or current controlled or uncontrolled hypertension or systolic blood 
pressure > 140 mmHg or diastolic blood pressure > 90 mmHg confirmed by repeat 
measurement. 
7. History of alcoholism or drug/chemical abuse within 2 years prior to Check-in 
(Day -1). 
8. Alcohol consumption of > 21 units per week for males and > 14 units per week for 
females. One unit of alcohol equals ½ pint (285 mL) of beer or lager, 1 glass 
(125 mL) of wine, or 1/6 gill (25 mL) of spirits. 
9. Positive alcohol breath test result or positive urine drug screen (confirmed by repeat) 
at Screening or Check-in (Day -1). 
10. Positive hepatitis panel and/or positive human immunodeficiency virus test 
(Appendix 2). 
11. Participation in a clinical study involving administration of an investigational drug 
(new chemical entity) in the past 90 days prior to dosing. 
12. Use or intend to use any medications/products known to alter drug absorption, 
metabolism, or elimination processes, including St. John’s Wort, within 30 days prior 
to dosing, unless deemed acceptable by the Investigator (or designee). 
13. Use or intend to use any prescription medications/products other than hormone 
replacement therapy, oral, implantable, transdermal, injectable, or intrauterine 
contraceptives within 14 days prior to dosing, unless deemed acceptable by the 
Investigator (or designee). 
14. Use or intend to use slow release medications/products considered to still be active 
within 14 days prior to Check-in (Day -1), unless deemed acceptable by the 
Investigator (or designee). 
15. Use or intend to use any non-prescription medications/products including vitamins, 
minerals, and phytotherapeutic/herbal/plant-derived preparations within 7 days prior 
to Check-in (Day -1), unless deemed acceptable by the Investigator (or designee). 


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16. Use of tobacco- or nicotine-containing products within 3 months prior to Check-in 
(Day -1) or positive cotinine at Screening or Check-in (Day -1). 
17. Ingestion of poppy seeds, Seville orange, or grapefruit-containing foods or beverages 
within 7 days prior to Check-in (Day -1). 
18. Subjects who are vegetarians, vegans, or are unable to consume the high-fat breakfast 
(subjects who will participate in a food-effect evaluation [planned to be Group A3] 
only). 
19. Receipt of blood products within 2 months prior to Check-in (Day -1). 
20. Donation of blood from 3 months prior to Screening, plasma from 2 weeks prior to 
Screening, or platelets from 6 weeks prior to Screening. 
21. Poor peripheral venous access. 
22. Have previously completed or withdrawn from this study or any other study 
investigating AM1476, and have previously received AM1476. 
23. Subjects who are not willing to minimise or avoid exposure to natural or artificial 
sunlight (tanning beds or UVA/B treatment) following administration of study drug 
until 2 weeks after the last dose. 
24. Subjects who, in the opinion of the Investigator (or designee), should not participate 
in this study. 
Subjects may previously have been screened on a generic basis to determine their eligibility 
for inclusion in Phase I clinical studies conducted at the CRU. If generic screening was 
performed within the specified study screening window, selected study-specific procedures 
will be repeated either at an additional Screening visit or on admission to the CRU on Day -1. 
4.3. 
Rescreening of Subjects 
Subjects who are not eligible for inclusion in the study may not be rescreened. Subjects who 
are eligible for inclusion in the study, but are not dosed within 28 days of Screening, may 
subsequently be included in the study providing they continue to meet the criteria for 
inclusion in the study during rescreening. 
4.4. 
Subject Number and Identification 
Subjects will have a unique identification number used at Screening. Subjects will be 
assigned a subject number at the time of their randomisation. Assignment of subject numbers 
will be in ascending order in each part and no numbers will be omitted (eg, in 
Part A Subjects 0101, 0102, etc, in Part B Subjects 0201, 0202, etc). 
Replacement subjects (Section 4.5) will be assigned a subject number corresponding to the 
number of the subject he/she is replacing plus 1000 (eg, Subject 1101 replaces Subject 0101). 
Subjects will be identified by Screening identification number or subject number only on all 
study documentation. A list identifying the subjects by subject number will be kept in the Site 
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4.6. 
Study Termination 
The study may be discontinued at the discretion of the Investigator (or designee), Sponsor, or 
Sponsor’s Medical Monitor if any of the following criteria are met: 
• AEs unknown to date (ie, not previously reported in any similar investigational 
study drug trial with respect to their nature, severity, and/or duration) 
• increased frequency, severity, and/or duration of known, anticipated, or previously 
reported AEs (this may also apply to AEs defined at Check-in [Day -1] as baseline 
signs and symptoms) 
• medical or ethical reasons affecting the continued performance of the study 
• difficulties in the recruitment of subjects 
• cancellation of drug development. 
5. STUDY TREATMENTS 
5.1. 
Description, Storage, Packaging, and Labelling 
Active pharmaceutical ingredient (API; AM1476 powder) will be supplied by the Sponsor, 
along with the batch/lot number and Certificate of Analysis, Transmissible Spongiform 
Encephalopathy (TSE) statements, and a declaration of Good Manufacturing Practice (GMP). 
A Certificate of Release authorised by a Qualified Person in the European Union will also be 
issued, by Covance CRU Qualified Person, for each batch of IMP prior to administration to 
subjects. 
The Sponsor will supply a sufficient quantity of API for the manufacture of the unit doses at 
Covance CRU. All excipients will be sourced by Covance. 
The API and IMP will be stored according to the instructions on the label at the CRU in a 
location that is locked with restricted access. 
5.2. 
Study Treatment Administration 
Full details on dietary restrictions for dose administration are described in Section 6.2. 
Each dose of AM1476 and placebo will be administered orally with approximately 240 mL of 
room-temperature water. In Part A, all doses will be administered after an overnight fast of at 
least 10 hours, with the exception of Group A3, where the dose given in Treatment Period 2 
will be administered 30 minutes after starting a high-fat breakfast. The dietary status for 
dosing in Part B will be determined following review of the PK data from the fed/fasted 
comparison in Part A. 
Subjects will be administered the IMP in numerical order while standing and will not be 
permitted to lie supine for 2 hours after dosing, except as necessitated by the occurrence of an 
AE(s) and/or study procedures. 


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5.3. 
Randomisation 
The randomisation code will be produced by the statistics department at Covance using a 
computer-generated pseudo-random permutation procedure. 
In Part A, 6 subjects per group will be randomly assigned to receive AM1476 and 2 subjects 
per group will be randomly assigned to receive placebo, and subjects in Group A3 will 
receive the same treatment in Treatment Periods 1 and 2. For all groups in Part A, sentinel 
dosing will occur whereby 2 subjects (1 active and 1 placebo) will be dosed on 1 day and, 
providing no safety concerns arise, the remaining 6 subjects (5 active and 1 placebo) will be 
dosed after at least 24 hours. 
In Part B, 6 subjects will be randomly assigned to receive AM1476 and 2 subjects per group 
will be randomly assigned to receive placebo. 
5.4. 
Blinding 
The following controls will be employed to maintain the double-blind status of the study: 
• The placebo capsules will be identical in appearance to the AM1476. 
• The Investigator and other members of staff (with the exception of pharmacy 
staff) involved with the study will remain blinded to the treatment randomisation 
code during the conduct of the study. 
• Interim bioanalytical data will be provided to Covance in a blinded manner. 
To maintain the blind, the Investigator will be provided with a sealed randomisation code for 
each subject, containing details of their treatment. These individual sealed envelopes will be 
kept in a limited access area that is accessible 24 hours a day. In order to manage subject 
safety or to support dose escalation decisions (in the event of possibly treatment-related SAEs 
or severe AEs), the decision to unblind resides solely with the Investigator. Whenever 
possible, and providing it does not interfere with or delay any decision in the best interest of 
the subject, the Investigator will discuss the intended code-break with the Sponsor. If it 
becomes necessary to break the code during the study, the date, time, and reason will be 
recorded in the subject’s source data and on the individual envelope and will be witnessed by 
a second person. 
5.5. 
Treatment Compliance 
The following measures will be employed to ensure treatment compliance: 
• All doses will be administered under the supervision of suitably qualified study 
site staff. 
• Immediately after dose administration, visual inspection of the mouth and hands 
will be performed for each subject. 
• At each dosing occasion, a predose and postdose inventory of IMP will be 
performed on the dose containers. 


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5.6. 
Drug Accountability 
The Investigator (or designee) will maintain an accurate record of the receipt of the study 
supplies received, dispensed, and destroyed. In addition, an accurate drug disposition record 
will be kept, specifying the amount dispensed to each subject and the date of dispensing. This 
drug accountability record will be available for inspection at any time. At the completion of 
the study, the original drug accountability record will be available for review by the Sponsor 
upon request. 
For each batch of unit doses, the empty used unit dose containers will be discarded upon 
satisfactory completion of the compliance and accountability procedures. Any unused 
assembled unit doses will be retained until completion of the study. 
At the completion of the study, all unused supplies will be returned to the Sponsor or 
disposed of by the study site, per the Sponsor’s written instructions. 
6. CONCOMITANT THERAPIES AND OTHER RESTRICTIONS 
6.1. 
Concomitant Therapies 
Subjects will refrain from use of any prescription or non-prescription medications/products 
during the study until the Follow-up visit, unless the Investigator (or designee) and/or 
Sponsor have given their prior consent. 
Paracetamol/acetaminophen (2 g/day for up to 3 consecutive days), hormone replacement 
therapy, oral, implantable, transdermal, injectable, or intrauterine contraceptives are 
acceptable concomitant medications. The administration of any other concomitant 
medications during the study is prohibited without prior approval of the Investigator (or 
designee), unless its use is deemed necessary for treatment of an AE. Any medication taken 
by a subject during the course of the study and the reason for its use will be documented in 
the source data. 
6.2. 
Diet 
While confined at the study site, subjects will receive a standardised diet at scheduled times 
that do not conflict with other study-related activities. Subjects will be fasted (at least 
8 hours) before collection of blood samples for clinical laboratory evaluations. 
On the days with intensive PK assessments (Day 1 for Part A, and Days 1 and 10 for Part B), 
meals will be identical for each group with the exception of the high-fat breakfast for 
Group A3. 
On Day 1 in Part A, subjects will be fasted for at least 10 hours prior to dosing until 
approximately 4.5 hours after dosing, when lunch will be provided. With the exception of 
water given with the dose, subjects will not be allowed fluids from 1 hour prior to until 
2 hours after dosing. Meals will be provided as appropriate at other times. Other than the 
fluid restrictions on dosing days, water will be freely available at all times. 
Subjects in Group A3 in Treatment Period 2 will consume a high-fat breakfast (contents are 
detailed in Table 7) before dosing. Subjects should start the meal 30 minutes prior to 


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administration of the IMP. Study subjects should eat this meal in 30 minutes or less. The drug 
product should be administered 30 minutes after start of the meal. Subjects will be fasted for 
approximately 4.5 hours after dosing and will not be allowed fluids until 2 hours after dosing. 
Table 7: 
High-fat Breakfast Content 
High-fat Breakfast 
120 g fried eggs (2 eggs) in vegetable oil 
50 g bacon (2 rashers) 
72 g toasted white bread (2 slices) 
13 g butter (2 pats) 
108 g hash brown (3 each) 
240 g whole milk 
Total calories: 973 kcal 
This high-fat breakfast contains the equivalent of approximately 150 protein calories, 
250 carbohydrate calories, and 500 to 600 fat calories. 
In Part B, the time interval between meals and dosing will be determined by the PK data from 
Part A and will be documented in the TMF. Meals will be provided as appropriate at other 
times. With the exception of water given with the dose, subjects will not be allowed fluids 
from 1 hour prior to dosing until 2 hours after dosing. Other than these fluid restrictions, 
water will be freely available at all times. 
Foods and beverages containing poppy seeds, grapefruit, or Seville oranges will not be 
allowed from 7 days prior to Check-in (Day -1) until the Follow-up visit. 
Caffeine-containing foods and beverages will not be allowed from 36 hours before Check-in 
(Day -1) until Discharge. 
Consumption of alcohol will not be permitted from 36 hours prior to Check-in (Day -1) until 
Discharge. Up to 2 units/day of alcohol are permitted from Discharge until 36 hours before 
the Follow-up visit or 36 hours before Check-in (Day -1) in each treatment period. 
6.3. 
Smoking 
Subjects will not be permitted to use tobacco- or nicotine-containing products within 
3 months prior to Check-in (Day -1) until the Follow-up visit. 
6.4. 
Exercise 
Subjects are required to refrain from strenuous exercise from 7 days before Check-in (Day -1) 
until the Follow-up visit and will otherwise maintain their normal level of physical activity 
during this time (ie, will not begin a new exercise program nor participate in any unusually 
strenuous physical exertion). 
6.5. 
Blood Donation 
Subjects are required to refrain from donation of blood from 3 months prior to Screening, 
plasma from 2 weeks prior to Screening, and platelets from 6 weeks prior to Screening until 
3 months after the Follow-up visit. 


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6.6. 
Exposure to Ultraviolet Light 
Subjects should minimise or avoid exposure to natural or artificial sunlight (tanning beds or 
UVA/B treatment) following administration of study drug until 2 weeks after the last dose. If 
subjects need to be outdoors during this period, they should wear loose fitting clothes that 
protect skin from sun exposure and discuss other sun protection measures with the 
Investigator. 
7. STUDY ASSESSMENTS AND PROCEDURES 
Study assessments and procedures will be performed at the timepoints indicated in the 
Schedule of Assessments in Appendix 6 for Part A and Appendix 7 for Part B. 
Every effort will be made to schedule and perform the procedures as closely as possible to the 
nominal time, giving considerations to appropriate posture conditions, practical restrictions, 
and the other procedures to be performed at the same timepoint. 
The highest priority procedures will be performed closest to the nominal time. The order of 
priority for scheduling procedures around a timepoint is (in descending order of priority): 
• dosing 
• blood samples (for AM1476 assay) 
• urine samples (for AM1476 assay) 
• any other procedures. 
Where activities at a given timepoint coincide, consideration must be given to ensure that 
vital signs and single 12-lead ECGs are measured and
 
 occurs before blood draws. 
7.1. 
Pharmacokinetic Assessments 
7.1.1. 
Sample Collection and Processing 
Blood samples (approximately 1 × 3.0 mL) will be collected by venepuncture or cannulation 
at the times indicated in the Schedule of Assessments in Appendix 6 for Part A and 
Appendix 7 for Part B. Furthermore, up to 3 additional blood samples may be taken from 
each subject per treatment period, with the maximum volume of blood withdrawn per subject 
not exceeding the limit detailed in Appendix 3. Any changes to the scheduled times of PK 
assessments will be agreed with the Sponsor and documented in the TMF. Samples taken 
from subjects who received placebo will not be analysed. 
Procedures for collection, processing, and shipping of PK blood samples will be detailed in a 
separate document. 
Urine samples will be collected into pre-weighed polyethylene containers over the time 
intervals indicated in the Schedule of Assessments in Appendix 6 for Part A and Appendix 7 
for Part B. Procedures for collection, processing, and shipping of urine samples will be 
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will be performed at the times indicated in the Schedule of Assessments in Appendix 6 for 
Part A and Appendix 7 for Part B. 
An Investigator (or designee) will perform a clinical assessment of all clinical laboratory 
data. 
7.2.3. 
Vital Signs 
Supine blood pressure, supine pulse rate, respiratory rate, and oral body temperature will be 
assessed at the times indicated in the Schedule of Assessments in Appendix 6 for Part A and 
Appendix 7 for Part B. Vital signs may also be performed at other times if judged to be 
clinically appropriate or if the ongoing review of the data suggests a more detailed 
assessment of vital signs is required. 
Day 1 predose blood pressure, pulse rate, and respiratory rate will be measured in triplicate at 
approximately 2-minute intervals. The median value will be used as the baseline value in the 
data analysis. Oral body temperature will be measured singly. All subsequent measurements 
will be performed singly and repeated once if outside the relevant clinical reference ranges.  
Subjects must be supine for at least 5 minutes before blood pressure and pulse rate 
measurements. 
For orthostatic vital sign measurements, the supine blood pressure and pulse rate will be 
measured after the subject has been supine for at least 5 minutes. The subject will then stand 
for at least 2 minutes and the standing blood pressure and pulse rate will be measured. 
7.2.4. 
Electrocardiograms 
7.2.4.1. 
12-lead Electrocardiograms 
Resting 12-lead ECGs will be recorded after the subject has been supine and at rest for at 
least 5 minutes at the times indicated in the Schedule of Assessments in Appendix 6 for 
Part A and Appendix 7 for Part B. All scheduled 12-lead ECGs will be measured in triplicate 
at approximately 1-minute intervals. The mean values at each timepoint will be used in the 
data analysis.  
Additional 12-lead ECGs may be performed at other times if judged to be clinically 
appropriate or if the ongoing review of the data suggests a more detailed assessment of ECGs 
is required. The Investigator (or designee) will perform a clinical assessment of each 12-lead 
ECG. 
7.2.4.2. 
Telemetry 
Cardiac rhythm will be monitored by telemetry at the times indicated in the Schedule of 
Assessments in Appendix 6 for Part A. 
Telemetry is not planned for Part B of the study but may be implemented if any clinically 
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In Part A, where data are available, AM1476 dose proportionality will be examined across 
dose groups. The PK parameters, AUC0-∞, AUC0-tlast, and Cmax, will be analysed for dose 
proportionality using a power model approach or analysis of variance (ANOVA) model as 
appropriate. Where data are available, the effect of food at 1 dose level in Part A will be 
investigated using ANOVA. To investigate the effect of food on the PK of AM1476, the 
log-transformed AUC0-∞, AUC0-tlast, and Cmax values for AM1476 administered with and 
without food will be analysed using a linear mixed-effects model with treatment as fixed 
effect and subject as a random effect. Point estimates and 90% confidence intervals (CIs) for 
differences between the treatments (fed versus fasted) on the log scale will be exponentiated 
to obtain estimates for the ratios of geometric means and respective 90% CIs on the original 
scale. 
In Part B, AUC0-τ and Cmax on Day 10 will be analysed for dose proportionality using a power 
model approach or ANOVA model as appropriate. 
Additional details will be presented in the Statistical Analysis Plan (SAP). 
8.4. 
Safety Analysis 
Safety parameters will be listed and summarised using descriptive statistics. No formal 
statistical analysis of safety data is planned. Each AE will be coded using the Medical 
Dictionary for Regulatory Activities. 
8.5. 
Interim Analysis 
No formal interim analyses are planned for this study. 
9. REFERENCES 
1.  Mann DA, Oakley F. Serotonin paracrine signaling in tissue fibrosis. Biochim Biophys 
Acta. 2013 Jul;1832(7):905–10.  
2.  Dees C, Akhmetshina A, Zerr P, Reich N, Palumbo K, Horn A, et al. Platelet-derived 
serotonin links vascular disease and tissue fibrosis. J Exp Med. 2011 May 9;208(5):961–
72.  
3.  Königshoff M, Dumitrascu R, Udalov S, Amarie OV, Reiter R, Grimminger F, et al. 
Increased expression of 5-hydroxytryptamine2A/B receptors in idiopathic pulmonary 
fibrosis: a rationale for therapeutic intervention. Thorax. 2010 Nov;65(11):949–55.  
4.  Rosenbloom J, Macarak E, Piera-Velazquez S, Jimenez SA. Human Fibrotic Diseases: 
Current Challenges in Fibrosis Research. Methods Mol Biol. 2017;1627:1–23.  
5.  Distler JHW, Györfi A-H, Ramanujam M, Whitfield ML, Königshoff M, Lafyatis R. 
Shared and distinct mechanisms of fibrosis. Nat Rev Rheumatol. 2019 Dec;15(12):705–
30.  
6.  AnaMar AB. AM1476 – Investigator’s Brochure. (Version 2). 27 August 2020.  


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7.  The Serotonin Receptor 2 Inhibitor Terguride Has Beneficial Effects on Skin Fibrosis: 
Results from a Phase 2 Proof of Concept Study [Internet]. ACR Meeting Abstracts. 
Available from: https://acrabstracts.org/abstract/the-serotonin-receptor-2-inhibitor-
terguride-has-beneficial-effects-on-skin-fibrosis-results-from-a-phase-2-proof-of-
concept-study/ 
8.  Distler O, Eich W, Dokoupilova E, Dvorak Z, Fleck M, Gaubitz M, et al. Evaluation of 
the efficacy and safety of terguride in patients with fibromyalgia syndrome: Results of a 
twelve-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group 
study. Arthritis & Rheumatism. 2010;62(1):291–300.  
 
 


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10. APPENDICES 


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Appendix 1: Adverse Event Reporting 
Definitions 
An adverse event (AE) is any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product, which does not necessarily have 
a causal relationship with this treatment. An AE can therefore be any unfavourable and/or 
unintended sign (including a clinically significant abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a study treatment, whether or not related to the 
study treatment. 
Assessment of Severity 
The Investigator will be asked to provide an assessment of the severity of the AE using the 
following categories: 
• Mild: Usually transient and may require only minimal treatment or therapeutic 
intervention. The event does not generally interfere with usual activities of daily 
living. 
• Moderate: Usually alleviated with additional specific therapeutic intervention. 
The event interferes with usual activities of daily living, causing discomfort but 
poses no significant or permanent risk of harm to the subject. 
• Severe: Interrupts usual activities of daily living, or significantly affects clinical 
status, or may require intensive therapeutic intervention. 
Relationship to Study Treatment 
The Investigator (or designee) will make a determination of the relationship of the AE to the 
study treatment using a 4-category system according to the following guidelines: 
• Not Related: The AE is definitely caused by the subject’s clinical state or the 
study procedure/conditions. 
• Unlikely Related: The temporal association between the AE and the drug is such 
that the drug is not likely to have any reasonable association with the AE. 
• Possibly Related: The AE follows a reasonable temporal sequence from the time 
of drug administration but could have been produced by the subject’s clinical state 
or the study procedures/conditions. 
• Related: The AE follows a reasonable temporal sequence from administration of 
the drug, abates upon discontinuation of the drug, follows a known or 
hypothesised cause-effect relationship, and (if appropriate) reappears when the 
drug is reintroduced. 
Follow-up of Adverse Events 
Every reasonable effort will be made to follow-up with subjects who have AEs. Any subject 
who has an ongoing AE that is possibly related or related to the investigational medicinal 
product (IMP) or study procedures at the Follow-up visit will be followed up, where possible, 


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until resolution or until the unresolved AE is judged by the Investigator (or designee) to have 
stabilised. This will be completed at the Investigator’s (or designee’s) discretion. Any subject 
who has an ongoing AE that is not related or unlikely related to the IMP or study procedures 
at the Follow-up visit can be closed out as ongoing at the Investigator’s discretion. 
Adverse Drug Reactions 
All noxious and unintended responses to an IMP (ie, where a causal relationship between an 
IMP and an AE is at least a reasonable possibility) related to any dose should be considered 
adverse drug reactions. 
For marketed medicinal products, a response to a drug which is noxious and unintended and 
which occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of diseases 
or for modification of physiological function is to be considered an adverse drug reaction. 
An unexpected adverse drug reaction is defined as an adverse reaction, the nature or severity 
of which is not consistent with the applicable product information (eg, Investigator’s 
Brochure [IB] for an unapproved IMP). 
Serious Adverse Events 
A serious adverse event (SAE) is defined as any untoward medical occurrence that at any 
dose either: 
• results in death 
• is life-threatening 
• requires inpatient hospitalisation or prolongation of existing hospitalisation 
• results in persistent or significant disability/incapacity (disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions) 
• results in a congenital anomaly/birth defect 
• results in an important medical event (see below). 
Important medical events that may not result in death, be life-threatening, or require 
hospitalisation may be considered SAEs when, based upon appropriate medical judgment, 
they may jeopardise the subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition. 
Instances of death or congenital abnormality, if brought to the attention of the Investigator at 
any time after cessation of the study treatment and considered by the Investigator to be 
possibly related to the study treatment, will be reported to the Sponsor. 
Definition of Life-threatening 
An AE is life-threatening if the subject was at immediate risk of death from the event as it 
occurred (ie, does not include a reaction that might have caused death if it had occurred in a 
more serious form). For instance, drug-induced hepatitis that resolved without evidence of 
hepatic failure would not be considered life-threatening even though drug-induced hepatitis 
can be fatal. 


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Definition of Hospitalisation 
Adverse events requiring hospitalisation should be considered serious. In general, 
hospitalisation signifies that the subject has been detained (usually involving an overnight 
stay) at the hospital or emergency ward for observation and/or treatment that would not have 
been appropriate at the Clinical Research Unit (CRU). When in doubt as to whether 
hospitalisation occurred or was necessary, the AE should be considered as serious. 
Hospitalisation for elective surgery or routine clinical procedures, which are not the result of 
an AE, need not be considered AEs and should be recorded on a Clinical Assessment Form 
and added to the electronic Case Report Form. If anything untoward is reported during the 
procedure, this must be reported as an AE and either ‘serious’ or ‘non-serious’ attributed 
according to the usual criteria. 
Serious Adverse Event Reporting 
Covance Drug Safety Services (DSS) Europe, Maidenhead, United Kingdom, are responsible 
for coordinating the reporting of SAEs in accordance with the European Directive 
2001/20/EC. 
The Investigator will complete an SAE report form and forward it by facsimile or email to 
DSS and the Sponsor immediately (within 24 hours) upon becoming aware of an SAE. 
The responsibilities of Covance DSS include the following: 
• Prepare an AE reporting plan prior to the start of the study. Where this plan differs 
from the applicable CRU standard operating procedure on SAE reporting, the 
Safety Management Plan will always take precedence. 
• Receive and review SAE report forms from the CRU and inform the Sponsor of 
the SAE within 1 working day of the initial notification to DSS. Drug Safety 
Services will delete any information from the SAE report forms that may identify 
the subject. 
• Write case narratives and enter the case into Covance’s safety database as defined 
in the AE reporting plan. 
• Produce appropriate reports of all Suspected Unexpected Serious Adverse 
Reactions and forward to the Ethics Committee, Medicines and Healthcare 
Products Regulatory Agency, Principal Investigator, and the Sponsor within the 
timeframes stipulated in the Clinical Trials Directive Guideline (ENTR/CT 3). 
The responsibility for reporting SAEs will be transferred to the Sponsor 28 days after the end 
of the study. 
Pregnancy 
Pregnancy (maternal or paternal exposure to study treatment) does not meet the definition of 
an AE. However, to fulfil regulatory requirements any pregnancy should be reported 
following the SAE process to collect data on the outcome for both mother and foetus. 


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Appendix 2: Clinical Laboratory Evaluations 
Clinical chemistry: 
Haematology: 
Urinalysis: 
Alanine aminotransferase (ALT) 
Albumin 
Alkaline phosphatase (ALP) 
Aspartate aminotransferase (AST) 
Calcium 
Chloride 
Cholesterol 
Creatinine 
Direct bilirubin 
Gamma-glutamyl transferase (GGT) 
Glucose 
Inorganic phosphate 
Potassium 
Sodium 
Total bilirubin 
Total CO2 
Total protein 
Uric acid 
Haematocrit 
Haemoglobin 
Mean cell haemoglobin 
Mean cell haemoglobin 
concentration 
Mean cell volume 
Platelet count 
Red blood cell (RBC) count 
White blood cell (WBC) count 
WBC differential: 
    Basophils 
    Eosinophils 
    Lymphocytes 
    Monocytes 
    Neutrophils 
Blood 
Glucose 
Ketones 
pH 
Protein 
Specific gravity 
Urobilinogen 
Microscopic examination 
Coagulation profile 
Activated partial thromboplastin 
time 
International normalised ratio 
Prothrombin time 
Drug screen: 
Hormone panel - females only: 
Including but not limited to: 
Amphetamines/methamphetamines 
Barbiturates 
Benzodiazepines 
Cocaine (metabolite) 
Methadone 
Phencyclidine 
Opiates 
Tetrahydrocannabinol/cannabinoids 
Tricyclic antidepressants 
Cotinine test 
Follicle-stimulating hormonea 
Serum pregnancy test (human 
chorionic gonadotropin)b 
Urine pregnancy testb 
Serology:a 
Anti-hepatitis B surface antibody 
Hepatitis B surface antigen 
Hepatitis C antibody 
Human immunodeficiency (HIV-1 
and HIV-2) antibodies and p24 
antigen 
a. Performed at Screening only. 
b. For all females, performed in serum at Screening and in urine at all other times. A positive urine pregnancy test will be 
confirmed with a serum pregnancy test. 






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Appendix 4: Contraception Guidance 
Definitions 
Women of Childbearing Potential: premenopausal females who are anatomically and 
physiologically capable of becoming pregnant following menarche. 
Women of Non-childbearing Potential: 
1. Surgically sterile: females who are permanently sterile via hysterectomy, 
bilateral salpingectomy, and/or bilateral oophorectomy by reported medical 
history and/or medical records. Surgical sterilisation to have occurred a minimum 
of 6 weeks, or at the Investigator’s discretion, prior to Screening. 
2. Postmenopausal: Females at least 45 years of age with amenorrhoea for 
12 months without an alternative medical reason with confirmatory 
follicle-stimulating hormone (FSH) levels of ≥ 40 mIU/mL. The amenorrhoea 
should not be induced by a medical condition such as anorexia nervosa, 
hypothyroid disease or polycystic ovarian disease, or by extreme exercise. It 
should not be due to concomitant medications that may have induced the 
amenorrhoea such as oral contraceptives, hormones, gonadotropin-releasing 
hormones, anti-oestrogens, or selective oestrogen receptor modulators. Females 
on hormone replacement therapy with FSH levels < 40 mIU/mL may be included 
at the discretion of the Investigator. 
Fertile male: a male that is considered fertile after puberty. 
Infertile male: permanently sterile male via bilateral orchiectomy. 
Contraception Guidance 
Female Subjects 
Female subjects who are of non-childbearing potential will not be required to use 
contraception. Female subjects of childbearing potential must be willing to use 2 methods 
(1 primary highly effective and 1 secondary method) of birth control from the time of signing 
the Informed Consent Form (ICF) until 90 days after the Follow-up visit. Primary highly 
effective methods of contraception include: 
• surgical method performed at least 3 months prior to the Screening visit: 
o 
bilateral tubal ligation 
o 
Essure® (hysteroscopic bilateral tubal occlusion) with confirmation of 
occlusion of the fallopian tubes 
• hormonal implant eg, Implanon (as prescribed) 
• hormonal or non-hormonal intrauterine device (IUD) with appropriate re-insertion 
period (as prescribed) 


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• vasectomised male partner (sterilisation performed at least 90 days prior to the 
Screening visit, with verbal confirmation of surgical success, and the sole partner 
for the female subject). 
Secondary (barrier) methods of contraception include: 
• male condom with spermicide 
• female condom with spermicide 
• over-the-counter sponge with spermicide 
• cervical cap with spermicide (as prescribed) 
• diaphragm with spermicide (as prescribed). 
Female subjects can only choose a cervical cap or diaphragm if they have already had a 
prescription and fitting by their healthcare provider to ensure protocol requirements are met. 
Female subjects of childbearing potential should refrain from donation of ova from Check-in 
(Day -1) until 90 days after the Follow-up visit. 
Male Subjects 
Male subjects (even with a history of vasectomy) with partners of childbearing potential must 
use a male barrier method of contraception (ie, male condom with spermicide) in addition to 
a second method of acceptable contraception from Check-in (Day -1) until 90 days after the 
Follow-up visit. Acceptable methods of contraception for female partners include: 
• hormonal injection 
• combined oral contraceptive pill or progestin/progestogen-only pill 
• combined hormonal patch 
• combined hormonal vaginal ring 
• surgical method (bilateral tubal ligation or Essure® [hysteroscopic bilateral tubal 
occlusion]) 
• hormonal implant 
• hormonal or non-hormonal IUD 
• over-the-counter sponge with spermicide 
• cervical cap with spermicide 
• diaphragm with spermicide. 
An acceptable second method of contraception for male subjects is vasectomy that has been 
performed at least 90 days prior to the Screening visit, with verbal confirmation of surgical 
success. 
For male subjects (even with a history of vasectomy), sexual intercourse with female partners 
who are pregnant or breastfeeding should be avoided unless condoms are used from the time 


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of the first dose until 90 days after the Follow-up visit. Male subjects are required to refrain 
from donation of sperm from Check-in (Day -1) until 90 days after the Follow-up visit. 
Sexual Abstinence and Same-sex Relationships 
Subjects who practice true abstinence, because of the subject’s lifestyle choice (ie, the subject 
should not become abstinent just for the purpose of study participation), are exempt from 
contraceptive requirements. Periodic abstinence (eg, calendar, ovulation, symptothermal, 
post-ovulation methods) and withdrawal are not acceptable methods of contraception. If a 
subject who is abstinent at the time of signing the ICF becomes sexually active they must 
agree to use contraception as described previously. 
For subjects who are exclusively in same-sex relationships, contraceptive requirements do not 
apply. If a subject who is in a same-sex relationship at the time of signing the ICF becomes 
engaged in a heterosexual relationship, they must agree to use contraception as described 
previously. 


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Appendix 5: Regulatory, Ethical, and Study Oversight Considerations 
Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with the following: 
• Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines. 
• Applicable International Conference on Harmonisation (ICH) Good Clinical 
Practice (GCP) Guidelines. 
• Applicable laws and regulations. 
The protocol, protocol amendments, Informed Consent Form (ICF), Investigator Brochure 
(IB), and other relevant documents must be submitted to an Ethics Committee (EC) by the 
Investigator and reviewed and approved by the EC before the study is initiated. 
Any substantial protocol amendments, likely to affect the safety of the subjects or the conduct 
of the study, will require EC and regulatory authority (as locally required) approval before 
implementation of changes made to the study design, except for changes necessary to 
eliminate an immediate hazard to study subjects or any non-substantial changes, as defined 
by regulatory requirements. 
The Investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the EC annually or more 
frequently in accordance with the requirements, policies, and procedures 
established by the EC. 
• Notifying the EC of serious adverse events or other significant safety findings as 
required by EC procedures. 
• Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 Code of Federal Regulations (CFR), ICH guidelines, the EC, 
European Directive 2001/20/EC for clinical studies (if applicable), and all other 
applicable local regulations. 
Finances and Insurance 
Financing and insurance will be addressed in a separate agreement. 
Informed Consent 
Prior to starting participation in the study, each subject will be provided with a study-specific 
ICF giving details of the study treatments, procedures, and potential risks of the study. 
Subjects will be instructed that they are free to obtain further information from the 
Investigator (or designee) and that their participation is voluntary and they are free to 
withdraw from the study at any time. Subjects will be given an opportunity to ask questions 
about the study prior to providing consent for participation. 


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Following discussion of the study with Clinical Research Unit (CRU) personnel, subjects will 
sign 2 copies of the ICF in the presence of a suitably trained member of staff to indicate that 
they are freely giving their informed consent. One copy will be given to the subject, and the 
other will be maintained in the subject’s records. 
Subjects must be re-consented to the most current version of the ICF(s) during their 
participation in the study. 
Subject Data Protection 
Subjects will be assigned a unique identifier and will not be identified by name in electronic 
Case Report Forms (eCRFs), study-related forms, study reports, or any related publications. 
Subject and Investigator personal data will be treated in compliance with all applicable laws 
and regulations. In the event the study protocol, study report, or study data are included in a 
public registry, all identifiable information from individual subjects or Investigator(s) will be 
redacted according to applicable laws and regulations. 
The subject must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the subject. The subject must also be informed that his/her study-related data 
may be examined by Sponsor or Contract Research Organisation (CRO) auditors or other 
authorised personnel appointed by the Sponsor, by appropriate EC members, and by 
inspectors from regulatory authorities. 
Disclosure 
All information provided regarding the study, as well as all information collected and/or 
documented during the course of the study, will be regarded as confidential. The Investigator 
(or designee) agrees not to disclose such information in any way without prior written 
permission from the Sponsor. 
The following data quality steps will be implemented: 
• All relevant subject data relating to the study will be recorded on eCRFs unless 
directly transmitted to the Sponsor or designee electronically (eg, laboratory data). 
The Investigator is responsible for verifying that data entries are accurate and 
correct by electronically signing the eCRF. 
• The Investigator must maintain accurate documentation (source data) that 
supports the information entered in the eCRF. 
• The Investigator must permit study-related monitoring, audits, EC review, and 
regulatory agency inspections and provide direct access to source data documents. 
• Covance is responsible for the data management of this study including quality 
checking of the data. Predefined agreed risks, monitoring thresholds, quality 
tolerance thresholds, controls, and mitigation plans will be documented in a risk 
management register. Additional details of quality checking to be performed on 
the data may be included in a Data Management Plan. 
• A Study Monitor will perform ongoing source data verification to confirm that 
data entered into the eCRF by authorised site personnel are accurate, complete, 


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and verifiable from source documents; that the safety and rights of subjects are 
being protected; and that the study is being conducted in accordance with the 
currently approved protocol and any other study agreements, ICH GCP, and all 
applicable regulatory requirements. 
• Records and documents, including signed ICFs, pertaining to the conduct of this 
study must be retained by the Investigator in the study site archive for at least 
5 years after the end of the study 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 the Sponsor. No records may be 
transferred to another location or party without written notification to the Sponsor. 
Investigator Documentation Responsibilities 
All individual, subject-specific study data will also be entered into a 21 CFR 
Part 11-compliant electronic data capture (EDC) system on an eCRF in a timely fashion. 
All data generated from external sources (eg, laboratory and bioanalytical data), and 
transmitted to Covance electronically, will be integrated with the subject’s eCRF data in 
accordance with the Data Management Plan. 
An eCRF must be completed for each enrolled subject who undergoes any screening 
procedures, according to the eCRF completion instructions. The Sponsor, or CRO, will 
review the supporting source documentation against the data entered into the eCRFs to verify 
the accuracy of the electronic data. The Investigator will ensure that corrections are made to 
the eCRFs and that data queries are resolved in a timely fashion by the study staff. 
The Investigator will sign and date the eCRF via the EDC system’s electronic signature 
procedure. These signatures will indicate that the Investigator reviewed and approved the 
data on the eCRF, data queries, and site notifications. 
Publications 
• The results of this study may be published or presented at scientific meetings. If 
this is foreseen, the Investigator agrees to submit all manuscripts or abstracts to 
the Sponsor before submission. This allows the Sponsor to protect proprietary 
information and to provide comments. 
• The Sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicentre studies only in their entirety and not as 
individual site data. In this case, a Coordinating Investigator will be designated by 
mutual agreement. 
• Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 


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Appendix 6: Schedule of Assessments – Part A (Single-dose, Incorporating a Food-effect 
Evaluation) 


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Schedule of Assessments – Part A (Single Dose) 
Study Procedures 
Screeningl 
(Days -28 to -2) 
Treatment Period 1 (and 2 for Group A3) 
Follow-up 
(7 to 10 days 
postdose) 
Day -1 
Days 1 to 3 
Informed consent 
X 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
Demographic data 
X 
 
 
 
Medical history 
X 
Xa 
 
 
Urinary drug screen, including 
cotinine test 
X 
X 
 
 
Alcohol breath test 
X 
X 
 
 
Serology 
X 
 
 
 
Pregnancy testb 
X 
X 
 
X 
FSH 
X 
 
 
 
Height and body weightc 
X 
X 
 
 
 
 
 
 
 
Study residency: 
 
 
 
 
Check-in 
 
X 
 
 
Check-out 
 
 
Day 3 (48 hours postdose) 
 
Non-residential visit 
X 
 
 
X 
Study treatment administration: 
 
 
 
 
AM1476 or placebo 
 
 
Day 1 (0 h) 
(30 minutes after starting a high-fat breakfast in Treatment Period 2 for 
Group A3) 
 
Pharmacokinetics: 
 
 
 
 
Blood samplinge,f 
 
 
Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, and 48 hours postdose 
 
Urine samplinge,f 
 
 
Predose (spot collection), 0 to 12, 12 to 24, and 24 to 48 hours postdose 
 
Safety and tolerability: 
 
 
 
 
Adverse event recording 
X 
X 
Ongoing 
X 
Prior/concomitant medication 
monitoring 
X 
X 
Ongoing 
X 




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Protocol Reference: 1476-291-001 
Protocol Version 5, 06 January 2021 
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Appendix 7: Schedule of Assessments – Part B (Multiple-dose) 


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Schedule of Assessments – Part B (Multiple Dose) 
Study Procedures 
Screening 
(Days -28 to -2) Day -1 
Days 1 to 12 
Follow-up 
(7 to 10 days 
post-final dose) 
Informed consent 
X 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
Demographic data 
X 
 
 
 
Medical history 
X 
Xa 
 
 
Urinary drug screen, including 
cotinine test 
X 
X 
 
 
Alcohol breath test 
X 
X 
 
 
Serology 
X 
 
 
 
Pregnancy testb 
X 
X 
 
X 
FSH 
X 
 
 
 
Height and body weightc 
X 
X 
 
 
 
 
 
 
 
Study residency: 
 
 
 
 
Check-in 
 
X 
 
 
Check-out 
 
 
Day 12 (48 hours postdose) 
 
Non-residential visit 
X 
 
 
X 
Study treatment 
administration: 
 
 
 
 
AM1476 or placebo 
 
 
Day 1 to 10 (0 hour) 
 
Pharmacokinetics: 
 
 
 
 
Blood samplinge,f 
 
 
Day 1: predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16 and 24 hours postdose 
Days 4, 6, 7, 8, and 9: predose 
Day 10: predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36 and 48 hours 
postdose 
 
Urine samplinge,f 
 
 
Day 1: predose (spot collection), 0 to 24 hours postdose 
Day 10: 0 to 24 hours postdose 
 




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f. Timepoints may be changed based on emerging data. Any changes to the scheduled times of PK assessments will be agreed with the Sponsor and documented in the TMF. 
g. Symptom-directed neurological examination(s) will be performed on Day 3, Day 6, Day 9, and Day 12. 
h. Full physical examination. 
i. Symptom-directed physical examination(s). 


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Protocol Reference: 1476-291-001 
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Appendix 8: Summary of Amended Protocol Changes 
The following changes were made: 
  
2. A typographical error in the Schedule of Assessments for Part A was corrected. 
3. An assessment of blood pressure, pulse rate, respiratory rate, and oral body 
temperature was added to the Schedule of Assessments at Follow-up for Part B. 
 

SAP_001.pdf: 
 
 
 
 
Statistical Analysis Plan 
AM1476 - A Phase I, Double-blind, Placebo-controlled, Single- and 
Multiple-oral Dose, Safety, Tolerability, and Pharmacokinetic Study in 
Healthy Subjects 
SAP Status: Final 
SAP Version: 1.0 
SAP Date: 17MAY2021 
Investigational Medicinal Product: AM1476 
Protocol Reference: 1476-291-001 
Covance Study: 8417263 
 
 
Sponsor: 
AnaMar AB 
Medicon Village 
Scheeletorget 1 
SE-223 81 Lund 
Sweden 
Study Site: 
Covance Clinical Research Unit (CRU) Ltd. 
Springfield House 
Hyde Street 
Leeds, LS2 9LH 
United Kingdom 
 
 
 
Principal Investigator: 
 
 
 
Information described herein is confidential and may be disclosed only with the express 
written permission of the sponsor. 
 


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Protocol Reference: 1476-291-001 
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ST-AD-031 Version 02 
TABLE OF CONTENTS 
TITLE PAGE ............................................................................................................................. 1 
TABLE OF CONTENTS ........................................................................................................... 2 
LIST OF IN-TEXT TABLES AND FIGURES ......................................................................... 3 
LIST OF ABBREVIATIONS .................................................................................................... 4 
1. INTRODUCTION ................................................................................................................. 6 
2. STUDY OBJECTIVES .......................................................................................................... 6 
3. STUDY ENDPOINTS ........................................................................................................... 7 
3.1. Primary Endpoints ........................................................................................................... 7 
3.2. Secondary Endpoints ....................................................................................................... 7 
4. STUDY DESIGN................................................................................................................... 8 
4.1. Part A .............................................................................................................................. 8 
4.2. Part B ............................................................................................................................. 11 
5. SAMPLE SIZE JUSTIFICATION ...................................................................................... 12 
6. STUDY TREATMENTS ..................................................................................................... 12 
7. DEFINITIONS OF POPULATIONS .................................................................................. 14 
7.1. All Subjects Population ................................................................................................. 14 
7.2. Safety Population .......................................................................................................... 14 
7.3. Pharmacokinetic Population ......................................................................................... 14 
8. STATISTICAL METHODOLOGY .................................................................................... 15 
8.1. General .......................................................................................................................... 15 
8.1.1. Handling of Data Quality Issues Due to Coronavirus Disease 2019 and Related 
Restrictions ....................................................................................................................... 15 
8.1.2. Calculation of the Summary Statistics ................................................................... 16 
8.1.3. Triplicate Readings................................................................................................. 16 
8.1.4. Repeat and Unscheduled Readings ........................................................................ 17 
8.1.5. Definitions of Baseline and Change from Baseline ............................................... 17 
8.2. Subject Disposition and Population Assignment .......................................................... 17 
8.3. Screening Demographics .............................................................................................. 17 
8.4. Prior and Concomitant Medication ............................................................................... 18 
8.5. Pharmacokinetic Assessments ...................................................................................... 18 
8.5.1. Pharmacokinetic Analysis ...................................................................................... 18 
8.5.2. Presentation of Pharmacokinetic Data ................................................................... 22 


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ST-AD-031 Version 02 
8.5.3. Pharmacokinetic Statistical Methodology .............................................................. 23 
8.6. Safety and Tolerability Assessments ............................................................................ 25 
8.6.1. Adverse Events ....................................................................................................... 25 
8.6.2. Clinical Laboratory Parameters .............................................................................. 27 
8.6.3. Vital Signs Parameters ........................................................................................... 27 
8.6.4. 12-lead Electrocardiogram Parameters .................................................................. 27 
8.6.5. Other Assessments ................................................................................................. 28 
8.6.6. Safety and Tolerability Statistical Methodology .................................................... 28 
9. INTERIM ANALYSES ....................................................................................................... 28 
10. SIGNIFICANT CHANGES FROM THE PROTOCOL-SPECIFIED ANALYSES ........ 28 
11. REFERENCES .................................................................................................................. 28 
12. APPENDICES ................................................................................................................... 30 
Appendix 1: 
Document History ................................................................................ 30 
 
LIST OF IN-TEXT TABLES AND FIGURES 
Table 1: 
Presentation of Study Treatments in TFLs (Part A) ............................................. 13 
Table 2: 
Presentation of Study Treatment Sequences in Listings (Food-effect Group(s) in 
Part A Only) .......................................................................................................... 13 
Table 3: 
Presentation of Study Treatments in TFLs (Part B) .............................................. 14 
 
Figure 1: 
Study Schematic (Part A) for Groups A1, A2, and A4 to A6 ............................... 10 
Figure 2: 
Study Schematic (Part A) for Food-effect Evaluation(s) ...................................... 10 
Figure 3: 
Planned Dose Levels (Part A) ............................................................................... 10 
Figure 4: 
Study Schematic (Part B) ...................................................................................... 11 
Figure 5: 
Planned Dose Levels (Part B) ............................................................................... 12 
 


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Protocol Reference: 1476-291-001 
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ST-AD-031 Version 02 
LIST OF ABBREVIATIONS 
Abbreviations pertain to the statistical analysis plan (SAP) only (not the tables, figures, and 
listings [TFLs]). 
ADaM 
Analysis Data Model 
AE 
adverse event 
Aet1-t2 
amount of the dose administered recovered over the time interval t1 to t2 
ANOVA 
analysis of variance 
AUC 
area under the concentration-time curve 
AUC0-∞ 
area under the concentration-time curve from time 0 to infinity 
AUC0-tlast 
area under the concentration-time curve from time 0 to the time of the last 
quantifiable concentration 
AUC0-τ 
area under the concentration-time curve over a dosing interval (τ) 
BID 
twice daily  
BLQ 
below the limit of quantification 
CDISC 
Clinical Data Interchange Standards Consortium 
CI 
confidence interval 
CL/F 
apparent total clearance 
CLR 
renal clearance 
Cmax 
maximum observed concentration 
Cmin 
minimum observed concentration 
COVID-19 
coronavirus disease 2019 
CRU 
Clinical Research Unit 
CSR 
clinical study report 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CV 
coefficient of variation 
DAUC0-∞ 
AUC0-∞ normalised by dose administered 
DAUC0-tlast 
AUC0-tlast normalised by dose administered 
DAUC0-τ 
AUC0-τ normalised by dose administered 
DCmax 
Cmax normalised by dose administered 
DMP 
data management plan 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
fet1-t2 
percentage of the dose administered recovered over the time interval 
t1 to t2 
GLSM 
geometric least squares mean 
ICH 
International Council for/Conference on Harmonisation 
LLOQ 
lower limit of quantification 
ln 
natural log 


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ST-AD-031 Version 02 
LSM 
least squares mean 
MedDRA 
Medical Dictionary for Regulatory Activities 
PK 
pharmacokinetic(s) 
QD 
once daily 
QTcB 
QT interval corrected for heart rate using Bazett’s formula 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
R2-adj 
adjusted coefficient for determination of exponential fit 
RAAUC0-τ 
observed accumulation ratio based on AUC0-τ 
RACmax 
observed accumulation ratio based on Cmax 
SAP 
statistical analysis plan 
SD 
standard deviation 
SDV 
source document verification 
t1/2 
apparent terminal elimination half-life 
TEAE 
treatment-emergent adverse event 
TFL 
table, figure, and listing 
tlast 
time of the last quantifiable concentration 
tmax 
time of the maximum observed concentration 
Vz/F 
apparent volume of distribution 
WHODrug 
World Health Organization Drug Dictionary  
λz 
apparent terminal elimination rate constant 
λz Lower 
start of exponential fit 
λz N 
number of data points included in the log-linear regression 
λz Span Ratio time period over which λz was determined as a ratio of t1/2 
λz Upper 
end of exponential fit 


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Protocol Reference: 1476-291-001 
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ST-AD-031 Version 02 
1. INTRODUCTION 
This SAP has been developed after review of the clinical study protocol (Final Version 5 
dated 06 January 2021) and electronic case report form (eCRF).  
This SAP describes the planned analysis of the pharmacokinetic (PK), safety, and tolerability 
data from this study. A detailed description of the planned TFLs to be presented in the 
clinical study report (CSR) is provided in the accompanying TFL shells document.  
In general, the analyses are based on information from the protocol, unless they have been 
modified by agreement with AnaMar AB. A limited amount of information about this study 
(eg, objectives, study design) is given to help the reader’s interpretation.  
This SAP must be finalised prior to any unblinding of study data for analysis purposes 
(interim or final). Additionally, the SAP and TFL shells should be finalised prior to any 
programming activities commencing. 
This SAP supersedes any statistical considerations identified in the protocol; where 
considerations are substantially different, they will be so identified. If additional analyses are 
required to supplement the planned analyses described in this SAP, they may be performed 
and will be identified accordingly in the CSR. Any substantial deviations from this SAP will 
be agreed with AnaMar AB and identified in the CSR.  
This SAP is written with consideration of the recommendations outlined in the International 
Conference on Harmonisation (ICH) E3 guideline Structure and Content of Clinical Study 
Reports, ICH E8 guideline General Considerations for Clinical Trials, and ICH E9 guideline 
Statistical Principles for Clinical Trials.1,2,3 
The document history is presented in Appendix 1.  
2. STUDY OBJECTIVES  
The primary objective of the study is: 
● to determine the safety and tolerability of single and multiple oral doses of AM1476 in 
healthy subjects. 
The secondary objectives of the study are: 
● to determine the single- and multiple-oral dose PK of AM1476 in healthy subjects. 
● to determine the effect of food on the single-oral dose PK of AM1476 in healthy 
subjects.  


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ST-AD-031 Version 02 
3. STUDY ENDPOINTS  
3.1. Primary Endpoints 
The primary safety endpoints for this study are as follows: 
● incidence and severity of adverse events (AEs) 
● incidence of laboratory abnormalities, based on haematology, clinical chemistry, 
coagulation, and urinalysis test results 
● vital signs measurements 
● 12-lead electrocardiogram (ECG) parameters 
● telemetry 
● neurological examinations 
● Columbia-Suicide Severity Rating Scale (C-SSRS) 
● physical examinations. 
3.2. Secondary Endpoints 
For Part A, the single-ascending dose and food (fed versus fasted dietary status at dosing), 
PK outcome endpoints of AM1476 are as follows: 
● area under the concentration-time curve from time 0 to infinity (AUC0-∞) 
● area under the concentration-time curve from time 0 to the time of the last quantifiable 
concentration (AUC0-tlast) 
● maximum observed concentration (Cmax) 
● time of the maximum observed concentration (tmax) 
● apparent terminal elimination half-life (t½) 
● apparent total clearance (CL/F) 
● apparent volume of distribution (Vz/F) 
● renal clearance (CLR) 
● amount of the dose administered recovered over the time interval t1 to t2 (Aet1-t2) 
● percentage of the dose administered recovered over the time interval t1 to t2 (Fet1-t2). 


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ST-AD-031 Version 02 
For Part B, the multiple-ascending dose PK outcome endpoints of AM1476 are as follows: 
● area under the concentration-time curve over a dosing interval (AUC0-τ) 
● AUC0-∞ (Day 1 only) 
● Cmax 
● minimum observed concentration (Cmin) 
● tmax 
● t½ 
● CL/F 
● Vz/F 
● observed accumulation ratio based on AUC0-τ (RAAUC0-τ) 
● observed accumulation ratio based on Cmax (RACmax) 
● CLR 
● Ae 
● Fe. 
Other PK parameters may also be reported. 
4. STUDY DESIGN  
This will be a double-blind, randomised, placebo-controlled, single- and multiple-oral dose 
study conducted in 2 parts. 
4.1. Part A 
Part A will comprise a single-ascending dose, sequential-group design incorporating a 
single-group, 2-period crossover arm incorporating a food-effect evaluation. Overall, 
48 subjects will be studied in 6 groups (Groups A1 to A6), with each group consisting of 
8 subjects. 
Potential subjects will be screened to assess their eligibility to enter the study within 28 days 
prior to the first dose administration (within 35 days for Group A1). Each subject will 
participate in 1 treatment period only, except for those participating in a food-effect 
evaluation, where each subject will participate in 2 treatment periods separated by a 
minimum of 6 days. 


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ST-AD-031 Version 02 
Subjects will reside at the Clinical Research Unit (CRU) from Day -1 (the day before dosing) 
to Day 3 of each treatment period, as applicable. All subjects will return for a Follow-up visit 
7 to 10 days after their final dose. 
Based on the ongoing review of the safety, tolerability, and PK results, additional 
non-residential visits may be required. The number of additional visits per subject will not 
exceed 3 per period and will not extend beyond 28 days after each final dosing occasion. 
In each of Groups A1 to A6, 6 subjects will receive AM1476 and 2 subjects will receive 
placebo. 
Groups A1, A2, and A4 to A6 
It is planned for each subject in Groups A1, A2, and A4 to A6 to receive only a single dose of 
AM1476 or placebo during the study. Doses will be administered in the fasted state in 
accordance with a randomisation schedule on the morning of Day 1. 
Group A3 
It is planned for each subject in Group A3 to have the same treatment in both treatment 
period such that each subject will receive 2 single doses of AM1476 or placebo during the 
study. On Day 1 in Treatment Period 1, doses will be administered in the fasted state in 
accordance with a randomisation schedule. On Day 1 in Treatment Period 2, doses will be 
given 30 minutes after starting a standard high-fat breakfast. Although a food-effect 
evaluation is planned to occur in Group A3, this may be subject to change depending upon 
ongoing review of the PK data. 
Additional Groups (Groups A7 to A9) 
If it is decided to enrol additional groups, the effect of food on the PK of AM1476 may 
further be evaluated as described for Group A3. However, fasting requirements, meal 
compositions, and timing of doses will be determined following review of the available PK 
data. 
Sentinel Dosing 
All groups in Part A will be divided into 2 cohorts, with each cohort being dosed at least 
24 hours apart. The first cohort will comprise 2 subjects, with 1 subject receiving AM1476 
and 1 subject receiving placebo. The second cohort will comprise 6 subjects, with 5 subjects 
receiving AM1476 and 1 subject receiving placebo. For groups participating in a food-effect 
evaluation, sentinel dosing will only be utilised in Treatment Period 1 when AM1476 or 
placebo are administered in the fasted state. Dosing of subjects in the second cohort will not 
continue if any of the dose escalation stopping criteria are met by the sentinel subjects (first 
cohort). 
The total duration of study participation for each subject (from Screening through Follow-up 
visit) is anticipated to be approximately 6 weeks for subjects not participating in the 
food-effect evaluation (approximately 7 weeks for Group A1) and approximately 7 weeks for 
those participating in the food-effect evaluation. 
An overview of the study design is shown in Figure 1 and Figure 2, and the planned dose 
levels in Figure 3.  


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ST-AD-031 Version 02 
Figure 1: Study Schematic (Part A) for Groups A1, A2, and A4 to A6 
 
Abbreviations: CRU = Clinical Research Unit; N = number of subjects. 
Note: Group A1: Screening period from Day -35 to Day -2 (approximately 5 weeks) 
Figure 2: Study Schematic (Part A) for Food-effect Evaluation(s) 
 
Abbreviations: CRU = Clinical Research Unit; N = number of subjects. 
Figure 3: Planned Dose Levels (Part A) 
 
Abbreviations: N = number of subjects; PK = pharmacokinetic(s); TBD = to be determined. 
NOTE: dose levels may be adjusted based on the ongoing review of the safety, tolerability, and PK data. Doses will be 
administered in an escalating manner following satisfactory review by the Sponsor and Investigator of the safety and 
tolerability data (up to 48 hours post-final dose) and plasma PK data (up to 24 hours post-final dose [ie, Day 1 in Part A]) 
from the lower dose levels. 
Although the food-effect evaluation is planned to occur in Group A3, this may be subject to change depending upon ongoing 
review of the PK data. 


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ST-AD-031 Version 02 
4.2. Part B 
Part B will comprise a multiple-ascending dose, sequential-group design. Overall, it is 
planned for 24 subjects to be studied in 3 groups (Groups B1 to B3), with each group 
consisting of 8 subjects. Part B may start following review of the safety and tolerability and 
PK data for Group A4, at a dose equal or less than given in Groups A1 to A4, provided the 
predicted exposure is not expected to exceed an exposure already shown to be safe and well 
tolerated. The dose level cannot be equal to a dose level from Part A if that dose met any of 
the dose escalation stopping rules. 
Potential subjects will be screened to assess their eligibility to enter the study within 28 days 
prior to the first dose administration. Each subject will participate in 1 treatment period only 
and reside at the CRU from Day -1 until the morning of Day 12. All subjects will return for a 
Follow-up visit 7 to 10 days after their final dose. 
Based on the ongoing review of available safety, tolerability, and PK data, up to 3 additional 
non-residential visits may be required. The number of additional visits per subject will not 
exceed 3 and will not extend beyond 28 days after each final dosing occasion. 
In each of Groups B1 to B3, 6 subjects will receive AM1476 and 2 subjects will receive 
placebo. The dietary state for dosing in Part B will be subject to review of the PK data from 
the fed/fasted comparison in Part A. For all subjects, dosing is planned to be once daily (QD) 
on Days 1 to 10, inclusive. However, the dietary state (including fasting requirement and 
meal compositions), dosing duration, and dosing frequency may be changed following review 
of safety, tolerability, and PK data from Part A or earlier groups in Part B. The dose regimen 
will comprise no less than once every 2 days and will not exceed twice daily (BID) dosing. 
The predicted total daily exposure at the selected dose administered will not exceed an 
exposure shown to be safe and well-tolerated in Part A. The dosing duration will comprise no 
fewer than 7 consecutive days and will not exceed 28 consecutive days. There will be a 
minimum of 6 days between dose escalations for each group. 
The total duration of study participation for each subject (from Screening through Follow-up 
visit) is anticipated to be approximately 7 weeks. 
An overview of the study design is shown in Figure 4 and the planned dose levels in Figure 5.  
Figure 4: Study Schematic (Part B) 
 
Abbreviations: BID = twice daily; CRU = Clinical Research Unit; N = number of subjects; QD = once daily. 
a. 
Dosing is planned to be QD on Days 1 to 10, inclusive. The dosing regimen in Part B may be changed following 
review of data from groups in Part A or earlier groups in Part B. The dose regimen will comprise no less than once every 


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ST-AD-031 Version 02 
2 days and will not exceed BID dosing. The dosing duration will comprise no fewer than 7 consecutive days and will not 
exceed 28 consecutive days. 
Figure 5: Planned Dose Levels (Part B) 
 
Abbreviations: BID = twice daily; N = number of subjects; QD = once daily; TBD = to be determined. 
NOTE: doses will be administered in an escalating manner following satisfactory review by the Sponsor and Investigator of 
the safety and tolerability data (up to 48 hours post-final dose) and plasma PK data (up to 24 hours post-final dose [ie, Day 1 
in Part A and Day 10 in Part B]) from Part A or earlier groups in Part B. 
a. 
Dosing is planned to be QD on Days 1 to 10, inclusive. The dosing regimen in Part B may be changed following 
review of data from groups in Part A or earlier groups in Part B and will not exceed BID dosing. 
5. SAMPLE SIZE JUSTIFICATION  
No formal statistical assessment, in terms of sample size, has been conducted as this is the 
first time AM1476 is being administered to humans. However, the number of subjects in each 
part of the present study is common in early clinical pharmacology studies and is considered 
sufficient to achieve the objectives of the study.  
6. STUDY TREATMENTS  
The study treatment names and ordering to be used in the TFLs for Part A are presented in 
Table 1 and for Part B in Table 3. The study treatment sequence names and ordering to be 
used in listings for food-effect group(s) in Part A only are presented in Table 2. 


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ST-AD-031 Version 02 
Table 1: 
Presentation of Study Treatments in TFLs (Part A) 
Group 
Study Treatment 
Order in TFLs 
A1 to A9 
Placeboa 
1 
A1 
1 mg AM1476 (Fasted) 
2 
A2 
XX mg AM1476 (Fasted) 
3 
A3 
XX mg AM1476 (Fasted) 
4 
 
XX mg AM1476 (Fed) 
5 
A4 
XX mg AM1476 (Fasted) 
6 
A5 
XX mg AM1476 (Fasted) 
7 
A6 
XX mg AM1476 (Fasted) 
8 
A7b 
XX mg AM1476 (Fasted) 
9 
 
XX mg AM1476 (Fed)c 
10 
A8b 
XX mg AM1476 (Fasted) 
11 
 
XX mg AM1476 (Fed)c 
12 
A9b 
XX mg AM1476 (Fasted) 
13 
 
XX mg AM1476 (Fed)c 
14 
a. 
Placebo will be pooled across all groups and fasting conditions 
b. 
Optional group, to be included if required 
c. 
Optional group may or may not include food-effect evaluation  
Table 2: 
Presentation of Study Treatment Sequences in Listings (Food-effect 
Group(s) in Part A Only) 
Group 
Study Treatment Sequence 
Order in TFLs 
A3 
Placebo (Fasted) / Placebo (Fed) 
1 
 
XX mg AM1476 (Fasted) / XX mg AM1476 (Fed) 
2 
A7a,b 
Placebo (Fasted) / Placebo (Fed) 
3 
 
XX mg AM1476 (Fasted) / XX mg AM1476 (Fed) 
4 
A8a,b 
Placebo (Fasted) / Placebo (Fed) 
5 
 
XX mg AM1476 (Fasted) / XX mg AM1476 (Fed) 
6 
A9a,b 
Placebo (Fasted) / Placebo (Fed) 
7 
 
XX mg AM1476 (Fasted) / XX mg AM1476 (Fed) 
8 
a. 
Optional group, to be included if required 
b. 
Optional group may or may not include food-effect evaluation  


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ST-AD-031 Version 02 
Table 3: 
Presentation of Study Treatments in TFLs (Part B) 
Group 
Study Treatment 
Order in TFLs 
B1 to B6 
Placeboa 
1 
B1 
XX mg AM1476 (QD) (Fasted) 
2 
B2 
XX mg AM1476 (QD) (Fasted) 
3 
B3 
XX mg AM1476 (QD) (Fasted) 
4 
B4b 
XX mg AM1476 (QD) (Fasted) 
5 
B5b 
XX mg AM1476 (QD) (Fasted) 
6 
B6b 
XX mg AM1476 (QD) (Fasted) 
7 
Abbreviations:  QD = once daily 
a. 
Placebo will be pooled across all groups 
b. 
Optional group, to be included if required 
All TFLs will be based on actual treatments (eg, if subject was assigned to receive placebo 
but was wrongfully dosed with active treatment they would be summarised and listed under 
active treatment). 
All dose levels described above are the potential dose levels, and therefore are subject to 
change. The TFLs will reflect the dose levels utilised in the study, and these will be displayed 
in increasing order. 
All fasting conditions described above are the potential fasting conditions, and therefore are 
subject to change. The TFLs will reflect the fasting conditions utilised in the study. 
All food-effect groups described above are the potential food-effect groups, and therefore are 
subject to change. The TFLs will reflect the food-effect groups utilised in the study. 
7. DEFINITIONS OF POPULATIONS  
Any protocol deviations, including those due to coronavirus disease 2019 (COVID-19) and 
related restrictions (see Section 8.1.1), will be considered prior to database lock for their 
importance and taken into consideration when assigning subjects to populations. 
7.1. All Subjects Population  
The all subjects population will include all subjects who signed the informed consent form 
and had any study assessment recorded in the database per the protocol.  
7.2. Safety Population  
The safety population will include all subjects who received at least 1 dose of study treatment 
(AM1476 or placebo). 
7.3. Pharmacokinetic Population  
The PK population will include all subjects who received at least 1 dose of active study 
treatment (AM1476) and have at least 1 valid PK concentration. 


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8. STATISTICAL METHODOLOGY  
8.1. General  
Listings will be provided for all data captured in the database, with the exception of medical 
history. Listings will include all subjects assigned to the all subjects population and include 
data up to the point of study completion or discontinuation. Subjects are generally considered 
to have completed the study if they complete the scheduled follow-up visit (rather than early 
termination visit). Any subject who discontinues the study will be identified accordingly in 
the listings. Summaries and statistical analyses will include the subjects assigned to the 
relevant population based on data type. 
Analysis Data Model (ADaM) datasets will be prepared using Clinical Data Interchange 
Standards Consortium (CDISC) ADaM Version 2.1 (or higher if a new version is issued 
during the study) and CDISC ADaM Implementation Guide Version 1.1 (or higher if a new 
version is issued during the study). Pinnacle 21 Community Validator Version 3.0.2 (or 
higher if a new version is issued during the study) will be utilised to ensure compliance with 
CDISC standards. 
For all statistical analyses, the hypothesis testing will be 2-sided and carried out on 0.05 
significance level, unless specifically stated otherwise. 
Caution should be used when interpreting results from the statistical analyses conducted in 
this study because the sample size is not based on power calculations. 
Where reference is made to ‘valid’ data, this refers to non-missing data which meet the 
predetermined criteria (eg, are not flagged for exclusion).  
Where reference is made to ‘all calculations’, this includes, but is not limited to, summary 
statistics, statistical analyses, baseline derivation, and changes from baseline. 
All figures will be produced on linear-linear or discrete-linear scales, as applicable, unless 
specifically stated otherwise. 
8.1.1. Handling of Data Quality Issues Due to Coronavirus Disease 2019 and Related 
Restrictions 
Due to COVID-19 and related restrictions, there is a high risk for impact to data integrity, 
with the recognised potential for: 
● Missed visits, caused by, for example: 
o Subject unable to travel to site due to restrictions, the need to quarantine, or 
COVID-19 infection 
o Subject unwilling to go to site due to fear of COVID-19 infection 
o Site postponing subject’s visit due to investigator not being available (eg, if they 
have been dispatched to hospital handling COVID-19 infections) 


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● Site unable to replenish supply of investigational product 
● Incomplete data entry by sites due to limited resources to support study or no access to 
source documents or to eCRF 
● Outstanding source document verification (SDV) due to sponsor or country restrictions 
on remote SDV, or no or limited access to site(s) for on-site visits 
● Unanswered queries 
At the time of the reporting of the study results, all protocol deviations due to COVID-19 or 
related restriction will be assessed for their severity and impact on the analyses. If needed, 
appropriate statistical methods will be applied as a mitigating action (eg, data might be 
categorised into 2 analysis groups, with and without COVID-19 and related restrictions 
impact); however, this will exclude any imputations of the missing values. Any mitigating 
actions will be agreed with AnaMar AB in advance and identified in the CSR. 
8.1.2. Calculation of the Summary Statistics  
For continuous data the following rules will be applied:  
● Missing values will not be imputed, unless specifically stated otherwise.  
● Unrounded data will be used in the calculation of summary statistics.  
● In general, as early termination data are not associated with any scheduled timepoint, 
they will be excluded from all calculations of summary statistics. Exceptions may be 
made where justified. 
For categorical data the following rules will be applied:  
● For ordered categorical data (eg, AE severity), all categories between the possible 
minimum and maximum categories will be included, even if n = 0 for a given category.  
● For non-ordered categorical data (eg, race), only those categories for which there is at 
least 1 subject represented will be included; unless specifically stated otherwise.  
● Missing values will not be imputed, unless specifically stated otherwise. A ‘missing’ 
category will be included for any parameter for which information is missing. This will 
ensure that the population size totals are consistent across different parameters.  
8.1.3. Triplicate Readings  
For vital signs data only, where triplicate readings are taken, the median of triplicate readings 
will replace the separate individual triplicate readings in all calculations.  
For 12-lead ECG data only, where triplicate readings are taken, the mean of triplicate 
readings will replace the separate individual triplicate readings in all calculations.  


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In case of incomplete triplicate readings (eg, only 2 out of 3 readings were recorded), the 
mean and/or medians will be calculated, as appropriate, based on the number of readings 
available.  
8.1.4. Repeat and Unscheduled Readings  
For vital signs and 12-lead ECG data only, any predose value recorded in addition to the 
original value or a postdose value recorded within 15 minutes of the original value will be 
defined as a repeat value; any postdose value recorded more than 15 minutes after the 
original value will be defined as an unscheduled value. For all other data types (eg, laboratory 
parameters), any value recorded in addition to the original value will be defined as an 
unscheduled value.  
The original value will be replaced by the last associated repeat value in all calculations, with 
the exception of the 12-lead ECG outlier analysis (see Section 8.6.4). 
As unscheduled values are not associated with any scheduled timepoint, they will be 
excluded from all calculations, with the exception of the baseline derivation (see 
Section 8.1.5) and 12-lead ECG outlier analysis (see Section 8.6.4).  
8.1.5. Definitions of Baseline and Change from Baseline 
The baseline will be defined as the last value recorded prior to the first dose. If the date/time 
of the value is incomplete or missing, it will be excluded from the baseline calculation, unless 
the incomplete date/time indicates the value was recorded prior to the first dose. 
Individual changes from baseline will be calculated by subtracting the individual subject’s 
baseline value from the value at the postdose timepoint. 
The summary statistics for change from baseline will be derived from individual subjects’ 
values (eg, mean change from baseline will be the mean of the individual changes from 
baseline for all subjects, rather than difference between the mean value at the postdose 
timepoint and mean value at baseline). 
See Section 8.1.4 for more detail on handling repeat and unscheduled readings in the 
calculations. See Section 8.1.3 for more detail on handling of triplicate readings in the 
calculations.  
8.2. Subject Disposition and Population Assignment  
Subject disposition and population assignment will be listed. A summary table by treatment 
will be provided, based on the safety population. 
8.3. Screening Demographics 
The screening demographics including age, sex, height, body weight, and body mass index 
will be listed. A separate summary table by treatment will be provided, based on the safety 
and PK populations. 


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8.4. Prior and Concomitant Medication  
Prior medication will be defined as medication that ends prior to the first dose. Concomitant 
medication will be defined as medication that starts during or after the first dose or starts but 
does not end prior to the first dose. 
Prior and concomitant medications will be coded using the World Health Organization Drug 
Dictionary (WHODrug) Global, Format B3, Version September 2020 (or later if a new 
version is issued during the study; see the data management plan [DMP] for more details). 
Prior and concomitant medications will be listed. 
8.5. Pharmacokinetic Assessments 
8.5.1. Pharmacokinetic Analysis  
The following PK parameters will be determined where possible from the plasma and urine 
concentrations of AM1476 using noncompartmental methods in validated software program 
Phoenix WinNonlin (Certara, Version 8.1 or higher): 
Part A (Single Dose) 
Parameter 
Unitsa 
Definition 
AUC0-tlast 
ng*h/mL 
area under the concentration-time curve from time 0 to the time of 
the last quantifiable concentration (tlast)b 
AUC0-∞ 
ng*h/mL 
area under the concentration-time curve from time 0 extrapolated 
to infinity b,c 
Cmax 
ng/mL 
maximum observed concentration 
tmax 
h 
time of the maximum observed concentration 
tlast 
h 
time of the last quantifiable concentration 
t1/2 
h 
apparent terminal elimination half-life 
CL/F 
L/h 
apparent total clearance 
Vz/F 
L 
apparent volume of distribution during the terminal phase 
CLR 
L/h 
renal clearance 
Aet1-t2 
mg 
amount of the dose administered recovered over the time interval 
t1 to t2 
fet1-t2 
% 
percentage of the dose administered recovered over the time 
interval t1 to t2 
DAUC0-tlast 
h*ng/mL/mg 
AUC0-tlast normalised by dose administered d 
DAUC0-∞ 
h*ng/mL/mg 
AUC0-∞ normalised by dose administered d 
DCmax 
ng/mL/mg 
Cmax normalised by dose administered d 
Abbreviations: AUC = area under the concentration-time curve; PK = pharmacokinetic(s). 
a. 
Units are based on concentration units (provided by the bioanalytical lab or preferred units for presentation of PK 
parameters) and dose units used in the study. 
b. 
The AUC will be calculated using the linear trapezoidal rule for increasing concentrations and the logarithmic rule for 
decreasing concentrations (linear up/log down rule).  
c. 
Based on the last observed quantifiable concentration 
d. 
Calculated by dividing the parameter by the dose (mg) 


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Part B (Multiple-dose) 
Parameter 
Unitsa 
Definition 
AUC0-τ 
ng*h/mL 
area under the concentration-time curve over a dosing interval 
(τ) b 
AUC0-∞ 
ng*h/mL 
area under the concentration-time curve from time 0 to infinity 
(Day 1 only) b,c 
Cmax 
ng/mL 
maximum observed concentration 
Cmin 
ng/mL 
minimum observed concentration 
tmax 
h 
time of the maximum observed concentration 
t1/2 
h 
apparent terminal elimination half-life 
CL/F 
L/h 
apparent total clearance 
Vz/F 
L 
apparent volume of distribution during the terminal phase 
RAAUC0-τ 
 
observed accumulation ratio based on AUC0-τ 
RACmax 
 
observed accumulation ratio based on Cmax 
CLR 
L/h 
renal clearance 
Aet1-t2 
mg 
amount of the dose administered recovered over the time 
interval t1 to t2 
fet1-t2 
% 
percentage of the dose administered recovered over the time 
interval t1 to t2 
DAUC0-τ 
h*ng/mL/mg AUC0-τ normalised by dose administered d 
DCmax 
ng/mL/mg 
Cmax normalised by dose administered d 
Abbreviations: AUC = area under the concentration-time curve; PK = pharmacokinetic(s). 
a. 
Units are based on concentration units (provided by the bioanalytical lab or preferred units for presentation of PK 
parameters) and dose units used in the study. 
b. 
The AUC will be calculated using the linear trapezoidal rule for increasing concentrations and the logarithmic rule for 
decreasing concentrations (linear up/log down rule).  
c. 
Based on the last observed quantifiable concentration 
d. 
Calculated by dividing the parameter by the dose (mg) 
Additional PK parameters may be calculated, as appropriate.   
Pharmacokinetic analysis will be carried out where possible using actual blood sampling 
times postdose. If an actual time is missing, the sample concentration result will be treated as 
missing unless there is scientific justification to include the result using the nominal time.  
Cmax, Cmin, tlast and tmax will be obtained directly from the concentration-time profiles. If Cmax 
occurs at more than 1 timepoint, tmax will be assigned to the first occurrence of Cmax.  
The accumulation ratio(s) (ARAUC and ARCmax) will be calculated as follows: 
RAAUC0-τ = AUC0-τ profile day 10 / AUC0-τ profile day 1 
RACmax = Cmax profile day 10 / Cmax profile day 1 
The parameter AUC0-tlast or other common partial area may be used to determine RAAUC0-τ if 
AUC0-τ cannot be reliably calculated for the majority of subjects. 


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8.5.1.1. Criteria for the Calculation of Apparent Terminal Elimination Rate Constant 
and Half-Life 
The start of the terminal elimination phase for each subject will be defined by visual 
inspection and generally will be the first point at which there is no systematic deviation from 
the log-linear decline in concentrations.  
The apparent terminal elimination rate constant (λz) will only be calculated when a reliable 
estimate can be obtained using at least 3 data points, preferably not including Cmax, and the 
adjusted coefficient for determination of exponential fit (R2-adj) of the regression line is ≥0.7. 
Parameters requiring λz in their calculation (eg, AUC0-∞, t1/2, CL/F [profile day 1 only] and 
Vz/F) will only be calculated if the R2-adj value of the regression line is ≥0.7.  
The following regression-related diagnostic PK parameters will be determined where 
possible: 
Parameter 
Unitsa 
Definition 
λz 
1/h 
apparent terminal elimination rate constant 
λz Upper 
h 
end of exponential fit 
λz Lower 
h 
start of exponential fit 
λz N 
 
number of data points included in the log-linear regression 
λz Span Ratio 
 
time period over which λz was determined as a ratio of t1/2 
R2-adj 
 
adjusted coefficient for determination of exponential fit 
Where possible, the span of time used in the determination of λz (ie the difference between λz 
Upper and λz Lower) should be ≥2 half-lives. If the λz Span Ratio is <2, the robustness of the 
t1/2 values will be discussed in the CSR. 
8.5.1.2. Criteria for Calculation and Reporting of Area Under the Concentration-time 
Curve 
The minimum requirement for the calculation of area under the concentration-time curve 
(AUC) will be the inclusion of at least 3 consecutive concentrations above the lower limit of 
quantification (LLOQ). If there are only 3 consecutive concentrations, at least 1 should 
follow Cmax. 
If the extrapolated area is >20%, AUC0-∞ (and derived parameters) may be excluded from 
summary statistics and statistical analysis at the discretion of the sponsor or 
pharmacokineticist. 
If AUC0-∞ cannot be determined reliably for all subjects and/or dose levels, an alternative 
AUC measure, such as AUC to a fixed timepoint or AUC0-tlast, may be used in the statistical 
analysis of dose proportionality/food-effect. 
If the end of the dosing interval PK blood sample is collected slightly early (ie, the 24 hour 
sample), the actual sampling time of the scheduled τ sample (24 hours) may be used for the 


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calculation of AUC0-τ. However, the AUC0-τ parameter will be calculated if the τ sample is 
within 60 minutes of the nominal sampling time. 
8.5.1.3. Calculation of Urinary Parameters   
The amount of drug excreted in urine (Ae) in urine for AM1476 and urine collection interval 
(t1-t2) will be calculated as the product of urine AM1476 concentration and urine volume. 
Where only urine sample weight is supplied, a specific gravity of 1 g/mL will be assumed, 
and it will be considered equivalent to urine volume. A total cumulative Ae0-x h will be 
calculated by summing the Aet1-t2 values over the 0-x h interval, where x = the end of the last 
collection time interval.  
The percentage of the dose administered over the time interval t1 to t2 (fet1-t2) as AM1476 
will be calculated for each urine collection interval as follows:  
fet1-t2 = (Aet1-t2 / dose) × 100. 
Cumulative fe0-x h will be calculated by summing the fet1-t2 values over the 0-x h period in the 
same manner as Ae0-x h. 
Renal clearance (CLR) will be calculated over 0-t2 according to the following formula, where 
cumulative Ae and AUC are calculable to the same end time (t2):  
CLR = Ae0-t2 / AUC0-t2.  
Alternatively, AUC0-∞ may be used (applicable to profile day 1 only) if urinary excretion of 
the dose is considered to be complete and AUC0- is well characterised. 
8.5.1.4. Criteria for Handling Concentration Below the Limit of Quantification or 
Missing Concentrations for Pharmacokinetic Analysis 
Plasma concentrations below the limit of quantification (BLQ) will be assigned a value of 0 
before the first measurable concentration and thereafter BLQs will be treated as missing. The 
following rules apply with special situations defined below: 
● If an entire concentration-time profile is BLQ, it will be excluded from PK analysis. 
● Where 2 or more consecutive concentrations are BLQ at the end of a profile, the profile 
will be deemed to have terminated and any further quantifiable concentrations will be 
set to missing for the calculation of the PK parameters, unless they are considered to be 
a true characteristic of the profile of the drug. 
● If a predose plasma concentration is missing, it may be set to 0 by default. 
● For multiple dose occasion parts of the study only (profile day 10), if the concentration 
at τ (Cτ) is missing, this may be substituted with the predose concentration. Similarly, if 
the predose concentration is missing, this may be substituted with Cτ. 
Urine concentrations that are BLQ will be set to 0 for the calculation of Aet1-t2. 


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8.5.1.5. Treatment of Outliers in Pharmacokinetic Analysis 
If a value is considered to be anomalous due to being inconsistent with the expected PK 
profile, it may be appropriate to exclude this point from the PK analysis. However, the 
exclusion of data must have strong justification and will be documented in CSR.   
Any quantifiable predose concentration value on the first dosing day of all parts of the study 
(profile day 1) will be considered anomalous and set to missing for the PK analysis. This will 
be set to 0 by default in Phoenix WinNonlin. 
8.5.2. Presentation of Pharmacokinetic Data 
All PK concentrations and parameters will be listed.  
Summary tables, arithmetic mean (+ standard deviation [SD]) figures, overlaying individual 
figures, and individual figures by treatment and time postdose will be provided for plasma 
PK concentrations. All figures will be produced on both linear-linear and linear-logarithmic 
scales, with the exception of figures across all days, which will be produced on the 
linear-linear scale only. The +SD bars will only be displayed on the linear-linear scale.  
Summary tables by treatment will be provided for all PK parameters, with the exception of 
diagnostic regression-related PK parameters. Separate summary tables by treatment and time 
interval will be provided for excretion parameters and cumulative excretion parameters.  
A subject may be excluded from the PK summary statistics and statistical analysis if the 
subject has an AE of vomiting that occurs at or before 2 times the median tmax. 
Any exclusions from PK summary statistics and/or statistical analysis will be identified by 
pharmacokineticist and will be agreed with AnaMar AB. 
If the actual time of sample collection deviates from the nominal time by more than ±10%, 
the concentration will be flagged and excluded from summary statistics. Individual 
concentrations that are deemed to be anomalous will be flagged in the listings and excluded 
from the summary statistics.   
For PK concentration data the following rules will apply: 
● Values that are BLQ will be set to 0 for the calculation of summary statistics. 
● Arithmetic mean or median values that are BLQ will be presented as 0. 
For PK parameters the following rule will apply: 
● Geometric mean and coefficient of variation (CV) will not be calculated for tlast and 
tmax.  


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8.5.3. Pharmacokinetic Statistical Methodology  
8.5.3.1. Dose Proportionality Assessment  
A statistical analysis will be conducted to investigate the dose proportionality of AUC0-tlast, 
AUC0-∞, and Cmax on profile day 1 for Part A and AUC0-τ and Cmax on profile day 10 for Part 
B (only for plasma AM1476). 
The PK parameters will be analysed using a power model4 that will have the following form: 
parameter = intercept × doseslope × random error 
Using the natural log (ln) transformation,5 a power model can be expressed as a linear 
regression equation: 
ln(parameter) = intercept + slope × ln(dose) + random error 
For dose proportionality, the slope of the regression line is equal to 1; for dose independence, 
it is equal to 0.  
For each PK parameter separately, a pooled estimate (across all doses) of slope, 
corresponding 95% confidence interval (CI), and between-subject CV will be calculated. 
Figures (on the logarithmic-logarithmic scale) containing individual values, power model line 
(95% CI), and dose proportionality line (defined as the power model line with slope of 1) will 
be created for each PK parameter. Additionally, figures (on the logarithmic-linear scale) 
containing individual values and geometric means will be created for each corresponding PK 
parameter normalised by dose administered.  
The lack of fit test will be conducted for the statistical assessment of linearity assumption, 
and thus appropriateness of a power model. The lack of fit model will be the same as the 
power model fitted, but with dose included as additional fixed effect. The statistical 
assessment will rule the linearity assumption acceptable if the diagnostic plots appear 
reasonable and the lack of fit 2-sided p-value >0.05 (dose effect is not significant at the 0.05 
level of significance). The assessment of linearity assumption may also occur via visual 
examination of the figures by the pharmacokineticist. This assessment may override the 
statistical assessment; where this occurs, it will be detailed in the CSR.  
It will be concluded that PK parameter is dose proportional for the dose range studied if the 
assumption of linearity is ruled acceptable and the 95% CI for the slope spans 1.  
If the assumption of linearity is ruled unacceptable for any PK parameter, its corresponding 
PK parameter normalised by dose administered will be ln-transformed and analysed using an 
analysis of variance (ANOVA) model.6 The model will include dose as a factor.  
For each PK parameter separately, the geometric least squares mean (GLSM) for each dose, 
p-values for the overall, and pairwise dose comparisons will be calculated. Residual plots will 
be produced to assess the adequacy of the model(s) fitted.  
Examples of the SAS code that will be used are as follows: 


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Power Model Analysis  
proc mixed data = <data in> alpha = 0.05; 
 by parcat1n parcat1 pkday paramn param; 
 model lpk = ldose / cl residual ddfm = kr2; 
 ods output solutionf = <data out>; 
run; 
Power Model Analysis (Between-subject Variability) 
proc mixed data = <data in> covtest alpha = 0.05; 
 by parcat1n parcat1 pkday paramn param; 
 class ldose; 
 model lpk = ldose / cl residual ddfm = kr2; 
 ods output covparms = <data out>; 
run; 
(Note: Pooled Geometric CV (%) = 100*(sqrt(exp(estimate)-1))) 
Power Model Analysis (Lack of Fit Test) 
proc mixed data = <data in>; 
 by parcat1n parcat1 pkday paramn param; 
 class dose; 
 model lpk = ldose dose / htype = 1 ddfm = kr2; 
 ods output tests1 = <data out>; 
run; 
ANOVA Model Analysis 
proc mixed data = <data in> alpha = 0.05; 
 by parcat1n parcat1 pkday paramn param; 
 class dose; 
 model ldnpk = dose / cl residual ddfm = kr2; 
 lsmeans dose / cl pdiff;  
 ods output lsmeans = <data out>;  
 ods output diffs = <data out>; 
 ods output tests3 = <data out>; 
run; 
8.5.3.2. Food-effect Assessment 
A statistical analysis will be conducted to investigate the food-effect on the treatment by 
comparing AM1476 (fed) treatment to AM1476 (fasted) at the same dose level. 
The hypothesis testing will be 2-sided and carried out on both 0.05 and 0.1 significance 
levels. 
The ln-transformed5 AUC0-tlast, AUC0-∞, and Cmax on profile day 1 for food-effect group(s) in 
Part A (only for plasma AM1476) will be analysed using a mixed model.7 The model will 
include actual treatment as fixed effect and subject as a random effect.  
For each PK parameter separately, the least squares mean (LSM) for each treatment, 
difference in LSMs between the fed and fasted treatments, and corresponding 90% and 95% 
CIs will be calculated; these values will then be back-transformed to give the GLSM, ratio of 
GLSMs, and corresponding 90% and 95% CIs. 


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Additionally, the pooled estimate (across treatments) of the within-subject CV will be 
calculated, and residual plots will be produced to assess the adequacy of the model(s) fitted.  
Examples of the SAS code that will be used are as follows: 
Mixed Model Analysis 
proc mixed data = <data in>; 
 by parcat1n parcat1 pkday paramn param; 
 class trtan usubjid; 
 model lpk = trtan / cl residual ddfm = kr2; 
 lsmeans trtan / cl pdiff = control('1') alpha = 0.1; 
 lsmeans trtan / cl pdiff = control('1') alpha = 0.05; 
 random intercept / subject = usubjid;  
 ods output lsmeans = <data out>;  
 ods output diffs = <data out>; 
 ods output covparms = <data out>; 
run; 
8.6. Safety and Tolerability Assessments  
8.6.1. Adverse Events  
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
Version 23.1 (or higher if a new version is issued during the study; see the DMP for more 
details). 
A treatment-emergent adverse event (TEAE) will be defined as an AE that starts during or 
after the first dose, or starts prior to the first dose and increases in severity after the first dose. 
A treatment-related TEAE will be defined as a TEAE with a relationship of possibly related 
or related to the study treatment, as determined by the investigator. 
All AEs will be listed. In addition to the data recorded in the database, the listings will 
include derived onset time and duration. Onset time will be calculated from the time of the 
last associated dose for TEAEs only. Where the last associated dose is referring to the last 
dose received prior to the start of a TEAE. 
The frequency of subjects with TEAEs and the number of TEAEs will be summarised for the 
following categories:  
● TEAEs (overall, serious, leading to discontinuation, and leading to death) by treatment  
● TEAEs by severity and treatment  
● Treatment-related TEAEs (overall, serious, leading to discontinuation, and leading to 
death) by treatment  
● Treatment-related TEAEs by severity and treatment  


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The frequency of subjects will be summarised separately for TEAEs and treatment-related 
TEAEs by the following:  
● System organ class, preferred term, and treatment  
● Preferred term and treatment  
For the AE data the following rules will apply:  
● For the derivation of relationship (applicable to AEs captured on the ‘change in the 
severity’ eCRF form only): The relationship to study treatment is not captured on the 
AE change in severity eCRF form because it is always assumed to be the same as the 
relationship captured on the first eCRF form completed for this AE (initial severity). 
Therefore, for these cases the missing relationship will be set to that captured on the 
first form completed for this AE. 
● For the derivation of treatment-emergent status (applicable to all AEs): If the start 
date/time of an AE is incomplete or missing, an AE will be assumed to not be a TEAE, 
unless the incomplete start date/time or the end date/time indicates an AE started after 
the first dose. 
● For the derivation of treatment-related status (applicable to TEAEs only): If the study 
treatment relationship for a TEAE is missing, a TEAE will be assumed to not be a 
treatment-related TEAE.  
● For the derivation of onset time (applicable to TEAEs only): If the start date/time of a 
TEAE is missing, onset time will not be calculated. If the start date/time of a TEAE is 
incomplete, where possible, the minimum possible onset time will be calculated and 
presented in ‘≥DD:HH:MM’ format (eg, if the date/time of the last associated dose is 
01MAY2019/08:00 and recorded start date/time of a TEAE is 03MAY2019, then the 
minimum possible onset time will be calculated by assuming a TEAE started at the first 
hour and minute of 03MAY2019 [03MAY2019/00:00], thus will be presented as onset 
time ≥01:16:00 in the listing). If the start date of a TEAE is the same as the date of the 
last associated dose but the start time of a TEAE is missing, an onset time will be 
presented as ‘≥00:00:01’. Any clock changes will be accounted for in the derivation. 
● For the derivation of duration (applicable to all AEs): If the end date/time of an AE is 
missing, duration will not be calculated. If the start or end date/time of an AE is 
incomplete, where possible, the maximum possible duration will be calculated and 
presented in ‘≤DD:HH:MM’ format (eg, if the start of an AE date/time is 
01MAY2019/08:00 and its recorded end date/time is 03MAY2019, then the maximum 
possible duration will be calculated by assuming an AE ended at the last hour and 
minute of 03MAY2019 [03MAY2019/23:59], thus will be presented as 
duration ≤02:15:59 in the listing). Any clock changes will be accounted for in the 
derivation.  
● For the calculation of TEAE summary statistics: If the severity of a TEAE is missing, 
that TEAE will be counted under the ‘missing’ category. 


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● For the calculation of TEAE summary statistics: If a subject experienced multiple 
TEAEs with the same preferred term for the same treatment, this will be counted as 1 
TEAE for that treatment under the maximum severity recorded.  
8.6.2. Clinical Laboratory Parameters  
All clinical laboratory parameters will be listed; any value outside the clinical reference range 
will be flagged. Separate listings will be provided for any parameter for which there is any 
individual subject value outside the respective clinical reference range. 
Summary tables and boxplots by treatment and timepoint will be provided for clinical 
chemistry, haematology, and coagulation parameters. 
Values recorded as <x, ≤x, >x, or ≥x will be displayed in the listings as recorded. For the 
derivation of listing flags, all calculations, and presentation in the figures, <x and ≤x values 
will be set to half of x, whereas >x and ≥x values will be set to x. 
8.6.3. Vital Signs Parameters  
For systolic and diastolic blood pressure and pulse rate, orthostatic parameters will be 
calculated as the supine value (recorded prior to the standing value) subtracted from the 
standing value. If the time between the supine and standing values used for derivation of the 
orthostatic value is <2 min, this orthostatic value will be flagged and excluded from all 
calculations. 
All vital signs parameters and their changes from baseline will be listed, as applicable; any 
value outside the clinical reference range will be flagged. This will include any instances of 
orthostatic systolic blood pressure <-20 mmHg, orthostatic diastolic blood pressure 
<-10 mmHg, and orthostatic pulse rate >30 beats/min. 
Summary tables and boxplots by treatment and timepoint will be provided for all vital signs 
parameters and their changes from baseline, as applicable. 
8.6.4. 12-lead Electrocardiogram Parameters  
All 12-lead ECG parameters and their changes from baseline will be listed; any value outside 
the clinical reference range will be flagged. 
Summary tables and boxplots by treatment and timepoint will be provided for all 12-lead 
ECG parameters and their changes from baseline. 
An outlier analysis will be performed for QT interval corrected for heart rate using Bazett’s 
formula (QTcB) and QT interval corrected for heart rate using Fridericia’s formula (QTcF). 
The analysis will include all individual original, repeat, and unscheduled postdose values.  
The maximum postdose values will be summarised by treatment according to the following 
categories:  
● ≤450 ms  


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● >450 and ≤480 ms (all instances flagged in the listing)  
● >480 and ≤500 ms (all instances flagged in the listing)  
● >500 ms (all instances flagged in the listing)  
The maximum increases from baseline will be summarised by treatment according to the 
following categories:  
● ≤30 ms  
● >30 and ≤60 ms (all instances flagged in the listing)  
● >60 ms (all instances flagged in the listing)  
8.6.5. Other Assessments  
Medical history will not be listed. 
Telemetry, neurological examinations, and C-SSRS data will be listed. 
All other safety and tolerability assessments not detailed in the above sections will be listed 
only.  
8.6.6. Safety and Tolerability Statistical Methodology  
No inferential statistical analyses are planned. 
9. INTERIM ANALYSES  
No formal interim analyses are planned for this study. 
10. SIGNIFICANT CHANGES FROM THE PROTOCOL-SPECIFIED ANALYSES  
There were no significant changes from the protocol-specified analyses.  
11. REFERENCES  
1. ICH. ICH Harmonised Tripartite Guideline: Structure and content of clinical study reports 
(E3). 30 November 1995.  
2. ICH. ICH Harmonised Tripartite Guideline: General considerations for clinical trials (E8). 
17 July 1997.  
3. ICH. ICH Harmonised Tripartite Guideline: Statistical principles for clinical trials (E9). 
5 February 1998.  
4. Gough K, Hutchinson M, Keene O, et al. Assessment of dose proportionality: report from 
the statisticians in the pharmaceutical industry/Pharmacokinetics UK Joint Working Party. 
Drug Inf J. 1995;29(3):1039-1048. 


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5. Keene ON. The log transformation is special. Stat Med. 1995;14(8):811-819. 
6. Snedecor GW, Cochran WG. Statistical Methods. 8th ed. Ames, IA: Iowa State University 
Press, 1989. 
7. Lehmann EL. Nonparametrics: Statistical Methods Based on Ranks. San Francisco, CA: 
Holden-Day; 1975. 
8. Brown H, Prescott R. Applied Mixed Models in Medicine. Chichester: John Wiley & 
Sons, 1999. 
 


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12. APPENDICES 
Appendix 1: 
Document History 
Status and Version 
Date of Change 
Summary/Reason for Changes 
Final Version 1.0 
NA 
NA; the first version. 
NA = not applicable