Conditions: Myoclonus Epilepsies, Progressive
Keywords: MEAK EPM7
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 6
Healthy volunteers: no

Brief summary:
A randomized, double-blind, placebo-controlled, crossover study to assess the safety, tolerability, and pharmacokinetics of single doses of AUT00201 at 100 mg or matching placebo in patients with myoclonus epilepsy and ataxia due to potassium channel mutation (MEAK).

Detailed description:
6 to 10 patients aged 18 years and older, diagnosed with MEAK will be enrolled in the study. Patients will be administered a single dose of AUT00201 and matching placebo in a crossover design. The study is comprised of an outpatient screening and procedure orientation followed by approximately 5 days of an inpatient stay at a clinical research unit. After screening/orientation (Visit 1), and baseline assessments (Visit 2), patients will be administered a single dose of 100 mg of AUT00201 or matching placebo the morning of Visit 3. PK assessments will be done at Visits 3, 4, 5, and 6 from predose and up to 27 hours postdose. Visit 4 will be a washout day for patients. At Visit 5 patients will be administered the crossover treatment. At Visit 6 patients will be discharged from the unit. Safety and tolerability assessments will be conducted throughout. PD parameters will also be assessed. Patients will be followed up by telephone 14 days after discharge.

Arms:
arm 1: Single dose (oral, capsule) of AUT00201 arm 2: Single dose matching placebo oral capsules

Interventions: intervention 1: AUT00201 intervention 2: Placebo
Intervention descriptions: intervention 1: Single oral dose intervention 2: Single oral dose

Protocol document:
Prot_000.pdf: 
Protocol Amendment 03 
 Study: 000000233834 
CONFIDENTIAL 
Sponsor Reference: AUT022201 
Protocol Amendment 03, 30 October 2023 
Page 1 of 5 
 
 
 
Summary of Amended Protocol Changes 
A Randomized, Double-blind, Placebo-controlled, Crossover Study of the Effects of Single 
Doses of AUT00201 in Patients with Myoclonus Epilepsy and Ataxia due to Potassium (K+) 
Channel Mutation (MEAK) 
 
 
 
Protocol Amendment Status: Final 
Original Protocol Date: 03 June 2022 
Protocol Amendment 01 (Version 2.0) Date: 21 September 2022 
Protocol Amendment 02 (Version 3.0) Date: 24 January 2023 
Protocol Amendment 03 (Version 4.0) Date: 30 October 2023 
Investigational Product: AUT00201 
 
Sponsor Reference Number: AUT022201 
 Study: 000000233834 
IND Number: 160082 
 
 
Sponsor: 
Autifony Therapeutics Ltd 
Stevenage Bioscience Catalyst 
Gunnels Wood Road 
Stevenage 
SG1 2FX 
United Kingdom 
Study Site: 
 
 
 
Sponsor Signatory: 
 
Principal Investigator: 
 
 
 
 
Information described herein is confidential and may be disclosed only with the express 
written permission of the sponsor. 
 
 




Protocol Amendment 03 
 Study: 000000233834 
CONFIDENTIAL 
Sponsor Reference: AUT022201 
Protocol Amendment 03, 30 October 2023 
Page 3 of 5 
 
 
 
4. The Background and Benefit-risk Assessment sections (Sections 1.2 and 1.3, 
respectively) have been updated to reflect the study conditions, to reflect changes made to 
protocol, and to provide better clarity. 
5. The number of patients anticipated to be enrolled has been updated to approximately 
6 to 10 patients instead of 8 to 10 patients reflecting more realistic recruitment estimates. 
6. The duration of patient participation has been updated throughout the protocol from 
approximately 1.5 days to up to 2 days for total outpatient participation, and from 
approximately 4.5 to 5 days for inpatient stay for consistency and clarity. 
7. The Discussion of Study Design (Section 3.3) Section has been updated to include the 
details that patient’s history of fever and any perceived improvement of symptoms will 
be captured as part of their medical history. A corresponding Medical History section 
(Section 7.6.1) has been added with detailed guidance to ensure proper collection of 
medical history. 
8. The Discontinuation of Study Treatment section (Section 4.4.2) and the Follow-up of 
Patients Prematurely Discontinued from the Study Treatment Regimen or Withdrawn 
from Study section (Section 4.4.5) have been updated so that other than safety 
assessments, a PK sample may also be collected at the discretion of the Investigator, as it 
would be good to have a PK sample to assess PK/tolerability relationship if the subject 
withdraws due to an adverse event postdose. 
9. The Prohibited Medications section (Section 6.2) has been updated to specify that 
acetaminophen for pain relief may be taken without prior consent from the Investigator. 
10. The Study Assessments and Procedures section (Section 7) has been updated to remove 
the statement that the detailed procedure to be followed for assessments, which involves 
patients’ activity or measurements based on physical activities, will be described in the 
study manual. 
11. In the Vital Signs, Physical Examination, and Other Safety Evaluations section 
(Section 7.3) and the Benefit-risk Assessment section (Section 1.3), the position for blood 
pressure and other vital sign measurements has been updated from supine to sitting to 
reduce patient burden and accommodate site logistics. 
12. The Changes in Myoclonus as Assessed by electromyography (EMG) and Accelerometer 
Data section (Section 7.5.2) has been updated to reflect the presence of an EMG and 
accelerometer manual. 
13. In the Unified Myoclonus Rating Scale section (Section 7.5.4), an additional assessment 
of the non-dominant arm has been added to the standard Unified Myoclonus Rating Scale 
Section 5 to obtain a more complete data set. 
14. The Measure of Ataxic Dysarthria: Speech and Vocal Tests section (Section 7.5.5) has 
been updated to include the details that the patient’s native language, including country of 
origin (eg, English – USA) will be captured as part of patient’s demographics. The 
Demographic Data section (Section 7.6) has been updated accordingly to reflect the 
change and to provide clarity. 


Protocol Amendment 03 
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CONFIDENTIAL 
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Protocol Amendment 03, 30 October 2023 
Page 4 of 5 
 
 
 
15. The pharmacodynamic (PD) population in the Analysis Populations section (Section 8.2) 
has been updated to include all patients in the Safety Population with an evaluable 
baseline and at least 1 evaluable postbaseline measurement for at least 1 PD parameter. 
The postbaseline measurement can now be any PD parameter instead of paired-pulse 
TMS measurement only. 
16. The baseline definition in the General Considerations section (Section 8.3) has been 
updated to allow the use of the average across Visits 2 and 4 as baseline if review of 
blinded data indicates a stability of the measurement on days when patients do not 
receive treatment. 
17. A Study Design/Study Schema (Figure 1) has been updated to provide greater clarity. 
18. In the Schedule of Assessments (Appendix 4), the predose pharmacokinetic (PK) 
sampling timing at Visits 3 and 5 has been revised as follows because there is no 
scientific rationale why predose PK sampling needs to be collected 1 hour predose 
±10 minutes as previously specified. 
• For Visit 3: predose PK can be any time in the morning of dosing as long as it is 
predose. 
• For Visit 5: predose PK can be any time after 47 hours post Visit 3 dosing and 
prior to Visit 5 dosing. 
19. In the Schedule of Assessments (Appendix 4), the allowable time window to collect 
non-predose PK sample has been specified (ie, the time window only applies to PK 
sampling timepoints other than predose) and updated from 10 minutes to 15 minutes. The 
additional 5-minute window allows flexibility if a pre-sample assessment is taking longer 
to conduct than anticipated, so it is not interrupted by the sampling requirement. For the 
PK modeling, the most important data is having the exact time the PK sample was drawn 
documented. 
20. In the Schedule of Assessments (Appendix 4), the time to take off the EMG and 
accelerometer device on Visit 4 has been corrected from 13:00 to 14:00 (ie, 1 hour 
longer), as the planned analysis of the EMG and accelerometer data requires a longer data 
capture and comparable time windows (now with the same time window as Visit 6). 
21. In the Schedule of Assessments (Appendix 4), the time to insert a cannula has been 
updated from 8:00 on Visit 3 to “on admission” prior to Visit 3 based on local procedure. 
The local procedure is to insert the cannula on admission, which allows for any required 
rescue medications to be administered in an expedited fashion. A footnote has been added 
to provide clarity. 
Minor changes: 
1. The synopsis has been updated according to the changes in the protocol body, as 
applicable. 
2. The amendment/version number and date have been updated throughout the protocol. 
3. Typographical errors and formatting errors have been corrected, as necessary. 


Protocol Amendment 03 
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CONFIDENTIAL 
Sponsor Reference: AUT022201 
Protocol Amendment 03, 30 October 2023 
Page 5 of 5 
 
 
 
4. Editorial changes have been made, as appropriate. 
5. Administrative changes have been made (eg, 
 
 
 
), as appropriate. 
6. Abbreviations have been added and removed, as appropriate. 
A detailed summary of changes is presented below: 
The detailed changes can be reviewed in the track changes version of the protocol. 


30 OCT 2023 
Page 1 of 73 
 
TITLE PAGE 
Protocol 
A Randomized, Double-blind, Placebo-controlled, Crossover Study of the 
Effects of Single Doses of AUT00201 in Patients with Myoclonus Epilepsy and 
Ataxia due to Potassium (K+) Channel Mutation (MEAK) 
Protocol Status: Final 
Protocol Date: 30 OCT 2023 
Protocol Version: 4.0 
Investigational Product: AUT00201 
Protocol Reference Number: AUT022201 
IND Number: 160082 
 
Sponsor: 
Autifony Therapeutics Ltd 
Stevenage Bioscience Catalyst 
Gunnels Wood Road 
Stevenage 
SG1 2FX 
United Kingdom 
Sponsor Signatory: 
 
Information described herein is confidential and may be disclosed only with the express 
written permission of the sponsor. 






Protocol 
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30 OCT 2023 
Page 4 of 73 
 
 
SYNOPSIS 
 
Title of study: A Randomized, Double-blind, Placebo-controlled, Crossover Study of the 
Effects of Single Doses of AUT00201 in Patients with Myoclonus Epilepsy and Ataxia due to 
Potassium (K+) Channel Mutation (MEAK) 
Indication: MEAK 
Number of Investigators and study centers: 1 site 
Development phase: Phase 1b 
Objectives: 
The objectives are: 
Primary 
• 
To evaluate the safety and tolerability of single doses of AUT00201 in patients with 
MEAK. 
Secondary 
• 
To evaluate the effects of single doses of AUT00201 on short interval cortical inhibition 
(SICI) as measured by paired-pulse transcranial magnetic stimulation (TMS) 
• 
To evaluate the effects of single doses of AUT00201 on dysarthria as measured by 
automated speech and vocal assessments 
• 
To evaluate the effects of single doses of AUT00201 on myoclonus index (MI) by 
capturing the amount and time periods with positive myoclonus during a prespecified time 
period as measured by electromyography (EMG) and accelerometer 
• 
To assess the pharmacokinetic (PK) profile of AUT00201 after single doses of AUT00201 
in patients with MEAK 
• 
To evaluate correlations between exposure to AUT00201 and changes in these 
biomarkers. 
Exploratory 
• 
To evaluate the effects of single doses of AUT00201 on long interval cortical inhibition 
(LICI) as measured by paired-pulse TMS 
• 
To evaluate the effects of single doses of AUT00201 on myoclonus as assessed by 
Sections 4 and 5 of the Unified Myoclonus Rating Scale (UMRS) and sub-sections D and 
E of Section 4 
• 
To evaluate the effects of single doses of AUT00201 on the amount of negative 
myoclonus (short periods of loss of muscle tone) during a prespecified time period as 
measured by EMG and accelerometer 
• 
To evaluate the effects of single doses of AUT00201 on quantitative 
electroencephalogram (EEG) and on EEG frequency responses to chirp stimuli 
• 
To evaluate the effects of single doses of AUT00201 on measures of early visual 
processing 
• 
To evaluate the effects of single doses of AUT00201 on auditory measures 
• 
To evaluate correlations between exposure to AUT00201 and changes in these 
biomarkers. 


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Methodology/study design: 
This is a Phase 1b study to investigate the safety, tolerability, PK, and pharmacodynamic (PD) 
effects on biomarkers of AUT00201 in patients with MEAK. Approximately 6 to 10 patients, 
aged 18 years or older, diagnosed with MEAK, based on documented genetic evidence of the 
presence of the KCNC1 variant will participate in the study. 
The study is a double-blind, randomized, placebo-controlled treatment in which patients will be 
administered a single dose of 100 mg AUT00201 and matching placebo in a crossover design. 
There is an initial outpatient screening and procedure orientation which can be spread over 
2 days, followed by a 5-day inpatient stay at a clinical research unit. 
After screening/orientation (Visit 1) and baseline assessments (Visit 2), patients will be 
administered a single dose of 100 mg AUT00201 or matching placebo the morning of Visit 3. 
PK assessments will be done at Visits 3, 4, 5, and 6 from predose and up to 27 hours postdose. 
Visit 4 will be a washout day for patients. The washout period of 48 hours is deemed 
appropriate based on the half-life observed in the first-in-human (FIH) study. At Visit 5, 
patients will be administered the crossover treatment. At Visit 6, patients will be discharged 
from the unit. Safety and tolerability assessments will be conducted throughout. PD parameters 
will also be assessed. 
Follow-up will be conducted over the phone 14 days ±2 days after discharge (Visit 7). 
Safety, tolerability, PK, and biomarker assessments will be conducted throughout the study as 
detailed in the Schedule of Assessments. Figure 1 provides a study schema. 
Figure 1. Study design 
Number of patients: It is anticipated that approximately 6 to 10 patients will be enrolled in 
this study. 
Diagnosis and criteria for inclusion and exclusion: 
The following are the inclusion criteria at Screening Visit (Visit 1) unless otherwise stated: 
1. Male or female patients aged 18 years or older at the time of consenting 
2. Diagnosed with MEAK, based on documented genetic evidence of the presence of the 
KCNC1 (c.959G>A; p.Arg320His) variant 
3. If taking anticonvulsants, must be on a stable anticonvulsant regimen for at least 
30 days prior to Visit 1 and anticipated to remain stable throughout the study, or if not 
on an anticonvulsant regimen, must be stable in regards to seizures for at least 30 days 
prior to Visit 1 and anticipated to remain stable throughout the study 
4. Must be able to participate and willing to give written informed consent. If patient is 
unable to provide written informed consent, a legally authorized representative can 
sign on their behalf. 
5. Must be willing to perform study assessments and comply with the study protocol 
6. If the patient is dependent on a caregiver and/or will need assistance either travelling to 
the site, whilst attending clinic visits and/or helping to document study assessment 


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responses provided by the patient (eg, questionnaires administered on a tablet device), 
they must have an identified caregiver, considered reliable by the Investigator, to 
provide support to the patient for the duration of the study. The caregiver must be 
willing and able to provide support to the patient and, if required, stay for the duration 
of the study. 
7. Medically stable based on Investigator’s judgment for at least 90 days prior to Visit 1 
8. Women of childbearing potential must have a negative urine pregnancy test on Visit 2 
(Baseline Visit) 
9. If a vagal nerve stimulator is used, it must be implanted at least 150 days before 
Visit 1, and parameters must be stable for at least 30 days before Visit 1 and be 
expected to remain stable throughout the study 
10. If a ketogenic diet is followed, it must be stable for at least 30 days before Visit 1 and 
be expected to remain stable throughout the study 
11. Willing to comply with contraceptive requirements. See Section 4. 
12. Able to speak, read and understand spoken English at a fluent level. 
The following are the exclusion criteria at Screening Visit (Visit 1) unless otherwise stated: 
1. Known pathogenic mutation in another gene that causes epilepsy or a different 
mutation in the KCNC1 gene than the c.959G>A variant 
2. Clinically significant metabolic, hepatic, hematological, pulmonary, cardiovascular, 
gastrointestinal, or urological disorder 
3. Clinically significant abnormal vital signs or laboratory test results 
4. Hypersensitivity to AUT00201 or any of the excipients 
5. Any medical condition or other factors, as judged by the Investigator, which may 
interfere with the patient’s participation in this study and/or compromise the patient’s 
ability to safely complete the study 
6. Known to abuse drugs or those who test positive on urine screen for drugs of abuse 
will be excluded based on Investigator’s judgment 
7. Positive hepatitis B surface antigen or hepatitis C antibody 
8. Clinically significant abnormality on the 12-lead electrocardiogram (ECG) 
9. Having received an investigational product (IP) 90 days prior to Visit 1 
10. Currently using felbamate <1 year prior to Visit 1, or any evidence of ongoing hepatic 
or bone marrow dysfunction associated with current/prior felbamate treatment. Patients 
who are currently using felbamate for >1 year prior to Visit 1 and have no evidence of 
ongoing hepatic or bone marrow dysfunction associated with felbamate treatment are 
allowed 
11. Currently using vigabatrin and having received vigabatrin for <2 years prior to Visit 1 
12. Suicidal ideation with some intent to act within 6 months prior to Visit 1 based upon a 
response in the Columbia-Suicide Severity Rating Scale positive response to questions 
4 or 5 of the suicidal ideation section) and as judged by the Investigator as having a 
significant impact on trial participation or patient safety. History of suicidal behavior 
within 1 year prior to Visit 1. 


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Test products, dose, and mode of administration: 
Patients will receive one of the following sequences of treatment: 
• 
A single 100 mg dose of AUT00201, oral capsule then matching placebo, oral capsule 
• 
A matching placebo, oral capsule then a single 100 mg dose of AUT00201, oral capsule. 
Reference therapy, dose, dose form, and mode of administration: 
Patients will receive matching placebo capsules in a crossover design. There is no active 
comparator product in the study. 
Duration of patient participation in study: 
Total outpatient participation: Up to 2 days 
Total inpatient participation: Approximately 5 days 
Planned follow-up: 14 days ±2 days after discharge 
Total duration of study participation: Up to 3.5 weeks 
Study populations: 
• 
Safety Population: All patients who received at least 1 dose of IP 
• 
PK Concentration Population: All patients who received at least 1 dose of IP with at least 
1 quantifiable PK concentration at any scheduled PK timepoint 
• 
PK Parameter Population: All patients in the PK Concentration Population for whom PK 
parameters can be derived 
• 
PD Population: All patients in the Safety Population who have an evaluable baseline and 
at least 1 evaluable postbaseline measurement for at least 1 PD parameter. 
In all populations, patients will be analyzed according to treatment actually received during the 
specific treatment period (before and after the crossover) regardless of the treatment to which 
they were randomized. 
Evaluation: Safety, Tolerability, PK, and PD 
The endpoints are: 
Primary Endpoint: 
• 
Safety and tolerability of single doses of AUT00201 in patients with MEAK: 
o Change from screening/baseline in laboratory assessments (routine hematology, 
biochemistry, and urinalysis) 
o Incidence of clinically significant laboratory findings 
o Change from baseline in vital signs 
o Change from baseline physical examination findings approximately 24 hours after 
IP administration 
o Change from screening in 12-lead ECG findings 
o Incidence of adverse events (AEs). 
Secondary Endpoints: 
• 
Change from baseline in cortical inhibition as assessed with paired-pulse TMS EMG: 
o SICI as measured by paired-pulse TMS EMG 
• 
Change from baseline in: 
o Measures of dysarthria as assessed by automated standardized speech and vocal 
tests 
o MI (positive myoclonus) evaluated with EMG and accelerometer 
• 
PK parameters following single doses of AUT00201: maximum (peak) plasma 
concentration (Cmax) and area under the plasma concentration-time curve from time zero to 
24 hours (AUC24) of AUT00201. 
Exploratory Endpoints: 
• 
Change from baseline in cortical inhibition as assessed with paired-pulse TMS EMG: 
o LICI as measured by paired-pulse TMS EMG. 


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• 
Change from baseline in: 
o Amount of negative myoclonus evaluated with EMG and accelerometer over time 
and during each UMRS action myoclonus Section 4: D and E and each UMRS 
Sections 4 and 5 
o UMRS subscale scores: Sections 4 and 5 
o UMRS action myoclonus scores Section 4: D and E 
o Quantitative EEG measures (absolute and relative power of predefined frequency 
bands) 
o EEG power and phase locking factor induced by chirp stimulus in predefined 
frequency bands 
o Measures of early visual processing as assessed by: 
 
Binocular rivalry 
 
An internal noise estimation. 
o Measures of auditory processing as assessed by: 
 
Otoacoustic Emissions (OAEs) 
 
Words-in-Noise (WIN) test performance (signal-to-noise ratio [SNR]). 
o Changes in biomarkers as compared to exposure to AUT00201. 
Statistical methods: 
All statistical analysis will conform to the relevant International Council for Harmonisation 
(ICH) requirements, including but not limited to those set out in ICH documents E3 and E9. 
Statistical Analysis Software (SAS) version 9.2 or later will be used for the analysis. 
A detailed Statistical Analysis Plan (SAP) will be finalized prior to database lock and data 
unblinding. The SAP will document all analyses procedures. 
Sample Size Determination 
MEAK is an ultra-rare disorder. The global prevalence is estimated at <1 in 1 000 000 
(ORPHA: 435438). There are only 10 patients known to the Epilepsy Neurogenetics Initiative 
at the Children’s Hospital of Philadelphia which keeps registry of patients who have 
KCNC1-related disorders in North America. 
It is hoped that approximately 6 to 10 patients can be recruited. 
Therefore, a formal power analysis to estimate a desired sample size is not useful. Primary 
endpoint is safety and tolerability of AUT00201. Nonetheless, a sample size of 8 provides an 
80% power to detect an effect size of approximately 0.8 in a paired sample t-test at a one-sided 
alpha level of 0.1 (as will be used for the primary outcome measure, the composite response 
score). 
General Considerations for Data Analyses 
Standard summary statistics for continuous baseline and outcome variables are: N, mean, 
standard deviation (SD), median, quartiles, minimum, maximum, and 95% confidence intervals 
at baseline and each timepoint at which the measures are obtained. In addition, the same 
descriptive statistics will be obtained for change from baseline in each treatment period for 
each timepoint at which the measures are obtained. The standard summary statistics for 
categorical baseline and outcome variables are: count and proportion (expressed as a 
percentage). Geometric mean and coefficient of variation will also be presented for PK 
concentrations and the PK parameters. 
The minimum and maximum values will be presented to the same number of decimal places as 
the raw data collected on the electronic case report form (or to 3 significant figures for derived 
parameters). The mean, median, and percentiles (eg, Q1 and Q3) will be presented to one 
additional decimal place. The SD and standard error will be presented to 2 additional decimal 
places. 
In general, baseline will be defined as the last measurement obtained before IP administration. 
However, if review of blinded data indicates a stability of the measurement on days when 


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patients do not receive treatment, baseline may also be defined as the average across Visits 2 
and 4. This will be described in the SAP. 
All summaries will be presented by treatment group unless otherwise specified. Summary 
tables and figures will be supported by full patient listings in each treatment period. 
A response matrix will be used to assess the overall effect of AUT00201 on signs and 
symptoms of MEAK. A response matrix will guard against ‘cherry picking’ of results but 
ensure the detection of a clinically meaningful signal. Details will be provided in a separate 
SAP. 


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TABLE OF CONTENTS 
TITLE PAGE ............................................................................................................................................1 
SPONSOR APPROVAL ............................................................................................................................2 
INVESTIGATOR AGREEMENT ..............................................................................................................3 
SYNOPSIS ................................................................................................................................................4 
TABLE OF CONTENTS ......................................................................................................................... 10 
LIST OF TABLES AND FIGURES ......................................................................................................... 12 
LIST OF ABBREVIATIONS................................................................................................................... 13 
1. 
INTRODUCTION ................................................................................................................... 15 
1.1. 
Study Rationale .................................................................................................................... 16 
1.2. 
Background .......................................................................................................................... 17 
1.3. 
Benefit-risk Assessment ........................................................................................................ 20 
2. 
OBJECTIVES AND ENDPOINTS .......................................................................................... 23 
2.1. 
Study Objectives ................................................................................................................... 23 
2.2. 
Endpoints ............................................................................................................................. 24 
3. 
INVESTIGATION PLAN ....................................................................................................... 26 
3.1. 
Overall Study Design and Plan Description ........................................................................... 26 
3.2. 
Replacement Patients ............................................................................................................ 27 
3.3. 
Discussion of Study Design .................................................................................................. 27 
3.4. 
End of Study Definition ........................................................................................................ 28 
3.5. 
Selection of Doses in the Study ............................................................................................. 28 
4. 
SELECTION OF STUDY POPULATION ............................................................................... 31 
4.1. 
Inclusion Criteria .................................................................................................................. 31 
4.2. 
Exclusion Criteria ................................................................................................................. 32 
4.3. 
Lifestyle Restrictions ............................................................................................................ 33 
4.4. 
Discontinuation Criteria ........................................................................................................ 34 
4.4.1. 
Screen Failures ..................................................................................................................... 34 
4.4.2. 
Discontinuation of Study Treatment ...................................................................................... 34 
4.4.3. 
Lost to Follow-up ................................................................................................................. 34 
4.4.4. 
Replacement Procedures ....................................................................................................... 35 
4.4.5. 
Follow-up of Patients Prematurely Discontinued from the Study Treatment Regimen or 
Withdrawn from Study ......................................................................................................... 35 
4.5. 
Stopping Rules ..................................................................................................................... 36 
4.6. 
Study Termination ................................................................................................................ 36 
5. 
STUDY TREATMENTS ......................................................................................................... 37 
5.1. 
Treatments Administered ...................................................................................................... 37 
5.2. 
Preparation, Storage, Handling, and Accountability ............................................................... 37 
5.3. 
Method of Treatment Assignment ......................................................................................... 38 
5.4. 
Blinding ............................................................................................................................... 38 
5.5. 
Treatment Compliance .......................................................................................................... 38 
6. 
CONCOMITANT THERAPIES AND OTHER RESTRICTIONS ............................................ 40 
6.1. 
Concomitant Therapy ........................................................................................................... 40 
6.2. 
Prohibited Medications ......................................................................................................... 40 
7. 
STUDY ASSESSMENTS AND PROCEDURES ..................................................................... 41 
7.1. 
Safety and Tolerability Assessments ...................................................................................... 41 
7.1.1. 
Adverse Events ..................................................................................................................... 41 
7.1.2. 
Reporting Serious Adverse Events ........................................................................................ 42 
7.1.3. 
Pregnancy............................................................................................................................. 43 
7.2. 
Clinical Laboratory Evaluations ............................................................................................ 43 
7.3. 
Vital Signs, Physical Examination, and Other Safety Evaluations ........................................... 43 
7.3.1. 
Height and Weight ................................................................................................................ 44 
7.3.2. 
Electrocardiogram ................................................................................................................. 44 
7.3.3. 
Columbia-Suicide Severity Rating Scale ............................................................................... 44 
7.4. 
Pharmacokinetic Analysis ..................................................................................................... 44 
7.5. 
Biomarker Assessments ........................................................................................................ 46 


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7.5.1. 
Cortical Inhibition as Assessed with Paired-Pulse TMS EMG ................................................ 46 
7.5.2. 
Changes in Myoclonus as Assessed by EMG and Accelerometer Data.................................... 46 
7.5.3. 
Action-induced Myoclonus ................................................................................................... 47 
7.5.4. 
Unified Myoclonus Rating Scale ........................................................................................... 47 
7.5.5. 
Measure of Ataxic Dysarthria: Speech and Vocal Tests .......................................................... 48 
7.5.6. 
Measures of Early Visual Processing ..................................................................................... 49 
7.5.7. 
Measures of Auditory Processing: Audiology Tests ............................................................... 49 
7.5.8. 
Electroencephalogram during Resting State and Presentation of Chirp Stimuli........................ 50 
7.5.9. 
Clinician and Patient Impressions of Treatment ..................................................................... 50 
7.6. 
Demographic Data ................................................................................................................ 50 
7.6.1. 
Medical History .................................................................................................................... 51 
7.6.2. 
Patient-reported Outcome Measurement - Ataxia ................................................................... 51 
7.6.3. 
Patient Top 3 Concerns ......................................................................................................... 51 
8. 
SAMPLE SIZE AND DATA ANALYSES .............................................................................. 52 
8.1. 
Sample Size Determination ................................................................................................... 52 
8.2. 
Analysis Populations ............................................................................................................. 52 
8.3. 
General Considerations ......................................................................................................... 52 
8.4. 
Disposition of Patients .......................................................................................................... 53 
8.5. 
Demographic and Baseline Characteristics............................................................................. 53 
8.6. 
Medical History and Prior/Concomitant Medication............................................................... 53 
8.7. 
Safety Analysis ..................................................................................................................... 53 
8.7.1. 
Adverse Events ..................................................................................................................... 53 
8.7.2. 
Clinical Laboratory Evaluations ............................................................................................ 54 
8.7.3. 
Other Safety Measures .......................................................................................................... 54 
8.8. 
Secondary Analysis .............................................................................................................. 54 
8.9. 
Pharmacokinetic Analysis ..................................................................................................... 54 
8.10. 
Exploratory Analysis ............................................................................................................ 55 
8.11. 
Interim Analysis ................................................................................................................... 55 
9. 
REFERENCES........................................................................................................................ 56 
10. 
APPENDICES ........................................................................................................................ 59 
Appendix 1 – Adverse Event Definitions .................................................................................................. 59 
Appendix 2 – Clinical Laboratory Evaluations .......................................................................................... 63 
Appendix 3 – Regulatory, Ethical, and Study Oversight Considerations ..................................................... 64 
Appendix 4 – Schedule of Assessments .................................................................................................... 67 


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LIST OF TABLES AND FIGURES 
Table 1: 
First-in-Human Study (AUT011201) Part A1 Single Doses of AUT00201 .......................................... 28 
Table 2: 
Description of Study Treatment and Placebo ...................................................................................... 37 
Table 3: 
Pharmacokinetic Parameters............................................................................................................... 45 
Table 4: 
Schedule of Assessments ................................................................................................................... 67 
Figure 1: Study Design ......................................................................................................................................... 27 
Figure 2: Maximum Plasma Concentrations AUT011201 Part A ............................................................................ 29 


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LIST OF ABBREVIATIONS 
 
Abbreviation 
Definition 
AE 
adverse event 
AED 
antiepileptic drug 
AUC24 
area under the plasma concentration-time curve from time zero to 24 hours 
BID 
twice daily 
BLQ 
below the limit of quantification 
BP 
blood pressure 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
Cmax 
maximum (peak) plasma concentration 
CNS 
central nervous system 
CRO 
Contract Research Organization 
CS 
conditioning stimulus 
C-SSRS 
Columbia-Suicide severity rating scale 
CYP 
cytochrome P450 
DDK 
diadochokinetic rate 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EEG 
electroencephalogram 
EMG 
electromyography 
EPM7 
progressive myoclonic epilepsy type 7 
ETP 
end-of-treatment period 
FIH 
first-in-human 
FMRP 
fragile X mental retardation protein 
GABA 
gamma-aminobutyric acid 
GCP 
Good Clinical Practice 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IP 
investigational product 
IRB 
Institutional Review Board 
ISI 
interstimulus interval 
K+ 
potassium 
Kv 
voltage-gated potassium channel 
LICI 
long interval cortical inhibition 
MEAK 
myoclonus epilepsy and ataxia due to potassium (K+) channel mutation 
MedDRA 
Medical Dictionary for Regulatory Activities 
MOC 
medial olivocochlear 
MI 
myoclonus index 
NOAEL 
no observed-adverse effect level 
OAE 
Otoacoustic Emission 
PD 
pharmacodynamic 
PK 
pharmacokinetic 
PME 
progressive myoclonic epilepsy 
p.o. 
orally 


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Abbreviation 
Definition 
PROM 
patient-reported outcome measurement 
PSS 
Patient Safety Solutions 
PT 
preferred term 
PTZ 
pentylenetetrazole 
PV 
parvalbumin 
PV+ 
parvalbumin-positive 
QTcB 
QT interval corrected for heart rate by Bazett’s formula 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAS 
Statistical Analysis Software 
SD 
standard deviation 
SE 
standard error 
SICI 
short interval cortical inhibition 
SNR 
signal-to-noise ratio 
SOC 
system organ class (MedDRA classification) 
SOP 
standard operating procedure 
TEAE 
treatment-emergent adverse event 
tmax 
time to reach maximum (peak) plasma concentration 
TMS 
transcranial magnetic stimulation 
UMRS 
Unified Myoclonus Rating Scale 
WIN 
Words-in-Noise test 


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1. INTRODUCTION 
AUT00201 is a small molecule developed as a potent and selective modulator of human 
voltage-gated potassium (K+) ion channels (Kv): Kv3.1 and Kv3.2. The Kv3 family includes 
4 members: Kv3.1, Kv3.2, Kv3.3, and Kv3.4. Kv3 channels are activated by depolarization of the 
neuronal plasma membrane to potentials typically above -20 mV. These channels open rapidly 
during the depolarizing phase of the neuronal action potential in order to initiate repolarization 
and prevent significant sodium channel inactivation. As the neuron begins to repolarize, the 
channels deactivate quickly and thus do not contribute significantly to the 
after-hyperpolarization. 1,2 These distinct properties allow the channels to terminate the action 
potential rapidly without compromising the action potential threshold, rise time, magnitude, or 
increasing the duration of the refractory period. As a consequence, neurons expressing 
Kv3 channels are able to sustain action potential firing at high frequencies. Kv3 channel subtypes 
are differentially expressed by subclasses of interneuron in corticolimbic brain areas,3,4,5,6 in the 
thalamus,7 and cerebellum.8 Kv3.1 and Kv3.3 channels are also expressed at high levels in 
auditory brainstem nuclei.9,10 Kv3.1 and Kv3.2 channels are particularly expressed by 
fast-spiking, parvalbumin-positive (PV+) interneurons in corticolimbic circuits, including motor 
and sensorimotor cortex. They are the critical component to enable the accurate, high-frequency 
firing of these interneurons which give rise to gamma frequency oscillations that underlie 
attention, sensory processing, and cognition. Genetic deletion of Kv3.1, Kv3.2, and Kv3.3 
channels are associated with altered sensitivity to seizure.11,12 
Pathogenic variants in the KCNC1 gene, which encodes the Kv3.1 channel, have been linked 
recently to a spectrum of epilepsy and intellectual disability phenotypes. A recurrent pathogenic 
variant of KCNC1 (c.959G>A; p.Arg320His) results in a form of progressive myoclonic 
epilepsy (PME) called MEAK (myoclonus epilepsy and ataxia due to K+ channel mutation).13 
The loss of Kv3.1 channel function is suggested to lead to reduced cortical inhibition, which 
gives rise to motor and sensorimotor cortex hyperexcitability.14 This hyperexcitability underlies 
the susceptibility to rhythmic myoclonic activity in MEAK and similar hyperexcitability caused 
by the reduced Kv3 channel function in cerebellar neurons is likely to give rise to the progressive 
ataxia observed in these patients. 
MEAK is an ultra-rare disorder. Based on a mutational model, which takes into account both the 
local sequence context of the mutation site and regional factors, Muona et al estimated the 
incidence to be 1 in 5,700,000 conceptions.13 Given a birth number of 3,605,201 in 2020 in the 
US, in 2 years only 1 to 2 people are born in the US with this mutation. Consistently, there are 
currently 10 patients known to the registry at the Children’s Hospital of Philadelphia which was 
built through the Epilepsy Neurogenetics Initiative. 
MEAK is a severe and debilitating condition. On a background of usually normal development, 
the first symptom in the majority of patients is myoclonus (sometimes reported as tremor), 
mostly action-induced, at the ages of 6 to 14 years. Progressive ataxia develops in parallel but is 
usually overshadowed by myoclonus as the major motor impediment although it has presented as 
an initial symptom in some cases. Despite its designation as myoclonic epilepsy both myoclonic 
and tonic-clonic seizures are infrequent in all patients. During adolescence myoclonus generally 
becomes very severe, limiting ambulation, and requiring a walking aid or wheelchair by mid to 
late teens. There is notable preservation of cognition in the context of severe motor disability. 




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order to capture signals of efficacy in this population and will provide the first proof-of- 
mechanism that this class of drugs can be effective in patients with a PME syndrome. 
Another important aim of this study is the characterization of the cortical pathophysiology and 
biomarker profile of MEAK patients. A better understanding of the pathophysiology of these 
patients may help to optimize their treatment and will also allow comparison to other forms of 
PME where AUT00201 could have potential to improve symptoms. Such a characterization may 
also support the use of these biomarkers in future studies in other indications in which 
dysfunction of PV+ interneurons has been implicated. These biomarkers will include 
paired-pulse transcranial magnetic stimulation (TMS) to probe motor cortex excitability and 
measures of auditory and visual information processing that have been associated with 
dysfunction of PV+ interneurons that express Kv3 channels. We predict that we will observe 
evidence for reduced cortical inhibition in the MEAK patients and subtle but consistent 
abnormalities in early auditory and visual information processing. Previous studies have shown 
reduced cortical inhibition in other forms of myoclonic epilepsy, such as Unverricht-Lundborg 
syndrome.17,18,19 On this basis, there would be a reasonable rationale to explore the therapeutic 
potential of AUT00201 in these other epilepsy syndromes. 
Prior to the development of AUT00201, the sponsor has conducted clinical studies with 2 other 
Kv3 modulators (AUT00063; IND 122711), and AUT00206 (EudraCT numbers: 2015-002364- 
16, 2016-000216-14, 2016-002704-63, 2021-003211-26), the latter of which is being progressed 
for certain neuropsychiatric indications, such as Fragile X Syndrome. This study plans to enroll 
patients aged 18 years and older diagnosed with MEAK (see Section 4.1). The safety and 
tolerability of AUT00201 at exposures exceeding those proposed to be used in the current study 
has been established in a first-in-human (FIH) study in healthy volunteers (see Section 3.5). 
1.2. 
Background 
Pathogenic variants in the KCNC1 gene, which encodes the Kv3.1 channel, have been linked 
recently to a spectrum of epilepsy and intellectual disability phenotypes.13,14,20,21,22 A pathogenic 
variant of KCNC1 results in a form of PME called MEAK, this is a severe and debilitating, 
ultra-rare disease which has been described in approximately 40 individuals in the medical 
literature. 
This recurrent de novo mutation in KCNC1 leading to PME was first uncovered in a study 
evaluating whole exome sequencing in 2 unrelated cohorts of patients with PME of unknown 
etiology. From these 2 cohorts, 16 cases (13 unrelated) were identified with a KCNC1 
c.959G>A; p.Arg320His mutation.13 The expression of Kv3.1 is mainly limited to the central 
nervous system (CNS) and a specific subset of gamma-aminobutyric acid (GABA)ergic 
inhibitory interneurons known as PV+ fast-spiking interneurons, which are critical components 
of cortical circuits, including motor and sensorimotor cortex. Kv3.1 channels are also particularly 
expressed in the cerebellum and auditory brainstem. Thus, p.Arg320His substitution in Kv3.1 
may result in cortical disinhibition due to the impaired firing of fast-spiking GABAergic 
interneurons, leading to myoclonus and seizures as well as ataxia and motor impairments that 
may arise from dysfunction of cerebellar neurons. Alterations of auditory and visual function 
have not been reported in patients with MEAK, although appropriate tests to discern such 
impairments most likely have not been applied. Small molecule positive modulators that 


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selectively target Kv3.1 channels have been developed by Autifony Therapeutics and have the 
potential to be used in treatment of KCNC1-related disorders, including MEAK. Nonclinical 
studies in cellular systems and transgenic mice expressing MEAK mutant Kv3.1 channels 
support this potential. 
Twenty patients with the recurrent KCNC1 c.959G>A; p.Arg320His mutation were described in 
the original study. 14 Of these, 14 were sporadic (unrelated) cases, 4 were from 1 family, and 2 
were a mother-child pair). The patients were 17 to 63 years of age when they were studied. Onset 
of neurologic symptoms was at a median of 9.5 years (range 3 to 15 years). In the majority, the 
first symptom was myoclonus (brief jerks). Three patients presented with ataxia (with or without 
myoclonus) and 3 presented with generalized tonic-clonic seizures between the ages of 9 and 14 
years without prior myoclonus. All of these patients were described as having progressively 
severe and frequent (daily) myoclonus which was action-induced and often resulted in falls, 
ataxia primary factor limiting ambulation. About half of the patients became wheelchair- 
dependent, with severe myoclonus noted as the predominant reason. Myoclonus is also reported 
as being so severe as to interfere with daily activities such as being able to eat independently and 
over half of the 20 patients needed assistance with all functions of daily living, reported as fully 
or mostly dependent. 
A diurnal pattern was noted – myoclonus was worse in the morning. Other exacerbating factors 
included stress, anxiety, startle, or menses. Generalized tonic-clonic seizures were rare, occurring 
most often during teenage years. At the time of the report, all of the patients were being treated 
with 1 or more anti-seizure medications, with variable efficacy. In this cohort of 20 patients, the 
progression of the disorder appeared to stabilize in adulthood and did not appear to result in early 
death. The description of these findings was based on retrospective review of information 
collected for clinical purposes and did not utilize standardized instruments, thus limiting 
quantitative data which could be followed over time.23 
As discussed by Oliver et al, the loss of Kv3.1 channel function is suggested to lead to reduced 
cortical inhibition, which gives rise to motor and sensorimotor cortical hyperexcitability.14 This 
hyperexcitability underlies the susceptibility to rhythmic myoclonic activity in MEAK as well as 
in a broader range of PMEs due to other genetic causes. The synchronized discharges of 
pyramidal neurons transferred through the pyramidal tract to the peripheral motor system results 
in synchronous motor unit discharges that lead to rhythmic myoclonic jerks, rather than normal 
integrated movements. 
Cortical excitability has been investigated with the help of TMS. In particular, paired-pulse TMS 
allows measurement of the function of GABA-dependent cortical interneuron circuits which is 
especially relevant in the context of genetic epilepsies like MEAK in which abnormal 
interneuron function in strongly implicated.24 In other PMEs, decreased cortical inhibition has 
been demonstrated using this approach.25 The measures of interest include short interval cortical 
inhibition (SICI) and long interval cortical inhibition (LICI). 
Reduced inhibitory control in MEAK is consistent with the high expression of Kv3.1 channels on 
PV+ GABA interneurons where they enable these neurons to fire rapidly and accurately. 22 Loss 
of Kv3.1 function is therefore likely to result in reduced activity of this important class of 
interneuron. Studies have demonstrated that normal functioning of PV+ interneurons is critical 


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for the generation of highly synchronized gamma oscillations which are important for enhancing 
signal transmission in the neocortex by reducing circuit noise and amplifying circuit signals. 23 
Dysfunction of PV+ interneurons is associated with reduced phase synchrony of evoked gamma 
oscillations associated with increased power of resting state gamma oscillations. 26 This has been 
observed in other indications where PV+ interneuron dysfunction has been implicated; for 
example, studies in fragile X mental retardation protein (FMRP) knock-out mice and patients 
with Fragile X Syndrome show identical electroencephalogram (EEG) abnormalities, strongly 
suggesting that desynchronized but increased resting state gamma oscillations represent a 
translational biomarker of PV+ interneuron dysfunction.27 In patients with MEAK, resting state 
gamma oscillations have not been investigated, but it is plausible to assume that similar 
abnormalities should be observed. Thus, measures of evoked gamma synchrony and resting state 
gamma frequency power using EEG may serve as a further biomarker for the underlying 
pathophysiology in MEAK. 
Finally, Kv3.1 channels play a key role in the auditory brainstem, where they contribute to the 
accurate firing of auditory projection neurons. In a related ataxia disorder caused by mutation in 
the KCNC3 gene that codes for Kv3.3, alterations in inter-aural sound discrimination could be 
detected.26 Although specific measures of central auditory processing have not been investigated 
in patients with MEAK, we can speculate that some dysfunction in these processes could be 
present due to reduced Kv3.1 channel function in auditory neurons. 
Dysfunction of inhibitory interneurons and GABAergic transmission in primary and secondary 
visual cortices has also been implicated in subtle abnormalities in early visual perceptual 
processes like contour integration, contrast sensitivity, visual orientation discrimination, and 
binocular rivalry.28,29 These visual processes have not been investigated in patients with MEAK. 
Their evaluation will complement the assessment of auditory functioning and provide a 
comprehensive characterization of potential biomarker abnormalities associated with reduced 
Kv3.1 channel function. 
The study will investigate safety, tolerability, PK, and pharmacodynamic (PD) outcomes of a 
Kv3.1/Kv3.2 modulator, AUT00201 in MEAK patients following a single dose of AUT00201. It 
will investigate biomarkers of cortical excitability, and PV+ interneuron function in patients with 
MEAK. Exploration of measures of speech, central auditory, and visual function will also be 
included where this is feasible without overburdening the patients. 
The study will aim to validate and extend the use of biomarkers of PV+ interneuron dysfunction 
and cortical hyperexcitability, respectively, in the MEAK population. Cortical excitability using 
TMS has already been explored in patients with other forms of PME. 27,30 It is expected that 
patients with MEAK will demonstrate EEG abnormalities mentioned earlier, as well as the 
paired-pulse TMS abnormalities observed in other PMEs. In addition, subtle abnormalities in 
auditory and visual information processing and perception may be observed. If indeed these 
abnormalities can be demonstrated and prove to be susceptible to treatment with AUT00201, 
then they could be used in the future to identify patients with PME and possibly other 
neuropsychiatric disorders in which PV+ interneuron dysfunction and cortical hyperexcitability 
play a prominent role or have been implicated. 


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1.3. 
Benefit-risk Assessment 
AUT00201 is the third orally administered positive modulator of Kv3 channels to enter human 
evaluation. The first was AUT00063, which was evaluated in 1 Phase 1a and 3 Phase 2a studies. 
The second was AUT00206, which was evaluated in 2 Phase 1a and 2 Phase 1b studies. The 
nonclinical and Phase 1 clinical safety of AUT00201 appears similar to both AUT00063 and 
AUT00206 at the same stage of development. No deaths or suspected unexpected serious 
adverse events (SAEs) have occurred following administration of any of these compounds. 
The prior FIH study with AUT00201 (AUT011201) established the safety and tolerability of the 
drug in healthy volunteers for single oral doses of up to 320 mg once daily and 200 mg twice 
daily (BID), and repeat doses of up to 100 mg BID for 14 days. All reported adverse events 
(AEs) were mild to moderate and there was no notable relationship between AUT00201 dose and 
the frequency or severity of reported AEs compared to placebo. There were no deaths or SAEs 
reported in patients. No adverse cardiac signals were observed in the completed Phase 1 study of 
AUT011201, nor in the completed or ongoing clinical studies with the structurally-related Kv3 
modulator AUT00206. 
Based upon its structure, the available nonclinical and clinical safety data, and clinical data from 
the mechanistic and structurally-related compound AUT00206, AUT00201 is considered as a 
Low Risk Molecule. 
In this study, AUT00201 will be administered to MEAK patients. MEAK is caused by a 
recurrent de novo heterozygous mutation in the KCNC1 gene which encodes for the Kv3.1 
protein. Treatment with AUT00201 provides an opportunity to test a targeted therapy in patients 
with a known dysfunction in the Kv3.1 channel. This precision medicine approach is supported 
by the nonclinical data, which shows that AUT00201 can positively modulate Kv3.1 current, 
even in the presence of the MEAK mutation in vitro, and completely reverse the observed 
seizure sensitivity and ataxia phenotype in the mice in vivo. 
Currently, there is no specific treatment for MEAK. Therapy focuses on symptomatic relief, 
using primarily broad spectrum antiepileptics.14,15,31 However, while these treatments may target 
the rare occurrence of tonic-clonic seizures they have no or only very limited efficacy against 
MEAK patients’ primary symptoms of action-induced myoclonus and ataxia. There is no 
treatment for action-induced myoclonus. Clonazepam is the only drug approved by the US Food 
and Drug Administration as monotherapy for the treatment of myoclonic seizures, but these are 
not the key disabling symptoms of these patients. In addition, clonazepam is associated with 
significant side effects such as sedation and dependence. The efficacy of AUT00201 in humans 
with MEAK has not been evaluated to date. It is anticipated that continued exposure to 
AUT00201 will act on Kv3.1 channels on specific populations of neurons in the cortex and 
cerebellum, restoring their ability to sustain rapid firing required for normal function. It is 
postulated that this will reverse the reduced cortical inhibition and will in turn normalize motor 
and sensorimotor cortical hyperexcitability. This hyperexcitability underlies the susceptibility to 
rhythmic myoclonic activity in MEAK; thus AUT00201 may be an effective treatment for 
myoclonus. Furthermore, improved function of cerebellar neurons with AUT00201 treatment 
may reduce symptoms of ataxia. Thus, AUT00201 has the potential to provide therapeutic 




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assessments will be scheduled to be conducted at around the anticipated time to reach maximum 
(peak) plasma concentration (tmax) and therefore the patients will be under direct supervision 
during this time. 
For safety reporting purposes, all SAEs will be considered unexpected. 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of AUT00201 may be found in the IB. 


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2. OBJECTIVES AND ENDPOINTS 
2.1. 
Study Objectives 
The primary objective is: 
• To evaluate the safety and tolerability of single doses of AUT00201 in patients with 
MEAK. 
The secondary objectives are: 
• To evaluate the effects of single doses of AUT00201 on SICI as measured by 
paired-pulse TMS 
• To evaluate the effects of single doses of AUT00201 on dysarthria as measured by 
automated speech and vocal assessments 
• To evaluate the effects of single doses of AUT00201 on myoclonus index (MI) by 
capturing the amount and time periods with positive myoclonus during a prespecified 
time period as measured by electromyography (EMG) and accelerometer 
• To assess the PK profile of AUT00201 after single doses of AUT00201 in patients with 
MEAK 
• To evaluate correlations between exposure to AUT00201 and changes in these 
biomarkers. 
The exploratory objectives are: 
• To evaluate the effects of single doses of AUT00201 on LICI as measured by 
paired-pulse TMS 
• To evaluate the effects of single doses of AUT00201 on myoclonus as assessed by 
Sections 4 and 5 of the Unified Myoclonus Rating Scale (UMRS) and sub-sections D and 
E of Section 4 
• To evaluate the effects of single doses of AUT00201 on the amount of negative 
myoclonus (short periods of loss of muscle tone) during a prespecified time period as 
measured by EMG and accelerometer 
• To evaluate the effects of single doses of AUT00201 on quantitative EEG and on EEG 
frequency responses to chirp stimuli 
• To evaluate the effects of single doses of AUT00201 on measures of early visual 
processing 
• To evaluate the effects of single doses of AUT00201 on auditory measures 
• To evaluate correlations between exposure to AUT00201 and changes in these 
biomarkers. 


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2.2. 
Endpoints 
The primary endpoints are: 
• Safety and tolerability of single doses of AUT00201 in patients with MEAK: 
o Change from screening/baseline in laboratory assessments (routine hematology, 
biochemistry, and urinalysis) 
o Incidence of clinically significant laboratory findings 
o Change from baseline in vital signs 
o Change from baseline physical examination findings approximately 24 hours after 
investigational product (IP) administration 
o Change from screening in 12-lead ECG findings 
o Incidence of AEs. 
The secondary endpoints are: 
• Change from baseline in cortical inhibition as assessed with paired-pulse TMS EMG: 
o SICI as measured by paired-pulse TMS EMG 
• Change from baseline in: 
o Measures of dysarthria as assessed by automated standardized speech and vocal tests 
o MI (positive myoclonus) evaluated with EMG and accelerometer 
• PK parameters following single doses of AUT00201: maximum (peak) plasma 
concentration (Cmax) and area under the plasma concentration-time curve from time zero 
to 24 hours (AUC24) of AUT00201. 
The exploratory endpoints are: 
• Change from baseline in cortical inhibition as assessed with paired-pulse TMS EMG: 
o LICI as measured by paired-pulse TMS EMG 
• Change from baseline in: 
o Amount of negative myoclonus evaluated with EMG and accelerometer over time 
and during each UMRS action myoclonus Section 4: D and E and each UMRS 
Sections 4 and 5 
o UMRS subscale scores: Sections 4 and 5 
o UMRS action myoclonus scores Section 4: D and E 
o Quantitative EEG measures (absolute and relative power of predefined frequency 
bands) 
o EEG power and phase locking factor induced by chirp stimulus in predefined 
frequency bands 


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o Measures of early visual processing as assessed by: 
 Binocular rivalry 
 An internal noise estimation 
o Measures of auditory processing as assessed by: 
 Otoacoustic Emissions (OAEs) 
 Words-in-Noise (WIN) test performance (signal-to-noise ratio [SNR]) 
o Changes in biomarkers as compared to exposure to AUT00201. 




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Figure 1: Study Design 
 
3.2. 
Replacement Patients 
It is not possible to replace patients in this study given the rarity of MEAK and the known patient 
population. However, if any technical issues or important protocol deviations occur during a 
patient’s participation that are likely to make the primary, secondary, or exploratory endpoint 
data unevaluable or impact their validity, the patient may be invited back to participate in the 
study again, if the sponsor and Investigator are in agreement. 
If a patient is invited back to participate a second time, they will be given a new screening 
number and treated as a new patient, including consideration for inclusion and exclusion criteria. 
There will therefore be a minimum of 90 days between the last dose of IP in the first particpation 
and the first dose of IP in the second partcipation. Their data from the first particpation, with the 
exception of safety and PK data, will not be included in the statistical analysis. All data will be 
listed, with clear indictaion if a patient is a repeat participant. 
There are no safety concerns for rechallenging the patients. Participants in the FIH study 
received up to 4 single doses separated by 10-day washout periods; they received escalating 
doses, the highest of which was 160 mg to 200 mg BID (400 mg total dose). 
There is no impact on the data integrity by rechallenging patients. The assessments have been 
selected for the crossover design of the study and no learning effect is expected. 
3.3. 
Discussion of Study Design 
The study will be double-blind to avoid bias in the collection and evaluation of data during its 
conduct. The Investigator and sponsor will remain blinded to the treatment randomization code 
until after the database has been locked. Placebo has been chosen as the control to assess whether 
any observed effects are treatment-related or simply reflect the study conditions. A crossover 
design is used to increase the power of the study and reduce the influence of confounding 
covariates since each patient serves as its own control. 
It is reported that patients have noted transient improvement in gait and myoclonus with high 
fever. 14 This typically lasted just hours or a few days while the patient was febrile, but was 
noticeable. This has been attributed to the temperature-dependent leftward shift in activation of 
wild-type KV3.1 subunit–containing channels, which would counter the loss of function observed 
for mutant channels. Therefore, it is postulated that improvements following a relatively short 






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assessments. The PK of AUT00201 is expected to be similar in healthy volunteers and MEAK 
patients. AUT00201 is not an inhibitor of cytochrome P450 (CYP) enzymes and is metabolized 
by multiple CYP isoforms (predominantly CYP3A4 and CYP2C9, and possibly CYP2C19), 
therefore the likelihood of a significant PK interaction with any of the expected anticonvulsant 
concomitant medications that the MEAK patient will be taking is considered low. 
Based upon the clinical experience already available on AUT00201, patients will be monitored 
within the clinical inpatient unit for the duration of dosing, and the expected duration of exposure 
to the IP the sponsor considers a single dose of 100 mg AUT00201 to be acceptable for this 
study. 
As the effect of drug in pregnant women is not known, AUT00201 will be discontinued in the 
patients who may conceive or are tested positive for pregnancy during the study. From safety 
perspective, study treatment will be discontinued per criteria listed in Section 4.4.2. Further, the 
stopping rules for study treatment are provided in Section 4.5. 


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4. SELECTION OF STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
There are only 10 patients known to the Epilepsy Neurogenetics Initiative at the Children’s 
Hospital of Philadelphia. It is hoped approximately 6 to 10 patients who are over the age of 
18 years will participate. 
4.1. 
Inclusion Criteria 
Patients must satisfy all the following criteria at Screening Visit (Visit 1) unless otherwise stated: 
1. Male or female patients aged 18 years or older at the time of consenting 
2. Diagnosed with MEAK, based on documented genetic evidence of the presence of the 
KCNC1 (c.959G>A; p.Arg320His) variant 
3. If taking anticonvulsants, must be on a stable anticonvulsant regimen for at least 30 days 
prior to Visit 1 and anticipated to remain stable throughout the study, or if not on an 
anticonvulsant regimen, must be stable in regards to seizures for at least 30 days prior to 
Visit 1 and anticipated to remain stable throughout the study 
4. Must be able to participate and willing to give written informed consent. If patient is 
unable to provide written informed consent, a legally authorized representative can sign 
on their behalf 
5. Must be willing to perform study assessments and comply with the study protocol 
6. If the patient is dependent on a caregiver and/or will need assistance either travelling to 
the site, whilst attending clinical visits and/or helping to document study assessment 
responses provided by the patient (eg, questionnaires administered on a tablet device) 
they must have an identified caregiver, considered reliable by the Investigator, to provide 
support to the patient for the duration of the study. The caregiver must be willing and 
able to provide support to the patient and, if required, stay for the duration of the study. 
7. Medically stable based on Investigator’s judgment for at least 90 days prior to Visit 1 
8. Women of childbearing potential must have a negative urine pregnancy test on Visit 2 
(Baseline Visit) 
9. If a vagal nerve stimulator is used, it must be implanted at least 150 days before Visit 1, 
and parameters must be stable for at least 30 days before Visit 1 and be expected to 
remain stable throughout the study 
10. If a ketogenic diet is followed, it must be stable for at least 30 days before Visit 1 and be 
expected to remain stable throughout the study 
11. Willing to comply with contraceptive requirements (see below). 
12. Able to speak, read and understand spoken English at a fluent level. 


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Contraceptive requirements: Men 
Male patients must not plan to father a child or donate sperm, during the study and for 90 days 
after their follow-up visit. 
Male patients must not have sex without using a condom, during the study and for 90 days after 
their follow-up visit, if their partner is a woman of childbearing potential. They do not need to 
use any contraception if: they had a vasectomy and surgical success has been confirmed by 
medical assessment, or their partner is not of childbearing potential. Partners who are not of 
childbearing potential are defined as: men; postmenopausal women (no menstrual periods for at 
least 365 days); or women who have no uterus, ovaries, or fallopian tubes. 
During the study, patients must not have sex with a woman who is pregnant or breastfeeding, 
without using a condom. 
Contraceptive requirements: Women 
Women of childbearing potential must use a highly effective method of contraception with 
low-user dependency during the study. They must have been using that method for at least 
28 days before Visit 1 and continue to use it for 180 days (6 months) after their last dose of study 
medication. Highly effective methods of contraception include: 
• intrauterine device 
• intrauterine hormone-releasing system 
• established use of oral, injected, or implanted hormonal methods of contraception 
• bilateral tubal occlusion 
• vasectomized partner (with surgical success confirmed by medical assessment). 
A woman is considered to be of non-childbearing potential if she meets one of the following 
criteria: 
• is postmenopausal (the last menstrual period was at least 365 days ago, and follicle- 
stimulating hormone at Screening confirms postmenopausal status) 
• has no uterus, ovaries, or fallopian tubes. 
Patients who practice true abstinence or who only have same-sex relationships need not use 
contraception, provided it is in line with their preferred and usual lifestyle (Note: periodic 
abstinence [eg, calendar, ovulation, symptothermal, and postovulation methods] and withdrawal 
are not acceptable methods of contraception). Should any such patient stop practicing true 
abstinence, they must use contraception as described above. 
4.2. 
Exclusion Criteria 
Patients will be excluded from the study if they satisfy any of the following criteria at Screening 
Visit (Visit 1) unless otherwise stated: 


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1. Known pathogenic mutation in another gene that causes epilepsy or a different mutation 
in the KCNC1 gene than the c.959G>A variant 
2. Clinically significant metabolic, hepatic, hematological, pulmonary, cardiovascular, 
gastrointestinal, or urological disorder 
3. Clinically significant abnormal vital signs or laboratory test results 
4. Hypersensitivity to AUT00201 or any of the excipients 
5. Any medical condition or other factors, as judged by the Investigator, which may 
interfere with the patient’s participation in this study and/or compromise the patient’s 
ability to safely complete the study 
6. Known to abuse drugs or those who test positive on urine screen for drugs of abuse will 
be excluded based on Investigator’s judgment 
7. Positive hepatitis B surface antigen or hepatitis C antibody 
8. Clinically significant abnormality on the 12-lead ECG 
9. Having received an IP 90 days prior to Visit 1 
10. Currently using felbamate for <1 year prior to Visit 1 or any evidence of ongoing hepatic 
or bone marrow dysfunction associated with current/prior felbamate treatment. Patients 
who are currently using felbamate for >1 year prior to Visit 1 and have no evidence of 
ongoing hepatic or bone marrow dysfunction associated with felbamate treatment are 
allowed 
11. Currently using vigabatrin and having received vigabatrin for <2 years prior to Visit 1 
12. Suicidal ideation with some intent to act within 6 months prior to Visit 1 based upon a 
response in the C-SSRS (positive response to questions 4 or 5 of the suicidal ideation 
section) and as judged by the Investigator as having a significant impact on trial 
participation or patient safety. History of suicidal behavior within 1 year prior to Visit 1. 
4.3. 
Lifestyle Restrictions 
AUT00201 is predominately metabolized by CYP3A4 and CYP2C9. Accordingly, the 
consumption of dietary supplements (eg, St. John’s wort), foods, and forms of fruit juice (eg, 
Seville oranges, grapefruit juice) that may affect the expression or function of CYP3A4 or 
CYP2C9 will not be allowed beginning 7 days before Visit 1 and continuing whilst inpatient. 
No alcohol will be allowed during the period from 24 hours before Screening until the end of the 
inpatient stay. Patients who regularly drink caffeinated drinks will be asked to maintain their 
routine, but nonregular drinkers will be asked to avoid all caffeine. Restrictions on smoking 
whilst inpatient will be discussed with the patients at Screening. 


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4.4. 
Discontinuation Criteria 
4.4.1. 
Screen Failures 
Screen failures are defined as patients who consent to participate in the clinical study but are not 
subsequently entered in the study. A minimal set of screen failure information is required to 
ensure transparent reporting of screen failure patients to meet the Consolidated Standards of 
Reporting Trials publishing requirements and to respond to queries from regulatory authorities. 
Minimal information includes demography, screen failure details, eligibility criteria, and any 
SAEs with concomitant medication details. 
When 1 or more correctable inclusion or exclusion criteria are found at Screening, after 
appropriate management, the patient can be rescreened at the discretion of the Investigator and if 
approved by the sponsor or sponsor designee in writing. 
4.4.2. 
Discontinuation of Study Treatment 
Patients may withdraw from the study at any time at his/her own request or legal guardian’s 
request (if applicable), or may be withdrawn at any time at the discretion of the Investigator for 
safety, behavioral, or administrative reasons. If the patient withdraws consent for disclosure of 
future information, the sponsor may retain and continue to use any data collected before such a 
withdrawal of consent. Additionally, patients may request destruction of any samples taken and 
not tested, and the Investigator must document this in the site study records. A patient that 
withdraws from the study may be asked to stay in the clinic for a further day in order to complete 
safety assessments such as ECG, vital signs, and safety laboratory tests. These assessments will 
be at the discretion of the Investigator in order to ensure safety can be reviewed prior to the 
patient’s discharge. A PK sample may also be collected at the discretion of the Investigator. 
Refer to the Schedule of Assessments (Appendix 4) for potential data to be collected at the time 
of study discontinuation and follow-up and for any further evaluations that need to be completed. 
Additional reasons for discontinuation can include, but are not limited to: 
• Administration of treatments not allowed in the protocol 
• AE 
• Lack of efficacy 
• Pregnancy 
• Sponsor determination 
• Investigator’s decision 
• Death. 
4.4.3. 
Lost to Follow-up 
A patient will be considered lost to follow-up if he/she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site. 


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The following actions must be taken if a patient fails to return to the clinic for a required study 
visit: 
• The site must attempt to contact the patient and reschedule the missed visit as soon as 
possible, counsel the patient or legal guardian on the importance of maintaining the 
assigned visit schedule, and ascertain whether or not the patient wishes to and/or should 
continue in the study. 
• In cases in which the patient is deemed lost to follow-up, the Investigator or designee 
must make every effort to regain contact with the patient or legal guardian (if applicable) 
(where possible, 3 telephone calls and, if necessary, a certified letter to the patient’s last 
known mailing address or local equivalent methods). These contact attempts should be 
documented in the patient’s medical record. 
• Should the patient or legal guardian (if applicable) continue to be unreachable, he/she 
will be considered to have withdrawn from the study with a primary reason of lost to 
follow-up. 
4.4.4. 
Replacement Procedures 
Patients who withdraw from the study or who are withdrawn by the Investigator for safety 
reasons will not be replaced. However, if a patient discontinues the study for technical issues or 
important protocol deviations that are likely to make the primary, secondary, or exploratory 
endpoint data unevaluable or impact their validity, the patient may be invited back to participate 
in the study again, if the sponsor and Investigator are in agreement. 
If a patient is invited back to participate a second time, they will be treated as a new patient, 
including consideration for inclusion and exclusion criteria. There will therefore be a minimum 
of 90 days between the last dose of IP in the first participation and the first dose of IP in the 
second partcipation. Their data from the first particpation, with the exception of safety and PK 
data, will not be included in the statistical analysis. All data will be listed, with clear indictaion if 
a patient is a repeat participant. 
There are no safety concerns for rechallenging the patients. Participants in the FIH study 
received up to 4 single doses separated by 10-day washout periods; they received escalating 
doses, the highest of which was 160 mg to 200 mg BID (400 mg total dose). 
There is no impact on the data integrity by rechallenging patients. The assessments have been 
selected for the crossover design of the study and no learning effect is expected. 
4.4.5. 
Follow-up of Patients Prematurely Discontinued from the Study Treatment 
Regimen or Withdrawn from Study 
Due to the continued scientific importance of patient data even if study treatment is discontinued 
early, patients who withdraw from the study may be asked to stay in the clinic for a further day 
in order to complete safety assessments such as ECG, vital signs, and safety laboratory tests. 
These assessments will be at the discretion of the Investigator in order to ensure safety can be 
reviewed prior to the patient’s discharge. A PK sample may also be collected at the discretion of 
the Investigator. Refer to the Schedule of Assessments (Appendix 4) for potential data to be 


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collected at the time of study discontinuation and follow-up and for any further evaluations that 
need to be completed. Patients who are no longer hospitalized due to early IP discontinuation 
may complete their assessments by telephone or via telemedicine or other means of remote 
communication. Laboratory assessment will be done at on-site visits. 
All treatment-related (S)AEs that are ongoing at the time of discontinuation, or that develop 
before the protocol-specified follow-up visit, will be followed for 30 days, or until resolution or 
stabilization. 
4.5. 
Stopping Rules 
Dosing of additional patients may be paused and a safety review meeting, including the 
Investigator, sponsor, and medical monitor will be convened if any of the following criteria are 
met: 
• If 2 or more patients experience a similar severe (Grade 3) AE or SAE 
• A life-threatening or fatal (Grade 4 or 5) SAE in any patient. 
4.6. 
Study Termination 
The sponsor reserves the right to close the study site or terminate the study at any time for any 
reason at the sole discretion of the sponsor. The study site will be closed upon study completion. 
The study site is considered closed when all required documents and study supplies have been 
collected and a study site closure visit has been performed. Reasons for study termination may 
include, but are not limited to: 
• AEs unknown to date (ie, not previously reported in any similar investigational study drug 
trial with respect to their nature, severity, and/or duration) 
• Increased frequency and/or severity and/or duration of known, anticipated, or previously 
reported AEs (this may also apply to AEs defined as baseline signs and symptoms) 
• Medical or ethical reasons affecting the continued performance of the study 
• Difficulties in the recruitment of patients 
• Cancellation of drug development. 
The Investigator may initiate study site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. Reasons for the early 
closure of a study site by the sponsor or Investigator may include, but are not limited to: 
• Failure of the Investigator to comply with the protocol, the requirements of the 
Institutional Review Board (IRB) or local health authorities, the sponsor's procedures, or 
Good Clinical Practice guidelines 
• Inadequate recruitment of participants by the Investigator. 


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5. STUDY TREATMENTS 
Study treatment is defined as any investigational treatment(s), marketed product(s), placebo, or 
medical device(s) intended to be administered to a study patient according to the study protocol. 
5.1. 
Treatments Administered 
Each patient will receive oral doses of AUT00201 or matching placebo as capsules. AUT00201 
will be administered as capsules containing 100 mg (size 0) or matching placebo capsules 
(Table 2). 
Patients will receive a single dose of 100 mg AUT00201 or matching placebo (one 100 mg 
capsule) at Visits 3 and 5, approximately 30 minutes after completion of a standard meal 
provided by the clinical site. 
Table 2: 
Description of Study Treatment and Placebo 
 
Study Treatment 
Name: 
AUT00201 
Placebo 
Dosage 
Formulation: 
Swedish orange-colored, hard gelatin 
capsules of size 0 
Matching placebo capsules (Swedish 
orange-colored, hard gelatin capsules of 
size 0) 
Unit Dose 
Strengths: 
100 mg (size 0) 
To match active 
Route of 
Administration: 
Oral 
Oral 
Dosing 
Instructions: 
Randomized, double-blind: 1 × 100 mg 
capsules (size 0), 30 minutes after a 
standard meala 
As for active 
Packaging and 
Labeling: 
AUT00201 capsules will be provided as 
blinded medication in HDPE bottles. 
Each bottle will be labeled in a manner 
that is indistinguishable from the 
placebo. 
Placebo capsules will be provided as blinded 
medication in HDPE bottles. Each placebo 
bottle will be labeled in a manner that is 
indistinguishable from the active study 
treatment. 
Abbreviations: HDPE = high-density polyethylene. 
a As provided by the clinical site. 
 
5.2. 
Preparation, Storage, Handling, and Accountability 
The study drug will be supplied by the sponsor (or designee), along with the batch/lot numbers 
and Certificates of Analysis. The study treatment will be provided in opaque white, high-density 
polyethylene bottles with child-resistant closures. The recommended storage conditions, and 
expiry date (wherever required), will be stated on the product label. 
The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study treatments received and any discrepancies are reported and 
resolved before use of the study treatment. 


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All study treatments must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labeled storage conditions with access limited 
to the Investigator and authorized site staff. 
Only patients enrolled in the study may receive study treatment and only authorized site staff 
may supply or administer study treatment while patient is inpatient. The Investigator, institution, 
or the head of the medical institution (where applicable) is responsible for study treatment 
accountability, reconciliation, and record maintenance (ie, receipt, reconciliation, and final 
disposition records). 
Further guidance and information for the final disposition of unused study treatment are provided 
in the Pharmacy Manual. 
5.3. 
Method of Treatment Assignment 
Patients will be assigned a unique code number (randomization number) at Visit 3. The patient 
number will encode the patient’s assignment either to study treatment or to placebo arm of the 
study, according to the randomization schedule generated prior to the study by 
 Each 
patient will be dispensed blinded study treatment or placebo, labeled with his/her unique patient 
number, and traceable to the batch number of the medication. 
5.4. 
Blinding 
The study will be a double-blind, crossover, placebo-controlled, where the patients will receive 
blinded single doses of AUT00201 or matching placebo treatment that is identical in appearance 
and similar in taste and smell. 
The specific blinded treatment to be taken by a patient will be assigned using randomization 
schedule. The study treatment will be dispensed per the randomization schedule by the 
pharmacy. Active and placebo treatments will be labeled such that it is not possible to distinguish 
between them. Unblinding should occur only in the event of medical emergency, given the 
knowledge of the study drug is essential for clinical management or welfare of the patient. In the 
event of emergency unblinding by the Investigator, the sponsor must be informed as soon as 
possible. The date and reason that the blind was broken must be recorded in the source 
documentation and electronic case report form (eCRF), as applicable. Once the study is 
complete, all envelopes (sealed and opened) must be inventoried and returned to the sponsor. 
5.5. 
Treatment Compliance 
Records shall be maintained of the delivery of the study treatment to the study site, the inventory 
at the study site, the use for each patient, and the return to the sponsor or destruction. 
These records shall include dates, quantities, expiry dates, and the unique code numbers assigned 
to the study treatment and study patients. 
The Investigator shall be responsible for ensuring that the records adequately document that the 
patients were provided the doses specified in the protocol and that all study treatment received 


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from the sponsor is reconciled; dates and times of dosing will be recorded and entered in 
patient’s eCRF. 


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6. CONCOMITANT THERAPIES AND OTHER RESTRICTIONS 
6.1. 
Concomitant Therapy 
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the patient is receiving at the time of enrollment or receives 
during the study must be recorded in the eCRF along with: 
• reason for use 
• dates of administration including start and end dates 
• dosage information including dose and frequency. 
Patients must be instructed not to take any new medications or change their current regimen, 
including over-the-counter products, without first consulting with the Investigator. The medical 
monitor should be contacted if there are any questions regarding concomitant or prior therapy. 
Medications that are necessary for the patient’s safety and well-being are permitted at the 
discretion of the Investigator. It is not recommended that patients are withdrawn from any of 
their currently prescribed medications for the study. Data on all concomitant drugs administered, 
doses and duration of concomitant use, and the specific timing of administration relative to the 
administration of AUT00201 or placebo will be captured in the source documents and eCRF 
throughout the study. 
6.2. 
Prohibited Medications 
Patients will refrain from use of any new prescription or nonprescription medications/products 
during the study until the follow-up unless the Investigator (or designee) has given their prior 
consent (with the sole exception for acetaminophen for pain relief). 
The use of any other investigational agents is not allowed during the study. 


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7. STUDY ASSESSMENTS AND PROCEDURES 
Study procedures and their timing are summarized in the Schedule of Assessments (Appendix 4). 
Protocol waivers or exemptions are not allowed, with the exception of mitigating immediate 
safety concerns, if immediate safety concerns are identified, these should be discussed with the 
sponsor immediately upon occurrence or awareness to determine if the patient should continue or 
discontinue the study. Adherence to the study design requirements, including those specified in 
the Schedule of Assessments, is essential and required for study conduct. 
All screening evaluations must be completed and reviewed to confirm that potential patients 
meet all eligibility criteria. The Investigator will maintain a screening log to record details of all 
patients screened and to confirm eligibility or record reasons for screening failure 
(Section 4.4.1), as applicable. Procedures conducted as part of the patient’s routine clinical 
management (eg, blood count) and obtained before signing the informed consent form (ICF) may 
be utilized for screening or baseline purposes provided the procedure met the protocol-specified 
criteria and was performed within the timeframe defined in the Schedule of Assessments. 
With the sponsor’s approval, additional blood sampling timepoints may be introduced, and 
changes to timepoints may be made if there is a scientific reason to believe that the additional 
blood sampling might improve the quality of the data (for example, the scenario, where an 
important effect of the IP is being observed, but no measurements are scheduled for that 
timepoint), or if extra procedures are needed in the interest of the patients’ safety. 
Overall, the maximum amount of blood collected from each patient over the duration of the 
study, including any extra assessments that may be required (for the reasons stated above), will 
not exceed the blood volume collection limitations established by local IRB. Repeat or 
unscheduled samples may be taken for safety reasons or for technical issues with the samples. 
A prescreening telephone questionnaire, approved by the IRB, will be developed to collect basic 
information on the patients before patients visit the site (eg, has their current medication regimen 
been stable for last 90 days?). This will help to reduce the risk of screen failure and also patient 
burden of travelling to the site. 
A pre-study ICF may be used to obtain basic patient identifiers so that patient travel may be 
scheduled prior to the Screening Visit. 
The study-related questionnaires are required to be filled by the patient within the timeframe 
defined in the Schedule of Assessments. Alternatively, where the patient is unable to complete 
due to physical disabilities, caregiver can assist these patients to complete the questionnaires by 
helping to document the responses provided by the patient. 
7.1. 
Safety and Tolerability Assessments 
7.1.1. 
Adverse Events 
Adverse event definitions and assignment of severity and causality are detailed in Appendix 1. 


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Adverse events, based on clinical signs and symptoms and laboratory measurements, will be 
monitored throughout the study, and will be collected from the time the ICF is signed until 
follow-up (end of study) visit. 
Adverse events will be elicited from the patient (or when appropriate, the patient’s legally 
authorized representative) by the study site staff using a nonleading question such as “How are 
you feeling today?” or “Have you had any health concerns since your last visit?” Patients will 
also be encouraged to spontaneously report AEs occurring at any other time during the study. 
The Investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE and remain responsible for following up AEs 
that are serious, considered related to the study treatment or the study, or that caused the patient 
to discontinue the study drug (see Section 4.4.2). 
7.1.2. 
Reporting Serious Adverse Events 
All SAEs, occurring after the signing of the ICF until end of study and regardless of study drug 
relationship, must be entered into the clinical database and the Investigator or delegate must 
report the SAE(s) to the sponsor or designee within 24 hours of obtaining knowledge of the 
event. The SAE should be reported by completing the paper SAE Form, provided in the 
Investigator/delegate site file. The completed, signed, and dated paper SAE Form must, within 
24 hours, be scanned and emailed to: 
. The study site should notify the 
site monitor via phone or email about the submission of the SAE report. 
The SAE Form will collect data surrounding the event (eg, the nature of the symptom[s], time of 
onset in relation to initiation of therapy, duration, intensity, and whether or not therapy was 
interrupted or discontinued). The Investigator’s assessment of the probable cause of the event 
will also be included. In addition, relevant medical history, concomitant medications, laboratory 
and diagnostic tests reports, and procedures as well as all pertinent medical information related 
to the event will also be collected. 
 Patient Safety Solutions (PSS) will forward SAE queries requesting incomplete or 
missing information directly to the Investigator. It is the Investigator’s responsibility to be 
diligent in providing this information back to 
 PSS as soon as it is available. 
The site will follow their institutional requirements for submission of SAEs to their IRB. 
Additional reporting requirements are noted in the Safety Management Plan, if applicable. 
Follow-up of Adverse Events/Serious Adverse Events 
Adverse events/SAEs will be followed up to 30 days or until resolution or stabilization of the 
event, completion of the patient’s participation, or study termination, or the Investigator or 
designee and sponsor agree that follow-up is no longer necessary, whichever occurs first. 
Assessments should be made each day (or more frequently, if necessary) of any changes in the 
severity, the relationship to the study drug intervention required to treat it, and the outcome. 


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Side effects known for AUT00201 are provided in the IB. All AEs will be immediately recorded 
in the source documents. 
7.1.3. 
Pregnancy 
For female patients of childbearing potential, a urine pregnancy test will be performed at Visit 2 
(at time of admission). A patient who tests positive at any time should be immediately 
discontinued from the study. Appropriate contraceptive measures must be adhered to for the 
duration of the study and 180 days (6 months) after their last dose of study medication. 
Although not considered an AE, it is the responsibility of the Investigator or their designee to 
report any pregnancy in a patient or the patient’s sexual partner that occurs during the study. All 
patients who become pregnant must immediately discontinue the study drug and be withdrawn 
from the study. The patient will be followed to completion/termination of the pregnancy. This 
information is important for both drug safety and public health concerns. If a patient or the 
patient’s sexual partner is found to be pregnant after the study treatment was administered, the 
Investigator should report this to the 
 and sponsor immediately and document the 
pregnancy on the Pregnancy Form in the eCRF. 
The Investigator must make every effort to follow the patient or the patient’s sexual partner until 
completion of pregnancy. If the events during the pregnancy and/or outcome of pregnancy (ie, 
complications regarding mother/fetus) meet the criteria for classification of an SAE, the 
Investigator must follow the procedures for reporting SAEs. 
7.2. 
Clinical Laboratory Evaluations 
Laboratory tests during the study will be performed by a local laboratory. Blood and urine 
samples will be collected for clinical laboratory evaluations at the timepoints indicated in the 
Schedule of Assessments (Appendix 4). Clinical laboratory evaluations are listed in Appendix 2. 
Urine will be tested for drugs of abuse according to the laboratory’s standard operating 
procedure (SOP). Tests will include amphetamines, cocaine, opiates, cannabis, barbiturates, 
benzodiazepines. Patients known to abuse drugs or those who test positive at Visit 1 may be 
excluded from the study based on Investigator’s judgment. Additional clinical laboratory 
evaluations will be performed at other times if judged to be clinically appropriate or if the 
ongoing review of the data suggests a more detailed assessment of clinical laboratory safety 
evaluations is required. 
An Investigator (or designee) will perform a clinical assessment of all clinical laboratory data. 
Abnormal/out of range clinically significant laboratory findings (based on Investigator’s 
judgment) will be recorded as AEs and will be flagged for out of reference ranges per site 
standards. 
7.3. 
Vital Signs, Physical Examination, and Other Safety Evaluations 
Sitting and standing blood pressure (BP), sitting pulse rate, respiratory rate, and body 
temperature will be assessed at the timepoints indicated in the Schedule of Assessments 
(Appendix 4). Unscheduled measurement of vital signs may also be performed at other times if 
judged to be clinically appropriate or if the ongoing review of the data suggests a more detailed 


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assessment of vital signs is required. Body temperature, BP, respiratory rate, and pulse rate will 
be measured singly and repeated once if outside the relevant clinical reference ranges. Patients 
must be sitting for at least 5 minutes before BP and pulse rate measurements. 
A full physical examination will be performed at Visits 1 and 2 and a brief or targeted physical 
examination will be performed at Visits 4 and 6 (approximately 24 hours after each IP 
administration) as specified in the Schedule of Assessments (Appendix 4). 
7.3.1. 
Height and Weight 
Height and weight will be obtained at the timepoints specified in the Schedule of Assessments 
(Appendix 4). If height cannot be reliably obtained, the measure length of forearm (ulna) from 
the point of the elbow (olecranon process) and the midpoint of the prominent bone of the wrist 
(styloid process) will be used to predict height. This procedure will be described in the study 
manual. 
7.3.2. 
Electrocardiogram 
The 12-lead ECGs will be obtained at the timepoints specified in the Schedule of Assessments 
(Appendix 4). 
7.3.3. 
Columbia-Suicide Severity Rating Scale 
The C-SSRS will be administered at the timepoints specified in the Schedule of Assessments 
(Appendix 4). The C-SSRS is a clinician-rated instrument that captures the occurrence, severity, 
and frequency of suicidal ideation and/or behavior during the assessment period. The scale 
includes suggested questions to solicit the type of information needed to determine if suicidal 
ideation and/or behavior occurred. During study, the C-SSRS interview format will be 
administered by trained site staff. The C-SSRS will monitor for any changes in suicide ideation 
and/or behavior in patients participating in this trial of a centrally-acting drug. Patients that 
exhibit suicide ideations and/or behaviors as assessed by C-SSRS or otherwise clinically should 
be referred for immediate evaluation and treatment per investigational site procedures. The 
screening C-SSRS will be used at Visit 1, and the since last visit C-SSRS will be used at all other 
timepoints. 
7.4. 
Pharmacokinetic Analysis 
A blood sample for the determination of AUT00201 plasma concentrations will be collected at 
the timepoints specified in the Schedule of Assessments (Appendix 4). 
A central laboratory will measure the plasma concentrations of AUT00201. Derivation of PK 
parameters will be performed at the end of study. Actual times will be used to derive PK 
parameters. Missing data will not be imputed. For calculation of all PK parameters, and for 
individual concentration-time plots, plasma concentrations below the limit of quantification of 
the assay (BLQ) will be treated as follows: values that occur before tmax will be taken as zero; all 
other values will be taken as missing. For calculation of plasma concentration summary 
statistics, BLQ values will be taken as zero, unless they fall between 2 quantifiable 
concentrations, in which case they will be treated as missing. 




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Text 
Symbol/Abbreviation 
Definition 
Calculation 
MRT 
Mean Residence Time 
The mean residence time will be calculated using: 
MRT = AUMC 
AUC∞ 
Instructions for collection, handling, processing, storage, and shipment of PK samples will be 
included in the laboratory manual. 
Concentrations of antiepileptic drugs (AEDs) may be determined, from the samples collected: 
predose/postdose on Visit 3 and Visit 5. The testing will be performed, if there is a commercially 
available analytical test procedure (anticipated current AEDs include: valproate, topiramate, 
zonisamide, clonazepam, levetiracetam, acetazolamide, perampanel, brivaracetam). 
7.5. 
Biomarker Assessments 
7.5.1. 
Cortical Inhibition as Assessed with Paired-Pulse TMS EMG 
• SICI 
• LICI 
Paired-pulse TMS allows measurement of cortical inhibitory circuit functions. In paired-pulse 
TMS protocols, 2 consecutive pulses are delivered to the hand motor region at a fixed 
interstimulus interval (ISI) such that the motor-evoked potential, captured by surface EMG 
sensors, resultant from the second (test) stimulus is modulated by an antecedent (conditioning) 
stimulus. Depending on stimulus intensity and the ISI, paired-pulse TMS can reveal the 
magnitude of regional inhibitory signaling strength. A tracking threshold approach will be used 
to assess intracortical inhibition as it has been shown to have better reliability than the classical 
approach. 
SICI will be elicited with a conditioning stimulus (CS) and interstimulus interval of 1, 2.5, and 
3 ms; LICI will be elicited with a CS that precedes the test stimulus by 100 or 200 ms. SICI at 
1 ms is considered to reflect “ambient” GABAergic, that is inhibitory tone, SICI at 2 to 3 ms is 
considered to reflect GABAA-mediated inhibition whereas LICI is thought to reflect 
GABAB-mediated inhibition. It is expected that patients with MEAK will show reduced SICI at 
all ISIs and possibly also alterations in LICI. 
The exact duration and timings of the paired-pulse TMS assessments will be described in a study 
manual. The initial assessment will be timed to coincide with the anticipated tmax, between 
2 to 4 hours postdose, and will be conducted at Visits 2, 3, 4, 5, and 6 at corresponding times. A 
second assessment will be conducted approximately 6 hours postdose, at Visits 3 and 5. TMS is a 
noninvasive procedure. The risks associated with paired-pulse TMS are very low.32 
7.5.2. 
Changes in Myoclonus as Assessed by EMG and Accelerometer Data 
Surface EMG and accelerometry can provide valuable information about the nature and the 
source of symptoms (eg, tremor and myoclonus) in movement disorders. Surface EMG shows 
the pattern of a single myoclonus discharge, the rhythmicity of consecutive myoclonus 


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discharges, and the spread of myoclonus among different muscles. Accelerometry measures the 
amplitude and frequency of myoclonus. At rest, positive myoclonus occurs in EMG as a burst of 
brief (duration of around 100 ms) myoclonic potentials that may occur synchronously in agonist 
and antagonist muscles. During muscle contraction, it occurs as a brief (duration 50 to 100 ms) 
suppression of muscle activity.33 This is referred to as ‘positive myoclonus’. However, patients 
can also experience short periods of loss of muscle tone. This is referred to as a ‘negative 
myoclonus’. 
The successful development of wearable sensors has enabled continuous objective measurement 
of physiological signals, movement, and physical activity during daily activities in patients 
suffering from both positive and negative myoclonus. The specific method used in this study has 
been validated in patients with progressive myoclonic epilepsy type 1 (EPM1, Unverricht– 
Lundborg disease; caused by a mutation in the CSTB gene).33 
Patients will wear the wireless device(s) whilst inpatient; the exact number, placement of the 
devices, timing, and duration will be described in the EMG and accelerometer manual but it is 
anticipated that 1 sensor will be worn on each arm from Visit 2 through Visit 6. The devices will 
remain on the patient for the duration of the inpatient portion of the study, except when they are 
charged each evening; patients will be able to complete all daily activities and the devices can be 
removed during showering. The long-term data capture will enable evaluation of the fluctuation 
of myoclonus over the day. 
The patients will also wear the devices whilst completing the UMRS Sections 4 and 5 
assessments and UMRS Section 4: D and E action- induced myoclonus/arm movement 
assessments (see Section 7.5.3). The EMG and accelerometer recordings are noninvasive and are 
not associated with any risks. 
7.5.3. 
Action-induced Myoclonus 
The patients’ predominant symptom is an action-induced myoclonus (“positive myoclonus”). To 
ensure assessment of this symptom over the duration of the study, the patients will need to be 
active at regular intervals. At specified timepoints, as per the Schedule of Assessments 
(Appendix 4) and the study manual, the patient will be asked to complete a set of movements of 
their arms in accordance with the UMRS action myoclonus Section 4: Parts D and E. The study 
staff will provide instructions to the patients. The time and duration of the test will be noted. 
These assessments will also be videoed for centralized clinical assessment. 
7.5.4. 
Unified Myoclonus Rating Scale 
The UMRS is a quantitative 73-item clinical rating instrument developed to evaluate myoclonus 
and response, of patients with myoclonus, to antimyoclonic therapy. 
The scale consists of 8 sections.34 
• Section 1 – patient questionnaire completed by the patient (help to document the answer 
may be provided by caregiver) (11 items) 
• Section 2 – myoclonus at rest (frequency and amplitude, 16 items) 


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• Section 3 – assesses stimulus sensitivity of myoclonus (17 items) 
• Section 4 – severity of myoclonus with action (frequency and amplitude, 20 items) 
• Section 5 – assess performance on functional tests (5 items) 
• Section 6 – physician rating of patient’s global disability (1 item) 
• Section 7 – presence of negative myoclonus (1 item) 
• Section 8 – severity of negative myoclonus (1 item). 
Each item is rated on a scale of 0 to 4, except for section 3 (where stimulus sensitivity is either 
present [score 1] or absent [score 0]), section 7 (negative myoclonus present [score 1] or absent 
[score 0]), and section 8 (scores: 0 to 3). 
Total scores for sections 1, 3, 5, 6, 7, and 8 of the UMRS are calculated by simple addition. The 
maximum scores for these sections are 44, 17, 28, 4, 1, and 3, respectively. Sections 2 and 4 
include ratings of frequency and amplitude of myoclonic jerks affecting each body region. The 
scores of these sections are calculated by multiplying frequency by amplitude scores for each 
body region. The maximum score for sections 2 and 4 are 128 and 160, respectively. 
In this study, only the UMRS Sections 4 and 5 will be evaluated at Visit 2 (baseline) and Visits 3 
and 5. Change from baseline in UMRS subscore Sections 4 and 5 will be an exploratory 
endpoint. Additional assessment of the non-dominant arm has been added to the standard UMRS 
Section 5 to obtain a more complete data set. The UMRS is the most widely used standardized 
assessment of myoclonus and is appropriate in this patient population as a measure of the action- 
induced myoclonus symptom associated with MEAK. It is unknown whether the sensitivity of 
this measure will allow for an effect to be detected in an acute dose study, but completion of the 
UMRS will allow for a robust and standardized assessment to complete with the EMG and 
accelerometer device recoding myoclonus and allow for characterizing data to be collected in 
anticipation of repeat dose studies in this population. 
The UMRS will be conducted while the patients are wearing the EMG- accelerometer device. 
This provides a structured set of activities that will produce action-induced myoclonus and ataxia 
that can be measured clinically via UMRS scoring and objectively using the EMG and 
accelerometer data. The UMRS assessment will be videoed by trained study staff, as per the 
videography instructions provided in the original paper by Frucht et al. The videos will not be 
blurred to obscure patients’ faces as this will compromise the ability for centralized/independent 
rating of the videoed assessment. 
7.5.5. 
Measure of Ataxic Dysarthria: Speech and Vocal Tests 
Speech analysis has been clinically and technically validated to assess motor, respiratory, and 
cognitive symptomatology associated with a number of neuropsychiatric disorders. In particular, 
speech analysis can pick up subtle signs of dysarthria – a common sign in patients with MEAK 
who show ataxic dysarthria due to cerebellar dysfunction and characterized by an abnormality in 
speech articulation and prosody (also referred to as cerebellar ‘scanning’ speech). 


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A battery of speech tests will be utilized to assess patients’ speech and derive specific measures 
of dysarthria. These tests will include: Sentence Reading (2 minutes), Diadochokinetic Rate 
(DDK) (<1 minute), Picture Description (1 minute), and Sustained Phonation (<1 minute). A full 
description of the assessments will be included in the manual. These assessments are not 
associated with any risks. 
Speech tests will be conducted at Visit 2 (baseline) and Visits 3, 4, 5, and 6. The patient’s native 
language, including country of origin (eg, English – USA), will be captured as part of patient’s 
demographics. 
7.5.6. 
Measures of Early Visual Processing 
The measures of early visual processing will include tests of binocular rivalry (10 minutes) and 
internal noise estimation (15 minutes). The performance of these tasks is assumed to depend on 
proper inhibitory interneuron functioning in visual cortex. 
Measures of visual processing will be conducted on Visit 2 (baseline) and Visits 3 and 5. Full 
details will be included in a separate manual. The tests will be administered through a virtual 
reality headset. All responses from the patient will be verbal and will be entered on a laptop by 
trained study staff. It is possible that patients may experience some motion sickness while using 
the virtual reality headset, the likelihood is considered low but patients can stop the test at any 
time if it is not tolerated. 
7.5.7. 
Measures of Auditory Processing: Audiology Tests 
Otoacoustic Emissions 
The OAEs are recordable sounds generated by the inner ear when tones are played to the ears of 
the patient. OAEs assess the functioning of the medial olivocochlear (MOC) efferent system and 
bilateral connections between the 2 ears which rely on fast neuronal relays that express Kv3.1 
and Kv3.3 channels. The MOC branch of the auditory efferent system consists of fibers that 
predominately project from the medial superior olive to synapse on the outer hair cells of the 
opposite cochlea. This auditory efferent system modifies peripheral hearing function to improve 
sound detection in noise and to protect the periphery from acoustic trauma. 
When OAEs are recorded, no response from the patient is required and they will sit quietly while 
tones are played to their ears. The OAEs will be collected for each ear.35 There are no known 
risks for OAEs and the process is well tolerated. 
The OAEs will be assessed on Visit 2 (baseline) and Visits 3 and 5. 
Words-in-Noise (WIN) Test Performance 
The WIN test was developed as an instrument to quantify the ability of listeners to recognize 
monosyllabic words in background noise36 It provides a quantified measurement of auditory 
processing by determining the SNR needed for speech perception and is a measure of the ability 
of cortical circuits to separate relevant from irrelevant information. There is evidence that 
inhibitory interneurons play a critical part in this function. 


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The WIN test involves the presentation of target words in a background of multi-talker babble 
set at SNRs from 24- to 0-dB in 4-dB decrements. The patient will have to repeat the word that 
they hear back to the trained study staff. The outcome measure is the SNR at which 50% of 
words can be correctly identified as calculated using the Spearman-Kärber equation. 
In a previous study, treatment with a related compound (AUT00206) led to an improved ability 
of patients with schizophrenia to perform this task; that is, they were able to recognize words at 
more difficult listening levels (ie, lower SNRs). 
The WIN test will be assessed during Visit 2 (baseline) and Visits 3 and 5. 
7.5.8. 
Electroencephalogram during Resting State and Presentation of Chirp Stimuli 
The EEG will be recorded at resting state and during the presentation of an auditory chirp 
stimulus. About 300 chirp stimuli will be presented separated by an intertrial interval randomly 
jittered between 1500 and 2000 ms. Induced and evoked power and intertrial phase synchrony 
will be evaluated over all frequency bands. Nonclinical studies in rodents and pharmacological 
challenge studies in healthy volunteers have provided convincing evidence that dysfunction of 
PV interneurons affects both resting state as well as stimulus induced and evoked gamma 
oscillations (power and phase synchrony) with an increase of power of resting state gamma but a 
decrease of power in the stimulus induced and evoked gamma oscillations and reduced phase 
synchrony. 
It is expected that patients with MEAK will show such changes, ie, increased power in resting 
state gamma but deficits in evoked and induced gamma frequency during the presentation of the 
chirp stimulus in both power and phase synchrony. Treatment with AUT00201 is expected to 
normalize such abnormalities. 
EEG recordings are noninvasive and are not associated with any risks. 
A resting state EEG recoding will be conducted on Visit 2 (baseline) and Visits 3 and 5. 
7.5.9. 
Clinician and Patient Impressions of Treatment 
The clinician and the patient will be asked (separately) if they believe they received active or 
placebo treatment at Visits 4 and 6 (24 hours ±2 hours after each dose) and if they perceived any 
change in their condition. 
7.6. 
Demographic Data 
The following demographic data will be collected: year of birth and age (in years) at baseline, 
gender, race, ethnicity, height, weight, body mass index, dominant arm, whether they have a 
vagal nerve stimulator, whether they follow a ketogenic diet, native language (specified by 
country of origin [eg, English – USA]), and for females only, start date of last menstrual cycle 
and normal cycle length (in days). 


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7.6.1. 
Medical History 
The patient’s relevant medical history will be collected. The patient will be asked specifically 
regarding their history of seizures, headaches/migraines, and episodes of dizziness. They will 
also be asked regarding their history of fever and if they/their caregiver had any impression of an 
improvement of MEAK symptoms during the fever. 
7.6.2. 
Patient-reported Outcome Measurement - Ataxia 
The patient-reported outcome measurement (PROM) of ataxia is a valid and reliable measure of 
motor ataxia, quality of life, and mental health.36 It is a 70-item questionnaire completed on a 
5-point Likert scale. It will be evaluated on Visit 1 (Screening). 
7.6.3. 
Patient Top 3 Concerns 
Patients will be asked at Visit 1 (Screening) to give their top 3 concerns regarding their condition 
and functioning in their daily life. They will be then asked to score the severity of the concern on 
a 7-point Likert scale. 


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8. SAMPLE SIZE AND DATA ANALYSES 
All statistical analysis will conform to the relevant International Council for Harmonisation 
(ICH) requirements, including but not limited to those set out in ICH documents E3 and E9. 
Statistical Analysis Software (SAS) version 9.2 or later will be used for the analysis. 
A detailed Statistical Analysis Plan (SAP) will be finalized prior to database lock and data 
unblinding. The SAP will document all analyses procedures. 
8.1. 
Sample Size Determination 
MEAK is an ultra-rare disorder. This study will aim to include all adult patients with MEAK 
known to the Principal Investigator and sub-investigator(s). It is hoped that approximately 
6 to 10 patients can be recruited. 
Therefore, a formal power analysis to estimate a desired sample size is not useful. Primary 
endpoint is safety and tolerability of AUT00201. Nonetheless, a sample size of 8 provides an 
80% power to detect an effect size of approximately 0.8 in a paired sample t-test at a one-sided 
alpha level of 0.1 (as will be used for the primary outcome measure, the composite response 
score). 
8.2. 
Analysis Populations 
The following analysis populations will be included for this study: 
Safety Population: All patients who received at least 1 dose of IP. 
Pharmacokinetic Concentration Population: All patients who received at least 1 dose of IP 
with at least 1 quantifiable PK concentration at any scheduled PK timepoint. 
Pharmacokinetic Parameter Population: All patients in the PK Concentration Population for 
whom PK parameters can be derived. Further details will be provided in the SAP. 
Pharmacodynamic Population: All patients in the Safety Population who have an evaluable 
baseline and at least 1 evaluable postbaseline measurement for at least 1 PD parameter. 
In all populations, patients will be analyzed according to treatment actually received during the 
specific treatment period (before and after the crossover) regardless of the treatment to which 
they were randomized. 
8.3. 
General Considerations 
Standard summary statistics for continuous baseline and outcome variables are: N, mean, 
standard deviation (SD), median, quartiles, minimum, and maximum, and 95% confidence 
intervals (CIs) at baseline and each timepoint at which the measures are obtained. In addition, the 
same descriptive statistics will be obtained for change from baseline for each timepoint at which 
the measures are obtained. The standard summary statistics for categorical baseline and outcome 


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variables are: count and proportion (expressed as percentage). Geometric mean and coefficient of 
variation will also be presented for PK concentrations and the PK parameters. 
The minimum and maximum values will be presented to the same number of decimal places as 
the raw data collected on the eCRF (or to 3 significant figures for derived parameters). The 
mean, median, and percentiles (eg, Q1 and Q3) will be presented to one additional decimal place. 
The SD and standard error will be presented to 2 additional decimal places. 
In general, baseline will be defined as the last measurement obtained before IP administration. 
However, if review of blinded data indicates a stability of the measurement on days when 
patients do not receive treatment, baseline may also be defined as the average across Visits 2 
and 4. This will be described in the SAP. 
All summaries will be presented by treatment group unless otherwise specified. Summary tables 
and figures will be supported by full patient listings in each treatment period. 
8.4. 
Disposition of Patients 
The disposition of all patients in the safety population will be summarized including: number of 
patients randomized, number completing the study and by treatment, and number discontinued 
from the study. 
8.5. 
Demographic and Baseline Characteristics 
Demographic and other baseline characteristics will be presented overall using descriptive 
statistics for continuous and categorical data. 
8.6. 
Medical History and Prior/Concomitant Medication 
Medical history records will be summarized overall using descriptive statistics by system organ 
class (SOC) and preferred term (PT). 
Prior or concomitant medications will be summarized separately using descriptive statistics for 
continuous and categorical data. 
8.7. 
Safety Analysis 
Summaries and listings of safety data will use the safety population. 
8.7.1. 
Adverse Events 
Adverse events will be coded using the version of the Medical Dictionary for Regulatory 
Activities (MedDRA) current at the time of database lock. All AEs will be listed. The number of 
patients with at least 1 TEAE will be tabulated by actual treatment and MedDRA SOC and PT. 


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For each of the following, the number of patients with AEs will be summarized by treatment as 
follows: 
• TEAEs by SOC and PT 
• Drug-related TEAEs by SOC and PT. 
Patients with one or more TEAE will be counted only once, at the maximum causality, for each 
SOC and PT. AEs with missing severity and/or causality will be treated as severe and possibly 
related, respectively. Adverse events leading to withdrawal, deaths, and SAEs will be listed 
separately (fatal events will be listed separately from nonfatal events). 
8.7.2. 
Clinical Laboratory Evaluations 
Data from hematology and clinical biochemistry will be summarized by treatment. Any 
laboratory value outside the reference interval for that variable will be flagged per Site’s standard 
process. 
8.7.3. 
Other Safety Measures 
Vital signs at each planned assessment, and change in vital signs from baseline at each planned 
postbaseline assessment, will be summarized by treatment. Vital signs of potential clinical 
importance will be listed separately. 
ECG variables will be summarized by treatment. Changes from Screening will be summarized 
by treatment. QT interval will be corrected using Bazett’s (QTcB) formula. QT or QTcB 
>450 ms and increases in QT or QTcB from Screening (Visit 1) of >30 ms will be considered to 
be potentially clinically important. 
Abnormal physical examination findings considered clinically significant by the Investigator will 
be listed. 
8.8. 
Secondary Analysis 
Descriptive statistics will be provided for the paired-pulse TMS outcome measures, measures of 
dysarthria and MI. If indicated, outcome measures will be evaluated using paired t-tests, repeated 
measures analysis of covariance, and McNemar tests or an alternative test for non-binary 
categorical data, if applicable, for change from baseline of continuous and categorical data. 
The overall effect of AUT00201 on secondary and selected exploratory outcome measures will 
be evaluated with the help of a predefined response matrix. This approach should guard against 
‘cherry picking’ as well as missing a weak but potentially relevant treatment effect. 
Details will be provided in the SAP. 
8.9. 
Pharmacokinetic Analysis 
Plasma concentrations and PK parameters will be listed and summarized, by treatment, using 
descriptive statistics, including: N (number of patients receiving the treatment in the population), 


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n (number of observations), arithmetic mean, median, minimum, maximum, SD, % coefficient of 
variation and the 95% CI of the arithmetic mean. For log-transformed variables, all of the above 
plus the geometric mean, its 95% CI, and the SD of the log-transformed variables will be 
provided. 
Plasma concentrations and PK parameters will be listed and summarized, by treatment, using 
descriptive statistics. Individual and mean (±SD) plasma concentration-time profiles will be 
presented graphically. All available data will be used to derive PK parameters in individual 
patients. 
Individual and mean (±SD) plasma concentration-time profiles will be presented graphically. All 
available plasma concentrations will be used to derive PK parameters in individual patients. 
Plasma concentrations for AEDs for which assays are commercially available at the sponsor’s 
chosen bioanalytical laboratory will be listed only. 
8.10. Exploratory Analysis 
Descriptive statistics will be provided for all exploratory measures. If indicated, exploratory 
outcome measures will be evaluated using paired t-tests, repeated measures analysis of 
covariance and McNemar tests, or an alternative test for non-binary categorical data, if 
applicable, for change from baseline of continuous and categorical (ie, nominal data). Details 
will be provided in the SAP. 
A response matrix will be used to assess the overall effect of AUT00201 on signs and symptoms 
of MEAK. A response matrix will guard against ‘cherry picking’ of results but ensure the 
detection of a clinically meaningful signal. Details will be provided in a separate SAP. 
8.11. Interim Analysis 
No planned interim analysis. 


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as a tool to understand genetic conditions associated with epilepsy. Epilepsia. 
2020;61(9):1818-1839. doi:10.1111/epi.16634 
25. Peixoto Pinheiro B, Vona B, Löwenheim H, Rüttiger L, Knipper M, Adel Y. Age-related 
hearing loss pertaining to potassium ion channels in the cochlea and auditory pathway. 
Pflugers Arch. 2021;473(5):823-840. doi:10.1007/s00424-020-02496-w 
26. Middlebrooks JC, Nick HS, Subramony SH, et al. Mutation in the Kv3.3 Voltage-Gated 
Potassium Channel Causing Spinocerebellar Ataxia 13 Disrupts Sound-Localization 
Mechanisms. PLOS ONE. 2013;8(10):e76749. doi:10.1371/journal.pone.0076749 
27. Badawy RAB, Macdonell RAL, Jackson GD, Berkovic SF. Can changes in cortical 
excitability distinguish progressive from juvenile myoclonic epilepsy? Epilepsia. 
2010;51(10):2084-2088. doi:10.1111/j.1528-1167.2010.02557.x 
28. Shaw AD, Knight L, Freeman TCA, et al. Oscillatory, Computational, and Behavioral 
Evidence for Impaired GABAergic Inhibition in Schizophrenia. Schizophr Bull. 
2020;46(2):345-353. doi:10.1093/schbul/sbz066 
29. Silverstein SM, Demmin DL, Bednar JA. Computational Modeling of Contrast Sensitivity 
and Orientation Tuning in First-Episode and Chronic Schizophrenia. Comput Psychiatry 
Camb Mass. 2017;1:102-131. doi:10.1162/CPSY_a_00005 


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30. Valzania F, Strafella AP, Tropeani A, Rubboli G, Nassetti SA, Tassinari CA. Facilitation of 
rhythmic events in progressive myoclonus epilepsy: a transcranial magnetic stimulation 
study. Clin Neurophysiol. 1999;110(1):152-157. doi:10.1016/S0013-4694(98)00115-1 
31. Holmes GL. Drug Treatment of Progressive Myoclonic Epilepsy. Paediatr Drugs. 
2020;22(2):149-164. doi:10.1007/s40272-019-00378-y 
32. Tsuboyama M, Lee Kaye H, Rotenberg A. Biomarkers Obtained by Transcranial Magnetic 
Stimulation of the Motor Cortex in Epilepsy. Front Integr Neurosci. 2019;13. Accessed 
September 15, 2022. https://www.frontiersin.org/articles/10.3389/fnint.2019.00057 
33. Rissanen SM, Hyppönen J, Silvennoinen K, et al. Wearable monitoring of positive and 
negative myoclonus in progressive myoclonic epilepsy type 1. Clin Neurophysiol. 
2021;132(10):2464-2472. doi:10.1016/j.clinph.2021.06.026 
34. The Unified Myoclonus Rating Scale - PubMed. Accessed May 11, 2022. 
https://pubmed.ncbi.nlm.nih.gov/11968461/ 
35. Mertes IB, Leek MR. Concurrent measures of contralateral suppression of transient-evoked 
otoacoustic emissions and of auditory steady-state responses. J Acoust Soc Am. 
2016;140(3):2027. doi:10.1121/1.4962666 
36. Wilson RH, Carnell CS, Cleghorn AL. The Words-in-Noise (WIN) test with multitalker 
babble and speech-spectrum noise maskers. J Am Acad Audiol. 2007;18(6):522-529. 
doi:10.3766/jaaa.18.6.7 
37. Schmahmann JD, Pierce S, MacMore J, L’Italien GJ. Development and Validation of a 
Patient-Reported Outcome Measure of Ataxia. Mov Disord Off J Mov Disord Soc. 
2021;36(10):2367-2377. doi:10.1002/mds.28670 


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10. APPENDICES 
Appendix 1 – Adverse Event Definitions 
Definitions 
An adverse event (AE) is any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related. This includes the following: 
• Any clinically significant worsening of a pre-existing condition. 
• Note: Emergence of a new pathogen associated with a clinical event during therapy at a 
site other than the initial site of infection will be considered to be an AE. 
• Any recurrence of a pre-existing condition. 
• An AE occurring from overdose of a sponsor study drug whether accidental or intentional 
(ie, a dose higher than that prescribed by a health care professional for clinical reasons). 
• An AE occurring from abuse of a sponsor study drug (ie, use for nonclinical reasons). 
• An AE that has been associated with the discontinuation of the use of a sponsor study 
drug. 
Note: A procedure is not an AE, but the reason for a procedure may be an AE. 
A pre-existing condition is a clinical condition (including a condition being treated) that is 
diagnosed before the patient signs the informed consent form (ICF) and diagnosed prior to or at 
the latest during screening procedure. These medical occurrences should be documented as part 
of the patient’s medical history. 
The questions concerning whether the condition existed before the start of the active phase of the 
study and whether it has increased in severity and/or frequency will be used to determine 
whether an event is a treatment-emergent adverse event (TEAE). An AE is considered to be 
treatment-emergent if (1) it is not present when the active phase of the study begins and is not a 
chronic condition that is part of the patient’s medical history, or (2) it is present at the start of the 
active phase of the study or as part of the patient’s medical history, but the severity or frequency 
increases during the active phase. The active phase of the study begins at the time of the first 
dose of the study drug. The active phase of the study ends at the follow-up visit. 
Reporting of Adverse Events 
At each visit, the Investigator, or delegate, will determine whether or not any AEs have occurred. 
Nonleading questions such as “How are you feeling today?” or “Have you had any health 
concerns since your last visit?” should be used to elicit the patient to report any possible AEs. 
Independently from the time of the next visit, the patient can revisit the Investigator in case of an 
AE. If any AEs have occurred, they will be recorded in the AE section of the electronic case 
report form (eCRF) and in the patient’s source documents. If known, the diagnosis should be 
recorded, in preference to listing the individual signs and symptoms. 


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Adverse event reporting begins from the time of informed consent and ends at follow-up (end of 
study) visit. 
Assessment of Severity 
The Investigator will be asked to provide an assessment of the severity of the AE using the 
following categories: 
• Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated 
• Grade 2: Moderate; minimal, local, or noninvasive intervention indicated; limiting age- 
appropriate instrumental activities of daily living 
• Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
activities of daily living 
• Grade 4: Life-threatening consequences; urgent intervention indicated 
• Grade 5: Death related to AE. 
Relationship to Study Treatment 
The Investigator will make a determination of the relationship of the AE to the study drug using 
a four-category system according to the following guidelines: 
• Not related: when the AE is definitely caused by the patient’s clinical state, or the study 
procedure/conditions. 
• Unlikely Related: when the temporal association between the AE and the drug is such 
that the drug is not likely to have any reasonable association with the AE. 
• Possibly Related: when the AE follows a reasonable temporal sequence from the time of 
drug administration but could have been produced by the patient’s clinical state or the 
study procedures/conditions. 
• Related: when the AE follows a reasonable temporal sequence from administration of the 
drug, abates upon discontinuation of the drug, follows a known or hypothesized cause- 
effect relationship, and (if appropriate) reappears when the drug is reintroduced. 
Action Taken for Adverse Events 
The Investigator or designee will record the action taken for the AE in the eCRF. Actions taken 
will include: 
• Patient withdrawn: The medication schedule was modified through termination of the 
prescribed regimen of medication and the patient was withdrawn from the study. 
• No action taken. 


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Follow-up of Adverse Events 
All (Serious)AEs that are ongoing at the time of discontinuation, or that develop prior to the final 
Follow-up Telephone Call, will be followed for 30 days, or until resolution or stabilization. 
Adverse Drug Reactions 
All noxious and unintended responses to an investigational product (IP) (ie, where a causal 
relationship between an IP and an AE is at least a reasonable possibility) related to any dose 
should be considered adverse drug reactions. 
For marketed medicinal products, a response to a drug which is noxious and unintended and 
which occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of diseases or 
for modification of physiological function, is to be considered an adverse drug reaction. 
An unexpected adverse drug reaction is defined as an adverse reaction, the nature or severity of 
which is not consistent with the applicable product information (eg, Investigator’s Brochure [IB] 
for an unapproved IP). 
Serious Adverse Events 
An SAE is any AE occurring at any dose that meets 1 or more of the following criteria: 
• Results in death 
• Is life-threatening (see below) 
• Requires patient hospitalization or prolongation of an existing hospitalization (see below) 
• Results in a persistent or significant disability or incapacity (see below) 
• Results in a congenital anomaly or birth defect 
• Results in an important medical event (see below). 
Additionally, important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered SAEs when, based on appropriate medical judgment, 
they may jeopardize the patient and may require medical or surgical intervention to prevent one 
of the outcomes listed above. Examples of such events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do 
not require hospitalization, or development of drug dependency or drug abuse. 
A life-threatening adverse event is any AE that places the patient at immediate risk of death 
from the event as it occurred. A life-threatening event does not include an event that might have 
caused death had it occurred in a more severe form but that did not create an immediate risk of 
death as it actually occurred. For example, drug-induced hepatitis that resolved without evidence 
of hepatic failure would not be considered life-threatening, even though drug-induced hepatitis 
of a more severe nature can be fatal. Hospitalization is to be considered only as an overnight 
admission. 


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Hospitalization or prolongation of a hospitalization is a criterion for considering an AE to be 
serious. In the absence of an AE, the participating Investigator should not report hospitalization 
or prolongation of hospitalization. This is the case in the following situations: 
• Hospitalization or prolongation of hospitalization is needed for a procedure required by 
the protocol. Day or night survey visits for biopsy or surgery required by the protocol are 
not considered serious. 
• Hospitalization or prolongation of hospitalization is part of a routine procedure followed 
by the study center (eg, stent removal after surgery). This should be recorded in the study 
file. 
• Hospitalization for survey visits or annual physicals fall in the same category. 
In addition, a hospitalization planned before the start of the study for a pre-existing condition that 
has not worsened does not constitute an SAE (eg, elective hospitalization for a total knee 
replacement due to a pre-existing condition of osteoarthritis of the knee that has not worsened 
during the study). 
Disability is defined as a substantial disruption in a person’s ability to conduct normal life 
functions (ie, the AE resulted in a significant, persistent, or permanent change, impairment, 
damage, or disruption in the patient’s bodily function/structure, physical activities, or quality of 
life). 
Medical and scientific judgment should be exercised in deciding whether a case is serious in 
those situations where important medical events may not be immediately life-threatening or 
result in death, hospitalization, disability, or incapacity. These include events that may jeopardize 
the patient or may require medical intervention to prevent 1 or more outcomes listed in the 
definition of serious. Such events should usually be considered as serious. 


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Appendix 2 – Clinical Laboratory Evaluations 
The following clinical laboratory analytes will be assessed during the study at the visits as 
defined in the Schedule of Assessments (Appendix 4). Instructions on sample collection, 
processing, storage, packaging, and shipping will be provided in the laboratory manual. 
Urine will be tested for drugs of abuse according to the laboratory’s SOP. Tests will include 
amphetamines, cocaine, opiates, cannabis, barbiturate, and benzodiazepines. Patients known to 
abuse drugs or those who test positive at Screening will be excluded from the study based on 
Investigator’s judgment. 
 
Biochemistry: 
Hematology (CBC): 
Albumin 
Hematocrit 
ALP 
Hemoglobin 
ALT 
MCH 
AST 
MCHC 
BUN 
MCV 
Calcium 
Platelet count 
Chloride 
RBC count 
Cholesterol 
WBC count 
Creatinine 
WBC differential 
GGT 
(% & Abs): 
Globulin 
Basophils 
Glucose 
Eosinophils 
LDH 
Lymphocytes 
Phosphate 
Monocytes 
Potassium 
Neutrophils 
Sodium 
Total Bilirubin 
Total Protein 
For Women Only: 
Triglycerides 
Urine Pregnancy Test 
Uric acid 
Serology (Screening only): 
Complete Urinalysis: Dipstick 
Hepatitis B (hepatitis B surface antigen) 
Color and appearance 
Hepatitis C antibody 
pH and specific gravity 
Bilirubin 
Urobilinogen 
Glucose 
Ketones 
Hormone Panel: 
Leukocyte esterase 
TSH 
Nitrite 
Free triiodothyronine (T3) 
Blood 
Free thyroxine (T4) 
Protein 
FSH 
Microscopica 
Abbreviations: Abs = absolute; ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
BUN = blood urea nitrogen; CBC = complete blood count; FSH = follicle-stimulating hormone; GGT = gamma glutamyl 
transferase; LDH = lactate dehydrogenase; MCH = mean corpuscular hemoglobin; MCHC = mean corpuscular hemoglobin 
concentration; MCV = mean corpuscular volume; RBC = red blood cell; TSH = thyroid-stimulating hormone; WBC = white 
blood cell. 
a Only if dipstick test for protein, blood, leukocyte esterase, or nitrites is abnormal. 


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Appendix 3 – Regulatory, Ethical, and Study Oversight Considerations 
Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with the following: 
• Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
International Ethical Guidelines 
• Applicable ICH Good Clinical Practice (GCP) Guidelines 
• Applicable laws and regulations. 
The protocol, protocol amendments, informed consent form (ICF), Investigator’s Brochure, and 
other relevant documents (eg, advertisements) must be submitted to an Institutional Review 
Board (IRB) by the Investigator and reviewed and approved by the IRB before the study is 
initiated. 
• Any amendments to the protocol will require IRB approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an 
immediate hazard to study participants. 
• In case of nonsubstantial protocol amendments which do not require Competent 
Authority’s and/or IRB approval, the reasoning should be documented, referenced with 
applicable laws and regulations (if any), and signed by the responsible managers. 
The Investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the IRB annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB 
• Notifying the IRB of serious adverse event (SAEs) or other significant safety findings as 
required by IRB procedures 
• Providing oversight of the conduct of the study at the site and adherence to requirements 
of 21 Code of Federal Regulations (CFR), ICH guidelines, the IRB, and all other 
applicable local regulations. 
Finances and Insurance 
Financing and insurance will be addressed in a separate agreement. 
Informed Consent 
Prior to starting participation in the study, each patient or his/her legally authorized 
representative will be provided with a study-specific ICF giving details of the study drugs, 
procedures, and potential risks of the study. Patients on his/her legally authorized representative 
will be instructed that they are free to obtain further information from the Investigator (or 


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designee) and that their participation is voluntary and they are free to withdraw from the study at 
any time. Patients or his/her legally authorized representative will be given an opportunity to ask 
questions about the study prior to providing consent for participation. 
Patients or his/her legally authorized representative will be required to sign a statement of 
informed consent that meets the requirements of local regulations, ICH guidelines, and the IRB 
or study center, where applicable. The patient or his/her legally authorized representative will be 
given a copy of the signed ICF and the original will be maintained with the patient’s records. 
Patients must be re-consented to the most current version of the ICF(s) during their participation 
in the study, as appropriate. 
Patient Data Protection 
Patients will be assigned a unique identifier and will not be identified by name in electronic case 
report forms (eCRFs), study-related forms, study reports, or any related publications. Patient and 
Investigator personal data will be treated in compliance with all applicable laws and regulations. 
In the event the study protocol, study report, or study data are included in a public registry, all 
identifiable information from individual patients or Investigators will be redacted according to 
applicable laws and regulations. 
The patient must be informed that his/her personal study-related data will be used by the sponsor 
in accordance with local data protection law. The level of disclosure must also be explained to 
the patient. The patient must also be informed that his/her medical records may be examined by 
sponsor or Contract Research Organization (CRO) auditors or other authorized personnel 
appointed by the sponsor, by appropriate IRB members, and by inspectors from regulatory 
authorities. 
Disclosure 
All information provided regarding the study, as well as all information collected and/or 
documented during the course of the study, will be regarded as confidential. The Investigator (or 
designee) agrees not to disclose such information in any way without prior written permission 
from the sponsor. 
Data Quality Assurance 
The following data quality steps will be implemented: 
• All patient data relating to the study will be recorded on eCRFs unless directly 
transmitted to the sponsor or designee electronically (eg, laboratory data). The 
Investigator is responsible for verifying that data entries are accurate and correct by 
electronically signing the eCRF. 
• The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. 
• The Investigator must permit study-related monitoring, audits, IRB review, and 
regulatory agency inspections and provide direct access to source data documents. 


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• The sponsor or designee is responsible for the data management of this study including 
quality checking of the data. Predefined, agreed risks, monitoring thresholds, quality 
tolerance thresholds, controls, and mitigation plans will be documented in a risk 
management register. Additional details of quality checking to be performed on the data 
may be included in a Data Management Plan. 
• 
 will be responsible for clinical monitoring of the study. Study monitors will 
perform ongoing source data verification to confirm that data entered into the eCRF by 
authorized site personnel are accurate, complete, and verifiable from source documents; 
that the safety and rights of patients are being protected; and that the study is being 
conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements. 
• Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the Investigator in accordance with 21 CFR 312.62(c) unless local 
regulations or institutional policies require a longer retention period, unless local 
regulations or institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the sponsor. No 
records may be transferred to another location or party without written notification to the 
sponsor. 
Investigator Documentation Responsibilities 
All individual, patient-specific study data will be entered into a 21 CFR Part 11-compliant 
electronic data capture (EDC) system on an eCRF in a timely fashion. All data generated from 
external sources (eg, central laboratory of pharmacokinetics, pharmacodynamics) and 
transmitted to the sponsor or designee electronically will be integrated with the patient’s eCRF 
data in accordance with the Data Management Plan. 
An eCRF must be completed for each patient who signs an ICF and undergoes any pre-screening 
or screening procedures, according to the eCRF completion instructions. The sponsor, or CRO, 
will review the supporting source documentation against the data entered into the eCRFs to 
verify the accuracy of the electronic data. The Investigator will ensure that corrections are made 
to the eCRFs and that data queries are resolved in a timely fashion by the study staff. 
The Investigator will sign and date the eCRF via the EDC system’s electronic signature 
procedure. These signatures will indicate that the Investigator reviewed and approved the data on 
the eCRF, the data queries, and the site notifications. 
Publications 
All data generated in this study will be the property of Autifony Therapeutics Ltd. Any 
publication of the study results shall be patient to the prior written approval by Autifony 
Therapeutics Ltd. Study results may not be published, presented, or referred to, in whole or in 
part, by the CRO, its affiliates, its permitted third-party vendors or external consultants, or any 
center or Investigator involved in the performance of the study, without the prior expressed 
written consent of the sponsor, which it may withhold in its sole discretion. 














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h The cannula will be inserted on admission to the hospital, as required by local procedure. The cannula will be 
inserted prior to Visit 3. 
i For Visit 3: predose PK can be any time in the morning of dosing as long as it is predose. 
j For Visit 5: predose PK can be any time after 47 hours post Visit 3 dosing and prior to Visit 5 dosing. 

SAP_001.pdf: 
Statistical Analysis Plan for Study AUT022201 
Version 2.0 – 24 May 2024 
CONFIDENTIAL 
ST-002-T01-V04, 11Mar2022 
Page 1 of 54 
 
 
Title: Statistical Analysis Plan for AUT022201 
Compound Name/Number: AUT00201 
 
Effective Date: [24 May 2024] 
 
Study Title: A Randomized, Double-blind, Placebo-controlled, Crossover Study of the 
Effects of Single Doses of AUT00201 in Patients with Myoclonus Epilepsy and Ataxia due to 
Potassium (K+) Channel Mutation (MEAK) 
 
Subject: MEAK, AUT00201, Phase 1b study 
 
 
 
 
 
 
 
 
 
 
 
 
Author’s Name and Title: 
 
Information described herein is confidential and unauthorized copying or use of this 
information is prohibited without the express written permission of Autifony Therapeutics 
Limited. 


Statistical Analysis Plan for Study AUT022201 
Version 2.0 – 24 May 2024 
CONFIDENTIAL 
ST-002-T01-V04, 11Mar2022 
Page 2 of 54 
 
 
 
SIGNATURE PAGE 
The signatories on the following pages have all read and approved this present version of the 
document. 
Approved by: 
I certify that I have read this version of the Statistical Analysis Plan and approve its contents. 
NAME: 
 
TITLE: 
Senior Statistician I, 
 
SIGNATURE 
AND DATE: 
 
Approved by: 
I certify that I have read this version of the Statistical Analysis Plan and approve its contents. 
NAME: 
 
TITLE: 
Consultant Statistician, 
 Limited 
SIGNATURE 
AND DATE: 
 
Approved by: 
I certify that I have read this version of the Statistical Analysis Plan and approve its contents. 
NAME: 
 
TITLE: 
Chief Medical Officer, Autifony Therapeutics Limited 
SIGNATURE 
AND DATE: 


Statistical Analysis Plan for Study AUT022201 
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TABLE OF CONTENTS 
SIGNATURE PAGE .................................................................................................................. 2 
TABLE OF CONTENTS............................................................................................................. 3 
ABBREVIATIONS .................................................................................................................... 6 
TRADEMARK INFORMATION ................................................................................................ 7 
REVISION HISTORY ................................................................................................................ 7 
1. 
INTRODUCTION............................................................................................................ 8 
2. 
STUDY OBJECTIVES AND ENDPOINTS ........................................................................... 8 
2.1 
Study objectives ......................................................................................... 8 
2.1.1 
Primary objectives ...................................................................................... 8 
2.1.2 
Secondary objectives .................................................................................. 8 
2.1.3 
Exploratory objectives ................................................................................ 8 
2.2 
Study estimands ......................................................................................... 9 
2.3 
Study endpoints .......................................................................................... 9 
2.3.1 
Primary endpoints ...................................................................................... 9 
2.3.2 
Secondary endpoints .................................................................................. 9 
2.3.3 
Exploratory endpoints .............................................................................. 10 
2.4 
Statistical hypotheses ............................................................................... 10 
3. 
STUDY DESIGN ........................................................................................................... 10 
4. 
TIMING OF PLANNED ANALYSES ................................................................................ 12 
4.1 
Interim analyses ........................................................................................12 
4.2 
Final analysis ........................................................................................... 12 
5. 
SAMPLE SIZE CONSIDERATIONS ................................................................................. 12 
6. 
ANALYSIS POPULATIONS ........................................................................................... 12 
6.1 
Screen population ..................................................................................... 13 
6.2 
Safety population ......................................................................................13 
6.3 
Pharmacokinetic concentration (PKC) population..................................... 13 
6.4 
Pharmacokinetic parameter (PKP) population........................................... 13 
6.5 
Pharmacodynamic (PD) population .......................................................... 13 


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6.6 
Modified pharmacodynamic (mPD) population ........................................ 13 
7. 
PROTOCOL DEVIATIONS............................................................................................. 13 
8. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES .................................................... 13 
8.1 
Standard summary statistics ..................................................................... 13 
8.2 
Treatment definition ................................................................................. 14 
8.3 
Baseline definition ................................................................................... 14 
8.4 
Study Day definition ................................................................................ 14 
8.5 
Strata and covariates ................................................................................. 14 
8.6 
Standard comparison methods .................................................................. 15 
8.7 
Statistical significance .............................................................................. 15 
8.8 
Examination of subgroups ........................................................................ 15 
9. 
DATA HANDLING CONVENTIONS ............................................................................... 15 
9.1 
Premature withdrawal and missing data .................................................... 15 
9.2 
Derived and transformed data ................................................................... 15 
9.2.1 
Study Population ...................................................................................... 15 
9.2.2 
Pharmacodynamic tests ............................................................................ 16 
9.2.3 
Safety derivations ......................................................................................26 
9.2.4 
Patient reported measures ......................................................................... 28 
9.3 
Clinical pharmacology.............................................................................. 29 
9.3.1 
Derivation of pharmacokinetic parameters ................................................ 29 
9.4 
Assessment time windows ........................................................................ 30 
10. 
STATISTICAL ANALYSES AND METHODOLOGY ........................................................... 31 
10.1 
Study population ...................................................................................... 31 
10.1.1 
Disposition of participants ........................................................................ 31 
10.1.2 
Protocol deviations ................................................................................... 31 
10.1.3 
Demographic and baseline characteristics ................................................. 31 
10.1.4 
Treatment administration .......................................................................... 31 
10.1.5 
Patient reported measures ......................................................................... 32 
10.2 
Pharmacodynamic analyses ...................................................................... 32 
10.2.1 
Pharmacodynamic endpoints .................................................................... 32 
10.2.2 
Determination of a positive impact with AUT00201 ................................. 39 
10.2.3 
Assessing clinical meaningfulness ............................................................ 42 


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10.3 
Safety analyses ..........................................................................................43 
10.3.1 
Adverse events ......................................................................................... 43 
10.3.2 
Clinical laboratory evaluations ................................................................. 44 
10.3.3 
Vital signs ................................................................................................ 44 
10.3.4 
Physical examination ................................................................................ 44 
10.3.5 
ECGs ....................................................................................................... 44 
10.3.6 
C-SSRS .................................................................................................... 44 
10.4 
Clinical pharmacology.............................................................................. 44 
10.4.1 
AUT00201 pharmacokinetics ................................................................... 44 
10.4.2 
Antiepileptic pharmacokinetics ................................................................. 45 
11. 
CHANGES FROM THE PROTOCOL-SPECIFIED ANALYSIS .............................................. 46 
12. 
BIBLIOGRAPHY ........................................................................................................... 47 
13. 
APPENDIX A – SCHEDULE OF ASSESSMENTS .............................................................. 48 




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WIN 
Words-in-Noise 
 
 
TRADEMARK INFORMATION 
SAS 
SAS (Statistical Analysis Software) is a registered trademark of SAS Institute 
Inc. 
 
REVISION HISTORY 
Version Date 
Summary of revisions 
1.0 
[24 April 2024] 
Initial version 
2.0 
[24 May 2024] 
• Section 2.3.3 – Exploratory endpoint wording clarified as 
negative myoclonus during UMRS Sections 4 and 5 is 
collected as one measurement, rather than two separate ones. 
• Section 8.3 – Baseline definition updated to clarify that only 
scheduled measurements are considered. 
• Section 9.2.2.2 – Speech test parameters selected to 
investigate the secondary endpoint have been changed. Full 
rationale is included within the text. 
• Section 9.2.2.3 – Updates made to EMG and accelerometer 
parameters due to clarification of the data being recorded. 
• Section 9.2.2.6 – Updates to the list of quantitative EEG 
parameters due to a clarification of the data being recorded. 
• Section 9.3.1 – Updates on how to handle BLQ 
measurements in the summarization of PK concentrations. 
• Section 10.2.1 – Updates to Table 4 to align with updates 
discussed above for Sections 9.2.2.2 and 9.2.2.3. 
• Section 10.2.2 – Updates to Table 5 
o Updates to Tier 1 and 2 with regards to speech test 
measures. 
o Updates to Tier 2 with regards to quantitative EEG. 
o Added column indicating the anticipated direction of 
change with improvement. 
• Section 10.2.2 – Update to false positive rate following 
changes to Tier 1 and Tier 2 criteria, and knowledge of 
missing participant data. 
• Section 10.4.1 – Updates to which speech test parameters are 
to be plotted against AUT00201 Cmax. 


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1. 
INTRODUCTION 
This is a randomized, double-blind, placebo-controlled, Phase 1b crossover study of the 
effects of single doses of AUT00201 in patients with myoclonus epilepsy and ataxia due to 
potassium (K+) channel mutation (MEAK). 
This Statistical Analysis Plan (SAP) provides details of the summaries and analyses to be 
performed to report the findings of the study. It should be read in conjunction with the 
Clinical Study Protocol (CSP); AUT022201, Version 4.0, 30 October 2023. 
2. 
STUDY OBJECTIVES AND ENDPOINTS 
2.1 
STUDY OBJECTIVES 
2.1.1 PRIMARY OBJECTIVES 
The primary objective is: 
• To evaluate the safety and tolerability of single doses of AUT00201 in patients with 
MEAK. 
2.1.2 SECONDARY OBJECTIVES 
The secondary objectives are: 
• To evaluate the effects of single doses of AUT00201 on short interval cortical 
inhibition (SICI) as measured by paired-pulse transcranial magnetic stimulation 
(TMS) 
• To evaluate the effects of single doses of AUT00201 on dysarthria as measured by 
automated speech and vocal assessments 
• To evaluate the effects of single doses of AUT00201 on myoclonus index (MI) by 
capturing the amount and time periods with positive myoclonus during a prespecified 
time period as measured by electromyography (EMG) and accelerometer 
• To assess the pharmacokinetic (PK) profile of AUT00201 after single doses of 
AUT00201 in patients with MEAK 
• To evaluate correlations between exposure to AUT00201 and changes in these 
biomarkers. 
2.1.3 EXPLORATORY OBJECTIVES 
The exploratory objectives are: 
• To evaluate the effects of single doses of AUT00201 on long interval cortical 
inhibition (LICI) as measured by paired-pulse TMS 
• To evaluate the effects of single doses of AUT00201 on myoclonus as assessed by 
Sections 4 and 5 of the Unified Myoclonus Rating Scale (UMRS) and sub-sections D 
and E of Section 4 
• To evaluate the effects of single doses of AUT00201 on the amount of negative 
myoclonus (short periods of loss of muscle tone) during a prespecified time period as 
measured by EMG and accelerometer 


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• To evaluate the effects of single doses of AUT00201 on quantitative 
electroencephalogram (EEG) and on EEG frequency responses to chirp stimuli 
• To evaluate the effects of single doses of AUT00201 on measures of early visual 
processing 
• To evaluate the effects of single doses of AUT00201 on auditory measures 
• To evaluate correlations between exposure to AUT00201 and changes in these 
biomarkers. 
2.2 
STUDY ESTIMANDS 
No primary estimand will be defined as the primary objective of this study is to evaluate the 
safety and tolerability of single doses of AUT00201 in patients with MEAK. Refer to Section 
10.3 for details on the reporting of safety outcomes. 
Whilst estimand strategies have not been explicitly defined in the study protocol, the analysis 
of pharmacodynamic (PD) outcomes will include all data collected for a participant 
belonging to the analysis set under investigation (modified pharmacodynamic population) 
and reported under the treatment which the participant received at the date of assessment. 
2.3 
STUDY ENDPOINTS 
2.3.1 PRIMARY ENDPOINTS 
The primary endpoints are: 
• Safety and tolerability of single doses of AUT00201 in patients with MEAK: 
o Change from screening/baseline in laboratory assessments (routine 
hematology, biochemistry, and urinalysis) 
o Incidence of clinically significant laboratory findings 
o Change from baseline in vital signs 
o Change from baseline physical examination findings approximately 24 hours 
after investigational product (IP) administration 
o Change from screening in 12-lead ECG findings 
o Incidence of adverse events (AEs) 
2.3.2 SECONDARY ENDPOINTS 
The secondary endpoints are: 
• Change from baseline in cortical inhibition as assessed with paired-pulse TMS EMG: 
o SICI as measured by paired-pulse TMS EMG 
• Change from baseline in: 
o Measures of dysarthria as assessed by automated standardized speech and 
vocal tests 
o Myoclonus Index (MI; a measure of positive myoclonus) evaluated with EMG 
and accelerometer 
• PK parameters following single doses of AUT00201: maximum (peak) plasma 
concentration (Cmax) and area under the plasma concentration-time curve from time 
zero to 24 hours (AUC24) of AUT00201. 


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2.3.3 EXPLORATORY ENDPOINTS 
The exploratory endpoints are: 
• Change from baseline in cortical inhibition as assessed with paired-pulse TMS EMG: 
o LICI as measured by paired-pulse TMS EMG 
• Change from baseline in: 
o Amount of negative myoclonus evaluated with EMG and accelerometer over 
time and during each UMRS action myoclonus Section 4: D and E and UMRS 
Sections 4 and 5 
o UMRS subscale scores: Sections 4 and 5 
o UMRS action myoclonus scores Section 4: D and E 
o Quantitative EEG measures (absolute and relative power of predefined 
frequency bands) 
o EEG power and phase locking factor induced by chirp stimulus in predefined 
frequency bands 
o Measures of early visual processing as assessed by: 
 Binocular rivalry 
 An internal noise estimation 
o Measures of auditory processing as assessed by: 
 Otoacoustic Emissions (OAEs) 
 Words-in-Noise (WIN) test performance (signal-to-noise ratio [SNR]) 
2.4 
STATISTICAL HYPOTHESES 
No formal hypothesis testing will be performed as the primary objective of this study is to 
evaluate the safety and tolerability of single doses of AUT00201 in patients with MEAK. 
3. 
STUDY DESIGN 
This is a Phase 1b study to investigate the safety, tolerability, PK, and PD effects on 
biomarkers of AUT00201 in patients with MEAK. 
The study will be conducted at 1 hospital research center. It was planned that approximately 6 
to 10 patients aged 18 years or older, diagnosed with MEAK, based on documented genetic 
evidence of the presence of the KCNC1 variant would participate in the study. 
The study is a double-blind, randomized, placebo-controlled treatment in which participants 
will be administered a single dose of 100 mg AUT00201 and matching placebo in a crossover 
design. There is an initial outpatient screening and procedure orientation which can be spread 
over 2 days, followed by a 5-day inpatient stay at a clinical research unit. 
Assessments will be conducted throughout the study as detailed in Appendix A – Schedule of 
assessments. 
Figure 1 provides an illustration of the study design. Outpatient screening and procedure 
orientation (Visit 1) will occur up to 1 week prior to Visit 2 when participants will be 
admitted to the clinic for a 5-day inpatient stay. Baseline assessments (Visit 2) will be 
completed on the first inpatient day. Participants will then be administered a single dose of 
100 mg AUT00201 or matching placebo on the second inpatient day (Visit 3). The third 


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inpatient day (Visit 4) will be a washout day for participants. On the fourth inpatient day 
(Visit 5), participants will be administered the crossover treatment. On the fifth inpatient day 
(Visit 6), participants will be discharged from the unit. Participants will be followed up by 
phone 14 days ±2 days after discharge (Visit 7). 
Figure 1: Study Design 
 
It is not possible to replace participants in this study, due to the rarity of the disorder. 
However, if any technical issues or important protocol deviations occur during a participant’s 
participation that are likely to make the primary, secondary, or exploratory endpoint data 
unevaluable or impact their validity, the participant may be invited back to participate in the 
study again, if the sponsor and Investigator are in agreement. If a participant is invited back 
to participate a second time, they will be given a new screening number and treated as a new 
participant, including consideration for inclusion and exclusion criteria. Data from the first 
participation, with the exception of safety and PK data, will not be included in the statistical 
analysis. All data will be listed, with clear indication if a participant is a repeat participant. 
Participants will be assigned a unique code number (randomization number) at Visit 3. The 
randomization number will encode the participant’s assignment to a treatment sequence, 
according to the randomization schedule generated prior to the study by Fortrea. 
For reporting, Study Day 1 is the first day of study treatment. Therefore, visits are linked to 
study days as follows: 
• Visit 1 – Screening 
• Visit 2 – Admission on Study Day -1 (day before first dose) 
• Visit 3 – Study Day 1 (first treatment received) 
• Visit 4 – Study Day 2 (washout) 
• Visit 5 – Study Day 3 (second treatment received) 
• Visit 6 – Study Day 4 (washout/discharge) 
• Visit 7 – phone follow-up 
Participants will receive one of the following sequences of treatment: 
• A single 100 mg dose of AUT00201, oral capsule, on Study Day 1 and then matching 
placebo, oral capsule, on Study Day 3 
• A matching placebo, oral capsule, on Study Day 1 and then a single 100 mg dose of 
AUT00201, oral capsule, on Study Day 3. 


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Their single doses on Study Day 1 (Visit 3) and Study Day 3 (Visit 5) will be taken 
approximately 30 minutes after completion of a standard meal provided by the clinical site. 
Total duration of study participation per participant is up to 3.5 weeks. More specifically, 
duration can be described as follow: 
• Total outpatient participation: Up to 1 week 
• Total inpatient participation: Approximately 5 days 
• Planned follow-up: 14 days ±2 days after discharge 
A participant is considered to have completed the study if he/she has completed all visits of 
the study. The end of the study is defined as the date of final follow-up (planned as a 
telephone call) by the last participant in the study. 
4. 
TIMING OF PLANNED ANALYSES 
4.1 
INTERIM ANALYSES 
No interim analysis is planned. 
4.2 
FINAL ANALYSIS 
The final analysis is planned for after study completion (see Section 3 for the definition of 
end of study), database lock and unblinding of the study randomization. 
5. 
SAMPLE SIZE CONSIDERATIONS 
MEAK is an ultra-rare disorder. This study will aim to include all adult patients with MEAK 
known to the Principal Investigator and sub-investigator(s). It was hoped that approximately 
6 to 10 patients could be recruited. 
At the time of writing this SAP, a total of 5 participants will be enrolled in the study (one of 
which was rescreened and participated twice in the study). Recruitment was lower than 
anticipated as contact could not be made with all patients, and not all patients contacted 
agreed to participate. The SAP has been written with this lower recruitment taken into 
account. 
6. 
ANALYSIS POPULATIONS 
This section outlines the analysis populations that will be included for this study. In all 
populations, participants will be analyzed according to treatment actually received during the 
specific treatment period (before and after the crossover) regardless of the treatment to which 
they were randomized. 
Please note the addition of the modified pharmacodynamic population to the SAP, to handle 
subjects who participate in the study twice appropriately in PD analyses. 


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6.1 
SCREEN POPULATION 
All participants who signed the informed consent and are screened for participation in this 
study. This population will only be used for the purposes of describing participant 
disposition. 
6.2 
SAFETY POPULATION 
All participants who received at least 1 dose of AUT00201 or placebo. Unless otherwise 
specified, this analysis population will be used for all safety analyses and listings. 
6.3 
PHARMACOKINETIC CONCENTRATION (PKC) POPULATION 
All participants who received at least 1 dose of AUT00201 with at least 1 evaluable (i.e., not 
impacted by any important protocol deviations or other events) PK concentration (even if 
below the limit of quantification). 
6.4 
PHARMACOKINETIC PARAMETER (PKP) POPULATION 
All participants in the PK concentration population for whom at least one PK parameter can 
be derived. 
6.5 
PHARMACODYNAMIC (PD) POPULATION 
All participants in the safety population who have an evaluable baseline and at least 1 
evaluable postbaseline measurement for at least 1 PD parameter. A PD parameter includes 
any parameter outlined in Section 9.2.2. 
6.6 
MODIFIED PHARMACODYNAMIC (MPD) POPULATION 
All participants in the pharmacodynamic population with the following stipulation: for re- 
screened participants, data collected under a previous participant number will be excluded 
from this analysis population. Unless otherwise specified, this analysis population will be 
used for all PD analyses. 
7. 
PROTOCOL DEVIATIONS 
The Protocol Deviation Plan describes how protocol deviations are collected and handled. 
Notably, deviations that impact data relating to the secondary endpoints will be classified as 
“important”. Deviations will be reviewed on a monthly basis. 
A per-protocol analysis excluding participants with specific important protocol deviations is 
not planned. 
8. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES 
8.1 
STANDARD SUMMARY STATISTICS 
To fit better with the lower than anticipated recruitment, the protocol text on standard 
summary statistics has been modified, as follows. 
Continuous data will be summarized using the summary statistics: number of observations 
(n), mean, standard deviation, minimum, median and maximum. Geometric mean and 
coefficient of variation will also be presented for appropriate PK parameters. Categorical data 


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will be summarized using the count of participants and/or events. “Missing” categories 
(corresponding to participants with missing data for the variable being summarized) may be 
added as the last category in the list of categories being summarized. 
The minimum and maximum values will be presented to the same number of decimal places 
as the raw data collected on the electronic case report form (eCRF) (or to 3 significant figures 
for derived parameters). The mean, standard deviation and median will be presented to one 
additional decimal place. 
8.2 
TREATMENT DEFINITION 
“Treatment” is used in this SAP to refer to either the AUT00201 or placebo treatment. 
Treatment sequence refers to the sequence in which participants received treatment. There are 
two planned sequences participants can follow: 
• “AUT00201/Placebo” for participants receiving AUT00201 on Study Day 1, and 
placebo on Study Day 3 
• “Placebo/AUT00201” for participant s receiving placebo on Study Day 1, and 
AUT00201 on Study Day 3 
Summaries will be presented by treatment, unless otherwise specified. 
Observations made on or after Study Day 1 treatment administration up to Study Day 3 
treatment administration will be summarized under the treatment received at Study Day 1. 
Similarly, observations made on or after Study Day 3 treatment administration up to follow- 
up will be summarized under the treatment received at Study Day 3. 
8.3 
BASELINE DEFINITION 
In general, baseline is defined as the last scheduled measurement obtained before the first 
dose of study treatment. For pharmacodynamic data, the measurement to be used as baseline 
is defined more precisely in Section 9.2.2. 
8.4 
STUDY DAY DEFINITION 
Study Day is derived based on the date of first treatment (Visit 3). If an assessment/event date 
is before the date of first treatment, then Study Day is defined as: 
(Assessment/event date) – (Date of first treatment). 
If an assessment/event date is on or after the date of first treatment, then Study Day is defined 
as: 
(Assessment/event date) – (Date of first treatment) + 1. 
8.5 
STRATA AND COVARIATES 
Given the small sample size, no formal stratification was used for the randomization. 
A crossover design is used to reduce the influence of confounding covariates since each 
participant serves as their own control. As there will be no statistical modelling of the data 
the use of covariates for analyses is not relevant. 


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8.6 
STANDARD COMPARISON METHODS 
Primary, secondary and exploratory endpoints will be summarized descriptively by treatment 
and, where specified in sections below, differences between treatments will be summarized. 
8.7 
STATISTICAL SIGNIFICANCE 
Not Applicable, see Section 2.4. 
8.8 
EXAMINATION OF SUBGROUPS 
Given the small sample size, no subgroups will be investigated. 
9. 
DATA HANDLING CONVENTIONS 
9.1 
PREMATURE WITHDRAWAL AND MISSING DATA 
Unless specified, all missing or incomplete data, including dates and times, will be treated as 
missing. Missing test results or assessments will not be imputed. 
9.2 
DERIVED AND TRANSFORMED DATA 
9.2.1 STUDY POPULATION 
9.2.1.1 DEMOGRAPHICS AND BASELINE CHARACTERISTICS 
Demographics and baseline characteristics are recorded at Visit 1 (screening). 
If required, the following conversions will be used: 
• Height collected in inches will be converted into cm using the formula: 
Height (cm) = Height (inches) / 2.54 
• Weight collected in pounds will be converted into kg using the formula: 
Weight (kg) = Weight (pounds) / 2.205 
9.2.1.2 MEDICAL HISTORY 
The participant’s relevant medical history will be collected and coded using version 26.1 of 
the Medical Dictionary for Regulatory Activities (MedDRA). The participants will be asked 
specifically regarding their history of seizures, headaches/migraines, and episodes of 
dizziness. They will also be asked regarding their history of fever and if they/their caregiver 
had any impression of an improvement of MEAK symptoms during the fever. 
9.2.1.3 PRIOR AND CONCOMITANT MEDICATIONS 
Any medication or vaccine that the participant is receiving at Visit 1 (screening) or receives 
during the study through Visit 7 (follow-up) will be collected on the eCRF. Details for 
medication taken before screening may also be recorded. All medications will be coded 
according to version September 2022 of the World Health Organization Drug Dictionary 
(WHODD). 
A prior medication is defined as any medication taken prior to the first dose of treatment. A 
concomitant medication is defined as any medication continued or newly received on or after 


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the first dose of treatment. Partial or missing start and stop dates will not be imputed as 
outlined in Section 9.1. 
In the prior and concomitant medication listing, medications will be flagged as either prior, 
concomitant or both, using the flags P, C and PC, respectively. If there is insufficient 
information from the start and end dates/times to attribute a medication to one of these 
categories no flag will be presented. 
9.2.1.4 TREATMENT ADMINISTRATION 
Participants will receive a single dose of 100 mg AUT00201 or matching placebo (one 100 
mg capsule) on Study Days 1 and 3, approximately 30 minutes after completion of a standard 
meal provided by the clinical site. Date and time of administration, time meal was completed, 
and reason for not taking a dose if applicable will be captured in the eCRF. 
9.2.2 PHARMACODYNAMIC TESTS 
9.2.2.1 PAIRED-PULSE TMS EMG 
Paired-pulse TMS allows for measurement of cortical inhibition. The two key outcome 
measures are short interval cortical inhibition (SICI) and long interval cortical inhibition 
(LICI). 
SICI has been shown to be reduced in other myoclonic epilepsies (Unverricht-Lundborg 
disease (ULD) and Lafora body disease [LBD]; (Canafoglia, 2010)). It is postulated that 
MEAK patients will show a similar deficit. A defective in LICI was found in LBD but not 
ULD patients; it is unknown whether MEAK patients will have a LICI deficit. 
Initially, the resting motor threshold will be recorded, which is defined as the lowest stimulus 
intensity (expressed as a percentage of maximal stimulator output, %MSO) required to 
induce motor evoked potentials of 50μV. 
SICI will be elicited with a conditioning stimulus of 70% of resting motor threshold 
(0.7*rMT) and interstimulus interval of 1, 2.5, and 3 ms; LICI will be elicited with a 
conditioning stimulus of 120% the resting motor threshold (1.2*rMT) that precedes the test 
stimulus by 100 and 200 ms. 
SICI 1ms is considered to be mediated by tonic γ-aminobutyric acid (GABA). SICI 2.5 and 3 
ms are mediated by synaptic GABAA, as evidenced that GABAA agonists enhance SICI 
(Ziemann, 2004). It is proposed that LICI is mediated by activation of inhibitory post- 
synaptic GABAB receptors (Ziemann, 2004). 
At each SICI/LICI interval, an observation will be reported in %-inhibition. 
The initial assessment will be timed to coincide with the anticipated AUT00201 tmax, between 
2 to 4 hours postdose. The assessment will take place between 11am and 1pm on Study Days 
-1, 1, 2, 3 and 4, as the participant will take their study treatment at 9am on Study Days 1 and 
3. A second assessment will be conducted approximately 6 hours postdose, on Study Days 1 
and 3. The data collected at the second timepoint will be listed and may be used to inform the 
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o Measures of dysarthria as assessed by automated standardized speech and 
vocal tests 
will be investigated using the changes from baseline in speaking rate and buttercup count. 
Both are expected to increase with successful treatment. The other metrics are considered as 
exploratory endpoints. 
9.2.2.3 EMG AND ACCELEROMETER 
Surface EMG and accelerometry can provide valuable information about the nature and the 
source of symptoms (e.g., tremor and myoclonus) in movement disorders. 
Participants will wear EMG and Accelerometer devices on their dominant arm (bicep brachii 
[BB] muscle) and non-dominant arm (extensor digitorum communis [EDC] muscle on the 
forearm) from Visit 2 (Study Day -1) through Visit 6 (Study Day 4), the duration of the 
inpatient portion of the study. These devices will take measurements to assess positive and 
negative myoclonus. 
Participants will have ‘action myoclonus’ assessments on Study Days -1, 1, 2, 3 and 4 where 
they complete sub-sections 4D and 4E of the Unified Myoclonus Rating Scale (UMRS) 
assessment. The UMRS tasks are described below in Section 9.2.2.4. On Study Days -1, 1 
and 3, the assessments will be at specified timepoints from 8am till 5pm (see Appendix A – 
Schedule of assessments, relating to 1 hour predose until 8 hours postdose on Study Days 1 
and 3). On Study Days 2 and 4, the assessments will be at specified timepoints from 8am 
until 1pm (see Appendix A – Schedule of assessments). Note the 9am timepoint on Study 
Days 1 and 3 is postdose. At each timepoint participants will be asked to complete a set of 
movements of their arms in accordance with the UMRS Section 4: Parts D and E. At 11am 
(relating to 2 hours postdose) on Study Days -1, 1 and 3, UMRS Sections 4 and 5 will be 
performed. The positive myoclonus index and negative myoclonus for each arm will be 
calculated during the 20 minutes that the participants complete the UMRS Section 4 and 5 
assessments; they will also be calculated during the specific sub-sections 4D and 4E at this 
timepoint separately. 
The measurements collected on Admission (Study Day -1) will be used to derive the baseline. 
If an endpoint involves averaging measurements across arms or across timepoints, then the 
baseline derivation will follow the same approach. 
Positive myoclonus, assessed using the Myoclonus Index (MI) 
Positive myoclonus means an involuntary and quick jerk of muscles that may occur 
spontaneously. The positive myoclonus will be quantified using the myoclonus index (MI), 
for each arm, over the duration of each action myoclonus assessment. MI is calculated 
(Rissanen, 2021) as a score >0, expressed as a decimal. 
The most interesting period of assessment is up to 4 hours postdose (anticipated to cover 
tmax). To investigate this period, at each timepoint from 9am until 1pm, measurements across 
action myoclonus assessments from both arms will be averaged to calculate a single MI. For 
the 11am timepoint, there will be one UMRS Section 4 and 5 MI measurement (UMRS 4 and 
5 is combined) for each arm as they complete both tasks, the MI from the two arms will be 
averaged to provide the 2 hour postdose MI. These single MI measurements from the 9am to 


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1pm timepoints will then be averaged. The calculation of MI during the sub-sections 4D and 
4E at 11am will not be used in any analyses. 
The secondary endpoint 
• Change from baseline in: 
o MI (positive myoclonus) evaluated with EMG and accelerometer 
will be investigated using the changes from baseline in the average MI across each action 
myoclonus/UMRS assessment from both arms, from 9am until 1pm (using the UMRS 4 and 
5 score at 11am). Positive myoclonus is expected to decrease with successful treatment. 
The MI measured for each arm (dominant and non-dominant, rather than left and right) 
separately and averaged across arms during each action myoclonus assessment, during 
UMRS Section 4 and during UMRS Section 5 are considered exploratory endpoints. 
Negative myoclonus 
Negative myoclonus means a sudden and brief loss of muscular tone that may lead, for 
example, to the loss of posture or the dropping of objects from hands. Negative myoclonus is 
recorded as a count, for each arm, which reflects the frequency of negative myoclonus over 
the duration of each action myoclonus assessment (Rissanen, 2021). 
As with positive myoclonus, to investigate the up to 4 hours postdose period, at each 
timepoint from 9am until 1pm, measurements across action myoclonus assessments from 
both arms will be averaged to calculate a single negative myoclonus. As above, for the 11am 
timepoint, UMRS Section 4 and 5 measurements from the two arms will be averaged and will 
be used as the 2 hour postdose negative myoclonus. These single MI measurements from the 
9am to 1pm timepoints will then be averaged. 
The exploratory endpoint 
• Change from baseline in: 
o Amount of negative myoclonus evaluated with EMG and accelerometer over 
time and during each UMRS action myoclonus Section 4: D and E and each 
UMRS Sections 4 and 5. 
will be investigated using the same methods as described for positive myoclonus. Negative 
myoclonus is expected to decrease with successful treatment. 
9.2.2.4 UMRS SECTIONS 4 AND 5 (CLINICAL RATING) 
The UMRS is a quantitative 73-item clinical rating instrument developed to evaluate 
myoclonus and response, of patients with myoclonus, to antimyoclonic therapy. The scale 
consists of 8 sections. The UMRS is the most widely used standardized assessment of 
myoclonus and is appropriate in this patient population as a measure of the action induced 
myoclonus symptom associated with MEAK. 
In this study, only UMRS Sections 4 and 5 will be evaluated on Admission (Study Day -1), 
and Study Days 1 and 3 at 11am (i.e., relating to 2 hours postdose on Study Days 1 and 3). 
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assessment (two items) of the non-dominant arm has been added to the standard UMRS 
Section 5 to obtain a more complete data set. 
Section 4 – severity of myoclonus with action (frequency and amplitude, 10 items) 
• Items are: eyelids (A), neck (B), trunk (C), right arm (D), left arm (E), right leg (F), 
left leg (G), arising (H), standing (I), walking (J) 
Section 5 – assess performance on functional tests (7 items) 
• Items are: writing (A), right hand spiral (B), left hand spiral (C), pouring water 
(dominant hand) (D1), pouring water (non-dominant hand) (D2), soup spoon 
(dominant hand) (E1), soup spoon (non-dominant hand) (E2) 
Participants will be videoed performing the assessment, and the videos are submitted for 
scoring by a single centralized scorer. The scorer is blinded to the order of the videos and no 
cues are included in the video as to the timepoint of the assessment. 
Following the scoring instruction provided in the original paper (Frucht, 2002), Section 4 
includes ratings of frequency and amplitude of myoclonic jerks each on a scale of 0 to 4 
affecting each body region. Total score for Section 4 is calculated by multiplying frequency 
by amplitude scores for each body region, and then adding, with a maximum score of 160. 
Section 5 includes ratings on a scale of 0 to 4, each to assess performance on different 
functional tests. Total score for Section 5 of the UMRS is calculated by simple addition, with 
a maximum score of 28. 
The exploratory endpoint 
• Change from baseline in: 
o UMRS subscale clinical scores: Sections 4 and 5 
will be investigated by using the changes from baseline in the Section 4 and Section 5 total 
scores. UMRS scores are expected to decrease with successful treatment, however it is not 
expected that a clinical rating will be sensitive enough to capture a drug effect after a single 
dose treatment. 
9.2.2.5 UMRS SECTION 4: PARTS D AND E 
A predominant symptom for patients is an action-induced myoclonus. To ensure assessment 
of this symptom over the duration of the study, the participants will need to be active at 
regular intervals, more than the assessments for UMRS Sections 4 and 5 alone. 
At the specified assessments, participants will be asked to complete a set of movements of 
their arms in accordance with the UMRS Section 4: Parts D (for the right arm) and E (for the 
left arm). As in Section 9.2.2.4, participants are videoed, and the video is scored by a single 
centralized scorer. Items D and E are rated on a scale of 0 to 4 for amplitude and frequency 
and the frequency and amplitude scores are multiplied to produce a maximum total 
myoclonus clinical score of 16 for each item. When analyzing these data, the Part D and E 
scores will be mapped to the dominant and non-dominant arms. 
The measurements collected on Admission (Study Day -1) will be used as baselines for the 
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The exploratory endpoint 
• Change from baseline in: 
o UMRS action myoclonus clinical scores: Section 4: D and E 
will be investigated using the changes from baseline in the dominant and non-dominant arm 
scores. 
9.2.2.6 ELECTROENCEPHALOGRAMS (EEGS) 
An EEG is a test that measures electrical activity in the brain. The EEG will be recorded in 
the resting state, with eyes open and eyes closed, on Admission (Study Day -1) and Study 
Days 1 and 3, at 1pm (relating to 4 hours postdose on Study Days 1 and 3). The 
measurements collected on Admission (Study Day -1) will be the baseline for the calculation 
of changes from baseline. 
Quantitative EEG measures 
During a resting state, at electrodes Fz and Pz, absolute power (μV2/Hz) in the following 
canonical frequency bands will be collected: θ, δ, α, β, γ1 (low-gamma), γ2 (high gamma). In 
addition to absolute power in the above frequency bands, absolute total power (μV2/Hz) will 
also be collected at electrodes Fz and Pz. Relative power (%) is calculated for each of the 
frequency bands selected for reporting, by calculating the absolute power as a percentage of 
absolute total power at the electrode at which it is measured. 
The most appropriate frequencies, electrodes and states were selected for reporting: 
• absolute γ1 (low gamma) power at Fz during eyes-closed 
• relative γ1 (low gamma) power at Fz during eyes-closed 
• absolute γ1 (low gamma) power at Fz during eyes-open 
• relative γ1 (low gamma) power at Fz during eyes-open 
• absolute γ2 (high gamma) power at Fz during eyes-closed 
• relative γ2 (high gamma power at Fz during eyes-closed 
• absolute γ2 (high gamma power at Fz during eyes-open 
• relative γ2 (high gamma power at Fz during eyes-open 
• absolute α (alpha) power at Pz during eyes-closed 
• relative α (alpha) power at Pz during eyes-closed 
• absolute α (alpha) power at Pz during eyes-open 
• relative α (alpha) power at Pz during eyes-open 
• α (alpha) spectral centroid at Pz during eyes-closed 
• α (alpha) spectral centroid at Pz during eyes-open 
• absolute total power at Fz during eyes-closed 
• absolute total power at Fz during eyes-open 
• absolute total power at Pz during eyes-closed 
• absolute total power at Pz during eyes-open 


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The exploratory endpoint 
• Change from baseline in 
o Quantitative EEG measures (absolute and relative power of predefined 
frequency bands) 
will be investigated using the changes from baseline in absolute and relative power, for all 
frequency bands above. The primary focus will be γ1 (low gamma) absolute power at the Fz 
electrode in the eyes open state. It is expected that patients with MEAK will show increased 
power in resting state gamma (γ1). Successful treatment is expected to normalize such 
abnormalities. 
The alpha spectral centroid indicates the frequency within the alpha band that shows the 
highest power. It is speculated that patients with MEAK show a left shift (to lower 
frequencies) of the alpha spectral centroid. Successful treatment is expected to shift it to the 
right (to higher frequencies). 
EEG Power and Phase Synchrony Induced by Chirp Stimulus 
An EEG will also be recorded during the presentation of an auditory chirp stimulus. About 
300 chirp stimuli will be presented separated by an intertrial interval randomly jittered 
between 1500 and 2000 ms. Induced and evoked power of gamma oscillations, and phase 
synchrony, will be evaluated in 8 predefined frequency bands ranging from 20 to 84 Hz (in 
steps of 8 Hz), with the lowest frequency band being 20-28 Hz. Power and phase synchrony 
will be measured at both electrodes Fz and Cz. 
The exploratory endpoint 
• Change from baseline in: 
o EEG power and phase locking factor induced by chirp stimulus in predefined 
frequency bands 
will be investigated using the changes from baseline in absolute power and phase synchrony 
at electrode Fz, for the 8 frequency bands defined above. The primary focus will be absolute 
power and phase synchrony at electrode Fz at 40 Hz (low gamma), which corresponds to the 
36-44 Hz frequency band. It is expected that patients with MEAK will show decreases both 
in power of evoked and induced gamma frequency and in phase synchrony during the 
presentation of the chirp stimulus. Successful treatment is expected to normalize such 
abnormalities. 
9.2.2.7 EARLY VISUAL PROCESSING TESTS 
The measures of early visual processing will include tests of binocular rivalry (10 minutes) 
and internal noise estimation (15 minutes). All responses from the participant will be verbal. 
These will be conducted on Admission (Study Day -1) and following dosing on Study Days 1 
and 3. The measurements collected on Admission (Study Day -1) will be the baseline for the 
calculation of changes from baseline. 
Binocular rivalry is made up of two components, whilst internal noise estimation is made up 
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 Words-in-noise (WIN) test performance (signal-to-noise ratio [SNR]) 
will be investigated using the changes from baseline in the SNRs from the 70-dB HL and 40- 
dB HL tests separately. SNRs are expected to be smaller with successful treatment. 
9.2.3 SAFETY DERIVATIONS 
9.2.3.1 ADVERSE EVENTS 
Adverse events, based on clinical signs and symptoms and laboratory measurements, will be 
monitored throughout the study and will be collected from the time the informed consent is 
signed until their follow-up (end of study) phone call. The term AE is used to include both 
serious and non-serious AEs. 
A treatment-emergent adverse event (TEAE) is defined as any AE that begins, or any pre- 
existing AE that worsens in severity or frequency, on or after the first dose of treatment, but 
no later than the 48 hours after the participant’s last treatment. Any pre-existing AE that 
worsens in severity or frequency will be recorded as a new AE in the eCRF. 
An adverse event will be regarded as treatment-emergent unless there is clear evidence to 
indicate it started before dosing on Study Day 1: 
• there is sufficient information from the partial end date/time to indicate the event 
ended before the participant’s first dose (Study Day 1). 
• there is sufficient information from the partial start date/time to indicate the event 
started before the participant’s first dose (Study Day 1). 
TEAEs before study dosing on Study Day 3 will be summarized under the treatment 
received on Study Day 1. TEAEs on or after dosing on Study Day 3 treatment 
administration, but no later than 48 hours after dosing, will be summarized under the 
treatment received on Study Day 3. A TEAE will be summarized under both treatments 
unless there is clear evidence to indicate it either started before or after dosing on Study Day 
3: 
• there is sufficient information from the partial end date/time to indicate the event 
ended before the participant’s second dose (Study Day 3). 
• there is sufficient information from the partial start date/time to indicate the event 
started after the participant’s second dose (Study Day 3). 
AEs recorded between the screening visit and dosing on Study Day 1 will be reported as pre- 
treatment AEs and those from 48 hours after the participant’s last treatment will be recorded 
as follow-up AEs. Listings will identify whether an AE is pre-treatment, treatment-emergent 
or during follow-up. 
The following variables will be collected on the eCRF for each AE: 
• AE term (verbatim) 
• Date/time when the AE started and stopped 
• Severity (Grade 1 - mild, Grade 2 - moderate, Grade 3 - severe, Grade 4 – life 
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• Seriousness (yes or no) 
• Relationship to study treatment (not related, unlikely related, possibly related, related) 
• Action taken with study treatment (dose not changed, drug withdrawn, not applicable, 
unknown) 
• Outcome (fatal, not recovered/not resolved, recovered/resolved, recovered/resolved 
with sequelae, recovering/resolving, unknown) 
• Did the AE cause the participant to be discontinued from the study (yes or no) 
Adverse events will be coded using version 26.1 of the MedDRA. 
TEAEs with missing severity and/or causality will be treated as severe and possibly related, 
respectively, for tabulations. The information will be presented as missing in the listing. 
For TEAE summaries, TEAEs summarized as treatment-related are defined as those 
classified as either “possibly related” or “related” to treatment by the Investigator in the 
eCRF. 
The duration of an AE is calculated as follows: 
Duration (hours)= (End datetime of AE – Start datetime of AE) 
If start or end datetime is partially or completely missing, then duration will be set to missing. 
9.2.3.2 CLINICAL LABORATORY EVALUATIONS 
Samples for clinical chemistry, hematology, urinalysis, hormones and serology will be 
assessed during the study at the visits as defined in Appendix A – Schedule of assessments. 
Additional safety samples may be collected if clinically indicated at the discretion of the 
Investigator. Units will be standardized if samples are assayed using different laboratories. 
Change from baseline (Screening Visit 1 measurement) will be calculated for each continuous 
laboratory parameter. 
9.2.3.3 VITAL SIGNS 
Sitting and standing (where feasible) blood pressure, sitting pulse rate, respiratory rate, and 
body temperature will be assessed at the timepoints indicated in Appendix A – Schedule of 
assessments. Unscheduled measurement of vital signs may also be performed at other times if 
judged to be clinically appropriate or if the ongoing review of the data suggests a more 
detailed assessment of vital signs is required. Body temperature, blood pressure, respiratory 
rate, and pulse rate will be measured singly and repeated once if outside the relevant clinical 
reference ranges. 
Body temperature collected in degrees Fahrenheit (°F) will be converted into degrees Celsius 
(°C) using the formula: 
Temperature (°C) = (Temperature (°F) - 32) × 5/9 
Change from baseline (Study Day -1 measurement) will be calculated for each vital sign. 


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9.2.3.4 PHYSICAL EXAMINATION 
A full physical examination will be performed at screening (Visit 1) and admission on Day -1 
(Visit 2) and a brief or targeted physical examination will be performed approximately 24 
hours after each treatment (i.e., Study Days 2 and 4). 
The Study Day -1 measurement will be used as baseline when assessing changes from 
baseline. 
9.2.3.5 ECGS 
The 12-lead ECGs will be obtained at the timepoints specified in Appendix A – Schedule of 
assessments. 
Change from baseline (Screening Visit 1 measurement) will be calculated for each ECG 
parameter. 
9.2.3.6 COLUMBIA-SUICIDE SEVERITY RATING SCALE (C-SSRS) 
The C-SSRS will be administered at the timepoints specified in Appendix A – Schedule of 
assessments. The C-SSRS is a clinician-rated instrument that captures the occurrence, 
severity, and frequency of suicidal ideation and/or behavior during the assessment period. 
During study, the C-SSRS interview format will be administered by trained site staff. The C- 
SSRS will monitor for any changes in suicide ideation and/or behavior in patients 
participating in this trial. The “screening” C-SSRS will be used at Visit 1 to capture suicidal 
ideation in the past 6 months and suicidal behavior in the past 1 year, and the “since last 
visit” C-SSRS will be used at all other timepoints. 
9.2.4 PATIENT REPORTED MEASURES 
Patient-Reported Outcome Measurement (PROM) – ataxia 
The PROM of ataxia is a valid and reliable measure of motor ataxia, quality of life, and 
mental health. It is a 70-item questionnaire completed on a 5-point Likert scale (scores range 
from 0-4, with a maximum possible total score of 280), and will be evaluated at screening 
(Visit 1). The questionnaire is comprised of the following subsections: physical, activities of 
daily living, mental 1 (symptoms of depression and anxiety) and mental 2 (cognition). 
Patient/clinician impression of treatment 
The participant and clinician will be asked (separately) if they believe the participant received 
AUT00201 or placebo 24 hours ±2 hours after each dose (i.e., Study Days 1 and 3) and if 
they perceived any change in their condition. 
Patient top 3 concerns 
Participants will be asked to give their top 3 concerns (responses as free text) regarding their 
condition and functioning in their daily life, at screening (Visit 1). They will then be asked to 
score the severity of the concern on a 7-point Likert scale (scores range from 1-7). 






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10. 
STATISTICAL ANALYSES AND METHODOLOGY 
10.1 STUDY POPULATION 
10.1.1 DISPOSITION OF PARTICIPANTS 
The number of participants will be tabulated for the following: 
1. Screened (including rescreened participants) 
2. Rescreened 
3. Screen failure (with reasons) 
4. Dosed on Study Day 1 
5. Dosed on Study Day 3 
6. Completed Period 1 
7. Completed Period 2 
8. Completed the Study (all visits including phone follow-up) 
9. Discontinued the Study (with reasons) 
Rows (1) - (9) will be tabulated over all participants in the screened population. The number 
of participants in each analysis population will also be tabulated over all participants in the 
screened population. Participant disposition will be listed. 
10.1.2 PROTOCOL DEVIATIONS 
A listing of all participants with one or more important/non important protocol deviations 
will be presented for the screened population. The listing will identify the last treatment 
received prior to the deviation; no treatment will be listed if the deviation is prior to any 
treatment. 
10.1.3 DEMOGRAPHIC AND BASELINE CHARACTERISTICS 
The following analyses and listings will apply to the safety population. 
Age, sex, race, ethnicity, height, weight and body mass index (BMI) will be summarized. All 
demographic data will be listed. 
Medical history (including MedDRA system organ class [SOC] and preferred term [PT]), 
history of fever and whether an improvement of MEAK symptoms during fever was observed 
will be listed. 
Prior and concomitant medications will be listed with each medication being identified as 
either prior, concomitant or both (P, C or PC, respectively). Study day and treatment 
sequence will be included to help identify when the medication was taken in relation to study 
treatment. 
Regular concomitant medication administration dates and times through Visits 3 to 6 will 
also be listed. 
10.1.4 TREATMENT ADMINISTRATION 
Dates and times of treatment administration, time meal was completed prior to this, and 
reason for not taking a dose if applicable will be listed. 


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10.1.5 PATIENT REPORTED MEASURES 
The following patient reported measures will be listed: 
• PROM – ataxia 
• Patient/clinician impression of treatment 
• Patient top 3 concerns 
10.2 PHARMACODYNAMIC ANALYSES 
10.2.1 PHARMACODYNAMIC ENDPOINTS 
Table 4 shows the timepoints at which each of the PD assessments are collected, and outlines 
each of the analyses that will be performed for the secondary and exploratory endpoints. 
Analyses will include summary statistics for the change from baseline for participants in the 
mPD population. To produce placebo-controlled PD outcomes measures, within-participant 
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Criterion 3: 
≥2 Tier 1 outcome measures have positive outcomes from ≥3 
participants AND ≥3 Tier 2 outcome measures have positive 
outcomes from ≥ 3 participants. 
Please note that it could be a different set of participants fulfilling 
the Tier 1 and Tier 2 components of this criteria. 
The difference between the outcome measures on the treatment days (AUT00201 - Placebo) 
will be calculated for each participant and tabulated as ‘+’ (i.e., positive outcome, AUT00201 
better than placebo), ‘=’ (i.e., equivalent outcome) or ‘–‘ (i.e., negative outcome, placebo 
better than AUT00201). 
Within each tier, the total numbers of participants with ’+’ outcomes will then be tabulated 
for each outcome measure and the total number of outcome measures with ’+’ outcomes will 
be tabulated for each participant. 
To assess the false positive rates of each criterion simulations were performed. These 
simulations took into account the knowledge that 5 participants will be included in the mPD 
population; however, one participant will only have treatment comparison data for one Tier 1 
outcome measure and three Tier 2 outcome measures, and another participant will only have 
treatment comparison data for two Tier 1 outcome measures and three Tier 2 outcome 
measures. 
The false positive rates for criteria (1) - (3) were calculated as: 
• Criteria 1: 1.17% 
• Criteria 2: 1.95% 
• Criteria 3: 3.76% 
Overall, the false positive rate is calculated to be 6.22%. However, these calculations assume 
independence of the outcome measures. This is unlikely to be the case, but there is 
insufficient information to take this into account in the calculations. 
10.2.3 ASSESSING CLINICAL MEANINGFULNESS 
While the analysis outlined in Section 10.2.2 assesses if the pattern of observed results 
indicates a positive effect of AUT00201 it does not assess the clinical meaningfulness of the 
observed results. The clinical meaningfulness will be assessed as follows for each outcome 
measure: 
1. The standard deviation (SD) and mean will be calculated for Study Days -1, 2 and 4, 
(i.e., when participants did not receive any study treatment). Note SD and mean will 
only be calculated for Study Day 1 for endpoints that do not collect data on Study 
Days 2 and 4. 
2. The median SD will be determined from the SDs calculated in (1). 
3. The changes from baseline will be calculated for both treatments for each participant. 
4. The difference between treatments (AUT00201 – placebo) will be calculated for each 
participant. 
5. The changes from baseline [calculated in (3)] and the difference between treatments 
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sampling relative to dosing and the deviation (in minutes) from the scheduled time. In cases 
where a planned PK parameter could not be calculated (e.g., all concentrations are non- 
measurable), the result will be listed as “Not Calculable” (NC). 
The individual concentration profiles (presented on a linear scale) against actual time 
postdose will be plotted with all participants on the same plot. The pre-dose timepoint will be 
set to time=0. 
Additional plots will be generated to assess the relationship between PD assessment 
differences from placebo and AUT00201 exposure. The difference between treatments 
(AUT00201 – placebo) will be plotted against the AUT00201 Cmax (Study Day 1 or 3, as 
applicable) for the following: 
1. SICI - the average of the SICI 2.5ms and 3ms data derived from the assessments 2 
to 4 hours postdose on Study Days 1 and 3. 
2. MI - the average of the action myoclonus assessments from 9am to 1pm, i.e., 0-4 
hours postdose on Study Days 1 and 3. 
3. Speaking rate 1 hour postdose on Study Days 1 and 3. 
4. Buttercup count 1 hour postdose on Study Days 1 and 3. 
For each of the above, all participants will be presented on the same plot. 
The difference between treatments (AUT00201 – placebo) will also be plotted for MI against 
time, with the plasma concentration curve overlaid (Study Day 1 or 3, as applicable). Each 
participant will be displayed on separate plots. 
10.4.2 ANTIEPILEPTIC PHARMACOKINETICS 
Plasma concentrations for antiepileptic drugs (AEDs), for which assays are commercially 
available to the clinical site, will be listed, for the safety population. 


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11. 
CHANGES FROM THE PROTOCOL-SPECIFIED ANALYSIS 
The following planned changes are listed below: 
• Removed the final exploratory endpoint “Change from baseline in: Changes in 
biomarkers as compared to exposure to AUT00201.” In hindsight it was felt that this 
covered a set of analyses, rather than being an endpoint. Outputs comparing exposure 
(via PK parameters) to biomarkers are described in Section 10.4.1. 
• Added the modified pharmacodynamic population to the SAP, to handle subjects who 
participate in the study twice appropriately in PD analyses. 
• Minor changes to the presentation of summary statistics (including PK analyses) have 
been made to account for anticipated smaller sample size. 
• No reference to the mean (±SD) plasma concentration-time profiles discussed in the 
protocol. Individual profiles will be presented. 
• Table 3 of the Protocol refers to Ctrough and AUC24; these have been changed to 
Cpredose for a more accurate term for the single-dose design of the study and AUCt 
to account for the 27-hour PK sample timepoint. 


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12. 
BIBLIOGRAPHY 
Canafoglia, L. (2010). Short and long interval cortical inhibition in patients with Unverricht- 
Lundborg and Lafora body disease. Epilepsy research, 89(2-3), 232-237. 
Cohen, J. (1988). Statistical power analysis for the behavioral sciences. New York: 
Routledge. 
Frucht, S. J. (2002). The unified myoclonus rating scale. Adv Neurol, 89, 361. 
Norman, G. R. (2003). Interpretation of changes in health-related quality of life: the 
remarkable universality of half a standard deviation. Medical care, 41(5), 582-592. 
Rissanen, S. M. (2021). Wearable monitoring of positive and negative myoclonus in 
progressive myoclonic epilepsy type 1. Clinical Neurophysiology, 132(10), 2464- 
2472. 
Ziemann, U. (2004). Cortical threshold and excitability measurements. Handbook of Clinical 
Neurophysiology (Vol. 4), 317-35. 


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13. 
APPENDIX A – SCHEDULE OF ASSESSMENTS 
All timings are provided as a guide only for the order of assessments. However, it is 
important to note: 
• At times where pharmacokinetics is assessed, it should be drawn immediately after 
the action myoclonus assessment (or UMRS Sections 4 and 5 assessment) is 
performed 
• TMS should be performed at consistent times throughout 
• UMRS (Sections 4 and 5) should be performed prior to TMS. 
 


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