Clinical trial NCT04571385
Conditions: Atrial Fibrillation
Sponsor: Acesion Pharma
Start date: 2019-09-09; Completion date: 2023-01-23
Enrollment: 66 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will evaluate the efficacy, safety, tolerability and pharmacokinetics (PK) of one or more doses of AP30663 for cardioversion in adult participants with AF.

Detailed description:

Arms: arm 1: Participants will receive single dose of AP30663. arm 2: Participants will receive placebo matched to AP30663. arm 3: Participants will receive a single dose of one of the multiple dose levels of AP30663. arm 4: Participants will receive placebo matched to AP30663.
Interventions: intervention 1: AP30663 intervention 2: Placebo
Intervention descriptions: intervention 1: Administer by intravenous infusion. intervention 2: Placebo matched to AP30663.

Protocol documents:
Prot_000.pdf: 
 
 
CLINICAL STUDY PROTOCOL 
A Double-Blind, Randomised, Placebo-Controlled, Parallel-Group Study 
of AP30663 Given Intravenously for Cardioversion in Patients with 
Atrial Fibrillation  
 
 
Protocol Number: 
AP30663 – 2001 
IND Number:  
Not applicable 
EudraCT Number: 
2018-004445-17 
Syneos Health Study Number: 
7000776 
Investigational Product: 
AP30663 
Phase: 
Phase 2a 
Sponsor: 
Acesion Pharma ApS  
Ole Maaløes Vej 3 
DK-2200 Copenhagen N 
Denmark 
Contract Research Organisation: Syneos Health 
1030 Sync Street 
Morrisville, NC 27560 
United States 
Protocol Date: 
23 Mar 2022 
Protocol Version: 
Version 4.0, Final (DK and HU) 
Version 3.1, Final (DK) 
Version 3.0, Final (HU) 
Version 2.0, Final (HU) 
Version 1.1, Final (HU) 
 
 
 
CONFIDENTIAL 
This protocol may not be reproduced or communicated to a third party without the 
written permission of Acesion Pharma ApS. 


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1
PROTOCOL APPROVAL SIGNATURES
Protocol Title:
A Double-Blind, Randomised, Placebo-Controlled, Parallel-Group Study 
of AP30663 Given Intravenously for Cardioversion in Patients with Atrial 
Fibrillation
Protocol Number:
AP30663 – 2001
This study will be conducted in compliance with the clinical study protocol (and 
amendments), International Council for Harmonisation (ICH) guidelines for current Good 
Clinical Practice and applicable regulatory requirements.
Sponsor Signatory
Acesion Pharma ApS
Ole Maaløes Vej 3
DK-2200 Copenhagen N 
Denmark
Signature
Date
Elec
ed
by
Reason  I am the
approver
Date  Mar 24, 2022
08 07 GMT+1
PPD
PPD
PPD
PPD


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Sponsor Signatory 
 
 
 
  
Acesion Pharma ApS 
Ole Maaløes Vej 3 
DK-2200 Copenhagen N  
Denmark 
Signature 
Date 
 
 
 
 
Electronically signed
by
Reason  I am the
approver
Date  Mar 24, 2022
08 17 GMT+1
PPD
PPD
PPD
PPD




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Contract Research Organisation (CRO) 
Signatory  
 
Biostatistician  
 
 
Senior Principal Biostatistician 
Syneos Health 
1 Pinehurst Road  
Farnborough, Hampshire 
GU14 7BF  
UK 
Signature 
Date 
 
Electronically signed
by
Reason  I am the
author
Date  Mar 24, 2022
09 34 GMT
PPD
PPD
PPD




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ECG Laboratory 
Company Name: Clario 
Address: 
Lynchwood House 
Peterborough Business Park 
Peterborough PE2 6FZ 
United Kingdom 
Telephone No.: +44 1733 374800 
 
Clinical Laboratory 
Company Name: Eurofins Central Laboratory, B.V. 
Address: 
Bergschot 71 
4817 PA 
Breda 
The Netherlands 
Telephone No.: +31 76 572 72 72 
 


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3 
SYNOPSIS 
Protocol Number: 
AP30663 - 2001 
Title: 
A Double-Blind, Randomised, Placebo-Controlled, Parallel-Group Study of AP30663 Given Intravenously for 
Cardioversion in Patients with Atrial Fibrillation.  
Investigational Product: 
AP30663 
Study Centres: 
Approximately 15 centres in EU. 
Phase: 
2a 
Objectives: 
Primary objective:  
x 
To demonstrate the efficacy of 1 or more dose levels of AP30663 on the basis of the ability to convert 
atrial fibrillation (AF) after intravenous administration. 
Secondary objectives: 
x 
To study the stability of rhythm control (immediate relapse of AF [IRAF], i.e. within 5 min after 
conversion from AF). 
x 
To study the importance of AF duration with respect to the efficacy and safety of 1 or more dose levels 
of AP30663. 
x 
To evaluate the safety and tolerability of 1 or more dose levels of AP30663. 
x 
To study the relationship between systemic exposure and response, with special regard to the 
conversion from AF and the effect on QRS and QTcF. 
Exploratory objectives:  
x 
To study demographic and echocardiographic variables, concomitant diseases, and concurrent 
medication with respect to the efficacy and safety of 1 or more dose levels of AP30663. 
x 
To evaluate the pharmacokinetics (PK) of AP30663, including influence of dose, concomitant 
medication, concurrent diseases, and demographic variables. 
x 
To explore the proportions of patients on AP30663 converting from AF and of patients randomised to 
placebo and converting at direct-current (DC) cardioversion.  
Study Design: 
This is a double-blind, randomised, placebo-controlled, parallel-group Phase 2a study of 1 or more doses of 
AP30663 for cardioversion in adult patients with AF. The study will be conducted in 2 parts (Part 1 and 2): Part 
1 of the study is a fixed randomisation, placebo-controlled, parallel design, and Part 2 will be an adaptive 
design conducted with 1 or more further doses of AP30663 versus placebo. The study is designed to identify 
the dose of AP30663 to be evaluated further in later-phase research. Though the study investigates multiple 
doses of AP30663 versus placebo, the participating patients will be randomised to receive one dose of 
AP30663 (i.e. patients will not receive multiple dose levels). 
In Part 1 of the study, up to 36 patients will be randomised on Day 1 in a fixed 1:1 ratio to receive AP30663 at 
3 mg/kg or matching placebo as a single 30-minute intravenous infusion. Their participation will last until the 


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completion of their follow-up visit at Day 30. An interim analysis including efficacy, PK/PD, safety and 
tolerability data analyses will be conducted once the randomised patients have completed Day 2 assessments or 
terminated the study, to determine the starting dose(s) for Part 2 of the study. An independent data monitoring 
committee (DMC) will be convened to review the accumulating unblinded efficacy (including ECG and  
Holter ECG), PK/pharmacodynamics (PD), safety and tolerability data for the study collected up to the time of 
the interim analysis (IA).  
Part 2 of the study is an adaptive design, conducted in a minimum of 18 and a maximum of 72 patients with 
1 or more doses of AP30663 (Dose [d] where d = 2, 4, 5, or 6 mg/kg) or placebo (d = 0). The maximum dose 
of 6 mg/kg AP30663 should not be exceeded under any circumstances, and the doses assessed during Part 2 
will depend upon the cumulative results achieved across both Part 1 and Part 2. Based on the results seen at the 
end of Part 1 IAs and the decision made by the DMC regarding efficacy, safety and tolerability, the 3 mg/kg 
dose arm of AP30663 will be stopped, a 5 mg/kg dose arm of AP30663 will be opened and if high efficacy is 
seen (AF conversion rate > 0.65) then a 2 mg/kg AP30663 arm will also be opened. During Part 2, patients will 
be randomised in a ratio of 2:1 cumulatively in cohorts of 18 patients to a number of pre-defined doses of 
AP30663 versus placebo. After each cohort of 18 randomised patients has completed Day 2 assessments or 
terminated the study, an IA will be conducted to assess the AF conversion rate and subsequent dose arms to be 
assessed, with the following rules applied:  
x 
If an open Dose d has at least 10 randomised patients who have completed Day 2 assessments, and 
satisfies: (ܲd > 0.65) ≥ 0.90 then Dose d will be closed for sufficient efficacy response. 
o 
If the dose one level below this dose has never been opened, then dose d-1 is opened. 
x 
If an open Dose d has at least 10 randomised patients who have completed Day 2 assessments, and 
satisfies (ܲd > 0.65) < 0.10 then Dose d will be closed.  
o 
If Dose d was the largest dose thus far open, and Dose d is d < 6, then dose d+1 will be opened. 
During Part 2, IAs will occur when 18, 36, and 54 patients have been randomised to open-doses including 
placebo, and have completed Day 2 assessments or terminated the study.  
For Part 2, the DMC will give their recommendations regarding continuation or early termination of the study. 
Decision rules will be based on the AF conversion rate; however the DMC will also have the option to stop a 
dose arm (or the study) due to unacceptable safety and tolerability (including but not limited to increase in 
QTcF interval and number and severity of local injection site reactions), to be reviewed at fixed time points 
(see DMC Charter). Provided the study is not stopped at the end of Part 1 IA, Part 2 will include a minimum of 
18 and a maximum of 72 additional patients.  
Data monitoring committee  
An independent DMC will be convened to review the unblinded data from the IA and to provide 
recommendations for Part 2 (see above). The DMC will also review accumulating efficacy, PK/PD, safety and 
tolerability data obtained at a subsequent IA in Part 2 of the study at defined time points. The safety and 
tolerability signal includes but not limited to increase in QTcF internal and number and severity of local 
injection site reactions. 
Number of Patients:  
Approximately 41, 62, 82, 103, or 123 patients will need to be screened to achieve up to 36, 54, 72, 90, or 108 
randomised patients, respectively, who have completed Day 2 assessments or terminated the study, depending 
on the study design and recommendations of the DMC at each of the IAs. The number of patients screened is 
based on a screen failure rate of 12%. 
Treatment: 
In Part 1, study treatment will either be AP30663 3 mg/kg or matching placebo, randomised in a 1:1 ratio; both 
will be administered as an intravenous infusion for 30 min on Day 1. The DMC may either recommend to stop 
the study at the end of Part 1 IA, or may recommend to increase the dose of AP30663 to 4, 5, or 6 mg/kg, or 


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decrease to 2 mg/kg, alongside placebo during Part 2 of the study, dependent on the pre-defined decision criteria 
for efficacy and/or safety and tolerability review. 
Study Duration: 
Study drug infusion is planned for 30 min for each patient.  
The overall study duration for each patient is up to a maximum of 42 days. The screening and randomisation will 
occur within 7 days (inclusive) from onset of AF. The duration of treatment and post-treatment follow-up will 
be 30 days ± 5 days from start of infusion to the follow-up visit. 
Study Population: 
Inclusion criteria:  
1. 
Provision of written informed consent. 
2. 
Clinical indication for cardioversion of atrial fibrillation. 
3. 
Current episode of symptomatic atrial fibrillation lasting between 3 h and 7 days inclusive at randomisation. 
4. 
Adequate anticoagulation according to international and/or national guidelines. 
5. 
Body weight 50 to 110 kg inclusive (with clothes, without shoes).  
6. 
Male patients and postmenopausal women aged 18 to 80 years inclusive.  
- 
Male patients who are sexually active must agree to abstain from sexual activity or be willing to use a 
double-barrier method of birth control (i.e. any double combination of male or female condom with 
spermicidal gel, diaphragm, sponge or cervical cap with spermicidal gel) if they become sexually active 
from the time of consent and for 90 days after the infusion day.  
- 
Post-menopausal women are defined as being >12 months after last menstrual period.  
- 
Women can also be included if permanently sterilised since ≥6 weeks (i.e. documented hysterectomy, 
bilateral salpingectomy, bilateral oophorectomy). Breastfeeding women are excluded. 
Exclusion criteria:  
1. 
Significant clinical illness or surgical procedure within 4 weeks preceding the screening visit. 
2. 
Present renal dysfunction (estimated glomerular filtration rate [eGFR] <30 mL/min), hepatic dysfunction 
(alanine aminotransferase [ALT] or aspartate aminotransferase [AST] >3 × upper limit of normal), or 
uncontrolled hyperthyroidism or hypothyroidism. 
3. 
History of significant mental, renal or hepatic disorder, chronic obstructive pulmonary disease or other 
significant disease, as judged by the investigator. 
4. 
Any cardioversion attempt of AF or atrial flutter within 1 week preceding randomisation. 
5. 
Prior failed attempt (no conversion) of pharmacological or DC cardioversion of previous or current AF 
episode. 
6. 
Failure to find a large antecubital (or equivalent) vein for the infusion. 
7. 
Any of the following events, or any other significant cardiovascular event as judged by the investigator, 
during the last 6 weeks before randomisation: myocardial infarction, unstable angina pectoris or other signs 
of myocardial ischaemia, stroke or transient ischaemic attack, myocardial revascularisation (percutaneous 
coronary intervention [PCI], coronary artery bypass graft [CABG]), or other revascularisation procedure. 
8. 
Haemodynamically unstable condition as judged by the investigator; systolic blood pressure (BP) <90 mm 
Hg or >180 mm Hg, or diastolic BP >105 mm Hg at randomisation.  
9. 
Blood haemoglobin <100 g/L at screening. 
10. Congestive heart failure New York Heart Association class III or IV. Left ventricular ejection fraction <40% 
on echocardiography, or other clinically significant abnormality on the echocardiogram (not older than 6 
months) as judged by the investigator. 
11. Known hypertrophic cardiomyopathy or significant left ventricular hypertrophy (free wall or septal 
thickness >13 mm). 


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12. Any clinically significant valvular heart disease. 
13. History or previous signs of sinus nodal disease. 
14. Pacemaker or implantable cardioverter defibrillator therapy. 
15. Personal or family history of Torsades de Pointes, any other polymorphic ventricular tachycardia, sustained 
ventricular tachycardia, long QT syndrome, and/or Brugada syndrome. 
16. QTc (Fridericia, QTcF) interval >450 ms at randomisation. (When measured during AF, the mean heart rate 
should be 50 to 100 bpm. The QTcF should be calculated at AF as the mean of at least 5 consecutive RR 
intervals with consecutive QT intervals). 
17. QRS duration >120 ms at randomisation. 
18. Known atrioventricular (AV)-block I (prolonged PQ [PR] interval >220 ms), AV-block II, AV-block III, or 
complete bundle branch block (BBB). 
19. Potassium in serum below 3.5 or above 5.3 mmol/L at randomisation. Patients with low potassium levels 
at screening may be appropriately supplemented with potassium before baseline, according to the local 
standards. A re-test of the potassium level is required, and the patient can be randomised after the 
potassium has returned to reference range. 
20. Anticipated change in dose or initiation of loop diuretic from screening to the end of infusion. 
21. Use of any antiarrhythmic drug class I and/or III within 7 days or, for amiodarone specifically, 12 
weeks before randomisation. 
22. Use of QT-prolonging drug, and/or drug that inhibits cytochrome P450 (CYP)3A4, as well as St John's 
Wort within 10 days before randomisation. 
23. Administration of an investigational drug within the preceding 3 months before randomisation. 
24. Administration of AP30663 at any time before randomisation. 
25. History of drug addiction and/or alcohol abuse within the last 12 months at the discretion of the investigator. 
26. Blood or plasma donation within the preceding 4 weeks before randomisation. 
27. Any suspected or manifested clinically significant infection as judged by the investigator. 
28. Involvement in the planning and conduct of the study (applies to Acesion Pharma staff, Syneos Health staff, 
and staff at the investigational site). 
29. Clinical judgement by the investigator that the patient should not participate in the study. 
30. Any malignant cancer within 3 years (except for successfully treated in-situ non-melanoma skin cancer and 
in-situ cervical cancer) of signing the informed consent form (ICF). 
Primary Endpoint: 
x 
The proportion of patients that have converted from AF within 90 min from the start of infusion and 
subsequently have no AF recurrence within 1 min of conversion from AF. 
Secondary Endpoints: 
Efficacy 
x 
The time to conversion from AF from start of infusion. 
x 
The proportion of patients with relapse of AF within 5 min (IRAF) after pharmacological or DC 
cardioversion. 
x 
The proportion of patients in SR at 3 h ± 1 h after start of infusion. 
x 
The proportion of patients in SR at 24 h ± 2 h after start of infusion. 
x 
The proportion of patients in SR at 30 days ± 5 days after start of infusion. 
Safety 
x 
Adverse events (AEs), electrocardiogram (ECG) variables including significant arrhythmia, physical 
examination, vital signs, and laboratory evaluations. 


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x 
Changes in QTcF interval data over time. 
Pharmacokinetics 
x 
Systemic exposure derived from the population PK model. 
x 
Population PK model parameter estimates derived from plasma concentrations of AP30663. 
Efficacy: 
Efficacy assessments include conversion from AF, which will be determined by the investigator. Holter will be 
used to record ECG continuously, to detect conversion from AF as well as to monitor sustainability of the rhythm 
after conversion. 
Pharmacokinetics: 
Venous blood sampling will be performed to determine plasma concentrations of AP30663 pre- and post-
infusion at each time point.  
Safety: 
Safety assessments include review of AEs, clinical laboratory evaluations, vital signs (BP, heart rate and heart 
rhythm from ECG), physical examination, ECG and concomitant medications.  
Laboratory assessments include haematology (haemoglobin, haematocrit, red blood cells [erythrocytes], white 
blood cells [leukocytes, total and differential], basophils, eosinophils, lymphocytes, monocytes, neutrophils, and 
platelets); clinical chemistry (alanine aminotransferase [ALT], aspartate aminotransferase [AST], bilirubin 
[direct, indirect, total], creatinine, gamma-glutamyltransferase, glucose [random], estimated glomerular filtration 
rate [eGFR], urea [blood urea nitrogen, BUN], magnesium, sodium, calcium, and potassium). Other laboratory 
variables determined are international normalised ratio (INR)/activated partial thromboplastin time (APTT) and 
thyroid stimulating hormone (TSH). 
ECG used for safety assessments comprises 12-lead digital ECG, telemetry, and Holter.  
Statistical Analysis: 
Continuous data will be presented using descriptive summaries (e.g. mean, standard deviation, minimum, 
maximum, median, lower quartile, and upper quartile). Categorical data will be presented using the number of 
observations and relative (%) frequency. 
Unless otherwise stated, the baseline value for any parameter will be the latest non-missing value taken prior to 
the infusion of study treatment on Day 1. Pre-infusion Day 1 assessments will be included in this derivation of 
baseline.  
For the analysis of the primary endpoint (proportion of patients who have cardioversion within 90 min from the 
start of infusion) a Bayesian model will be utilised. The prior probability of success at a dose, d, is modelled with 
a Beta prior (uniform) for each dose. The posterior distribution is calculated for each dose independently using a 
Beta posterior distribution, Pd ~ Beta (1 + Xd, 1 + Nd – Xd). 
This modelling will occur for each interim analysis, and at the final analysis as primary method. At the conclusion 
of the study, each AP30663 dose will be considered to be superior to placebo, if the posterior probability of 
AP30663 dose has a higher success rate than placebo is greater than 0.95.  
Further to this, for the final analysis, the primary endpoint will also be analysed by means of a logistic regression 
model. Relevant covariates at baseline may be added into the model after reviewing baseline imbalances. 
Secondary endpoints relating to proportions will be analysed using a logistic regression model in a similar manner 
to that of the primary endpoint. Time to conversion will be analysed using Kaplan-Meier method and, if met, the 
median time to conversion will be presented, along with the corresponding Kaplan-Meier plot stratified by 
treatment group. 


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Interim analysis 
The study is conducted in 2 parts (Part 1 and 2). For all interim analyses (IAs) during the study, a separate 
unblinded biostatistical team will prepare and present the unblinded analysis, and the DMC will be convened to 
review the data and will give their recommendations pertaining to continuation or early termination of the study, 
and as well as whether or not to increase/decrease the dose per the algorithm below and/or any other available 
data. 
The first IA will be conducted once all randomised patients have completed Day 2 assessments or terminated the 
study. The DMC will be convened to review unblinded data on the primary efficacy endpoint, PK/PD, safety 
and tolerability data during this IA.  
If the DMC decides that the study should continue, then Part 2 of the study will be enacted. During Part 2, IAs 
will be conducted when 18, 36, and 54 randomised have completed Day 2 assessments or terminated the study.  
For each IA, the success rate for any single dose level d, Pd, will be analysed using a Bayesian model, and the 
decision criteria as stated above will be implemented. The study will continue until all doses of AP30663 have 
been closed or the maximum of 72 patients during Part 2 (up to 108 patients total across Parts 1 and 2) have been 
enrolled.  
Interim Analysis at End of Part 1: 
During the first IA the following will occur, regardless of the response seen for the AP30663 3 mg/kg dose: 
x 
Dose 3 (3 mg/kg AP30663) will be stopped. 
x 
Dose 5 (5 mg/kg AP30663 versus placebo) will be opened.  
Additionally, the following decision will be made dependent on the response rate seen for 3 mg/kg AP30663:  
x 
If the proportion of patients achieving a response under AP30663 3 mg/kg is > 0.65 then Dose 2 (2 
mg/kg AP30663) will additionally be opened for Part 2 (in parallel to Dose 5). 
Interim Analyses during Part 2: 
Interim analyses will occur when 18, 36, and 54 randomised patients have completed Day 2 assessments or 
terminated the study in Part 2. At these IAs the following rules will be utilised: 
x 
If an open Dose d has at least 10 randomised patients having completed Day 2 assessments and satisfies: 
(ܲd > 0.65) ≥ 0.90 then Dose d will be closed for sufficient efficacy response. 
o 
If the dose one level below this dose has never been opened, then dose d-1 is opened. 
x 
If an open Dose d has at least 10 randomised patients having completed Day 2 assessments and satisfies 
(ܲd > 0.65) < 0.10 then Dose d will be closed. 
o 
If Dose d was the largest dose thus far open, and Dose d is d < 6, then dose d+1 will be opened. 
The study will continue until all doses of AP30663 have been closed or the maximum of 72 patients during Part 
2 (up to 108 patients total across Part 1 and Part 2) have been enrolled.  
While the algorithm, and the DMC’s decision for dose increase/decrease, is based on AF conversion rate only, 
the DMC will also convene to review safety and tolerability data at defined time points; review of this data may 
also lead to further decisions being made by the DMC. 
Further details of the IAs and the decision rules to be implemented will be detailed in the statistical analysis 
plan (SAP) and the DMC Charter.  
Sample size 
The study is proof of concept, designed to allow for a considered testing of a range of doses of AP30663, 
compared with placebo. Based on the study design, the sample size for randomisation will range from up to 
36 patients (for Part 1) to up to 108 patients (for Parts 1 and 2 cumulatively). The total sample size is dependent 
on the AP30663 dose arms opened on the decision of the DMC. A total of 4 IAs and a final analysis are 


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included in the design, and so it is foreseen that the total number of randomised patients will be up to 36, 54, 
72, 90, or 108 to have sufficient numbers of patients evaluable for AF conversion at each IA.  
The adaptive design utilises the probability that the response rate at a dose d is greater than a success rate of 
65% (Pd > 0.65, where d is the dose arm of AP30663), based on a Bayesian modelling procedure.  


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4 
TABLE OF CONTENTS 
1 
PROTOCOL APPROVAL SIGNATURES ................................................... 2 
2 
STUDY PERSONNEL ..................................................................................... 6 
3 
SYNOPSIS ........................................................................................................ 8 
4 
TABLE OF CONTENTS ............................................................................... 15 
4.1 
List of In-text Tables ........................................................................................ 18 
4.2 
List of In-text Figures ....................................................................................... 18 
5 
LIST OF ABBREVIATIONS ........................................................................ 19 
6 
INTRODUCTION .......................................................................................... 21 
7 
STUDY OBJECTIVES AND ENDPOINTS ................................................ 24 
7.1 
Study Objectives............................................................................................... 24 
7.1.1 
Primary Objective............................................................................ 24 
7.1.2 
Secondary Objectives ...................................................................... 24 
7.1.3 
Exploratory Objectives .................................................................... 24 
7.2 
Study Endpoints ............................................................................................... 24 
7.2.1 
Primary Endpoint ............................................................................ 24 
7.2.2 
Secondary Endpoints ....................................................................... 25 
7.2.2.1 
Efficacy Endpoints .......................................................................... 25 
7.2.2.2 
Safety Endpoints.............................................................................. 25 
7.2.2.3 
PK Endpoints ................................................................................... 25 
7.2.3 
Exploratory Endpoints ..................................................................... 25 
8 
INVESTIGATIONAL PLAN ........................................................................ 26 
8.1 
Overall Study Design and Plan: Description .................................................... 26 
8.1.1 
Study Design ................................................................................... 29 
8.1.2 
Schedule of Assessments................................................................. 30 
8.2 
Discussion of Study Design ............................................................................. 33 
8.2.1 
Study Rationale ............................................................................... 33 
8.2.2 
Quality Management and Risk Evaluation ...................................... 34 
8.3 
Selection of Study Population .......................................................................... 34 
8.3.1 
Number of Planned Patients ............................................................ 34 
8.3.2 
Inclusion Criteria ............................................................................. 34 
8.3.3 
Exclusion Criteria ............................................................................ 35 
8.3.4 
Removal of Patients From Therapy or Assessments ....................... 37 


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8.3.4.1 
Patient Discontinuation/Withdrawal From the Study ..................... 37 
8.3.4.2 
Treatment Discontinuation (Stop of Infusion) ................................ 38 
8.4 
Investigational Products ................................................................................... 39 
8.4.1 
Investigational Products Administered ........................................... 39 
8.4.2 
Identity and Preparation of Investigational Products ...................... 40 
8.4.3 
Packaging and Labelling ................................................................. 41 
8.4.4 
Method of Assigning Patients to Treatment Groups ....................... 42 
8.4.5 
Selection of Doses in the Study ....................................................... 42 
8.4.6 
Selection and Timing of Dose for Each Patient .............................. 42 
8.4.7 
Blinding ........................................................................................... 42 
8.4.8 
Prior and Concomitant Therapy ...................................................... 43 
8.4.8.1 
Prohibited Medication and Procedures............................................ 44 
8.4.8.2 
Rescue Medication .......................................................................... 46 
8.4.9 
Treatment Compliance .................................................................... 46 
9 
TIMING OF STUDY PROCEDURES ......................................................... 47 
9.1 
Screening Visit ................................................................................................. 47 
9.2 
Day 1 – Pre-infusion (Baseline) ....................................................................... 48 
9.3 
Day 1 – During Infusion ................................................................................... 48 
9.4 
Day 1 – Post-Infusion ....................................................................................... 49 
9.5 
Day 2 ................................................................................................................ 50 
9.6 
Follow-up/Discontinuation Visit (Day 30)....................................................... 50 
9.7 
Duration of Treatment ...................................................................................... 50 
10 
EFFICACY, PHARMACOKINETICS, AND SAFETY 
VARIABLES ................................................................................................... 51 
10.1 Efficacy, Pharmacokinetics, and Safety Measurements ................................... 51 
10.1.1 
Efficacy Variables ........................................................................... 51 
10.1.1.1 24-Hour Holter ................................................................................ 51 
10.1.2 
Pharmacokinetic Variables .............................................................. 52 
10.1.2.1 Plasma Concentrations of AP30663 ................................................ 52 
10.1.3 
Safety Assessments ......................................................................... 52 
10.1.3.1 Adverse Events ................................................................................ 52 
10.1.3.2 Clinical Laboratory Evaluation ....................................................... 57 
10.1.3.3 Vital Signs ....................................................................................... 58 
10.1.3.4 Physical Examination and Brief Physical Examination .................. 58 
10.1.3.5 Electrocardiogram ........................................................................... 58 
10.2 Independent Data Monitoring Committee ........................................................ 59 
10.3 Appropriateness of Measurements ................................................................... 60 


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11 
STATISTICAL METHODS .......................................................................... 61 
11.1 Statistical and Analytical Plans ........................................................................ 61 
11.1.1 
Datasets or Populations Analysed ................................................... 61 
11.1.2 
Demographic and Other Baseline Characteristics .............................. 62 
11.1.3 
Efficacy Variables ............................................................................ 62 
11.1.4 
Safety Variables .............................................................................. 63 
11.1.5 
PK Variables.................................................................................... 64 
11.1.6 
Interim Analyses.............................................................................. 66 
11.1.7 
Handling of Missing Data ............................................................... 67 
11.2 Determination of Sample Size .......................................................................... 67 
11.3 Protocol Deviations .......................................................................................... 68 
12 
QUALITY ASSURANCE AND QUALITY CONTROL .............................. 69 
12.1 Audit and Inspection ........................................................................................ 69 
12.2 Monitoring ........................................................................................................ 69 
12.3 Data Management and Coding ......................................................................... 69 
12.4 Quality Management and Risk Evaluation ....................................................... 69 
13 
RECORDS AND SUPPLIES ......................................................................... 70 
13.1 Drug Accountability ......................................................................................... 70 
13.2 Financing and Insurance ................................................................................... 70 
14 
ETHICS ........................................................................................................... 71 
14.1 Independent Ethics Committee ........................................................................ 71 
14.2 Regulatory Authorities ..................................................................................... 71 
14.3 Ethical Conduct of the Study............................................................................ 71 
14.4 Informed Consent ............................................................................................. 71 
14.5 Patient Confidentiality ...................................................................................... 72 
15 
REPORTING AND PUBLICATION, INCLUDING ARCHIVING ......... 73 
16 
REFERENCES ............................................................................................... 74 
17 
APPENDICES ................................................................................................ 75 
17.1 Investigator Signature Page .............................................................................. 75 
17.2 Blood Sampling ................................................................................................ 76 
17.3 Distribution of Patients Scenarios .................................................................... 77 


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4.1 
List of In-text Tables 
Table 1 
Composition of AP30663 Concentrate for Solution for Infusion ... 40 
Table 2 
Prohibited Medication ..................................................................... 45 
Table 3 
Physical Examination ...................................................................... 58 
 
4.2 
List of In-text Figures 
Figure 1 Study Schema ................................................................................................... 29 
 


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5 
LIST OF ABBREVIATIONS 
AE 
Adverse event 
AERP 
Atrial effective refractory period 
AF 
Atrial fibrillation 
ALT 
Alanine aminotransferase 
APTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
AUC 
Area under the concentration time curve 
AV 
Atrioventricular 
BBB 
Bundle branch block 
BP 
Blood pressure 
bpm 
Beats per minute 
BUN 
Blood urea nitrogen 
Ca 
Calcium 
CABG 
Coronary artery bypass graft 
Cmax 
Observed peak plasma concentration 
CYP 
Cytochrome P450 
DC 
Direct-current 
DMC 
Data monitoring committee 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
eGFR 
Estimated glomerular filtration rate 
EMA 
European Medicines Agency 
EU 
European Union 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyltransferase 
GLP 
Good Laboratory Practice 
IC50 
Half maximal inhibitory concentration 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent ethics committee 
INR 
International normalised ratio 
IRAF 
Immediate relapse of atrial fibrillation 


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IWRS 
Interactive web randomisation system 
Kel 
Elimination rate constant 
LS 
Least squares 
LV 
Left ventricle 
LVEF 
Left ventricular ejection fraction 
MedDRA 
Medical Dictionary for Regulatory Activities 
MTD 
Maximum tolerated dose 
NOAEL 
No observed adverse effect level 
PCI 
Percutaneous coronary intervention 
PD 
Pharmacodynamics 
PK 
Pharmacokinetic 
QTc 
Corrected QT interval  
SAE 
Serious adverse reaction 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SOC 
System organ class 
SOP 
Standard operating procedure 
SR 
Sinus rhythm 
SUSAR 
Suspected unexpected serious adverse reaction 
t1/2 
Terminal half-life 
TEAE 
Treatment-emergent adverse event 
Tmax 
Time at which Cmax occurs 
TSH 
Thyroid stimulating hormone 
TTE 
Transthoracic echo 
WHO 
World Health Organisation 
 


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6 
INTRODUCTION 
Atrial fibrillation (AF) is the most common cardiac arrhythmia (irregular heart beat) and 
is characterised by chaotic electrical signals in the upper chambers of the heart. This is 
seen as a very rapid frequency and malfunctioning contraction in the atria that may lead 
to impaired quality of life, reduced work productivity, and increased rate of 
hospitalisation. A severe consequence of AF is a 5-fold increased risk of stroke and 
1.9-fold increased mortality. AF-related strokes account for up to 20% of all strokes and 
are therefore a major cause of this debilitating and often fatal disease. AF has reached 
epidemic proportions and affects up to 5 million people in the European Union (EU). 
Prevalence of AF has grown to 2% of the population, double that reported in the last 
decade, and the estimated number of patients with AF in 2030 in the EU will have 
grown to 14 to 17 million (Zoni-Berisso et al. 2014). Risk of AF increases with age, and 
approximately 70% of patients suffering from AF are between 65 and 85 years of age 
(Feinberg et al. 1995). The latest European AF treatment guidelines from the European 
Society of Cardiology (Kirchhof et al. 2016) favour the principle “safety first”, implying 
that the recommended first-line agents are only moderately effective. There is currently 
no gold standard treatment for AF in the EU and a large unmet medical need exists for 
developing and introducing novel compounds for treating the increasing number of AF 
patients. 
AP30663 is being developed by Acesion Pharma for the conversion of AF by a 
30-minute intravenous infusion in patients with episodes of AF. AP30663 is a small 
molecule drug product candidate able to inhibit the small-conductance Ca2+-activated 
potassium channels (SK channels), a novel and functionally atrial-selective ion channel 
target for the treatment of AF.  
Mechanistically, AP30663 inhibits human SK channels at sub-micromolar 
concentrations with an in vitro half maximal inhibitory concentration (IC50) (SK3) of 
0.77 μM. In pigs, AP30663 has demonstrated significant and pronounced prolongation 
of the atrial effective refractory period and ability to convert AF to normal sinus rhythm 
(SR) while at the same time being well tolerated and not prolonging the QT interval 
significantly. 
Pharmacokinetic (PK) studies in landrace pigs, as well as the Good Laboratory Practice 
(GLP) safety studies conducted in rat and minipig, demonstrate that AP30663 is rapidly 
distributed in plasma after start of infusion and that an apparent steady-state plasma 
level is reached well before the end of the 30- to 60-minutes continuous infusion. 
Immediately after the end of the infusion, the plasma levels drop rapidly due to the 
kinetics of the distribution phase. From a safety-risk assessment viewpoint, this fast and 
significant drop of plasma concentration after termination of the infusion is considered a 
means to help effectively minimise transient Cmax-related adverse effects, should they 
occur. 
Binding of AP30663 to plasma proteins has been determined in vitro for a number of 
species and plasma protein binding of 93.2% was determined in human plasma. In 
comparison, plasma protein binding in the 2 GLP safety-toxicology species rat and 


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minipig were 92.6% and 79.9%, respectively. For comparison, the plasma protein 
binding in landrace pigs was 86.4%. 
The AP30663 drug product is a concentrate for solution for infusion containing 
200 mg/mL AP30663. The drug concentrate should be stored in the original container at 
-15ºC to -25ºC until 30 to 60 min before start of preparation. The drug concentrate is 
diluted with sterile 5% glucose solution for infusion to a concentration of 2 mg/mL prior 
to administration. The final solution for infusion must be stored at room temperature 
and must be used within 24 h after start of preparation. 
In the conducted GLP toxicology programme, AP30663 was not associated with any 
adverse toxicity in the doses and exposures tested, except for infusion site reactions in 
the rat. The single dose maximum tolerated dose (MTD) in minipigs was defined as 
40 mg/kg, at which dose one episode of convulsion appeared in one minipig 50 min into 
an intended 60-minute infusion period. In rats, the single dose MTD was defined as 
90 mg/kg based on a combination of signs and symptoms, i.e. decreased activity, 
piloerection, semi-closed eyes, and dyspnoea. 
The no observed adverse effect level (NOAEL) in minipig after 2 weeks of daily single 
dose intravenous treatment with AP30663 was 25 mg/kg/day, which was the highest 
dose tested. 
In rats, daily 1-hour infusions for 2 weeks caused a reversible dose-related local 
infusion site inflammation at all dose levels, with associated lung inflammation and 
thromboembolism. No other toxicity of human relevance was observed up to the highest 
dose tested, 90 mg/kg/day, which was considered the NOAEL for toxicity not related to 
the local infusion site reactions. 
The maximally tolerated exposure in minipigs and rats appeared to be comparable, 
meaning that the 2 species may be regarded as similarly sensitive. A total (free and 
bound) exposure level (Cmax) of approximately 11,000 ng/mL was seen at the highest 
dose in both minipigs (25 mg/kg) and rats (90 mg/kg), and this dose level should not be 
exceeded in humans unless carefully evaluated. 
 
Two phase 1 Single Ascending Dose trials investigating the safety and tolerability of 
AP30663 in healthy male subjects at doses up to 8 mg/kg have been completed. The 
trials showed that the infusion with AP30663 caused mild and transient infusion site 
reactions as well as prolongation of the QTcF-interval but was otherwise well tolerated 
at all administered dose levels. The effect on QTcF was dose and plasma concentration 
related with a peak estimated mean QTcF prolongation of 45.2 ms for the dose of 6 
mg/kg. The QTcF effect was transient and a return to baseline level was observed 8 
hours after the start of administration for the 6 mg/kg dose, consistent with low plasma 
concentrations at this timepoint. 


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No effects were found on heart rate, blood pressure or other ECG markers. No CNS 
effects were found, including based on a sensitive assessment of tremors 
(tremorography). 
 
The aim of this study is to show proof of concept, (i.e. the ability of AP30663 to 
terminate ongoing AF episodes) and 1 or more dose levels will be compared with 
placebo.  


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7 
STUDY OBJECTIVES AND ENDPOINTS 
7.1 
Study Objectives 
7.1.1 Primary Objective 
The primary objective of the study is to demonstrate the efficacy of 1 or more dose 
levels of AP30663 on the basis of the ability to convert AF after intravenous 
administration. 
7.1.2 Secondary Objectives 
The secondary objectives of the study are as follows: 
x To study the stability of rhythm control (immediate relapse of AF [IRAF], i.e. 
within 5 min after conversion from AF). 
x To study the importance of AF duration with respect to the efficacy and safety of 
1 or more dose levels of AP30663. 
x To evaluate the safety and tolerability of 1 or more dose levels of AP30663. 
x To study the relationship between systemic exposure and response, with special 
regard to the conversion from AF and the effect on QRS and QTcF. 
7.1.3 Exploratory Objectives 
The exploratory objectives of the study are as follows: 
x To study demographic and echocardiographic variables, concomitant diseases, 
and concurrent medication with respect to the efficacy and safety of 1 or more 
dose levels of AP30663. 
x To evaluate the PK of AP30663, including influence of dose, concomitant 
medication, concurrent diseases, and demographic variables. 
x To explore the proportions of patients on AP30663 converting from AF and of 
patients randomised to placebo and converting at direct-current (DC) 
cardioversion.  
7.2 
Study Endpoints 
7.2.1 Primary Endpoint 
The proportion of patients that have converted from AF within 90 min from the start of 
infusion and subsequently have no AF recurrence within 1 min of conversion from AF. 


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7.2.2 Secondary Endpoints 
7.2.2.1 Efficacy Endpoints 
x The time to conversion from AF from start of infusion. 
x The proportion of patients with relapse of AF within 5 min (IRAF) after 
pharmacological or DC cardioversion. 
x The proportion of patients in SR at 3 h ± 1 h after start of infusion. 
x The proportion of patients in SR at 24 h ± 2 h after start of infusion. 
x The proportion of patients in SR at 30 days ± 5 days after start of infusion. 
7.2.2.2 Safety Endpoints 
x Adverse events (AEs) and electrocardiogram (ECG) variables, including 
significant arrhythmia, physical examination, vital signs, and laboratory 
evaluations. 
x Changes in QTcF interval data over time. 
7.2.2.3 PK Endpoints 
x Systemic exposure derived from the population PK model. 
x Population PK model parameter estimates derived from plasma concentrations 
of AP30663. 
7.2.3 Exploratory Endpoints 
x Correlation of drug exposure (plasma Cmax and area under the concentration time 
curve [AUC]) and the time of conversion. 
x Correlation of atrial size and conversion rate. 
x Correlation of atrial size to relapse or failure. 
x Correlation of gender and age and conversion rate. 
x Correlation of duration of current AF, conversion rate and duration of SR after 
conversion. 


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8 
INVESTIGATIONAL PLAN 
8.1 
Overall Study Design and Plan: Description 
This is a double-blind, randomised, placebo-controlled, parallel-group Phase 2a study of 
1 or more doses of AP30663 for cardioversion in adult patients with AF. The study will 
be conducted in 2 parts (Part 1 and 2): Part 1 of the study is a fixed randomisation 
placebo-controlled parallel design, and Part 2 will be an adaptive design conducted in 
1 or more further doses of AP30663 versus placebo. The study is designed to identify 
the dose of AP30663 to be evaluated further in later-phase research. 
For both parts of the study, qualified patients will be randomised (Day 1) as soon as it is 
practically possible after providing their written informed consent and completion of 
screening procedures, but no later than 7 days after onset of the AF episode. The study 
drug (AP30663 or placebo) will be administered as a single intravenous infusion for 
30 min on Day 1. Administration should take place as fast as possible after 
randomisation, and preferably no later than 12 h after randomisation. Patients may be 
discharged from the study site after all Day 1 procedures are completed. They will 
return to the study site the following day (Day 2) and for a follow-up visit on Day 30.  
In Part 1 of the study, up to 36 patients will be randomised in a 1:1 ratio to receive 
AP30663 at 3 mg/kg or matching placebo. Their participation will last until the 
completion of their follow-up visit at Day 30. An interim analysis (IA) will be 
conducted once the randomised patients in Part 1 have completed Day 2 assessments or 
terminated the study. An independent data monitoring committee (DMC) will be 
convened to review the unblinded efficacy (including ECG and Holter ECG), PK/PD, 
safety and tolerability data during this IA. The recommendations of the DMC at the IA 
will determine the design and starting dose(s) for assessment during Part 2 of the study; 
the DMC may also recommend that the study to be stopped after Part 1.  
Part 2 of the study is an adaptive design, conducted in a minimum of 18 and a maximum 
of 72 patients, in 1 or more doses of AP30663 (Dose [d] where d = 2, 4, 5, or 6 mg/kg) 
or placebo (d = 0). The maximum dose of 6 mg/kg AP30663 should not be exceeded 
under any circumstances, and the doses assessed during Part 2 will depend upon the 
cumulative results achieved across both Part 1 and Part 2. The IAs during Part 2 will 
occur after cohorts of 18 randomised patients have completed Day 2 assessments or 
terminated the study; thus, IAs will occur when 18, 36, and 54 randomised patients have 
completed Day 2 assessments or terminated the study (i.e. up to 54, 72, 90, and 
108 patients cumulatively). 
During the enrolment period, an IA may be planned on a reduced cohort if preliminary 
blinded safety and efficacy data indicate that current enrolment is sufficient for the 
DMC to provide a recommendation for Part 2. 
During Part 2, dose decisions made by the DMC at each IA is based primarily on the AF 
conversion response. Any efficacy criteria assessed at each IA will also be 


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supplemented with safety review by the DMC, at aligned timelines with the IAs 
described. Further details of DMC review will be provided in the DMC Charter. 
Randomisation during Part 2 of the study will be in 2:1, where all active arms will be 
randomised equally and cumulatively. The potential doses of AP30663 that could be 
assessed (randomised to) during Part 2 are 2, 4, 5, or 6 mg/kg (in addition to placebo). 
For example, if Doses 2 and 5 are open then randomisation will be 1:1:1 for 
Dose 2: Dose 5: Placebo for the cohort of 18 patients to be enrolled (i.e. 2:1 in total for 
AP30663 versus Placebo). If 1 dose of AP30663 is open versus placebo, then the 
randomisation will be 2:1. 
Algorithm for Dose Assessment During Part 2 
The following algorithm will be used for selection of dose levels of AP30663 during 
Part 2 of the study. For each analysis, the success rate for any single dose level d, Pd, 
will be analysed using a Bayesian model, whereby the prior probability of success at a 
dose d is modelled with a uniform Beta prior, and the posterior distribution is modelled 
for each dose independently using a Beta posterior distribution. The design utilises the 
probability that the response rate at a dose is greater than a 65% success rate 
(Pd > 0.65). Further details are provided in Section 17.3.  
Interim Analysis at End of Part 1: 
During the first IA, conducted once up to 36 patients randomised in Part 1 have 
completed Day 2 assessments or terminated the study, the following will occur, 
regardless of the response seen for the AP30663 3 mg/kg dose: 
x Further randomisation to Dose 3 (3 mg/kg AP30663) will be stopped. 
x Dose 5 (5 mg/kg AP30663 versus placebo) will be opened. 
Additionally, the following decision will be made dependent on the response rate seen 
for 3 mg/kg AP30663:  
x If the proportion of patients achieving a response with AP30663 3 mg/kg is 
> 0.65 then Dose 2 (2 mg/kg AP30663) will additionally be opened for Part 2 (in 
parallel to Dose 5). 
Interim Analyses During Part 2: 
Interim analyses will occur when 18, 36, and 54 randomised patients have completed 
Day 2 assessments or terminated the study in Part 2. At these IAs the following rules 
will be utilised: 
a) If an open Dose d has at least 10 randomised patients who have completed Day 
2 assessments and satisfies: (ܲd > 0.65) ≥ 0.90 then Dose d will be closed for 
sufficient efficacy response. 
x If the dose one level below this dose has never been opened, then dose d-
1 is opened. 


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b) If an open Dose d has at least 10 randomised patients who have completed Day 
2 assessments and satisfies (ܲd > 0.65) < 0.10 then Dose d will be closed. 
x If Dose d was the largest dose thus far open, and Dose d is < 6 mg/kg, 
then dose d+1 will be opened. 
During Part 2, all active doses will be equally randomised; for each of these IAs, 
randomisation will occur 2:1 across all open AP30663 doses combined versus placebo. 
For further details/examples of decision scenarios during Part 2, please see Section 17.3. 
The study will continue until all doses of AP30663 have been closed or the maximum of 
72 patients during Part 2 (up to 108 patients total across Parts 1 and 2) have been 
enrolled. Further details of the IAs and the decision rules to be implemented will be 
detailed in the statistical analysis plan (SAP). 
 


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8.1.1 Study Design 
Figure 1 Study Schema 
 
Abbreviations: N=number of patients enrolled, P3=conversion ratio at 3 mg/kg, Pd=conversion ratio at d mg/kg, Pr=probability. 
*All active AP30663 arms will be randomised equally for each interim analysis; randomisation will occur cumulatively in 2:1 ratio to receive either AP30663 or placebo across all 
open AP30663 arms.  
†If one level below this dose (d-1) has never been opened, then dose d-1 will be opened 
‡If dose ‘d’ is the highest dose opened so far, and dose ‘d’ is <6 mg/kg, then dose ‘d+1’ will be opened. 
Part 1
N=36
Part 2
N=18 to 72
Placebo
N=18
AP30663 (3 mg/kg)
N=18
1:1
IA #1 will be conducted once all 
randomized patients have completed Day 
2 assessments or terminated the study
AP30663 2 mg/kg
AP30663 5 mg/kg
If P3>0 65
Subsequent IAs will be conducted in Part 2 
when 18/36/54 randomized patients have 
completed Day 2 assessments or terminated 
the study
AP30663 ‘d’ mg/kg will be 
closed for strong efficacy†
AP30663 ‘d’ mg/kg will be 
closed‡
Pr (Pd >0 65) ≥0 90
Pr (Pd >0 65) <0 10
Placebo
2:1*
Study will close once 72 
patients are enrolled or 
all doses are closed


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8.1.2 Schedule of Assessments 
The schedule of the planned study assessments during Part 1 is shown in the following table. The planned study assessments during 
Part 2 are same to those that are planned for Part 1. 
 
Screening 
(within 7 days 
of onset of AF) 
Day 1 
Day 1 
Day 1 a 
Day 2  
Day 30 (± 
5 days) 
Baseline 
(pre-infusion) 
During 
infusion 
Post-infusion 
Follow-up/ 
Discontinuation 
Visit 
Informed consent 
X 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
 
Medical/surgical history  
X 
 
 
 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
Physical examination b 
X 
 
 
 
 
 
Brief physical examination c 
 
X 
 
 
 
X 
Vital signs (BP, heart rate, heart rhythm from ECG) 
X 
X 
X 
X 
X 
X 
Weight & height 
X 
 
 
 
  
  
Haematology d 
X 
X e 
 
 
  
X  
Clinical chemistry f 
X 
X e 
 
 
X  
X  
Serum magnesium (Mg++), sodium (Na+), calcium (Ca++) 
X 
 
 
 
  
  
Serum potassium (K+) h 
X 
 
 
 
 
 
Urea (BUN) 
X 
 
 
 
 
X 
INR/APTT g 
X 
X i 
 
 
  
X 
TSH 
X j 
 
 
 
  
  
Randomisation k 
  
X 
 
 
  
  
Study drug administration l 
  
  
X 
 
  
  




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l 
Study drugs must be administered as soon as possible after randomisation and preferably not later than 12 h after randomisation. 
m 
Plasma samples will be taken at baseline (pre-infusion) and at the following time points after start of infusion: 5 min ± 1 min, 15 min ± 1 min, 25 min ± 1 min, 
30 min - 1 min (the infusion will not be stopped before the 30-min PK sample has been collected), 45 min ± 5 min, 1 h ± 5 min, 1 h 30 min ± 5 min, 4 h ± 5 min, 8 h ± 
5 min, and 24 h ± 2h. In the case of conversion from atrial fibrillation within 90 min from the start of infusion, an additional sample will be taken immediately after 
conversion. 
n 
ECG print-outs: within 15 min before infusion start, at 10 min after infusion start, and, in case of conversion from AF, within 1 min after conversion BUT before infusion 
stop. Diagnosis of AF (defined as absence of discrete P waves and an irregular ventricular rate) to be confirmed based on a 12-lead ECG. On Day 2 the ECG should be 
completed 24 h +/- 2 hours after infusion start.  
o 
Continued assessment to start 30 min before infusion. Holter to stop after the PK sampling at 8 h. Telemetry to continue for minimum 8 h after infusion start. 
p 
Should be done in all patients; mandatory if not done within 6 months (inclusive) before randomisation. 
q 
Heart rhythm, LV size, LV area, LVEF, atrial area and size as well as other clinically significant finding results to be provided or requested if available.  
r 
In case of AF persistence at 90 min after start of infusion, a direct-current electrical cardioversion is to be done within 180 min post-infusion start (200 J biphasic 
synchronised). 
s 
Recording of any AEs/SAEs will start after the ICF has been signed. From infusion start, special attention should be paid to AEs related to the central nervous system 
including tremors. 
  


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8.2 
Discussion of Study Design 
8.2.1 Study Rationale 
This is a proof-of-concept study aiming to show the ability of AP30663 to terminate 
ongoing AF episodes. 
The study was designed to allow for modifications to the AP30663 dose without 
undermining the validity and integrity of this study. After all randomised patients have 
completed Day 2 assessments of the study (or terminated), an interim analysis will be 
conducted to determine whether or not the study can be continued to Part 2 and, if to be 
continued, to determine the starting dose(s) of AP30663 to be used in Part 2 of the 
study. Further IAs will be conducted during Part 2 to allow for additional doses to be 
tested, or poor-performing doses to be stopped. This is expected to determine a dose of 
AP30663 with adequate efficacy and minimal adverse effects. No Type II error 
correction will be taken into account due to this being a proof-of-concept study. 
Choice of placebo comparator 
Currently, there is no gold standard treatment for AF in the EU and the recommended 
first-line agents are only moderately effective. A placebo group was chosen as control 
group to prevent bias and as there is no standard treatment for AF in the EU. Treatment 
with placebo is short (30 min infusion) and patients will receive DC electrical 
cardioversion if AF is still ongoing 90 min after the infusion start.  
Rationale for dose selection 
In the completed phase 1 trials a dose and plasma concentration related effect on QTcF 
was found with a peak estimated mean QTcF prolongation of 45.2 ms for the dose of 6 
mg/kg. The QTcF effect was transient and a return to baseline level was observed 8 
hours after the start of administration for the 6 mg/kg dose consistent with low plasma 
concentrations at this timepoint. No other dose related effects were found.  
For the starting dose of 3 mg/kg preclinical data support the assumption that it will 
result in a sufficiently high free plasma concentration to be effective in conversion.  
The increase of the QTcF would serve as a safety parameter, but might also be a marker 
of a higher increase of the atrial effective refractory period (AERP) and thereby be 
indicative of a higher chance of conversion. In this study, the continuous monitoring of 
the patients during and after the 30-minute infusion in combination with predefined 
stopping criteria (see Section 8.3.4.2) will guarantee the safety of the patients. 
The low-dose alternative of 2 mg/kg is the lowest AP30663 dose that produced a free 
plasma concentration at which it is reasonable to expect an effect on conversion. The 
lower dose of 2 mg/kg AP30663 may be an option, if the starting dose shows excellent 
or good efficacy but insufficient safety or tolerability. 


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Details regarding reasonably anticipated adverse events (AEs) as well as known or 
anticipated benefits and risks for AP30663, may be found in the investigator’s brochure. 
8.2.2 Quality Management and Risk Evaluation 
This protocol was evaluated to identify those processes and data that were critical to 
ensure human patient protection and reliability of study results. 
Risk control measures will be periodically reviewed to ascertain whether the 
implemented quality management activities remain effective and relevant, taking into 
account emerging knowledge and experience. 
8.3 
Selection of Study Population 
8.3.1 Number of Planned Patients  
Approximately 41, 62, 82, 103, or 123 patients will need to be screened in 
approximately 15 centres in EU to achieve up to 36, 54, 72, 90, or 108 randomised 
patients, respectively, who have completed Day 2 assessments or terminated the study, 
depending on the study design and recommendation of the DMC at each of the IAs. The 
number of patients screened is based on a screen failure rate of 12%. 
Examples of scenarios for the distribution of patients across dose arms during Part 1 and 
Part 2 are provided in Section 17.3. 
The statistical considerations on which the sample size is based are provided in 
Section 11.2. Patient replacement is described in Section 8.3.4.1. 
8.3.2 Inclusion Criteria 
To be eligible for study entry, patients must satisfy all of the following criteria: 
1. Provision of written informed consent. 
2. Clinical indication for cardioversion of atrial fibrillation. 
3. Current episode of symptomatic atrial fibrillation lasting between 3 h and 7 days 
inclusive at randomisation. 
4. Adequate anticoagulation according to international and/or national guidelines. 
5. Body weight 50 to 110 kg, inclusive (with clothes, without shoes).  
6. Male patients and postmenopausal women aged 18 to 80 years, inclusive.  
- 
Male patients who are sexually active must agree to abstain from sexual 
activity or be willing to use a double-barrier method of birth control (i.e. any 
double combination of male or female condom with spermicidal gel, 
diaphragm, sponge or cervical cap with spermicidal gel) if they become 


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sexually active from the time of consent and for 90 days after the infusion 
day.  
- 
Post-menopausal women are defined as being >12 months after last 
menstrual period.  
- 
Women can also be included if permanently sterilised since ≥6 weeks (i.e. 
documented hysterectomy, bilateral salpingectomy, bilateral oophorectomy). 
Breastfeeding women are excluded. 
8.3.3 Exclusion Criteria 
Patients will be excluded from the study if 1 or more of the following criteria are 
applicable: 
1. Significant clinical illness or surgical procedure within 4 weeks preceding the 
screening visit. 
2. Present renal dysfunction (estimated glomerular filtration rate [eGFR] 
< 30 mL/min), hepatic dysfunction (alanine aminotransferase [ALT] or aspartate 
aminotransferase [AST] > 3 × upper limit of normal), or uncontrolled 
hyperthyroidism or hypothyroidism. 
3. History of significant mental, renal or hepatic disorder, chronic obstructive 
pulmonary disease or other significant disease, as judged by the investigator. 
4. Any cardioversion attempt of AF or atrial flutter within 1 week preceding 
randomisation. 
5. Prior failed attempt (no conversion) of pharmacological or DC cardioversion of 
previous or current AF episode. 
6. Failure to find a large antecubital (or equivalent) vein for the infusion. 
7. Any of the following events, or any other significant cardiovascular event as 
judged by the investigator, during the last 6 weeks before randomisation: 
myocardial infarction, unstable angina pectoris or other signs of myocardial 
ischaemia, stroke or transient ischaemic attack, myocardial revascularisation 
(percutaneous coronary intervention [PCI], coronary artery bypass graft 
[CABG]), or other revascularisation procedure. 
8. Haemodynamically unstable condition as judged by the investigator; systolic BP 
<90 mm Hg or >180 mm Hg, or diastolic BP >105 mm Hg at randomisation.  
9. Blood haemoglobin <100 g/L at screening. 
10. Congestive heart failure New York Heart Association class III or IV. Left 
ventricular ejection fraction <40% on echocardiography, or other clinically 
significant abnormality on the echocardiogram (not older than 6 months) as 
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11. Known hypertrophic cardiomyopathy or significant left ventricular hypertrophy 
(free wall or septal thickness >13 mm). 
12. Any clinically significant valvular heart disease. 
13. History or previous signs of sinus nodal disease 
14. Pacemaker or implantable cardioverter defibrillator therapy. 
15. Personal or family history of Torsades de Pointes, any other polymorphic 
ventricular tachycardia, sustained ventricular tachycardia, long QT syndrome, 
and/or Brugada syndrome. 
16. QTc (Fridericia, QTcF) interval >450 ms at randomisation. (When measured 
during AF, the mean heart rate should be 50 to 100 bpm. The QTcF should be 
calculated at AF as the mean of at least 5 consecutive RR intervals with 
consecutive QT intervals). 
17. QRS duration >120 ms at randomisation. 
18. Known atrioventricular (AV)-block I (prolonged PQ [PR] interval >220 ms), 
AV-block II, AV-block III, or complete bundle branch block (BBB) . 
19. Potassium in serum below 3.5 or above 5.3 mmol/L at randomisation. Patients 
with low potassium levels at screening may be appropriately supplemented with 
potassium before baseline, according to the local standards. A re-test of the 
potassium level is required, and the patient can be randomised after the 
potassium has returned to reference range. 
20. Anticipated change in dose or initiation of loop diuretic from screening to the 
end of infusion. 
21. Use of any antiarrhythmic drug class I and/or III within 7 days or, for 
amiodarone specifically, 12 weeks before randomisation.  
22. Use of QT-prolonging drug, and/or drug that inhibits cytochrome P450 
(CYP)3A4, as well as St John's Wort within 10 days before randomisation. 
23. Administration of an investigational drug within the preceding 3 months before 
randomisation. 
24. Administration of AP30663 at any time before randomisation. 
25. History of drug addiction and/or alcohol abuse within the last 12 months at the 
discretion of the investigator. 
26. Blood or plasma donation within the preceding 4 weeks before randomisation. 
27. Any suspected or manifested clinically significant infection as judged by the 
investigator. 
28. Involvement in the planning and conduct of the study (applies to Acesion 
Pharma staff, Syneos Health staff, and staff at the investigational site). 


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29. Clinical judgement by the investigator that the patient should not participate in 
the study. 
30. Any malignant cancer within 3 years (except for successfully treated in-situ 
non-melanoma skin cancer and in-situ cervical cancer) of signing the informed 
consent form (ICF). 
8.3.4 Removal of Patients From Therapy or Assessments 
8.3.4.1 Patient Discontinuation/Withdrawal From the Study 
Patients may be withdrawn from the study for any of the following reasons: 
x Patient request. 
x Patient non-compliance with the study protocol. 
x Use of non-permitted concurrent therapy. 
x Lost to follow-up. 
x Occurrence of adverse events (AEs) not compatible with the continuation of 
patient participation in the study, in the investigator’s opinion, or unacceptable 
to the patient to continue. 
x If the pre-infusion ECG QTcF is above 450 ms the infusion with the IMP should 
not be initiated and the patient should be registered as an Early Termination. 
x Investigator request. 
x Request by Acesion Pharma. 
Patient replacement 
x Patients who spontaneously convert to SR before randomisation are screen 
failures. Re-screening of such patients is not allowed. 
x Patients who spontaneously convert to SR after randomisation and before 
infusion start are considered dropouts and will be replaced. 
x Patients who have a QTcF above 450 ms at pre-infusion.  
x Patients who do not meet inclusion criterion #2 (clinical indication for 
cardioversion of AF) will be replaced. Patients who stop study drug for any 
other reason will not be replaced. 
Patients are free to withdraw from the study at any time without providing reason(s) for 
withdrawal and without prejudice to further treatment. The reason(s) for withdrawal will 
be documented in the electronic case report form (eCRF). 


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Patients withdrawing from the study will be encouraged to complete the same final 
evaluations as patients completing the study according to this protocol, particularly 
safety evaluations. The aim is to record data in the same way as for patients who 
completed the study. 
Reasonable efforts will be made to contact patients who are lost to follow-up. These 
efforts must be documented in the patient’s file.  
Acesion Pharma has the right to terminate the study at any time in case of serious AEs 
(SAEs) or if special circumstances concerning the investigational product or the 
company itself occur making further treatment of patients impossible. In this event, the 
investigator(s) will be informed of the reason for study termination. 
8.3.4.2 
Treatment Discontinuation (Stop of Infusion) 
The planned duration of drug infusion is described in Section 8.4.1.  
Criteria for stop of drug infusion prior to cardioversion or prior to the infusion 
duration of 30 min are as follows:  
x Developing hemodynamic instability (drop in BP, drop in heart rate, unless 
caused by conversion) including but not limited to  
- 
systolic BP decrease to <90 mm Hg or significant decrease from baseline 
(e.g. >40 mm Hg), or mean BP decrease <70 mm Hg (calculated as  
 [systolic BP + 2 × diastolic BP] / 3). 
- 
systolic BP increase to >190 mm Hg or 
- 
heart rate <40 bpm or 
- 
intolerable side effects. 
x Developing changes in ECG variables (compared with pre-infusion ECG):  
- 
QRS +50% and/or development of BBB. 
- 
QTcF +60 ms. 
- 
QTcF >500 ms. 
x Developing tremors (involuntary, rhythmic muscle contraction leading to 
shaking movements in one or more parts of the body) 
x Per investigator decision, when it is not in the patient’s best interest to continue 
infusion. Specific attention should be paid to any other AEs related to the central 
nervous system and/or any local infusion site reactions. 


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Pregnancy 
Patients will be instructed that known or suspected pregnancy occurring during the 
study, in female patients or female partners of male patients, should be confirmed and 
reported to the investigator. The investigator should also be notified of any pregnancy 
occurring during the study but confirmed only after completion of the study. In the 
event that a patient is subsequently found to be pregnant after inclusion in the study, any 
pregnancy will be followed to term, and the status of mother and child will be reported 
to Acesion Pharma after delivery. 
Full details will be recorded in the eCRF and a pregnancy reporting form will be 
completed (see Section 10.1.3.1.1). 
8.4 
Investigational Products 
8.4.1 Investigational Products Administered 
Study drugs will either be AP30663 or placebo; both will be administered as an 
intravenous infusion for 30 min.  
Prior to the interim analysis (Part 1 of the study), patients randomised to the AP30663 
arm will receive AP30663 at a dose of 3 mg/kg.  
The starting AP30663 dose(s) for Part 2 of the study will be determined during DMC 
review of the interim analysis at the end of Part 1. In Part 2, patients randomised to 
AP30663 may receive one of the following AP30663 doses: 2, 4, 5, or 6 mg/kg 
dependent on the results seen for the decision criteria, and the subsequent dose 
recommended by the DMC. 
Patients randomised to the placebo arm will receive matching placebo infusion.  
The following instructions apply for intravenous infusion of study drugs:  
x The patient should be in (semi-) supine position. 
x A large peripheral vein (e.g. antecubital) should be chosen. 
x For each patient, the largest clinically feasible cannula size should be used at the 
discretion of the investigator to avoid local injection site reactions. 
x After end of infusion, the intravenous lines should be flushed with 5% glucose 
solution.  
Study drugs must be administered as soon as possible after randomisation and 
preferably not later than 12 h after randomisation.  




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Body weight [kg] rounded to nearest integer × intended AP30663 dose [mg] ÷ 2 mg/mL 
The following rule applies: Body weight decimals 0.1 kg to 0.4 kg will be rounded 
down and 0.5 to 0.9 kg will be rounded up. 
Detailed instructions for the preparation and handling of the final AP30663 solution for 
infusion including a detailed and easily read checklist and a dose calculation nomogram 
will be provided in the pharmacy manual. Careful training of unblinded site staff with 
regards to the reconstitution will be conducted. 
Placebo solution is not frozen and will be administered as a 5% glucose solution in the 
same way as AP30663. To ensure blinding, volume and/or weight of the placebo 
solution will be adjusted to match that of the AP30663 dose provided. Detailed 
instructions for the preparation and handling of the placebo solution including a detailed 
and easily read checklist and a dose calculation nomogram will be provided in the 
pharmacy manual as well.  
Specific procedures to ensure blinding are described in Section 8.4.7.  
All investigational products will be manufactured and, if applicable, imported according 
to the relevant regulatory requirements. 
8.4.3 Packaging and Labelling 
AP30663 will be manufactured by Onyx/IPCA, Sunderland, United Kingdom. 
Manufacturing, packaging, and labelling of the AP30663 drug concentrate for infusion 
will be performed by Recipharm AB, Stockholm, Sweden. All packaging and labelling 
operations will be performed according to Good Manufacturing Practice for Medicinal 
Products and the relevant regulatory requirements. 
Packaging and labelling of the AP30663 drug concentrate vials will be performed by the 
central drug depot Almac (location for packaging/labelling/shipping: Craigavon, UK; 
back-up location for shipping: Dundalk, Ireland). Glucose solution for infusion and 
empty infusion bags will be centrally purchased and supplied by Almac. 
Labelling by Almac will include the following: 
1. Labelling of the active vial and its respective carton with a booklet label which 
also includes kit numbering; frozen conditions are required. 
2. Production of another carton (kit) which will contain a 500 mL bag of 5% 
glucose and an empty infusion bag. The label on the carton and the additional 
booklet label for the empty infusion bag will have additional text/numbering. 
Almac Clinical Services will also provide labels for the infusion bags that will be 
shipped to the investigational site and labelled by unblinded site staff. 


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8.4.4 Method of Assigning Patients to Treatment Groups 
For Part 1 of the study, eligible patients will be randomised 1:1 (approximately 
36 patients randomised to AP30663 or placebo). An additional 18 to 72 patients will be 
randomised cumulatively in a 2:1 ratio to 1 or more doses of AP30663 (dependent on 
dose arms open at time of randomisation) or placebo in Part 2 using an interactive web 
randomisation system (IWRS).  
Two separate lists will be utilised for the study, one for Part 1 and a separate one for 
Part 2. Both lists will be provided by a separate unblinded biostatistical team and 
provided to the IWRS.  
8.4.5 Selection of Doses in the Study 
The patients randomised to the active treatment arm in Part 1 of the study will be given 
an AP30663 dose of 3 mg/kg.  
In Part 2, patients randomised to AP30663 may receive one of the following AP30663 
doses: 2, 4, 5, or 6 mg/kg. The final decision on AP30663 doses for Part 2 of the study 
will be taken based on the DMC recommendation based on review of the IAs. 
Further details on study design options and associated AP30663 dose levels in Part 2 of 
the study are described in Section 8.1. 
A justification for the selection of AP30663 doses is given in Section 8.2.1.  
8.4.6 Selection and Timing of Dose for Each Patient 
Patients will be randomly allocated to receive either AP30663 or placebo. Each patient 
will receive a single intravenous infusion of either AP30663 or placebo on Day 1.  
Details of duration of infusion, instructions for infusion, and dose levels before and after 
the IAs are included in Section 8.4.1. 
Calculation of individual doses based on the patient’s body weight is described in 
Section 8.4.2. 
8.4.7 Blinding 
This is a double-blind study. Acesion Pharma, investigators, and patients will remain 
blinded to the study treatment allocation until the end of the study. The randomisation 
list will be kept secure from the study team, investigators, and patients throughout the 
conduct of the study and until unblinding is authorised by Acesion Pharma and the 
blinded lead study statistician. The DMC will be unblinded according to the DMC 
Charter, and a separate unblinded statistical team will be assigned to provide the 


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analyses to the DMC. Further details of blinded and unblinded personnel will be 
included in the DMC Charter. 
One or more unblinded site staff will be identified at each centre, whose role will be 
limited to handling the study treatment. Treatment allocation via the IWRS will be 
provided only to the unblinded site staff and will be sent to the pre-specified fax/email 
accessible only to unblinded team members.  
The unblinded site staff will prepare infusion bags of AP30663 and placebo, label the 
final infusion bags, and provide them to the investigator in a blinded manner. This 
procedure is described in the pharmacy manual.  
The assessors (e.g. the investigators and site personnel assessing safety and efficacy) as 
well as the study patients must remain blinded to the treatment assignments throughout 
the study. 
The only planned unblinding other than at the IAs will be at the conclusion of the study, 
when the database has been cleaned, statistical populations have been defined, and 
approval for database lock has been given by Acesion Pharma.  
The IWRS will be programmed with blind-breaking instructions. The study blind may 
be broken if, in the opinion of the investigator, it is in the participant’s best interest to 
know the study treatment assignment. Acesion Pharma must be notified before the blind 
is broken unless identification of the study treatment is required for a medical 
emergency in which the knowledge of the specific blinded study treatment will affect 
the immediate management of the participant’s condition (e.g. antidote is available). In 
this case, Acesion Pharma must be notified within 24 h after breaking the blind. The 
date and reason for breaking the blind must be recorded in the source documentation 
and eCRF, as applicable. 
In case of an SAE that is unexpected and suspected to be causally related to the study 
drug and that potentially requires expedited reporting to regulatory authorities, the 
treatment code will be broken for the individual patient by the Safety and 
Pharmacovigilance Department. 
8.4.8 Prior and Concomitant Therapy 
Prior therapy with any prescribed/over-the-counter medications within 14 days prior to 
screening, as well as with all current medications and those initiated after signing of ICF 
should be recorded as concomitant therapy. 
When the patient requires anticoagulation because of an AF episode, anticoagulation 
should be initiated and maintained according to the current international and national 
guidelines. 


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Patients with low potassium or magnesium levels at screening may be appropriately 
supplemented with potassium or magnesium, respectively, before baseline, according to 
the local standards. A re-test of the potassium level is required. The patient can be 
randomised after the potassium has returned to reference range (3.5 to 5.3 mmol/L). 
The investigator should consult the medical monitor if there is any uncertainty regarding 
patient use of a particular drug or drug class. 
8.4.8.1 Prohibited Medication and Procedures 
Table 2 provides a listing of specific restrictions for concomitant therapy use, with all 
necessary washout periods described. The table provides examples of prohibited drug 
categories; however, it is not a comprehensive list of all restricted medications.  
If, before the start of study drug infusion, there is a clinical indication in a randomised 
patient for any therapy that is specifically prohibited, the patient should be discontinued 
from the study. 
Use of prohibited medications and procedures for treatment of AEs in randomised 
patients after the end of infusion is allowed at the investigator’s discretion and is not 
regarded as a protocol deviation. 
The investigator should actively discuss any questions regarding prohibited 
medications/procedures with the medical monitor before randomising the patient to 
study treatment or before study treatment initiation.  


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Table 2 
Prohibited Medication 
Drug class/  
specific compound 
Examples* 
(including but not limited to) 
Washout period/comments 
Antiarrhythmic class I 
Examples: ajmaline, disopyramide, 
flecainide, lidocaine, mexiletine, 
quinidine, phenytoin, prajmaline, 
procainamide, propafenone, tocainide 
7 days before randomisation and 
until the completion of the Day 2 
visit. 
Antiarrhythmic class III 
 
Examples: dofetilide, dronedarone, 
ibutilide, sotalol,  
7 days before randomisation and 
until the completion of the Day 2 
visit. 
Amiodarone 
Amiodarone 
12 weeks before randomisation 
and until the completion of the 
Day 2 visit. 
CYP3A4 inhibitors 
Examples: cannabinoids, 
clarithromycin, cimethidine, 
cyclosporine, dexamethasone, 
diltiazem, disulfiram, doxycycline, 
fluoxetine, itrakonazole, 
ketoconazole, loperamide, 
metronidazole, naloxone, nefazodone, 
norfloxacilin, sertraline, terfenadine, 
valproic acid, voriconazole, several 
antiretroviral drugs 
10 days and until the completion 
of the Day 2 visit. 
Loop diuretics 
Examples: bumetanide, ethacrynic 
acid, furosemide, torsemide 
Anticipated change in dose or 
initiation dose is prohibited from 
screening visit to the end of the 
infusion 
QT-prolonging drugs 
Examples: azithromycin, 
clarithromycin, erythromycin, 
roxithromycin, fluconazole, 
ketoconazole, chloroquine, 
amitriptyline, doxepin, imipramine, 
haloperidol, risperidone, clozapine, 
pimozide, droperidol, terfenadine, 
astemizole, probucol, cisapride 
10 days and until the completion 
of the Day 2 visit. 
St John’s Wort 
 - 
10 days and until the completion 
of the Day 2 visit. 
Any other investigational 
drug 
 
3 months before randomisation 
and during the study 
AP30663 
 
Any previous administration 
*Please consult the prescription information of a specific drug for more details. 
The following procedures are prohibited: 


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1. Any cardioversion attempt of AF or atrial flutter within 1 week preceding 
randomisation. 
2. Prior failed attempt (no conversion) of pharmacological or DC cardioversion of 
previous or current AF episode.  
3. Significant surgical procedure within 4 weeks preceding the screening visit. 
4. Pacemaker or implantable cardioverter defibrillator therapy prior to 
randomisation and during the treatment phase of the study. 
5. Myocardial revascularisation (PCI or CABG) or other revascularisation 
procedure during the last 6 weeks before randomisation. 
8.4.8.2 Rescue Medication 
All patients who will not convert from AF during infusion of the study drug or within 
90 min after the infusion start should undergo DC electrical cardioversion within 
180 min from the time the infusion started. DC electrical cardioversion should be 
performed using biphasic synchronised cardioverter with energy of 200 J. 
All medications necessary for direct-current electrical cardioversion (e.g. sedatives) 
should be administered per local standards, observing limitations from Section 8.4.8.1 
(Prohibited Medication and Procedures), and should be recorded as concomitant 
medications. 
8.4.9 Treatment Compliance 
The study drug will only be applied by the investigator on Day 1. The timing and 
duration of the infusion as well as the dose calculation depending on the patient’s 
weight will be noted in the patient’s medical file and recorded in the eCRF (day of 
application). Early termination of infusion and reason for termination will also be 
recorded in the eCRF. 


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9 
TIMING OF STUDY PROCEDURES 
The planned study assessments are listed in Section 8.1.2. 
9.1 
Screening Visit  
Patients will need to provide written informed consent before any study-related 
procedures are performed. 
x Record any AEs that have occurred and any changes in concomitant medication 
since signing of the informed consent. 
x Assess for eligibility (against the inclusion and exclusion criteria). 
x Collect full medical and surgical history, including concomitant 
illnesses/diseases and concomitant medications. 
x Record demographic data, such as date of birth or age (according to applicable 
regulations), ethnic origin, and sex. 
x Perform a full physical examination, including body weight and height. 
x Record vital signs ([semi]supine BP, heart rate, heart rhythm from ECG). 
x Collect blood samples for haematology and clinical chemistry (refer to the 
Schedule of Assessments in Section 8.1.2 for parameters included), urea (blood 
urea nitrogen [BUN]), electrolytes (magnesium, sodium, calcium, potassium), 
International normalised ratio (INR)/activated partial thromboplastin time 
(APTT), and thyroid stimulating hormone (TSH).  
 
Note:  
If TSH levels were tested within 1 week before randomisation at a local 
laboratory certified for the study, those results will be acceptable and should not 
be re-tested at screening. 
One coagulation parameter (either INR or APTT) is required for an individual 
patient. The investigator should decide which parameter is relevant for a given 
patient, taken into consideration clinical presentation and concomitant 
medications used by that patient. The same coagulation parameter should be 
consistently analysed throughout the study in an individual patient. 
x Perform a 12-lead ECG. 
x Perform a transthoracic echo (TTE) if TTE done within 6 months (inclusive) is 
not available. 


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9.2 
Day 1 – Pre-infusion (Baseline) 
The baseline visit on Day 1 with pre-infusion assessments will take place within 7 days 
of onset of AF. The following procedures will be performed at the baseline visit prior to 
study drug infusion: 
x Reassess for eligibility against the inclusion and exclusion criteria. 
x Randomisation1 will take place for eligible patients, and each will be assigned a 
patient number. 
x Record any AEs that have occurred and any changes in concomitant medication 
since the previous visit. 
x Perform a brief physical examination (general appearance, cardiovascular, 
respiratory, gastrointestinal, other). 
x Record vital signs ([semi]supine BP, heart rate, heart rhythm from ECG). 
x Collect blood samples for haematology and clinical chemistry (refer to the 
Schedule of Assessments in Section 8.1.2 for parameters included) if not already 
assessed <72 h before baseline. 
x Collect blood sample for INR/APTT for all patients on heparin or vitamin K 
antagonists when screening >24 h before start of infusion. 
x Collect baseline PK plasma sample. 
x Perform a 12-lead ECG with ECG print-outs within 15 min before infusion start. 
Confirm diagnosis of AF (defined as absence of discrete P waves and an 
irregular ventricular rate) based on the 12-lead ECG.  
If QTcF is above 450 ms the infusion should not be initiated. 
x Perform 12-lead Holter monitoring (start 30 min before infusion start). 
x Perform telemetry (start 30 min before infusion start). 
9.3 
Day 1 – During Infusion 
When all the baseline procedures have been performed and the investigator has 
confirmed the patient’s eligibility for the study, study drug will be administered as a 
single intravenous infusion for 30 min on Day 1. The following procedures will be 
performed during infusion on Day 1: 
x Administer study drug as intravenous infusion.  
 
1 Note, if the patient is found eligible, the randomisation should be planned in such a way that all logistics 
will occur in the protocol-specified timeframe, including timely reconstitution of study drug, infusion 
start and – if applicable - DC cardioversion in non-responders within 180 min from infusion start. 


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x Record any AEs that have occurred since the pre-infusion status and any 
changes in concomitant medication. Special attention should be paid to 
monitoring for AEs related to the central nervous system including tremors. 
Please also refer to section 8.2.4.2 for stop of infusion criteria. 
x Record vital signs ([semi]supine BP, heart rate, heart rhythm from ECG). 
x Collect PK plasma samples 5 min ± 1 min, 15 min ± 1 min, 25 min ± 1 min, and 
30 min - 1 min after start of infusion. The infusion should not be stopped before 
the 30 min - 1 min PK sample has been collected. In the case of conversion from 
atrial fibrillation during infusion, an additional PK sample will be taken 
immediately after conversion. 
x Perform a 12-lead digital ECG (with ECG print-outs 10 min after infusion start 
and, in case of conversion from AF, within 1 min after conversion BUT before 
infusion stop). 
x Continue 12-lead Holter monitoring. 
x Continue telemetry. 
9.4 
Day 1 – Post-Infusion 
The following procedures will be performed post-infusion on Day 1: 
x Record any AEs that have occurred and any changes in concomitant medication 
since the infusion. Special attention should be paid to monitoring for AEs related 
to the central nervous system including tremors. 
x Record vital signs ([semi]supine BP, heart rate, heart rhythm from ECG). 
Should be recorded before an electrical cardioversion, if applicable.  
x Collect PK plasma samples at 45 min ± 5 min, 1 h ± 5 min, 1 h 30 min ± 5 min, 
4 h ± 5 min, and 8 h ± 5 min after start of infusion. 
x Continue 12-lead Holter monitoring until after the 8 h PK sample is collected. 
x Perform  telemetry until at least 8h after infusion start. 
x Do electrical cardioversion in case of AF persistence (refer to the Schedule of 
Assessments in Section 8.1.2 for exact timing and parameters). 
Prior to discharge of the patient, the Day 2 follow-up visit will be scheduled.   
 
 
 


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9.5 
Day 2 
The following procedures will be performed on Day 2: 
x Record any AEs that have occurred since Day 1 and any changes in concomitant 
medication. Special attention should be paid to monitoring for AEs related to the 
central nervous system including tremors.  
x Record vital signs (BP, heart rate, heart rhythm from ECG). 
x Collect blood samples for clinical chemistry (refer to the Schedule of 
Assessments in Section 8.1.2 for parameters included).  
x Collect PK plasma samples 24 h ± 2 h after start of infusion. 
x Perform a 12-lead ECG 24h ± 2 h after start of infusion. 
The Day 30 follow-up visit will be scheduled.  
9.6 
Follow-up/Discontinuation Visit (Day 30) 
The follow-up visit will take place 30 days ± 5 days after the previous visit. The 
following procedures will be performed at the follow-up visit (Day 30): 
x Record any AEs that have occurred and any changes in concomitant medication 
since the previous visit. 
x Perform a brief physical examination (general appearance, cardiovascular, 
respiratory, gastrointestinal, other). 
x Record vital signs ([semi]supine BP, heart rate, heart rhythm from ECG). 
x Collect blood samples for haematology and clinical chemistry (refer to the 
Schedule of Assessments in Section 8.1.2 for parameters included), urea (BUN), 
and INR/APTT. 
x Perform a 12-lead ECG. 
9.7 
Duration of Treatment 
Study drug infusion is planned for 30 min for each patient. 
Regardless of which study part (Part 1 or 2) the patient participates in, the overall study 
duration for each patient is up to a maximum of 42 days. The screening and 
randomisation will occur within 7 days (inclusive) from onset of AF. The duration of 
treatment and post-treatment follow-up will be 30 days ± 5 days from start of infusion 
to the follow-up visit. 


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10 
EFFICACY, PHARMACOKINETICS, AND SAFETY VARIABLES  
The planned schedule of assessments is shown in Section 8.1.2. The schedule is same 
for both parts of the study (Parts 1 and 2). 
10.1 
Efficacy, Pharmacokinetics, and Safety Measurements  
10.1.1 Efficacy Variables  
10.1.1.1 Holter Recording 
ECG assessments for primary efficacy endpoint will be based on Holter ECG. 
Conversion from AF will be determined by the investigator and documented with a 
rhythm strip confirming conversion; time of conversion will be recorded in minutes 
after start of infusion.  
In addition, the Holter will record ECG continuously and detect conversion from AF as 
well as monitor sustainability of the rhythm after conversion. The 12-lead Holter 
monitoring equipment will be centrally provided by Clario. Analysis of the primary and 
secondary efficacy endpoints will be based on Holter ECG and ECGs collected by the 
site. The Holter ECG recording will be initiated 30 min before the planned start of study 
drug infusion and will be continued for at least 8 h until after the last PK sampling on 
Day 1. Records will be available for assessment by the DMC at the IAs, will be used for 
the analysis of the primary and secondary efficacy endpoints, and may be further used 
for retrospective safety analyses (Section 10.1.3.5).  
The following measurements will be provided for all ECGs extracted from the Holter 
recording: RR, PR, QRS, QT, QTcF, QTcB (optional), heart rate, T- and U- wave 
morphology classifications. 
Triplicate ECGs will be extracted at the same time points as PK sampling except the 
24h PK sampling (see Schedule of Assessments in Section 8.1.2) and will be read in a 
semi-automated manner by a blinded cardiologist. The arithmetic mean of the replicate 
values was used as the value for that time point. 
The ECG laboratory processes all ECGs to produce regulatory-ready research data with 
all ECG interval duration measurement quality control and quality assurance processes 
completed on a continuing basis according to ERT’s quality assurance guidelines and 
standard operating procedures (SOPs). 
Central reading in the ECG core laboratory adheres to the following principles:  
x The actual times of dosing, extraction windows, and PK sampling are 
communicated to the central ECG laboratory by the site. 


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x The central ECG laboratory identifies periods of stable heart rate on the 
continuous 12-lead ECG tracing within the 3-minute extraction window. 
x Review of ECGs from a particular patient is performed by a single reader. 
x Baseline and on-treatment ECGs are based on the same lead ECGs from a single 
patient. 
x The primary analysis lead is Lead II. If Lead II is not analysable, then primary 
lead of analysis is changed to another lead for the entire patient dataset. 
Bedside safety ECGs will be collected by the site as described in Section 10.1.3.5.  
10.1.2 Pharmacokinetic Variables  
10.1.2.1 Plasma Concentrations of AP30663 
Venous blood samples for the determination of plasma concentrations of AP30663 will 
be collected at the times indicated in the Schedule of Assessments in Section 8.1.2. 
At each of the 11 (or 12 in case of conversion from AF) sampling time points for PK 
assessment, 4 mL of venous blood will be collected. The date and the time of each 
sample collection will be recorded in the eCRF, with the time of study drug injection (or 
missed injection, if applicable). 
Concentration of AP30663 in the plasma will be determined using 2 analyses as 
outlined in Section 11.1.5 where concentration-derived PK parameters are also 
described. 
10.1.3 Safety Assessments 
10.1.3.1 Adverse Events 
Adverse Event Definition 
An AE is defined as any untoward medical occurrence in a clinical study patient 
administered a medicinal product which does not necessarily have a causal relationship 
with this treatment. An AE can therefore be any unfavourable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational) product, whether or not it is related to the 
medicinal (investigational) product. This includes an exacerbation of pre-existing 
conditions or events, intercurrent illnesses, drug interaction or the significant worsening 
of the indication under investigation that is not recorded elsewhere in the eCRF under 
specific efficacy assessments. Anticipated fluctuations of pre-existing conditions, 
including the disease under study, that do not represent a clinically significant 
exacerbation or worsening need not be considered AEs. 


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It is the responsibility of the investigator to document all AEs that occur during the 
study. AEs will be collected from study assessments including laboratory parameters, 
physical examination and vital signs and also be elicited by asking the patient a non-
leading question, for example, “Have you experienced any new or changed symptoms since 
we last asked/since your last visit?” AEs should be reported on the appropriate pages of the 
eCRF. 
When collecting AEs, special attention should be paid to AEs related to the risks 
described in the investigator’s brochure section 7 “Summary of Data and Guidance for 
the Investigator”. 
Assessment of Severity 
Each AE will be assigned a category by the investigator as follows: 
Mild: 
An AE that is easily tolerated by the patient, causes minimal discomfort, and 
does not interfere with everyday activities. 
Moderate: 
An AE that is sufficiently discomforting to interfere with normal everyday 
activities; intervention may be needed. 
Severe: 
An AE that prevents normal everyday activities; treatment or other 
intervention usually needed. 
If there is a change in severity of an AE, it must be recorded as a separate event. 
All local infusion site reactions will be regarded as AEs and reported accordingly. Specific 
detailed instruction on a standardised assessment of infusion site AEs is provided in the 
Study Drug Administration Manual. 
Assessment of Causality 
Every effort will be made by the investigator to assess the relationship of the AE, if any, to 
the study drug. Causality should be assessed using the categories presented in the following 
table: 
Unrelated: 
Clinical event with an incompatible time relationship to study drug 
administration, and that could be explained by underlying disease or 
other drugs or chemicals or is incontrovertibly not related to the study 
drug. 
Unlikely: 
Clinical event whose time relationship to study drug administration 
makes a causal connection improbable, but that could plausibly be 
explained by underlying disease or other drugs or chemicals. 
Possible: 
Clinical event with a reasonable time relationship to study drug 
administration, but that could also be explained by concurrent disease or 
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Probable: 
Clinical event with a reasonable time relationship to study drug 
administration, and is unlikely to be attributed to concurrent disease or 
other drugs or chemicals. 
Very 
Likely/Certain: 
Clinical event with plausible time relationship to study drug 
administration, and that cannot be explained by concurrent disease or 
other drugs or chemicals. 
Action Taken 
The investigator will describe the action taken in the appropriate section of the eCRF, as 
follows: 
x None 
x Study drug stopped 
x Study drug temporarily interrupted 
x Concomitant medication 
x Other, specify. 
Follow-up of Adverse Events 
All investigators should follow patients with AEs until the event is resolved or until, in 
the opinion of the investigator, the event is stabilised or determined to be chronic. 
Details of AE resolution must be documented in the eCRF. 
Patients should be followed for 30 days after receiving the study drug, and any AEs that 
occur during this time should be reported according to the procedures outlined below. 
Documentation and Reporting of Adverse Events 
AEs should be reported and documented in accordance with the procedures outlined 
below. All AEs occurring during the study must be documented in the relevant eCRF 
pages. The following data should be documented for each AE: 
x Description of the event 
x Classification of “serious” or “not serious” 
x Severity 
x Date of first occurrence and date of resolution (if applicable) 
x Action taken 
x Causal relationship 


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x Outcome of event (unknown, recovered, not yet recovered, recovered with 
sequelae, death [with date and cause reported]) 
10.1.3.1.1 Serious Adverse Events 
Serious Adverse Event Definition 
An SAE is any untoward medical occurrence or effect that, at any dose, 
x Results in death. 
x Is life-threatening. (An AE is life-threatening if the patient was at immediate risk 
of death from the event as it occurred, i.e. it does not include a reaction that 
might have caused death if it had occurred in a more serious form.) 
x Requires or prolongs inpatient hospitalisation. (Complications occurring during 
hospitalisation are AEs and are SAEs if they cause prolongation of the current 
hospitalisation. Hospitalisation for elective treatment of a pre-existing 
non-worsening condition is not, however, considered an AE. The details of such 
hospitalisations must be recorded on the medical history or physical examination 
page of the eCRF.) 
x Results in persistent or significant disability/incapacity. (An AE is incapacitating 
or disabling if it results in a substantial and/or permanent disruption of the 
patient’s ability to carry out normal life functions.) 
x Results in a congenital anomaly/birth defect. 
In addition, medical and scientific judgement is required to decide if prompt notification 
is required in situations other than those defined for SAEs above. This may include any 
event that the investigator regards as serious that did not strictly meet the criteria above 
but may have jeopardised the patient or required intervention to prevent one of the 
outcomes listed above, or that would suggest any significant hazard, contraindication, 
side effect, or precaution that may be associated with the use of the investigational 
product. 
Note that if DC cardioversion is performed as indicated in the schedule of assessments 
(Section 8.1.2), it should not be reported as AE/SAE.  
Reporting of Serious Adverse Events 
Any SAE must be reported by the investigator if it occurs during the clinical study from 
signing of the ICF or within 30 days of receiving the study drug, whether or not the 
SAE is considered to be related to the investigational product. An SAE report consists 
of the SAE form. A copy of these forms must be faxed within 24 h for the attention of 
the product safety scientist at 
 
 


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Syneos Health Safety and Pharmacovigilance Department  
Fax: +1-877-464-7787 or  
Email: SafetyReporting@SyneosHealth.com 
The investigator should not wait to receive additional information to document the event 
fully before notification of an SAE, though additional information may be requested. 
Where applicable, information from relevant laboratory results, hospital case records, 
and autopsy reports should be obtained. 
Instances of death, congenital abnormality, or an event that is of such clinical concern as 
to influence the overall assessment of safety, if brought to the attention of the 
investigator at any time after cessation of study drug administration and linked by the 
investigator to this study, should be reported to the study monitor. 
Acesion Pharma and/or Syneos Health will promptly notify all relevant investigators 
and the regulatory authorities of findings that could adversely affect the safety of 
patients, impact on the conduct of the study, or alter the independent ethics committee 
(IEC) approval/favourable opinion of the study. In addition, Syneos Health, on behalf of 
Acesion Pharma, will expedite the reporting to all concerned investigators, to the IECs, 
where required, and to the regulatory authorities of all adverse reactions that are both 
serious and unexpected. 
Reporting of Pregnancies 
All pregnancies that occur in a patient or patient’s partner during the study will be 
reported using a separate pregnancy reporting form. Reporting follows the same process 
as described above for SAE reporting. If there is also an SAE reported or suspected, an 
SAE form should also be completed and sent to the Syneos Health Safety and 
Pharmacovigilance Department as described above. 
Further details of the procedures to be followed if a pregnancy occurs are provided in 
Section 8.3.4.2. 
10.1.3.1.2 Unexpected Adverse Reactions 
Unexpected Adverse Reaction Definition 
An unexpected adverse reaction is any untoward and unintended response that is related 
to the administration of the study drug at any dose that is not consistent with the 
applicable product information (e.g. investigator’s brochure for an unauthorised 
investigational medicinal product or summary of product characteristics for an 
authorised product). 
All suspected unexpected serious adverse reactions (SUSARs) will be the subject of 
expedited reporting. Only SUSARs assessed to be possibly, probably, or very 


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likely/certainly related to study drug are considered to have a reasonable causal 
relationship to study drug and are subject to reporting to regulatory authorities. 
Acesion Pharma and/or Syneos Health shall ensure that all relevant information about a 
SUSAR that is fatal or life-threatening is reported to the relevant competent authorities 
and IEC within 7 days after knowledge by Acesion Pharma of such a case and that 
relevant follow-up information is communicated within an additional 8 days. All other 
SUSARs will be reported to the relevant competent authorities and IEC within 15 days 
after knowledge by Acesion Pharma of such a case. All investigators should follow 
SUSARs until the event is resolved or until, in the opinion of the investigator, the event 
is stabilised or determined to be chronic. Post-study SUSARs that occur after the patient 
has completed the clinical study must be reported by the investigator to Acesion 
Pharma. 
Warnings and Precautions  
There are no specific warnings associated with AP30663 administration.  
Precautions to avoid local infusion site reactions are described in Section 8.4.1.  
Please refer to the most current version of the investigator’s brochure for warnings and 
precautions.  
10.1.3.2 Clinical Laboratory Evaluation 
The haematology and clinical chemistry laboratory analyses will be performed at local 
laboratories. Reference ranges will be supplied by local laboratories and used by the 
investigator to assess the laboratory data for clinical significance and pathological 
changes. The following laboratory safety tests will be performed at the times outlined in 
the Schedule of Assessments in Section 8.1.2.  
The total amount of blood to be taken during the study from screening until the end of 
the 30-day study period amounts to a maximum of 131 mL (including blood samples for 
PK analyses). See Section 17.2 for an overview of blood samples and volumes 
collected. 
Haematology 
Haemoglobin, haematocrit, red blood cells (erythrocytes), white blood cells (leukocytes, 
total and differential), basophils, eosinophils, lymphocytes, monocytes, neutrophils, and 
platelets. 
Clinical Chemistry 
ALT, AST, bilirubin, creatinine, gamma-glutamyltransferase, glucose (random), eGFR, 
urea (BUN), sodium, potassium, calcium, and magnesium. 


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Other Laboratory Variables 
INR/APTT and TSH 
 
10.1.3.3 Vital Signs 
Vital signs will be recorded as indicated in the Schedule of Assessments in 
Section 8.1.2. They will include BP, heart rate, and heart rhythm (from ECG) and will 
be recorded in a standardised manner, i.e. after the patient has rested in the (semi)supine 
position for 5 min and before blood sampling or laboratory tests. Vital signs 
measurements will be repeated in case of clinically significant abnormalities.  
10.1.3.4 Physical Examination and Brief Physical Examination 
At screening, weight and height will be recorded and a physical examination will be 
performed, followed by a brief physical examination at baseline (pre-infusion on Day 1) 
and Day 30. Any changes from the screening and baseline visit to Day 30 will be 
recorded. Full and brief physical examination will include the following assessments:  
Table 3 
Physical Examination 
Assessment 
Full physical examination 
Brief physical examination 
General appearance 
X 
x 
Head, ears, eyes, nose, throat 
X 
- 
Cardiovascular 
X 
x 
Respiratory 
X 
x 
Gastrointestinal 
X 
x 
Dermatological 
X 
- 
Neurological 
X 
- 
Musculoskeletal 
X 
- 
Lymphatic 
X 
- 
Other (at the investigator’s 
discretion) 
X 
x 
 
10.1.3.5 Electrocardiogram 
10.1.3.5.1 12-lead Digital Electrocardiogram  
A 12-lead digital ECG will be performed at the times outlined in the Schedule of 
Assessments in Section 8.1.2 in a standardised manner (i.e. after the patient has rested in 
the [semi]supine position for at least 5 min).  
The investigator will assess ECG abnormalities (e.g. ischaemia, conduction 
abnormalities, and rhythm abnormalities) and define the ECG intervals as part of the 


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screening of eligibility and according to the inclusion/exclusion criteria, and as part of 
an adverse event assessment. 
The following measurements will be provided for all PK time points: RR, PR, QRS, 
QT, QTcF (Fridericia’s correction of QT interval), QTcB (optional), heart rate, as well 
as T- and U-wave morphology classifications. 
Bedside safety ECGs will be collected by the site, printed and reviewed by the 
investigator on site. 
ECG intervals based on these safety ECGs will only be recorded if part of an adverse 
event. 
10.1.3.5.2 Telemetry 
Heart rhythm will be recorded by telemetric monitoring as outlined in the Schedule of 
Assessments in Section 8.1.2. Lead positioning on the patient for telemetric monitoring 
will be performed per local standards and local requirements of the telemetry 
equipment. During the 8 h post-infusion of study drug, the patient will remain under 
continuous medical observation. Should any significant heart rhythm changes occur 
during this observation, the recording from telemetry should be printed out, assessed for 
clinical significance, and recorded in the eCRF.  
10.1.3.5.3 Holter Recording 
A Holter recording will be performed the first 8 hours after infusion start for efficacy 
assessments and evaluated centrally as outlined in Section 10.1.1.1. Sites will be 
contacted by email or telephone if clinical alerts have been detected on the extracted 
ECG or Holter reports overread by the central ECG laboratory.  
Holter data will be retained in case additional retrospective analysis should be necessary 
for safety. 
10.2 
Independent Data Monitoring Committee 
Safety, tolerability, PK/PD and efficacy will be regularly reviewed by an unblinded 
independent DMC to advise on dose escalation, de-escalation, and study progression 
decisions at the interim analyses. The DMC will also periodically review accumulating 
safety, tolerability, efficacy and PK/PD data throughout the study. 
At the end of Part 1, after up to 36 initial patients receiving AP30663 and placebo have 
completed Day 2 assessments of the study (or terminated the study), the DMC will be 
convened to review the accumulating unblinded efficacy (including ECG and Holter 
ECG), PK/PD, safety and tolerability data for the study in an interim analysis, and 
provide a recommendation on dose escalation, de-escalation, and study 
progression/early termination in case there is a concern regarding safety (see Section 8.1 


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for options regarding Part 2 study design). A pre-determined efficacy algorithm will be 
put in place to guide the independent DMC in its decision. Decision rules will be based 
on the AF conversion rate, safety and tolerability signals including but not limited to 
increase in QTcF interval and number and severity of local injection site reactions. 
During the enrolment period, an IA may be planned on a reduced cohort if preliminary 
blinded safety and efficacy data indicate that current enrolment is sufficient for the 
DMC to provide a recommendation for Part 2. 
Full details of composition, operational aspects, and data to be reviewed and 
recommendations to be made by the DMC will be described in the DMC Charter. 
Detailed decision rules will be outlined in the DMC Charter or the SAP. 
10.3 
Appropriateness of Measurements 
The efficacy and safety assessments planned for this study are widely used and 
generally recognised as reliable, accurate, and relevant to the disease condition. 


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11 
STATISTICAL METHODS 
11.1 
Statistical and Analytical Plans 
The statistical analysis will be performed using SAS® version 9.4 or higher. The main 
population for efficacy analysis will be the Full Analysis Set; supportive analyses will 
also be performed using the Per-Protocol Set.  
Continuous data will be presented using descriptive summaries (e.g. mean, standard 
deviation [SD], minimum, maximum, median, lower quartile, and upper quartile). 
Categorical variables will be presented by the number of observations and relative (%) 
frequency. 
Unless otherwise stated, the baseline value for any variable will be the last non-missing 
value taken prior to the infusion of the double-blind study treatment on Day 1. 
Pre-infusion Day 1 assessments will be included in this derivation of baseline. 
Unless otherwise stated, all statistical tests will be 2-sided and conducted at the 5% 
level. All presented confidence intervals will be 2-sided 95% confidence intervals. 
The SAP will be developed and finalised before database lock and will describe the 
selection of participants to be included in the analysis and procedures for accounting for 
unused and spurious data. 
11.1.1 Datasets or Populations Analysed 
For the purposes of analysis, the following populations are defined for both Parts 1 and 
2. Any decisions required for inclusion/exclusion of a population (for example, Per-
Protocol Set) will be made for all patients across both Parts 1 and 2. 
Population 
Description 
Enrolled Set 
The Enrolled Set will include all participants who sign the ICF. 
Randomised Set 
The Randomised Set will include all participants who signed the 
ICF and were subsequently randomised into the study, 
regardless of study treatment administration. 
Full Analysis Set 
The Full Analysis Set will serve as the primary population for 
the analysis of efficacy and will consist of all randomised 
participants who were administered double-blind study 
treatment and have an evaluable AF conversion status within 90 
min from the start of infusion. Participants will be analysed 
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Population 
Description 
Per-Protocol Set 
The Per-Protocol Set includes all participants from the Full 
Analysis Set who have been treated according to the protocol 
and fulfil the following criteria (to be further described in the 
SAP): 
1. All inclusion/exclusion criteria satisfied 
2. Absence of relevant protocol violations with respect to 
factors likely to affect the efficacy of treatment where the 
nature of protocol violation will be defined before 
breaking the blind 
3. Adequate study drug compliance, which will be 
determined before breaking the blind 
Participants will be analysed according to the randomised 
treatment. 
Safety Set 
All randomised participants who were administered double-
blind study treatment. Participants will be analysed according to 
the treatment received. 
PK Set  
The PK Set will include all participants in the Safety Set who 
have at least one evaluable post-baseline drug concentration 
value. 
Abbreviations: AF = atrial fibrillation, ICF = informed consent form, PK = pharmacokinetic, SAP = statistical 
analysis plan. 
11.1.2 Demographic and Other Baseline Characteristics 
Descriptive statistical methods will be used to tabulate and summarise demographics and 
baseline characteristics. 
11.1.3 Efficacy Variables 
Definition of Primary Efficacy Endpoint 
The primary efficacy endpoint is defined as the proportion of patients who have converted 
from AF within 90 min from the start of infusion, and subsequently have no AF recurrence 
within 1 min of conversion from AF. 
Definition of Secondary Efficacy Endpoints 
x The time to conversion from AF from start of infusion. 
x The proportion of patients with relapse of AF within 5 min (IRAF) after 
pharmacological or DC cardioversion. 
x The proportion of patients in SR at 3 h ± 1 h after start of infusion. 
x The proportion of patients in SR at 24 h ± 2 h after start of infusion. 
x The proportion of patients in SR at 30 days ± 5 days after start of infusion. 


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Methods of Analysis 
For the analysis of the primary endpoint (proportion of patients who have cardioversion 
within 90 min from the start of infusion) a Bayesian model will be utilised. The prior 
probability of success at a dose, d, is modelled with a Pd ~ Beta (1,1) prior (uniform) for 
each dose. Across both Parts 1 and 2 of the study, the potential doses (arms) in the trial 
are d = 0 (placebo), 2, 3, 4, 5, and 6 (all mg/kg dose units).  
Let Xd be the number of successes and Nd be the number of observations at dose d. The 
posterior distribution is calculated for each dose independently using a Beta posterior 
distribution,  
Pd ~ Beta (1 + Xd, 1 + Nd – Xd). 
The adaptive design utilises the probability that the response rate at a dose is greater 
than a 65% success rate. This is (ܲd > 0.65), for each dose d. 
This modelling will occur for each interim analysis, and at the final analysis as primary 
method. At the conclusion of the study, each AP30663 dose will be considered to be 
superior to placebo, if the posterior probability of AP30663 dose has a higher success 
rate than placebo is greater than 0.95. 
Further to the above, for the final analysis the primary endpoint will also be analysed by 
means of a logistic regression model. Relevant covariates at baseline may be added into 
the model after reviewing baseline imbalances. 
Secondary endpoints relating to proportions will be analysed using a logistic regression 
model in a similar manner to that of the primary endpoint. Time to conversion will be 
analysed using Kaplan-Meier methods and, if met, the median time to conversion will 
be presented, along with the corresponding Kaplan-Meier plot stratified by treatment 
group. 
Full details of all statistical analyses will be provided in the SAP. 
11.1.4 Safety Variables 
The safety endpoints are as follows: 
x AEs, ECG variables including significant arrhythmia, physical examination, 
vital signs, and laboratory variables. 
x Changes in QTcF interval data over time. 
Methods of Analysis 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). 
Summaries will be presented by system organ class (SOC) and preferred term. 
Treatment-emergent AEs (TEAEs) are defined as any AE occurring or worsening on or 


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after the first dose of study medication. If a participant experiences the same preferred 
term multiple times, the event will be counted only once overall and by the greatest 
severity. 
The frequency and incidence of TEAEs will be presented by SOC and preferred term 
for each treatment group (number and percentage of patients experiencing at least one 
TEAE per preferred term as well as the number of observed events per preferred term). 
Separate tables will be presented by severity and by relationship, and for SAEs, related 
TEAEs, and TEAEs leading to study discontinuation. All AEs will be presented in full 
in a comprehensive listing including participant number, treatment regimen, severity, 
seriousness, action taken, outcome, relationship to treatment, onset/stop, and duration. 
Details of SAEs and AEs leading to withdrawal will be listed separately. 
For ECG values, a categorical analysis of outliers (e.g. number of ECGs where 
QTc >450 ms, and QTc >500 ms and change from baseline of >30 ms and >60 ms) will 
be computed and summarised. 
Changes in QTcF intervals over time will be summarised by means of a shift table. 
Abnormal findings (“normal”, “abnormal, not clinically significant”, and “abnormal, 
clinically significant”) will be summarised by the number and percentage within each 
category, and change from baseline will be summarised within shift tables. 
11.1.5 PK Variables 
The PK endpoints are as follows: 
x Systemic exposure derived from the population PK model. 
x Population PK model parameter estimates derived from plasma concentrations 
of AP30663. 
Methods of Analysis 
The concentration at each time point will be summarised as arithmetic mean, SD, 
median, minimum, and maximum. 
Descriptive statistics (n, arithmetic mean, SD, minimum, median, maximum) by 
treatment group will be calculated for all derived PK endpoints. 
Concentration of AP30663 in the plasma will be determined using 2 analyses.  
x A static analysis based on plasma concentration will be performed using a non-
compartmental analysis. Data from patients with missing concentration values 
(missing samples) may be used if PK parameters can be estimated using the 
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x In addition, PK parameters will be derived using a non-linear mixed-effect 
modelling approach with NONMEM. A pre-specified population PK model 
based on existing information from previous Phase 1 study (structural model) 
will be updated with the AP30663 plasma concentrations obtained in this study. 
For the non-compartmental analysis, the following PK parameters will be determined 
for each patient based on plasma concentrations:  
x AUC0-0.5: Area under the concentration time curve from pre-dose concentration 
up to 30 min. AUC0-0.5 includes the plasma drug concentration up to the end of 
infusion 
x AUC0-t: Area under the concentration time curve up to the last measurable 
concentration 
x AUC0-inf: Area under the concentration time curve from pre-dose through 
concentration to infinity (extrapolated), calculated as AUC0-t + Ct/Kel, where Ct 
is the last observed non-zero concentration 
x Cmax: The observed peak plasma drug concentration 
x Tmax: The time at which Cmax occurs 
x t1/2: the terminal half-life value will be calculated using the equation ln2/ Kel, 
with Kel being the elimination rate constant 
x Kel: Elimination rate constant. This parameter will be the negative of the 
estimated slope of the linear regression of the ln-transformed concentration 
versus time profile in the terminal elimination phase. At least 3 concentration 
points will be used in estimating Kel. The time point where ln-linear Kel 
calculation begins (Kel Lower), and the actual sampling time of the last 
quantifiable concentration used to estimate the Kel (Kel Upper) will be reported 
with the correlation coefficient from the linear regression to calculate Kel 
From the developed population PK model, PK parameters like volume of distribution 
and clearance will be estimated. Additional PK parameters including but not limited to 
area under the curve at steady-state will be derived from the individual Bayes estimates 
from the population PK model. 
Software 
Population PK analyses will be performed using NONMEM® version 7.4. Analysis 
datasets and graphical analyses other than non-linear mixed-effect modelling will be 
performed using R v3.5.0. 


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Population PK Approach 
The population PK model will be developed using the analysis dataset and guided by 
the results of exploratory analysis. During the model development process, the 
structural, statistical, and covariate model will be selected. The model developed will be 
internally qualified using several diagnostics and statistical techniques as non-
parametric bootstrap. A complete description of the population PK approach will be 
presented in a separate PK modelling analysis plan. 
11.1.6 Interim Analyses 
The study is conducted in 2 parts (Part 1 and 2). For all IAs during the study, a separate 
unblinded biostatistical team will prepare and present the unblinded analysis, and the 
DMC will be convened to review the data and will give their recommendations 
pertaining to continuation or early termination of the study, and as well as whether or 
not to increase/decrease the dose per the algorithm below and/or any other available 
data. 
The first IA will be conducted after all randomised patients have completed Day 2 
assessments or terminated the study during Part 1. The DMC will be convened to 
review unblinded data on the primary efficacy endpoint, PK/PD, safety and tolerability 
data during this IA.  
If the DMC decides that the study should continue, then Part 2 of the study will be 
enacted. During Part 2, IAs will be conducted when 18, 36, and 54 randomised patients 
have completed Day 2 assessments or terminated the study during Part 2.  
For each IA, the success rate for any single dose level d, Pd, will be analysed using a 
Bayesian model as described in Section 11.1.3, and the following decision criteria will 
be implemented, dependent on the IA to be reviewed: 
Interim Analysis at End of Part 1: 
During the first IA the following will occur, regardless of the response seen for the 
AP30663 3 mg/kg dose: 
x Dose 3 (3 mg/kg AP30663) will be stopped. 
x Dose 5 (5 mg/kg AP30663 versus placebo) will be opened.  
Additionally, the following decision will be made dependent on the response rate seen 
for 3 mg/kg AP30663:  
x If the proportion of patients achieving a response under AP30663 3 mg/kg is 
> 0.65 then Dose 2 (2 mg/kg AP30663) will additionally be opened for Part 2 (in 
parallel to Dose 5). 


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Interim Analyses During Part 2: 
Interim analyses will occur when 18, 36, and 54 randomised patients have completed 
Day 2 assessments or terminated the study in Part 2. At these IAs the following rules 
will be utilised: 
a) If an open Dose d has at least 10 randomised patients having completed Day 2 
assessments and satisfies: (ܲd > 0.65) ≥ 0.90 then Dose d will be closed for 
sufficient efficacy response. 
x If the dose 1one level below this dose has never been opened, then dose 
d-1 is opened. 
b) If an open Dose d has at least 10 randomised patients having completed Day 2 
assessments and satisfies (ܲd > 0.65) < 0.10 then Dose d will be closed. 
x If Dose d was the largest dose thus far open, and Dose d is < 6 mg/kg, 
then dose d + 1 will be opened. 
The study will continue until all doses of AP30663 have been closed or the maximum of 
72 patients during Part 2 (up to 108 patients total across Part 1 and Part 2) have been 
enrolled.  
While the algorithm, and the DMC’s decision for dose increase/decrease, is based on 
AF conversion rate only, the DMC will also convene to review safety and tolerability 
data at defined time points; review of this data may also lead to further decisions being 
made by the DMC. 
Further details of the IAs and the decision rules to be implemented will be detailed in 
the SAP and the DMC Charter. 
11.1.7 Handling of Missing Data 
No imputation of missing data will be performed.  
11.2 
Determination of Sample Size 
The study is proof of concept, designed to allow for a considered testing of a range of 
doses of AP30663, compared with placebo. Based on the study design, the sample size 
for randomisation will range from up to 36 patients (for Part 1) to up to 108 patients (for 
Parts 1 and 2 cumulatively). The total sample size is dependent on the AP30663 dose 
arms opened on the decision of the DMC. A total of 4 IAs and a final analysis are 
included in the design, and so it is foreseen that the total number of randomised patients 
will be up to 36, 54, 72, 90, or 108 patients to have a sufficient number of patients 
evaluable for AF conversion at each IA.  


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The adaptive design utilises the probability that the response rate at a Dose d is greater 
than a success rate of 65% (Pd > 0.65, where d is the dose arm of AP30663), based on a 
Bayesian modelling procedure as stated in Section 11.1.3. 
11.3 
Protocol Deviations 
The investigator should not implement any deviation from the protocol without prior 
review and agreement by Acesion Pharma and in accordance with the IECs and local 
regulations, except when necessary to eliminate an immediate hazard to study patients. 
Such contact must be made as soon as possible to permit a review by the investigator/ 
Acesion Pharma to determine the impact of the deviation on the patient and/or the 
study. Any significant protocol deviations affecting patient eligibility and/or safety must 
be reviewed and/or approved by the IEC, as applicable, before implementation. Protocol 
deviations will be listed in the clinical study report.  


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12 
QUALITY ASSURANCE AND QUALITY CONTROL 
12.1 
Audit and Inspection 
Study centres and study documentation may be subject to quality assurance audit during the 
course of the study by Acesion Pharma or its nominated representative. In addition, 
inspections may be conducted by regulatory authorities at their discretion. 
12.2 
Monitoring 
Data for each patient will be recorded in an eCRF. Data collection must be completed for 
each patient who signs an ICF and is administered study drug. 
In accordance with current Good Clinical Practice and International Council for 
Harmonisation (ICH) guidelines, the study monitor will carry out source document 
verification at regular intervals to ensure that the data collected in the eCRF are accurate 
and reliable.  
The investigator must permit the monitor, the IEC, Acesion Pharma’s internal auditors, and 
representatives from regulatory authorities direct access to all study-related documents and 
pertinent hospital or medical records for confirmation of data contained within the eCRFs. 
12.3 
Data Management and Coding 
Syneos Health will be responsible for activities associated with the data management of this 
study. This will include setting up a relevant database and data transfer mechanisms, along 
with appropriate validation of data and resolution of queries. Data generated within this 
clinical study will be handled according to the relevant SOPs of the data management and 
biostatistics departments of Syneos Health. 
Study centres will enter data directly into an electronic data capture (EDC) system by 
completing the eCRF via a secure internet connection. Data entered in the eCRF must be 
verifiable against source documents at the study centre. Data to be recorded directly in the 
eCRF will be identified and the eCRF will be considered the source document. Any 
changes to the data entered into the EDC system will be recorded in the audit trail and will 
be FDA CFR 21 Part 11 compliant. 
Medical coding will use MedDRA for concomitant diseases and AEs and WHODrug for 
medications. 
Missing or inconsistent data will be queried in writing to the investigator for clarification. 
Subsequent modifications to the database will be documented. 
12.4 
Quality Management and Risk Evaluation 
Details are provided in Section 8.2.2. 


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13 RECORDS AND SUPPLIES 
13.1 
Drug Accountability 
On receipt of the study drug (including rescue medication, if relevant), the delegated 
unblinded site staff will conduct an inventory of the supplies and verify that study drug 
supplies are received intact and in the correct amounts before completing a supplies 
receipt. The unblinded monitor may check the clinical study supplies at each study 
centre at any time during the study. 
It is the responsibility of the unblinded study monitor to ensure that the delegated 
unblinded site staff have correctly documented the amount of the study drug received, 
dispensed, and returned on the dispensing log that will be provided. A full drug 
accountability log will be maintained at the study centre at all times. The unblinded 
study monitor will arrange collection of unused study drug. The unblinded study 
monitor will also perform an inventory of study drug before or during the close-out visit 
to the study centre. All discrepancies must be accounted for and documented. 
Drug accountability will be performed by the unblinded site staff and verified by the 
unblinded study monitor. Responsibilities of the unblinded site staff and the unblinded 
study monitor will not overlap with responsibilities of the blinded site staff and the 
blinded study monitor. 
13.2 
Financing and Insurance 
Financing and insurance of this study will be outlined in a separate agreement between 
Syneos Health and Acesion Pharma. 
 


Acesion Pharma ApS                                                                                                                                      23 Mar 2022 
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14 ETHICS 
14.1 
Independent Ethics Committee 
Before initiation of the study at each study centre, the protocol, the ICF, other written 
material given to the patients, and any other relevant study documentation will be 
submitted to the appropriate IEC. Written approval of the study and all relevant study 
information must be obtained before the study centre can be initiated or the study drug 
is released to the investigator. Any necessary extensions or renewals of IEC approval 
must be obtained for changes to the study such as amendments to the protocol, the ICF 
or other study documentation. The written approval of the IEC with the approved ICF 
must be filed in the study files. 
The investigator will report promptly to the IEC any new information that may 
adversely affect the safety of the patients or the conduct of the study. The investigator 
will submit written summaries of the study status to the IEC as required. On completion 
of the study, the IEC will be notified that the study has ended. 
14.2 
Regulatory Authorities 
Relevant study documentation will be submitted to the regulatory authorities of the 
participating countries, according to local/national requirements, for review and 
approval before the beginning of the study. On completion of the study, the regulatory 
authorities will be notified that the study has ended. 
14.3 
Ethical Conduct of the Study 
The investigator(s) and all parties involved in this study should conduct the study in 
adherence to the ethical principles based on the Declaration of Helsinki, GCP, ICH 
guidelines, and the applicable national and local laws and regulatory requirements. 
14.4 
Informed Consent 
The process of obtaining informed consent must be in accordance with applicable 
regulatory requirement(s) and must adhere to GCP. 
The investigator is responsible for ensuring that no patient undergoes any study-related 
examination or activity before that patient has given written informed consent to 
participate in the study. 
The investigator or designated personnel will inform the patient of the objectives, 
methods, anticipated benefits, and potential risks and inconveniences of the study. The 
patient should be given every opportunity to ask for clarification of any points she/he 
does not understand and, if necessary, ask for more information. At the end of the 
interview, the patient will be given ample time to consider the study. Patients will be 
required to sign and date the ICF. After signatures are obtained, the ICF will be kept and 


Acesion Pharma ApS                                                                                                                                      23 Mar 2022 
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archived by the investigator in the investigator’s study file. A signed and dated copy of 
the patient ICF will be provided to the patient or their authorised representative. 
It should be emphasized that the patient may refuse to enter the study or to withdraw 
from the study at any time, without consequences for her/his further care or penalty or 
loss of benefits to which the patient is otherwise entitled. Patients who refuse to give or 
who withdraw written informed consent should not be included in or continue in the 
study. 
If new information becomes available that may be relevant to the patient’s willingness 
to continue participation in the study, a new ICF will be approved by the IEC(s) (and 
regulatory authorities, if required). The study patients will be informed about this new 
information and reconsent will be obtained. 
14.5 
Patient Confidentiality 
Monitors, auditors, and other authorised agents of Acesion Pharma and/or its designee, 
the IEC(s) approving this research, as well as that of any other applicable agency(ies), 
such as the European Medicines Agency (EMA), will be granted direct access to the 
study patients’ original medical records for verification of clinical study procedures 
and/or data, without violating the confidentiality of the patients to the extent permitted 
by the law and regulations. In any presentations of the results of this study or in 
publications, the patients’ identity will remain confidential. 


Acesion Pharma ApS                                                                                                                                      23 Mar 2022 
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15 REPORTING AND PUBLICATION, INCLUDING ARCHIVING 
Essential documents are those documents that individually and collectively permit 
evaluation of the study and quality of the data produced. After completion of the study 
(end of study defined as the date of the last visit of the last patient), all documents and 
data relating to the study will be kept in an orderly manner by the investigator in a 
secure study file. This file will be available for inspection by Acesion Pharma or its 
representatives. Essential documents should be retained for (whichever takes longer) 
25 years after the completion of the study, for 2 years after the final marketing approval 
in an ICH region, or for at least 2 years since the discontinuation of clinical 
development of the investigational product. It is the responsibility of Acesion Pharma to 
inform the study centre when these documents no longer need to be retained. The 
investigator must contact Acesion Pharma before destroying any study-related 
documentation. In addition, all patient medical records and other source documentation 
will be kept for the maximum time permitted by the hospital, institution, or medical 
practice. 
Acesion Pharma must review and approve any results of the study or abstracts for 
professional meetings prepared by the investigator(s). Published data must not 
compromise the objectives of the study. Data from individual study centres in 
multicentre studies must not be published separately. 


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16 REFERENCES 
Feinberg WM, Blackshear JL, Laupacis A, Kronmal R, Hart RG. Prevalence, age 
distribution, and gender of patients with atrial fibrillation. Analysis and implications. 
Arch Intern Med. 1995;155(5):469-473. 
Kirchhof P, Benussi S, Kotecha D, et al. 2016 ESC Guidelines for the management of 
atrial fibrillation developed in collaboration with EACTS. Europace. 
2016;18(11):1609-1678. 
Zoni-Berisso M, Lercari F, Carazza T, Domenicucci S. Epidemiology of atrial 
fibrillation: European perspective. Clin Epidemiol. 2014;6:213-220. 


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17 APPENDICES 
17.1 
Investigator Signature Page 
Protocol Title: 
A Double-Blind, Randomised, Placebo-Controlled, Parallel-Group Study 
of AP30663 Given Intravenously for Cardioversion in Patients with Atrial 
Fibrillation 
Protocol Number: 
AP30663 - 2001 
Confidentiality and Current Good Clinical Practice Compliance Statement 
I, the undersigned, have reviewed this protocol (and amendments), including 
appendices, and I will conduct the study as described in compliance with this protocol 
(and amendments), GCP, and relevant ICH guidelines. 
Once the protocol has been approved by the IEC, I will not modify this protocol without 
obtaining prior approval of Acesion Pharma and of the IEC. I will submit the protocol 
amendments and/or any ICF modifications to Acesion Pharma and IEC, and approval 
will be obtained before any amendments are implemented. 
I understand that all information obtained during the conduct of the study with regard to 
the patients’ state of health will be regarded as confidential. No patients’ names will be 
disclosed. All patients will be identified by assigned numbers on all eCRFs, laboratory 
samples, or source documents forwarded to Acesion Pharma. Clinical information may 
be reviewed by Acesion Pharma or its agents or regulatory agencies. Agreement must 
be obtained from the patient before disclosure of patient information to a third party. 
Information developed in this clinical study may be disclosed by Acesion Pharma, to 
other clinical investigators, regulatory agencies, or other health authority or government 
agencies as required. 
 
Investigator Signature 
Date 
 
Printed Name 
 
Institution 


Acesion Pharma ApS                                                                                                                                      23 Mar 2022 
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17.2 
Blood Sampling 
Laboratory test 
Maximum number of 
samples collected 
Maximum volume per 
test 
Total volume 
Haematology 
3 
3 - 4 mL 
9 - 12 mL 
Clinical chemistry 
3 - 4 
8.5 - 10 or 14 mLa 
25.5 - 56 mL 
Blood ions 
1 - 2 
included in chemistry 
included in chemistry 
Coagulation (INR/APTT) 
2 - 3 
2.7 - 5 mL 
5.4 – 15 mL 
TSH 
1 
included in chemistry 
included in chemistry 
PK 
11 - 12 
2 - 4 mL 
22 - 48 mL 
Abbreviations: ALT = alanine aminotransferase, APTT = activated partial thromboplastin time, AST = aspartate 
aminotransferase, INR = international normalised ratio, PK = pharmacokinetic, TSH = thyroid stimulating hormone. 
a 
Clinical chemistry: 8.5 - 10 mL (including TSH); if ALT/AST tested separately – additional 4 mL. 











SAP_001.pdf: 
 
 
 
 
 
 
T hi s d o c u m e nt i s c o nfi d e nti al. 
S A P V er si o n : S A P v er si o n 4. 0 –  2 0 F e b 2 0 2 3 
C o ntr oll e d D o c u m e nt I D: 
, Eff e cti v e D at e 2 9- O ct- 2 0 1 8 
Fili n g r e q uir e m e nt s: T M F 
P a g e 1  of 4 7  
 
St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s 
 
S p o n s or N a m e: A c e si o n P h ar m a A p S 
 
Pr ot o c ol N u m b er : A P 3 0 6 6 3 - 2 0 0 1 
Pr ot o c ol Titl e:  A D o u bl e- Bli n d, R a n d o mi s e d, Pl a c e b o- C o ntr oll e d, P ar all el- Gr o u p St u d y of A P 3 0 6 6 3 
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Pr ot o c ol V er si o n a n d D at e: V er si o n 4. 0, Fi n al  2 3- M ar- 2 0 2 2 
 
S y n e o s H e alt h Pr oj e ct C o d e: 7 0 0 0 7 7 6 
 
A ut h or s:
 Pri n ci p al Bi o st ati sti ci a n 
S e ni or P h ar m a c o ki n eti ci st  
 
 
 
 
 
 
 
N oti c e of C o nfi d e nti al a n d Pr o pri et ar y I nf or m ati o n: 
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S y n e o s H e alt h s h o ul d b e n otifi e d pr o m ptl y. 
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St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s
A c e si o n P h ar m a A p S -  Pr ot o c ol N o: A P 3 0 6 6 3 - 2 0 0 1
T hi s d o c u m e nt i s c o nfi d e nti al.
S A P V er si o n : S A P v er si o n 4. 0 – 2 0 F e b 2 0 2 3
C o ntr oll e d D o c u m e nt I D: 
, Eff e cti v e D at e 2 9- O ct- 2 0 1 8
Fili n g r e q uir e m e nt s: T M F
P a g e 4 of 4 7
T a bl e of C o nt e nt s
R e vi si o n Hi st or y ............................................................................................................... ........... 2
A p pr o v al s .................................................................................................................................. 3
Gl o s s ar y of A b br e vi ati o n s................................................................................................... 8
P ur p o s e........................................................................................................................ .... 1 0
St u d y O bj e cti v e s .............................................................................................................. 1 1
E n d p oi nt s ......................................................................................................................... 1 4
A n al y si s S et s.................................................................................................................. .. 1 5
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s
A c e si o n P h ar m a A p S -  Pr ot o c ol N o: A P 3 0 6 6 3 - 2 0 0 1
T hi s d o c u m e nt i s c o nfi d e nti al.
S A P V er si o n : S A P v er si o n 4. 0 – 2 0 F e b 2 0 2 3
C o ntr oll e d D o c u m e nt I D: 
, Eff e cti v e D at e 2 9- O ct- 2 0 1 8
Fili n g r e q uir e m e nt s: T M F
P a g e 5 of 4 7
G e n er al A s p e ct s f or St ati sti c al A n al y si s ........................................................................... 1 7
D e m o gr a p hi c, Ot h er B a s eli n e C h ar a ct eri sti c s a n d M e di c ati o n ......................................... 2 0
Effi c a c y ....................................................................................................................... ..... 2 2
A n al y si s of P h ar m a c o ki n eti c s ........................................................................................... 2 4
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s
A c e si o n P h ar m a A p S -  Pr ot o c ol N o: A P 3 0 6 6 3 - 2 0 0 1
T hi s d o c u m e nt i s c o nfi d e nti al.
S A P V er si o n : S A P v er si o n 4. 0 – 2 0 F e b 2 0 2 3
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Fili n g r e q uir e m e nt s: T M F
P a g e 6 of 4 7
S af et y............................................................................................................................... 2 7
I nt eri m A n al y s e s...............................................................................................................3 1
C h a n g e s fr o m A n al y si s Pl a n n e d i n Pr ot o c ol ..................................................................... 3 2
R ef er e n c e Li st ................................................................................................................. . 3 3
Pr o gr a m mi n g C o n si d er ati o n s ........................................................................................... 3 4
Q u alit y C o ntr ol ................................................................................................................ . 3 9
I n d e x of T a bl e s................................................................................................................. 4 0
I n d e x of Fi g ur e s................................................................................................................ 4 3
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St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s
A c e si o n P h ar m a A p S -  Pr ot o c ol N o: A P 3 0 6 6 3 - 2 0 0 1
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S A P V er si o n : S A P v er si o n 4. 0 – 2 0 F e b 2 0 2 3
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A p p e n di c e s ..................................................................................................................... . 4 6
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A E
A d v er s e e v e nt
A E R P
Atri al eff e cti v e r efr a ct or y p eri o d
A F
Atri al fi brill ati o n
A L T
Al a ni n e a mi n otr a n sf er a s e
A P T T
A cti v at e d p arti al t hr o m b o pl a sti n ti m e
A S T
A s p art at e a mi n otr a n sf er a s e
A U C
Ar e a u n d er t h e c o n c e ntr ati o n ti m e c ur v e
A V
Atri o v e ntri c ul ar
B B B
B u n dl e br a n c h bl o c k
B P
Bl o o d pr e s s ur e
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B e at s p er mi n ut e
B U N
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D at a M o nit ori n g C o m mitt e e
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El e ctr o ni c C a s e R e p ort F or m
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El e ctr o ni c d at a c a pt ur e
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E sti m at e d gl o m er ul ar filtr ati o n r at e
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G C P
G o o d cli ni c al pr a cti c e
G G T
G a m m a- gl ut a m yltr a n sf er a s e
G L P
G o o d L a b or at or y Pr a cti c e
I C5 0
H alf m a xi m al i n hi bit or y c o n c e ntr ati o n
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s  
A c e si o n P h ar m a A p S -  Pr ot o c ol N o: A P 3 0 6 6 3 - 2 0 0 1 
 
 
 
T hi s d o c u m e nt i s c o nfi d e nti al. 
 
S A P V er si o n : S A P v er si o n 4. 0 –  2 0 F e b 2 0 2 3 
C o ntr oll e d D o c u m e nt I D: 
, Eff e cti v e D at e 2 9- O ct- 2 0 1 8 
Fili n g r e q uir e m e nt s: T M F 
P a g e 9  of 4 7  
 
I C D 
I m pl a nt a bl e c ar di o v ert er d efi brill at or 
I C F 
I nf or m e d c o n s e nt f or m 
I C H 
I nt er n ati o n al C o u n cil f or H ar m o ni s ati o n 
I E C 
I n d e p e n d e nt et hi c s c o m mitt e e 
I N R 
I nt er n ati o n al n or m ali s e d r ati o 
I R A F 
I m m e di at e r el a p s e of atri al fi brill ati o n 
I W R S 
I nt er a cti v e w e b r a n d o mi z ati o n s y st e m 
K el 
Eli mi n ati o n r at e c o n st a nt 
L V 
L eft v e ntri cl e 
L V E F 
L eft v e ntri c ul ar ej e cti o n fr a cti o n 
M e d D R A 
M e di c al Di cti o n ar y f or R e g ul at or y A cti viti e s 
M T D 
M a xi m u m t ol er at e d d o s e 
N C A 
N o n- c o m p art m e nt al a n al y si s 
N O A E L 
N o o b s er v e d a d v er s e eff e ct l e v el 
P CI 
P er c ut a n e o u s c or o n ar y i nt er v e nti o n 
P D 
P h ar m a c o d y n a mi c s 
P K 
P h ar m a c o ki n eti c 
Q T c 
C orr e ct e d Q T i nt er v al  
S A E 
S eri o u s a d v er s e r e a cti o n 
S A P 
St ati sti c al a n al y si s pl a n 
S D 
St a n d ar d d e vi ati o n 
S O C 
S y st e m or g a n cl a s s 
S O P 
St a n d ar d o p er ati n g pr o c e d ur e 
S R 
Si n u s r h yt h m 
t1/ 2  
T er mi n al h alf-lif e 
T E A E 
Tr e at m e nt- e m er g e nt a d v er s e e v e nt 
T m a x  
Ti m e at w hi c h C m a x  o c c ur s 
T S H 
T h yr oi d sti m ul ati n g h or m o n e 
T T E 
Tr a n st h or a ci c e c h o 
W H O 
W orl d h e alt h or g a ni s ati o n 
 
 
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s
A c e si o n P h ar m a A p S -  Pr ot o c ol N o: A P 3 0 6 6 3 - 2 0 0 1
T hi s d o c u m e nt i s c o nfi d e nti al.
S A P V er si o n : S A P v er si o n 4. 0 – 2 0 F e b 2 0 2 3
C o ntr oll e d D o c u m e nt I D: 
, Eff e cti v e D at e 2 9- O ct- 2 0 1 8
Fili n g r e q uir e m e nt s: T M F
P a g e 1 0 of 4 7
P ur p o s e
T h e p ur p o s e of t hi s st ati sti c al a n al y si s pl a n ( S A P) i s t o e n s ur e t h at t h e d at a li sti n g s, s u m m ar y t a bl e s a n d 
fi g ur e s  w hi c h  will  b e  pr o d u c e d,  a n d  t h e  st ati sti c al m et h o d ol o gi e s  t h at  will  b e  u s e d,  ar e  c o m pl et e  a n d  
a p pr o pri at e t o all o w v ali d c o n cl u si o n s r e g ar di n g t h e st u d y o bj e cti v e s.
R e s p o n si biliti e s
S y n e o s H e alt h  will p erf or m t h e st ati sti c al a n al y s e s a n d ar e r e s p o n si bl e f or t h e pr o d u cti o n a n d q u alit y c o ntr ol 
of all t a bl e s, fi g ur e s a n d li sti n g s. P h ar m a c o ki n eti c a n al y si s will al s o b e c arri e d o ut b y S y n e o s H e alt h.
Ti mi n g s of A n al y s e s
T h e st u d y will b e c o n d u ct e d i n t w o p art s ( P art s 1 a n d 2): P art 1 of t h e st u d y i s a fi x e d r a n d o mi s ati o n 
pl a c e b o- c o ntr oll e d p ar all el d e si g n, a n d P art 2 will b e a n  a d a pti v e d e si g n c o n d u ct e d i n o n e or m or e f urt h er 
d o s e s of A P 3 0 6 6 3 v s Pl a c e b o. 
I n P art 1 of t h e st u d y, u p t o 3 6 p ati e nt s will b e r a n do mi s e d i n a 1: 1 r ati o t o r e c ei v e A P 3 0 6 6 3 at 3  m g/ k g or 
m at c hi n g pl a c e b o. A n i nt eri m a n al y si s (I A) will b e c o n d u ct e d o n c e t h e r a n d o mi s e d p ati e nt s i n P art 1 h a v e 
c o m pl et e d D a y 2 a s s e s s m e nt s or t er mi n at e d t h e st u d y( s e e s e cti o n 8. 1 of t h e pr ot o c ol).
A n i nt eri m a n al y si s ( P art 1) i n cl u di n g effi c a c y, P K/ P D, s a f et y a n d t ol er a bilit y d at a will b e c o n d u ct e d aft er 
all  r a n d o mi s e d p ati e nt s h a v e c o m pl et e d D a y 2 a s s e s s m e nt s of t h e st u d y, i n or d er t o d et er mi n e t h e 
st arti n g d o s e( s) f or P art 2 of t h e st u d y. F or f urt h er i nf or m ati o n s e e s e cti o n 1 1. A n i n d e p e n d e nt d at a 
m o nit ori n g c o m mitt e e ( D M C) will b e c o n v e n e d t o r e vi e w t h e a c c u m ul ati n g u n bli n d e d effi c a c y (i n cl u di n g 
E C G a n d H olt er E C G), P K/ P D, s af et y a n d t ol er a bilit y d at a  f or t h e st u d y at t h e ti m e of t h e i nt eri m a n al y si s.
D uri n g P art 2, I A s will o c c ur w h e n 1 8, 3 6 a n d 5 4 p ati e nt s h a v e b e e n r a n d o mi s e d t o o p e n- d o s e s i n cl u di n g 
pl a c e b o, a n d h a v e c o m pl et e d D a y 2 a s s e s s m e nt s or t er mi n at e d t h e st u d y.
F or P art 2, t h e D M C will gi v e t h eir r e c o m m e n d ati o n s r e g ar di n g c o nti n u ati o n or e arl y t er mi n ati o n of t h e 
st u d y. D e ci si o n r ul e s will b e b a s e d o n t h e A F c o n v er si o n r at e; h o w e v er t h e D M C will al s o h a v e t h e o pti o n 
t o st o p a d o s e ar m ( or t h e st u d y) d u e t o u n a c c e pt a bl e s af et y a n d t ol er a bilit y (i n cl u di n g b ut n ot li mit e d t o 
i n cr e a s e i n Q T c F i nt er v al a n d n u m b er a n d s e v erit y of l o c al i nj e cti o n sit e r e a cti o n s).
A n u n bli n d e d t e a m ( u n bli n d e d st ati sti ci a n a n d u n bli n d e d pr o gr a m mi n g t e a m) will b e r e s p o n si bl e f or 
g e n er ati n g a n d d eli v eri n g u n bli n d e d T F L s t o t h e D M C m e m b er s. T a bl e s t h at will b e d eli v er e d f or t h e 
i nt eri m a n al y si s ar e d et ail e d i n S e cti o n 1 6.
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s
A c e si o n P h ar m a A p S -  Pr ot o c ol N o: A P 3 0 6 6 3 - 2 0 0 1
T hi s d o c u m e nt i s c o nfi d e nti al.
S A P V er si o n : S A P v er si o n 4. 0 – 2 0 F e b 2 0 2 3
C o ntr oll e d D o c u m e nt I D: 
, Eff e cti v e D at e 2 9- O ct- 2 0 1 8
Fili n g r e q uir e m e nt s: T M F
P a g e 1 1 of 4 7
St u d y O bj e cti v e s
Pri m ar y O bj e cti v e
T h e pri m ar y o bj e cti v e of t h e st u d y i s t o d e m o n str at e t h e effi c a c y of o n e or m or e d o s e l e v el s of A P 3 0 6 6 3 
o n t h e b a si s of t h e a bilit y t o c o n v ert atri al fi brill ati o n ( A F) aft er i ntr a v e n o u s a d mi ni str ati o n.
S e c o n d ar y O bj e cti v e s
T h e s e c o n d ar y o bj e cti v e s of t h e st u d y ar e a s f oll o w s:
T o st u d y t h e st a bilit y of r h yt h m c o ntr ol (i m m e di at e r el a p s e of A F [I R A F], i. e. wit hi n 5  mi n aft er 
c o n v er si o n fr o m A F).
T o st u d y t h e i m p ort a n c e of A F d ur ati o n wit h r e s p e ct t o t h e effi c a c y a n d s af et y of o n e or m or e 
d o s e l e v el s of A P 3 0 6 6 3.
T o e v al u at e t h e s af et y a n d t ol er a bilit y of o n e or m or e d o s e l e v el s of A P 3 0 6 6 3.
T o st u d y t h e r el ati o n s hi p b et w e e n s y st e mi c e x p o s ur e a n d r e s p o n s e, wit h s p e ci al r e g ar d t o t h e 
c o n v er si o n fr o m A F a n d t h e eff e ct o n Q R S a n d Q T c F.
E x pl or at or y O bj e cti v e s
T h e e x pl or at or y o bj e cti v e s of t h e st u d y ar e a s f oll o w s:
T o st u d y d e m o gr a p hi c a n d e c h o c ar di o gr a p hi c v ari a bl e s, c o n c o mit a nt di s e a s e s, a n d c o n c urr e nt 
m e di c ati o n wit h r e s p e ct t o t h e effi c a c y a n d s af et y of o n e or m or e d o s e l e v el s of A P 3 0 6 6 3.
T o e v al u at e t h e P K of A P 3 0 6 6 3, i n cl u di n g i nfl u e n c e of d o s e, c o n c o mit a nt m e di c ati o n, c o n c urr e nt 
di s e a s e s, a n d d e m o gr a p hi c v ari a bl e s.
T o e x pl or e t h e pr o p orti o n s of p ati e nt s o n A P 3 0 6 6 3 c o n v erti n g fr o m A F a n d of p ati e nt s 
r a n d o mi s e d t o pl a c e b o a n d c o n v erti n g at D C c ar di o v er si o n. 
Bri ef D e s cri pti o n
T hi s i s a d o u bl e- bli n d, r a n d o mi s e d, pl a c e b o- c o ntr oll e d, p ar all el- gr o u p P h a s e 2 a  st u d y of o n e or m or e 
d o s e l e v el s of A P 3 0 6 6 3 f or c ar di o v er si o n i n a d ult p ati e nt s wit h A F. 
T h e st u d y will b e c o n d u ct e d i n t w o p art s ( P art 1 a n d 2): P art 1 of t h e st u d y i s a fi x e d r a n d o mi s ati o n 
pl a c e b o- c o ntr oll e d p ar all el d e si g n a n d P art 2 will b e a n  a d a pti v e d e si g n c o n d u ct e d i n o n e or m or e f urt h er 
d o s e s of A P 3 0 6 6 3 v s Pl a c e b o. T h e st u d y i s d e si g n e d t o i d e ntif y t h e d o s e of A P 3 0 6 6 3 t o b e e v al u at e d 
f urt h er i n l at er- P h a s e r e s e ar c h. T h o u g h t h e st u d y i n v e sti g at e s m ulti pl e d o s e s of A P 3 0 6 6 3 v er s u s 
pl a c e b o, t h e p arti ci p ati n g p ati e nt s will b e r a n d o mi s e d  t o r e c ei v e o n e d o s e of A P 3 0 6 6 3 (i. e. p ati e nt s will 
n ot r e c ei v e m ulti pl e d o s e l e v el s).
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s
A c e si o n P h ar m a A p S -  Pr ot o c ol N o: A P 3 0 6 6 3 - 2 0 0 1
T hi s d o c u m e nt i s c o nfi d e nti al.
S A P V er si o n : S A P v er si o n 4. 0 – 2 0 F e b 2 0 2 3
C o ntr oll e d D o c u m e nt I D: 
, Eff e cti v e D at e 2 9- O ct- 2 0 1 8
Fili n g r e q uir e m e nt s: T M F
P a g e 1 2 of 4 7
Fi g ur e 1 St u d y S c h e m a
A b br e vi ati o n s: N = n u m b er of p ati e nt s e nr oll e d, P 3 = c o n v er si o n r ati o at 3 m g/ k g, P d = c o n v er si o n r ati o at d m g/ k g, 
P r = pr o b a bilit y.
*All a cti v e A P 3 0 6 6 3 ar m s will b e r a n d o mi s e d e q u all y f or e a c h i nt eri m a n al y si s; r a n d o mi s ati o n will o c c ur c u m ul ati v el y 
i n 2: 1 r ati o t o r e c ei v e eit h er A P 3 0 6 6 3 or pl a c e b o a cr o s s all o p e n A P 3 0 6 6 3 ar m s.
† If o n e l e v el b el o w t hi s d o s e ( d- 1) h a s n e v er b e e n o p e n e d, t h e n d o s e d- 1 will b e o p e n e d
‡ If d o s e ‘ d’ i s t h e hi g h e st d o s e o p e n e d s o f ar, a n d d o s e ‘ d’ i s < 6 m g/ k g, t h e n d o s e ‘ d + 1’ will b e o pe n e d.
P ati e nt S el e cti o n
I n cl u si o n Crit eri a
S e e s e cti o n 8. 3. 2 of t h e pr ot o c ol
E x cl u si o n Crit eri a
S e e s e cti o n 8. 3. 3 of t h e pr ot o c ol
D et er mi n ati o n of S a m pl e Si z e
T h e st u d y i s a pr o of of c o n c e pt, d e si g n e d t o all o w f or a c o n si d er e d t e sti n g of a r a n g e of d o s e s of 
A P 3 0 6 6 3, c o m p ar e d wit h pl a c e b o. B a s e d o n t h e st u d y d e si g n, t h e s a m pl e si z e f or r a n d o mi s ati o n will 
r a n g e fr o m u p t o 3 6 t o u p t o 1 0 8. T h e t ot al s a m pl e siz e i s d e p e n d e nt o n t h e A P 3 0 6 6 3 d o s e ar m s o p e n e d 
Part 1
N = 3 6
Part 2
N = 1 8 t o 7 2
Pl ace b o
N = 1 8
A P 3 0 6 6 3 ( 3 mg/ kg)
N = 1 8
1 1
I A # 1 will be c o nd ucte d  o nce all 
r a nd o mi ze d pati e nts ha ve c o mpl ete d Da y 
2 ass ess me nts or ter mi nate d t he st u d y
A P 3 0 6 6 3 2 mg/ kg
A P 3 0 6 6 3 5 mg/ kg
If P 3> 0. 6 5
S ubs e q ue nt I As will be c o nd ucte d i n Part 2 
w he n 1 8/ 3 6/ 5 4 r a nd o mi ze d pati e nts ha ve 
c o mpl ete d Da y 2 ass ess me nts or ter mi nate d 
t he st ud y
A P 3 0 6 6 3 ‘ d  mg/ kg  will be 
cl os e d f or str o ng  effi cac y †
A P 3 0 6 6 3 ‘ d  mg/ kg  w ill be 
cl os e d ‡
Pr (P d > 0. 6 5) ≥0. 9 0
Pr (P d > 0. 6 5) < 0. 1 0
Pl ace b o
2 1 *
St ud y will cl os e o nce 7 2 
pati e nts ar e e nr oll e d or 
all d oses ar e cl ose d
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s
A c e si o n P h ar m a A p S -  Pr ot o c ol N o: A P 3 0 6 6 3 - 2 0 0 1
T hi s d o c u m e nt i s c o nfi d e nti al.
S A P V er si o n : S A P v er si o n 4. 0 – 2 0 F e b 2 0 2 3
C o ntr oll e d D o c u m e nt I D: 
, Eff e cti v e D at e 2 9- O ct- 2 0 1 8
Fili n g r e q uir e m e nt s: T M F
P a g e 1 3 of 4 7
o n t h e d e ci si o n of t h e D M C. A t ot al of 4 I A s a n d a fi n al a n al y si s ar e i n cl u d e d i n t h e d e si g n, a n d s o it i s 
f or e s e e n t h at t h e t ot al n u m b er of r a n d o mi s e d p ati e nt s will b e eit h er u p t o 3 6, 5 4, 7 2, 9 0 or 1 0 8 p ati e nt s t o 
h a v e a s uffi ci e nt n u m b er of p ati e nt s e v al u a bl e f or A F c o n v er si o n at e a c h I A. 
T h e a d a pti v e d e si g n utili s e s t h e pr o b a bilit y t h at t h e r e s p o n s e r at e at a D o s e d i s gr e at er t h a n a s u c c e s s 
r at e of 6 5 % (P d > 0. 6 5, w h er e d i s t h e d o s e ar m of A P 3 0 6 6 3), b a s e d o n a B a y e si a n m o d elli n g pr o c e d ur e.
Tr e at m e nt A s si g n m e nt & Bli n di n g
F or P art 1 of t h e st u d y, eli gi bl e p ati e nt s will b e r a n d o mi s e d 1: 1 ( a p pr o xi m at el y 3 6 p ati e nt s r a n d o mi s e d t o 
A P 3 0 6 6 3 or pl a c e b o). A n a d diti o n al 1 8  t o 7 2 p ati e nt s will b e r a n d o mi s e d c u m ul ati v el y i n a 2: 1 r ati o t o 1 or 
m or e d o s e s of A P 3 0 6 6 3 ( d e p e n d e nt o n  d o s e ar m s o p e n at ti m e of r a n d o mi s ati o n) or pl a c e b o i n P art 2 
u si n g a n i nt er a cti v e w e b r a n d o mi s ati o n s y st e m (I W R S). 
T w o s e p ar at e li st s will b e utili s e d f or t h e st u d y, o n e f o r P art 1 a n d a s e p ar at e o n e f or P art 2. B ot h li st s will 
b e pr o vi d e d b y a s e p ar at e u n bli n d e d bi o st ati sti c al t e a m a n d pr o vi d e d t o t h e I W R S.
A c e si o n P h ar m a, i n v e sti g at or s, a n d p a ti e nt s will r e m ai n bli n d e d t o t h e st u d y tr e at m e nt all o c ati o n u ntil t h e 
e n d of t h e st u d y. T h e r a n d o mi s ati o n li st will b e k e pt s e c ur e fr o m t h e st u d y t e a m, i n v e sti g at or s, a n d 
p ati e nt s t hr o u g h o ut t h e c o n d u ct of t h e st u d y a n d u nti l u n bli n di n g i s a ut h ori s e d b y A c e si o n P h ar m a a n d 
t h e bli n d e d l e a d st u d y st ati sti ci a n. T h e D M C will b e u n bli n d e d a c c or di n g t o t h e D M C c h art er, a n d a 
s e p ar at e u n bli n d e d st ati sti c al t e a m will b e a s si g n e d t o pr o vi d e t h e a n al y s e s t o t h e D M C a n d I nt eri m 
A n al y si s. F urt h er d et ail s of bli n d e d a n d u n bli n d e d p er s o n n el will b e i n cl u d e d i n t h e D M C c h art er.
A d mi ni str ati o n of St u d y M e di c ati o n
St u d y dr u g s will eit h er b e A P 3 0 6 6 3 or pl a c e b o. 
Pri or t o t h e i nt eri m a n al y si s ( P art 1 of t h e st u d y), p ati e nt s r a n d o mi s e d t o t h e A P 3 0 6 6 3 ar m will r e c ei v e 
A P 3 0 6 6 3 at a d o s e of 3  m g/ k g. 
T h e st arti n g A P 3 0 6 6 3 d o s e( s) f or P art 2 of t h e st u d y will b e d et er mi n e d d uri n g D M C r e vi e w of t h e i nt eri m 
a n al y si s at t h e e n d of P art 1. I n P art 2, p ati e nt s r a n d o mi s e d t o A P 3 0 6 6 3  m a y r e c ei v e o n e of t h e f oll o wi n g 
A P 3 0 6 6 3 d o s e s: 2, 4, 5, or 6  m g/ k g d e p e n d e nt o n t h e r e s ult s s e e n f or t h e d e ci si o n crit eri a, a n d t h e 
s u b s e q u e nt d o s e r e c o m m e n d e d b y t h e D M C.
P ati e nt s r a n d o mi s e d t o t h e pl a c e b o ar m will r e c ei v e m at c hi n g pl a c e b o i nf u si o n. 
St u d y Pr o c e d ur e s a n d Fl o w c h art
T h e s c h e d ul e of t h e pl a n n e d st u d y a s s e s s m e nt s d uri n g  P art 1 a n d P art 2 i s i n s e cti o n 8. 1. 2 fr o m t h e 
pr ot o c ol. T h e pl a n n e d st u d y a s s e s s m e nt s d uri n g P art 2 ar e t h e s a m e a s t h o s e t h at ar e pl a n n e d f or P art 1.
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s
A c e si o n P h ar m a A p S -  Pr ot o c ol N o: A P 3 0 6 6 3 - 2 0 0 1
T hi s d o c u m e nt i s c o nfi d e nti al.
S A P V er si o n : S A P v er si o n 4. 0 – 2 0 F e b 2 0 2 3
C o ntr oll e d D o c u m e nt I D: 
, Eff e cti v e D at e 2 9- O ct- 2 0 1 8
Fili n g r e q uir e m e nt s: T M F
P a g e 1 4 of 4 7
E n d p oi nt s
Pri m ar y Effi c a c y E n d p oi nt
T h e pr o p orti o n of p ati e nt s t h at h a v e c o n v ert e d fr o m A F wit hi n 9 0 mi n fr o m t h e st art of i nf u si o n a n d 
s u b s e q u e ntl y h a v e n o A F r e c urr e n c e wit hi n 1  mi n of c o n v er si o n fr o m A F.
S e c o n d ar y Effi c a c y E n d p oi nt s
T h e ti m e t o c o n v er si o n fr o m A F fr o m st art of i nf u si o n.
T h e pr o p orti o n of p ati e nt s wit h r el a p s e of A F wit hi n 5 mi n (I R A F) f oll o wi n g p h ar m a c ol o gi c al or 
dir e ct- c urr e nt ( D C) c ar di o v er si o n.
T h e pr o p orti o n of p ati e nt s i n S R at  3 h ± 1 h aft er st art of i nf u si o n.
T h e pr o p orti o n of p ati e nt s i n S R at 2 4 h ± 2 h aft er st art of i nf u si o n.
T h e pr o p orti o n of p ati e nt s i n S R at 3 0 d a y s ± 5 d a y s aft er st art of i nf u si o n.
E x pl or at or y E n d p oi nt s
C orr el ati o n of dr u g e x p o s ur e ( pl a s m a C m a x a n d ar e a u n d er t h e c o n c e ntr ati o n ti m e c ur v e [ A U C]) 
a n d t h e ti m e of c o n v er si o n.
C orr el ati o n of atri al si z e a n d c o n v er si o n r at e.
C orr el ati o n of atri al si z e t o r el a p s e or f ail ur e.
C orr el ati o n of g e n d er a n d a g e a n d c o n v er si o n r at e.
C orr el ati o n of d ur ati o n of c urr e nt A F, c o n v er si o n r at e a n d - si n u s r h yt h m at s o m e ti m e p oi nt  .
P h ar m a c o ki n eti c E n d p oi nt s
T h e P K e n d p oi nt s ar e a s f oll o w s:
S y st e mi c e x p o s ur e d eri v e d fr o m t h e p o p ul ati o n P K m o d el.
P o p ul ati o n P K m o d el p ar a m et er e sti m at e s d eri v e d fr o m pl a s m a c o n c e ntr ati o n s of A P 3 0 6 6 3.
C o n c e ntr ati o n- d eri v e d P K p ar a m et er s of pl a s m a A P 3 0 6 6 3  will b e d et er mi n e d u si n g 2 a p pr o a c h e s:
• A st ati c a n al y si s b a s e d o n pl a s m a c o n c e ntr ati o n will b e p erf or m e d u si n g a no n- c o m p art m e nt al 
a n al y si s ( N C A);
• P K p ar a m et er s will al s o b e d eri v e d u si n g a n o n-li n e ar  mi x e d- eff e ct m o d eli n g a p pr o a c h. 
S af et y E n d p oi nt s
A d v er s e e v e nt s ( A E s), el e ctr o c ar di o gr a m ( E C G) v ari a bl e s i n cl u di n g si g nifi c a nt arr h yt h mi a, 
p h y si c al e x a mi n ati o n, vit al si g n s, a n d l a b or at or y e v al u ati o n s.
C h a n g e s i n Q T c F i nt er v al d at a o v er ti m e.
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s
A c e si o n P h ar m a A p S -  Pr ot o c ol N o: A P 3 0 6 6 3 - 2 0 0 1
T hi s d o c u m e nt i s c o nfi d e nti al.
S A P V er si o n : S A P v er si o n 4. 0 – 2 0 F e b 2 0 2 3
C o ntr oll e d D o c u m e nt I D: 
, Eff e cti v e D at e 2 9- O ct- 2 0 1 8
Fili n g r e q uir e m e nt s: T M F
P a g e 1 5 of 4 7
A n al y si s S et s
F or p ur p o s e s of a n al y si s, t h e f oll o wi n g p o p ul ati o n s ar e d efi n e d f or b ot h P art s 1 a n d 2.
E nr oll e d S et
T h e E nr oll e d S et will i n cl u d e all p ati e nt s  w h o si g n t h e I C F.  U nl e s s s p e cifi e d ot h er w i s e, t hi s s et will b e 
u s e d f or p ati e nt li sti n g s a n d f or s u m m ari e s of p ati e nt di s p o siti o n. T hi s s et will i n cl u d e s cr e e n f ail ur e s.
R a n d o mi s e d S et
T h e R a n d o mi s e d S et will i n cl u d e all p ati e nt s w h o si g n e d t h e I C F a n d w er e s u b s e q u e ntl y r a n d o mi s e d i nt o 
t h e st u d y ( S cr e e n f ail ur e ar e e x cl u d e d), r e g ar dl e s s of st u d y tr e at m e nt a d mi ni str ati o n.
F ull A n al y si s S et 
T h e F ull A n al y si s S et will s er v e a s t h e pri m ar y p o p ul ati o n f or t h e a n al y si s of effi c a c y a n d will c o n si st of all 
r a n d o mi s e d p arti ci p a nt s w h o w er e a d mi ni st er e d d o u bl e- bli n d st u d y tr e at m e nt a n d h a v e a n e v al u a bl e A F 
c o n v er si o n st at u s  wit hi n 9 0 mi n fr o m t h e st art of i nf u si o n. 
P ati e nt s will b e a n al y s e d a c c or di n g t o t h e r a n d o mi s e d tr e at m e nt.
P er Pr ot o c ol S et 
T h e P er- Pr ot o c ol S et i n cl u d e s all p ati e nt s fr o m t h e F u ll A n al y si s S et w h o h a v e b e e n tr e at e d a c c or di n g t o 
t h e pr ot o c ol a n d f ulfil t h e f oll o wi n g crit eri a:
1. 
All i n cl u si o n/ e x cl u si o n crit eri a s ati sfi e d a c c or di n g t o t h e l at e st A P 3 0 6 6 3- 2 0 0 1 Pr ot o c ol V er si o n 4. 0
2. 
A b s e n c e  of  r el e v a nt  pr ot o c ol  vi ol ati o n s  wit h r e s p e ct  t o  f a ct or s  li k el y  t o  aff e ct  t h e  effi c a c y  of  
tr e at m e nt w h er e t h e n at ur e of pr ot o c ol vi ol ati o n will b e d efi n e d b ef or e br e a ki n g t h e bli n d
3. 
A d e q u at e st u d y dr u g c o m pli a n c e, w hi c h will b e d et er mi n e d b ef or e br e a ki n g t h e bli n d
P ati e nt s  will b e a n al y s e d a c c or di n g t o t h e r a n d o mi s e d tr e at m e nt.
S af et y S et  
All r a n d o mi s e d p ati e nt s  w h o w er e a d mi ni st er e d d o u bl e - bli n d st u d y tr e at m e nt. P ati e nt s will b e a n al y s e d 
a c c or di n g t o t h e tr e at m e nt r e c ei v e d. T h e S af et y S et wi ll b e u s e d f or all a n al y s e s of s af et y e n d p oi nt s.
P h ar m a c o ki n eti c ( P K)  S et   
T h e P K S et will i n cl u d e all p ati e nt s i n t h e S af et y S et w h o h a v e at l e a st o n e e v al u a bl e p o st-i nf u si o n dr u g 
c o n c e ntr ati o n v al u e.
Pr ot o c ol D e vi ati o n s
I m p ort a nt pr ot o c ol d e vi ati o n s will b e c oll e ct e d i n t h e e C T M S. E a c h i n st a n c e of a pr ot o c ol d e vi ati o n will b e 
r e vi e w e d b y t h e S p o n s or a n d d et er mi n e d t o b e eit h er m aj or or mi n or b ef or e D B L. 
T h e m aj or pr ot o c ol d e vi ati o n s i n cl u d e, b ut ar e n ot li mit e d t o t h e f oll o wi n g (t o b e fi n ali z e d b ef or e D B L): 
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s  
A c e si o n P h ar m a A p S -  Pr ot o c ol N o: A P 3 0 6 6 3 - 2 0 0 1 
 
 
 
T hi s d o c u m e nt i s c o nfi d e nti al. 
 
S A P V er si o n : S A P v er si o n 4. 0 –  2 0 F e b 2 0 2 3 
C o ntr oll e d D o c u m e nt I D: 
, Eff e cti v e D at e 2 9- O ct- 2 0 1 8 
Fili n g r e q uir e m e nt s: T M F 
P a g e 1 6  of 4 7  
 
  
Eli gi bilit y d e vi ati o n s (I n cl u si o n/ E x cl u si o n crit eri a) 
  
I m pr o p er r e c o n stit uti o n a n d a d mi ni str ati o n of st u d y m e di c ati o n 
  
N o n c o m pli a n c e wit h st u d y m e di c ati o n ( st o p of dr u g i nf u si o n pri or t o 3 0 mi n) 
  
N o n c o m pli a n c e wit h st u d y pr o c e d ur e s if t h e c on s e q u e n c e of n o n c o m pli a n c e w o ul d c o m pr o mi s e 
eit h er t h e p ati e nt ’ s s af et y a n d/ or t h e st u d y i nt e grit y, pri m ar y e n d p oi nt, a n d/ or i s n ot i n li n e wit h 
G C P/I C H g ui d eli n e s 
  
U s e of pr o hi bit e d c o n c o mit a nt t h er a pi e s 
P ati e nt s wit h a n y m aj or pr ot o c ol d e vi ati o n s t h at li k el y aff e ct t h e effi c a c y of tr e at m e nt will n ot b e i n cl u d e d i n 
t h e P P p o p ul ati o n. 
N u m b er ( %) of p ati e nt s wit h at l e a st o n e m aj or pr ot o c ol d e vi ati o n will b e i n cl u d e d i n a s u m m ar y t a bl e, 
u si n g t h e R a n d o mi s e d S et. 
All pr ot o c ol d e vi ati o n s will b e li st e d f or all p ati e nt s  i n t h e R a n d o mi s e d S et, i n cl u di n g t h eir a s si g n m e nt of 
mi n or, m aj or or criti c al, a n d t h e d at e t h e d e vi ati o n o c c urr e d. 
 
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s
A c e si o n P h ar m a A p S -  Pr ot o c ol N o: A P 3 0 6 6 3 - 2 0 0 1
T hi s d o c u m e nt i s c o nfi d e nti al.
S A P V er si o n : S A P v er si o n 4. 0 – 2 0 F e b 2 0 2 3
C o ntr oll e d D o c u m e nt I D: 
, Eff e cti v e D at e 2 9- O ct- 2 0 1 8
Fili n g r e q uir e m e nt s: T M F
P a g e 1 7 of 4 7
G e n er al A s p e ct s f or St ati sti c al A n al y si s
G e n er al M et h o d s
S A S V er si o n 9. 4 or hi g h er will b e u s e d f or pr o gr a m mi n g a n d pr o d u cti o n
T h e st ati sti c al a n al y si s b a s e d o n pl a s m a c o n c e ntr ati o n will b e p erf or m e d u si n g a n o n-
c o m p art m e nt al a n al y si s ( N C A), t h e P K a n al y s e s wi ll b e p erf or m e d b y S y n e o s H e alt h u si n g P h o e ni x 
Wi n N o nli n ® (r el e a s e 8. 0 or hi g h er) a n d all ot h er a n al y s e s a n d s u m m ari e s will b e pr o d u c e d u si n g 
St ati sti c al A n al y si s S y st e m ( S A S ®) v er si o n 9. 4 ( or hi g h er). 
P K p ar a m et er s  will b e d eri v e d u si n g a n o n-li n e ar mi x e d- eff e ct m o d eli n g a p pr o a c h,  P K a n al y s e s 
will b e p erf or m e d b y S y n e o s H e alt h u si n g N O N M E M ® v er si o n 7. 4.  
U nl e s s ot h er wi s e s p e cifi e d, s u m m ari e s will b e pr e s e nt e d f or e a c h tr e at m e nt a n d o v er all.
U nl e s s ot h er wi s e s p e cifi e d, c o nti n u o u s v ari a bl e s will b e s u m m ari z e d u si n g t h e n u m b er of 
o b s er v ati o n s ( n), m e a n, st a n d ar d d e vi ati o n ( S D), m e di a n, mi ni m u m, a n d m a xi m u m. C at e g ori c al 
v ari a bl e s will b e s u m m ari z e d u si n g n u m b er of o b s er v ati o n s ( n), fr e q u e n c y a n d p er c e nt a g e s of 
p ati e nt s .
All r el e v a nt p ati e nt d at a will b e i n cl u d e d i n li sti n g s. All p ati e nt s e nt er e d i n t o t h e d at a b a s e will b e 
i n cl u d e d i n p ati e nt d at a li sti n g s.
H a n dli n g of r e p e at e d m e a s ur e m e nt s at t h e s a m e vi sit 
If m e a s ur e m e nt s w er e r e p e at e d at t h e s a m e s c h e d ul e d vi sit, t h e v al u e a ct u all y fl a g g e d a s 
s c h e d ul e d will b e t h e 
L a st n o n- mi s si n g r e p e at e d m e a s ur e m e nt, if vi sit i s b ef or e st art of i nf u si o n, a n d 
Fir st n o n- mi s si n g r e p e at e d m e a s ur e m e nt, if vi sit i s aft er st art of i nf u si o n. 
G e n er all y, o nl y s c h e d ul e d m e a s ur e m e nt s will b e u s e d f or st ati sti c al s u m m ari e s a n d a n al y si s. 
U n s c h e d ul e d m e a s ur e m e nt s will n ot u s e d f or a n al y si s, b ut o nl y li st e d.
K e y D efi niti o n s
B a s eli n e V al u e
U nl e s s ot h er wi s e s p e cifi e d, t h e b a s eli n e v al u e f or a n y v ari a bl e will b e t h e l a st v al u e t a k e n pri or t o t h e 
i nf u si o n of t h e d o u bl e- bli n d st u d y tr e at m e nt o n D a y 1. T hi s i n cl u d e s pr e- d o s e D a y 1 a s s e s s m e nt s.
L a st a s s e s s m e nt
U nl e s s ot h er wi s e s p e cifi e d, l a st a s s e s s m e nt i s d efi n e d a s D a y 3 0 vi sit or e arl y di s c o nti n u ati o n vi sit.
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s
A c e si o n P h ar m a A p S -  Pr ot o c ol N o: A P 3 0 6 6 3 - 2 0 0 1
T hi s d o c u m e nt i s c o nfi d e nti al.
S A P V er si o n : S A P v er si o n 4. 0 – 2 0 F e b 2 0 2 3
C o ntr oll e d D o c u m e nt I D: 
, Eff e cti v e D at e 2 9- O ct- 2 0 1 8
Fili n g r e q uir e m e nt s: T M F
P a g e 1 8 of 4 7
Mi s si n g D at a
U nl e s s ot h er wi s e s p e cifi e d, n o i m p ut ati o n  will b e p erf or m e d f or mi s si n g d at a.
Mi s si n g D at e s f or pri or or c o n c o mit a nt m e di c ati o n s
F or pri or a n d c o n c o mit a nt m e di c ati o n s wit h i n c o m pl et e d at e s, t h e f oll o wi n g r ul e s will b e u s e d t o i m p ut e 
st art a n d/ or st o p d at e s f or t h e p ur p o s e s of d et er mi ni n g w h et h er a m e di c ati o n i s pri or or c o n c o mit a nt o nl y. 
F or st art d at e s:
-if d a y i s mi s si n g t h e fir st d a y of t h e m o nt h will b e u s e d. 
-If d a y a n d m o nt h i s mi s si n g, 1st of J a n u ar y will b e u s e d. 
-If t h e st art d at e i s mi s si n g c o m pl et el y, t h e d at e of i nf u si o n will b e u s e d. 
-If t h e st o p d at e i s c o m pl et e a n d t h e i m p ut e d st art d at e i s aft er t h e a ct u al st o p d at a, t h e n t h e st art 
d at e will b e i m p ut e d a s t h e st o p d at e. 
F or st o p d at e s:
-if t h e d a y i s mi s si n g t h e n t h e l a st d a y of t h e m o nt h will b e u s e d. 
-If t h e d a y a n d m o nt h i s mi s si n g, t h e n 3 1st D e c e m b er will b e u s e d. 
-If t h e st o p d at e i s c o m pl et el y mis si n g, t h e n t h e d at e of i nf u si o n  will  b e u s e d. If t h e st art d at e i s 
c o m pl et e a n d t h e i m p ut e d st o p d at e  i s e arli er t h a n t h e a ct u al st art d at e, t h e st o p d at e will b e 
i m p ut e d a s t h e st art d at e. 
Mi s si n g D at e s f or a d v er s e e v e nt
If t h e a d v er s e e v e nt st art d at e i s p arti all y or c o m pl et el y mi s si n g, t h e n t h e f oll o wi n g r ul e s will b e u s e d t o 
i m p ut e t h e st art d at e f or t h e p ur p o s e s of d et er mi ni n g tr e at m e nt e m er g e n c e st at u s o nl y :
If t h e w h ol e st art d at e i s mi s si n g t h e n t h e d at e of i nf u si o n  will b e u s e d.
mi s si n g m o nt h : if t h e A E h a s o c c urr e d t h e s a m e y e ar a s t h e d at e of i nf u si o n, r e pl a c e t h e mi s si n g 
m o nt h of o n s et b y t h e m o nt h of d at e of i nf u si o n.
If t h e A E h a s o c c urr e d t h e s u b s e q u e nt y e ar aft er t h e y e ar of d at e of i nf u si o n, r e pl a c e t h e mi s si n g 
m o nt h of o n s et b y J a n u ar y.
If t h e A E h a s o c c urr e d t h e pr e vi o u s y e ar of t h e y ear of d at e of i nf u si o n, r e pl a c e t h e mi s si n g m o nt h 
of o n s et b y D e c e m b er.
mi s si n g d a y
: r e pl a c e it b y ‘ 0 1’, a n d v erif y t h at t h e c o m pl et e d d at e i s gr e at er or e q u al t o t h e d at e of 
i nf u si o n. If n ot, r e pl a c e t h e i n c o m pl et e d at e of o n s et b y t h e d at e of i nf u si o n.
Vi sit Wi n d o w s
N ot a p pli c a bl e
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s
A c e si o n P h ar m a A p S -  Pr ot o c ol N o: A P 3 0 6 6 3 - 2 0 0 1
T hi s d o c u m e nt i s c o nfi d e nti al.
S A P V er si o n : S A P v er si o n 4. 0 – 2 0 F e b 2 0 2 3
C o ntr oll e d D o c u m e nt I D: 
, Eff e cti v e D at e 2 9- O ct- 2 0 1 8
Fili n g r e q uir e m e nt s: T M F
P a g e 1 9 of 4 7
P o oli n g of C e ntr e s
N ot a p pli c a bl e
S u b gr o u p s
N o s u b gr o u p  f or t hi s st u d y.
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s
A c e si o n P h ar m a A p S -  Pr ot o c ol N o: A P 3 0 6 6 3 - 2 0 0 1
T hi s d o c u m e nt i s c o nfi d e nti al.
S A P V er si o n : S A P v er si o n 4. 0 – 2 0 F e b 2 0 2 3
C o ntr oll e d D o c u m e nt I D: 
, Eff e cti v e D at e 2 9- O ct- 2 0 1 8
Fili n g r e q uir e m e nt s: T M F
P a g e 2 0 of 4 7
D e m o gr a p hi c, Ot h er B a s eli n e C h ar a ct eri sti c s a n d  M e di c ati o n
P ati e nt  Di s p o siti o n a n d Wit h dr a w al s
T h e f oll o wi n g fr e q u e n ci e s ( n u m b er a n d p er c e nt) will b e di s pl a y e d i n t h e p ati e nt di s p o siti o n t a bl e, b y 
tr e at m e nt gr o u p a n d o v er all:
N u m b er of p ati e nt s e nr oll e d; 
N u m b er of p ati e nt s s cr e e n f ail ur e;
N u m b er of p ati e nt s r a n d o mi s e d;
N u m b er ( %) of p ati e nt s i n t h e F A S s et ( F ull A n al y si s S et s e e d efi niti o n i n s e cti o n 5); 
N u m b er ( %) of p ati e nt s i n t h e P P s et ( P er- Pr ot o c ol S et, s e e d efi niti o n i n s e cti o n 5); 
N u m b er ( %) of p ati e nt s i n t h e P K s et ( P h ar m a c o ki n eti c S et, s e e d efi niti o n i n s e cti o n 5); 
N u m b er ( %) of p ati e nt s i n t h e S af et y s et ( s e e d efi niti o n i n s e cti o n 5); 
N u m b er ( %) of p ati e nt s  w h o c o m pl et e d t h e st u d y; 
N u m b er ( %) of p ati e nt s w h o di s c o nti n u e d t h e st u d y e arl y, a n d r e a s o n s f or di s c o nti n u ati o n. 
T h e a n al y s e s of di s p o siti o n will b e b a s e d o n t h e E nr oll e d S et. T h e d e n o mi n at or s f or t h e p er c e nt 
c al c ul ati o n s will b e t h e n u m b er of p ati e nt s i n t h e R a n d o mi s e d S et.
T a bl e f or P ati e nt Di s p o sti o n will b e pr e s e nt e d b y c o h ort at e a c h I nt eri m a n al y si s.
P ati e nt c o m pl eti o n st at u s, d at e of c o m pl eti o n/ di s c o nti n u ati o n a n d r e a s o n f or di s c o nti n u ati o n will b e li st e d .
D e m o gr a p hi c a n d Ot h er B a s eli n e C h ar a ct eri sti c s
G e n d er a n d c hil d- b e ari n g p ot e nti al (f e m al e p ati e nt s o nl y), et h ni cit y will b e s u m m ari z e d b y t h e n u m b er 
a n d p er c e nt a g e of p ati e nt s i n e a c h  tr e at m e nt gr o u p. A g e ( y e ar s)  will b e s u m m ari z e d u si n g d e s cri pti v e 
s u m m ar y st ati sti c s.
D e m o gr a p hi c s p ar a m et er s  will b e al s o pr e s e n t e d b y c o h ort at e a c h I nt eri m A n al y si s.
D at a fr o m tr a n st h or a ci c e c h o ( T T E) will b e pr e s e n t e d u si n g s u m m ar y st ati sti c s.  H ei g ht a n d b a s eli n e 
w ei g ht will b e al s o s u m m ari z e d.
D ur ati o n of c urr e nt A F e pi s o d e (i n h o ur s) ( d eri v ati o n s e e s e cti o n 8. 1) a n d ti m e si n c e i niti al A F di a g n o si s 
(i n y e ar s) will b e s u m m ari z e d i n a d diti o n.
Ti m e si n c e i niti al A F di a g n o si s (i n y e ar s) = d at e of r a n d o mi z ati o n – d at e of i niti al A F di a g n o si s ( b a s e d o n 
M H D E C O D = ‘ Atri al Fi brill ati o n’ )
I n c a s e of a n i n c o m pl et e d at e of i niti al A F di a g n o si s, t h e fir st d a y of t h e m o nt h will b e u s e d f or a mi s si n g 
d a y, 1 st J a n u ar y will b e u s e d f or a mi s si n g d a y a n d m o nt h.  
All d e m o gr a p hi c d at a will b e pr e s e nt e d i n a d at a li sti n g.
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St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s
A c e si o n P h ar m a A p S -  Pr ot o c ol N o: A P 3 0 6 6 3 - 2 0 0 1
T hi s d o c u m e nt i s c o nfi d e nti al.
S A P V er si o n : S A P v er si o n 4. 0 – 2 0 F e b 2 0 2 3
C o ntr oll e d D o c u m e nt I D: 
, Eff e cti v e D at e 2 9- O ct- 2 0 1 8
Fili n g r e q uir e m e nt s: T M F
P a g e 2 1 of 4 7
M e di c al Hi st or y a n d C o n c o mit a nt Di s e a s e s
M e di c al hi st or y will b e c o d e d t o s y st e m or g a n cl a s s ( S O C) a n d pr ef err e d t er m ( P T) u si n g M e di c al 
Di cti o n ar y f or R e g ul at or y A cti viti e s ( M e d D R A) v er si o n 2 1. 1 or a n u p d at e d v er si o n.
D at a will b e s u m m ari z e d b y S O C a n d P T a n d s ort e d al p h a b eti c all y.  C o n diti o n s t h at ar e r e p ort e d m or e 
t h a n o n c e f or a gi v e n S O C a n d P T will b e c o u nt e d o nl y o n c e p er p ati e nt o n t h e P T l e v el f or e a c h S O C
A c orr e s p o n di n g d at a li sti n g will b e pr e s e nt e d. 
M e di c ati o n
S e cti o n 6. 3. 1 d e s cri b e s h o w mi s si n g d at e s will b e i m p ut e d f or t h e p ur p o s e of d et er mi ni n g 
pri or/ c o n c o mit a nt m e di c ati o n st at u s. 
Pri or M e di c ati o n
Pri or a n d c o n c o mit a nt m e di c ati o n s will b e c o d e d b y t h e A n at o mi c al T h er a p e uti c C h e mi c al ( A T C) 
cl a s sifi c ati o n s y st e m a c c or di n g t o t h e W orl d H e alt h Or g a ni z ati o n Dr u g Di cti o n ar y ( W H O D R U G),
W H O Dr u g Gl o b al B 3 S e p 2 0 1 8.
Pri or m e di c ati o n s will i n cl u d e m e di c a ti o n s st art e d a n d st o p p e d pri or t o t h e i nf u si o n d at e of t h e st u d y dr u g. 
F or t h e s u m m ar y t a bl e s, t h e c o u nt a n d p er c e nt a g e of p ati e nt s u n d er e a c h a n at o mi c al t h er a p e uti c 
c h e mi c al ( A T C) cl a s s l e v el 2 a n d P T will b e s u m m ari z e d b y tr e at m e nt gr o u p. 
If a p ati e nt  h a s t a k e n pri or m e di c ati o n s m or e t h a n o n c e, t h e p ati e nt  will b e c o u nt e d o nl y o n c e u n d er a n y 
gi v e n dr u g cl a s s.
C o n c o mit a nt M e di c ati o n
C o n c o mit a nt m e di c ati o n s will i n cl u d e m e di c ati o n st art e d o n or aft er t h e i nf u si o n d at e of st u d y dr u g. 
M e di c ati o n t h at st art e d b ef or e t h e i nf u si o n of st u d y dr u g a n d c o nti n u e d o n or aft e r t h e i nf u si o n d at e will b e 
c o n si d er e d a s c o n c o mit a nt m e di c ati o n. 
F or t h e s u m m ar y t a bl e s, t h e c o u nt a n d p er c e nt a g e of p ati e nt s u n d er e a c h a n at o mi c al t h er a p e uti c 
c h e mi c al ( A T C) cl a s s l e v el 2 a n d P T will b e s u m m ari z e d b y tr e at m e nt gr o u p. 
If a p ati e nt h a s t a k e n c o n c o mit a nt  m e di c ati o n s m or e t h a n o n c e, t h e p ati e nt will b e c o u nt e d o nl y o n c e 
u n d er a n y gi v e n dr u g cl a s s.
A li sti n g of pri or a n d c o n c o mit a nt m e di c ati o n s will b e pr o vi d e d f or all p ati e nt s i n t h e s af et y s et. A fl a g will 
b e i n cl u d e d i n t h e li sti n g t o di sti n g ui s h pri or a n d c o n c o mit a nt m e di c ati o n s.
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St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s
A c e si o n P h ar m a A p S -  Pr ot o c ol N o: A P 3 0 6 6 3 - 2 0 0 1
T hi s d o c u m e nt i s c o nfi d e nti al.
S A P V er si o n : S A P v er si o n 4. 0 – 2 0 F e b 2 0 2 3
C o ntr oll e d D o c u m e nt I D: 
, Eff e cti v e D at e 2 9- O ct- 2 0 1 8
Fili n g r e q uir e m e nt s: T M F
P a g e 2 2 of 4 7
Effi c a c y
Pri m ar y Effi c a c y E n d p oi nt a n d A n al y si s
T h e pri m ar y effi c a c y e n d p oi nt i s d efi n e d a s t h e pr o p or ti o n of p ati e nt s w h o h a v e c o n v ert e d fr o m A F wit hi n 
9 0 mi n fr o m t h e st art of i nf u si o n, a n d s u b s e q u e ntl y h a v e n o A F r e c urr e n c e wit hi n 1 mi n of c o n v er si o n 
fr o m A F.
F or t h e a n al y si s of t h e pri m ar y e n d p oi nt ( pr o p orti o n of  p ati e nt s w h o h a v e c ar di o v er si o n wit hi n 9 0 mi n fr o m 
t h e st art of i nf u si o n) a B a y e si a n m o d el will b e utili se d. T h e pri or pr o b a bilit y of s u c c e s s at a d o s e, d, i s 
m o d ell e d wit h a P d ~ B et a ( 1, 1) pri or ( u nif or m) f or e a c h d o s e. A cr o s s b ot h P art s 1 a n d 2 of t h e st u d y, t h e 
p ot e nti al d o s e s ( ar m s) i n t h e tri al ar e d = 0 ( pl a c e b o), 2, 3, 4, 5, a n d 6 ( all m g/ k g d o s e u nit s). 
L et X d b e t h e n u m b er of s u c c e s s e s a n d N d b e t h e n u m b er of o b s er v ati o n s at d o s e d. T h e p o st eri or 
di stri b uti o n i s c al c ul at e d f or e a c h d o s e i n d e p e n d e ntl y u si n g a B et a p o st eri or di stri b uti o n, 
P d ~ B et a ( 1 + X d , 1 + Nd – X d ).
T h e a d a pti v e d e si g n utili s e s t h e pr o b a bilit y t h at t h e r e s p o n s e r at e at a d o s e i s gr e at er t h a n a 6 5 % 
s u c c e s s r at e. T hi s i s (
d > 0. 6 5), f or e a c h d o s e d.
T hi s m o d elli n g will o c c ur f or e a c h i nt eri m a n al y si s, a n d at t h e fi n al a n al y si s a s pri m ar y m et h o d. At t h e 
c o n cl u si o n of t h e st u d y, e a c h A P 3 0 6 6 3 d o s e will b e c o n si d er e d t o b e s u p eri or t o pl a c e b o, if t h e p o st eri or 
pr o b a bilit y of A P 3 0 6 6 3 d o s e h a vi n g a hi g h er s u c c e s s r at e t h a n pl a c e b o i s gr e at er t h a n 0. 9 5.
F urt h er t o t h e a b o v e, t h e pri m ar y e n d p oi nt  will al s o b e  a n al y s e d b y m e a n s of a l o gi sti c r e gr e s si o n m o d el. 
T h e m o d el will i n cl u d e tr e at m e nt a n d d ur ati o n of c urr e nt A F e pi s o d e.
D ur ati o n of c urr e nt A F e pi s o d e (i n h o ur s) = d at e/ti m e of r a n d o mi s ati o n –
d at e/ti m e of A F s y m pt o m o n s et
If n o ti m e of A F s y m pt o m o n s et i s a v ail a bl e, ’ 0 0: 0 0’ will b e u s e d f or t h e c al c ul ati o n of t h e d ur ati o n. 
All st ati sti c al t e st s will b e 2- si d e d a n d c o n d u ct e d at  t h e 5 % si g nifi c a n c e l e v el. All pr e s e nt e d c o nfi d e n c e 
i nt er v al s will b e 2- si d e d 9 5 % c o nfi d e n c e i nt er v al s.
S e c o n d ar y Effi c a c y E n d p oi nt( s) a n d A n al y s e s
Ti m e t o c o n v er si o n fr o m A F fr o m st art of i nf u si o n
T h e ti m e t o c o n v er si o n fr o m A F fr o m st art of i nf u si o n  will b e a n al y s e d u si n g K a pl a n- M ei er m et h o d s. T h e 
n u m b er of p ati e nt s t h at r e a c h e d c ar di a c c o n v er si o n wit h i n 9 0 mi n s of st art of st u d y dr u g i nf u si o n will b e 
s u m m ari z e d u si n g t h e m e di a n ti m e t o c ar di a c c o n v er si o n al o n g wit h t h e i nt er q u artil e r a n g e (I Q R) .
A K a pl a n M eir pl ot str atifi e d b y tr e at m e nt gr o u p will b e pr e s e nt e d. A l o gr a n k t e st will b e u s e d t o c o m p ar e 
tr e at m e nt gr o u p s.
Ti m e t o c o n v er si o n (i n mi n)  will b e c al c ul at e d u si n g t h e f or m ul a e:
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St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s
A c e si o n P h ar m a A p S -  Pr ot o c ol N o: A P 3 0 6 6 3 - 2 0 0 1
T hi s d o c u m e nt i s c o nfi d e nti al.
S A P V er si o n : S A P v er si o n 4. 0 – 2 0 F e b 2 0 2 3
C o ntr oll e d D o c u m e nt I D: 
, Eff e cti v e D at e 2 9- O ct- 2 0 1 8
Fili n g r e q uir e m e nt s: T M F
P a g e 2 3 of 4 7
Ti m e t o c o n v er si o n (i n mi n) = ( Ti m e of c o n v er si o n or c e n s ori n g - ti m e of st art of i nf u si o n).
I n c a s e of A F p er si st e n c e at 9 0 mi n aft er st art of i nf usi o n, a dir e ct- c urr e nt ( D C) el e ctri c al c ar di o v er si o n i s 
t o b e d o n e wit hi n 1 8 0 mi n p o st-i nf u si o n st art.  P atie nt s w h o h a v e el e ctri c al c ar di o v er si o n will b e c e n s or e d. 
T h e ti m e of c e n s ori n g  will b e 9 0 mi n.
Pr o p orti o n of p ati e nt s wit h r el a p s e of A F wit hi n 5 mi n (I R A F) 
T h e pr o p orti o n of p ati e nt s wit h r e l a p s e of A F wit hi n 5 mi n (I R A F) f oll o wi n g p h ar m a c ol o gi c al or D C
c ar di o v er si o n will b e pr e s e nt e d b y tr e at m e nt a n d a n al y s e d  u si n g a l o gi sti c r e gr e s si o n m o d el. T h e m o d el 
will i n cl u d e tr e at m e nt, a n d d ur a ti o n of c urr e nt A F e pi s o d e.
I n a d diti o n t h e s a m e a n al y si s will b e d o n e f or t h e pro p orti o n of p ati e nt s wit h r e l a p s e of A F wit hi n 5 mi n 
(I R A F) f oll o wi n g p h ar m a c ol o gi c al c ar di o v er si o n o nl y. 
Pr o p orti o n of p ati e nt s i n S R 
T h e pr o p orti o n of p ati e nt s i n S R aft er st art of i nf u si o n at diff er e nt ti m e p oi nt s ( 3 h ± 1 h, 2 4 h ± 2 h a n d 3 0 
d a y s ± 5 d a y s aft er st art of i nf u si o n) will b e pr e s e nt e d b y tr e at m e nt gr o u p  a n d  a n al y s e d  u si n g a l o gi sti c 
r e gr e s si o n m o d el. T h e m o d el wil i n cl u d e tr e at m e nt a n d d ur ati o n of c urr e nt A F e pi s o d e. 
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St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s
A c e si o n P h ar m a A p S -  Pr ot o c ol N o: A P 3 0 6 6 3 - 2 0 0 1
T hi s d o c u m e nt i s c o nfi d e nti al.
S A P V er si o n : S A P v er si o n 4. 0 – 2 0 F e b 2 0 2 3
C o ntr oll e d D o c u m e nt I D: 
, Eff e cti v e D at e 2 9- O ct- 2 0 1 8
Fili n g r e q uir e m e nt s: T M F
P a g e 2 4 of 4 7
A n al y si s of P h ar m a c o ki n eti c s
All P K a n al y s e s will b e c o n d u ct e d u si n g t h e P K S et.
P K S a m pli n g S c h e d ul e 
Pl a s m a s a m pl e s will b e t a k e n at b a s eli n e ( pr e-i nf u si o n) a n d at t h e f oll o wi n g ti m e p oi nt s aft er st art of
i nf u si o n: 5  mi n ± 1  mi n, 1 5  mi n ± 1  mi n, 2 5  mi n ± 1  mi n, 3 0  mi n - 1  mi n  (t h e i nf u si o n will n ot b e st o p p e d
b ef or e t h e 3 0- mi n pl a s m a s a m pl e h a s b e e n c oll e ct e d), 4 5  mi n ± 5  mi n, 1 h ± 5  mi n, 1 h 3 0 ± 5  mi n, 4 h ±
5  mi n, 8 h ± 5  mi n, a n d 2 4 h ± 2 h o ur ( b a s e d o n pr ot o c ol v er si o n 4. 0). I n t h e c a s e of c o n v er si o n fr o m 
atri al fi brill ati o n d uri n g i nf u si o n, a n a d diti o n al s a m pl e will b e t a k e n i m m e di at el y aft er c o n v er si o n.
D eri v e d a n d I m p ut e d D at a f or P K E n d p oi nt
F or all s a m pli n g ti m e s, t h e a ct u al s a m pli n g ti m e s will b e c al c ul at e d a s t h e diff er e n c e b et w e e n t h e s a m pl e 
c oll e cti o n a ct u al cl o c k ti m e a n d t h e a ct u al cl o c k ti m e of st art of t h e i nf u si o n of A P 3 0 6 6 3. T h e a ct u al 
p o st- d o s e s a m pli n g ti m e s e x pr e s s e d i n h o ur s a n d r o u n d e d off t o t hr e e d e ci m al di git s will b e u s e d t o 
c al c ul at e t h e P K p ar a m et er s, e x c e pt f or pr e- d o s e s a m pl e s o c c urri n g pri or t o i nf u si o n, w hi c h will al w a y s b e 
r e p ort e d a s z er o ( 0. 0 0 0), r e g ar dl e s s of t h e ti m e diff er e n c e. 
F or N C A a p pr o a c h, t h e f oll o wi n g P K p ar a m et er s i n cl u di n g, b ut n ot li mit e d t o,  will b e d et er mi n e d f or e a c h 
p ati e nt b a s e d o n pl a s m a c o n c e ntr ati o n s:
A U C 0- 0. 5 : Ar e a u n d er t h e c o n c e ntr ati o n ti m e c ur v e fr o m pr e- d o s e c o n c e ntr ati o n u p t o 3 0 mi n. 
A U C 0- 0. 5 i n cl u d e s t h e pl a s m a dr u g c o n c e ntr ati o n u p t o t h e e n d of i nf u si o n
A U C 0-t : Ar e a u n d er t h e c o n c e ntr ati o n ti m e c ur v e u p t o t h e l a st m e a s ur a bl e c o n c e ntr ati o n
A U C 0-i nf : Ar e a u n d er t h e c o n c e ntr ati o n ti m e c ur v e fr o m pr e- d o s e t hr o u g h c o n c e ntr ati o n t o i nfi nit y 
( e xtr a p ol at e d), c al c ul at e d a s A U C0-t + C t/ Kel , w h er e Ct i s t h e l a st o b s er v e d n o n- z er o c o n c e ntr ati o n
C m a x : T h e o b s er v e d p e a k dr u g c o n c e ntr ati o n
T m a x : T h e ti m e at w hi c h Cm a x o c c ur s
t1/ 2 : t h e t er mi n al h alf-lif e v al u e will b e c al c ul at e d u si n g t h e e q u ati o n l n 2/ Kel , wit h Kel b ei n g t h e 
eli mi n ati o n r at e c o n st a nt
K el : Eli mi n ati o n r at e c o n st a nt. T hi s p ar a m et er will b e t h e n e g ati v e of t h e e sti m at e d sl o p e of t h e 
li n e ar r e gr e s si o n of t h e l n-tr a n sf or m e d c o n c e ntr ati on v er s u s ti m e pr ofil e i n t h e t er mi n al eli mi n ati o n 
p h a s e. At l e a st 3 c o n c e ntr ati o n p oi nt s will b e u s e d i n e sti m ati n g K el. T h e ti m e p oi nt w h er e l n-
li n e ar Kel c al c ul ati o n b e gi n s ( K el L o w er), a n d t h e a ct u al s a m pli n g ti m e of t h e l a st q u a ntifi a bl e 
c o n c e ntr ati o n u s e d t o e sti m at e t h e K el ( Kel U p p er) will b e r e p ort e d wit h t h e c orr el ati o n c o effi ci e nt 
fr o m t h e li n e ar r e gr e s si o n t o c al c ul at e Kel .
Fr o m t h e d e v el o p e d p o p ul ati o n P K m o d el ( P o p- P K), P K p ar a m et er s li k e v ol u m e of di stri b uti o n a n d 
cl e ar a n c e will b e e sti m at e d. A d diti o n al P K p ar a m et er s  i n cl u di n g, b ut n ot li mit e d t o, ar e a u n d er t h e c ur v e 
at st e a d y- st at e ( A U C S S ) will b e d eri v e d fr o m t h e i n di vi d u al B a y e s e sti m at e s fr o m t h e p o p- P K m o d el. A 
s e p ar at e a n al y si s pl a n will b e cr e at e d t o d et ail t hi s a p pr o a c h.
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St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s
A c e si o n P h ar m a A p S -  Pr ot o c ol N o: A P 3 0 6 6 3 - 2 0 0 1
T hi s d o c u m e nt i s c o nfi d e nti al.
S A P V er si o n : S A P v er si o n 4. 0 – 2 0 F e b 2 0 2 3
C o ntr oll e d D o c u m e nt I D: 
, Eff e cti v e D at e 2 9- O ct- 2 0 1 8
Fili n g r e q uir e m e nt s: T M F
P a g e 2 6 of 4 7
N C A:
M e a n ( ± S D) A P 3 0 6 6 3 Pl a s m a C o n c e ntr ati o n s - Li n e ar a n d s e mi- L o g S c al e s – P K S et
O v erl a y of I n di vi d u al a n d M e a n A P 3 0 6 6 3 Pl a s m a C o n c e ntr ati o n s b y Tr e at m e nt - Li n e ar a n d s e mi-
L o g S c al e s - P K S et
T h e s e fi g ur e s will b e al s o pr o vi d e d d uri n g P art 2 w h er e I A s will o c c ur w h e n 1 8, 3 6 a n d 5 4 p ati e nt s h a v e 
b e e n r a n d o mi s e d t o o p e n- d o s e s i n cl u di n g pl a c e b o, a n d h a v e c o m pl et e d D a y 2 a s s e s s m e nt s or t er mi n at e d 
t h e st u d y. 
P o p- P K m o d el:
I nt eri m r e s ult s i n cl u di n g a v er a g e P K p ar a m et er s d et er mi n ati o n  will b e pr o vi d e d u si n g d e s cri pti v e st ati sti c s 
a n d gr a p hi c al e v al u ati o n. A s u m m ar y r e p ort i n cl u di n g c o n c l u si o n/r e c o m m e n d ati o n f or t h e d o s e of P art 2 will 
b e g e n er at e d.
D e vi ati o n fr o m A n al y s e s Pl a n n e d i n Pr ot o c ol
N o d e vi ati o n fr o m P K a n al y s e s d e s cri b e d  i n t h e Pr ot o c ol i s pl a n n e d.
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s
A c e si o n P h ar m a A p S -  Pr ot o c ol N o: A P 3 0 6 6 3 - 2 0 0 1
T hi s d o c u m e nt i s c o nfi d e nti al.
S A P V er si o n : S A P v er si o n 4. 0 – 2 0 F e b 2 0 2 3
C o ntr oll e d D o c u m e nt I D: 
, Eff e cti v e D at e 2 9- O ct- 2 0 1 8
Fili n g r e q uir e m e nt s: T M F
P a g e 2 7 of 4 7
S af et y
T h e p o p ul ati o n u s e d f or s af et y a n al y s e s will b e t h e S af e t y S et ( S S).  S af et y will b e a s s e s s e d o n t h e b a si s 
of a d v er s e e v e nt ( A E) or a d v er s e dr u g r e a cti o n s ( A D R)  r e p ort s, cli ni c al l a b or at or y d at a, E C G p ar a m et er s, 
p h y si c al e x a mi n ati o n s, a n d vit al si g n s . 
E xt e nt of E x p o s ur e
E xt e nt of e x p o s ur e will b e s u m m ari z e d b y tr e at m e nt gr o u p f or d ur ati o n of i nf u si o n . 
D ur ati o n of i nf u si o n will b e d eri v e d a s:
D ur ati o n of i nf u si o n (i n mi n) = ( St o p Ti m e of St u d y Dr u g I nf u si o n- St art Ti m e of St u d y Dr u g I nf u si o n) –
d ur ati o n of i nf u si o n i nt err u pti o n 
E xt e nt of e x p o s ur e ( e x p e ct e d t ot al v ol u m e t o i nf u s e a n d i nf u s e d v ol u m e)  will b e s u m m ari z e d b y 
tr e at m e nt gr o u p.
Tr e at m e nt C o m pli a n c e 
N u m b er ( %) of p ati e nt s c o m pl eti n g t h e f ull i nf u si o n tr e at m e nt, n u m b er ( %) of p ati e nt s wit h i nf u si o n 
i nt err u pti o n a n d r e a s o n s f or st o p pi n g will al s o b e s u m m ari z e d.
A d v er s e E v e nt s / A d v er s e Dr u g R e a cti o n s
A E s will b e c o d e d u si n g t h e M e di c al Di cti o n ar y f or R e g ul at or y A cti viti e s ( M e d D R A) v er si o n 2 1. 1 or a n 
u p d at e d v er si o n. S u m m ari e s will b e pr e s e nt e d b y  s y st e m or g a n cl a s s ( S O C) a n d pr ef err e d t er m. 
Tr e at m e nt- e m er g e nt A E s ( T E A E s) ar e d efi n e d a s a n y A E o c c urri n g or w or s e ni n g o n or aft er t h e fir st d o s e 
of st u d y m e di c ati o n. P arti al A E d at e s will b e i m p ut e d.
T h e fr e q u e n c y a n d i n ci d e n c e of T E A E s will b e pr e s e nt e d b y S O C a n d pr ef err e d t er m f or e a c h tr e at m e nt 
gr o u p ( n u m b er a n d p er c e nt a g e of p ati e nt s e x p eri e n ci n g at l e a st o n e T E A E p er pr ef err e d t er m a s w ell a s 
t h e n u m b er of o b s er v e d e v e nt s p er pr ef err e d t er m; p er c e nt a g e s will b e b a s e d o n t h e n u m b er of p ati e nt s 
i n t h e s af et y s et). 
T h e s u m m ari e s pr e s e nti n g fr e q u e n c y of A E s b y S O C a n d P T will b e or d er e d b y o v er all d e s c e n di n g 
fr e q u e n c y of S O C a n d t h e n, wit hi n a S O C, b y o v er all d e s c e n di n g fr e q u e n c y of P T.
S e p ar at e t a bl e s will b e pr e s e nt e d b y s e v erit y a n d b y r el ati o n s hi p, a n d f or S A E s, r el at e d T E A E s, a n d 
T E A E s l e a di n g t o st u d y di s c o nti n u ati o n.
R el ati o n s hi p s of ‘ v er y li k el y’, ‘ pr o b a bl e ’ a n d ‘ p o s si ble ’ ar e t o b e c o n si d er e d a s r el at e d t o st u d y dr u g f or t h e 
s u m m ar y t a bl e s. R e l ati o n s hi p s of ‘ u nli k el y’ a n d ‘ u nr el at e d’ ar e t o b e c o n si d er e d n ot r el at e d t o st u d y dr u g.
I n c a s e of mi s si n g r el ati o n s hi p s, A E s will b e c o n si d er e d a s r el at e d.
All A E s will b e pr e s e nt e d i n f ull i n a c o m pr e h e n si v e li sti n g i n cl u di n g p ati e n t n u m b er, tr e at m e nt gr o u p, 
s e v erit y, s eri o u s n e s s, a cti o n t a k e n, o ut c o m e, r el ati o n s hi p t o tr e at m e nt, o n s et/ st o p, a n d d ur ati o n. T E A E s 
will b e fl a g g e d i n t h e li sti n g s.
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s
A c e si o n P h ar m a A p S -  Pr ot o c ol N o: A P 3 0 6 6 3 - 2 0 0 1
T hi s d o c u m e nt i s c o nfi d e nti al.
S A P V er si o n : S A P v er si o n 4. 0 – 2 0 F e b 2 0 2 3
C o ntr oll e d D o c u m e nt I D: 
, Eff e cti v e D at e 2 9- O ct- 2 0 1 8
Fili n g r e q uir e m e nt s: T M F
P a g e 2 8 of 4 7
D et ail s of S A E s a n d A E s l e a di n g t o wit h dr a w al will b e li st e d s e p ar at el y.
L a b or at or y E v al u ati o n s
T h e h a e m at ol o g y a n d cli ni c al c h e mi str y l a b or at or y a n al y s e s will b e p erf or m e d at l o c al l a b or at ori e s.
R ef er e n c e r a n g e s will b e s u p pli e d b y l o c al l a b or at ori e s a n d u s e d b y t h e i n v e sti g at or t o a s s e s s t h e 
l a b or at or y d at a f or cli ni c al si g nifi c a n c e a n d p at h ol o gic al c h a n g e s. T h e f oll o wi n g l a b or at or y s af et y t e st s will 
b e p erf or m e d at t h e ti m e s o utli n e d i n t h e St u d y Pr o c e d ur e s a n d Fl o w c h art i n S e cti o n 3. 9.
H a e m at ol o g y
H a e m o gl o bi n, h a e m at o crit, r e d bl o o d c ell s ( er yt hr o c yt e s), w hit e bl o o d c ell s (l e u k o c yt e s, t ot al a n d 
diff er e nti al), b a s o p hil s, e o si n o p hil s, l y m p h o c yt e s, m o n o c yt e s, n e utr o p hil s, a n d pl at el et s.
Cli ni c al C h e mi str y
A L T, A S T, bilir u bi n ( dir e ct, i n dir e ct, t ot al), cr e ati n i n e, g a m m a- gl ut a m yltr a n sf er a s e, gl u c o s e (r a n d o m), 
e G F R, ur e a ( B U N), s o di u m, p ot a s si u m, c al ci u m, a n d m a g n e si u m.
Ot h er L a b or at or y V ari a bl e s
I N R/ A P T T a n d T S H. T h e s e v ari a bl e s will b e s u m m ari z e d a n d li st e d wit hi n cli ni c al c h e mi str y.
F or all l a b or at or y p ar a m et er s, t h e f oll o wi n g s u m m ar y t a bl e s will b e pr e s e nt e d b y vi sit a n d tr e at m e nt f or 
e a c h t e st:  
A ct u al a n d c h a n g e s fr o m b a s eli n e f or c o nti n u o u s v ari a bl e s
S hift fr o m b a s eli n e 
N u m b er a n d p er c e nt of p ati e nt s wi t h cli ni c all y si g nifi c a nt c h a n g e s
All l a b or at or y r e s ult s i n SI u nit s will b e i n cl u d e d i n d a t a li sti n g s. T e st s will b e li st e d i n al p h a b eti c al or d er. 
A b n or m al l a b v al u e s will b e fl a g g e d i n t h e li sti n g .
Vit al Si g n s 
Vit al si g n s will b e r e c or d e d a s i n di c at e d i n t h e St u d y Pr o c e d ur e s a n d Fl o w c h art  i n S e cti o n 3. 9. Bl o o d 
Pr e s s ur e, h e art r at e, a n d h e art r h yt h m (fr o m E C G) wi ll b e i n cl u d e d a n d r e c or d e d i n a st a n d ar di z e d 
m a n n er, i. e., aft er t h e p ati e nt h a s r e st e d i n t h e ( s e mi) s u pi n e p o siti o n f or 5  mi n a n d b ef or e bl o o d s a m pli n g 
or l a b or at or y t e st s. Vit al si g n s m e a s ur e m e nt s will b e r e p e at e d i n c a s e of cli ni c all y si g nifi c a nt 
a b n or m aliti e s. 
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s
A c e si o n P h ar m a A p S -  Pr ot o c ol N o: A P 3 0 6 6 3 - 2 0 0 1
T hi s d o c u m e nt i s c o nfi d e nti al.
S A P V er si o n : S A P v er si o n 4. 0 – 2 0 F e b 2 0 2 3
C o ntr oll e d D o c u m e nt I D: 
, Eff e cti v e D at e 2 9- O ct- 2 0 1 8
Fili n g r e q uir e m e nt s: T M F
P a g e 2 9 of 4 7
All vit al si g n s ( a b s ol ut e v al u e s a n d c h a n g e fr o m b a s e li n e) will b e s u m m ari z e d b y vi sit, h e art r h yt h m a n d 
ti m e p oi nt f or e a c h tr e at m e nt gr o u p.
All vit al si g n s d at a will b e li st e d c hr o n ol o gi c a ll y b y p ar a m et er a n d i n cl u d e d i n d at a li sti n g s.
E C G
A 1 2-l e a d di git al E C G will b e p erf or m e d at t h e ti m e s o utli n e d i n t h e St u d y Pr o c e d ur e s a n d Fl o w c h art i n 
S e cti o n 3. 9 i n a st a n d ar di z e d m a n n er ( i. e. aft er t h e p ati e nt h a s r e st e d i n t h e [ s e mi] s u pi n e p o siti o n f or at 
l e a st 5 mi n). 
T h e i n v e sti g at or will a s s e s s E C G a b n or m aliti e s ( e. g. i s c h e mi a, c o n d u cti o n a b n or m aliti e s, a n d r h yt h m 
a b n or m aliti e s) a n d d efi n e t h e E C G i nt er v al s a s p art of t h e s cr e e ni n g of eli gi bilit y a n d a c c or di n g t o t h e 
i n cl u si o n/ e x cl u si o n crit eri a, a n d a s p art of a n a d v er s e e v e nt a s s e s s m e nt.
1 2-l e a d di git al E C G will b e o v err e a d b y t h e c e ntr al E C G l a b or at or y. T h e f oll o wi n g m e a s ur e m e nt s will b e 
pr o vi d e d f or all P K ti m e p oi nt s: R R, P R, Q R S, Q T, Q T c F ( Fri d eri ci a’ s c orr e cti o n of Q T i nt er v al), h e art r at e, 
a s w ell a s T- a n d U- w a v e m or p h ol o g y cl a s sifi c ati o n s.    
B e d si d e s af et y E C G s will b e c oll e ct e d b y t h e sit e, pri nt e d a n d r e vi e w e d b y t h e i n v e sti g at or o n sit e.
E C G i nt er v al s b a s e d o n t h e s e s af et y E C G s will o nl y b e r e c or d e d if p art of a n a d v er s e e v e nt.
A s u m m ar y t a bl e f or a ct u al a n d c h a n g e fr o m b a s eli n e will b e pr o vi d e d b y tr e at m e nt. 
R e s ult s f or 1 2- L e a d E C G s will b e s u m m ari z e d b y t h e n u m b er a n d p er c e nt a g e wit hi n e a c h c at e g or y
(“ n or m al”, “ a b n or m al, n ot cli ni c all y si g nifi c a nt”, a n d “ a b n or m al, cli ni c all y si g nifi c a nt”) .
A b n or m al r e s ult s f or 1 2- L e a d E C G s will b e s u m m ari z e d a s b el o w:
A b s ol ut e Q T c i nt er v al pr ol o n g ati o n:
-  Q T c F i nt er v al > 4 5 0 m s
-  Q T c F i nt er v al > 5 0 0 m s
C h a n g e fr o m b a s eli n e i n Q T c i nt er v al:
-  Q T c F i nt er v al i n cr e a s e s fr o m b a s eli n e > 3 0 m s
-  Q T c F i nt er v al i n cr e a s e s fr o m b a s eli n e > 6 0 m s
E C G d at a will b e li st e d f or all p ati e nt s, a n d a n y cli ni c all y si g nifi c a nt fi n di n g s i n E C G v al u e s  will b e fl a g g e d.
A c ar di a c St ati sti c al A n al y si s Pl a n will b e d e v el o p e d b y Cl ari o.
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s
A c e si o n P h ar m a A p S -  Pr ot o c ol N o: A P 3 0 6 6 3 - 2 0 0 1
T hi s d o c u m e nt i s c o nfi d e nti al.
S A P V er si o n : S A P v er si o n 4. 0 – 2 0 F e b 2 0 2 3
C o ntr oll e d D o c u m e nt I D: 
, Eff e cti v e D at e 2 9- O ct- 2 0 1 8
Fili n g r e q uir e m e nt s: T M F
P a g e 3 0 of 4 7
P h y si c al E x a mi n ati o n
At s cr e e ni n g, w ei g ht a n d h ei g ht will b e r e c or d e d a n d a p h y si c al e x a mi n ati o n will b e p erf or m e d, f oll o w e d 
b y a bri ef p h y si c al e x a mi n ati o n at b a s eli n e ( pr e-i nf u si o n o n D a y 1) a n d D a y 3 0. A n y c h a n g e s fr o m t h e 
s cr e e ni n g a n d b a s eli n e vi sit t o D a y 3 0 will b e r e c or d e d. F ull a n d bri ef p h y si c al e x a mi n ati o n will i n cl u d e 
t h e f oll o wi n g a s s e s s m e nt s: 
A s s e s s m e nt
F ull p h y si c al e x a mi n ati o n
Bri ef p h y si c al e x a mi n ati o n
G e n er al a p p e ar a n c e
x
x
H e a d, e ar s, e y e s, n o s e, 
t hr o at
x
-
C ar di o v a s c ul ar
x
x
R e s pir at or y
x
x
G a str oi nt e sti n al
x
x
D er m at ol o gi c al
x
-
N e ur ol o gi c al
x
-
M u s c ul o s k el et al
x
-
L y m p h ati c
x
-
Ot h er ( at t h e i n v e sti g at or’ s 
di s cr eti o n)
x
x
B o d y s y st e m s will b e cl a s sifi e d a s “ N or m al”, “ A b n or m al Cli ni c all y Si g nifi c a nt” a n d “ A b n or m al N ot Cli ni c all y
Si g nifi c a nt”. S hift t a bl e s c o m p ari n g p h y si c al e x a mi n ati o n r e s ul t s fr o m b a s eli n e t o l a st a s s e s s m e nt  will b e 
pr e s e nt e d b y tr e at m e nt.
P h y si c al e x a mi n ati o n d at a will al s o b e li st e d.
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s
A c e si o n P h ar m a A p S -  Pr ot o c ol N o: A P 3 0 6 6 3 - 2 0 0 1
T hi s d o c u m e nt i s c o nfi d e nti al.
S A P V er si o n : S A P v er si o n 4. 0 – 2 0 F e b 2 0 2 3
C o ntr oll e d D o c u m e nt I D: 
, Eff e cti v e D at e 2 9- O ct- 2 0 1 8
Fili n g r e q uir e m e nt s: T M F
P a g e 3 1 of 4 7
I nt eri m A n al y s e s
A n i nt eri m a n al y si s f or effi c a c y (i n cl u di n g E C G a n d H olt er E C G), P K/ P D, s af et y a n d t ol er a bilit y will b e 
c o n d u ct e d aft er all r a n d o mi s e d p ati e nt s h a v e b e e n r e cr uit e d i nt o P art 1 of t h e st u d y a n d eit h er c o m pl et e d 
D a y 2 or t er mi n at e d t h e st u d y.
I nt eri m A n al y si s at E n d of P art 1:
D uri n g t h e fir st I A t h e f oll o wi n g will o c c ur, r e g ar dl e s s of t h e r e s p o n s e s e e n f or t h e A P 3 0 6 6 3 3 m g/ k g 
d o s e:
D o s e 3 ( 3 m g/ k g A P 3 0 6 6 3) will b e st o p p e d.
D o s e 5 ( 5 m g/ k g A P 3 0 6 6 3 v er s u s pl a c e b o) will b e o p e n e d. 
A d diti o n all y, t h e f oll o wi n g d e ci si o n will b e m a d e d e p e n d e nt o n t h e r e s p o n s e r at e s e e n f or 3 m g/ k g 
A P 3 0 6 6 3: 
If t h e pr o p orti o n of p ati e nt s a c hi e vi n g a r e s p o n s e u n d er A P 3 0 6 6 3 3 m g/ k g i s > 0. 6 5 t h e n D o s e 2 
( 2 m g/ k g A P 3 0 6 6 3) will a d diti o n all y b e o p e n e d f or P art 2 (i n p ar all el t o D o s e 5).
I nt eri m A n al y s e s d uri n g P art 2:
I nt eri m a n al y s e s will o c c ur w h e n 1 8, 3 6 a n d 5 4 r a n d o mi s e d p ati e nt s h a v e c o m pl et e d D a y 2 a s s e s s m e nt s 
or t er mi n at e d t h e st u d y i n P art 2. At t h e s e I A s t h e f oll o wi n g r ul e s will b e utili s e d:
a) If a n o p e n D o s e d h a s at l e a s t 1 0 r a n d o mi s e d p ati e nt s h a vi n g c o m pl et e d D a y 2 a s s e s s m e nt s a n d 
s ati sfi e s: (
d > 0. 6 5) ≥ 0. 9 0 t h e n D o s e d will b e cl o s e d f or s uffi ci e nt effi c a c y r e s p o n s e.
If t h e d o s e o n e l e v el b el o w t hi s d o s e h a s n e v er b e e n o p e n e d, t h e n d o s e d- 1 i s o p e n e d.
b) If a n o p e n D o s e d h a s at l e a st 1 0 r a n d o mi s e d  p ati e nt s h a vi n g c o m pl et e d D a y 2 a s s e s s m e nt s a n d 
s ati sfi e s (
d > 0. 6 5) < 0. 1 0 t h e n D o s e d will b e cl o s e d.
If D o s e d w a s t h e l ar g e st d o s e t h u s f ar o p e n, a n d D o s e d i s < 6 m g/ k g, t h e n d o s e d + 1 
will b e o p e n e d.
T h e st u d y will c o nti n u e u ntil all d o s e s of A P 3 0 6 6 3 h a v e b e e n cl o s e d or t h e m a xi m u m of 7 2 p ati e nt s 
d uri n g P art 2 ( u p t o 1 0 8 p ati e nt s t ot al a cr o s s P art 1 a n d P art 2) h a v e b e e n e nr oll e d. 
W hil e t h e al g orit h m, a n d t h e D M C’ s d e ci si o n f or d o s e i n cr e a s e/ d e cr e a s e, i s b a s e d o n A F c o n v er si o n r at e 
o nl y, t h e D M C will al s o c o n v e n e t o r e vi e w s af et y a n d t o l er a bilit y d at a at d efi n e d ti m e p oi nt s; r e vi e w of t hi s 
d at a m a y al s o l e a d t o f urt h er d e ci si o n s b ei n g m a d e b y t h e D M C.
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s
A c e si o n P h ar m a A p S -  Pr ot o c ol N o: A P 3 0 6 6 3 - 2 0 0 1
T hi s d o c u m e nt i s c o nfi d e nti al.
S A P V er si o n : S A P v er si o n 4. 0 – 2 0 F e b 2 0 2 3
C o ntr oll e d D o c u m e nt I D: 
, Eff e cti v e D at e 2 9- O ct- 2 0 1 8
Fili n g r e q uir e m e nt s: T M F
P a g e 3 2 of 4 7
C h a n g e s fr o m A n al y si s Pl a n n e d i n Pr ot o c ol
N o n e
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s
A c e si o n P h ar m a A p S -  Pr ot o c ol N o: A P 3 0 6 6 3 - 2 0 0 1
T hi s d o c u m e nt i s c o nfi d e nti al.
S A P V er si o n : S A P v er si o n 4. 0 – 2 0 F e b 2 0 2 3
C o ntr oll e d D o c u m e nt I D: 
, Eff e cti v e D at e 2 9- O ct- 2 0 1 8
Fili n g r e q uir e m e nt s: T M F
P a g e 3 3 of 4 7
R ef er e n c e Li st
N o n e
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s
A c e si o n P h ar m a A p S -  Pr ot o c ol N o: A P 3 0 6 6 3 - 2 0 0 1
T hi s d o c u m e nt i s c o nfi d e nti al.
S A P V er si o n : S A P v er si o n 4. 0 – 2 0 F e b 2 0 2 3
C o ntr oll e d D o c u m e nt I D: 
, Eff e cti v e D at e 2 9- O ct- 2 0 1 8
Fili n g r e q uir e m e nt s: T M F
P a g e 3 4 of 4 7
Pr o gr a m mi n g C o n si d er ati o n s
All  t a bl e s,  fi g ur e s,  li sti n g s ( T F L s),  a n d  st ati sti c al  a n al y s e s  will  b e  g e n er at e d  u si n g  S A S  f or  Wi n d o w s,  
R el e a s e 9. 4. ( S A S I n stit ut e I n c., C ar y, N C, U S A) . C o m p ut er- g e n er at e d t a bl e, li sti n g a n d fi g ur e o ut p ut will 
a d h er e t o t h e f oll o wi n g s p e cifi c ati o n s. 
T h e st ati c a n al y si s b a s e d o n pl a s m a c o n c e ntr ati o n will b e p erf or m e d u si n g a n o n- c o m p art m e nt al a n al y si s 
( N C A), t h e P K a n al y s e s will b e p erf or m e d b y S y n e o s H e alt h u si n g P h o e ni x Wi n N o nli n ® (r el e a s e 8. 0 or 
hi g h er) a n d all ot h er a n al y s e s a n d s u m m ari e s will b e  pr o d u c e d u si n g St ati sti c al A n al y si s S y st e m ( S A S ® ) 
v er si o n 9. 4 ( or hi g h er).
P K a n al y s e s will b e p erf or m e d u si n g N O N M E M ® v er si o n 7. 4. 
G e n er al C o n si d er ati o n s
O n e S A S pr o gr a m c a n cr e at e s e v er al o ut p ut s
O n e o ut p ut fil e c a n c o nt ai n s e v er al o ut p ut s.
O ut p ut fil e s will b e d eli v er e d i n Ri c h T e xt F or m at ( R T F) t h at c a n b e  m a ni p ul at e d i n M S W or d
N u m b eri n g of T F L s will f oll o w I C H E 3 g ui d a n c e 
T a bl e, Li sti n g, a n d Fi g ur e F or m at
G e n er al
All T F L s will b e pr o d u c e d i n l a n d s c a p e f or m at o n A 4 p a p er si z e, u nl e s s ot h er wi s e s p e cifi e d.
All T F L s will b e pr o d u c e d u si n g t h e C o uri er N e w f o nt, si z e 8,  w hi c h i s t h e s m all e st a c c e pt a bl e 
p oi nt si z e f or t h e R e g ul at or y A ut h oriti e s.
T h e d at a di s pl a y s f or all T F L s will h a v e a mi ni m u m bl a n k 1-i n c h m ar gi n o n all 4 si d e s.
H e a d er s a n d f o ot er s f or fi g ur e s will b e i n C o uri er N e w f o nt, si z e 8,  w hi c h i s t h e s m all e st a c c e pt a bl e 
p oi nt si z e f or t h e R e g ul at or y A ut h oriti e s.
L e g e n d s will b e u s e d f or all fi g ur e s wit h m or e  t h a n 1 v ari a bl e, gr o u p, or it e m di s pl a y e d.
T F L s will b e i n bl a c k a n d w hit e ( n o c ol or), u nl e s s ot h er wi s e s p e cifi e d.
S p e ci ali z e d t e xt st yl e s, s u c h a s b ol di n g, it ali c s, b or d er s, s h a di n g, a n d s u p er s cri pt e d a n d 
s u b s cri pt e d t e xt, will n ot b e u s e d  i n t h e T F L s, u nl e s s ot h er wi s e s p e cifi e d. O n s o m e o c c a si o n s, 
s u p er s cri pt s 1, 2, or 3 m a y b e u s e d ( s e e b el o w).
O nl y st a n d ar d k e y b o ar d c h ar a ct er s will b e u s e d  i n t h e T F L s. S p e ci al c h ar a ct er s, s u c h a s n o n-
pri nt a bl e c o ntr ol c h ar a ct er s, pri nt er- s p e cifi c, or f o nt- s p e cifi c c h ar a ct er s, will n ot b e u s e d. 
H e x a d e ci m al- d eri v e d c h ar a ct er s wi ll b e u s e d, w h er e p o s si bl e, if t h e y ar e a p pr o pri at e t o h el p 
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s
A c e si o n P h ar m a A p S -  Pr ot o c ol N o: A P 3 0 6 6 3 - 2 0 0 1
T hi s d o c u m e nt i s c o nfi d e nti al.
S A P V er si o n : S A P v er si o n 4. 0 – 2 0 F e b 2 0 2 3
C o ntr oll e d D o c u m e nt I D: 
 Eff e cti v e D at e 2 9- O ct- 2 0 1 8
Fili n g r e q uir e m e nt s: T M F
P a g e 3 5 of 4 7
di s pl a y m at h s y m b ol s ( e. g. , μ ). C ert ai n s u b s cri pt s a n d s u p er s cri pt s (e. g ., c m 2, C m a x) will b e 
e m pl o y e d o n a c a s e- b y- c a s e b a si s.
Mi x e d c a s e will b e u s e d f or all titl e s, f o ot n ot e s,  c ol u m n h e a d er s, a n d pr o gr a m m er- s u p pli e d f or m at s, 
a s a p pr o pri at e.
H e a d er s
All o ut p ut s h o ul d h a v e t h e f oll o wi n g h e a d er at t h e t o p l eft of e a c h p a g e:
A c e si o n P h ar m a A p S
Pr ot o c ol: A P 3 0 6 6 3 - 2 0 0 1
Dr aft/ Fi n al R u n < d at e >
All o ut p ut s h o ul d h a v e P a g e n of N at t h e t o p or b ott o m ri g ht c or n er of e a c h p a g e. T F L s ar e
i nt er n all y p a gi n at e d i n r el ati o n t o t h e t ot al l e n gt h (i. e., t h e p a g e n u m b er s h o ul d a p p e ar s e q u e nti all y 
a s p a g e n of N, w h er e N i s t h e t ot al n u m b er of p a g e s i n t h e t a bl e).
T h e d at e/ti m e of t h e g e n er ati o n of t h e o ut p ut s h o ul d a p p e ar al o n g wit h t h e pr o gr a m n a m e a s a 
f o ot er o n e a c h p a g e.
Di s pl a y Titl e s
E a c h T F L i s i d e ntifi e d b y t h e d e si g n ati o n a n d a n u m er al. ( i. e., T a bl e 1 4. 1. 1). I C H E 3 n u m b eri n g. A 
d e ci m al s y st e m ( x. y a n d x. y. z) ar e u s e d t o i d e ntif y T F L s wit h r el at e d c o nt e nt s. T h e titl e i s c e nt er e d. 
T h e a n al y si s s et ar e i d e ntifi e d o n t h e li n e i m m e di at el y f oll o wi n g t h e titl e. T h e titl e a n d t a bl e 
d e si g n ati o n ar e si n gl e s p a c e d. A s oli d li n e s p a n ni n g t h e m ar gi n s will s e p ar at e t h e di s pl a y titl e s 
fr o m t h e
C ol u m n h e a d er s. T h er e will b e 1 bl a n k li n e b et w e e n t h e l a st titl e a n d t h e s oli d li n e.
T a bl e x. y. z
Fir st Li n e of Titl e
S e c o n d Li n e of Titl e if N e e d e d
F A S A n al y si s S et
C ol u m n H e a d er s
C ol u m n h e a di n g s ar e di s pl a y e d i m m e di at el y b el o w t h e s oli d li n e d e s cri b e d a b o v e i n i niti al u p p er-
c a s e c h ar a ct er s.
I n t h e c a s e of effi c a c y t a bl e s, t h e v ari a bl e ( or c h ar a ct eri sti c) c ol u m n will b e o n t h e f ar l eft f oll o w e d 
b y t h e tr e at m e nt gr o u p c ol u m n s a n d t ot al c ol u m n (if a p pli c a bl e). P- v al u e s m a y b e pr e s e nt e d u n d er 
t h e t ot al c ol u m n or i n s e p ar at e p- v al u e c ol u m n (if a p pli c a bl e). Wit hi n-tr e at m e nt c o m p ari s o n s m a y 
h a v e p- v al u e s pr e s e nt e d i n a r o w b e n e at h t h e s u m m ar y st ati sti c s f or t h at tr e at m e nt.
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s
A c e si o n P h ar m a A p S -  Pr ot o c ol N o: A P 3 0 6 6 3 - 2 0 0 1
T hi s d o c u m e nt i s c o nfi d e nti al.
S A P V er si o n : S A P v er si o n 4. 0 – 2 0 F e b 2 0 2 3
C o ntr oll e d D o c u m e nt I D: 
, Eff e cti v e D at e 2 9- O ct- 2 0 1 8
Fili n g r e q uir e m e nt s: T M F
P a g e 3 6 of 4 7
F or n u m eri c v ari a bl e s, i n cl u d e “ u nit” i n c ol u m n or r o w h e a di n g w h e n a p pr o pri at e.
A n al y si s s et si z e s will b e pr e s e nt e d f or e a c h tr e a t m e nt gr o u p i n t h e c ol u m n h e a di n g a s ( N = x x) ( or 
i n t h e r o w h e a di n g s, if a p pli c a bl e). T hi s i s di sti n ct fr o m t h e ‘ n’ u s e d f or t h e d e s cri pti v e st ati sti c s 
r e pr e s e nti n g t h e n u m b er of p ati e nt s i n t h e a n al y si s s et.
T h e or d er of tr e at m e nt s i n t h e t a bl e s a n d li sti n g s will b e Pl a c e b o fir st i n t h e c a s e of pl a c e b o 
c o ntr oll e d st u di e s a n d A cti v e c o m p ar at or s fir st i n t h e c a s e of a cti v e c o m p ar at or tri al s, f oll o w e d b y a 
t ot al c ol u m n (if a p pli c a bl e).
B o d y of t h e D at a Di s pl a y
1 4. 2. 5. 1.
G e n er al C o n v e nti o n s
D at a i n c ol u m n s of a t a bl e or li sti n g ar e f or m att e d a s f oll o w s:
Al p h a n u m eri c v al u e s ar e l eft-j u stifi e d;
W h ol e n u m b er s ( e. g. , c o u nt s) ar e ri g ht-j u stifi e d; a n d
N u m b er s c o nt ai ni n g fr a cti o n al p orti o n s ar e d e ci m al ali g n e d.
1 4. 2. 5. 2.
T a bl e C o n v e nti o n s
U nit s will b e i n cl u d e d w h er e a v ail a bl e
If t h e c at e g ori e s of a p ar a m et er ar e or d er e d, t h e n all c at e g ori e s b et w e e n t h e m a xi m u m a n d 
mi ni m u m c at e g or y ar e pr e s e nt e d i n t h e t a bl e, e v e n if n = 0 f or all tr e at m e nt gr o u p s i n a gi v e n 
c at e g or y t h at i s b et w e e n t h e mi ni m u m a n d m a xi m u m l e v el f or t h at p ar a m et er. F or e x a m pl e, t h e 
fr e q u e n c y di stri b uti o n f or s y m pt o m s e v erit y w o ul d a p p e ar a s:
S e v erit y 
R ati n g
N
s e v er e
0
m o d er at e
8
mil d
3
W h er e p er c e nt a g e s ar e pr e s e nt e d i n t h e s e t a bl e s, z er o  p er c e nt a g e s will n ot b e pr e s e nt e d a n d s o c o u nt s 
of 0 will b e pr e s e nt e d a s 0 a n d n ot a s 0 ( 0 %).
If t h e c at e g ori e s ar e n ot or d er e d (e. g. , M e di c al Hi st or y, R e a s o n s f or Di s c o nti n u ati o n fr o m t h e 
St u d y, et c.), t h e n o nl y t h o s e c at e g ori e s f or w hi c h t h er e i s at l e a st 1 p ati e nt r e pr e s e nt e d i n 1 or 
m or e gr o u p s ar e i n cl u d e d.
A n U n k n o w n or Mi s si n g c at e g or y ar e a d d e d t o e a c h p ar a m et er f or w hi c h i nf or m ati o n i s n ot 
a v ail a bl e f or 1 or m or e p ati e nt. 
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s  
A c e si o n P h ar m a A p S -  Pr ot o c ol N o: A P 3 0 6 6 3 - 2 0 0 1 
 
 
 
T hi s d o c u m e nt i s c o nfi d e nti al. 
 
S A P V er si o n : S A P v er si o n 4. 0 –  2 0 F e b 2 0 2 3 
C o ntr oll e d D o c u m e nt I D: 
, Eff e cti v e D at e 2 9- O ct- 2 0 1 8 
Fili n g r e q uir e m e nt s: T M F 
P a g e 3 7  of 4 7  
 
  U nl e s s ot h er wi s e s p e cifi e d, t h e e sti m at e d m e a n a n d m e di a n f or a s et of v al u e s ar e pri nt e d o ut t o 1 
m or e si g nifi c a nt di git t h a n t h e ori gi n al v al u e s, a n d st a n d ar d d e vi ati o n s ar e pri nt e d o ut t o 2 m or e 
si g nifi c a nt di git s t h a n t h e ori gi n al v al u e s. T h e mi ni m u m a n d m a xi m u m s h o ul d r e p ort t h e s a m e 
si g nifi c a nt di git s a s t h e ori gi n al v al u e s. F or e x a m pl e, f or s y st oli c bl o o d pr e s s ur e: 
N 
  X X 
M e a n 
X X X. X 
St d D e v 
X. X X 
M e di a n 
X X X. X 
Mi ni m u m 
X X X 
M a xi m u m 
X X X 
 
 P- v al u e s  ar e  o ut p ut i n t h e f or m at: “ 0. x x x”, w h er e x x x i s t h e v al u e r o u n d e d t o 3 d e ci m al pl a c e s. 
E v er y p- v al u e l e s s t h a n 0. 0 0 1 will b e pr e s e nt e d a s < 0. 0 0 1. If t h e p- v al u e ar e l e s s t h a n 0. 0 0 0 1, t h e n 
pr e s e nt a s < 0. 0 0 0 1. If t h e p- v al u e i s r et ur n e d a s > 0. 9 9 9, t h e n pr e s e nt a s > 0. 9 9 9 
  P er c e nt a g e v al u e s ar e pri nt e d t o o n e d e ci m al pl a c e, i n p ar e nt h e s e s wit h n o s p a c e s, o n e s p a c e 
aft er t h e c o u nt ( e. g. , 7 ( 1 2. 8), 1 3 ( 5. 4)). U nl e s s ot h er wi s e n ot ed, f or all p er c e nt a g e s, t h e n u m b er of 
p ati e nt s i n t h e a n al y si s s et f or t h e tr e at m e n t gr o u p w h o h a v e a n o b s er v ati o n will b e t h e 
d e n o mi n at or. P er c e nt a g e s aft er z e r o c o u nt s s h o ul d n ot b e di s pl a y e d a n d p er c e nt a g e s e q u ati n g t o 
1 0 0 % ar e pr e s e nt e d a s 1 0 0 %, wit h o ut d e ci m al pl a c e s.  
  T h e p er c e nt a g e of of p ati e nt s i s n or m all y c al c ulat e d a s a pr o p orti o n of t h e n u m b er of p ati e nt s 
a s s e s s e d i n t h e r el e v a nt tr e at m e nt gr o u p ( or o v er all) f or t h e a n al y si s s et pr e s e nt e d. H o w e v er, 
c ar ef ul c o n si d er ati o n i s r e q uir e d i n m a n y i n st a n c e s d u e t o t h e c o m pli c at e d n at ur e of s el e cti n g t h e 
d e n o mi n at or, u s u all y t h e a p pr o pri at e n u m b er of p a ti e nt s e x p o s e d. D e s cri b e d et ail s of t hi s i n 
f o ot n ot e s or pr o gr a m mi n g n ot e s. 
  F or c at e g ori c al s u m m ari e s ( n u m b er a n d p er c e nt a g e of p ati e nt s) w h er e a p ati e nt c a n b e i n cl u d e d i n 
m or e t h a n o n e c at e g or y, d e s cri b e i n a f o ot n ot e or  pr o gr a m mi n g n ot e if t h e p ati e nt ar e i n cl u d e d i n 
t h e s u m m ar y st ati sti c s f or all r el e v a nt c at e g ori e s or j u st 1 c at e g or y a n d t h e crit eri a f or s el e cti n g t h e 
crit eri a. 
  W h er e a c at e g or y wit h a s u b h e a di n g ( s u c h a s s y ste m or g a n cl a s s) h a s t o b e s plit o v er m or e t h a n 
o n e p a g e, o ut p ut t h e s u b h e a di n g f o ll o w e d b y “( c o nt)” at t h e t o p of e a c h s u b s e q u e nt p a g e.  T h e 
o v er all s u m m ar y st ati sti c s f or t h e s u b h e a di n g s h o ul d  o nl y b e o ut p ut o n t h e fir st r el e v a nt p a g e. 
1 4. 2. 5. 3. 
Li sti n g C o n v e nti o n s 
  Li sti n g s will b e s ort e d f or pr e s e nt ati o n i n ord er of tr e at m e nt gr o u p s a s a b o v e, p ati e nt n u m b er, 
vi sit/ c oll e cti o n d a y, a n d vi sit/ c oll e cti o n ti m e. 
 D at e s  ar e  pri nt e d i n S A S D A T E 9.f or m at (“ d d M M M y y y y”: 0 1 J U L 2 0 0 0). Mi s si n g p orti o n s of d at e s ar e 
r e pr e s e nt e d o n p ati e nt li sti n gs a s d a s h e s (-- J U L 2 0 0 0).  
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s
A c e si o n P h ar m a A p S -  Pr ot o c ol N o: A P 3 0 6 6 3 - 2 0 0 1
T hi s d o c u m e nt i s c o nfi d e nti al.
S A P V er si o n : S A P v er si o n 4. 0 – 2 0 F e b 2 0 2 3
C o ntr oll e d D o c u m e nt I D: 
, Eff e cti v e D at e 2 9- O ct- 2 0 1 8
Fili n g r e q uir e m e nt s: T M F
P a g e 3 8 of 4 7
All o b s er v e d ti m e v al u e s ar e t o b e pr e s e nt e d u si n g a 2 4- h o ur cl o c k H H: M M or H H: M M: S S f or m at 
(e. g ., 1 1: 2 6: 4 5, or 1 1: 2 6). Ti m e will o nl y b e r e p ort e d if it w a s m e a s ur e d a s p art of t h e st u d y.
U nit s will b e i n cl u d e d w h er e a v ail a bl e
1 4. 2. 5. 4.
Fi g ur e C o n v e nti o n s
U nl e s s ot h er wi s e s p e cifi e d, f or all fi g ur e s, st u d y vi sit s will b e di s pl a y e d o n t h e X- a xi s a n d e n d p oi nt 
(e. g. , tr e at m e nt m e a n c h a n g e fr o m B a s eli n e) v al u e s will b e di s pl a y e d o n t h e Y- a xi s.
F o ot n ot e s
A s oli d li n e s p a n ni n g t h e m ar gi n s will s e p ar at e t h e b o d y of t h e d at a di s pl a y fr o m t h e f o ot n ot e s. 
All f o ot n ot e s will b e l eft j u stifi e d wit h si n g l e-li n e s p a ci n g i m m e di at el y b el o w t h e s oli d li n e 
u n d er n e at h t h e d at a di s pl a y.
F o ot n ot e s s h o ul d al w a y s b e gi n wit h “ N ot e:” if a n i nf or m ati o n al f o ot n ot e, or 1, 2, 3, et c. if a 
r ef er e n c e f o ot n ot e. E a c h n e w f o ot n ot e s h o ul d st art o n a n e w li n e,  w h er e p o s si bl e.
P ati e nt s p e cifi c f o ot n ot e s ar e a v oi d e d, w h er e p o s si bl e.
F o ot n ot e s will b e u s e d s p ari n gl y a n d a d d v al u e t o t h e t a bl e, fi g ur e, or li sti n g. If m or e t h a n si x li n e s 
of f o ot n ot e s ar e pl a n n e d, t h e n a c o v er p a g e i s  str o n gl y r e c o m m e n d e d t o b e u s e d t o di s pl a y 
f o ot n ot e s, a n d o nl y t h o s e e s s e nti al t o c o m pr e h e n si o n of t h e d at a will b e r e p e at e d o n e a c h p a g e. 
T h e l a st li n e of t h e f o ot n ot e s e cti o n will b e a st a n d ar d s o ur c e li n e t h at i n di c at e s t h e n a m e of t h e 
pr o gr a m u s e d t o pr o d u c e t h e d at a di s pl a y, d at e/ti m e t h e pr o gr a m w a s r u n, a n d t h e li sti n g s o ur c e 
(i. e., ‘ Pr o gr a m : m y pr o gr a m. s a s    Li sti n g s o ur c e: 1 6. x. y. z’).
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s
A c e si o n P h ar m a A p S -  Pr ot o c ol N o: A P 3 0 6 6 3 - 2 0 0 1
T hi s d o c u m e nt i s c o nfi d e nti al.
S A P V er si o n : S A P v er si o n 4. 0 – 2 0 F e b 2 0 2 3
C o ntr oll e d D o c u m e nt I D: 
, Eff e cti v e D at e 2 9- O ct- 2 0 1 8
Fili n g r e q uir e m e nt s: T M F
P a g e 3 9 of 4 7
Q u alit y C o ntr ol
S A S pr o gr a m s ar e d e v el o p e d t o pr o d u c e o ut p ut s u c h a s a n al y si s d at a s et s, s u m m ar y t a bl e s, d at a li sti n g s, 
fi g ur e s or st ati sti c al a n al y s e s. A n o v er vi e w of t h e d ev el o p m e nt of pr o gr a m s i s d et ail e d i n S y n e o s H e alt h 
S O P D e v el o pi n g St ati sti c al Pr o gr a m s ( 3 9 0 7).
S y n e o s H e alt h S O P s D e v el o pi n g St ati sti c al Pr o gr a m s ( 3 9 0 7) a n d  C o n d u cti n g t h e Tr a n sf er of Bi o st ati sti c al 
D eli v er a bl e s ( 3 9 0 8) d e s cri b e s t h e q u alit y c o ntr ol pr o c e d ur e s t h at ar e p erf or m e d f or all S A S pr o gr a m s a n d 
o ut p ut. Q u alit y c o ntr ol i s d efi n e d h er e a s t h e o p er ati o n a l t e c h ni q u e s a n d a cti viti e s u n d ert a k e n t o v erif y t h at 
t h e S A S pr o gr a m s pr o d u c e t h e o ut p ut b y c h e c ki n g f or t h eir l o gi c, effi ci e n c y a n d c o m m e nti n g a n d b y r e vi e w 
of t h e pr o d u c e d o ut p ut.”  
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St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s
A c e si o n P h ar m a A p S -  Pr ot o c ol N o: A P 3 0 6 6 3 - 2 0 0 1
T hi s d o c u m e nt i s c o nfi d e nti al.
S A P V er si o n : S A P v er si o n 4. 0 – 2 0 F e b 2 0 2 3
C o ntr oll e d D o c u m e nt I D: 
, Eff e cti v e D at e 2 9- O ct- 2 0 1 8
Fili n g r e q uir e m e nt s: T M F
P a g e 4 6 of 4 7
A p p e n di c e s
A P P E N DI X I S A M P L E S A S C O D E I N S T A TI S TI C A L A N A L Y SI S
1) 
S a m pl e C o d e f or Effi c a c y A n al y si s 
T h e l o gi sti c r e gr e s si o n will b e u s e d t o a n al y z e all effi c a c y e n d p oi nt s r el ati n g t o pr o p orti o n s 
T h e f oll o wi n g i s a n e x a m pl e of t h e S A S c o d e s u s e d t o p erf or m t h e a n al y si s of t hi s L O GI S TI C m o d el.
************************************************************************
* S A S C o d e s: L O GI S TI C m o d el 
* V ari a bl e s i n t h e m o d el:  
* r e s p = pr o p orti o n of p ati e nt s  w h o h a v e c o n v ert e d fr o m A F wit hi n 9 0 m n fr o m t h e st art of i nf u si o n
* D ur ati o n of c urr e nt A F e pi s o d e = D ur
*trt p = tr e at m e nt pl a n n e d
***********************************************************************;
p r o c  l o g i s t i c  d a t a = e f f  d e s c e n d i n g ;
c l a s s  t r t p ( p a r a m = r e f  r e f = ' P l a c e b o ' ) ;
m o d e l  r e s p  ( e v e n t = ” Y e s ” ) =  t r t p d u r ;
c o n t r a s t  ' P a i r w i s e '   t r t  1  - 1
0  / e s t i m a t e = e x p ;
c o n t r a s t  ' P a i r w i s e '   t r t  1  0
- 1
/ e s t i m a t e = e x p ;
     
o d s  o u t p u t  C o n t r a s t e s t i m a t e = e s t ;
r u n ;
A K a pl a n- M ei er a n al y si s w a s u s e d f or ti m e t o c o n v er si o n. A n e x a m pl e of t h e S A S c o d e t o p erf or m t hi s 
a n al y si s i s b el o w.
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* S A S C o d e: K a pl a n- M ei er A n al y si s 
* V ari a bl e s i n t h e m o d el:  
* ti m e c o n v = T h e ti m e t o c o n v er si o n fr o m A F fr o m st art of i nf u si o n
* C e n s or =  c e n s or v ari a bl e ( 0 = p ati e nt s wit h c o n ver si o n, 1 = c e n s or e d p ati e nt s, n o p h ar m a c ol o gi c al 
c o n v er si o n)
*trt p = tr e at m e nt pl a n n e d
***********************************************************************;
p r o c  l i f e t e s t  d a t a = d a t a s e t p l o t ;
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St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s  
A c e si o n P h ar m a A p S -  Pr ot o c ol N o: A P 3 0 6 6 3 - 2 0 0 1 
 
 
 
T hi s d o c u m e nt i s c o nfi d e nti al. 
 
S A P V er si o n : S A P v er si o n 4. 0 –  2 0 F e b 2 0 2 3 
C o ntr oll e d D o c u m e nt I D: 
, Eff e cti v e D at e 2 9- O ct- 2 0 1 8 
Fili n g r e q uir e m e nt s: T M F 
P a g e 4 7  of 4 7  
 
t i m e  t i m e c o n v * c e n s o r ( 1 ) ;  
s t r a t a  t r t p /  t e s t = ( l o g r a n k )  d i f f = c o n t r o l ( ' P l a c e b o ' ) ;  
o d s  o u t p u t  q u a r t i l e s / q u a r t i l e  
r u n ;  
2)  S a m pl e C o d e f or gr a p h  
 
 
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* S A S C o d e: Gr a p h C o n c e ntr ati o n r e s p o n s e r el ati o n s hi p:  
 Q T c F v er s u s A P 3 0 6 6 3 pl a s m a c o n c e ntr ati o n s  
* P C T R E S N = Pl a s m a c o n c e ntr ati o n 
* A V A L = Q T c F 
***********************************************************************; 
 
 
p r o c  s g p l o t  d a t a = P K P D ;  
r e g  x = P C S T R E S N  y = A V A L  / C L M  a l p h a = . 0 5 ;  
r e f l i n e  0 / a x i s = y ;  
l a b e l  P C S T R E S N = " P l a s m a  c o n c e n t r a t i o n  ( u n i t ) " ;  
r u n ;  
 
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