Clinical trial NCT04369430
Conditions: Parkinson Disease
Keywords: Brain Diseases Central Nervous System Diseases Nervous System Diseases Neurodegenerative Diseases Neurocognitive Disorders Mental Disorders Parkinson's Disease Dementia Movement Disorder Shaking Palsy
Sponsor: Alkahest, Inc.
Start date: 2020-01-16; Completion date: 2021-03-10
Enrollment: 110 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will evaluate the efficacy and safety of AKST4290 in subjects with Parkinson's Disease who are currently on stable dopaminergic treatment.

Detailed description:

Arms: arm 1: Subjects will receive AKST4290, 400 mg twice daily, for 12 weeks. arm 2: Subjects will receive placebo, twice daily, for 12 weeks.
Interventions: intervention 1: AKST4290 intervention 2: Placebo
Intervention descriptions: intervention 1: Oral AKST4290 intervention 2: Oral Placebo

Protocol documents:
SAP_002.pdf: 
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STATISTICAL ANALYSIS PLAN 
 
 
Based on: 
Protocol Version 4.0, Dated 22-MAY-2020 
 
 
 
 
SPONSOR: 
Alkahest, Inc. 
 
PROTOCOL NUMBER: 
AKST4290-211 
 
PROTOCOL TITLE: 
A Randomized, Double-Blind, Placebo- 
Controlled Study to Evaluate the Efficacy and 
Safety of AKST4290 in Subjects with 
Parkinson’s Disease on Stable Dopaminergic 
Treatment 
 
ORIGINAL PROTOCOL DATE: 
10-JAN-2019 
 
 
 
 
 
 
 
 
 
 
Created by: 
Clinical Trial Data Services, Inc. 
40 Nagog Park, Suite 325 
Acton, MA 01720 


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SAP Approval 
 
By signing the following, I agree to the contents in the Statistical Analysis Plan and its 
associated attachments. Once the SAP has been signed, the analyses and programming of the 
TLFs based upon this document can proceed. Any modifications to the SAP and TLFs made 
after signing may result in a change order. 
 
 
Approved by: 
 
 
Name 
Title 
Signature 
Date 
Esther Rawner, MD 
Sr Medical Director of 
Clinical Development 
 
4/7/2021 
Maura Barstow, MPH 
Principal Consultant/ 
Project Manager 
07Apr2021 


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Abbreviations 
 
Abbreviation 
Definition 
ADLB 
Laboratory analysis dataset 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
ALR 
Alternating logistic regression 
ANCOVA 
Analysis of covariance 
ATC 
Anatomical therapeutic chemical 
AST 
Aspartate transaminase 
BMI 
Body mass index 
CI 
Confidence interval 
CISI-PD 
Clinical Impression of Severity Index – Parkinson's Disease 
CM 
Concomitant medication 
CSR 
Clinical study report 
CSF 
Cerebrospinal fluid 
CWS 
Comfortable walking speed 
DBP 
Diastolic blood pressure 
ECG 
Electrocardiogram 
EOT 
End of treatment 
FACS 
Fluorescence-activated cell sorting 
FCS MI 
Fully conditional specification 
FWS 
Fast walking speed 
GEE 
Generalized Estimating Equations 
ITT 
Intention-to-Treat 
LS 
Least-square 
MDS-UPDRS 
Movement Disorder Society's Unified Parkinson's Disease Rating Scale 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intention-to-Treat 
MMRM 
Mixed-effect model for repeated measures 
MoCA 
Montreal Cognitive Assessment 
PD 
Parkinson’s disease 
PDQ-39 
Parkinson’s Disease Quality of Life Questionnaire-39 
PP 
Per-Protocol 
PMM 
Predictive mean matching 
PT 
Preferred term 
QTc 
Corrected QT interval 
QTcF 
QT interval corrected by the Fridericia formula 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SBP 
Systolic blood pressure 
SE 
Standard error 


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SE-ADL 
Schwab and England Activities of Daily Living Scale 
SOC 
System organ class 
S-STS 
Sheehan-Suicidality Tracking Scale 
STD 
Standard deviation 
TEAE 
Treatment-emergent adverse events 
ULN 
Upper limit of normal 
WHO 
World Health Organization 
WOCBP 
Women of childbearing potential 


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Table of Contents 
STATISTICAL ANALYSIS PLAN ............................................................................................................................. 1 
SAP APPROVAL ......................................................................................................................................................... 2 
ABBREVIATIONS ...................................................................................................................................................... 3 
1 INTRODUCTION .............................................................................................................................................................................................. 7 
2 OBJECTIVES .................................................................................................................................................................................................... 7 
2.1 
Primary Objective ......................................................................................................................................... 7 
2.2 
Secondary Objectives ................................................................................................................................... 7 
2.3 
Exploratory Objectives ................................................................................................................................. 7 
3 ENDPOINTS ...................................................................................................................................................................................................... 7 
3.1 
Primary Endpoint ......................................................................................................................................... 7 
3.2 
Secondary Endpoints .................................................................................................................................... 7 
3.3 
Exploratory Endpoints ................................................................................................................................. 8 
4 STUDY OVERVIEW ........................................................................................................................................................................................ 8 
4.1 
Study Design ................................................................................................................................................ 8 
4.2 
Treatment Assignment and Dose Regimen ................................................................................................... 8 
4.3 
Statistical Hypothesis .................................................................................................................................... 9 
4.4 
Sample Size Justification .............................................................................................................................. 9 
4.5 
Randomization/Unblinding ........................................................................................................................... 9 
4.5.1 
Randomization........................................................................................................................................... 9 
4.5.2 
Unblinding ................................................................................................................................................ 9 
4.6 
Interim Analyses ......................................................................................................................................... 10 
4.7 
Study Assessment Time Points .................................................................................................................... 10 
4.8 
Schedule of Events ..................................................................................................................................... 11 
5 STATISTICAL METHODOLOGY ................................................................................................................................................................ 14 
5.1 
General Considerations ............................................................................................................................. 14 
5.2 
Study Populations for Analysis ................................................................................................................... 14 
5.2.1 
Intention-to-Treat (ITT) Population ........................................................................................................ 14 
5.2.2 
Modified Intention-to-Treat (mITT)/Evaluable Population ...................................................................... 14 
5.2.3 
Safety Evaluable Population ................................................................................................................... 15 
5.2.4 
Per-Protocol (PP) Population ................................................................................................................. 15 
5.3 
Subject Disposition ..................................................................................................................................... 15 
5.4 
Demographics and other Baseline Characteristics .................................................................................... 15 
5.4.1 
Demographics ......................................................................................................................................... 15 
5.4.2 
Baseline Characteristics .......................................................................................................................... 16 
5.4.3 
Medical History ....................................................................................................................................... 16 
5.5 
Protocol Deviations ................................................................................................................................... 16 
5.6 
Methods for Handling Missing Data ........................................................................................................... 16 
5.7 
Efficacy Analyses ....................................................................................................................................... 16 
5.7.1 
Primary Efficacy Endpoint ...................................................................................................................... 16 
5.7.1.1 
Sensitivity Analyses ............................................................................................................................... 17 
5.7.2 
Secondary Efficacy Endpoints ................................................................................................................. 18 
5.7.2.1 
MDS-UPDRS Parts 1-4 ........................................................................................................................ 18 
5.7.2.2 
Montreal Cognitive Assessment ............................................................................................................ 19 
5.7.2.3 
Schwab and England Activities of Daily Living Scale .......................................................................... 19 
5.7.2.4 
Clinical Impression of Severity Index – PD .......................................................................................... 19 
5.7.2.5 
PD Quality of Life Questionnaire-39 ................................................................................................... 20 
5.7.2.6 
Sheehan-Suicidality Tracking Scale ..................................................................................................... 20 
5.7.2.7 
10-Meter Timed Walk ........................................................................................................................... 21 
5.7.2.8 
Hauser 3-Day Patient Diary................................................................................................................. 21 
5.7.3 
Exploratory Endpoints ............................................................................................................................ 22 


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5.7.3.1 
Pharmacokinetics ................................................................................................................................. 22 
5.7.3.2 
Wearable Sensor Device ...................................................................................................................... 22 
5.8 
Safety Analyses ........................................................................................................................................... 23 
5.8.1 
Study Drug Accountability ........................................................................................................................ 23 
5.8.2 
Adverse Events ........................................................................................................................................ 23 
5.8.2.1 
Summary for All TEAEs ....................................................................................................................... 23 
5.8.2.2 
Summary for Serious TEAEs ................................................................................................................ 24 
5.8.2.3 
Summary for AESI ................................................................................................................................ 24 
5.8.2.5 
Deaths ................................................................................................................................................... 24 
5.8.3 
Laboratory Data ...................................................................................................................................... 24 
5.8.4 
Vital Signs ............................................................................................................................................... 25 
5.8.5 
12-lead ECG ........................................................................................................................................... 25 
5.8.6 
Physical Examination .............................................................................................................................. 26 
5.8.7 
Pregnancy tests ....................................................................................................................................... 26 
5.8.8 
Elevated Liver Enzyme Investigations ...................................................................................................... 26 
5.8.9 
Prior and Concomitant Medications ....................................................................................................... 26 
APPENDIX A - PROGRAMMING SPECIFICATIONS FOR TABLES AND LISTINGS ............................................................................... 28 
REFERENCES ........................................................................................................................................................................................................ 30 


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1 
Introduction 
This Statistical Analysis Plan (SAP) describes the planned statistical analyses to be performed 
for data from Protocol AKST4290-211, “A Randomized, Double-Blind, Placebo-Controlled 
Study to Evaluate the Efficacy and Safety of AKST4290 in Subjects with Parkinson’s Disease 
(PD)on Stable Dopaminergic Treatment”. This SAP was created using Clinical Protocol 
AKST4290-211Version 4.0 dated 22-MAY-2020.The table and listing shells will be provided in 
separate files as attachments to this SAP. 
 
2 
Objectives 
 
2.1 
Primary Objective 
To assess the effects of AKST4290 on motor function in the practically defined off 
medication state, defined as ≥12 hours off levodopa, in subjects with PD. 
 
2.2 
Secondary Objectives 
To assess the safety of AKST4290 in subjects with PD as well as the potential 
effects on clinical function and activities of daily living. 
 
2.3 
Exploratory Objectives 
• To analyze pharmacokinetic parameters following twice daily dosing with 
AKST4290. 
• To assess flow cytometry, pharmacogenomic, and biomarker evaluations conducted 
on blood and plasma samples. 
• To assess bradykinesia, tremor, general activity, and sleep using a wearable device 
• To evaluate fecal samples obtained at screening and following treatment for potential 
microbiome changes in consenting subjects. 
 
3 
Endpoints 
 
3.1 
Primary Endpoint 
Change from Baseline (Day 1) in motor function during the practically defined off- 
medication state, defined as ≥12 hours off levodopa, at Week 12 (Day 84) as measured 
by Movement Disorder Society's Unified Parkinson's Disease Rating Scale (MDS- 
UPDRS), Part 3. 
 
3.2 
Secondary Endpoints 
• Incidence of treatment-emergent adverse events (TEAEs) and serious adverse events 
(SAEs) identified by the Medical Dictionary for Regulatory Activities (MedDRA) 
preferred term (PT) and grouped by MedDRA System Organ Class (SOC). 
• Incidence of abnormalities or clinically-significant changes from Baseline in 
laboratory test data, vital sign measurements, and electrocardiograms (ECGs). 


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• Change from Baseline (Day 1) in clinical function, motor function, and activities of 
daily living at Week 12 (Day 84) during the on-medication state as assessed by: 
o MDS-UPDRS Parts 1-4 
o Montreal Cognitive Assessment (MoCA) 
o Schwab and England Activities of Daily Living (SE-ADL) Scale 
o Clinical Impression of Severity Index – PD (CISI-PD) 
o PD Quality of Life Questionnaire-39 (PDQ-39) 
o Sheehan-Suicidality Tracking Scale (S-STS) 
o 10-meter timed walk (will also be assessed in the off-medication state) 
o Hauser 3-Day Patient Diary 
 
3.3 
Exploratory Endpoints 
• Changes in concentration of AKST4290 or its major metabolites in plasma at various 
time points. 
• Flow cytometric analyses and evaluation of pharmacogenomic characteristics and 
biomarkers in blood and plasma samples. 
• Changes in bradykinesia, tremor, general activity, and sleep as measured by an 
FDA-cleared wearable sensor device. 
• In consenting subjects (optional): characterization of the composition and function of 
the fecal gut microbiome. 
 
4 
Study Overview 
 
4.1 
Study Design 
This is a phase 2, randomized, double-blind, placebo-controlled study to assess the 
efficacy and safety of AKST4290 in subjects with PD. 
 
The study will enroll approximately 120 subjects between 50 and 80 years of age with a 
diagnosis of PD on dopaminergic treatment from approximately 30 sites globally. 
Enrolled subjects will be randomized in a 1:1 ratio to active treatment in Arm 1 
(approximately 60 subjects) or placebo in Arm 2 (approximately 60 subjects). Subjects 
will take 400 mg of AKST4290 or placebo orally, twice per day (b.i.d.) for a total daily 
dose of 800 mg. The study duration for the subjects will be approximately 18weeks 
including screening, 12 weeks of treatment, and 4weeks of follow-up. A detailed 
overview of the timing of study assessments and interventions is presented in the 
Schedule of Events section below. 
 
4.2 
Treatment Assignment and Dose Regimen 
A subject number will be assigned once the subject has signed the informed consent 
form. Enrolled subjects that have met all eligibility criteria will be randomized to 
AKST4290 (Arm 1: active dosing) or placebo (Arm 2: placebo dosing). The study drug 
will be self-administered orally b.i.d. (2 x 200 mg per dose), approximately 12 hours 


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apart, for a total daily dose of 800 mg. Subjects will receive study drug or placebo for a 
total of 12 weeks, followed by 4weeks of follow-up. 
 
4.3 
Statistical Hypothesis 
The null and alternative hypotheses for primary endpoint analysis are: 
 
H0: µC = µT vs. HA: µC ≠ µT. 
 
The null hypothesis is that there is no difference in mean change (µ) from baseline motor 
function during the practically defined off-medication state at Week 12 - as measured by 
the MDS-UPDRS Part 3 - between the control (C) and treated (T) groups. The alternative 
hypothesis is that there is a difference in mean change from baseline motor function 
during the practically defined off-medication state at Week 12 between the control and 
treated groups. P-values for testing whether the differences are equal to zero will be 
provided. P-values will be compared against an alpha significance level of 0.1. 
 
4.4 
Sample Size Justification 
A total of approximately 120 subjects will be randomized in a 1:1 ratio to active 
treatment (approximately 60 subjects) or placebo (approximately 60 subjects), with the 
intent of obtaining ~108 evaluable subjects. 
 
The variability of change from baseline in the off-medication motor function as measured 
by MDS-UPDRS, Part 3 is approximately 6.4 and 7.6 points at Weeks 48 and 60, 
respectively, for the placebo group, and approximately 4.9 and 4.8 in a previous study of 
the compound Exenatide (Athauda, 2017). Assuming the variability at Week 12 is similar 
to that at Week 48, and assuming the variability in the AKST4290 treated group is similar 
to that of Exenatide-treated subjects, the sample size for the study will based on STD = 
6.4 and 4.9 for the control and treated respectively. With n=54 evaluable subjects in each 
arm, the study will have more than 85% power to detect a difference in means between 
arms when the true difference is 3 points based on a two-sided t-test at an alpha of 0.1. If 
the true difference is 4 points, the power increases to more than 95%. 
 
4.5 
Randomization/Unblinding 
This is a randomized and double-blind study. 
 
4.5.1 
Randomization 
A randomization list, permuted blocks and stratified by sex (Male and Female) 
was generated by an outside vendor and is outside the scope of this SAP. 
 
4.5.2 
Unblinding 
The study blind can be broken for safety reasons if the information is required for 
the management of SAEs, severe AEs, or pregnancies. The Investigator can 
obtain the treatment allocation for their subject through the web-based 


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randomization system (IRT). Else, the blinded code for the trial will be broken 
only after all subject data has been recorded and verified and the database locked. 
 
4.6 
Interim Analyses 
Safety will be monitored on an ongoing basis, and a Safety Evaluation Meeting may be 
triggered (see protocol section 8.5). Any such ad hoc interim safety analysis performed 
will be outside the scope of this SAP. 
 
4.7 
Study Assessment Time Points 
The study consists of 8 protocol-specified visits which will be assessed as nominal visits 
from an analysis perspective: 
 
• Visit 1, Screening Visit (Day -14 to -7) 
• Visit2, Baseline (Day 1): Subjects will be randomized after eligibility has been 
confirmed, study drug/placebo dispensed. 
• Visit 3 (Day 14 ± 2) 
• Visit 4 (Day 28 ± 2) 
• Visit 5 (Day 56 ± 2) 
• Visit 6 – End of Treatment (EOT) (Day 84 ± 2) 
• Visit 7 (Day 98 ± 3 or 14 days after Early Termination) 
• Safety Follow-Up (Day 114 ± 2 or 30 days after Early Termination): a documented 
phone call to record AEs and concomitant medications (CMs). 
• Early termination: In cases of early termination, if a subject has received at least 1 
dose (400 mg) of AKST4290 or placebo, the site should try to perform all 
assessments scheduled at the Visit 6 - EOT visit as well as the subsequent follow up 
visits unless the subject has withdrawn consent. 


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4.8 
Schedule of Events 
 


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5 
Statistical Methodology 
 
5.1 
General Considerations 
This section presents the statistical approaches that are anticipated for the analysis of the 
study data. These approaches may at times require modifications due to unanticipated 
features of the data. Deviations from analyses summarized in this document will be noted 
in the clinical study report (CSR). 
 
All statistical analyses will be performed using SAS® Version 9.4 or higher, unless 
otherwise noted. All summary statistics will be descriptive unless noted otherwise. 
Descriptive summaries will include mean, standard deviation (STD), median, and range 
for continuous variables and counts, and percentages for categorical variables. Two-sided 
95% confidence intervals (CIs) will be provided for the means and percentages as 
needed. For key outcome measures, the difference between the treatment arms and the 
95% CI of the difference will be computed, as necessary. Presentations will be by 
treatment group, unless otherwise noted. 
 
In general, all summary tables will be supported by a relevant subject data listing 
including all subjects who are randomized. The listings will include all data collected, 
and will be sorted by subject ID, and actual visit date, as applicable, unless otherwise 
noted. 
 
Concomitant medications will be coded by the World Health Organization (WHO)Drug 
Dictionary and adverse events and medical history will be coded using the MedDRA. The 
dictionary versions will be documented in the Data Management Plan for the study. 
 
Study day 1 is the first day of study treatment. Study day is the day relative to the study 
day 1. Baseline is the last non-missing valid value prior to study treatment. 
 
5.2 
Study Populations for Analysis 
 
5.2.1 
Intention-to-Treat (ITT) Population 
All subjects who were randomized into the study will be included in the ITT 
population. Analysis will be done according to the treatment subjects were 
randomized to. 
 
5.2.2 
Modified Intention-to-Treat (mITT)/Evaluable Population 
The mITT/evaluable population will be a subset of the ITT population that only 
includes subjects with non-missing baseline and Week 12 (Day 84) values for off- 
medication motor function as measured by the MDS-UPDRS Part 3. Analysis will 
be done according to the treatment subjects were randomized to. 


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5.2.3 
Safety Evaluable Population 
The safety population will consist of all subjects who received at least one dose of 
the study medication. All safety endpoints will be summarized for the safety 
population. Analysis will be done according to the actual treatment subjects 
received. 
 
5.2.4 
Per-Protocol (PP) Population 
The PP population will be a subset of the ITT population that only includes 
subjects who have complete baseline and Week 12 assessments without any 
protocol deviation(s)which would interfere with the assessment of efficacy. 
 
Such protocol deviations are departures from the approved protocol relating to the 
conduct of the study which may affect the rights, safety, and/or wellbeing of study 
participants or the study outcomes or data quality. A listing of study subjects with 
protocol deviations which would preclude inclusion in the PP population will be 
provided by the Sponsor prior to database lock. 
 
The PP population is a supportive analysis population for the primary and 
secondary efficacy endpoints, and will be used in sensitivity analyses as needed. 
Analysis will be done according to the treatment subjects were randomized to. 
 
5.3 
Subject Disposition 
All subjects who signed the informed consent will be accounted for in Subject 
Disposition. The following disposition information will be summarized by the number 
and percentages of subjects: 
• Subjects who signed the informed consent, and who comprise the ITT, 
mITT/Evaluable, Safety, and PP populations 
• Subjects who complete the study or withdraw prematurely along with the reason for 
discontinuation 
A listing of screen failure subjects, including age, sex, race, ethnicity, education, and the 
inclusion/exclusion criteria not met, will be provided. 
 
A listing of subjects excluded from each of the analysis populations, including population 
flags (Safety/mITT/Evaluable) and the reason for exclusion, will be provided. 
 
5.4 
Demographics and other Baseline Characteristics 
 
5.4.1 
Demographics 
Sex, age (in years), race, ethnicity, education, and baseline body mass index 
(BMI) (kg/m2) will be summarized by treatment group for the ITT and 
mITT/Evaluable populations. BMI (kg/m2) will be calculated as: 10,000*weight 
(kg) / the square of height (cm). If height is collected in inches, it will be 
converted to cm by dividing the value by 2.54. If weight is collected in pounds, it 
will be converted to kg by dividing the value by 2.205. 


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5.4.2 
Baseline Characteristics 
Baseline characteristics will be summarized by treatment group for the ITT and 
mITT/Evaluable populations. 
 
Baseline characteristics to be summarized are: 
• Disease Duration 
• Modified Hoehn and Yahr 
• MDS-UPDRS Parts 3 in the off-medication state 
 
5.4.3 
Medical History 
The number and percentage of subjects with any medical history will be 
summarized for the ITT population by treatment group, SOC, and PT using the 
MedDRA dictionary. 
 
The following will be provided in listings only: 
• Family history in biological parents, siblings, and offspring of PD, 
Alzheimer’s disease (AD), or other dementias or neurological disorders 
• Cause of parental death (if not living) 
• History of tobacco and substance use 
• Social history and exercise/activity level 
5.5 
Protocol Deviations 
Protocol deviations will be summarized by deviation category, major vs minor and 
treatment group for the ITT population, with flags for the mITT/Evaluable, Safety, and 
PP populations. 
 
5.6 
Methods for Handling Missing Data 
In order to minimize missing data, every effort will be made to obtain required data for 
all randomized subjects at each scheduled evaluation. However, in the event that more 
than 5% of data are missing, imputation methods will be used for analysis of the primary 
endpoint only. The imputation will be carried out in SAS version 9.4 or later using PROC 
MI. 
 
5.7 
Efficacy Analyses 
Efficacy analyses will evaluate the effects of AKST4290 on motor function in the off- 
medication state, as well as the potential effects on clinical function and activities of daily 
living. Efficacy endpoints will be evaluated using the mITT/Evaluable and PP 
populations. 
 
5.7.1 
Primary Efficacy Endpoint 
The primary endpoint is change from baseline at Week 12 (Day 84) in the off- 
medication motor function as measured by the MDS-UPDRS Part 3. The main 
analysis for the primary efficacy variable will be analyzed using mITT subjects. 


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The MDS-UPDRS (Fahn, 1987; Goetz, 2008) was developed to incorporate 
elements from existing scales to provide a comprehensive but efficient and 
flexible means to monitor PD-related disability and impairment. The MDS- 
UPDRS has four components (Part 1, Mentation, Behavior, and Mood; Part 2, 
Activities of Daily Living; Part 3, Motor; Part 4, Complications). The rating for 
each item is from 0 (normal) to 4 (severe). The score for each Part is obtained 
from the sum of the corresponding item scores. 
 
The null and alternative hypotheses for the primary endpoint are: 
H0: µC = µT vs. HA: µC ≠ µT. 
 
The null hypothesis states that there is no difference in mean change (µ) from 
baseline motor function during the practically defined off-medication state at 
Week 12 - as measured by the MDS-UPDRS Part 3 - between the control (C) and 
treated (T) groups. The alternative hypothesis states that there is a difference in 
mean change from baseline motor function during the practically defined off- 
medication state at Week 12 between the control and treated groups. 
 
The MDS-UPDRS Part 3 is administered in the off-medication state at Baseline 
(Study Day 1) and Weeks 4 (Day 28), 12 (Day 84), and 14 (Day 98). The sum of 
corresponding items for section 3 will be summarized descriptively at each 
scheduled visit. Additionally, the number and percentage of subjects with 
dyskinesia present during the evaluation, and whether that dyskinesia interfered 
with ratings, will be presented. 
 
A mixed-effect model for repeated measures (MMRM) will be employed to 
analyze the change from baseline scores at each visit over time up to Week 12. 
The model will include the fixed effects of treatment (stratified, by sex), baseline 
of the endpoint, visit, and treatment by visit interaction. An unstructured 
covariance structure will be used to model the within subject error. Least-square 
(LS) means, standard error (SE), and 95% CI of the LS mean will be provided for 
each treatment arm at each visit. The unadjusted mean change from baseline, and 
the difference in LS means between treatment arms and 95% CI of the difference 
will also be calculated. P-value for testing whether the difference is equal to zero 
will be provided. The p-value at Week 12 will be compared against the alpha 
significance level of 0.1. 
 
5.7.1.1 
Sensitivity Analyses 
The main analysis of the primary endpoint using the above MMRM will 
use all available data. To check the robustness of the results, the following 
sensitivity analyses will be performed: 


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• Analysis of covariance (ANCOVA) model on the observed change 
from baseline value at Week 12. The model includes treatment as 
the fixed effect and baseline of the endpoint as a covariate. 
• The same MMRM model on data from the PP subjects. 
• The same MMRM model on data from the ITT subjects. 
• Depending on the status of missing data among the mITT 
population, multiple imputations may be employed to handle 
missing data and apply the MMRM on the imputed datasets. See 
Methods for Handling Missing Data section (section 5.6) for 
details on imputation methods. 
 
5.7.2 
Secondary Efficacy Endpoints 
Secondary efficacy endpoints will be analyzed using the mITT/Evaluable, ITT, 
and PP populations. Please see Safety Analysis section (Section5.8) for 
information regarding analysis of safety endpoints. 
 
Secondary efficacy endpoints include the following: 
 
Change from Baseline (Day 1) in clinical function, motor function, and activities 
of daily living at Week 12 (Day 84) during the on-medication state as assessed by: 
▪ MDS-UPDRS Parts 1-4 
▪ Montreal Cognitive Assessment 
▪ Schwab and England Activities of Daily Living Scale 
▪ Clinical Impression of Severity Index – PD 
▪ PD Quality of Life Questionnaire-39 
▪ Sheehan-Suicidality Tracking Scale 
▪ 10-meter timed walk (will also be assessed in the off-medication state) 
▪ Hauser 3-Day Patient Diary 
 
5.7.2.1 
MDS-UPDRS Parts 1-4 
The MDS-UPDRS Parts 1-4 is administered in the on-medication state at 
Baseline and Weeks 2, 4, 8, 12, and 14. The scores for each section (i.e. 
sum of corresponding items for each section) will be summarized 
descriptively at each scheduled visit. Additionally, the difference in the 
MDS-UPDRS Part 3 between the on-medication and off-medication state 
will be reported. 
 
To evaluate change from baseline, the same MMRM model used to 
evaluate the primary endpoint will be employed to produce LS means, SE, 
and 95% CIs of the LS means for each treatment arm at each scheduled 
visit. The unadjusted mean change from baseline, and the difference in LS 


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means between treatment arms and 95% CI of the difference will also be 
calculated. 
 
5.7.2.2 Montreal Cognitive Assessment 
The MoCA (Nasreddine, 2005) is a screening test used to assess attention 
and concentration, executive function, memory, language, visuo- 
constructional skills, conceptual thinking, calculations, and orientation. 
The total possible score is 30 points with a score of 26 or 
more considered normal. 
 
The MoCA is administered at Baseline and Week 12 in the on-medication 
state. The total score will be summarized at each scheduled time point. To 
evaluate change from baseline, an analysis of covariance (ANCOVA) 
model will be used to produce the LS mean, SE, and 95% CI of the LS 
means for each treatment arm. The unadjusted mean change from baseline, 
and the difference in LS means between treatment arms and 95% CI of the 
difference will also be calculated. A summary of each cognitive domain 
will be provided as well. 
 
5.7.2.3 
Schwab and England Activities of Daily Living Scale 
The SE-ADL evaluates patients’ perceptions of global functional capacity 
and dependence (Schwab, 1968). Scoring is expressed in terms of 
percentage, in 10 steps from 100 to 0 (100%, normal status; 
0%, bedridden with impaired vegetative functions), so that the lower the 
score, the worse the functional status. 
 
Scores are collected at Baseline, and Weeks 2, 4, 8, 12, and 14. Scores will 
be summarized descriptively at each scheduled time point (i.e. n, %) by 
treatment group. A Generalized Estimating Equations (GEE) for 
alternating logistic regression (ALR) with an exchangeable working 
correlation structure will be employed to analyze change from baseline. 
The model will include the fixed effects of treatment, baseline of the 
endpoint, visit, and treatment by visit interaction. The common odds ratio 
and 95% CI for odds of higher versus lower SE-ADL scores between 
treatment groups will be presented. Mean scores at each timepoint, and 
change from baseline, will also be presented. 
 
5.7.2.4 
Clinical Impression of Severity Index – PD 
The CIS-IPD is a severity index formed by four items (motor signs, 
disability, motor complications, and cognitive status), rated 0 (not at all) to 
6 (very severe or completely disabled) (Martinez-Martin, 2006). A total 
score is calculated by summing the item scores. 
 
The CISI-PD is administered in the on-medication state at Baseline, and 
Weeks 2, 4, 8, 12, and 14. The total score will be summarized 


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descriptively at each scheduled visit. To evaluate change from baseline in 
the total score, the same MMRM model used to evaluate the primary 
endpoint will be employed to produce LS means, SE, and 95% CIs of the 
LS means for each treatment arm at each scheduled visit. The unadjusted 
mean change from baseline, and the difference in LS means between 
treatment arms and 95% CI of the difference will also be calculated. A 
summary of each parameter will be presented as well. 
 
5.7.2.5 
PD Quality of Life Questionnaire-39 
The PDQ-39 is a self-administered questionnaire of 39 questions relating 
to 8 key areas of health and daily activities, including both motor and non- 
motor symptoms (Peto, 1998). The eight dimensions include: mobility, 
activities of daily living, emotional well-being, stigma, social support, 
cognition, communication, and bodily discomfort. It is scored on a scale of 
0-100 with lower scores indicating better health and high scores indicating 
more severe symptoms. 
 
The PDQ-39 is collected at Baseline and Weeks 2, 4, 8, 12, and 14. The 
total scores for each of the eight dimensions and the overall total score 
will be summarized descriptively at each scheduled visit. To evaluate 
change from baseline, the same MMRM model used to evaluate the 
primary endpoint will be employed to produce LS means, SE, and 95% 
CIs of the LS means for each treatment arm at each scheduled visit. The 
unadjusted mean change from baseline, and the difference in LS means 
between treatment arms and 95% CI of the difference will also be 
calculated. 
 
5.7.2.6 
Sheehan-Suicidality Tracking Scale 
The S-STS was developed to provide a brief but efficient instrument for 
use in assessing change in suicidal ideation and behavior while providing 
a comprehensive description of suicidal ideation and behavior (Sheehan, 
2014). The standard version of the S-STS is a 16-item scale that assesses 
the seriousness of suicidality phenomena on a Likert-type scale (0-4) 
ranging from “not at all” (0) to “extremely” (4). It also assesses the 
frequency of key phenomena and the overall time spent in suicidality. 
 
The S-STS is collected at Baseline and Week 12. Total score will be 
summarized descriptively at each scheduled time point. To evaluate 
change from baseline, an analysis of covariance (ANCOVA) model will 
be used to produce the LS mean, SE, and 95% CI of the LS means for 
each treatment arm. The unadjusted mean change from baseline, and the 
difference in LS means between treatment arms and 95% CI of the 
difference will also be calculated. 


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5.7.2.7 
10-Meter Timed Walk 
The 10-meter walk test is a commonly used tool for assessing gait speed in 
individuals with gait limitations (Lang, 2016). Gait speed is positively 
correlated with the amount of community ambulation and quality of life, 
and it is an important measure of mobility in individuals with PD. 
 
The 10-meter timed walk is conducted in the on-medication state at 
Baseline and Weeks 2, 4, 8, 12, and 14, as well as the off-medication state 
at Baseline and Weeks 4, 12, and 14. Based on two consecutive 
measurements, average comfortable walking speed (CWS) (m/s) and fast 
walking speed (FWS)(m/s) will be calculated for each subject at each 
scheduled visit. CWS and FWS will then be summarized descriptively at 
each scheduled visit by treatment arm. The difference in both the CWS 
and FWS between the on-medication and off-medication state will also be 
reported. 
To evaluate change from baseline, the same MMRM model used to 
evaluate the primary endpoint will be employed to produce LS means, SE, 
and 95% CIs of the LS means for each treatment arm at each scheduled 
visit. The unadjusted mean change from baseline, and the difference in LS 
means between treatment arms and 95% CI of the difference will also be 
calculated. 
 
5.7.2.8 
Hauser 3-Day Patient Diary 
The Hauser Patient Diary was developed to assess functional status over a 
period of time in patients with motor fluctuations and dyskinesia (Hauser, 
2000). It is a self-completed reference diary designed to separate 
dyskinesia that had a negative impact on patient-defined functional status 
from dyskinesia that did not. With this diary, the effect of an intervention 
can be expressed as the change in off-medication time and the change in 
on-medication time with troublesome dyskinesia (bad time). The sum can 
be used as an outcome variable and compared to baseline or across groups. 
 
The Hauser 3-day patient diary is collected at Baseline and Week 12. 
Mean “bad time” (in hours) over the three days of collection will be 
summarized descriptively at both time points. Based on the research 
conducted by Hauser (2000, 2004), bad time is defined as the sum of off 
time and on time with troublesome dyskinesia. Mean “good time”, defined 
as on time without dyskinesia plus on time with non-troublesome 
dyskinesia, will also be summarized descriptively. Additionally, mean % 
day spent in “bad time” and “good time” will be summarized 
descriptively. Mean % day spent in “bad time” or “good time” is the mean 
number of hours spent in bad time or good time, divided by the mean 
number of waking hours over the three-day period. 


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To evaluate change from baseline in bad time, good time, mean % day 
spent in bad time, and mean % day spent in good time, an analysis of 
covariance (ANCOVA) model will be used to produce the LS mean, SE, 
and 95% CI of the LS means for each treatment arm. The unadjusted mean 
change from baseline, and the difference in LS means between treatment 
arms and 95% CI of the difference will also be calculated. 
 
5.7.3 
Exploratory Endpoints 
Exploratory endpoints will be analyzed using the mITT/Evaluable populations. 
Only descriptive statistics will be provided, treatment comparisons will not be 
performed. 
 
Exploratory endpoints included in this SAP are: 
• Changes in concentration of AKST4290 and its major metabolites in 
plasma at various time points. 
• Changes in bradykinesia, tremor, general activity, and sleep as measured 
by an FDA-cleared wearable sensor device. 
Analysis of other exploratory endpoints may be performed, and are outside the 
scope of this SAP. 
 
5.7.3.1 
Pharmacokinetics 
Plasma concentration measurements of AKST4290 and the major 
metabolites M227 and M373 will be collected to assess systemic exposure 
to the study agent. Pharmacokinetic samples will be collected immediately 
prior (-15 min) to study drug administration at Baseline and Weeks 2, 4, 8, 
12, and 14, as well as 1 hour and 2 hours after administration at Baseline 
and Weeks 4 and 12. A final PK sample will be collected at Follow-Up 
(Week 14). Concentration of AKST4290 in plasma will be summarized 
descriptively at each visit timepoint. 
 
5.7.3.2 
Wearable Sensor Device 
A wearable sensor device allowing for the continuous measurement of 
health-related symptoms, including the motor and nonmotor features of 
bradykinesia, tremor, general activity, and sleep, will be provided to 
applicable subjects at Screening, Week 4, and Week 8. Data will then be 
collected over a 6-day period and returned at the following visit (i.e. 
Baseline, Week 8, and End of Treatment). Bradykinesia, tremor, general 
activity, and sleep parameters will be summarized descriptively at each 
applicable timepoint. 
 
To evaluate change from baseline, the same MMRM model used to 
evaluate the primary endpoint will be employed to produce LS means, SE, 
and 95% CIs of the LS means for each treatment arm at each scheduled 


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visit. The unadjusted mean change from baseline, and the difference in LS 
means between treatment arms and 95% CI of the difference will also be 
calculated. 
 
5.8 
Safety Analyses 
Safety analysis includes study drug accountability, incidence and severity of treatment 
emergent adverse events, laboratory parameters, vital signs, 12-lead ECG, physical 
examination, pregnancy tests, and prior and concomitant medications. Unless otherwise 
specified, safety parameters will be summarized by treatment group using the safety 
population. 
 
5.8.1 
Study Drug Accountability 
The number of subjects receiving daily doses of 800 mg of study medication will 
be summarized over the entire course of study treatment and between baseline and 
Week 4, Week 4 and Week 8, and Week 8 and End of Treatment (Week 12) by 
treatment group, for the safety population. The number of subjects with missed or 
additional doses will also be summarized. 
 
5.8.2 
Adverse Events 
All TEAEs will be reported. A TEAE is defined as an AE that occurs on or after 
the date of the first study treatment. 
 
A summary of all TEAEs by the number and percentages of subjects who 
experienced any of the following will be provided: 
• Any TEAE, including severity (Mild, Moderate, and Severe), and 
relationship to study treatment (Unrelated, Possibly Related, Definitely 
Related), and AEs leading to discontinuation of study participation. 
• Any serious TEAE, including severity (Mild, Moderate, and Severe), and 
relationship to study treatment (Unrelated, Possibly Related, Definitely 
Related), and AEs leading to discontinuation of study participation. 
• Any event of Special Interest (AESI). 
• Any fatal TEAEs, including relationship to study treatment (Unrelated, 
Possibly Related, Definitely Related). 
 
5.8.2.1 
Summary for All TEAEs 
The number and percentage of subjects who experience TEAEs will be 
tabulated by SOC and PT using the MedDRA dictionary. Adverse events 
will be counted only once for a subject within each PT and SOC; thus, 
since a subject may have more than one PT within a SOC, percentages of 
PT may not sum to the percentages in the SOC. 
 
For all TEAEs the following will be summarized: 
• Overall summary of any TEAEs, presented by SOC/PT 


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• Overall summary of any TEAEs by worst severity, presented by 
SOC/PT 
• Overall summary of any TEAEs by closest relationship to study 
treatment, presented by SOC/PT 
 
A listing of all AEs will be provided. This listing will include a flag 
identifying if an AE is a TEAE. 
 
5.8.2.2 
Summary for Serious TEAEs 
For all serious TEAEs the following will be summarized: 
• Overall summary of any serious TEAEs by worst severity, 
presented by SOC/PT 
• Overall summary of any serious TEAEs by closest relationship to 
study treatment, presented by SOC/PT 
 
A listing of all serious AEs will be provided. This listing will include a 
flag identifying if an AE is a TEAE. 
 
5.8.2.3 
Summary for AESI 
The following will be considered AESI: 
• Drug-Induced Liver Injury defined by the following alterations of 
liver parameters: For subjects with normal liver function at 
baseline an elevation of Aspartate transaminase (AST) and/or 
Alanine aminotransferase (ALT) ≥ 3-foldupper limit of normal 
(ULN) combined with an elevation of total bilirubin > 2-fold ULN 
measured in the same blood draw sample. 
• Corrected QT interval (QTc)prolongation (> +60 ms from baseline 
and/or > 450 ms in men or > 470 ms in women using Fridericia’s 
formula). 
An overall summary of any AESIs by worst severity, presented by 
SOC/PT, will be provided. 
 
5.8.2.5 
Deaths 
Deaths, if any, will be provided in a listing only. 
 
5.8.3 
Laboratory Data 
Biological samples (e.g. whole blood, serum/plasma, urine) will be collected at all 
in-person visits (i.e. Visits 1-7) for laboratory evaluations. Laboratory test will 
include hematology, chemistry, coagulation, infectious disease serology, 
qualitative urinalysis, and pregnancy testing in women of childbearing potential 
(WOCBP). Laboratory data summaries will consist of the following: 


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• Observed values at screening, baseline and Weeks 2, 4, 8, 12, and 14 
along with change from baseline at each scheduled post-baseline visit. 
• Shift tables by treatment group and by out of range flag at Weeks 2, 4, 8, 
12, and 14, compared to baseline. 
• Number and percentage of subjects with abnormal laboratory tests at all 
visits. 
The tests will be presented in the original units collected. If the original value 
contains the “<” sign, AVAL in the laboratory analysis dataset (ADLB) dataset 
will be derived by extracting the numeric value from LBSTRESC and subtracting 
0.1(N+1) to that numeric value, where N is the number of decimals in the numeric 
value. For example, AVAL will be set to 0.29 if LBSTRESC =“< 0.3”. If the 
LBSTRESC value contains the “>” sign, AVAL in the ADLB dataset will be 
derived by extracting the numeric value from LBSTRESC and adding 0.1(N+1) to 
that numeric value, where N is the number of decimals in the numeric value. For 
example, if LBSTRESC =”>1000”, AVAL will be set to “1000.1”. Subject 
listings will present all data collected along with toxicity grading. 
 
Results for chemistry, hematology, urinalysis, coagulation, infectious serology, 
and pregnancy tests in WOCBP will be provided in separate listings. A listing of 
abnormal laboratory tests will also be provided. 
 
5.8.4 
Vital Signs 
Vital signs, including blood pressure (mmHg), heart rate (beats/min), respiratory 
rate (breaths/min), and body temperature (C), will be collected at all in-person 
visits (i.e. Visits 1-7). Observed values will be tabulated at screening, baseline, 
and at each scheduled post-baseline time point. Change from baseline at each 
scheduled post-baseline time point will also be summarized by treatment group. 
 
Vital signs at each scheduled time point will also be provided in subject data 
listings. 
 
5.8.5 
12-lead ECG 
A 12-lead ECG will be performed to obtain Heart rate (beats/min), QT interval 
(msec), and QT interval corrected by the Fridericia formula (QTcF). ECGs will be 
collected at Screening and at Weeks 4 and 12. Observed values, along with the 
change from baseline at each scheduled post-baseline visit, will be summarized by 
treatment group. Additionally, a frequency table detailing the overall 
interpretation of ECG findings will be provided. 
 
A listing of abnormal 12-lead ECG will also be generated. 


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5.8.6 
Physical Examination 
Full or targeted physical examinations will be conducted at every in-person study 
visit (i.e. Visits 1-7). The number and percentage of subjects with abnormal 
clinically significant and not clinically significant physical examination results 
will be summarized by the body systems at each scheduled visit. 
 
5.8.7 
Pregnancy tests 
Pregnancy test results will be provided for women of childbearing potential in a 
listing only. 
 
5.8.8 Elevated Liver Enzyme Investigations 
Adverse events of abnormal liver enzyme values meeting the following criteria 
may require additional investigation: 
 
• Elevations in ALT and/or AST ≥ 3x ULN but < 5x ULN without bilirubin 
elevations confirmed on repeat testing. 
• Elevations in ALT and/or AST ≥ 5x ULN without bilirubin elevations 
confirmed on repeat testing. 
• Drug-Induced Liver Injury 
Elevated liver enzyme investigations may include: imaging, repeat lab testing, and 
review of symptoms, medical history, and exposure to risk factors (e.g. 
concomitant drug and alcohol use, etc.). All elevated liver enzyme investigations 
will be provided in listings. The number and percentage of subjects that met the 
criteria for the above liver enzyme categories will be summarized from the 
laboratory data. 
 
5.8.9 Prior and Concomitant Medications 
The number and percentage of subjects taking any prior and concomitant 
medications will be summarized by anatomical therapeutic chemical (ATC) level 
3 terms and preferred medication names. 


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6 
Document Version Control 
Revision History: 
REVISION 
RELEASE 
DATE 
AUTHOR 
SUMMARY OF CHANGES 
A 
23Dec2020 
M. Arthur 
Original release 
B 
08Apr2021 
M. Arthur/M. 
Barstow 
-Modify specification of MMRM 
model to ANCOVA model, when 
only baseline and Week 12 data. 
-Per Sponsor request add ITT 
population for efficacy tables; add 
breakdown of each cognitive domain 
for MoCA, include mean scores for 
SE-ADL; add breakdown of each 
parameter for CISI-PD; include 
overall summaries for abnormal 
Chemistry lab summary table. 
-Other minor edits 


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Appendix A - Programming Specifications for Tables and Listings 
 
The following specifications will be used in the production of tables and listings. 
 
1. Page Setup 
Unless otherwise noted, tables and listings will use landscape orientation. Margins will be at 
least 3/4 of an inch on the left side of page, at least 3/4 of an inch at the top, and 3/8 of an 
inch on the other sides. 
Upper left: Sponsor name and protocol number 
• 
Center: CONFIDENTIAL; Database Download Date: ddmmmyy 
• 
 Upper right: Page number shown as Page n of N. Page numbers should be sequential 
within a table or listing. 
 
The footer should include: 
• Left: the name of the SAS program used to generate the output 
• Center: run date/time and the words “by CTDS”. 
• Right: output file name. 
 
2. Footnotes 
Unless otherwise specified, footnotes should appear on all pages within the table. 
 
3. Font 
Font will be 9-point Arial, or smaller if needed for space constraints. If possible, small tables 
should appear on one page. If tables continue on to multiple pages, there should be a page 
break after an assessment so that all the statistics for an assessment appear on the same page. 
4. Tables 
Table titles should reflect the content of the table. Under the main title, in parentheses, the 
name of the analysis population being summarized should appear. 
 
Summary Statistics - Continuous Data 
 
Unless otherwise noted, the mean and median and confidence interval (CI) of a set of 
values should be printed out to one decimal place more than the original value. The 
standard deviation and standard error should be printed out to 2 decimal places more 
than the original value. The number of subjects on whom the parameter is assessed 
should appear. Minimum and maximum should be consistent with the original value. 
 
Summary Statistics - Categorical Data 
Numbers of subjects are reported as whole numbers. Null counts are represented as 0. 
Table percentages should be reported to one decimal unless otherwise noted. Null 
percentages should be reported as 0.0. For all categories, the total number of subjects 
with data will be presented as N. 


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5. Subjects Included in Listings 
In general, subject data listings should include all subjects who are randomized. The 
population flag (Safety/mITT/Evaluable/PP) should be included in all listings as a column to 
indicate which population(s) a subject belongs to. If a listing includes a subset of subjects who 
meet a certain condition (e.g., subjects with SAEs) then this should be clear from the title of 
the listing. If there is no record for a listing, then a statement, such as There is no serious 
adverse events in any of the treatment groups, will be presented. 


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References 
 
Athauda D, Maclagan K, Skene SS, Bajwa-Joseph M, Letchford D, Chowdury K, et al. 
Exenatide once weeklyversus placebo in Parkinson's disease: a randomised, double-blind, 
placebo-controlled trial. Lancet.2017;390(10103):1664-1675. 
 
Fahn S, Elton RL. Unified Parkinson’s disease rating scale. In: Fahn S, Marsden CD, Calne D, 
Goldstein M, eds. Recent Developments in Parkinson’s Disease. Florham Park: 
Macmillan Health Care Information. 1987:153-163. 
 
Goetz CG, Tilley BC, Shaftman SR, Stebbins GT, Fahn S, Martinez-Martin P, et al. Movement 
Disorder SocietysponsoredrevisionoftheUnitedParkinson’sDiseaseRatingScale(MDS- 
UPDRS):ScalePresentationandClinimetricTestingResults.MovDisorders.2008;23(15):212 
9-2170. 
 
Hauser RA, Deckers F, Lehert P. Parkinson’s disease home diary: further validation and 
implications for clinical trials. Mov Disorders. 2004;19:1409-1413. 
 
Hauser RA, Friedlander J, Zesiewicz TA, Adler CH, Seeberger LC, O’Brien CF, et al. A home 
diary to assessfunctional status in patients with Parkinson’s disease with motor 
fluctuations and dyskinesia. ClinNeuropharmacol. 2000;23:75-81. 
 
Lang JT, Kassan TO, Devaney LL, Colon-Semenza C, Joseph ME. Test-retest reliability and 
minimal detectable change for the 10-meter walk test in older adults with Parkinson’s 
disease. J GeriatrPhyTher. 2016;39:165-170. 
 
Martinez-Martin P, Forjaz MJ, Cubo E, Frades B, de Pedro Cuesta J, ELEP Project Members. 
Global versusfactor-related impression of severity in Parkinson’s disease: a new 
clinimetric index (CISI-PD). Mov Disord.2006;21:208-214. 
 
Nasreddine ZS, Phillips NA, BedirianV,Charbonneau S, Whitehead V, Collin I, et al. The 
Montreal CognitiveAssessment, MoCA: a brief screening tool for mild cognitive 
impairment. Am Geriatr Soc. 2005;53:695-699. 
 
Peto V, Jenkinson C, Fitzpatrick R. PDQ-30: a review of the development, validation and 
application of aParkinson’s disease quality of life questionnaire and its associated 
measures. J Neurol. 1998;245[Suppl1]:S10S14. 
 
Schwab RS, England AC. Parkinson syndrome due to various and specific causes. In: Vinkin PJ, 
Bruyn, eds.Handbook of Clinical Neurology. Amsterdam: Elsevier North Holland. 1968: 
227-247. 
 
Sheehan DV, Giddens JM, Sheehan IS. Sheehan-Suicidality Tracking Scale (S-STS) 2014. Innov 
Clin Neurosci.2014;11(9-10):93-140. 

Prot_000.pdf: 
 
 
 
 
 
 
 
A Ra n d o mize d, D o u ble -Bli n d, Place b o -C o ntr olle d St u d y t o  
E val uate t he Efficac y a n d Safet y of A K S T 4 2 9 0 i n S u bjects wit h  
Par ki ns o n’s Disease o n Sta ble D o pa mi ner gic Treat me nt   
 
 
 
 
 
 
Pr ot oc ol N u m ber:  
A K S T 4 2 9 0 -2 1 1  
E u dr a C T N u m ber:  
2 0 1 9 -0 0 1 6 5 7 -4 2  
I N D N u m ber: 
1 4 2 5 9 7  
Cli nic al P h ase:  
2  
S p o ns or:  
Al ka hest, I nc.   
1 2 5  S h ore wa y R oa d, S uite D  
Sa n Carl os, C A 9 4 0 7 0  
St u d y  A ge nt : 
A K S T 4 2 9 0  
I n dic ati o ns: 
Par ki ns o n’s Disease  
A ut h orize d Re pres e nt ati ve:  
 
 
 
 
 
 
Versi o n N u m ber:  
V 4 .0  
Versi o n D ate  
2 2 M A Y 2 0 2 0  
Re pl aces Versi o n:  
V 3. 1, 0 6 JA N 2 0 2 0  
 
 
 
 
 
 
C O N FI D E N TI A L S T A T E M E N T  
T he i nf or mati o n c o ntai ne d i n t his d oc u me nt a n d all i nf or mati o n pr o vi de d as relate d t o t his cli nical st u d y are t he 
c o nfi de ntial a n d pr o prietar y i nf or mati o n of t he S p o ns or a n d e xce pt as ma y be re q uire d b y fe deral, state, or l ocal la ws or 
re g ulati o ns ma y n ot be discl ose d t o ot hers wit h o ut pri or writte n per missi o n of t he S p o ns or. T he Pri nci pal I n vesti gat or 
ma y, h o we v er, discl ose s uc h i nf or mati o n t o s u per vise d i n di vi d uals w or ki n g o n t he cli nical st u d y, pr o vi de d s uc h 
i n di vi d uals a gree t o mai ntai n t he c o nfi de ntialit y of s uc h i nf or mati o n. 
 




 
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C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                   Pa ge 3  of 9 9
 
 
 
5. 3  
S T R A T E GI E S F O R R E C R UI T M E N T A N D R E T E N TI O N  ............................................. 2 1  
5. 4  
S U B J E C T WI T H D R A W A L O R T E R MI N A TI O N  ............................................................ 2 1  
5. 4. 1  
R E A S O N S F O R WI T H D R A W A L O R T E R MI N A TI O N  ........................................................ 2 1  
5. 4. 2  
H A N D LI N G O F P A R TI CI P A N T WI T H D R A W A L S O R T E R MI N A TI O N  ........................... 2 2  
5. 5  
P R E M A T U R E T E R MI N A TI O N O R S U S P E N SI O N O F S T U D Y  .................................... 2 2  
6  
S T U D Y A G E N T  ..................................................................................................................... 2 2  
6. 1  
S T U D Y A G E N T A N D C O N T R O L D E S C RI P TI O N  .......................................................... 2 2  
6. 1. 1  
A C Q UI SI TI O N  ......................................................................................................................... 2 2  
6. 1. 2  
F O R M U L A TI O N, A P P E A R A N C E, P A C K A GI N G, A N D L A B E LI N G  ................................. 2 2  
6. 1. 3  
P R O D U C T S T O R A G E A N D S T A BI LI T Y .............................................................................. 2 3  
6. 1. 4  
D O SI N G A N D A D MI NI S T R A TI O N  ...................................................................................... 2 3  
6. 1. 5  
R O U T E O F A D MI NI S T R A TI O N  ............................................................................................ 2 3  
6. 2  
S T U D Y A G E N T A C C O U N T A BI LI T Y ................................................................................ 2 3  
7  
S T U D Y P R O C E D U R E S A N D S C H E D U L E  ....................................................................... 2 4  
7. 1  
S T U D Y P R O C E D U R E S/ E V A L U A TI O N S  .......................................................................... 2 4  
7. 1. 1  
S T U D Y S P E CI FI C P R O C E D U R E S  ........................................................................................ 2 4  
7. 2  
L A B O R A T O R Y P R O C E D U R E S/ E V A L U A TI O N S  ........................................................... 2 9  
7. 2. 1  
C LI NI C A L L A B O R A T O R Y E V A L U A TI O N S  ....................................................................... 2 9  
7. 2. 2  
O T H E R T E S T S O R P R O C E D U R E S  ....................................................................................... 2 9  
7. 3  
S T U D Y S C H E D U L E  .............................................................................................................. 3 0  
7. 3. 1  
S C R E E NI N G  ............................................................................................................................ 3 0  
7. 3. 2  
B A S E LI N E  ............................................................................................................................... 3 1  
7. 3. 3  
T R E A T M E N T  .......................................................................................................................... 3 2  
7. 3. 4  
F O L L O W -U P ............................................................................................................................ 3 3  
7. 3. 5  
E A R L Y T E R MI N A TI O N  ......................................................................................................... 3 4  
7. 3. 6  
S C H E D U L E O F E V E N T S T A B L E  .......................................................................................... 3 4  
7. 3. 7  
E N D O F T RI A L/ E N D O F S T U D Y  .......................................................................................... 3 4  
7. 4  
C O N C O MI T A N T M E DI C A TI O N S  ..................................................................................... 3 4  
7. 5  
P R O HI BI T E D M E DI C A TI O N S, T R E A T M E N T S, A N D P R O C E D U R E S  ...................... 3 4  
8  
A S S E S S M E N T O F S A F E T Y  ................................................................................................ 3 5  
8. 1  
S P E CI FI C A TI O N O F S A F E T Y P A R A M E T E R S  .............................................................. 3 5  
8. 1. 1  
D E FI NI TI O N O F A D V E R S E E V E N T S ( A E)  ......................................................................... 3 5  
8. 1. 2  
D E FI NI TI O N O F S E RI O U S A D V E R S E E V E N T S  ................................................................. 3 6  
8. 2  
C L A S SI FI C A TI O N O F A N A D V E R S E E V E N T  ................................................................ 3 7  
8. 2. 1  
S E V E RI T Y O F E V E N T  ........................................................................................................... 3 7  
8. 2. 2  
R E L A TI O N S HI P T O S T U D Y A G E N T  ................................................................................... 3 7  
8. 2. 3  
E X P E C T E D N E S S  .................................................................................................................... 3 7  


 
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C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                   Pa ge 4  of 9 9
 
 
 
8. 3  
TI M E P E RI O D/ F R E Q U E N C Y F O R E V E N T A S S E S S M E N T/ F O L L O W -U P  ................ 3 8  
8. 3. 1  
P O S T -S T U D Y A E A N D S A E  .................................................................................................. 3 8  
8. 4  
R E P O R TI N G P R O C E D U R E S  .............................................................................................. 3 8  
8. 4. 1  
A D V E R S E E V E N T R E P O R TI N G  ........................................................................................... 3 8  
8. 4. 2  
S E RI O U S A D V E R S E E V E N T R E P O R TI N G  ......................................................................... 3 9  
8. 4. 3  
 
8. 4. 4  
R E P O R TI N G O F P R E G N A N C Y  ............................................................................................. 4 1  
8. 5  
S T U D Y H A L TI N G R U L E S  ................................................................................................... 4 1  
8. 6  
S A F E T Y O V E R SI G H T  ......................................................................................................... 4 1  
9  
C LI NI C A L M O NI T O RI N G  ................................................................................................. 4 2  
1 0  
S T A TI S TI C A L C O N SI D E R A TI O N S  .................................................................................. 4 2  
1 0. 1  
S T A TI S TI C A L D E SI G N M O D E L A N D A N A L Y TI C A L P L A N S  .................................... 4 2  
1 0. 2  
S T A TI S TI C A L H Y P O T H E S E S  ........................................................................................... 4 2  
1 0. 3  
A N A L Y SI S D A T A S E T S  ........................................................................................................ 4 2  
1 0. 4  
D E S C RI P TI O N O F S T A TI S TI C A L M E T H O D S  ............................................................... 4 3  
1 0. 4. 1  G E N E R A L A P P R O A C H  .......................................................................................................... 4 3  
1 0. 4. 2  A N A L Y SI S O F T H E P RI M A R Y E N D P OI N T  ........................................................................ 4 3  
1 0. 4. 3  A N A L Y SI S O F T H E S E C O N D A R Y E N D P OI N T S  ................................................................ 4 3  
1 0. 4. 4  P L A N N E D I N T E RI M A N A L Y S E S  ......................................................................................... 4 4  
1 0. 4. 5  M U L TI P L E C O M P A RI S O N/ M U L TI P LI CI T Y  ....................................................................... 4 4  
1 0. 4. 6  E X P L O R A T O R Y A N A L Y S E S  ............................................................................................... 4 4  
1 0. 5  
S A M P L E SI Z E ........................................................................................................................ 4 4  
1 0. 6  
M E A S U R E S T O MI NI MI Z E BI A S  ...................................................................................... 4 4  
1 0 . 6. 1 E N R O L L M E N T/ R A N D O MI Z A TI O N/ M A S KI N G P R O C E D U R E S  ...................................... 4 4  
1 0. 6. 2  E V A L U A TI O N O F S U C C E S S O F B LI N DI N G  ...................................................................... 4 4  
1 0. 6. 3  B R E A KI N G T H E S T U D Y B LI N D/ S U BJ E C T C O D E  ............................................................ 4 5  
1 1  
S O U R C E D O C U M E N T S A N D A C C E S S T O S O U R C E D A T A/ D O C U M E N T S  ............ 4 5  
1 2  
E T HI C S/ P R O T E C TI O N O F H U M A N S U B J E C T S ........................................................... 4 5  
1 2. 1  
E T HI C A L S T A N D A R D  ......................................................................................................... 4 5  
1 2. 2  
I N S TI T U TI O N A L R E VI E W B O A R D ................................................................................. 4 5  
1 2. 3  
I N F O R M E D C O N S E N T P R O C E S S .................................................................................... 4 6  
1 2. 3 . 1 C O N S E N T F O R M S  .................................................................................................................. 4 6  
1 2. 3. 2  C O N S E N T P R O C E D U R E S A N D D O C U M E N T A TI O N  ........................................................ 4 6  
1 2. 4  
P A R TI CI P A N T A N D D A T A C O N FI D E N TI A LI T Y .......................................................... 4 6  


 
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C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                   Pa ge 5  of 9 9
 
 
 
1 2. 5  
F U T U R E U S E O F S T O R E D S P E CI M E N S  ......................................................................... 4 7  
1 3  
D A T A H A N D LI N G A N D R E C O R D K E E PI N G  ................................................................ 4 7  
1 3. 1  
D A T A C O L L E C TI O N A N D M A N A G E M E N T R E S P O N SI BI LI TI E S  ............................ 4 7  
1 3. 1. 1  I N V E S TI G A T O R R E S P O N SI BI LI TI E S ................................................................................. 4 8  
1 3. 1. 2  S T U D Y FI L E S  .......................................................................................................................... 4 8  
1 3. 2  
S T U D Y R E C O R D S R E T E N TI O N  ....................................................................................... 4 8  
1 3. 3  
P R O T O C O L D E VI A TI O N S  ................................................................................................. 4 8  
1 3. 4  
P U B LI C A TI O N A N D D A T A S H A RI N G P O LI C Y  ............................................................ 4 9  
1 4  
FI N A N CI A L DI S C L O S U R E A N D C O N F LI C T O F I N T E R E S T P O LI C Y  .................... 5 0  
1 5  
S C H E D U L E O F E V E N T S  .................................................................................................... 5 1  
1 6  
R E F E R E N C E S  ....................................................................................................................... 5 3  
1 6. 1  
P U B LI S H E D R E F E R E N C E S  ............................................................................................... 5 3  
1 6. 2  
U N P U B LI S H E D R E F E R E N C E S  .......................................................................................... 5 6  
1 7  
A P P E N DI C E S  ........................................................................................................................ 5 7  
1 7. 1  
M O V E M E N T DI S O R D E R S O CI E T Y’ S U NI FI E D P A R KI N S O N’ S DI S E A S E R A TI N G 
S C A L E  .................................................................................................................................................. 5 8  
1 7. 2  
M O N T R E A L C O G NI TI V E A S S E S S M E N T  ....................................................................... 6 4  
1 7. 3  
S C H W A B A N D E N G L A N D A C TI VI TI E S O F D AI L Y LI VI N G  ..................................... 6 5  
1 7. 4  
C LI NI C A L I M P R E S SI O N O F S E V E RI T Y I N D E X –  P A R KI N S O N’ S DI S E A S E  ......... 6 6  
1 7. 5  
P A R KI N S O N’ S DI S E A S E Q U A LI T Y O F LI F E Q U E S TI O N N AI R E -3 9  ........................ 6 7  
1 7. 6  
S H E E H A N S UI CI D A LI T Y T R A C KI N G S C A L E  .............................................................. 7 2  
1 7. 7  
M O V E M E N T DI S O R D E R S O CI E T Y’ S P A R KI N S O N’ S DI S E A S E C RI T E RI A  .......... 7 4  
1 7. 8  
H A U S E R 3 -D A Y P A TI E N T DI A R Y  .................................................................................... 7 5  
1 7. 9  
M O DI FI C A TI O N O F DI E T I N R E N A L DI S E A S E F O R M U L A  ...................................... 7 6  
1 7. 1 0  
 
 
 
 
 
 
 


 
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C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                   Pa ge 6  of 9 9
 
 
 
1 7. 1 1  C LI NI C A L E V A L U A TI O N O F LI V E R I N J U R Y  .............................................................. 7 8  
1 7. 1 1. 1  I N T R O D U C TI O N .................................................................................................................. 7 8  
1 7. 1 1. 2  P R O C E D U R E S  ....................................................................................................................... 7 9  
1 7. 1 2  P H A R M A C O KI N E TI C, BI O M A R K E R, P H A R M A C O G E N O MI C, A N D F A C S 
S A M P LI N G  .......................................................................................................................................... 8 1  
1 7. 1 2. 1  T A B L E O F P H A R M A C O KI N E TI C, BI O M A R K E R, P H A R M A C O G E N O MI C, A N D F A C S 
S A M P LI N G  ............................................................................................................................................ 8 1  
1 7. 1 3  P H A R M A C O KI N E TI C M E A S U R E S A N D E V A L U A TI O N  ............................................ 8 1  
1 7. 1 3. 1  TI MI N G O F P H A R M A C O KI N E TI C B L O O D S A M P LI N G  ................................................. 8 1  
1 7. 1 3. 2  P H A R M A C O KI N E TI C S A M P L E H A N D LI N G A N D S HI P M E N T  ..................................... 8 2  
1 7. 1 3. 3  P H A R M A C O KI N E TI C D A T A E V A L U A TI O N  ................................................................... 8 2  
1 7. 1 3. 4  H A N D LI N G O F MI S SI N G BI O A N A L Y TI C A L D A T A  ....................................................... 8 2  
1 8  
R E VI SI O N HI S T O R Y  ........................................................................................................... 8 3  
1 8. 1  
S U M M A R Y O F C H A N G E S  .................................................................................................. 8 3  
 
 
 
 


 
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C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                   Pa ge 7  of 9 9
 
 
 
L I ST O F A B B R E VI A TI O N S  
A D  
Al z h ei m er’s dis eas e  
A E  
A d v ers e e v e nt  
A E SI  
A d v ers e e v e nt of s p eci al i nt erest  
A L T  
Al a ni n e a mi n otr a nsf er as e  
A P  
Al k ali ne p h os p h at as e  
a P T T  
A cti vat e d p arti al t hr o m b o pl asti n  ti m e 
A S T  
As p art at e a mi n otr a nsf er as e  
A U C  
Are a u n d er t h e c ur v e  
B C R P  
Br e ast ca n c er r esist a n ce pr ot ei n  
b.i. d.  
T wi ce per d a y  
B L Q  
B el o w t h e li mit of q u a ntifi cati o n  
B P  
Bl o o d press ur e  
C B C  
C o m pl et e bl o o d c o u nt  
 
 
 
 
 
 
C F R  
C o d e of Fe d eral R e g ul ati o ns  
CI SI -P D  
Cli nic al I m pr essi o n of Se v erit y I n d e x –  Par ki ns o n’s Dise ase  
C K  
Cr e ati ni n e ki n as e  
C K -M B  
Cr e ati ni n e ki n as e -M B  
C LI A  
Cli nic al L a b or at or y I m pr o v e me nt A m e n d m e nts 
C ma x  
M a xi m u m pl as m a c o nc e ntrati o n  
C M P  
Cli nic al M o nit ori n g Pl a n  
C N S  
C e ntral n er v o us s yst e m  
C O VI D -1 9  
C or o n a vir us dis e as e 2 0 1 9  
C P K  
Cr e ati n e p h os p h o ki n as e  
C R A  
Cli nic al R es earc h A ss o ci at e 
C R F  
C as e R e p ort F or m  
C R O  
C o ntr a ct Rese ar c h Or g a nizati o n  
C R P  
C -r e acti v e pr otei n 
C S F  
C er e br os pi n al fl ui d  
 
 
DI LI  
Dr u g -i n d u ce d li v er i nj ur y 
D N A  
D e o x yri b o n u cl ei c a ci d  
E C G  
El e ctr o car di o gr a m  
E D T A  
Et h yle n e di a mi n et etr a ac eti c a ci d  
e G F R  
Esti mat e d g l o mer ular filtrati o n rat e  
E M A  
E ur o p e a n M e di ci n es A g e n c y  
E N T  
Ears, n os e , t hr oat 
 
 
E u dr a C T  
E ur o p e a n U ni o n Dr u g R e g ul ati n g A ut h oriti es Cli ni cal Tri als D at a b as e  
F A C S  
Fl o w c yt o metr y /fl u or es ce n c e-a cti vat e d cell s orti n g   


 
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C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                   Pa ge 8  of 9 9
 
 
 
F D A  
F o o d a n d Dr u g A d mi nistr ati o n  
G C P  
G o o d Cli nic al Pr a cti ce  
G F R  
Gl o m er ul ar filtrati o n r at e  
H B V  
H e p atitis B v ir us 
H C V  
H e p atitis C vir us  
H E V  
H e p atitis E vir us  
HI P A A  
H e alt h I ns ur a n c e P ort a bilit y a n d A c c o u nt a bilit y A ct  
HI V  
H u m a n i m m u n o d efi ci e n c y vir us  
H P L C -M S/ M S  
Hi g h p erf or ma n c e li q ui d c hr o m at o gr a p h y, ta n de m m ass sp e ctr o m etr y  
I C H 
I nt er nati o n al C o nf er e nc e o n H ar m o ni z ati o n 
I C H E 6 R 2 
I nter nati o nal C ou ncil f or  Har m o nizati o n of Tec h nical Re q uire me nts f or 
P har mace uticals f or H u ma n Use G ui da nce f or I n d ustr y, G o o d Cli nical Practice: 
C o ns oli date d G ui da nce, Re visi o n 2  
I E C  
I n d e p e n d e nt Et hi cs C o m mitt ee 
I g G 
I m m u n o gl o b uli n G 
I g M 
I m m u n o gl o b uli n M 
I N D 
I n v esti g ati o n N e w Dr u g A p pli c ati o n  
I N R 
I nt er nati o n al n or m ali ze d r ati o 
I R B 
I nstit uti o n al R e vi e w B o ar d  
I S F 
I n v esti g at or Sit e Fil e 
I T T 
I nt e nt-t o-tr e at 
L D H  
La ct at e d e h y dr o g e n ase  
 
 
M D S -P D  
M o v e m e nt Dis or d er S o ci et y’s Cli ni cal Di a g n osti c Crit eri a f or Par ki ns o n’s 
Dise ase  
M D S -U P D R S  
M o v e m e nt Dis or d er S o ci et y’s U nifi e d Par ki ns o n’s Dise ase R ati n g Sc al e  
M e d D R A  
M e di c al Dicti o n ar y f or R e g ul at or y A cti viti es  
mI T T  
M o difi e d i nte nt -t o-tr eat 
M o C A  
M o ntre al C o g niti ve Ass ess m e nt  
M P T P  
1 -m et h yl -4 -p h e n yl -1, 2, 3, 6 -t etr a h y dr o p yri di n 
N O A  
N ot a n al y ze d  
N O P  
N o p ea k d et ect a ble  
N O R  
N o v ali d r es ults  
N O S  
N o s a m ple a v ail a bl e  
 
 
 
 
P D  
Par ki ns o n’s dis ease  
P D D  
Par ki ns o n’s dis ease de m e nti a  
P D Q -3 9  
Par ki ns o n’s Dis e as e Q u alit y of Life Q u esti o n n aire -3 9  
 
 
P G X  
P h ar m a c o g e n o mi c  
p H  
P ot e nti al of h y dr o g e n  
P K  
P h ar m a c o ki neti c (s) 
P P  
P ol y pr o p yle n e  


 
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C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                   Pa ge 9  of 9 9
 
 
 
P T  
Pref err e d T er m  
Q R S  
Q R S i nt er val o n E C G  
Q T  
Q T i nt er v al o n E C G 
R B C  
R e d bl o o d c ell c o u nt  
R N A  
Ri b o n u cl ei c aci d  
S A E  
Seri o us a d vers e e v e nt  
S A P  
St atisti c al a n al yti c al p l a n 
S E -A D L  
Sc h w a b a n d E n gla n d A cti viti es of D ail y Li vi n g  
S O C  
S yst e m Or g a n Cl ass  
S -S T S  
S h e e h a n -S ui ci d alit y Tr ac ki n g Sc al e  
S U S A R  
S us p e ct e d u n e x p e ct e d s eri o us a d v ers e re a cti o n  
U L N  
U p p er li mit of n or m al  
U S  
U nit e d St at es  
w A M D  
W et a g e -r el at e d ma c ul ar d e g e ner ati o n 
W B C  
W hit e bl o o d c ell c o u nt  
W O C B P  
W o m e n of c hil d b e ari n g p ot e nti al  
 
 
 


 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1  
 
 
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                   Pa ge 1 0  of 9 9
 
 
 
P R O T O C O L A P P R O V A L P A G E  
 
 
 
St u d y Title:  
A Ra n d o mize d, D o u ble -Bli n d, Place b o -C o ntr olle d St u d y t o 
E val uate t he Efficac y a n d Safet y of A K S T 4 2 9 0 i n S u bjects wit h 
P ar ki ns o n’s Disease o n  Sta ble  D o pa mi ner gic Treat me nt  
Pr ot oc ol N u m ber:  
A K S T 4 2 9 0 -2 1 1  
Versi o n/ Date:  
V 4 .0 _ 2 2 M A Y 2 0 2 0  
S p o ns or Na me a n d 
A d dress:  
 
Al ka hest, I nc.  
1 2 5  S h ore wa y R oa d , S uite D 
Sa n Carl os, C A 9 4 0 7 0  
 
 
 
I, t he u n d ersi g ne d, h a ve rea d a n d a p pr o ve t his pr ot oc ol a n d a gree o n its c o nte nt. It is c o nfir me d t hat 
t he i nf or mati o n a n d g ui d a nce gi ve n i n t his pr ot oc ol c o m plies wit h scie ntific pri nci ples, t he g ui deli n es 
of G o o d Cli nical Practice, t he Declarati o n of Helsi n ki i n t he latest rele va nt versi o n, a n d a p plica ble 
le gal a n d re g ul at or y re q uire me nts. 
 
 
 
 
A p pr o ve d b y:  
 
 
  
 
 
 
 
 Ma y 2 2 , 2 0 2 0 
S p o ns or Re prese ntati ve ( pri nt)  
 Si g nat ure  
 Date  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1  
 
 
V 4. 0
2 2 M A Y 2 0 2 0  
 
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C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                   Pa ge 1 1  of 9 9
 
 
 
S T A T E M E N T  O F C O M P LI A N C E  
 
Pr ot oc ol Title:  
A Ra n d o mize d, D o u ble -Bli n d, Place b o -C o ntr olle d St u d y t o 
E val uate t he Efficac y a n d Safet y of A K S T 4 2 9 0 i n S u bjects 
wit h P ar ki ns o n’s Disease o n Sta ble D o pa mi ner gic 
Treat me nt  
Pr ot oc ol N u m ber:  
A K S T 4 2 9 0 -2 1 1  
 
Versi o n/ Date : 
V 4 .0 _ 2 2 M A Y 2 0 2 0  
 
 
B y m y si g nat ure, I:  
• 
C o nfir m t hat m y staff a n d I ha ve caref ull y rea d a n d u n dersta n d t his pr ot oc ol or pr ot oc ol a me n d me nt , 
ha ve recei ve d t he I n vesti gat or Br oc h ure , a n d are t h or o u g hl y fa miliar wit h t he a p pr o priate use of t he 
i n vesti gati o nal a ge nt  descri be d herei n.  
• 
A gree t o c o m pl y wit h t he c o n d uct a n d ter ms of t he st u d y s pecifie d h erei n a n d wit h a n y ot her st u d y 
c o n d uct pr oce d ures pr o vi de d b y t he S p o ns or, Al ka hest, I nc., or t heir desi g nee . 
• 
A gree t o ass u me res p o nsi bilit y f or t he pr o per c o n d uct of t he st u d y at t his site, i ncl u di n g c o m pl yi n g 
wit h c urre nt rele va nt versi o ns of t he F o o d a n d Dr u g A d mi nistrati o n ( F D A) re g ulati o ns, E ur o pea n 
Me dici nes A ge nc y ( E M A)  re g ulati o ns, l ocal dr u g la ws, t he I nter nati o nal C ou n cil f or Har m o nizati o n of 
Tec h nical Re q uire me nts f or P har mace uticals f or H u ma n Use  (I C H) G C P g ui deli nes, t he Declarati o n of 
Helsi n ki , a n d all a p plica ble r ules, re g ulati o ns, a n d fe deral, state, a n d l ocal la ws relati n g t o t he c o n d uct 
of cli nical st u dies a n d t he pr otecti o n of h u ma n s u bjects.  
• 
A gree n ot t o i m ple me nt de viati o ns fr o m or c ha n ges t o t he pr ot oc ol or pr ot oc ol a me n d me nts wit h o ut 
a gree me nt fr o m t he S p o ns or a n d pri or s u b missi o n t o a n d writte n a p pr o val ( w here re q uire d) fr o m t he 
I nstit uti o nal Re vie w B oar d (I R B) or I n de pe n de nt Et hics C o m mittee (I E C), e xce pt w he n necessar y t o 
eli mi nate a n i m me diate hazar d t o t he s u bjects, or f or a d mi nistrati ve as pects of t he st u d y ( w here 
per mitte d b y all a p plica ble re g ulat or y re q uire me nts).  
• 
A gree t o o nsite m o nit ori n g of all s o urce d oc u me nts b y Al ka hest, I nc.  or desi g nee a n d t o o nsite 
i ns pecti o n of s o urce d oc u me nts b y a p pr o priate re g ulat or y a ut h orities, i ncl u di n g b ut n ot li mite d t o t he 
F D A, E M A , l ocal g o ver ni n g re g ulat or y b o dies, a n d I R B/I E C i ns pect ors. 
 
 
 
 
 
 
I n v esti gat or's Si g nat ure 
 
Date  
 
 
 
Pri nt Na me  
 
 
 
 
 
 


 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
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C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 1 2  of 9 9   
 
P R O T O C O L S U M M A R Y  
 
 
Title:  
A Ra n d o mize d, D o u ble -Bli n d, Place b o -C o ntr olle d St u d y t o 
E val uate t he Efficac y a n d Safet y of A K S T 4 2 9 0 i n S u bjects wit h 
Par ki ns o n’s Disease o n Sta ble D o pa mi ner gic Treat me nt  
 
Précis:  
T his is a ra n d o mize d, d o u ble -bli n d, place b o -c o ntr olle d st u d y t o 
assess t he efficac y a n d safet y of  A K S T 4 2 9 0 i n s u bjects wit h  
Par ki ns o n’s d isease ( P D). 
 
T he st u d y  will e nr oll  a p pr o xi matel y 1 2 0  s u bjects w h o  will be 
ra n d o mize d i n a 1 : 1 rati o t o acti ve treat me n t i n Ar m 1 
(a p pr o xi matel y 6 0  s u bjects) or place b o i n Ar m 2 (a p pr o xi matel y 6 0  
s u bjects). S u bjects will ta ke 4 0 0 m g of A K S T 4 2 9 0 or place b o ta ke n 
orall y, t wice per da y (b.i. d. ) f or a t otal dail y d ose of 8 0 0 m g. T he 
st u d y d urati o n f or t he s u bjects will be a p pr o xi matel y  1 8  wee ks 
i ncl u di n g scree ni n g, 1 2 wee ks of treat me nt, a n d 4  wee ks of f oll o w -
u p.  
 
O bjecti ves:  
T he pri mar y o bjecti ve of t he st u d y is t o assess t he effects of 
A K S T 4 2 9 0 o n m ot or f u ncti o n i n t he practicall y defi ne d off -
me dicati o n state , defi ne d as ≥1 2 ho urs  off le v o d o pa,  i n s u bjects 
wit h P D. T he sec o n dar y o bjecti ves i ncl u de t he assess me nt of t he 
safet y of A K S T 4 2 9 0 i n s u bjects wit h P D as well as t he p ote ntial 
effects o n cli nical f u ncti o n a n d acti vities of dail y li vi n g. T he 
e x pl orat or y o bjecti ve s i ncl u de a nal ysis of p har mac o ki netic  ( P K) 
para meters f oll o wi n g t wice dail y d osi n g wit h A K S T 4 2 9 0. 
A d diti o nall y, fl o w c yt o metr y, p har mac o ge n o mic , a n d bi o mar ker 
e val uati o ns will be c o n d ucte d o n bl o o d a n d plas ma sa m ples . 
B ra d y ki nesia, tre m or, ge neral acti vit y, a n d slee p  ma y be assesse d 
wit h  a weara ble de vice.  I n c o nse nti n g s u bjects, fecal sa m ples will 
be o btai ne d at scree ni n g a n d f oll o wi n g treat me nt t o assess p ote ntial 
micr o bi o me c ha n ges .  
 
E n d p oi nts:  
Pri mar y E n d p oi nt s:  
• 
C ha n ge fr o m Baseli ne  ( Da y 1) i n m ot or f u ncti o n d uri n g t he 
practicall y defi ne d off -me dicati o n state , defi ne d as ≥1 2 
h o u rs off le v o d o pa,  at Wee k 1 2 ( Da y 8 4) as meas ure d b y 
M o ve me nt Dis or der S ociet y's U nifie d Par ki ns o n's Disease 
Rati n g Scale ( M D S -U P D R S), Part 3.  
 
Sec o n dar y E n d p oi nt s:  
• I nci de nce of treat me nt-e mer ge nt a d verse e ve nts ( A Es) a n d 
seri o us a d verse e ve nts ( S A Es) i de ntifie d b y t he Me dical 
Dicti o nar y f or Re g ulat or y Acti vities  ( Me d D R A) preferre d 
ter m ( P T) a n d gr o u pe d b y Me d D R A S yste m Or ga n Class 
( S O C). 
• 
I nci de nce of a b n or malities or cli nicall y -si g nifica nt c ha n ges 
fr o m Baseli ne  i n la b orat or y test data, vital si g n 
meas ure me nts, a n d electr ocar di o gra ms ( E C Gs) . 
• C ha n ge fr o m Baseli ne  ( Da y 1) i n cli nical f u ncti o n, m ot or 
f u ncti o n, a n d acti vities of dail y li vi n g at Wee k 1 2 ( Da y 8 4) 


 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
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C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 1 3  of 9 9   
 
d uri n g t he o n -me dicati o n state as assesse d b y:  
o  M D S -U P D R S Parts 1 -4  
o  M o ntreal C o g niti ve Assess me nt ( M o C A)  
o  S c h wa b a n d E n gla n d Acti vities of Dail y Li vi n g 
( S E-A D L) Scale  
o  Cli nical I m pressi o n of Se verit y I n de x –  P D ( CI SI -
P D)  
o  P D Q ualit y of Life Q uesti o n naire -3 9 ( P D Q -3 9)  
o  S he e ha n-S uici dalit y Trac ki n g Scale ( S-S T S)  
o  1 0 -meter ti me d wal k  ( will als o be assesse d i n t he 
off -me dicati o n state ) 
o  Ha user 3 -Da y Patie nt Diar y  
 
E x pl orat or y  E n d p oi nt s: 
• 
C ha n ges i n c o nce ntrati o n of A K S T 4 2 9 0 or its maj or 
meta b olites i n plas ma at vari o us ti me p oi nts.  
• 
Fl o w c yt o metric a nal yses a n d e val uati o n of 
p har mac o ge n o mic c haracteristics  a n d bi o mar kers i n bl o o d 
a n d plas ma sa m ples . 
• 
C ha n ges i n bra d y ki nesia , tre m or, ge neral acti vit y, a n d slee p  
as meas ure d b y a n F D A -clear e d weara ble se ns or de vice . 
• 
I n c o nse nti n g s u bjects ( o pti o nal): c haracterizati o n of  t he 
c o m p ositi o n a n d f u ncti o n of t he fecal g ut micr o bi o me.  
 
P o p ulati o n:  
A p pr o xi matel y 1 2 0  s u bjects bet wee n 5 0 a n d 8 0  years of a ge wit h a 
dia g n osis of P D  o n d o pa mi ner gic treat me nt . Ass u mi n g a dr o p -o ut 
rate of 1 0 %, e nr oll me nt at t his le vel will yiel d a p pr o xi matel y 1 0 8  
e val ua ble s u bjects . 
 
P hase:  
2  
 
N u m ber of Sites:  
A p pr o xi matel y 3 0 sites are pla n ne d gl o ball y  
Descri pti o n  of  St u d y A ge nt:  
A K S T 4 2 9 0 : 
 
 
St u d y D urati o n:  
A p pr o xi matel y 1 5  m o nt hs  
 
S u bject  Partici pati o n : 
 
A p pr o xi matel y 1 8  wee ks   
 
 




 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
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C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 1 5  of 9 9   
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 






 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
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C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 1 8  of 9 9   
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
3  
O B J E C TI V E S A N D P U R P O S E  
 
T he pri mar y o bjecti ve of t he st u d y is t o assess t he effects of A K S T 4 2 9 0 o n m ot or f u ncti o n i n t he practicall y 
defi ne d off -me dicati o n state i n s u bjects wit h P D. T he sec o n dar y o bjecti ves i ncl u de t he assess me nt of t he safet y of 
A K S T 4 2 9 0 i n s u bjects wit h P D as well as t he p ote ntial effects o n cli nical f u ncti o n , c o g niti o n, a n d acti vities of 
dail y li vi n g. T h e e x pl orat or y o bjecti ve s i ncl u de a nal ysis of P K  para meters f oll o wi n g t wice dail y d osi n g wit h 
A K S T 4 2 9 0. A d diti o nall y, fl o w c yt o metr y/fl u oresce nce-acti vate d cell s orti n g ( F A C S), p har mac o ge n o mic , a n d 
bi o mar ker e val uati o ns will be c o n d ucte d o n bl o o d a n d plas ma  sa m ples. Bra d y ki nesia, tre m or, ge neral acti vit y, a n d 
slee p ma y be assesse d wit h a weara ble se ns or de vice.  I n c o nse nti n g s u bjects, fecal sa m ples will be o btai ne d at 
scree ni n g a n d f oll o wi n g treat me nt t o assess p ote ntial micr o bi o me c ha n ges .  
 
4  
S T U D Y D E SI G N A N D E N D P OI N T S  
4. 1  
D E S C RI P TI O N O F T H E S T U D Y D E SI G N  
 
T his is a ra n d o mize d, d o u ble-bli n d, place b o -c o ntr olle d st u d y c o n d ucte d at a p pr o xi matel y 3 0 sites gl o ball y . 
D uri n g t he scree ni n g p eri o d ( Da y -1 4 t hr o u g h Da y -7 ), s u bjects will u n der g o  all scree ni n g a ssess me nts t o assess 
eli gi bilit y.  I n c o nse nti n g s u bjects, fecal sa m ples will als o be c ollecte d at scree ni n g f or micr o bi o me assess me nt. 
D uri n g t he B aseli ne Vi sit ( Da y 1 ), s u bjects will be ra n d o mize d i n a 1: 1 rati o t o A K S T 4 2 9 0 ( Ar m 1) or place b o 
( Ar m 2). Su b jects will t he n c o m plete  m ot or assess me nt i n b ot h o n-me dicati o n a n d off -me dicati o n states , as well 
as testi n g f or n o n-m ot or s y m pt o ms of P D,  acti vities of dail y li vi n g  a n d q ualit y of life .  
 
Safet y a n d t olera bilit y assess me nts will occ ur at e ver y visit . M ot or f u ncti o n a n d sec o n dar y e n d p oi nts will be 
c o n d ucte d  at Baseli ne a n d at peri o dic i nteri m visits f oll o wi n g d osi n g. I n t he e ve nt of earl y ter mi nati o n, a s u bject 
w h o has  recei ve d at least 1  d ose ( 4 0 0  m g) of A K S T 4 2 9 0  or place b o , will  u n der g o t he e n d of treat me nt pr oce d ures 
u nless t he s u bject has wit h dra w n c o nse nt . A c o m pre he nsi ve efficac y a n d safet y assess me nt of all data i n t ot o will 
be c o n d ucte d at t he e n d of t he st u d y.  
 
T he o verall d urati o n of t he st u d y /recr uit me nt peri o d is a p pr o xi matel y 1 0  m o nt hs fr o m st u d y i nitiati o n 
(i.e., foll o wi n g c o nse nt of f irst s u bject) t o st u d y c o m pleti o n (i.e., last s u bject, last visit). T he s u bject partici pati o n 
peri o d is a p pr o xi matel y 1 8  wee ks  fr o m S cree ni n g t hr o u g h E n d of S t u d y, u nless pre mat urel y disc o nti n ue d.  
 
4. 2  
S T U D Y E N D P OI N T S  
 
4. 2. 1  
P RI M A R Y E N D P OI N T  
 
Pri mar y E n d p oi nt:  
• 
C ha n ge fr o m Baseli ne ( Da y 1) i n m ot or f u ncti o n d uri n g t he practicall y defi ne d off -me dicati o n  state, 
defi ne d as ≥1 2 h o u rs off le v o d o pa,  at Wee k 1 2 ( Da y 8 4) as meas ure d b y t he M D S -U P D R S  Part 3.   


 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 1 9  of 9 9   
 
 
4. 2. 2  
S E C O N D A R Y E N D P OI N T S  
 
Sec o n dar y E n d p oi nt s:  
• 
I nci de nce of treat me nt-e mer ge nt A Es a n d S A Es i de ntifie d b y Me d D R A P T a n d gr o u pe d b y Me d D R A 
S O C.   
• 
I nci de nce of a b n or malities or cli nicall y-si g nifica nt c ha n ges fr o m Baseli ne i n la b orat or y test data, vital 
si g n meas ure me nts, a n d E C Gs. 
• 
Baseli ne ( Da y 1) a n d l o n git u di nal c ha n ge i n cli nical f u ncti o n, m ot or f u ncti o n, a n d acti vities of dail y 
li vi n g at Wee k 1 2 ( Da y 8 4) d uri n g t he o n-me dicati o n state as assesse d b y  t he f oll o wi n g:  
o  M D S -U P D R S  Parts 1 -4  (Fa h n 1 9 8 7 , G oetz 2 0 0 8 )(Secti o n 1 7 . 1) 
o  M o C A ( Nasre d di ne 2 0 0 5 )(Secti o n 1 7. 2 ) 
o  S E -A D L Scale  (Sc h wa b 1 9 6 8 )(Secti o n 1 7. 3 ) 
o  CI SI -P D ( Marti nez -Marti n 2 0 0 6 )(Secti o n 1 7. 4 )  
o  P D Q -3 9  (Pet o 1 9 9 8 )(Secti o n 1 7. 5 ) 
o  S -S T S ( S hee ha n 2 0 1 4 )(Secti o n 1 7. 6 ) 
o  1 0 -meter ti me d wal k  (La n g 2 0 1 6 )(als o assesse d i n t he off-me dicati o n state)  
o  Ha user 3 -Da y Patie nt Diar y ( Ha user 2 0 0 0 , Ha user 2 0 0 4 )(Secti o n 1 7. 8 ) 
 
4. 2. 3  
E X P L O R A T O R Y E N D P OI N T S  
 
E x pl orat or y E n d p oi nts:  
• 
C ha n ges i n c o nce ntrati o ns of A K S T 4 2 9 0 or its maj or meta b olites i n plas ma at vari o us ti me p oi nts. 
• 
Fl o w c yt o metric a nal yses ( F A C S) a n d e val uati o n of p har mac o ge n o mic c haract eristics  a n d bi o mar kers i n 
bl o o d a n d plas ma sa m ples . 
• 
C ha n ges i n bra d y ki nesia , tre m or, a n d slee p  acti vit y as meas ure d b y a weara ble se ns or de vice . 
• 
I n c o nse nti n g s u bjects ( o pti o nal): c haracterizati o n of  t he c o m p ositi o n a n d f u ncti o n of t he fecal g ut 
micr o bi o me  (Sc h wiertz 2 0 1 8 , Si n g h 2 0 1 9 ). 
 
5  
S T U D Y E N R O L L M E N T A N D WI T H D R A W A L  
5. 1  
I N C L U SI O N C RI T E RI A 
 
I n or der t o be eli gi ble f or i ncl usi o n, all s u bjects m ust meet t he f oll o wi n g criteri a: 
1.  A ge d 5 0 -8 0  years at ti me of e nr oll me nt, i ncl usi ve.  
2.  Dia g n osis of cli nicall y esta blis he d or cli nicall y pr o ba ble P D acc or di n g t o M D S -P D  criteria  
(P ost u ma  2 0 1 5 ) (Secti o n 1 7. 7 ) wit h at least 1 y ear of P D s y m pt o ms.  
3.  M o difie d H oe h n a n d Ya hr ≤2. 5 . 
4.  Ha ve n ota ble m ot or w orse ni n g d uri n g off -me dicati o n state.  
5.  Clear -c ut i m pr o ve me nt of m ot or res p o nse t o le v o d o pa me dicati o ns, as assesse d b y t he i n vesti gat or . 
6.  M ust be o n sta ble  d o pa mi ner gic t hera p y ( e. g., le v o d o pa, d o pa mi ne a g o nists, m o n oa mi ne o xi dase 
i n hi bit ors, catec h ol-O -met h yl tra nsferase i n hi bit ors, a ma nta di ne),  f or at least 8  wee ks pri or t o 
e nr oll me nt a n d re mai n o n sta ble d ose  d uri n g t he 1 2 -wee k treat me nt peri o d.  
7.  If o n me dicati o ns f or c o g niti o n (e. g., ri vasti g mi ne, gala nta mi ne, d o ne pezil, me ma nti ne), m ust be o n 
sta ble d osa ge f or at least 8 wee ks pri or t o baseli ne. 
8.  If o n a nti de pressa nt or ne ur ole ptic me dicati o ns, m ust be o n sta b le d osa ge f or at least 8 wee ks pri or t o 
e nr oll me nt. 
9.  A bilit y t o tra vel t o cli nic i n t he practicall y defi ne d off -me dicati o n state, defi ne d b y wit h dra wal of 
le v o d o pa pri or t o t he cli nic visit f or at least 1 2 h o urs, or a bilit y t o sta y o ver ni g ht i n a n i n patie nt  
me dical setti n g o ne ni g ht pri or t o off -me dicati o n assess me nt.  
1 0.  Fe male  s u bjects m ust n ot be pre g na nt or breastfee di n g. W o me n of c hil d beari n g p ote ntial  ( W O C B P) 
m ust ha ve a ne gati ve pre g na nc y test at Scree ni n g . W O C B P  m ust a gree t o use hi g hl y effecti ve 


 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 2 0  of 9 9   
 
c o ntrace pti o n  w hic h i ncl u des c o m bi ne d (estr o ge n a n d pr o gest o ge n c o ntai ni n g) h or m o nal 
c o ntrace pti o n ass ociate d wit h i n hi biti o n of o v ulati o n ( oral, i ntra va gi nal, tra ns der mal), pr o gest o ge n -
o nl y h or m o nal c o ntrace pti o n ass oci ate d wit h i n hi biti o n of o v ulati o n ( oral, i njecta ble, i m pla nta ble), 
i ntra uteri ne de vice, i ntra uteri ne h or m o ne-releasi n g s yste m, bilateral t u bal occl usi o n, or vasect o mize d 
part ner  (Cli nical Trial Facilitati o n Gr o u p 2 0 1 4 ) pri or t o st u d y e ntr y. A w o ma n is c o nsi dere d of 
c hil d beari n g p ote ntial f oll o wi n g me narc he a n d u nt il bec o mi n g p ost me n o pa usal ( n o me nses f or at 
least 2 years wit h o ut a n alter nati ve ca use). S h o ul d a w o ma n bec o me pre g na nt or s us pect s he is 
pre g na nt w hi le s he or her part ner is partici pati n g i n t he st u d y, s he s h o ul d i nf or m her treati n g 
p h ysicia n i m me diatel y . Male s u bjects m ust be willi n g t o use a barrier met h o d c o ntrace pti o n.  
1 1.  T he s u bject m ust be a ble t o f oll o w t he st u d y pr oce d ures , recei ve t he treat me nt in t he esta blis he d 
ti mefra me, a n d c o nti n ue d uri n g t he f oll o w-u p i nter val .  
1 2.  T he s u bject m ust be a ble t o u n dersta n d t he pr oce d ures a n d a gree t o c o m plete t he re q uire d 
assess me nts. 
1 3.  Pr o vi de a si g ne d a n d date d i nf or me d c o nse nt f or m i n acc or da nce wit h l ocal re g ula ti o ns a n d/ or 
I R B/I E C g ui deli nes.  
 
5. 2  
E X C L U SI O N C RI T E RI A  
 
A n i n di vi d u al  will n ot be eli gi ble f or i ncl usi o n if a n y of t he f oll o wi n g criteri a a p pl y : 
1.  Sec o n dar y or at y pical par ki ns o nia n s y n dr o mes, f or e xa m ple, patie nts wit h par ki ns o nis m fr o m 
e nce p halitis, meta b olic dis or ders, vasc ular par ki ns o nis m, dr u g -i n d uce d par ki ns o nis m, m ulti ple 
syste m atr o p h y, cortic o basal g a n glia d e ge nerati o n, p r o gressi ve su pra n uclear p als y, Le w y b o d y 
d e me ntia.   
2.  Me dical hist or y or c o n dit i o n:  
•  
U nc o ntr olle d dia betes mellit us, wit h he m o gl o bi n A 1c ( H b A 1c) > 8 % .  
•  
M y ocar dial i nfarcti o n or str o ke wit hi n 1 2 m o nt hs of scree ni n g . 
•  
Si g nifica nt car diac arr h yt h mia .  
•  
Acti ve blee di n g dis or der . 
•  
Maj or s ur ger y wit hi n 1 m o nt h of scree ni n g or pla n ne d wit hi n t he st u d y peri o d . 
•  
C urre nt, acti ve li ver disease: > 3 -f ol d ele vati o n of li ver e nz y mes (ala ni ne a mi n otra nsferase 
[ A L T] a n d as partate a mi n otra nsferase [ A S T] o ver u p per li mit of n or mal). 
•  
U nc o ntr olle d hi g h bl o o d press ure (s yst olic bl o o d press ure of 1 6 0 m m H g or hi g her a n d/ or 
diast olic bl o o d press ure of 1 0 0 m m H g or hi g her) des pite a de q uate treat me nt d uri n g t he 3 
m o nt hs pri or t o d osi n g . 
•  
P ositi ve scree ni n g  test res ult f or he patitis B vir us ( H B V) , he patitis C vir us ( H C V) , or h u ma n 
i m m u n o deficie nc y vir us ( HI V).  
3.  
 
  
4.  
 
 
5.  
 
6.  Re nal f u ncti o n as defi ne d b y esti mate d gl o mer ular filtrati o n rate (e G F R) < 4 5 m L/ mi n/ 1. 7 3 m 2 
usi n g t he M o dificati o n of Diet i n Re nal Disease ( M D R D) st u d y e q uati o n  (Secti o n 1 7. 9 ).  
7.  
 
 
8.  
 
9.  Hist or y of a n y brai n s ur ger y f or P D ( e. g., palli d ot o m y, dee p brai n sti m ulati o n, or fetal tiss ue 
tra ns pla nt). 
1 0.  
 
 
 
1 1.  Cli nicall y rele va nt a b n or mal la b orat or y  val ue at scree ni n g, i ncl u di n g he mat ol o g y, bl o o d c he mistr y, 


 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 2 1  of 9 9   
 
or uri nal ysis (la b orat or y testi n g ma y be re peate d o nce d uri n g t he scree ni n g p hase).  
1 2.  C o n diti o ns affecti n g t he peri p heral or ce ntral ner v o us s yste m, u nless relate d t o P D , t hat w o ul d 
affect t he a bilit y t o a de q uatel y perf or m t he M D S -U P D R S a n d m ot or assess me nts: i.e., se vere 
se ns or y ne ur o pat h y affecti n g ar m or le g f u ncti o n, or str o ke affecti n g m ot or or gait f u ncti o n.  
1 3.  Si g nifica nt alc o h ol or dr u g a b use wit hi n past 2 years.  
1 4.  Ba se d o n E C G rea di n g, s u bjects wit h a ris k of Q T pr ol o n gati o n i ncl u di n g: 
•  
A baseli ne pr ol o n gati o n of Q Tc ( usi n g Fri dericia’s f or m ula: ≥ 4 5 0 ms i n me n a n d ≥ 4 7 0 ms 
i n w o me n) wit h c o nfir mati o n o n a re peat E C G.  
•  
A hist or y of a d diti o nal ris k fact ors f or T orsa des de p oi ntes arr h yt h mia ( e. g., heart fail ure, 
h y p o kale mia, fa mil y hist or y of L o n g Q T S y n dr o me, etc.) . 
•  
T he use of c o nc o mita nt me dicati o ns k n o w n t o pr ol o n g t he Q T/ Q Tc i nter val . 
1 5.  Si g nifica nt me dical c o n diti o ns (as deter mi ne d b y me dical hist or y, e xa mi nati o n, a n d cli nical 
i n vesti gati o ns at scree ni n g) t hat ma y, i n t he o pi ni o n of t he i n vesti gat or, res ult i n t he a n y of t he 
f oll o wi n g:  
•  
P ut t he patie nt at ris k beca use of partici pati o n i n t he st u d y .  
•  
I nfl ue nce t he res ults of t he st u d y.  
•  
Ca use c o ncer n re gar di n g t he patie nt’s a bilit y t o partici pate i n t he st u d y . 
•  
I ncl usi o n of v ul nera ble pers o ns b y l ocal re g ulati o n (e. g., i m pris o ne d or i nstit uti o nalize d).  
1 6.  Mali g na nc y f or w hic h t he patie nt has u n der g o ne resecti o n, ra diati o n or c he m ot hera p y wit hi n past 
5  years (treate d ba sal cell carci n o ma or f ull y c ure d s q ua m o us cell carci n o ma are all o we d). 
1 7.  C o nc urre nt partici pati o n i n a n ot her i nter ve nti o nal cli nical trial ; pri or cli nical trial s u bjects m ust 
ha ve bee n off st u d y a ge nts f or at least 3 0 da ys f or s mall m olec ules, 4 m o nt hs f or disease m o dif yi n g 
t hera pies, a n d 1 year f or vacci ne or i m m u n ot hera p y trials pri or t o scree ni n g. 
 
5. 3  
S T R A T E GI E S F O R R E C R UI T M E N T A N D R E T E N TI O N  
 
T he S p o ns or d oes n ot a ntici pate a n y s pecific c halle n ges i n meeti n g recr uit me nt g oals of e nr olli n g a n d retai ni n g  a 
t otal of 1 2 0  s u bjects i n t his st u d y. S u bjects will be recr uite d c o nti n u o usl y u ntil t he pla n ne d  sa m ple size is 
ac hie ve d . S u bjects w h o wit h dra w or are wit h dra w n d uri n g S cree ni n g, as well as s u bjects w h o disc o nti n ue, ma y be 
re place d (see Secti o n 5. 4. 2 Ha n dli n g of Partici pa nt Wit h dra wals or Ter mi nati o n ).  
 
T he e x pecte d le n gt h of partici pati o n i n t he st u d y  of a p pr o xi matel y 1 8  wee ks  is n ot e x pecte d t o be c halle n gi n g t o  
s u bjects. F i na ncial s u p p ort f or meal an d miscella ne o us e x pe nses will be a vaila ble  d uri n g t he st u d y , as a p pr o priate  
a n d base d o n l ocal re g ulati o ns  a n d g ui deli nes . U se of visit tra ns p ort ser vices ma y als o be i nc or p orate d i nt o t he 
trial t o s u p p ort t he s u bject i n mai ntai ni n g st u d y visit c o m plia nce. A descri pti o n of t he st u d y will be i ncl u de d i n 
l ocal cli ni cal trial  data b ases, as re q uire d.  
 
5. 4  
S U B J E C T  WI T H D R A W A L O R T E R MI N A TI O N  
 
5. 4 . 1 
R E A S O N S F O R WI T H D R A W A L O R T E R MI N A TI O N  
 
 
 
 
A s u bject ma y  be  wit h dra w n fr o m  st u d y treat me nt f or t he f oll o wi n g me dical or a d mi nistrati ve reas o ns: 
• 
Occ urre nce of a n A E  t hat re prese nts a n u nacce pta ble ris k t o t he s u bject a n d w he n c o nti n ue d 
partici pati o n i n t he i n vesti gati o nal st u d y is n ot warra nte d, i n  t he j u d g me nt of t he i n vesti gat or, 
S p o ns or , or me dical m o nit or . T he i n vesti gat or m ust f oll o w t he s u bject u ntil t he A E res ol ves or is 
sta ble u nless t he s u bject is l ost t o f oll o w u p . 
• 
Treat me nt wit h a pr o hi bite d c o nc o mita nt me dicati o n ot her t ha n t he use of a p pr o priate me dicati o ns 
f or t he treat me nt of A Es u n der directi o n of t he i n vesti gat or. 
• 
S u bject n o nc o m plia nce, defi ne d as ref usal or i na bilit y t o a d h ere t o t he trial sc he d ule or pr oce d ures . 
• 
At t he re q uest of t he s u bject (e. g., s u bject wit h dra ws c o nse nt), i n vesti gat or, S p o ns or , or re g ulat or y 
a ut h orit y . 


 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 2 2  of 9 9   
 
• 
Pre g na nc y . 
 
5. 4 . 2 
H A N D LI N G O F P A R TI C IP A N T WI T H D R A W A L S O R T E R MI N A TI O N   
 
 
S u bjects will be e nc o ura ge d t o c o m plete t he st u d y a n d all assess me nts . S u bjects ma y v ol u ntaril y wit h dra w at 
a n y ti me, a n d t he i n vesti gat or ma y disc o nti n ue i n di vi d ual s u bjects fr o m t he st u d y at a n y ti me.  
 
A p pr o xi matel y 1 2 0  s u bjects (A K S T 4 2 9 0 : 6 0 ; place b o : 6 0 ) will be e nr olle d i n t he st u d y wit h t he i nte nt of 
o btai ni n g ~ 1 0 8  e val ua ble s u bjects . S u bjects w h o disc o nti n ue or are u n bli n de d pri or t o Visit 6 ma y be 
re place d. S u bjects w h o wit h dra w or are wit h dra w n d uri n g scree ni n g will be re place d . S u bjects w h o are 
wit h dra w n d ue t o a d verse dr u g e ve nts or a d verse reacti o ns base d o n st u d y pr oce d ures will n ot be re place d.  
 
S u bjects w h o ha ve recei ve d at least 1  d ose ( 4 0 0  m g)  b ut  are wit h dra w n  or wit h dra w  fr o m t he st u d y will be 
e nc o ura ge d t o c o m plete t he e n d of treat me nt pr oce d ures . T he pri mar y reas o n f or st u d y disc o nti n uati o n will be 
d oc u me nte d o n t he case re p ort f or m ( C R F).  
 
5. 5  
P R E M A T U R E T E R MI N A TI O N O R S U S P E N SI O N O F S T U D Y  
 
T he S p o ns or  reser ves t he ri g ht t o ter mi nate t he st u d y at a n y ti me. S h o ul d t his be necessar y, t he S p o ns or a n d/or 
t heir re prese ntati ves will arra n ge disc o nti n uati o n pr o ce d ures a n d n otif y t he a p pr o priate re g ulat or y a ut h orit y(ies), 
I R Bs, a n d I E Cs . I n ter mi nati n g t he st u d y, t he S p o ns or  a n d t he i n vesti gat or will c o nti n ue t o pr otect t he s u bjects’ 
pri vac y a n d i de ntit y as re q uire d b y rele va nt stat ues a n d re g ulati o ns.  
 
Al ka hest, I nc. has t he ri g ht t o ter mi nate a st u d y site fr o m partici pati n g i n t he st u d y at a n y ti me . Reas o ns f or st u d y 
or sit e ter mi nati o n ma y i ncl u de, b ut are n ot li mite d t o:  
• 
(I m me diate) ris k t o s u bject safet y. 
• 
U nsatisfact or y s u bject e nr oll me nt . 
• 
U nacce pta ble pr ot oc ol de viati o ns / vi olati o ns as assesse d b y t he me dical mo nit or . 
• 
I nacc urate or i nc o m plete data e ntr y a n d rec or di n g/fa bricate d data. 
• 
I n vesti gati o nal site n o n-c o m plia nce wit h I C H/ G C P . 
• 
U nacce pta ble e mer ge nt safet y pr ofile . 
 
6  
S T U D Y A G E N T  
6. 1  
S T U D Y A G E N T  A N D C O N T R O L  D E S C RI P TI O N  
 
 
6. 1. 1  
A C Q UI SI TI O N  
 
T he st u d y a ge nt will be ma n ufact ure d, la bele d, pac ka ge d, a n d distri b ute d b y Al ka hest, I nc.  
 
6. 1. 2  
F O R M U L A TI O N, A P P E A R A N C E, P A C K A GI N G, A N D L A B E LI N G  
 
A K S T 4 2 9 0  is a fil m-c oate d pi n k, o bl o n g ta blet ma n ufact ure d b y Al ka hest, I nc., wit h a u nit stre n gt h of 
2 0 0  m g . T he st u d y a ge nt  ( A K S T 4 2 9 0/ place b o) will be deli vere d t o t he site a n d la bele d f or i n vesti gati o nal use 
o nl y acc or di n g t o t he rele va nt re g ulat or y re q uire me nt s f or cli nical st u dies.  
 
F or f urt her details a n d i nf or mati o n o n A K S T 4 2 9 0, i ncl u di n g pac ka gi n g a n d la beli n g, see t he I n vesti gat or’s 
Br oc h ure .  
 
 
 
 


 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
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C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 2 3  of 9 9   
 
6. 1. 3  
P R O D U C T S T O R A G E A N D S T A BI LI T Y  
 
T he st u d y a ge nt will be ke pt i n its ori gi nal pac ka gi n g i n a sec ure li mite d access st ora ge area at 1 5° C - 3 0° C . 
A te m perat ure l o g m ust be mai ntai ne d t o ma ke certai n t he st u d y a ge nt is st ore d at t he c orrect te m perat ure. If 
t he st ora ge c o n diti o ns are f o u n d t o be o utsi de t he s pecifie d ra n ge, t he site m ust i m me diatel y n otif y t he 
s p o ns or or desi g nee. 
 
6. 1. 4  
D O SI N G A N D A D MI NI S T R A TI O N  
 
T he st u d y a ge nt will be self -a d mi nistere d orall y b.i. d.  ( 2 x 2 0 0 m g per d ose), a p pr o xi matel y 1 2 h o urs a part, 
f or a t otal dail y d ose of 8 0 0 m g. A K S T 4 2 9 0 s h o ul d be ta ke n 1 h o ur bef ore meals or 2 h o urs f oll o wi n g a meal. 
Trai ni n g o n st u d y a ge nt  a d mi nistrati o n will be c o n d ucte d pri or t o i nitial  d ose . D uri n g t he treat me nt peri o d  
( Visits 2-6) , s u bjects will  be i nstr ucte d t o wait t o a d mi nister t heir first dail y d ose u ntil t hey are as ke d  t o d o s o 
b y st u d y pers o n nel f or d oc u me ntati o n of precise a d mi nistrati o n ti mes (f oll o wi n g P K  testi n g).  
 
6. 1. 5  
R O U T E O F A D MI NI S T R A TI O N  
 
T he st u d y a ge nt will be a d mi nistere d orall y . 
  
6. 2  
S T U D Y A G E N T A C C O U N T A BI LI T Y  
 
T he i n vesti gat or a n d/ or p har macist will recei ve t he st u d y a ge nt a n d place b o deli vere d b y t he s p o ns or w he n t he 
f oll o wi n g re q uire me nts are f ulfille d: 
•  
A p pr o val of t he st u d y pr ot oc ol a n d inf or me d co nse nt (s) b y t he I R B or I E C . 
•  
A vaila bilit y of a si g ne d a n d date d cli nical trial c o ntract bet wee n t he s p o ns or a n d t he i n vesti gati o nal 
site. 
•  
A p pr o val/ n otificati o n of t he a p pr o priate re g ulat or y a ut h orit y (ies). 
•  
A vaila bilit y of t he c urric ul u m vitae of t he pri nci pal i n vesti gat or . 
•  
A vaila bilit y of a si g ne d a n d date d cli nical trial pr ot oc ol or i m me diatel y i m mi ne nt si g ni n g of t he cli nical 
trial pr ot oc ol. 
T he i n vesti gat or a n d/ or p har macist m ust mai ntai n rec or ds of t he st u d y a ge nt’s a n d place b o’s deli ver y t o t he trial 
site, t he i n ve nt or y at t he site, t he use b y eac h s u bject, a n d t he ret ur n t o t he s p o ns or or alter nati ve dis p ositi o n of 
u n use d st u d y a ge nt .  
T hese rec or ds will i ncl u de dates, q ua ntities, batc h/serial n u m bers, e x pir y (‘ use b y’) dates, a n d t he u ni q ue c o de 
n u m bers assi g ne d t o t he st u d y a ge nt , place b o , a n d trial s u bjects . T he i n vesti gat or/ p har macist will mai ntai n 
rec or ds t hat d oc u me nt a de q uatel y t hat t he s u bjects were pr o vi de d t he d oses s pecifie d b y t he pr ot oc ol a n d 
rec o ncile all st u d y a ge nt a n d place b o recei ve d fr o m t he s p o ns or. At t he ti me of fi nal st u d y a ge nt a n d place b o 
rec o nciliati o n, t he i n vesti gat or/ p har macist m ust verif y t hat all u n use d or partiall y use d p orti o n of st u d y a ge nt 
a n d place b o  ha ve bee n ret ur ne d b y t he cli nical trial s u bject a n d t hat n o re mai ni n g st u d y a ge nt a n d place b o is 
retai ne d b y t he i n vesti gat or.  
Acc o u nta bilit y rec or ds m ust be mai ntai ne d a n d rea dil y a vaila ble f or m o nit ori n g  a n d a u diti n g p ur p oses  b y 
re prese ntati ves of Al ka hest, I nc. or t heir desi g nee a n d are o pe n t o i ns pecti o n b y re g ulat or y a ut h orities at a n y 
ti me. T he acc o u nts of a n y st u d y a ge nt a n d place b o acci de ntall y waste d or i nte nti o nall y dis p ose d of m ust be 
mai ntai ne d.  
T he dis p osal of use d, partiall y use d, or waste d st u d y a ge nt a n d place b o m ust be c o n d ucte d  i n acc or da nce wit h 
t he i nstit uti o n’s dr u g dis p osal p olic y. At st u d y i nitiati o n, t he cli nical st u d y m o nit or will e val uate t he site’s 
sta n dar d o perati n g pr oce d ure f or st u d y a ge nt dis p osal/ destr ucti o n t o e ns ure it c o m plies wit h st u d y re q uire me nts . 
At t he e n d of t he st u d y, f oll o wi n g fi nal st u d y a ge nt a n d place b o rec o nciliati o n b y t he m o nit or, t he st u d y site will 
be i nstr ucte d b y t he s p o ns or t o ret ur n or destr o y all u n use d st u d y a ge nt  a n d place b o . A c o p y of t he i nstit uti o n’s 


 
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C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 2 4  of 9 9   
 
dr u g dis p osal p olic y s h o ul d be mai ntai ne d or refere nce d i n t he I n vesti gat or Site File (I S F) if ap plica ble . 
 
7  
S T U D Y P R O C E D U R E S A N D S C H E D U L E  
7. 1  
S T U D Y P R O C E D U R E S/ E V A L U A TI O N S  
 
7. 1. 1  
S T U D Y S P E CI FI C P R O C E D U R E S  
 
7. 1. 1. 1 Scree ni n g Pr oce d ures  
D uri n g scree ni n g, t he f oll o wi n g will be c o n d ucte d: 
•  
Assess me nt of P D , i ncl u di n g m o difie d H oe h n a n d Ya hr . 
•  
Me dical hist or y . 
•  
De m o gra p hics . 
•  
Re vie w of me dicati o ns . 
•  
Vital si g ns . 
•  
P h ysical e xa mi nati o n . 
•  
1 2 -Lea d E C G . 
•  
Bl o o d a n d uri ne c ollecti o n f or la b orat or y e val uati o ns . 
 
Detaile d descri pti o ns of eac h of t hese pr oce d ures are pr o vi de d i n t he secti o ns i m me diatel y f oll o wi n g. 
I nf or mati o n pertai ni n g t o all st u d y acti vities c o n d ucte d d uri n g scree ni n g, a n d t he se q ue nce of e ve nts, is 
pr o vi de d i n  Secti o n 7. 3. 1 Scree ni n g . 
 
7. 1. 1. 1. 1  Assess me nt of P ar ki ns o n’s Disease  a n d C o g niti ve I m pair me nt 
T he dia g n osis of P D  will be verifie d usi n g  M D S -P D criteria (P ost u ma 2 0 1 5 ) (Secti o n 1 7. 7 ). T he prere q uisite 
t o a p pl y t he M D S-P D criteria is t he  prese nce  of t he car di nal s y m pt o ms of Par ki ns o n’s Disease, defi ne d as 
bra d y ki nesia, i n c o m bi nati o n wit h eit her rest i n g tre m or, ri gi dit y, or b ot h. T hese feat ures m ust be clearl y 
de m o nstra ble a n d n ot attri b uta ble t o c o nf o u n di n g fact ors ( P ost u ma 2 0 1 5 ). T he sta ge of t he disease will be 
classifie d usi n g t he m o difie d H oe h n a n d Ya hr scale .  
 
7. 1. 1. 1. 2  Me dical Hist or y  
T he i n vesti gat or or desi g nee will o btai n a detaile d me dical hist or y t hr o u g h i nter vie w wit h t he s u bject d uri n g 
scree ni n g. T he me dical hist or y s h o ul d f oc us o n rece nt hist or y, wit h a n e m p hasis o n t he hist or y of m ot or 
s y m pt o ms relate d t o P D . A d diti o nall y, t he me dical hist or y s h o ul d i ncl u de:  
•  
C urre nt/ past ill nesses a n d c o n diti o ns . 
•  
C urre nt s y m pt o ms  of a n y acti ve me dical c o n diti o n . 
•  
S ur geries a n d pr oce d ures . 
•  
Aller gies . 
•  
Fa mil y hist or y  i n bi ol o gical pare nts, si bli n gs, a n d offs pri n g of P D, A D , or ot her de me ntias or 
ne ur ol o gical dis or ders . 
•  
S ocial hist or y ( e. g., e xercise, s m o ki n g, alc o h ol, ille gal s u bsta nces) a n d c urre nt li vi n g sit uati o n  
•  
Ca use of pare ntal deat h (if n ot li vi n g) . 
•  
Pri or i ma gi n g, C S F assess me nts, or  ot her rele va nt dia g n ostic test  res ults, i ncl u di n g ge netics. 
 
7. 1. 1. 1. 3  De m o gra p hics  
De m o gra p hic i nf or m ati o n s uc h as t he s u bject’s e d ucati o n  le vel, et h nicit y, a n d race will be c ollecte d b y 
i nter vie w wit h t he s u bject at scree ni n g. 
 
7. 1. 1. 1. 4  Re vie w of Me dicati o ns  
T he i n vesti gat or or desi g nee s h o ul d o btai n a c o m plete list of t he s u bject’s c urre nt me dicati o ns, i ncl u di n g 
o ver -t he-c o u nter dr u gs, her bal s u p ple me nts a n d/ or vita mi ns, as well as t h ose ta ke n b y t he s u bject i n t he past 


 
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C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 2 5  of 9 9   
 
1 2 m o nt hs  a n d a n y d ose c ha n ges of me dicati o ns f or P D  i n t he last 3 m o nt hs. Assess me nt of eli gi bilit y s h o ul d 
i ncl u de a re view of per mitte d a n d pr o hi bite d  me dicati o ns . A n y a d diti o ns,  disc o nti n uati o n , or d osa ge c ha n ges 
i n me dicati o n d uri n g t he c o urse of t he st u d y will be rec or de d. 
 
7. 1. 1. 1. 5  Vital Si g ns  
Vital si g ns will i ncl u de seate d s yst olic a n d diast olic bl o o d press ure ( m m  H g) , heart rate ( beats per mi n ute 
[ b p m]), res pirati o n rate ( breat hs per mi n ute), a n d b o d y  te m perat ure. Vital si g ns will be meas ure d after t he 
s u bject has bee n seate d f or 5 mi n utes.  
 
7. 1. 1. 1. 6  F ull P h ysical E xa mi nati o n  
A f ull p h ysical e xa mi nati o n will be perf or me d  a n d d oc u me nte d t o assess t he f oll o wi n g or ga n s yste ms: s ki n, 
E N T (ears, n ose, a n d t hr oat), hea d, e yes, l u n gs/c hest, heart, a b d o me n, m usc ul os keletal, e xtre mities, 
ne ur ol o gic a n d l y m p hatic s yste ms . T he c o m plete ne ur ol o gical e xa m i nati o n will i ncl u de , b ut n ot be li mite d t o 
me ntal stat us, cra nial ner ves ( vis ual fiel ds, f u n d osc o pic e xa m, p u pillar y li g ht refle x, e xtra oc ular m uscles, 
facial se nsati o n a n d s y m metr y, palate a n d t o n g ue, a n d hea d t ur ni n g a n d s h o ul der s hr u g); m uscle stre n gt h, 
t o ne, b ul k, a n d a b n or mal m o ve me nts; refle xes ( bice ps, trice ps, k nees, a n kles, a n d pla ntar); c o or di nati o n 
(fi n ger-t o-n ose, heel -k nee -s hi n); se ns or y f u ncti o n (li g ht t o uc h, pi n pric k , a n d vi brati o n ); a n d gait. Hei g ht will 
be meas ure d at scree n i n g a n d wei g ht will be m o nit ore d d uri n g t he trial.  
 
7. 1. 1. 1. 7  1 2 -Lea d E C G  
T wel ve -lea d E C Gs (I, II, III, a V R, a V L, a V F, V 1 - V 6) will be rec or de d usi n g a c o m p uterize d 
electr ocar di o gra p h. A 1 2 -lea d E C G will be perf or me d  after t he s u bject has reste d q uietl y f or at least 5 mi n utes 
i n a s u pi ne p ositi o n. I n s o me cases, it ma y be a p pr o priate t o re peat a b n or mal E C Gs t o r ule o ut tec h nical 
fact ors c o ntri b uti n g t o E C G artifacts or a b n or malit y. It is i m p orta nt t hat lea ds are placed i n t he sa me p ositi o ns 
eac h ti me f or c o nsiste nc y . T he o verall c o ncl usi o n wit h t he i nter pretati o n of t he E C Gs will be rec or de d o n t he 
a p pr o priate C R F . T he i nter pretati o n of t he E C Gs will be rec or de d as n or mal, a b n or mal b ut n ot cli nicall y 
si g nifica nt, or a bn or mal a n d cli nicall y si g nifica nt . C orrecte d Q Tc i nter vals will be calc ulate d usi n g 
Fri dericia’s c orrecti o n f or m ula  a n d e ntere d i nt o t he C R F .  
 
7. 1. 1. 1. 8  Scree ni n g Bi ol o gical S peci me n C ollecti o n  
F or scree ni n g e val uati o n, b l o o d will be dra w n b y a q ualifie d me dical pr o vi der, a n d uri ne s peci me ns will als o 
be c ollecte d  (see Secti o n 7. 1. 1. 2. 7 ).  
 
7. 1. 1. 1. 9  A d mi nistrati o n of D o pa mi ner gic Me dicati o n   
S u bjects will be i nstr ucte d b y site pers o n nel t o ta ke t heir prescri be d d o pa mi ner gic me dicati o n f oll o wi n g 
c o m pleti o n of t he off -me dicati o n assess me nts o n Visit 2 ( Da y 1), Visit 4 ( Da y 2 8), Visit 6 ( Da y 8 4), a n d Visit 
7 ( Da y 9 8).      
 
7. 1. 1. 2 Pr oce d ures t o Assess S afet y  
S u bjects e nr olle d i n t he trial will be m o nit ore d cl osel y t o assess safet y a n d t olera bilit y of t he st u d y a ge nt a n d 
i nter ve nti o n. St u d y -s pecific pr oce d ures t hat will be use d f or t his p ur p ose are s u m marize d bel o w . I nf or mati o n 
re gardi n g t he ti mi n g a n d fre q ue nc y of t hese pr oce d ures is pr o vi de d i n  Secti o n 7. 3 St u d y Sc he d ule .  
• 
Re vie w of A Es . 
• 
Re vie w of me dicati o ns . 
• 
Vital si g ns . 
• 
S -S T S . 
• 
1 2 -Lea d E C Gs . 
• 
Tar gete d p h ysical e xa m i nati o ns a n d wei g ht.  
• 
E n d o f St u d y ( or Earl y Ter mi nati o n) p h ysical exa m i nati o n. 
• 
Bl o o d d ra w a n d u ri ne collecti o n f or la b orat or y eval uati o ns . 
 


 
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C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 2 6  of 9 9   
 
7. 1. 1. 2. 1 Re vie w of A d verse E ve nts  
A Es will be re vie we d, d oc u me nte d, a n d re p orte d as re q uire d at eac h visit, be gi n ni n g at S cree ni n g . F or 
defi niti o ns, g ui da nce, a n d a d diti o nal i nf or mati o n re gar di n g A Es, refer t o  Secti o n 8 .  
 
7. 1. 1. 2. 2 Re vie w of Me dicati o ns  
T he i n vesti gat or or desi g nee s h o ul d re vie w t he s u bject’s c urre nt me dicati o ns, i ncl u di n g o ver -t he-c o u nter 
dr u gs, her bal s u p ple me nts a n d/ or vita mi ns, as well as t h ose ta ke n b y t he s u bject si nce t he last visit . C ha n ges 
t o t he s u bject’s list of me dicati o ns s ho ul d be re vie we d a n d rec or de d . Re vie w of me dicati o ns s h o ul d occ ur at 
e ver y visit. 
 
7. 1. 1. 2. 3 Vital Si g ns  
Refer t o Secti o n 7. 1. 1. 1. 5  f or a descri pti o n of v ital si g ns. Vital si g ns will be c ollecte d at e ver y visit (see t he 
Sc he d ule of E ve nts ).  
 
7. 1. 1. 2. 4 S hee ha n -S uici dalit y Trac ki n g Scale  
Refer t o Secti o n 7. 1. 1. 3 .6  f or a descri pti o n of t he S -S T S .  
 
7. 1. 1. 2. 5 1 2 -Lea d E C G  
Refer t o  Secti o n 7. 1. 1. 1. 7  f or i nf or mati o n pertai ni n g t o 1 2-Lea d E C Gs.  
 
7. 1. 1 . 2.6  Tar gete d P h ysical E xa m i nati o n 
D uri n g t he st u d y peri o d, a tar gete d p h ysical e xa m i nati o n, i ncl u di n g a usc ultati o n of t he heart a n d meas ure me nt 
of wei g ht, will be perf or me d  per t he Sc he d ule of E ve nts .  
 
7. 1. 1. 2. 7  Bl o o d a n d Uri ne C ollecti o n f or La b orat or y E val uati o ns  
Bl o o d sa m ples a n d uri ne will be c ollecte d ac c or di n g t o t he Sc he d ule of E ve nts . L a b orat or y tests will 
i ncl u de he mat ol o g y, c he mistr y, c oa g ulati o n, q ualitati ve uri nal ysis , a n d pre g na nc y testi n g i n W O C B P.  
•  
He mat ol o g y: he m o gl o bi n, he mat ocrit,  re d bl o o d cell ( R B C) c o u nt, w hite bl o o d cell ( W B C) 
c o u nt wit h differe ntial, platelets  
•  
C he mistr y: gl uc ose, s o di u m, p otassi u m, calci u m, i n or ga nic p h os p hate, c hl ori de, 
bicar b o nate, ma g nesi u m, creati ni ne, as partate a mi n otra nsferase ( A S T), ala ni ne 
a mi n otra nsferase ( A L T), al kali ne p h os p hatase ( AL P), lactate de h y dr o ge nase  ( L D H), t otal 
bilir u bi n, bl o o d urea  nitr o ge n , t otal pr otei n, al b u mi n, creati ne p h os p h o ki nase  ( C P K), 
c h olester ol (t otal), C -reacti ve pr otei n ( C R P) 
•  
Ser ol o g y  (c o n d ucte d  at Scree ni n g o nl y) : H B V, H C V, a n d HI V  
•  
C oa g ulati o n: acti vate d partial t hr o m b o plasti n  ti me (a P T T), pr ot hr o m bi n ti me/i nter nati o nal 
n or malize d rati o (I N R)  
•  
Uri n al ysis: p H, gl uc ose, er yt hr oc ytes, le u k oc ytes, pr otei n, nitrite 
 
A d diti o nal la b orat or y  para meters  ma y be  re p orte d as detaile d  i n t he la b orat or y ma n ual. Gl o mer ular 
filtrati o n rate ( G F R) will be esti mate d b y t he M D R D  F or m ula utilizi n g ser u m creati ni ne (see  Secti o n 
1 7. 9 ). All safet y la b orat or y meas ure me nts will be c o n d ucte d b y a C LI A -certifie d  la b orat or y. 
I n vesti gat ors will get g ui da nce a n d i nstr ucti o ns o n la b orat or y sa m pli n g a n d pr ocessi n g t hr o u g h a se parate 
La b orat or y  Ma n ual pr o vi de d b y t he ce ntral la b orat or y.  
 
Ser ol o g y will o nl y be c o n d ucte d at scree ni n g. P ote ntial s u bjects wit h p ositi ve scree ni n g test res ult f or H B V, 
H C V, or HI V will n ot be eli gi ble f or st u d y partici pati o n.  
 
T he i n vesti gat or is res p o nsi ble f or deter mi ni n g a n d d oc u me nti n g if o ut -of -ra n ge la b orat or y val ues are 
cli nicall y si g nifica nt . All cli nicall y si g nifica nt v al ues will be rec or de d as A Es i n t he C R F a n d f oll o we d 
u ntil res ol uti o n . O nce res ol ve d, t he a p pr o priate C R F pa ge(s) will be u p date d.  


 
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C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 2 7  of 9 9   
 
 
S a m ples ma y be use d f or re -testi n g, f urt her e val uati o n of a n A E a n d/ or assess me nt, a n d f oll o w-u p of ot her 
e x pl orat or y e n d p oi nts . Sa m ples t hat  re mai n after st u d y testi n g is c o m plete will be st ore d i n t he e ve nt 
a d diti o nal testi n g ( e. g., f urt her e val uati o n of a n A E or assess me nt of effect) is re q uire d. Sa m ples will be 
st ore d i n a dei de ntifie d c o de d f or m. S u bjects ca n o pt o ut of st ora ge of sa m ples f or f ut ure a nal ysis.  
 
7. 1. 1. 3 Pr oce d ures t o Assess Effic ac y  
Pr oce d ures t o assess efficac y i ncl u de m ot or a n d c o g niti ve  f u ncti o n testi n g, assess me nt of acti vities of dail y 
li vi n g, a n d, i n c o nse nti n g s u bjects, micr o bi o me assess me nt . I nf or mati o n re gar di n g t he ti mi n g a n d fre q ue nc y 
of t hese pr oce d ures is pr o vi de d i n  Secti o n 7. 3  a n d Secti o n 1 5 Sc he d ule of E ve nts . 
 
All  testi n g will be  c o n d ucte d  b y q ualifie d e val uat ors w h o ha ve u n der g o ne sta n dar dize d rater trai ni n g  a n d 
certifi cati o n, as a p pr o priate. T he sa me e val uat or s h o ul d be use d f or t he d urati o n of eac h s u bject’s 
partici pati o n u nless a c ha n ge i n rater is u na v oi da ble . T he M D S -U P D R S  Part 3 a n d 1 0 -meter ti me d wal k will 
be perf or me d  i n t he off -me dicati o n a n d o n -me dicati o n state s. A ll ot her assess me nts s h o ul d be c o n d ucte d  i n 
t he o n -me dicati o n state  as liste d i n Secti o n 7. 3 :  
 
• 
M D S -U P D R S  Parts 1 -4  
• 
M o C A   
• 
S E -A D L  
• 
CI SI -P D  
• 
P D Q -3 9  
• 
S -S T S  
• 
1 0 -meter ti me d wal k  
• 
Weara ble se ns or de vice  (as a p plica ble) 
• 
Fecal mar kers of i ntesti nal i nfla m mati o n a n d per mea bilit y ( o pti o nal)  
• 
Ha user 3 -Da y Patie nt Diar y  
 
Descri pti o ns of eac h assess me nt are pr o vi de d bel o w.  
 
7. 1. 1. 3. 1 M o ve me nt Dis or der S ociet y’s U nifie d Par ki ns o n’s Disease Rati n g Scale  
T he M D S -U P D R S ( Fa h n 1 9 8 7 , G oetz 2 0 0 8 ) (Secti o n 1 7. 1 ) was de vel o pe d t o i nc or p orate ele me nts fr o m 
e xisti n g scales t o pr o vi de a c o m pre he nsi ve b ut efficie nt a n d fle xi ble mea ns t o m o nit or P D -relate d disa bilit y 
a n d i m pair me nt. T he M D S -U P D R S has f o ur c o m p o ne nts ( Part 1 , Me ntati o n, Be ha vi or, a n d M o o d; Part 2 , 
Acti vities of Dail y Li vi n g; Part 3 , M ot or; Part 4 , C o m plicati o ns). O ne of t he c ore a d va nta ges of t he U P D R S is 
t hat it was de vel o pe d as a c o m p o u n d scale t o ca pt ure m ulti ple as pects of P D. T he rati n g f or eac h ite m is fr o m 
0 ( n or mal) t o 4 (se vere). T he t otal sc ore f or eac h Part is o btai ne d fr o m t he s u m of t he c orres p o n di n g ite m 
sc ores.  
 
7. 1. 1. 3. 2  M o ntreal C o g niti ve Assess me nt   
T he M o C A ( Nasre d di ne 2 0 0 5 ) (Secti o n 1 7. 2 ) is a scree ni n g test easil y a d mi nistere d b y n o n-s pecialist staff. It 
assesses atte nti o n a n d c o nce ntrati o n, e xec uti ve f u ncti o n, me m or y, la n g ua ge, vis u oc o nstr ucti o nal s kills, 
c o nce pt ual t hi n ki n g, calc ula ti o ns, a n d orie ntati o n. T he t otal p ossi ble sc ore is 3 0 p oi nts wit h a sc ore of 2 6 or 
m ore c o nsi dere d n or mal .  
 
7. 1. 1. 3. 3  Sc h wa b a n d E n gla n d Acti vities of Dail y Li vi n g Scale  
T he S E -A D L e val uates patie nts’ perce pti o n s of gl o bal f u ncti o nal ca pacit y a n d de pe n de nce ( Sc h wa b 1 9 6 8 ) 
(Secti o n 1 7. 3 ). Sc ori n g is e x presse d i n ter ms of perce nta ge, i n 1 0 ste ps fr o m 1 0 0 t o 0 ( 1 0 0 %, n or mal stat us; 
0 %, be dri d de n wit h i m paire d ve getati ve f u ncti o n s), s o t hat t he l o wer t he sc ore, t he w orse t he f u ncti o nal 
stat us. T he rati n g is ma de b y a  trai ne d cli nicia n. 
 


 
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C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 2 8  of 9 9   
 
7. 1. 1. 3. 4  Cli nical I m pressi o n of Se verit y I n de x –  Par ki ns o n’s Disease  
T he CI SI -P D is a se verit y i n de x f or me d b y f o ur ite ms ( m ot or si g ns, disa bilit y, m ot or c o m plicati o ns, a n d 
c o g niti ve stat us), rate d 0 ( n ot at all) t o 6 ( ver y se vere or c o m pletel y disa ble d) ( Marti nez -Marti n 2 0 0 6 ) 
(Secti o n 1 7. 4 ). A t otal sc ore is calc ulated b y s u m mi n g t he ite m sc ores. T he scale is c o m plete d b y a cli nicia n . 
It o nl y ta kes a fe w mi n utes t o c o m plete o nce t he state of t he s u bject is k n o w n. 
 
7. 1. 1. 3. 5  Par ki ns o n’s Disease Q ualit y of Life Q uesti o n naire -3 9  
T he P D Q -3 9 is a self -a d mi nistere d q uesti o n n aire of 3 9 q uesti o ns relati n g t o 8 ke y areas of healt h a n d dail y 
acti vities, i ncl u di n g b ot h m ot or a n d n o n -m ot or s y m pt o ms ( Pet o 1 9 9 8 )(Secti o n 1 7. 5 ). T he ei g ht di me nsi o ns 
i ncl u de: m o bilit y, acti vities of dail y li vi n g, e m oti o nal well-bei n g, sti g ma, s ocial s u p p ort, c o g niti o n , 
c o m m u nicati o n, a n d b o dil y disc o mf ort . It is sc ore d o n a scale of 0-1 0 0 wit h l o wer sc ores i n dicati n g better 
healt h a n d hi g h sc ores i n dicati n g m ore se vere s y m pt o ms .  
 
7. 1. 1. 3 .6  S hee ha n -S uici dalit y Trac ki n g Scale  
T he S -S T S was de vel o pe d t o pr o vi de a brief b ut efficie nt i nstr u me nt f or use i n assessi n g c ha n ge i n s uici dal 
i deati o n a n d be ha vi or w hile pr o vi di n g a c o m pre he nsi ve descri pti o n of s uici dal i deati o n a n d be ha vi or. T he 
pri mar y g oals i n t he desi g n of t he S -S T S were f or t he scale t o be: 1) sh ort a n d i ne x pe nsi ve; 2) si m ple, clear, 
a n d eas y t o a d mi nister or self -rate; 3) h i g hl y se nsiti ve (i.e., a ble t o detect a hi g h pr o p orti o n of patie nts w h o 
are s uici dal); 4) specific ( i.e., a ble t o scree n o ut t h ose w h o are n ot s uici dal); 5) se nsiti ve t o c ha n ge i n s uici dal 
i deati o n a n d be ha vi or; 6) co m pati ble wit h t he re g ulat or y cate g ories of assess me nt f or s uici dal i deati o n a n d 
be ha vi or; 7) u sef ul i n cli nical as well as researc h setti n gs; 8) u sef ul i n detecti n g a n efficac y si g nal f or a nti-
s uici dal me dicati o ns; a n d 9) ca pa ble of use i n pe diatric a n d geriatric setti n gs ( S hee ha n 2 0 1 4 ). T he sta n dar d 
versi o n of t he S -S T S ( Secti o n 1 7. 6 ) is a 1 6-ite m scale t hat assesses t he seri o us ness of s uici dalit y p he n o me na 
o n a Li kert -t y pe scale ( 0-4) ra n gi n g fr o m “n ot at all” ( 0) t o “e xtre mel y” ( 4) . It als o assesses t he fre q ue nc y of 
ke y p he n o me na a n d t he o verall ti me s pe nt i n s uici dalit y .  
 
7. 1. 1. 3 .7  1 0 -Meter Ti me d Wal k  
T he 1 0 -meter wal k test is a c o m m o nl y use d t o ol f or assessi n g gait s pee d i n i n di vi d uals wit h gait li mitati o ns  
(La n g 2 0 1 6 ). Gait s pee d is p ositi vel y c orrelate d wit h t he a m o u nt of  c o m m u nit y a m b ulati o n a n d q ualit y of life, 
a n d t heref ore  it is a n i m p orta nt meas ure of m o bilit y i n i n di vi d uals wit h P D.  T his test has bee n vali date d i n 
vari o us p o p ulati o ns  a n d is a rec o m me n de d o utc o me  meas ure f or use i n patie nts wit h P D  (La n g 2 0 1 6 ).  
 
7. 1. 1. 3. 8   Weara ble Se ns or De vice  
Weara ble se ns or de vices ha ve a d va nce d i n rece nt years t o e na ble c o nti n u o us meas ure me nt of  healt h -relate d 
s y m pt o ms, w hic h i n Par ki ns o n’s i ncl u de t he m ot or a n d n o n m ot or feat ures of bra d y ki nesia, tre m or, acti vit y , 
a n d slee p . As a p plica ble, s u bjects  will be s u p plie d t he weara ble se ns or de vices. F ull i nf or mati o n as t o t he 
o perati o n a n d data ca pt ure fr o m t he de vices will be i ncl u de d i n t he I n vesti gat or Site File (I S F). 
 
7. 1. 1. 3. 9   Fecal Mar kers of I ntesti nal I nfla m mati o n a n d Per mea bilit y  
I ntesti nal i nfla m mati o n a n d i ncrease i ntesti nal per mea bilit y ( b ot h p ossi bl y f uele d b y d ys bi osis) ha ve bee n 
i m plicate d i n t he m ultifact orial pat h o ge nesis of P D ( Sc h wiertz 2 0 1 8 ). I n c o nse nti n g s u bjects, fecal sa m ples 
will be c ollecte d at scree ni n g a n d at e n d of treat me nt a n d sa m ples will be flas h fr oze n f or assess me nt. F ull 
inf or mati o n as t o pr oce d ure f or c ollecti o n a n d pr ocessi n g of sa m ples will be i ncl u de d i n t he I S F.  
 
7. 1. 1. 3. 1 0  Ha user 3 -Da y Patie nt Diar y  
T he Ha user Patie nt Diar y was de vel o pe d t o assess f u ncti o nal stat us o ver a peri o d of ti me i n patie nts wit h 
m ot or fl uct uati o ns a n d d ys ki nesia (Ha user 2 0 0 0 )(Secti o n 1 7. 8 ). It is a self-c o m plete d refere nce diar y desi g ne d 
t o se parate d ys ki nesia t hat ha d a ne gati ve i m pact o n patie nt-defi ne d f u ncti o nal  stat us fr o m d ys ki nesia t hat di d 
n ot. Wit h t his diar y, t he effect of a n i nter ve nti o n ca n be e x presse d as t he c ha n ge i n off -me dicati o n ti me a n d 
t he c ha n ge i n o n-me dicati o n ti me wit h tr o u bles o me d ys ki nesia ( ba d ti me). T he s u m ca n be use d as a n o utc o me 
varia bl e a n d c o m pare d t o baseli ne or acr oss gr o u ps. I n a f oll o w -u p st u d y t o t he ori gi nal e val uati o n of t he 


 
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C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 2 9  of 9 9   
 
assess me nt, it was deter mi ne d t hat c o m plia nce di mi nis he d after 3 da ys, b ut diaries c o m plete d o n 3 
c o nsec uti ve da ys were si m ple, feasi ble, a n d i m pr o ve d c o m pl ia nce (Ha user 2 0 0 4 ). 
 
7. 2  
L A B O R A T O R Y P R O C E D U R E S/ E V A L U A TI O N S  
 
7. 2. 1  
C LI NI C A L L A B O R A T O R Y E V A L U A TI O N S  
 
Bi ol o gical sa m ples ( e. g., w h ole bl o o d, ser u m, uri ne) will be c ollecte d f or la b orat or y e val uati o ns i ncl u di n g 
pre g na nc y testi n g i n W O C B P i n acc or da nce wit h t he Sc he d ule of E ve nts . Refer t o t he st u d y’s la b orat or y 
ma n ual f or c o m plete i nf or mati o n re gar di n g all la b orat or y e val uati o ns t o be perf or me d, sa m ple c ollecti o n 
pr oce d ures, a n d relate d re q uire me nts.  
 
T he i n vesti gat or is res p o nsi ble f or deter mi ni n g a n d d oc u me nti n g w het her  o ut of ra n ge la b orat or y val ues are 
cli nicall y si g nifica nt . Al l cli nicall y si g nifica nt val ues will be rec or de d as A Es i n t he C R F a n d f oll o we d u ntil 
deter mi ne d t o be sta ble or res ol ve d u nless t he s u bject is l ost t o f oll o w u p . O nce res ol ve d, t he a p pr o priate C R F 
pa ge(s) will be u p date d.  
 
 
7. 2. 2  
O T H E R T E S T S  O R P R O C E D U R E S  
 
7. 2. 2. 1   
St u d y A ge nt C o nce ntr ati o n a n d P h ar m ac o ki netics  
Plas ma c o nce ntrati o n meas ure me nts of A K S T 4 2 9 0 a n d its  maj or  meta b olites will be c ollecte d t o assess 
s yste mic e x p os ure t o t he st u d y a ge nt. F or re q uire d a n d o pti o nal sa m pli n g ti me p oi nts a n d f urt her details, 
please refer t o  Secti o n  1 7. 1 2 .  
 
7. 2. 2 . 1. 1  P har mac o ki netic E n d p oi nts  
 
As far as feasi ble, t he f oll o wi n g P K para meter will be s u m marize d descri pti vel y:  
•  
C pre,ss, N  
Pre -d ose c o nce ntrati o n of A K S T 4 2 9 0 i n plas ma i m me diatel y bef ore   
                       a d mi nistrati o n of t he Nt h d ose  
 
7. 2. 2 .1. 2  Met h o ds of Sa m ple C ollecti o ns   
F or q ua ntificati o n of plas ma c o nce ntrati o ns of A K S T 4 2 9 0  a n d its maj or meta b olites, a n d f or bi o mar ker 
i n vesti gati o ns (see Secti o n 7. 2. 2. 3 ), o ne bl o o d sa m ple of a p pr o xi matel y 6 m L per sa m pli n g ti me p oi nt 
(see Secti o n 1 7. 1 2  Ta ble of P har mac o ki netic, Bi o mar ker, P har mac o ge n o mic , a n d F A C S Sa m pli n g ) will 
be ta ke n fr o m a n a ntec u bital or f orear m vei n i nt o a p otassi u m et h yle ne dia mi netetraacetic aci d ( E D T A)-
a ntic oa g ula nt bl o o d dra wi n g t u be.  
 
T he E D T A -a ntic oa g ulate d bl o o d sa m ples will be ce ntrif u ge d t o c ollect plas ma. F or P K  sa m ples o nl y, t he 
o btai ne d plas ma will be s plit i nt o 2 ali q u ots a n d st ore d i n p ol y pr o p yle ne t u bes. At t he selecte d ti me p oi nts 
wit h a d diti o nal bi o mar ker deter mi nati o ns, 5 i nstea d of 2 ali q u ots of at least 0. 5 m L plas ma eac h will be 
pre pare d fr o m t he bl o o d sa m ple. T he ti me fr o m bl o o d c ollecti o n u ntil t he tra nsfer of plas ma ali q u ots i nt o 
t he freezer s h o ul d n ot e xcee d 6 0 mi n utes, wit h interi m sa m ple st ora ge o n wet ice w he ne ver p ossi ble. 
Sa m ples will be p ositi o ne d u pri g ht a n d will be fr oze n at a p pr o xi matel y -2 0° C or bel o w u ntil s hi p me nt . 
T hese ali q u ots will be pr ocesse d b y t he ce ntral la b orat or y. Details of plas ma c ollecti o n, sa m ple ha n dl i n g, 
a n d s hi p me nt i nstr ucti o ns will be pr o vi de d i n t he La b Ma n ual.  
 
7. 2. 2. 1 . 3  A nal ytical Deter mi nati o ns  
 
C o nce ntrati o ns of A K S T 4 2 9 0 a n d meta b olites (if feasi ble) i n plas ma sa m ples will be deter mi ne d b y a 
vali date d hi g h -perf or ma nce li q ui d c hr o mat o gra p h y, t a n de m mass s pectr o metr y ( H P L C -M S/ M S) assa y . 
Left o ver sa m ples will be use d f or e x pl orat or y bi o mar ker assess me nt (see  Secti o n 7. 2. 2. 3 ). 


 
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C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 3 0  of 9 9   
 
 
7. 2. 2. 2   
P h ar m ac o ge n o mic E v al u ati o ns  
P har mac o ge netic a nal ysis of pres pecifie d ge n es is a n e x pl orat or y e n d p oi nt. S a m ples f or de o x yri b o n ucleic 
aci d ( D N A) ba n ki n g will be c ollecte d if partici pa nts si g ne d a se parate inf or me d co nse nt a n d is n ot re q uire d 
f or st u d y partici pati o n.  
 
• Pres pecifie d ge nes: D N A will be e xtracte d fr o m o ne bl o o d sa m ple a n d ge n ot y pe d f or c o m m o n ge netic 
varia nts of t he f oll o wi n g ge nes: 
  
 
S e veral ge ne m utati o ns ha ve bee n i m plicate d i n Par ki ns o n’s  disease, n ota bl y t he al p ha -s y n uclei n ge ne 
( S N C A), le uci ne-ric h re peate d ki nase 2 ( L R R K 2) ge ne, a n d t he P A R K N ge ne. 
 
 
 
 Pres pecifie d a nal yses will be perf or me d at t he e n d of t he trial a n d t he data w ill be part 
of t he re p ort. All re mai ni n g sa m ples will be destr o ye d after t he e n d of t he trial.  
 
• D N A ba n ki n g  ( o pti o nal): O ne bl o o d sa m ple will be c ollecte d f or retr os pecti ve, e x pl orat or y ge n ot y pi n g 
(e. g., t o a nal yze disease or treat me nt-relate d ge ne variants).  F or i nf or mati o n re gar di n g f ut ure use of st ore d 
sa m ples, see Secti o n 1 2. 5 F ut ure Use of St ore d S peci me ns . 
 
7. 2. 2. 3   
Pl as m a Bi o m ar kers  
Meas ure me nt of bi o mar kers is e x pl orat or y. I n vesti gati o ns mi g ht i ncl u de mec ha nis m relate d mar kers
 
w hic h c o ul d i de ntif y s u bsets of s u bjects 
w h o ma y be nefit m ost fr o m t he treat me nt wit h A K S T 4 2 9 0. Ot her disease -relate d mar kers ma y i ncl u de 
i nfla m mat or y me diat ors or mar kers of o xi dati ve stress. Bi o mar kers will be meas ure d i n plas ma sa m ples t o 
i n vesti gate a n y c ha n ge i n res p o nse t o treat me nt. After c o m pleti o n of t he st u d y, left o ver sa m ples ma y be use d 
f or f urt her met h o d ol o gical a n d/ or ot her, n o n-ge netic bi o mar ker i n vesti gati o ns eit her b y t he s p o ns or, or 
desi g nee. T he st u d y sa m ples will be discar de d after c o m pleti o n of t he a d diti o nal i n vesti gati o ns, b ut n ot later 
t ha n 3 years after t he fi nal st u d y re p ort has bee n arc hi ve d. T he e x pl orat or y bi o mar ker meas ure me nts will  be 
c o n d ucte d eit her at t he s p o ns or’s la b orat orie s or at e xter nal C R Os usi n g a p pr o priate met h o d ol o g y (e. g., 
i m m u n oassa ys, m ulti ple x tec h n ol o g y). A La b orat or y  Ma n ual/I S F will descri be t he ha n dli n g of t he sa m ples.  
 
7. 2. 2. 4   
Bl o o d Bi o m ar kers b y Fl o w C yt o metr y  
C haracterizati o n of i m m u ne cells usi n g F A C S /c o m plete bl o o d c o u nt ( C B C ) is e x pl orat or y. F or t he 
i n vesti gati o ns, o ne bl o o d sa m ple of a p pr o xi matel y 6 m L per sa m pli n g ti me p oi nt will be c ollecte d. S peci me ns 
m ust be tra ns p orte d f or testi n g wit hi n a s pecifie d t i me peri o d. T he e x pl orat or y bi o mar ker meas ure me nts usi n g 
F A C S/ C B C will be c o n d ucte d eit her at t he s p o ns or’s la b or at ories or at e xter nal C R Os usi n g a p pr o priate 
met h o d ol o g y ( e. g., i m m u n oassa ys, m ulti ple x tec h n ol o g y). A La borat or y  Ma n ual/I S F will descri be t he 
ha n dli n g of t he sa m ples.  
 
7. 3  
S T U D Y S C H E D U L E  
 
7. 3 .1  
S C R E E NI N G  
 
7. 3. 1. 1 Visit 1, Scree ni n g Visit ( D a y -1 4  t o -7 ) 
 
Assess me nts t o be c o n d ucte d  i n t he f oll o wi n g or der: 
□ Si g ni n g of all a p plica ble i nf or me d c o nse nt s m ust be c o m plete d  pri or t o a n y st u d y -relate d assess me nts. 
□ Verif y dia g n osis of P D  acc or di n g t o M D S P D  criteria , i ncl u di n g m o difie d H oe h n a n d Ya hr sta ge . 
 
Re mai ni n g assess me nts (m ay be c o n d ucte d i n a ny or der): 
□ O bta i n me dical hist or y, i ncl u di n g me dical rec or ds a n d test res ults  t o s u p p ort P D  dia g n osis if a vaila ble . 


 
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C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 3 1  of 9 9   
 
□ C ollect de m o gra p hic i nf or mati o n . 
□ Re vie w s u bject’s c urre nt a n d pri or me dicati o ns . 
□ Re vie w pr o hi bite d me dicati o ns  a n d s u bsta nces wit h t he s u bject . 
□ C ollect vital si g ns . 
□ C ollect (scree ni n g) la b orat or y sa m ples . 
□ Perf or m pre g na nc y testi n g a n d re vie w res ults i n W O C B P . 
□ Perf or m f ull p h ysical e xa m i nati o n (i ncl u di n g hei g ht). 
□ Perf or m 1 2 -lea d E C G. 
□ Verif y t he s u bject f ulfills all t he i ncl usi o n criteria a n d n o ne of t he e x cl usi o n criteria . 
□ F or eli gi ble s u bjects, re vie w i nstr ucti o ns f or P D Q-3 9 a n d  Ha user 3 -Da y Patie nt Diar y a n d  pr o vi de 
ass ociate d i nf or mati o n a n d assess me nt materials; s u bjects s h o ul d be i nstr ucte d t o bri n g c o m plete d 
materials t o Visit  2 . 
□ F or eli gi ble s u bjects , set u p, re vie w i nstr ucti o ns f or, a n d pr o vi de t he h o me -base d weara ble se ns or 
de vice  t o be c ollecte d at Visit 2. 
□ F or c o nse nti n g  s u bjects, fecal sa m ple c ollecti o n ( o pti o nal).  
 
 
7 . 3. 2 
B A S E LI N E  
 
7. 3. 2. 1 Visit 2, B aseli ne (D a y  1 ) 
 
Assess me nts t o be c o n d ucte d  i n t he f oll o wi n g or der, u nless ot her wise i n dic ate d : 
□ Perf or m pre g na nc y testi n g a n d re vie w res ults i n W O C B P . 
□ C o nfir m s u bject meets all eli gi bilit y criteria . 
□ R a n d o mize t o A K S T 4 2 9 0 or place b o.  
□ C o nfir m off -me dicati o n state  ( off-le v o do pa) . 
□ A ssess me nts t o be c o n d ucte d i n t he off-me dicati o n ( off -le v o d o pa) state (m ay be c o n d ucte d i n a ny 
or der ):  
o  M D S -U P D R S Part 3.  
o  1 0 -meter ti me d wal k.  
□ A d mi nistrati o n of d o pa mi ner gic me dicati o n (c o m me nce o n -me dicati o n state) f or re mai ni n g 
assess me nts t hat da y.  
 
T he f oll o wi n g assess me nts ma y be c o n d ucte d  i n a n y or der, after r a n d o miz ati o n a n d pri or t o st u dy a ge nt 
a d mi nistr ati o n : 
□ C ollect t he weara ble se ns or de vice . 
□ Re vie w A Es a n d c o nc o mita nt me dicati o ns.  
□ Perf or m tar gete d p h ysical e xa mi nati o n.  
□ C ollect vital si g ns.  
□ C ollect c o m plete d P D Q -3 9 a n d pr o vi de  f or t he ne xt visit. 
□ C ollect c o m plete d Ha user 3 -Da y Patie nt Diar y.  
□ C o nfir m ati o n of o n -me dicati o n state . 
□ Assess me nts t o be c o n d ucte d i n t he o n -me dicati o n state (m ay be c o n d ucte d  i n a ny or der ): 
o  M D S -U P D R S Parts 1 -4.  
o  M o C A.  
o  S E -A D L.  
o  CI SI -P D.  
o  S -S T S.  
o  1 0 -meter ti me d wal k.  
□ C ollect la b orat or y sa m ples.  
 
 


 
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C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 3 2  of 9 9   
 
Assess me nts t o be c o n d ucte d  i n t he f oll o wi n g or der, after all ot h er assess me nts are c o m plete d: 
□ C ollect i nitial P K  a n d bi o mar ker sa m ples 1 5 mi n utes pri or t o st u d y a ge nt a d mi nistrati o n (see Secti o ns 
7. 2. 2. 1 , 7. 2. 2. 3 , 1 7. 1 2 ). 
□ C ollect i nitial F A C S/ C B C sa m ples 1 5 mi n utes pri or t o st u d y a ge nt a d mi nistrati o n (see Secti o n s 
7. 2. 2. 4 , 1 7. 1 2 ). 
□ C ollect p har mac o ge n o mic sa m ple (see Secti o n s 7. 2. 2. 2 , 1 7. 1 2 ). 
□ Dis pe nse 5 -wee k s u p pl y of A K S T 4 2 9 0 or place b o.  
□ St u d y d r u g ( A K S T 4 2 9 0/ place b o) a d mi nistrati o n ( d ose a d mi nistere d a p pr o xi matel y 1 5 mi nutes  after 
ac q uisiti o n of i nitial P K  sa m ple).  
□ St u d y a ge nt acc o u nta bilit y.  
□ C ollect P K  a n d bi o mar ker sa m ples 1 h o ur f oll o wi n g st u d y a ge nt a d mi nistrati o n (see Secti o ns 7. 2. 2. 1 , 
7. 2. 2. 3 , 1 7. 1 2 ). 
□ C ollect F A C S/ C B C sa m ples  1 h o ur f oll o wi n g st u d y a ge nt a d mi nistrati o n (see Secti o n s 7. 2. 2. 4 , 1 7. 1 2 ). 
□ C ollect (o pti o n al , wit h c o nse nt) P K  sa m ple 2 h o urs f oll o wi n g st u d y a ge nt a d mi nistrati o n (see Secti o n s 
7. 2. 2. 1 , 1 7. 1 2 ). 
 
 
7. 3. 3  
T R E A T M E N T  
 
T he e xa mi nati o ns of eac h visit are s pecifie d i n Secti o n 1 5 Sc he d ule of E ve nts . I n a d diti o n, please see Secti o n 
1 7. 1 2  Ta ble of P har mac o ki netic, Bi o mar ker , P har mac o ge n o mic , a n d F A C S  Sa m pli n g  f or detaile d i nf or mati o n 
re gar di n g t hese e val uati o ns. I m p orta nt n ote: t o e ns ure acc urac y of P K  sa m pli n g, st u d y a ge nt 
(A K S T 4 2 9 0/ place b o) s h o ul d be a d mi nistere d d uri n g t he st u d y v isit t o e na ble a p pr o priate ti mi n g of P K  sa m ple 
ac q uisiti o n . 
 
7. 3. 3. 1  Visit 3 ( D a y 1 4   2 ) a n d Visit 5 ( D a y 5 6   2)  
 
Assess me nts t o be c o n d ucte d  i n t he f oll o wi n g or der: 
□ C ollect la b orat or y sa m ples. 
□ C ollect P K  sa m ple 1 5 mi n utes pri or t o st u d y a ge nt a d mi nistrati o n . 
□ St u d y a ge nt  ( A K S T 4 2 9 0/ place b o) a d mi nistrati o n ( d ose a d mi nistere d a p pr o xi matel y 1 5 mi n utes 
f oll o wi n g ac q uisiti o n of P K  sa m ple). 
 
Re mai ni n g assess me nts (m ay be c o n d ucte d  i n a ny or der): 
□ Perf or m pre g na nc y testi n g a n d re vie w res ults i n W O C B P.  
□ St u d y a ge nt acc o u nta bilit y . 
□ Re vie w A Es a n d c o nc o mita nt me dicati o ns . 
□ Perf or m tar gete d p h ysical e xa mi nati o n . 
□ C ollect vital si g ns . 
□ C ollect c o m plete d P D Q -3 9  a n d pr o vi de f or ne xt visit . 
□ Pr o vi de Ha user 3 -Da y  Patie nt Diar y f or ne xt visit ( Visit 5 o nl y ). 
□ Assess me nts t o be c o n d ucte d i n t he o n -me dicati o n state  (m ay be c o n d ucte d  i n a ny or der): 
o  M D S -U P D R S Parts 1 -4 .  
o  S E -A D L . 
o  CI SI -P D . 
o  1 0 -meter  ti me d wal k . 
□ Dis pe nse 5 -wee k s u p pl y of A K S T 4 2 9 0  or place b o ( Visit 5 O nl y ). 
□ C ollect weara ble se ns or de vice ( Visit 5 o nl y ). 
□ Pr o vi de weara ble se ns or de vice  t o be c ollecte d at Visit 6 (Visit 5 o nl y ). 
 
 
 


 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 3 3  of 9 9   
 
 
7. 3. 3. 2  Visit 4  ( D a y 2 8   2)  a n d Visit 6 –  E n d of Tre at me nt ( D a y 8 4  2)  or E arl y Ter mi n ati o n  
 
Assess me nts t o be c o n d ucte d  i n t he f oll o wi n g or der: 
□ C ollect la b orat or y sa m ples. 
□ C ollect i nitial P K sa m ple 1 5 mi n utes pri or t o st u d y a ge nt a d mi nistrati o n. 
□ C ollect b i o mar ker sa m ple 1 5 mi n utes  pri or t o st u d y a ge nt a d mi nistrati o n  (Visit 6 O nl y ).  
□ C ollect F A C S/ C B C sa m ples 1 5 mi n utes pri or t o st u d y a ge nt a d mi nistrati o n (Visit 6 O nl y ).   
□ St u d y a ge nt  ( A K S T 4 2 90/ place b o) a d mi nistrati o n ( d ose a d mi nistere d a p pr o xi matel y 1 5 mi n utes  after 
ac q uisiti o n of i nitial P K  sa m ple).  
□ C o nfir mati o n of off -me dicati o n state ( ≥1 2 h o urs si nce last le v o d o pa d ose ). 
□ Assess me nts t o be c o n d ucte d i n t he off -me dicati o n ( off -le v o d o pa) state a n d 4 5 mi n utes ( 1 5 mi n utes ) 
after  st u d y a ge nt  a d mi nistrati o n  (m ay be c o n d ucte d  i n a ny or der):  
o  M D S -U P D R S Part 3.  
o  1 0 -meter ti me d wal k.  
□ A d mi nistrati o n of d o pa mi ner gic me dicati o n (c o m me nce o n -me dicati o n state) f or re mai ni n g 
assess me nts t hat da y.  
 
Re mai ni n g assess me nts (m ay be c o n d ucte d  i n a ny or der): 
□ C ollect vital si g ns.  
□ Perf or m pre g na nc y testi n g a n d re vie w res ults i n W O C B P.  
□ Re vie w A Es a n d c o nc o mita nt me dicati o ns.  
□ Perf or m tar gete d p h ysical e xa mi nati o n.  
□ C ollect c o m plete d P D Q -3 9 a n d pr o vi de f or ne xt visit.  
□ C ollect c o m plete d Ha user 3 -Da y Patie nt Diar y ( Visit 6 o nl y ).  
□ Perf or m 1 2 -lea d E C G.  
□ St u d y a ge nt acc o u nta bilit y.  
□ C ollect (o pti o n al , wit h c o nse nt) P K sa m ple 1  h o ur f oll o wi n g  st u d y a ge nt a d mi nistrati o n (see Secti o ns 
7. 2. 2. 1 , 7. 2. 2. 3 , 1 7. 1 2 ). 
□ Pr o vi de weara ble se ns or de vice ( Visit 4 o nl y ). 
□ C ollect weara ble se ns or de vice ( Visit 6 o nl y ). 
□ Assess me nts t o be c o n d ucte d i n t he o n -me dicati o n state: ( m ay be c o n d ucte d  i n a ny or der) 
o  M D S -U P D R S Parts 1 -4.  
o  M o C A ( Visit 6 O nl y ).  
o  S E -A D L.  
o  CI SI -P D.  
o  S -S T S ( Visit 6 O nl y ).  
o  1 0 -meter ti me d wal k.  
o  Fecal sa m ple c ollecti o n ( o pti o n al , wit h c o nse nt) (Visit 6 O nl y ).  
□ Dis pe nse 5 -wee k s u p pl y of A K S T 4 2 9 0 or place b o ( Visit 4 O nl y ).  
□ C ollect (o pti o n al , wit h c o nse nt) P K sa m ple 2  h o urs f oll o wi n g st u d y a ge nt a d mi nistrati o n (see Secti o n s 
7. 2. 2. 1 , 1 7. 1 2 ). 
 
 
7. 3. 4  
F O L L O W -U P  
 
7. 3. 4 .1  Visit 7  ( D a y 9 8   3  or 1 4 d a ys after E arl y Ter mi n ati o n ) 
 
Assess me nts t o be c o n d ucte d  i n t he f oll o wi n g or der, u nless ot her wise i n dic ate d : 
□ C o nfir m off -me dicati o n state ( ≥ 1 2 h o urs off le v o d o pa) . 
□ Assess me nts t o be c o n d ucte d i n t he off -me dicati o n ( off-le v o d o pa) state (m ay be c o n d ucte d  i n a ny 
or der ): 


 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 3 4  of 9 9   
 
o  M D S -U P D R S Part 3 . 
o  1 0 -meter ti me d wal k . 
□ A d mi nistrati o n of d o pa mi ner gic me dicati o n (c o m me nce o n -me dicati o n state) f or re mai ni n g 
assess me nts t hat da y.  
□ Re vie w A Es a n d c o nc o mita nt me dicati o ns . 
□ Perf or m tar gete d p h ysical e xa mi nati o n . 
□ C ollect vital si g ns . 
□ C ollect la b orat or y, P K , a n d bi o mar ker sa m ples. 
□ Perf or m pre g na nc y testi n g a n d re vie w res ults i n W O C B P . 
□ C ollect c o m plete d P D Q -3 9 . 
□ Assess me nts t o be c o n d ucte d i n t he o n -me dicati o n state  (m ay be c o n d ucte d  i n a ny or der): 
o  M D S -U P D R S Parts 1 -4 .  
o  S E -A D L . 
o  CI SI -P D . 
o  1 0 -meter ti me d wal k. 
 
 
7. 3. 4 .2  S afet y F oll o w -U p: D oc u me nte d P h o ne C all  ( D a y 11 4   2  or 3 0  d a ys after E arl y Ter mi n ati o n ) 
 
□ Re vie w A Es a n d c o nc o mita nt me dicati o ns .  
 
7. 3. 5  
E A R L Y T E R MI N A TI O N  
 
I n cases of earl y ter mi nati o n, if a s u bject has recei ve d at least 1  d ose ( 4 0 0  m g) of A K S T 4 2 9 0  or place b o , t he 
site s h o ul d tr y t o perf or m all assess me nts sc he d ule d at t he Visit 6 - E n d of T reat me nt visit as well as t he 
s u bse q ue nt f oll o w u p visits u nless t he s u bject has wit h dra w n c o nse nt .  
 
7. 3. 6  
S C H E D U L E O F E V E N T S T A B L E  
 
A ta b ular s u m mar y of all pr oce d ures t hat wi ll be acc o m plis he d at eac h st u d y visit ca n be f o u n d i n Secti o n 1 5 
Sc he d ule of E ve nts.  
 
7. 3. 7  
E N D O F T RI A L/ E N D O F S T U D Y  
 
T he e n d of trial/e n d of st u d y will occ ur f oll o wi n g t he last s u bject’s last visit. T he a p pr o xi mate d urati o n t o 
c o n d uct t he trial t o s u p p ort f ull recr uit me nt is a p pr o xi matel y 1 0  m o nt hs.  
 
7. 4  
C O N C O MI T A N T M E DI C A TI O N S  
 
All prescri pti o n, o ver -t he-c o u nter, a n d n o n -prescri pti o n me dicati o ns (i ncl u di n g her bal t hera pies a n d s u p ple me nts) 
m ust be d oc u me nte d i n t he s o urce d oc u me nts a n d C R F . All s u bjects s h o ul d be mai ntai ne d o n t he sa me 
me dicati o ns at t he sa me d osa ge a n d a d mi nistrati o n t hr o u g h o ut t he e ntire st u d y peri o d, as me dicall y feasi ble, wit h 
n o i ntr o d ucti o n of ne w c hr o nic t hera pies. A n y c ha n ges i n m e dicati o ns s h o ul d be d oc u me nte d i n t he C R F wit h 
reas o n f or c ha n ge (e. g., A E ). 
 
7. 5  
P R O HI BI T E D M E DI C A TI O N S, T R E A T M E N T S, A N D P R O C E D U R E S  
 
 
 
 
 


 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
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C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 3 5  of 9 9   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
8  
A S S E S S M E N T O F S A F E T Y  
 
Assess me nt of safet y will be c o n d ucte d b y bli n de d st u d y pers o n nel e xce pt i n e xtra or di nar y circ u msta nces w here 
k n o wle d ge of w het her A K S T 4 2 9 0  or place b o was  recei ve d b y a s u bject is esse ntial. A n y i nsta nces of u n bli n di n g 
will be ma na ge d as i n dicate d i n Secti o n 1 0. 6. 3 Brea ki n g t he St u d y Bli n d/ S u bject  C o de.  
 
8 .1  
S P E CI FI C A TI O N O F S A F E T Y P A R A M E T E R S  
 
8. 1. 1  
D E FI NI TI O N O F A D V E R S E E V E N T S ( A E)  
 
Per 2 1 C F R 3 1 2. 3 2(a) a n A E  is a n y u nt o war d ( u nfa v ora ble, har mf ul, or pat h ol o gic) me dical occ urre nce i n a 
s u bject a d mi nistere d a p har mace utical  (i n vesti gati o nal) pr o d uct e ve n if t he e ve nt d oes n ot necessaril y ha ve a 
ca usal relati o ns hi p wit h t his treat me nt .  
 
A n A E ca n t heref ore be a ny  u nfa v ora ble a n d u ni nte n de d si g n (i ncl u di n g a n a b n or mal la b orat or y fi n di n g t hat 
is dee me d cli nicall y si g nifica nt), s y m pt o m, or disease te m p orall y ass ociate d wit h t he use of a me dici nal 
(i n vesti gati o nal) pr o d uct w het her or n ot relate d t o t he me dici nal  (i n vesti gati o nal) pr o d uct.  
 
A n A E d oes i ncl u de a n y:  
• 
E xacer bati o n of a pre -e xisti n g ill ness . 
• 
S u bjecti ve or o bjecti ve s y m pt o ms s p o nta ne o usl y offere d b y t he s u bject a n d/ or o bser ve d b y t he 
i n vesti gat or or st u d y staff. 
• 
I ncrease i n fre q ue nc y or i nte nsit y of a pre-e xisti n g e pis o dic e ve nt or c o n diti o n . 
• 
C o n diti o n detecte d or dia g n ose d after st u d y a ge nt a d mi nistrati o n e ve n t h o u g h it ma y ha ve bee n 
prese nt pri or t o t he start of t he st u d y ( u nless it ca n be de m o nstrate d b y me dical rec or d re vie w t hat 
t he o nset of t he e ve nt prece de d t he date/ti me of inf or me d co nse nt ). 
• 
C o nti n u o us persiste nt disease or s y m pt o ms prese nt at baseli ne t hat w orse n f oll o wi n g t he start of t he 
st u d y. 


 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
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C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 3 6  of 9 9   
 
• 
S y m pt o ms ass ociate d wit h disease n ot pre vi o usl y re p orte d b y t he s u bject . 
• 
U nt o war d me dical  occ urre nces c o nsi dere d b y t he i n vesti gat or t o be relate d t o st u d y -ma n date d 
pr oce d ures . 
• 
A b n or mal assess me nts ( e. g., c ha n ge o n p h ysical e xa mi nati o n, E C G fi n di n gs), if t he y re prese nt a 
cli nicall y si g nifica nt fi n di n g, t hat were n ot prese nt at Baseli ne or w ors e ne d d uri n g t he c o urse of t he 
st u d y. 
• 
La b orat or y test a b n or malities, if t he y re prese nt a cli nicall y si g nifica nt fi n di n g, s y m pt o matic or n ot, 
w hic h were n ot prese nt at Baseli ne or w orse ne d d uri n g t he c o urse of t he st u d y . 
 
A n A E D O E S N O T i ncl u de a/a n:  
• 
Electi v e me dical or s ur gical pr oce d ure ( e. g., s ur ger y, e n d osc o p y, t o ot h e xtracti o n, tra nsf usi on) .  
• 
Pre -e xisti n g diseases or c o n diti o ns prese nt or detecte d at t he start of t he st u d y t hat d o n ot w orse n . 
• 
Sit uati o ns w here a n u nt o war d me dical occ urre nce has n ot occ urr e d (e. g., h os pitalizati o n f or c os metic 
electi ve s ur ger y, s ocial a n d/ or c o n ve nie nce a d missi o ns) . 
• 
O ver d ose of eit her st u d y a ge nt or c o nc urre nt me dicati o n wit h o ut a n y si g ns or s y m pt o ms.  
• 
Pre g na nc y . 
 
8. 1. 2  
D E FI NI TI O N O F S E RI O U S A D V E R S E E V E N T S  
 
N ote : if eit her t he i n vesti gat or or t he S p o ns or belie ves t hat t he e ve nt is seri o us, t he e ve nt m ust be c o nsi dere d 
seri o us a n d e val uate d f or e x pe dite d re p orti n g.  
N ote : t he ter ms “se vere” a n d “seri o us” are n ot s y n o n y m o us. Se verit y ( or i nte nsit y) refers t o t he gra de of a n 
A E . “ Seri o us” is a re g ulat or y defi niti o n .  
A seri o us a d verse e ve nt (e x perie nce) or reacti o n is a n u nt o war d me dical occ urre nce t hat , at a n y d ose , f ulfills 
o ne or m ore of t he f oll o wi n g criteria:  
a. Res ults i n deat h ( i.e., t he A E act uall y ca uses or lea ds t o deat h) . 
b.  Is life-t hreate ni n g. 
• 
A n A E  is c o nsi dere d “life-t hreate ni n g” if, i n t he vie w of eit her t he i n vesti gat or or S p o ns or, its 
occ urre nce places t he patie nt or s u bject at i m me diate ris k of deat h; it d oes n ot i ncl u de A Es  w hic h, 
ha d it occ urre d i n  a m ore se vere f or m, mi g ht ha ve ca use d deat h . 
c. Res ults i n i n patie nt h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n.  
• 
H os pitalizati o n f or electi ve treat me nt of a pre -e xisti n g c o n diti o n t hat di d n ot w orse n d uri n g t he st u d y 
is n ot c o nsi dere d a n A E ; h os pitalizati o n f or partici pati n g i n t his st u d y is n ot c o nsi dere d a n A E. 
• 
C o m plicati o ns t hat occ ur d uri n g h os pitalizati o n are A Es; if a c o m plicati o n pr ol o n gs h os pitalizati o n, 
t he e ve nt is a n S A E. 
• 
“I n patie nt” h os pitalizati o n mea ns t he s u bject has bee n f o r mall y a d mitte d t o a h os pital f or me dical 
reas o ns t hat ma y or ma y n ot be o ver ni g ht; it d oes n ot i ncl u de prese ntati o n at a cas ualt y or e mer ge nc y 
r o o m u nless t he e ve nt meets t he defi niti o n of a n I m p orta nt Me dical E ve nt (i n t he o pi ni o n of t he 
I n vesti gat or or S p o ns or) . 
d.  Res ults i n persiste nt or si g nifica nt i nca pacit y or s u bsta ntial disr u pti o n of t he a bilit y t o c o n d uct n or mal life 
f u ncti o ns. 
• 
T he ter m ‘ disa bilit y’ mea ns a s u bsta ntial disr u pti o n of a pers o n’s a bilit y t o c o n d uct n or mal life 
f u ncti o ns; t his defi niti o n is n ot i nte n de d t o i ncl u de e x perie nces of relati vel y mi n or me dical 
si g nifica nce s uc h as u nc o m plicate d hea dac he, na usea, v o miti n g, diarr hea, i nfl ue nza, acci de ntal 
tra u ma (i.e., s prai ne d a n kle) t hat ma y i nterfere or pre ve nt e ver y da y life f u ncti o ns  b ut d o n ot c o nstit ute 
a s u bsta ntial disr u pti o n . 




 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
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C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 3 8  of 9 9   
 
i n vesti gat or br oc h ure referre d o nl y t o ele vate d he patic e nz y mes or he patitis. Si milarl y, cere bral 
t hr o m b oe m b olis m a n d cere bral vasc ulitis w o ul d be u ne x pecte d ( b y virt ue of greater s pecificit y) if t he 
In vesti gat or ’s B r oc h ure liste d o nl y cere bral vasc ular acci de nts. " U ne x pecte d" as use d i n t his defi niti o n, als o 
refers t o A E s or s us pecte d a d verse reacti o ns t hat are me nti o ne d i n t he I n vesti gat or’s Br oc h ure as occ urri n g 
wit h a class of dr u gs or as a ntici pate d fr o m t he p har mac ol o gical pr o perties of t he dr u g b ut are n ot s pecificall y 
me nti o ne d as occ urri n g wit h t he partic ular dr u g u n der i n vesti gati o n . F or e xa m ple, alt h o u g h a n gi oe de ma is 
a ntici pate d t o occ ur i n s o me patie nts e x p ose d t o dr u gs i n t he an gi ote nsi n -c o n verti n g e nz y me  (A C E ) i n hi bit or 
class a n d a n gi oe de ma w o ul d be descri be d i n t he In vesti gat or ’s B r oc h ure as a class effect, t he first case of 
a n gi oe de ma o bser ve d wit h t he dr u g u n der i n vesti gati o n s h o ul d be c o nsi dere d u ne x pecte d f or re p orti n g 
p ur p oses  (F D A 2 0 1 2 ). 
 
T his defi niti o n of “ u ne x pecte d” relies e ntirel y o n  t he Refere nce Safet y I nf or mati on  i n t he I n vesti gat or’s 
Br oc h ure as t he basis f or deter mi ni n g if ne wl y ac q uire d i nf or mati o n ge nerate d fr o m cli nical tr ials or re p orte d 
fr o m ot her s o urces is u ne x pecte d. T he s us pecte d a d verse reacti o ns liste d i n t he In vesti gat or ’s B r oc h ure (i.e., 
“e x pecte d”) are t h ose o bser ve d wit h t he i n vesti gati o nal dr u g a n d f or w hic h a ca usal relati o ns hi p bet wee n t he 
e ve nt a n d t he dr u g is s us pecte d or c o nfir me d. 
 
S p o ns or assess me nt of e x pecte d ness a n d relati o ns hi p t o st u d y a ge nt/ca usalit y will deter mi ne t he nee d f or 
e x pe dite d re p orti n g of A Es.  
 
8. 3  
TI M E P E RI O D/ F R E Q U E N C Y F O R E V E N T A S S E S S M E N T/ F O L L O W -U P  
 
At e ver y cli nic visit, s u bjects w h o ha ve gi ve n i nf or me d c o nse nt will be assesse d f or A Es a n d S A Es . After t he 
s u bject has ha d a n o p p ort u nit y t o s p o nta ne o usl y me nti o n a n y pr o ble ms, t he i n vesti gat or s h o ul d i n q uire a b o ut A Es 
b y as ki n g a n o n -lea di n g q uesti o n s uc h as t he f oll o wi n g:  
1.  
“ H o w are y o u feeli n g?”  
2.  
“ Ha ve y o u ha d a n y c ha n ges si nce y o ur last assess me nt/ visit?”  
3.  
“ Ha ve y o u ta ke n a n y ne w me dici nes si nce y o ur last assess me nt/ visit?”  
 
8. 3 .1  
P O S T -S T U D Y A E A N D S A E  
 
T he i n vesti gat or is n ot o bli gate d t o acti ve l y see k S A E i nf or mati o n i n f or mer st u d y s u bjects, b ut t he 
i n vesti gat or is e nc o ura ge d t o n otif y Al ka hest, I nc. or t heir desi g nee of a n y A E or S A E occ urri n g wit hi n 
3 0  da ys after a s u bject c o m pletes t he st u d y ( or has t heir last visit) t hat t he i n vesti gat or j ud ges ma y be 
reas o na bl y relate d t o st u d y treat me nt or st u d y partici pati o n. 
 
8. 4  
R E P O R TI N G P R O C E D U R E S  
 
8. 4. 1  
A D V E R S E E V E N T R E P O R TI N G  
 
All s u bjects w h o ha ve gi ve n i nf or me d c o nse nt will be e val uate d f or A Es . All A Es t hat occ ur after t he ti me of 
treat me nt wit h t he st u d y a ge nt will be c o nsi dere d treat me nt emer ge nt A Es . S u bjects wit h treat me nt-emer ge nt 
A Es m ust be f oll o we d u ntil t he A E is res ol ve d or is sta ble, u nless t he s u bject is l ost t o f oll o w u p.  
 
Eac h A E or  s us pecte d a d verse reacti o n m ust be descri be d as f oll o ws: t he date of o nset, date of res ol uti o n, 
se verit y ( mil d, m o derate, se vere), fre q ue nc y of t he e ve nt (si n gle e pis o de, i nter mitte nt, c o nti n u o us), acti o n 
ta ke n wit h st u d y treat me nt ( n o acti o n ta ke n, treatme nt hel d, treat me nt disc o nti n ue d), o utc o me, ca usalit y * 
( u nrelate d, p ossi bl y relate d, defi nitel y relate d), a n d seri o us ness criteria. Eac h A E or s us pecte d a d verse 
reacti o n m ust be rec or de d se paratel y. 
 
* N ote : Ca usalit y assess me nt will be ma de o nl y w he n t he A E occ urs after t he s u bject has i nitiate d at least 


 
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C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 3 9  of 9 9   
 
1  d ose  of t he st u d y a ge nt . A n A E occ urri n g bef ore t he s u bject’s e x p os ure t o st u d y a ge nt will al wa ys be 
la bele d as “ u nrelate d”. 
 
A n y A E occ urri n g d uri n g t he st u d y m ust be d oc u me nte d i n  t he s u bject’s me dical rec or ds a n d as a n A E i n t he 
C R F . A n y S A E occ urri n g d uri n g t he st u d y m ust be d oc u me nte d i n t he s u bject’s me dical rec or ds a n d as a n 
S A E i n t he C R F.  
 
A se parate set of S A E pa ges s h o ul d be use d f or e ac h S A E. H o we ver, if at t he ti me of i nitial re p orti n g, 
m ulti ple S A Es are prese nt t hat are te m p orall y a n d/ or cli nicall y relate d, t he y ma y be re p orte d o n t he sa me S A E 
pa ge.  
 
T he i n vesti gat or s h o ul d atte m pt t o esta blis h a dia g n osis of t he e ve nt (t hat meets t h e defi niti o n of a n A E or 
S A E) base d o n si g ns, s y m pt o ms, a n d/ or ot her cli nical i nf or mati o n . I n s uc h cases, t he dia g n osis s h o ul d be 
d oc u me nte d as t he A E a n d/ or S A E a n d n ot t he i n di vi d ual si g ns or s y m pt o ms . T he dia g n osis will bec o me t he 
basis f or t he ver bati m  ter m as re p orte d b y t he in vesti ga t or. If n o dia g n osis is k n o w n a n d cli nical si g ns a n d 
s y m pt o ms are n ot prese nt, t he a b n or mal fi n di n g s h o ul d be rec or de d. 
 
I n a d diti o n t o t he in vesti gat or’s o w n descri pti o n of t he A E , eac h A E will be e nc o de d acc or di n g t o t he 
Me d D R A . 
 
T he i n vesti gat or will ta ke all a p pr o priate a n d necessar y t hera pe utic meas ures re q uire d f or res ol uti o n of t he 
A E . A n y me dicati o n necessar y f or t he treat me nt of a n A E m ust be rec or de d o n t he c o nc o mita nt me dicati o n 
C R F .  
 
T he S A E pa ges of t he C R F s h o ul d be c o m plete d as t h or o u g hl y as p ossi ble a n d si g ne d b y t he i n vesti gat or or 
his/ her desi g nee bef ore tra ns mittal t o t he st u d y C o ntract Researc h Or ga nizati o n ( C R O) . It is ver y i m p orta nt 
t hat t he i n vesti gat or pr o vi de his/ her assess me nt of ca usalit y t o st u d y a ge nt  as well as a n a p plica ble dia g n osis 
at t he ti me of t he i nitial S A E re p ort.  
 
8. 4. 2  
S E RI O U S A D V E R S E E V E N T R E P O R TI N G  
 
8. 4. 2. 1  
Ti mefr a mes f or Re p orti n g S A Es  
U n der 2 1 C F R 3 1 2. 3 2(c), t he S p o ns or is re q uire d t o n otif y t he F D A , E M A, a n d all partici pati n g i n vesti gat ors 
i n a safet y re p ort of p ote ntiall y seri o us ris ks fr o m cli nical trials [i.e., S us pecte d U ne x pecte d Seri o us A d verse 
Reacti o ns ( S U S A R S) ], as s o o n as p ossi ble after t he S p o ns or recei ves t he safet y i nf or mati o n a n d deter mi nes 
t hat t he i nf or mati o n q ualifies f or re p orti n g: 
• 
N o later t ha n 7 cale n dar da ys f or e ve nts t hat are life t hreate ni n g (i n t he o pi ni o n of t he 
in vesti gat or or t he S p o ns or) or t hat i n v ol ve d eat h as a n o utc o me . 
• 
N o later t ha n 1 5 cale n dar da ys f or all ot her S U S A R S . 
 
As s uc h, pr o m pt n otificati o n of t he S p o ns or , a n d/ or t he S p o ns or’s re prese ntati ves, a n d pr o m ptl y pr o vi di n g 
re q ueste d f oll o w-u p i nf or mati o n re gar di n g S A Es is esse ntial s o t hat et hical a n d  re g ulat or y res p o nsi bilities a n d 
le gal o bli gati o ns ca n be satisfie d. I n vesti gat ors are res p o nsi ble f or re p orti n g S A Es acc or di n g t o t he f oll o wi n g 
ti mefra mes:  
 
•  
T he S A E Re p ort F or m a n d rele va nt s o urce d oc u me nts, if a p plica ble, m ust be c o m plete d a n d n otifie d, 
fa xe d, or e maile d t o  P P D P V G  i m me diatel y ( wit h o ut c ul pa ble dela y), b ut n o later t ha n 2 4 h o urs of 
o bser vati o n or lear ni n g of t he e ve nt.  
o  
 
 
 
 
 


 
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C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 4 0  of 9 9   
 
o  
 
•  
F oll o w -u p i nf or mati o n m ust  be se nt t o 
 i m me diatel y ( wit h o ut c ul pa ble dela y), b ut n o later 
t ha n 2 4 h o urs of recei pt of i nf or mati o n b y t he i n vesti gati o nal site.  
 
S A Es will be f oll o we d u ntil res ol uti o n, t he c o n diti o n sta bilizes, t he e ve nt is ot her wise e x plai ne d or is j u d ge d 
b y t he i n vesti gat or t o be n o l o n ger cli nicall y si g nifica nt, or u ntil t he s u bject is l ost t o f oll o w u p.  
 
8. 4. 2. 2  
S A E I nf or m ati o n t o Re p ort  
All i nf or mati o n a vaila ble re gar di n g a n S A E m ust be s u b mitte d i n t he ti mefra mes i n dicate d . At a mi ni m u m, 
S A E re p orts m ust c o ntai n t he s u bject I D, t he S A E  ver bati m ter m, o nset date, relati o ns hi p t o st u d y 
a ge nt/ca usalit y, a n d a brief narrati ve of t he e ve nt. Please n ote t hat rel ati o ns hi p t o st u d y a ge nt/c a us alit y as 
well as t he re p orte d ver b ati m ter m are ver y i m p ort a nt  a n d s h o ul d  be i ncl u de d i n t he i nitial re p ort as it 
ma y i m pact e x pe dite d re g ulat or y re p orti n g re q uire me nts f or t he e ve nt . T he date of S A E disc o ver y b y t he site 
staff s h o ul d be d oc u me nte d i n t he s o urce d oc u me nts. 
 
T he i n vesti gat or m ust rec or d all  rele va nt i nf or mati o n re gar di n g a n A E/ S A E i n t he a p plica ble secti o ns of t he 
C R F . It is n ot acce pta ble f or t he i n vesti gat or t o se n d p h ot oc o pies of t he s u bject’s me dical rec or ds i n lie u of 
c o m pleti o n of t he a p pr o priate A E/ S A E pa ges . H o we ver, t here ma y be i ns ta nces w he n c o pies of me dical 
rec or ds f or certai n cases are re q ueste d b y t he C R O a n d/ or t he S p o ns or. If me dical rec or ds are s u b mitte d t o t he 
C R O t he n all s u bject pers o nal i de ntifiers m ust be c o m pletel y a n d t h or o u g hl y re dacte d pri or t o s u b missi o n.  
 
A bla n k S A E Re p ort F or m a n d i nstr ucti o ns f or S A E re p orti n g will be pr o vi de d t o t he site a n d will be 
mai ntai ne d i n t he i n vesti gat or’s st u d y file. T he S A E Re p ort F or m m ust be c o m plete d a n d fa xe d or e maile d t o 
P P D  P V G  acc or di n g t o t he ti mefra mes s pecifie d i n Secti o n 8. 4. 2. 1 . T he S A E Re p ort F or m s h o ul d i ncl u de 
c o pies of rele va nt s o urce d oc u me nts, if a p plica ble . R ec o nciliati o n of a n y discre pa nc y n ote d d uri n g m o nit ori n g 
a n d a me n di n g t he e C R F is re q uire d.  
 
If ne w i nf or mati o n a b o ut a n S A E  is recei ve d or c orrecti o ns t o data are nee de d , t he i n vesti gat or s h o ul d 
c o m plete a ne w S A E Re p ort F or m a n d c hec k t he “f oll o w -u p” b o x o n t he f or m . T his f oll o w -u p S A E Re p ort 
F or m s h o ul d be s u b mitte d wit hi n 2 4 h o urs of lear ni n g of t he i nf or mati o n, es peciall y if t he ne w i nf or mati o n 
c o ncer ns seri o us ness, relate d ness, or t he e ve nt ter m of a n A E.  
 
Sites acti n g u n der t heir l ocal I R B/ IE C s h o ul d s u b mit all a p plica ble e ve nts, u na ntici pate d pr o ble ms, a n d safet y 
re p orts t o t he site’s l ocal I R B/IE C, if a p plica ble . All safet y re p ort i n g de viati o ns s h o ul d als o be s u b mitte d t o 
t heir l ocal I R B/IE C, if a p plica ble.  
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 4 1  of 9 9   
 
8. 4. 4  
R E P O R TI N G O F P R E G N A N C Y  
 
W hile pre g na nc y itself is n ot c o nsi dere d a n A E, pre g na nc y occ urri n g i n a cli nical st u d y m ust be f oll o we d t o 
c ollect i nf or mati o n re gar di n g t he e x perie nces of gestati o n a n d pre g na nc y wit h st u d y a ge nt e x p os ure . T he 
i n vesti gat or must re p ort a n y pre g na nc y t hat occ urs i n a fe male st u d y s u bject  or fe male part ner of a male 
s u bject s u bse q ue nt t o first e x p os ure t o t he st u d y a ge nt u ntil E n d of St u d y, or 3 m o nt hs f oll o wi n g a s u bject’s 
last d ose i n t he e ve nt of earl y ter mi nati o n. All pre g na ncies will be re p orte d t o t he I R B /I E C, S p o ns or, a n d 
C R O . I n t he e ve nt of a pre g na nc y, treat me nt will be disc o nti n ue d, a n d t he s u bject will u n der g o c o nti n ue d 
safet y f oll o w-u p t hr o u g h pre g na nc y o utc o me.  T he st u d y bli n d ca n be br o ke n f or safet y reas o ns if t he  
i nf or mati o n is re q uire d f or t he ma na ge me nt of pre g na nc y . A n y n ote d i nte nti o nal or u ni nte nti o nal brea ki n g of 
t he bli n d s h o ul d be re p orte d t o t he S p o ns or’s St u d y Tea m Lea d a n d Q ualit y Gr o u p (see Secti o n 1 0. 6. 3 ). 
 
A n y pre g na nc y m ust be f oll o we d b y t he in vesti gat or u ntil deli ver y or t o t he e n d of pre g na nc y . A n y 
a n o malies, c o m plicati o ns, a b n or mal o utc o mes, or birt h defect (s) o bser ve d i n t he c hil d m ust be re p orte d as a n 
S A E wit hi n 2 4 h o urs of t he i n vesti gat or or st u d y pers o n nel’s first k n o wle d ge.  
 
8. 5  
S T U D Y H A L TI N G R U L E S  
 
If a n y of t he f oll o wi n g safet y e ve nts occ ur, a Safet y E val uati o n Meeti n g ( defi ne d bel o w) will be tri g gere d: 
•  
T hree or m ore S A Es i n t he sa me s yste m/ or ga n/class ( S O C) t hat are assesse d as p ossi bl y or  defi nitel y 
relate d t o t he st u d y age nt b y t he i n vesti gat or a n d c o nfir me d as s uc h b y t he S p o ns or  (see Secti o n 8. 2. 2 
Relati o ns hi p t o St u d y A ge nt ). 
•  
Wit hi n or bet wee n a n y of t he d osi n g gr o u ps: a n o verall patter n of s y m pt o matic, cli nical, or la b orat or y 
e ve nts ass ociate d wit h t he st u d y age nt t hat t he S p o ns or’s Pr o gra m P h ysicia n  or desi g nee c o nsi der a 
seri o us p ote ntial safet y c o ncer n (e. g., s us pici o us o verall patter n). 
E ve nts t hat are m ore li kel y relate d t o a s pecific st u d y pr oce d ure, will n ot be c o nsi dere d “ dr u g relate d” a n d will n ot 
c o ntri b ute t o t he c o u nt of defi nitel y -relate d S A Es t hat w o ul d tri g ger a Safet y E val uati o n Meeti n g. 
 
S afety Ev al u ati o n Meeti n g  
 
If safet y e ve nts of p ote ntial c o ncer n occ ur d uri n g t he trial (i.e., 3 relate d e ve nts i n t he sa me S O C or a s us pici o us 
o verall patter n, as defi ne d a b o ve) a Safet y E val uati o n Meeti n g will be tri g gere d, a n d d osi n g ma y be te m p oraril y 
halte d base d o n t he o bser vati o ns . T he S p o ns or will i nf or m i n vesti gat ors a n d t he F D A  a n d E M A i n t he e ve nt of 
a n y te m p orar y halt i n d osi n g at a n y ti me d uri n g t he c o n d uct of t he st u d y . T he p ur p ose of t he meeti n g is f or 
i n vesti gat ors, t he S p o ns or, a n d t he C R O Me dical M o nit or (s) t o disc uss a n d e val uate t he safet y of t he s u bjects 
usi n g a vaila ble a g gre gate d safet y data a n d wit h o ut c o m pr o misi n g st u d y bli n di n g , u nless t he S p o ns or dee ms 
u n bli n di n g necessar y f or safet y e val uati o n .  
 
Atte n da nts at t he Safet y E val uati o n  Meeti n g  will i ncl u de t he Pr o gra m P h ysicia n  of Al ka hest ( or his/ her desi g nee), 
t he C R O  me dical m o nit or(s) , a n d availa ble  acti ve i n vesti gat ors partici pati n g i n t he trial . After s ufficie nt data 
re vie w t he S p o ns or will c h o ose o ne of t he f oll o wi n g c o urses of acti o n:  
1.  C o nti n ue d osi n g wit h n o c ha n ge t o pr ot oc ol . 
2.  H alt d osi n g i n all gr o u p s a n d st o p t he st u d y.  
3.  C o nti n ue wit h a m o difie d pr ot oc ol desi g n a n d a me n d t he pr ot oc ol as a p pr o priate.  
 
8. 6  
S A F E T Y O V E R SI G H T  
 
Safet y o versi g ht will be pr o vi de d b y t he S p o ns or’s Pr o gra m P h ysicia n  or his or her desi g nee a n d t he C R O’s 
Me dical M o nit or (s) i n c o ncert wit h t he site in vesti gat ors . T here will be n o f or mal Data Safet y M o nit ori n g B oar d 
( D S M B) esta blis he d. As nee de d, Safet y E val uati o n Meeti n gs will be c o n ve ne d as des cri be d i n  Secti o n 8. 5  t o 


 
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C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 4 2  of 9 9   
 
m o nit or t he o n g oi n g safet y of t he st u d y . T he S p o ns or’s Pr o gra m P h ysicia n  or desi g nee is t he fi nal a ut h orit y f or 
safet y o versi g ht i n t he st u d y. 
 
9  
C LI NI C A L M O NI T O RI N G  
 
Cli nical site m o nit ori n g is c o n d ucte d t o e ns ure t hat t he ri g hts a n d well -bei n g of h u ma n s u bjects are pr otecte d, t hat 
t he re p orte d trial data are acc urate, c o m plete, a n d verifia ble, a n d t hat t he c o n d uct of t he trial is i n c o m plia nce wit h 
t he c urre ntl y a p pr o ve d pr ot oc ol/ame n d me nt(s), wit h G C P, a n d wit h a p plica ble re g ulat or y re q uire me nt(s).  
 
• 
M o nit ori n g f or t his st u d y will be c o n d ucte d  b y t he st u d y C R O i n acc or da nce wit h t he Cli nical M o nit ori n g 
Pla n ( C M P) . 
• 
A mi x of o n -site a n d ce ntralize d ris k-base d m o nit ori n g will be c o n d ucte d t o ens ure t he safet y of cli nical 
s u bjects a n d t he acc urac y a n d c o m plete ness of st u d y data.  
• 
T he S p o ns or  will be pr o vi de d wit h c o pies of m o nit ori n g re p orts per t he ti meli nes s pecifie d wit hi n t he 
C M P . 
• 
Details of cli nical site m o nit ori n g tas ks a n d sc o pe are d oc u me nte d i n t he st u d y’s C M P . T he C M P 
descri bes i n detail w h o will c o n d uct m o nit ori n g, at w hat fre q ue nc y m o nit ori n g will be d o ne, at w hat le vel 
of detail m o nit ori n g will be c o n d ucte d , a n d t he distri b uti o n of m o nit ori n g re p orts. 
• 
I n de pe n de nt a u dits ma y  b e c o n d ucte d b y t he S p o ns or  i n acc or da nce wit h a st u d y-s pecific Qualit y 
Ass ura nce  P la n t o e ns ure m o nit ori n g practices are c o n d ucte d c o nsiste ntl y acr oss all partici pati n g sites , 
t hat m o nit ors are f oll o wi n g t he C M P a n d sites c o n d uct t he st u d y acc or di n g t o t he pr ot oc ol, G C P , a n d 
a p plica ble re g ulat or y re q uire me nt s. 
 
1 0  
S T A TI S TI C A L C O N SI D E R A TI O N S  
1 0 . 1 S T A TI S TI C A L D E SI G N M O D E L  A N D A N A L Y TI C A L P L A N S  
 
A Statistical A nal ysis Pla n ( S A P) wit h a nal ytical details a n d ass u m pti o n s will be de vel o pe d a n d fi nalize d  bef ore  
data base l oc k a n d u n bli n di n g of t he st u d y data.  
 
1 0 . 2 S T A TI S TI C A L H Y P O T H E S E S  
 
T he n ull a n d alter nati ve h y p ot heses f or t his st u d y are:  
H 0: µC  = µ T  
 vs  
H A : µC  ≠ µ T . 
N ote: T he s y m b ol “ µ ” de n otes t he mea n c ha n ge fr o m baseli ne i n m ot or f u ncti o n d uri n g t he practicall y defi ne d 
off -me dicati o n state at Wee k 1 2 as meas ure d b y t he M D S -U P D R S Part 3  f or t he c o ntr ol ( C) a n d treate d ( T) 
gr o u ps . 
 
1 0. 3  A N A L Y SI S D A T A S E T S  
 
St u d y data will be a nal yze d i n o ne of t he f oll o wi n g a nal ysis sets:  
•  
I nte nt-t o-Tre at (I T T)  set will i ncl u de all ra n d o mize d s u bjects. 
•  
M o difie d I nte nt -t o-Tre at ( mI T T) / E v al u a ble set will be a s u bset of t he I T T s u bjects wit h baseli ne 
a n d Wee k 1 2  val ue f or off -me dicati o n m ot or f u ncti o n as meas ure d b y t he M D S-U P D R S Part 3.  
•  
S afet y E v al u a ble  set will i ncl u de all ra n d o mize d s u bjects w h o recei ve at least 1 d ose of t he st u d y 
a ge nt. 
•  
Per -Pr ot oc ol ( P P) set is a s u bset of I T T s u bjects w h o f oll o w t he pr ot oc ol wit h o ut a n y major 
de viati o n(s). A detaile d descri pti o n of t he reas o ns f or e xcl usi o n fr o m t he P P p o p ulati o n will be 
i ncl u de d i n t he Statistical A nal ysis Pla n ( S A P) 
 


 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
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C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 4 3  of 9 9   
 
S u bjects will be a nal yze d i n t he treat me nt ar m assi g ne d at ra n d o mizati o n  f or t he I T T, mI T T, a n d P P sets. F o r t he 
Safet y E val ua ble set, s u bjects will be gr o u pe d acc or di n g t o act ual treat me nt recei ve d.  
 
1 0. 4  D E S C RI P TI O N O F S T A TI S TI C A L M E T H O D S  
 
1 0. 4. 1  
G E N E R A L A P P R O A C H  
 
S u bject dis p ositi o n a n d pr ot oc ol de viati o ns will be s u m marize d descri pti vel y b y treat me nt ar m. T he 
c o m para bilit y bet wee n t he treat me nt ar ms i n de m o gra p hics a n d baseli ne c haracteristics will be 
assesse d. Pri or a n d c o nc o mita nt me dicati o ns will als o be s u m marize d b y treat me nt ar m.  
 
All s u m mar y statistics will be descri pti ve u nless n ote d ot her wise . Descri pti ve s u m maries will i ncl u de 
mea n, sta n dar d de viati o n  ( S T D), me dia n, a n d ra n ge f or c o nti n u o us varia bles a n d c o u nts, a n d 
perce nta ges f or cate g orical varia bles. T w o -si de d 9 5 % c o nfi de nce i nter vals ( CIs) will be pr o vi de d f or 
t he mea ns a n d perce nta ges  as nee de d . F or ke y o utc o me meas ures, t he differe nce bet wee n t he treat me nt 
ar m a n d t he 9 5 % CI of t he differe nce will be c o m p ute d.  
 
Detaile d statistical met h o ds will be o utli ne d i n t he S A P f or t he st u d y.  
 
1 0. 4. 2  
A N A L Y SI S O F T H E P RI M A R Y E N D P OI N T  
 
T he pri mar y e n d p oi nt is c ha n ge fr o m baseli ne t o Wee k 1 2 i n t he off -me dicati o n m ot or f u ncti o n as meas ure d 
b y t he M D S -U P D R S Part 3 . T he mai n a nal ysis f or t he pri mar y efficac y varia ble will be a nal yze d usi n g mI T T 
s u bjects. 
 
A mi xe d -effect m o del f or re peate d m eas ures ( M M R M) will be e m pl o ye d t o a nal yze t he c ha n ge fr o m baseli ne 
sc ores at eac h visit o ver ti me u p t o Wee k 1 2. T he m o del will i ncl u de t he fi xe d effects of treat me nt  (stratifie d, 
b y se x) , baseli ne of t he e n d p oi nt, visit, a n d treat me nt b y visit i nteracti on. A n u nstr uct ure d c o varia nce 
str uct ure will be use d t o m o del t he wit hi n s u bject err or. Least -s q uare ( L S) mea n, sta n dar d err or ( S E), a n d 
9 5 % CI of t he L S mea n will be pr o vi de d f or eac h treat me nt ar m at eac h visit . T he differe nce i n L S mea ns 
bet wee n treat me nt ar ms a n d 9 5 % CI of t he differe nce will als o be calc ulate d . P -val ue f or testi n g w het her t he 
differe nce is e q ual t o zer o will be pr o vi de d . T he p -val ue at Wee k 1 2 will be c o m pare d a gai nst t he al p ha 
si g nifica nt le vel of 0. 1. 
 
T he mai n a nal ysis of t he pri mar y e n d p oi nt usi n g t he a b o ve M M R M will use all a vaila ble data. T o c hec k t he 
r o b ust ness of t he res ults, t he f oll o wi n g se nsiti vit y a nal yses will be perf or me d : 
•  
A nal ysis of c o varia nce ( A N C O V A) m o del o n t he o bser ve d c ha n ge fr o m baseli ne val ue at Wee k 1 2 . 
T he m o del i ncl u des treat me nt as t he fi xe d effect a n d baseli ne of t he e n d p oi nt as a c o variate.  
•  
T he sa me M M R M m o del o n data fr o m t he P P s u bjects.  
•  
De pe n di n g o n t he stat us of missi n g data, m ulti ple i m p utati o ns ma y be e m pl o ye d t o ha n dle missi n g 
data a n d a p pl y t he M M R M o n t he i m p ute d datasets.  
   
1 0. 4. 3  
A N A L Y SI S O F T H E S E C O N D A R Y E N D P OI N T S  
 
Sec o n dar y efficac y e n d p oi nts will be a nal yze d usi n g t he mI T T set. C o nti n u o us e n d p oi nts will be a nal yze d 
usi n g t he sa me M M R M m o del use d f or t he pri mar y e n d p oi nt. L o gistic re gr essi o n m o dels will be use d f or 
e n d p oi nts wit h cate g orical or or di nal res p o nses.  
 
Safet y data will be a nal yze d usi n g t he Safet y E val ua ble set. Treat me nt -e mer ge nt ad verse e ve nts will be 
s u m marize d b y Me d D R A c o di n g ter ms, a n d se parate ta b ulati o ns will be pr o d uce d f or treat me nt-relate d 
a d verse e ve nts, seri o us a d verse e ve nts , a n d disc o nti n uati o ns d ue t o a d verse e ve nts. Vital si g n data a n d 


 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
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C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 4 4  of 9 9   
 
fi n di n gs fr o m p h ysical e xa mi nati o ns will be ta b ulate d f or c ha n ges o ver ti me d uri n g t he  st u d y peri o d . 
La b orat or y para meters wi ll be s u m marize d f or c ha n ges acr oss t he st u d y peri o d  usi n g descri pti ve statistics.  
 
  
1 0. 4. 4  
P L A N N E D I N T E RI M A N A L Y S E S  
 
Safet y will be m o nit ore d o n a n o n g oi n g basis. If a Safet y E val uati o n Meeti n g is tri g gere d (see Sect i o n 8. 5), a n 
a d h oc i nteri m safet y a nal ysis will be perf or me d . If s uc h a n a d h oc safet y i nteri m a nal ysis is c o n d ucte d, t he 
treat me nt assi g n me nt will re mai n mas ke d, u nless u n bli n di n g is dee me d necessar y b y t he S p o ns or f or safet y 
e val uati o n.  
  
1 0. 4. 5  
M U L TI P L E C O M P A RI S O N/ M U L TI P LI CI T Y  
 
N o a dj ust me nts f or m ulti plicit y will be e m pl o ye d . All h y p ot hesis tests will be perf or me d  at a n al p ha le vel of 
0. 1.  
  
1 0. 4. 6   
E X P L O R A T O R Y A N A L Y S E S  
 
E x pl orat or y e n d p oi nts will be s u m marize d descri pti vel y . Treat me nt c o m paris o ns o n e x pl orat or y e n d p oi nts, if 
perf or me d , will be i n t he nat ure of h y p ot hesis ge nerati o n. 
  
1 0. 5  S A M P L E SI Z E  
 
A t otal of a p pr o xi matel y 1 2 0 s u bjects will be ra n d o mize d i n a 1: 1 rati o t o acti ve treat me nt (a p pr o xi matel y 6 0 
s u bjects) or place b o (a p pr o xi matel y 6 0 s u bjects), wit h t he i nte nt of o btai ni n g ~ 1 0 8  e val ua ble s u bjects.  
 
T he varia bilit y of c ha n ge fr o m baseli ne i n t he off -me dicati o n m ot or f u ncti o n as meas ure d b y M D S -U P D R S, 
Part  3 is a p pr o xi matel y 6. 4 a n d 7. 6 p oi nts at Wee ks 4 8 a n d 6 0, res pecti vel y, f or t he place b o gr o u p, a n d 
a p pr o xi matel y 4. 9 a n d 4. 8 i n a pre vi o us st u d y of t he c o m p o u n d E xe nati de ( At ha u da 2 0 1 7 ). Ass u mi n g t he 
varia bilit y at Wee k 1 2 is si milar t o t hat at Wee k 4 8, a n d ass u mi n g t he varia bilit y i n t he A K S T 4 2 9 0 treate d gr o u p 
is si milar t o t hat of E xenati de -treate d s u bjects, t he sa m ple size f or t he st u d y will base d o n S T D = 6. 4 a n d 4. 9 f or 
t he c o ntr ol a n d treate d res pecti vel y. Wit h n = 5 4  e val ua ble s u bjects i n eac h ar m, t he st u d y w ill ha ve m ore t ha n 8 5 % 
p o wer t o detect a differe nce i n mea ns bet wee n ar ms w he n t he tr ue differe nce is 3 p oi nts base d o n a t w o -si de d t-
test at a n al p ha of 0. 1. If t he tr ue differe nce is 4 p oi nts, t he p o wer i ncreases t o m ore t ha n  9 5 %.  
  
1 0. 6  M E A S U R E S T O MI NI MI Z E BI A S  
 
1 0. 6. 1  
E N R O L L M E N T/ R A N D O MI Z A TI O N/ M A S KI N G P R O C E D U R E S  
 
T o mi ni mize t he p ote ntial bias at t he ti me of ra n d o mizati o n, t he st u d y will be d o u ble -bli n de d a n d ra n d o mize d 
i n a 1: 1 rati o (acti ve: place b o) base d o n a bl oc k ra n d o mizati o n sc he ma stratifie d b y se x. T he ra n d o mizati o n 
will be we b -base d a n d ce ntralize d. T he ra n d o mizati o n c o des will be ge nerate d b y a statisticia n t hat has n o 
i n v ol veme nt i n t he st u d y ot her t ha n ge nerati o n a n d mai nte na nce of t he ra n d o mizati o n c o des.   
 
1 0. 6. 2  
E V A L U A TI O N O F S U C C E S S O F B LI N DI N G  
 
S uccess of bli n di n g will be assesse d base d o n all occ urre nces (i nte nti o nal or u ni nte nti o nal) of u n bli n di n g of 
bli n de d st u d y s u bjects or st u d y pers o n nel ( e. g., i n vesti gat ors, me dical pr o vi ders, c o g niti ve/ m ot or testi n g 
raters, t he S p o ns or or t heir re prese ntati ves). All i nte nti o nal a n d u ni nte nti o nal u n bli n di n g will be d oc u me nte d 
a n d re p orte d.  
  


 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
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C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 4 5  of 9 9   
 
1 0. 6. 3  
B R E A KI N G T H E S T U D Y B LI N D/ S U B J E C T C O D E  
 
T he st u d y bli n d ca n be br o ke n f or safet y reas o ns if t he i nf or mati o n is re q uire d f or t he ma na ge me nt o f S A Es, 
se vere A Es, or pre g na ncies . T he I n vesti gat or ca n o btai n t he treat me nt all ocati o n f or t heir s u bject t hr o u g h t he 
we b -base d ra n d o mizati o n s yste m  (I R T). In t he rare e ve nt t he we b -base d s yste m is u na vaila ble or t o c o ntact 
t he Me dical M o nit or, 
2 4 -h o ur e mer ge nc y Safet y H otli ne ma y be c o ntacte d at: 
 
 
  
 
 
Bef ore brea ki n g t he bli n d, e ver y atte m pt s h o ul d be ma de t o disc uss t he nee d wit h t he S p o ns or Pr o gra m 
P h ysicia n, or desi g nee. W he n s o me de gree of u n bli n di n g m ust occ ur, t his s h o ul d be li mite d t o t he fe west 
n u m ber of pe o ple o n a nee d -t o-k n o w basis.  
 
A n y n ote d i nte nti o nal or u ni nte nti o nal brea ki n g of t he bli n d s h o ul d be re p orte d t o t he S p o ns or’s St u d y Tea m 
Lea d  a n d Q ualit y Gr o u p . If u ni nte nti o nal u n bli n di n g occ urs d uri n g t he st u d y, r o ot ca use a nal ysis will be 
e val uate d, a n d c orrecti ve acti o ns i m ple me nte d.  
 
1 1  
S O U R C E D O C U M E N T S A N D A C C E S S T O S O U R C E D A T A/ D O C U M E N T S  
 
Eac h partici pati n g site will mai ntai n a p pr o priate me dical a n d researc h rec or ds f o r t his trial, i n c o m plia nce wit h  
I C H E 6 R 2 a n d re g ulat or y a n d i nstit uti o nal re q uire me nts f or t he pr otecti o n of c o nfi de ntialit y of s u bjects. Eac h site 
will per mit a ut h orize d re prese ntati ves of re g ulat or y a ge ncies, t he I R B/I E C, t he S p o ns or, or t he S p o ns or’s 
re prese ntati ves t o e xa mi ne (a n d w he n per mitte d b y a p plica ble la w, t o c o p y) cli nical rec or ds f or t he p ur p oses of 
q ualit y ass ura nce re vie ws, a u dits, a n d e val uati o n of t he st u d y safet y, pr o gress, a n d data vali dit y .  
 
S o urce data are all i nf or mati o n,  ori gi nal rec or ds of cli nical fi n di n gs, o bser vati o ns, or ot her acti vities i n a cli nical 
trial necessar y f or t he rec o nstr ucti o n a n d e val uati o n of t he trial. E xa m ples of t hese ori gi nal d oc u me nts a n d data 
rec or ds i ncl u de, b ut are n ot li mite d t o, h os pital rec or ds, cli nical a n d office c harts, la b orat or y n ot es, me m o ra n da, 
s u bject’s me m or y ai ds or e val uati o n c hec klists, p har mac y dis pe nsi n g rec or ds, rec or de d a u di o ta pes of c o u nseli n g 
sessi o ns, rec or de d data fr o m a ut o mate d i nstr u me nts, c o pies or tra nscri pti o ns certi fie d after verificati o n as bei n g 
attri b uta ble, le gi ble, acc urate a n d c o m plete, micr ofic hes, p h ot o gra p hic ne gati ves, micr ofil m or ma g netic me dia, x -
ra ys, a n d s u bject files a n d rec or ds ke pt at t he p har mac y, at t he la b orat ories, a n d me dic o-tec h nical de part me nts 
i n v ol ve d i n t he cli nical trial.  
 
It is n ot acce pta ble f or t he C R F t o be t he o nl y rec or d of a s u bject’s partici pati o n i n t he st u d y. T his is t o e ns ure t hat 
a n y o ne w h o w o ul d access t he s u bject’s me dical rec or d has a de q uate k n o wle d ge t hat t he s u bject is pa rtici pati n g i n a 
cli nical trial . S o urce d oc u me nt te m plates will be de vel o pe d f or t his st u d y.  
 
1 2  
E T HI C S/ P R O T E C TI O N O F H U M A N S U B J E C T S  
1 2 . 1 E T HI C A L S T A N D A R D  
 
T he i n vesti gat or will e ns ure t hat t his st u d y is c o n d ucte d i n f ull c o nf or mit y wit h Re g ulati o ns f or t he Pr otecti o n of 
H u ma n S u bjects of Researc h c o difie d i n 4 5 C F R Part 4 6, 2 1 C F R Part 5 0, 2 1 C F R Part 5 6, I C H E 6 R 2, 2 1 C F R, 
part 3 2 0, 1 9 9 3, Rete nti o n of Bi oa vaila bilit y a n d Bi oe q ui vale nce Testi n g Sa m ples a n d t he Declarati o n of Helsi n ki.  
 
1 2 . 2 I N S TI T U TI O N A L R E VI E W B O A R D 
 
T his pr ot oc ol a n d a n y acc o m pa n yi n g material t o be pr o vi de d t o t he s u bject (s uc h as a d vertise me nts, s u bject 
i nf or mati o n s heets, or descri pti o ns of t he st u d y use d t o o btai n i nf or me d c o nse nt) will be s u b mitte d b y t he 
i n vesti gat or t o a n I R B or IE C . A p pr o val fr o m t he I R B/ IE C m ust be o btai ne d bef ore starti n g t he st u d y a n d s h o ul d 


 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
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C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 4 6  of 9 9   
 
be d oc u me nte d i n a letter t o t he i n vesti gat or s pecif yi n g t he pr ot oc ol n u m ber, pr ot oc ol versi o n, d oc u me nts 
re vie we d, a n d date o n w hic h t he c o m mittee met a n d gra nte d t he a p pr o val.   
 
All c ha n ges t o t he c o nse nt f or m will be I R B /I E C a p pr o ve d; a deter mi nati o n will be ma de re gar di n g w het her 
pre vi o usl y c o nse nte d s u bjects nee d t o be re-c o nse nte d. 
 
A n y m o dificati o ns or a me n d me nt s t o t he pr ot oc ol m ust als o be s u b mitte d t o t he I R B/IE C f or a p pr o val pri or t o 
i m ple me ntati o n. 
 
1 2 . 3 I N F O R M E D C O N S E N T P R O C E S S 
 
1 2 . 3. 1 
C O N S E N T F O R M S  
 
C o nse nt f or ms descri bi n g i n detail t he st u d y a ge nt, st u d y pr oce d ures, a n d ris ks are gi ve n t o t he s u bject or 
h ealt hcare p o wer of att or ne y or e q ui vale nt le gal re prese ntati ve,  a n d writte n d oc u me ntati o n of i nf or me d 
c o nse nt is re q uire d pri or t o a n y st u d y -relate d pr oce d ures.  
 
1 2 . 3. 2 
C O N S E N T P R O C E D U R E S A N D D O C U M E N T A TI O N  
 
It is t he res p o nsi bilit y of t he i n vesti gat or or desi g nee t o o btai n writte n i nf or me d c o nse nt fr o m eac h s u bject 
partici pati n g i n t his st u d y after a de q uate e x pla nati o n of t he ai ms, met h o ds, o bjecti ves, a n d p ote ntial hazar ds 
of t he st u d y a n d pri or t o u n derta ki n g a n y st u d y -relate d pr oce d ures. 
 
S u bjects s h o ul d ha ve t he o p p ort u nit y t o disc uss t he st u d y wit h t heir fa mil y me m bers or ot her a d vis ors a n d t he 
ti me t o c o nsi der partici pati o n i n t he trial caref ull y. T he s u bjects ma y wit h dra w c o nse nt at a n y ti me t hr o u g h o ut 
t he c o urse of t he trial. T he ri g hts a n d welfare of t he s u bjects will be pr otecte d b y e m p hasizi n g t o t he m t hat t he 
q ualit y of t heir me dical care will n ot be a d versel y affecte d if t he y decli ne t o partici pate i n t his st u d y.  
 
T he i n vesti gat or or desi g nee m ust utilize a n I R B /I E C-a p pr o ve d c o ns e nt f or m t hat c o ntai ns t he ele me nts 
re q uire d b y I C H G C P a n d a p plica ble re g ulat or y re q uire me nts f or d oc u me nti n g writte n i nf or me d c o nse nt. 
Eac h i nf or me d c o nse nt will be a p pr o priatel y si g ne d a n d date d b y t he s u bject a n d t he pers o n o btai ni n g 
c o nse nt . A c o p y of  t he si g ne d c o nse nt f or m will be pr o vi de d t o t he s u bject. B y si g ni n g t he i nf or me d c o nse nt 
f or m, all parties a gree t he y will c o m plete t he e val uati o ns re q uire d b y t he st u d y, u nless t he y wit h dra w 
v ol u ntaril y or are ter mi nate d fr o m t he st u d y f or a n y reas o n.  
 
In vesti gat ors will be e x pecte d t o mai ntai n a scree ni n g l o g of all p ote ntial st u d y ca n di dates t hat i ncl u des 
li mite d i nf or mati o n a b o ut t he p ote ntial ca n di date (e. g., date of scree ni n g).  
 
All s u bjects w h o pr o vi de c o nse nt will be assi g ne d a u ni q ue st u d y n u m ber . T his n u m ber will be use d t o 
i de ntif y t he s u bject t hr o u g h o ut t he cli nical st u d y a n d m ust be use d o n all st u d y d oc u me ntati o n relate d t o t he 
st u d y s u bject. O nce a n u m ber is assi g ne d t o a s u bject, t hat n u m ber will re mai n wit h t hat st u d y s u bject a n d 
will n ot be re use d.  
 
If a n i n di vi d u al’s me di c al c h art or res ults of di a g n osti c t ests p erf or m e d  as part of a n i n di vi d u al’s r e g ular 
m e dic al  c ar e  ar e g oi n g  t o b e  us e d  f or s cre e ni n g, writt e n  i nf or me d c o nse nt  m ust  b e  o btai n e d  pri or  t o r e vie w 
of  t hat i nf or m ati o n i n a c c or d a n ce wit h HI P A A. 
 
1 2 . 4 P A R TI CI P A N T A N D D A T A C O N FI D E N TI A LI T Y  
 
S u bject c o nfi de ntialit y is hel d i n strict tr ust b y t he partici pati n g in vesti gat ors, t heir staff, t he S p o ns or , a n d t heir 
a ge nts . T his c o nfi de ntialit y is e xte n de d t o c o ver testi n g of bi ol o gical sa m ples a n d ge netic tests i n a d diti o n t o t he 
cli nical i nf or mati o n relati n g t o s u bjects. T heref ore, t he st u d y pr ot oc ol, d oc u me ntati o n, data, a n d all ot her 


 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
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C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 4 7  of 9 9   
 
i nf or mati o n ge nerate d will be hel d i n strict c o nfi de nce. N o i nf or mati o n c o ncer ni n g t he st u d y or data will be 
release d t o a n y u na ut h orize d t hir d part y wit h o ut pri or writte n a p pr o val of t he S p o ns or . 
 
T he st u d y m o nit or, ot her a ut h orize d re prese ntati ves of t he S p o ns or , re prese ntati ves of t he I R B/IE C , or 
g o ver n me nt re g ulat or y a ge ncies  ma y i ns pect d oc u me nts a n d rec or ds re q uire d t o be mai ntai ne d b y t he i n vesti gat or, 
i ncl u di n g b ut n ot li mite d t o, me dical rec or ds ( office, cli nic, or h os pital) a n d p har mac y rec or ds f or t he s u bjects i n 
t his st u d y. T he cli nical st u d y site will per mit  access t o s uc h rec or ds.  
 
T he i n vesti gat or m ust ass ure t hat s u bjects’ a n o n y mit y will be strictl y mai ntai ne d a n d t hat t heir i de ntities are 
pr otecte d fr o m u na ut h orize d parties . O nl y s u bject i nitials a n d a n i de ntificati o n c o de ( i.e., n ot na mes) s h o ul d be 
rec or de d o n n o n-l ocal la borat or y  sa m ples, re q uisiti o ns, a n d a n y d oc u me nts s u b mitte d t o t he C R O, S p o ns or , 
a n d/ or I R B /I E C. T he i n vesti gat or m ust kee p a s u bject l o g s h o wi n g c o des, na mes, a n d a d dresses f or all s u bjects 
scree ne d a n d for all s u bjects e nr olle d i n t he trial . T he st u d y s u bject’s c o ntact i nf or mati o n will be sec urel y st ore d 
at eac h cli nical site f or i nter nal use d uri n g t he st u d y . At t he e n d of t he st u d y, all rec or ds will c o nti n ue t o be ke pt i n 
a sec ure l ocati o n f or as l o n g a  peri o d as dictate d b y l ocal I R B /I E C a n d instit uti o nal re g ulati o ns. 
 
1 2 . 5 F U T U R E U S E O F S T O R E D S P E CI M E N S  
 
Wit h t he s u bject’s a p pr o val a n d as a p pr o ve d b y l ocal I R B /I E Cs, de-i de ntifie d bi ol o gical sa m ples ma y be st ore d at 
Al ka hest , or desi g nee, f or f ut ure use. T hese sa m ples c o ul d be use d f or researc h a n d t o i m pr o ve treat me nt . 
Al ka hest will als o be pr o vi de d wit h a c o de -li n k t hat will all o w li n ki n g t he bi ol o gical s peci me ns wit h t he s pecific 
data fr o m eac h s u bject, mai ntai ni n g t he mas ki n g of the i d e ntit y of t he st u d y s u bject. S u bjects ma y c h o ose w het her 
t he S p o ns or ca n st ore a n d use  sa m ples f or f urt her researc h.  
 
D uri n g t he c o n d uct of t he st u d y, a n i n di vi d ual s u bject ca n c h o ose t o wit h dra w c o nse nt t o ha ve bi ol o gical 
s peci me ns st ore d f or f ut ure researc h. H o we ver, wit h dra wal of c o nse nt f or bi os peci me n  st ora ge will n ot be 
p ossi ble after t he st u d y is c o m plete d.  
 
W he n t he st u d y is c o m plete d, access t o st u d y data a n d/ or sa m ples will be ma na ge d b y Al ka hest . I n t he e ve nt 
Al ka hest tra nsfers o w ners hi p t o a n ot her c o m mercial S p o ns or , o w ners hi p of t he sa m ples ma y be tra nsferre d as 
well.  
 
1 3  
D A T A H A N D LI N G A N D R E C O R D K E E PI N G  
1 3 . 1 D A T A C O L L E C TI O N A N D M A N A G E M E N T R E S P O N SI BI LI TI E S  
 
Data c ollecti o n is t he res p o nsi bilit y of t he cli nical trial staff at t he site u n der t he s u per visi o n of t he site 
i n vesti gat or. T he i n vesti gat or is res p o nsi ble f or e ns uri n g t he acc urac y, c o m plete ness, a n d ti meli ness of t he data 
re p orte d. 
 
S o urce d oc u me nts pr o vi de e vi de nce f or t he e xiste nce of t he s u bject a n d s u bsta ntiate t he  i nte grit y of t he data 
c ollecte d . S o urce d oc u me nts are file d at t he i n vesti gat or’s site . Data e ntere d i n t he C R F t hat are tra nscri be d fr o m 
s o urce d oc u me nts m ust be c o nsiste nt wit h t he s o ur ce d oc u me nts or t he discre pa ncies m ust be e x plai ne d . All 
s o urce d oc u me nts s h o ul d be c o m plete d i n a neat, le gi ble ma n ner t o e ns ure acc urate i nter pretati o n of data . Blac k 
or bl ue i n k is re q uire d t o e ns ure clarit y of re pr o d uce d c o pies . W he n ma ki n g c ha n ges or c orrecti o ns, cr oss o ut t he 
ori gi nal e ntr y wit h a si n gle li ne, a n d i nitial a n d date t he c ha n ge . D O N O T E R A S E, O V E R W RI T E, O R U S E 
C O R R E C TI O N F L UI D O R T A P E O N T H E O RI GI N A L . T he i n vesti gat or ma y nee d  t o re q uest pre vi o us me dical 
rec or ds or tra nsfer rec or ds, de pen di n g o n t he trial; als o , c urre nt  me dical rec or ds m ust be a vaila ble.  
 
F or eac h s u bject w h o recei ves t he st u d y a ge nt or place b o , t he C R F m ust be c o m plete d i n a ti mel y ma n ner . T he 
i n vesti gat or will re vie w a n d a p pr o ve t he C R F f or eac h st u d y s u bject after all data ha ve bee n e ntere d, t he C R Fs 
ha ve bee n s o u rce d oc u me nt verifie d, a n d all q ueries ha ve bee n res ol ve d. T his also a p plies t o rec or ds f or t h ose 


 
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C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 4 8  of 9 9   
 
su bjects w h o fai l t o c o m plete t he st u d y. If a su bject wit h dra ws fr o m t he st u d y, t he reas o n m ust be n ote d o n t he 
C R F . If a s u bject is wit h dra w n fr o m t he st u d y beca use of a n A E, t h or o u g h eff orts s h o ul d be ma de t o clearl y 
d oc u me nt t he o utc o me.  
 
All data c ollecti o n a n d rec or d kee pi n g pr oce d ure s m ust be c o m plia nt  wit h a p plica ble I C H G C P.  
 
1 3 . 1. 1 
I N V E S TI G A T O R R E S P O N SI BI LI TI E S  
 
T he i n vesti gat or will c o m pl y wit h t he pr ot oc ol ( w hic h has bee n a p pr o ve d/ gi ve n fa v ora ble o pi ni o n b y a n 
I R B/IE C), I C H G C P, a n d a p plica ble re g ulat or y re q uire me nts . T he i n vesti gat or is ulti matel y res p o nsi ble f or 
t he c o n d uct of all as pects of t he st u d y at t he st u d y site a n d verifies b y si g nat ure t he i nte grit y of all data 
tra ns mitte d t o t he S p o ns or . T he ter m “i n vesti gat or” as use d i n t his pr ot oc ol as well as i n ot her st u d y 
d oc u me nts, refers t o t he i n vesti gat or or a ut h orize d st u d y pers o n nel t hat t he i n vesti gat or has desi g nate d t o 
perf or m certai n d uties . S u b -i n vesti gat ors or ot her a ut h orize d st u d y pers o n nel are eli gi ble t o si g n f or t he 
i n vesti gat or, e xce pt w here t he i n vesti gat or’s si g nat ure is s pecificall y re q uire d. 
 
1 3 . 1. 2 
S T U D Y FI L E S  
 
T he i n vesti gat or m ust mai ntai n a de q uate a n d acc urate rec or ds t o e na ble t he c o n d uct of t he st u d y t o be f ull y 
d oc u me nte d a n d t he st u d y data t o be s u bse q ue ntl y verifie d . T hese d oc u me nts s h o ul d be classifie d i nt o t w o 
se parate cate g ories (alt h o u g h n ot li mite d t o) t he f ollo wi n g: ( 1) i n vesti gat or’s st u d y file, a n d ( 2) s u bject 
cli nical s o urce d oc u me nts.  
 
T he i n vesti gat or’s st u d y file will c o ntai n t he pr ot oc ol/a me n d me nts, C R F, I R B/ IE C a p pr o val wit h 
c orres p o n de nce, i nf or me d c o nse nt s, dr u g rec or ds, staff c urric ul u m vitae a n d a uth orizati o n f or ms, a n d ot her 
a p pr o priate d oc u me nts a n d  st u d y-s pecific ma n uals (e. g., la borat or y  m a n ual) . 
 
S u bject cli nical s o urce d oc u me nts w o ul d i ncl u de (alt h o u g h are n ot li mite d t o) t he f oll o wi n g: s u bject 
h os pital/cli nic rec or ds, p h ysicia n’s a n d n urse’s n otes, a p p oi nt me nt b o o k, ori gi nal la b orat or y re p orts, E C G, 
ra di ol o gic i ma gi n g, x -ra y, pat h ol o g y a n d s pecial assess me nt re p orts, c o ns ulta nt letters, scree ni n g a n d 
e nr oll me nt l o g, etc. 
 
1 3 . 2 S T U D Y R E C O R D S R E T E N TI O N  
 
All cli nical st u d y d oc u me nts m ust be retai ne d b y t he i n vesti gat or u ntil t w o years after t he st u d y is disc o nti n ue d 
a n d re g ulat or y a ut h orities ha ve be e n n otifie d . Bef ore t he i n vesti gat or destr o ys a n y material relate d t o t he cli nical 
st u d y, he/s he m ust o btai n a p pr o val i n writi n g fr o m t he S p o ns or . 
 
T he i n vesti gat or s h o ul d kee p a file w here t he f ull na me a n d a d dress of t he s u bject a n d all si g ne d i nf or me d 
co nse nts are i ncl u de d f or at least 1 5 years after c o m pleti o n of t he trial . A n y ori gi nal st u d y -relate d i nf or mati o n t hat 
per mits verificati o n of i ncl usi o n a n d e xcl usi o n criteria, i ncl u di n g cli nical hist or y, a c o p y of all data c ollecti o n 
l o gs, a n d d oc u me nts o n t he use of t he st u d y a ge nt, m ust be st ore d f or as l o n g a ti me peri o d as per mitte d b y t he 
ce nter.  
 
S h o ul d t he i n vesti gat or wis h t o m o ve st u d y rec or ds t o a n ot her l ocati o n, arra n ge me nts m ust be ma de t o st ore t hese 
i n seale d c o ntai ners s o t hat t he y ca n be ret ur ne d seale d t o t he i n vesti gat or i n case of a re g ulat or y a u dit. W here 
s o urce d oc u me nts are re q uire d f or t he c o nti n ue d care of t he su bject, a p pr o priate c o pies s h o ul d be ma de f or st ora ge 
o utsi de of t he site.  
 
1 3 . 3 P R O T O C O L D E VI A TI O N S  
 
A p r ot oc ol d e viati o n is a n y n o nc o m plia nce wit h t he cli nical trial prot oc ol or  wit h  G C P . T he n o nc o m plia nce ma y 


 
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C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 4 9  of 9 9   
 
be eit her o n t he part of t he s u bject, t he i n vesti gat or, or t he st u d y site staff. W he n de viati o ns  occ ur , c orrecti ve 
acti o ns are t o be de vel o pe d b y t he site a n d  i m ple me nte d pr o m ptl y. 
 
T hese practices are c o nsiste nt wit h I C H E 6:  
• 4. 5 C o m plia nce wit h Pr ot oc ol, secti o ns 4. 5. 1, 4. 5. 2, a n d  4. 5. 3 . 
• 5. 1 Q ualit y Ass ura nce a n d Q ualit y C o ntr ol, secti o n  5. 1. 1 . 
• 5. 2 0 N o nc o m plia nce, secti o ns 5. 2 0. 1, a n d  5. 2 0. 2.  
 
Pr ot oc ol d e viati o ns will be cate g orize d as eit her M aj or or M i n or a n d will be d efi ne d i n t he st u d y -s pecific Pr ot oc o l 
De viati o n Pla n  or e q ui vale nt d oc u me nt .  
 
M aj or Pr ot oc ol De vi ati o ns  are de part ure s fr o m t he a p pr o ve d pr ot oc ol relati n g t o t he c o n d uct of t he st u d y 
w hic h ma y affect t he ri g hts, safet y , a n d/ or well bei n g of st u d y partici pa nts or t he st u d y o utc o mes or data 
q ualit y . Maj or Pr ot oc ol De viati o ns ma y res ult i n data t hat are n ot dee me d e val ua ble f or t he per pr ot oc ol  
a nal ysis a n d/ or ma y re q uire t hat s u bjects are disc o nti n ue d fr o m t he st u d y . Maj or Pr ot oc ol De viati o ns are 
Si g nifica nt Cli nical Iss ues.   
N ote : O bserv ati o ns c ate g orize d as M aj or m ay i ncl u de t h ose sit u ati o ns w here t here is a p atter n of 
devi ati o n, n u mer o us M i n or o bserv ati o ns, or ot her si g nific a nt devi ati o n. 
 
Mi n or Pr ot oc ol De vi ati o ns  are de part ures fr o m t he a p pr o ve d pr ot oc ol relati n g t o t he c o n d uct of a st u d y 
t hat d oes n ot affect t he ri g hts, safet y, a n d/ or well bei n g of st u d y partici pa nts or t he st u d y o utc o mes or data 
q ualit y . Mi n or Pr ot oc ol De viati o ns d o n ot re q uire re vie w b y t he me dical m o nit or.  Mi n or Pr ot oc ol 
De viati o ns w o ul d n ot ge nerall y precl u de  s u bject data fr o m t he per pr ot oc ol  a nal ysis p o p ulati o n.   
N O T E: persiste ntly misse d  or i nc o m plete st u dy pr oce d ures  a n d / or st u dy ev al u ati o ns will be c o nsi dere d  
M aj or Pr ot oc ol Devi ati o n s. 
 
C or o n a vir us Dise ase 2 0 1 9 ( C O VI D-1 9) Pr ot oc ol De vi ati o ns  are de part ures fr o m t he a p pr o ve d pr ot oc ol 
relate d t o t he C O VI D -1 9 pa n de mic. Wi n d o w e xte nsi o ns a n d misse d pr ot oc ol assess me nts ma y be 
per mitte d t o re d uce t he ris k of C O VI D -1 9 e x p os ure . A n y de viati o n t o t he pr ot oc ol t o re d uce t he ris k of 
C O VI D -1 9 will be ca pt ured as a “Pr ot oc ol De viati o n relate d t o C O VI D -1 9 ” t o cate g orize t he a ntici pate d 
i ncrease i n pr ot oc ol de viati o ns d ue t o t he pa n de mic. I n a d diti o n, pr ot oc ol de viati o ns ha ve bee n 
pr os pecti vel y i de ntifie d t hat ca n be i m ple me nte d t o re d uce t he ris k of e x p os ure w h ile still mai ntai ni n g 
a p pr o priate safet y m o nit ori n g a n d i nte grit y of t he st u d y data. T hese pr os pecti ve de viati o ns (e. g. wi n d o w 
assess me nts a n d misse d assess me nts) are descri be d i n Secti o n 1 5 Sc he d ule of E ve nts.  T he se meas ur es are 
te m p orar y, a n d will be re peale d as s o o n as t he sit uati o n (e. g., g o ver n me ntal r ules, be nefit/ris k assess me nt 
f or t he trial, etc.) all o ws.  
 
All de viati o ns will be l o g ge d a n d trac ke d b y t he site a n d C R O . Peri o dic re vie w of p r ot oc ol d e viati o ns will ser ve 
a n i n dicat or  of site perf or ma nce.  
 
It is t he res p o nsi bilit y of t he site t o use c o nti n u o us vi gila nce t o i de ntif y a n d re p ort de viati o ns pr o m ptl y t o t he 
st u d y C R O a n d/ or S p o ns or. All de viati o ns m ust be a d dresse d i n st u d y s o urce d oc u me nts . N otificati o n of p r ot oc ol 
d e viati o ns m ust be se nt t o t he l ocal I R B/I E C per t heir g ui deli nes . T he site i n vesti gat or/st u d y staff is res p o nsi ble 
f or k n o wi n g a n d a d heri n g t o t heir I R B/I E C re q uire me nts. 
 
1 3 . 4 P U B LI C A TI O N A N D D A T A S H A RI N G P O LI C Y  
 
I n c o m plia nce wit h T he I nter nati o nal C o m mittee of Me dical J o ur nal E dit ors (I C MJ E) cli nical trials re gistrati o n 
p olic y a n d Secti o n 8 0 1 of t he F o o d a n d Dr u g A d mi nistrati o n A me n d me nts Act of 2 0 0 7, t his st u d y will be 
re gistere d b y t he S p o ns or i n Cli nical Trials. g o v, a p u blic trials re gistr y w hic h is s p o ns ore d b y t he Nati o nal Li brar y 
of Me dici ne.  


 
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C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 5 0  of 9 9   
 
 
N ot wit hsta n di n g t he S p o ns or’s re q uire me nts f or re gistrati o n a n d data s hari n g i n Cli nical Trials. g o v, a n y f or mal 
prese ntati o n or p u blicati o n of data c ollecte d as a direct or i n direct re s ult of t his trial will be c o nsi dere d as a j oi nt 
p u blicati o n b y t he i n vesti gat or(s) a n d t he S p o ns or . I n t he case of m ultice nter st u dies, it is ma n dat or y t hat t he first 
p u blicati o n be ma de base d o n t he t otalit y of data o btai ne d fr o m all ce nters, a nal yze d as  sti p ulate d i n t he pr ot oc ol, 
a n d prese nte d a n d i nter prete d as d oc u me nte d i n t he fi nal Cli nical St u d y Re p ort . T he res ulti n g p u blicati o n will 
na me i n vesti gat ors acc or di n g t o t he p olic y of t he c h ose n j o ur nal . W here it is n ot per mitte d f or all i n vesti gat ors t o  
be i ncl u de d as a ut h ors, t he p u blicati o n will na me all i n vesti gat ors wit hi n t he p u blicati o n.  
 
I n di vi d ual i n vesti gat ors ma y p u blis h data arisi n g fr o m t heir o w n s u bjects. T he i n vesti gat or will pr o vi de t he 
S p o ns or wit h c o pies of writte n p u blicati o ns (i ncl u di n g a bstracts a n d p osters) at least 6 0 da ys i n a d va nce of 
s u b missi o n. T his re vie w is t o per mit t he S p o ns or t o re vie w t he c o m m u nicati o n f or acc urac y (t h us a v oi di n g 
p ote ntial discre pa ncies wit h s u b missi o ns t o re g ulat or y a ut h orities), t o verif y t hat c o nfi de ntia l i nf or mati o n is n ot 
i na d verte ntl y di v ul ge d (i ncl u di n g pate nt pr otecti o n), t o all o w a de q uate i n p ut or s u p ple me ntar y i nf or mati o n t hat 
ma y n ot ha ve bee n a vaila ble t o t he i n vesti gat or, a n d t o all o w esta blis h me nt of c o -a ut h ors hi p. 
 
I n vesti gat ors partici pati n g i n m ultice nter st u dies m ust a gree n ot t o e n ga ge i n prese ntati o ns base d o n data gat here d 
i n di vi d uall y or b y a s u b gr o u p of ce nters bef ore p u blicati o n of t he first mai n p u blicati o n u nless t his has bee n 
a gree d ot her wise b y all ot her i n vesti gat ors a n d t he S p o ns or . H o we ver, i n t he e ve nt t hat n o p u blicati o n of t he 
o verall res ults has bee n s u b mitte d after a p pr o val of t he Cli nical St u d y Re p ort, i n vesti gat ors ma y p u blis h res ults of 
o ne or m ore ce nter’s s u bjects t o t he sa me re vie w as o utli ne d a b o ve . T he S p o ns or will c irc ulate pr o p ose d 
m ultice nter p u blicati o ns t o all i n vesti gat ors f or re vie w.  
 
Data will be re vie we d b y all partici pati n g i n vesti gat ors pri or t o p u blicati o n . T he st u d y S p o ns or will ha ve 9 0 da ys 
t o re vie w all defi niti ve p u blicati o ns, s uc h as ma n uscri pts a n d bo o k c ha pters, a n d a mi ni m u m of 3 0 da ys t o re vie w 
all a bstracts. 
 
1 4  
FI N A N CI A L DI S C L O S U R E A N D C O N F LI C T O F I N T E R E S T P O LI C Y  
 
A se parate fi na ncial discl os ure a gree me nt will be ma de bet wee n eac h P ri nci pal In vesti gat or a n d Al ka hest, I nc. or 
its a ut h orize d re prese ntati ve bef ore t he st u d y a ge nt  is s hi p pe d. Eac h i n vesti gat or will n otif y Al ka hest, I nc. or its 
a ut h orize d re prese ntati ve of a n y rele va nt c ha n ges d uri n g t he c o n d uct of t he st u d y a n d f or 1 year after t he st u d y has 
bee n c o m plete d . Al ka hest  a n d t he st u d y C R O  will e val uate a n y  discl ose d  c o nflicts of i nterest a n d will esta blis h a 
mec ha nis m f or t he ir ma na ge me nt.  
 
 


 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 5 1  of 9 9   
 
1 5  
S C H E D U L E O F E V E N T S  
 
Scree ni n g/ B aseli ne  
Tre at me nt  
F oll o w -U p  
Visit N u m ber  
D a y  
Wi n d o w ( d a ys)a 
Wee k  
1  
-1 4 t o - 7   
2  
1  
 
3  
1 4  
± 2  
2  
4  
2 8  
± 2  
4  
5  
5 6  
± 2  
8  
6/ E O T  
8 4  
± 2  
1 2  
7  
9 8  
± 3  
1 4  
P h o ne  C all  
1 1 4  
± 2  
1 5  
I nf or me d C o nse nt1/O pti o nal C o nse nt: fecal sa m ple 
X  
 
 
 
 
 
 
 
De m o gra p hics  
X  
 
 
 
 
 
 
 
Me dical hist or y  
X  
 
 
 
 
 
 
 
I ncl usi o n/e xcl usi o n criteria 
X  
X  
 
 
 
 
 
 
Ra n d o mizati o n t o A K S T 4 2 9 0 or place b o  
 
X  
 
 
 
 
 
 
M o difie d H oe h n a n d Ya hr  
X  
 
 
 
 
 
 
 
Pr o vi de P D Q -3 9 t o be c o m plete d pri or t o ne xt visit  
X  
X  
X  
X  
X  
X  
 
 
Pr o vi de Ha user 3 -Da y Diar y f or ne xt visit 
X  
 
 
 
X  
 
 
 
C o nfir mati o n of off -me dicati o n state  
 
X  
 
X  
 
X  
X  
 
F ull p h ysical e xa mi n ati o n  
X  
 
 
 
 
 
 
 
Tar gete d p h ysical e xa mi n ati o n  
 
X  
X  
X  
X  
X  
X  
 
Vital si g ns  
X  
X  
X  
X  
X  
X  
X  
 
La b orat or y tests  
X  
X  
X  
X  
X  
X  
X  
 
Pre g na nc y testi n g 2 
X  
X  
X  
X  
X  
X  
X  
 
1 2 -lea d E C G 
X  
 
 
X  
 
X  
 
 
M D S -U P D R S Part 3 –  O ff-me dicati o n  
 
X  
 
X  
 
X  
X  
 
1 0 -meter ti me d wal k  –  O ff-me dicati o n  
 
X  
 
X  
 
X  
X  
 
A d mi nistrati o n of d o pa mi n er gic me dicati o n  
 
X  
 
X  
 
X  
X  
 
M D S -U P D R S Part 1 -4  –  O n -me dicati o n  
 
X  
X  
X  
X  
X  
X  
 
1 0 -meter ti me d wal k  –  O n -me dicati o n  
 
X  
X  
X  
X  
X  
X  
 
M o C A  
 
X  
 
 
 
X  
 
 
S E -A D L  a n d CI SI -P D  
 
X  
X  
X  
X  
X  
X  
 
S -S T S  
 
X  
 
 
 
X  
 
 
C ollect P D Q -3 9  
 
X  
X  
X  
X  
X  
X  
 
C ollect Ha user 3 -Da y Patie nt Diar y  
 
X  
 
 
 
X  
 
 
Weara ble se ns or de vice
3 
X  
X  
 
X  
X  
X  
 
 
Fecal sa m ple ( o pti o nal)  
X  
 
 
 
 
X  
 
 
Dis pe nse 5 -wee k s u p pl y of A K S T 4 2 9 0/ p lace b o 
 
X  
 
X  
X  
 
 
 
St u d y a ge nt ad mi nistrati o n 4 
 
X  
X  
X  
X  
X  
 
 
St u d y a ge nt  acc o u nta bilit y 
 
X  
X  
X  
X  
X  
 
 
P har mac o ki n etics bl o o d sa m ple 5, 6  
 
X  
X  
X  
X  
X  
X  
 
B i o mar ker plas ma ali q u ots5, 6  
 
X  
 
 
 
X  
X  
 
F A C S / C B C bl o o d sa m ple 5 
 
X  
 
 
 
X  
 
 
P har mac o ge n o mics bl o o d sa m ple (a n d o pti o nal 
D N A ba n ki n g sa m ple)  
 
X  
 
 
 
 
 
 
A d verse e ve nts  
X  
X  
X  
X  
X  
X  
X  
X  
C o nc o mita nt me dicati o ns 7 
X  
X  
X  
X  
X  
X  
X  
X  
Trial c o m pleti o n  
 
 
 
 
 
 
 
X  
 N otes:  
  a.   Wi n d o w e xte nsi o ns a n d misse d pr ot oc ol assess me nts ma y be per mitte d t o re d uce t he ris k of C O VI D -1 9 e x p os ure. A n y de viati o n t o t he pr ot oc ol t o 
re d uce t he ris k of C O VI D-1 9 e x p os ure will be ca pt ure d as a “Pr ot oc ol De viati o n relate d t o C O VI D -1 9 ” t o cate g orize t he a ntici pate d i ncrease i n 
pr ot oc ol de viati o ns d ue t o t he pa n de mic. T hese meas ures are te m p orar y, a n d will be re peale d as s o o n as t he sit uati o n (e. g., g o ver n me ntal r ules, 
be nefit/ris k assess me nt f or t he trial, etc.) all o ws  (see Secti o n 1 3. 3 ). 
1.  All patie nts m ust si g n a n i nf or me d c o nse nt c o nsiste nt wit h I C H -G C P g ui deli nes pri or t o a n y trial relate d pr oce d ures, w hic h i ncl u des me dicati o n 
was h o uts a n d restricti o ns.  


 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 5 2  of 9 9   
 
2.  Pre g na nc y testi n g ma y be perf or me d us i n g ser u m or uri ne . Test s h o ul d be perf or me d at t he site a n d res ults re vie we d . P ositi ve res ults s h o ul d be 
c o nfir m e d b y t he ce ntral la b. 
3.  A n at h o me  weara ble watc h will be pr o vi de d i n cli nic o n Visits 1, 4 a n d 5 . T he wat c h will be c ollecte d at Visits 2 , 5, a n d 6.  
4.  St u d y a ge nt ( A K S T 4 2 9 0/ place b o) will be self-a d mi nistere d i n t he cli nic u n der s u per visi o n of st u d y pers o n nel d uri n g e ver y v isit of t he treat me nt 
peri o d ( Visits 2 -6). Trai ni n g o n st u d y a ge nt  a d mi nistrati o n will be c o n d ucte d at Visit 2.  St u d y a ge nt  a d mi nistrati o n will be perf or me d after all 
assess me nts d uri n g Visit 2 a n d at visit start at re mai ni n g visits (after c ollecti o n of i nitial P K sa m ple  1 5 mi n utes pri or t o st u d y a ge nt a d mi nistrati o n , if 
a p plica ble).  Please Secti o n 7. 3  f or ti mi n g de pe n de ncies.  
5.  T h e P K  sa m ple is dra w n ~ 1 5 mi n utes pri or t o st u d y a ge nt ( A K S T 4 2 9 0/ place b o) a d mi nistrati o n at Visit s 2 -6 . Bi o mar ker a n d F A C S / C B C sa m ples are 
dra w n ~ 1 5 mi n utes pri or t o st u d y a ge nt ( A K S T 4 2 9 0/ place b o) a d mi nistrati o n at Visits 2  a n d 6.  T he P K, b i o mar ker, a n d F A C S/ C B C sa m ples are 
dra w n ~ 1 h o ur after st u d y a ge nt a d mi nistrati o n  at Visit 2.  A d diti o nal (o pti o nal ) P K sa m ples are dra w n at ~ 2 h o ur s after st u d y a ge nt  a d mi nistrati o n  at 
Visit  2 . A d diti o nal (o pti o nal ) P K sa m ples are dra w n at ~ 1 h o ur a n d ~ 2 h o ur s after st u d y a ge nt  a d mi nistrati o n at Visit s 4  a n d 6 . F or a d diti o nal 
i nf or mati o n re gar di n g ti mi n g, see Secti o n 1 7. 1 2 . 
6.  Bi o mar ker plas ma ali q u ots are dra w n fr o m t he P K  bl o o d sa m ple.  
7.  
 
 
 
 
 


 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 5 3  of 9 9   
 
1 6  
R E F E R E N C E S  
1 6 .1  P U B LI S H E D R E F E R E N C E S  
 
Al Da k heel A, Kalia L V, La n g A E . Pat h o ge nesis -tar gete d, disease-m o dif yi n g t hera pies i n Par ki ns o n disease . 
Ne ur ot hera pe utics . 2 0 1 4; 1 1: 6 -2 3.  
 
At ha u da D, Macla ga n K, S ke ne S S, Baj wa -J ose p h M, Letc hf or d D, C h o w d ur y K, et al. E xe nati de o nce wee kl y 
vers us place b o i n Par ki ns o n's disease: a ra n d o mise d, d o u ble -bli n d, place b o -c o ntr olle d trial. La ncet. 
2 0 1 7; 3 9 0( 1 0 1 0 3): 1 6 6 4 -1 6 7 5.  
 
 
 
 
 
 
 
  
 
Be n ner EJ, Ba nerjee R, Re y n ol ds A D, S her ma n S, Pisare v V M, et al. Nitrate d α -s y n uclei n i m m u nit y accelerates 
de ge nerati o n of ni gral d o pa mi ner gic ne ur o ns. P L os O ne. 2 0 0 8; 3( 1): 1 -2 0.  
 
 
 
 
 
 
 
 
Cli nical Trial Facilitati o n Gr o u p . Rec o m me n dati o ns relate d t o c o ntrace pti o n a n d pre g na nc y testi n g i n cli nical 
trials. Versi o n 2 0 1 4-0 9 -1 5: 1 -1 3.  
 
C o n n oll y B S, La n g A E . P har mac ol o gical treat me nt of Par ki ns o n disease: a re vie w. J A M A. 2 0 1 4; 3 1 1( 1 6): 1 6 7 0-
1 6 8 3.  
 
D orse y E R, Bl oe m B R . T he Par ki ns o n pa n de mic –  a call t o acti o n . J A M A Ne ur ol. 2 0 1 8; 7 5: 9-1 0.  
 
Fa h n S, Elt o n R L. U nifie d Par ki ns o n’s disease rati n g scale. I n: Fa h n S, Mars de n C D, Cal ne D, G ol dstei n M, e ds. 
Rece nt Devel o p me nts i n P arki ns o n’s Dise ase . Fl or ha m Par k: Mac milla n Healt h Care I nf or mati o n. 1 9 8 7: 1 5 3 -1 6 3 .  
 
F o o d a n d Dr u g A d mi nistrati o n ( F D A), U. S. De part me nt of Healt h a n d H u ma n Ser vices. G ui da nce f or I n d ustr y 
a n d I n vesti gat ors: Safet y Re p orti n g Re q uire me nts f or I N Ds a n d B A/ B E St u dies. Dece m ber, 2 0 1 2.  
 
G oetz C G, Tille y B C, S haft ma n S R, Ste b bi ns G T, Fa h n S , Marti nez-Marti n P, et al. M o ve me nt Dis or der S ociet y -
s p o ns ore d re visi o n of the U nite d Par ki ns o n’s Disease Rati n g Scale ( M D S -U P D R S): Scale Prese n tati o n a n d 
Cli ni metric Testi n g Res ults. M o v Dis or ders. 2 0 0 8; 2 3( 1 5): 2 1 2 9 -2 1 7 0.  
 
G ol d ma n J G, Lit va n I . Mil d c o g niti ve i m pair me nt i n Par ki ns o n’s Disease . Mi ner va Me d. 2 0 1 1; 1 0 2: 4 4 1 -4 5 9.  
 
Ha user R A, Dec kers F, Le hert P. Par ki ns o n’s disease h o me diar y: f urt her vali dati o n a n d i m plicati o ns f or cli nical 
trials. M o v Dis or ders. 2 0 0 4; 1 9: 1 4 0 9-1 4 1 3.  
 
Ha user R A, Frie dla n der J, Zesie wicz T A, A dler C H, See ber ger L C, O’ Brie n C F, et al. A h o me diar y t o assess 


 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 5 4  of 9 9   
 
f u ncti o nal stat us i n patie nts wit h Par ki ns o n’s disease wit h m ot or fl uct uati o ns a n d d ys ki nesia. Cli n 
Ne ur o p har mac ol. 2 0 0 0; 2 3: 7 5 -8 1.  
 
Hirsc h E C, H u n ot  S . Ne ur oi nfla m mati o n i n Par ki ns o n's disease: a tar get f or ne ur o pr otecti o n? La ncet Ne ur ol. 
2 0 0 9; 8: 3 8 2 -3 9 7.  
 
 
 
 
Ja n vi n C C, Larse n J P, Aarsla n d D, H u g da hl K . S u bt y pes of mil d c o g niti ve i m pair me nt i n Par ki ns o n’s disease: 
pr o gressi o n t o de me ntia . M o v Dis or d. 2 0 0 6; 2 1: 1 3 4 3 -1 3 4 9.  
 
Lalli M A, Bettc her  B M , Arcila M L , Garcia G , G uz ma n C , Ma dri gal L , et al. W h ole -ge n o me se q ue nci n g s u g gests 
a c he m o ki ne ge ne cl uster t hat m o difies a ge at o nset i n fa milial Alz hei mer's disease. M ol Ps yc hiatr y . 
2 0 1 5; 2 0: 1 2 9 4 -1 3 0 0.  
 
La n g J T, Kassa n T O, De va ne y L L, C ol o n -Se me nza C, J ose p h M E. Test -retest relia bilit y a n d mi ni mal detecta ble 
c ha n ge f or t he 1 0 -meter wal k test i n ol der a d ults wit h Par ki ns o n’s disease. J Geriatr P h y T her. 2 0 1 6; 3 9: 1 6 5 -1 7 0.  
 
  
 
Marti nez -Marti n P, F orjaz MJ, C u b o E, Fra des B, de Pe dr o C uesta J, E L E P Pr oject Me m bers . Gl o bal vers us 
fact or-relate d i m pressi o n of se verit y i n Par ki ns o n’s disease: a ne w cli ni metric i n de x ( CI SI -P D). M o v Dis or d. 
2 0 0 6; 2 1: 2 0 8 -2 1 4.  
 
M urra y C, Sa n ders o n DJ, Bar k us C, Deac o n R M, Ra wli ns J N, Ba n ner ma n C M, et al. S yste mic i nfla m mati o n 
i n d uces ac ute w or ki n g me m or y deficits i n t he pri me d brai n: rele va nce f or deliri u m. Ne ur o bi ol A gi n g. 
2 0 1 2; 3 3( 3): 6 0 3 -6 1 6.  
 
Nasre d di ne Z S, P hilli ps N A, Be diria n V, C har b o n nea u S, W hite hea d V, C olli n I,  et al . T he M o ntreal C o g niti ve 
Assess me nt, M o C A: a brief scree ni n g t o ol f or mil d c o g niti ve i m pair me nt . A m Geriatr S oc . 2 0 0 5; 5 3: 6 9 5 -6 9 9.  
 
Ola n o w C W, Ster n M B, Set hi K . T he scie ntific a n d cli nical basis f or t he treat me nt of Par ki ns o n disease ( 2 0 0 9) . 
Ne ur ol o g y. 2 0 0 9; 7 2( S u p pl 4) S 2 -S 1 3 6.  
 
Par ki ns o n J . Essa y o n t he S ha ki n g Pals y . M o n o gra p h . L o n d o n: W hitti n g ha m a n d R o wla n d f or S her w o o d, Neel y 
a n d J o nes, 1 8 1 7. 
 
Pet o V, Je n ki ns o n C, Fitz patric k R . P D Q -3 0: a re vie w of t he de vel o p me nt, vali dati o n a n d a p plicati o n of a 
Par ki ns o n’s disease q ualit y of life q uesti o n naire a n d its ass ociate d meas ures . J Ne ur ol. 1 9 9 8; 2 4 5[ S u p pl 1]: S 1 0-
S 1 4.  
 
P o st u ma R B, Ber g D, Ster n M, P oe we W, Ola n o w C W, Oertel W, et al. M D S cli nical dia g n ostic criteria f or 
Par ki ns o n’s disease . M o v Dis or d. 2 0 1 5; 3 0: 1 5 9 1 -1 5 8 8.  
 
Sa vica R, Gr ossar dt B R, R occa W A, B o wer J H . Par ki ns o n disease wit h a n d wit h o ut de me ntia: a pre vale nce st u d y 
a n d f ut ure pr ojecti o ns . M o v Dis or d. 2 0 1 8 ; 3 3: 5 3 7-5 4 3 .  
 
Sc hlac hetz ki, J C, Wi n kler  J. T he i n nate i m m u ne s yste m i n Par ki ns o n's disease: a n o vel tar get pr o m oti n g 
e n d o ge n o us ne ur ore ge nerati o n. Ne ural Re ge n Res . 2 0 1 5; 1 0: 7 0 4 -7 0 6.  
 
Sc h nei der J S, Se n de k S, Y a n g C. Relati o ns hi p bet wee n m ot or s y m pt o ms, c o g niti o n, a n d de m o gra p hic 


 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 5 5  of 9 9   
 
c haracteristics i n treate d mil d/ m o derate Par ki ns o n’s disease . P L os O N E. 2 0 1 5; 1 0( 4):e 0 1 2 3 2 3 1.  
 
Sc h wa b R S,  E n gla n d  A C . Par ki ns o n s y n dr o me d ue t o vari o us a n d s pecific ca uses . I n: Vi n ki n PJ, Br u y n, e ds. 
H a n d b o ok of Cli nic al Ne ur ol o gy . A mster da m: Else vier N ort h H olla n d. 1 9 6 8: 2 2 7 -2 4 7.  
 
Sc h wiertz A, S pie gel J, Dill ma n n U, Gr u n d ma n n D, B ür ma n n J, Fa ß be n der  K, et al. Fecal mar kers of i ntesti nal 
i nfla m mati o n a n d i ntesti nal per mea bilit y are ele vate d i n Par ki ns o n’s disease. Par ki ns o nis m Relat Dis. 
2 0 1 8; 5 0: 1 0 4 -1 0 7.  
 
S hee ha n D V, Gi d de ns J M, S hee ha n I S . S hee ha n -S uici dalit y Trac ki n g Scale ( S -S T S ) 2 0 1 4. I n n o v Cli n Ne ur osci. 
2 0 1 4; 1 1( 9 -1 0) :9 3 -1 4 0.   
 
Si n g h  Y, El -Ha di di M, A d mar d J, Wass o u f Z, Sc h ulze-He ntric h J M, K hl h ofer U, et al. E nric he d e n vir o n me ntal 
c o n diti o ns m o dif y t he g ut micr o bi o me c o m p ositi o n a n d fecal mar kers of i nfla m mati o n i n Par ki ns o n’s disease. 
Fr o nt Ne ur osci. 2 0 1 9; 1 3: 1 0 3 2.  
 
S ulzer D, Alcala y  R N , Garretti F , C ote L , Ka nter E , A gi n-Lie bes  J, et al. T cells fr o m patie nts wit h Par ki ns o n's 
disease rec o g nize al p ha -s y n uclei n pe pti des. Nat ure. 2 0 1 7; 5 4 6: 6 5 6 -6 6 1.  
 
S ve n ni n gs s o n P, West ma n E, Ballar d C, Aarsla n d D . C o g niti ve i m pair me nt i n patie nts wit h Par ki ns o n’s disease: 
dia g n osis, bi o mar kers, a n d treat me nt . La ncet Ne ur ol. 2 0 1 2; 1 1: 6 9 7 -7 0 7.  
 
Ville da S A, L u o J, M os her KI, Z o u B, Britsc h gi M, Bieri G, et al . T he a gei n g s yste mic milie u ne gati vel y 
re g ulates ne ur o ge nesis a n d c o g niti ve f u ncti o n. Nat ure. 2 0 1 1; 4 7 7: 9 0-9 4.  
 
 
 
 
 
 
 
 
 
 


 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
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2 2 M A Y 2 0 2 0  
 
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C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 5 6  of 9 9   
 
1 6 .2  U N P U B LI S H E D R E F E R E N C E S  
 
 
 
 
 
 
D S U R: D e vel o p me nt  Safet y U p date Re p ort : Al ka hest, I nc.   
 
I n vesti gat or’s Br oc h ure –  A K S T 4 2 9 0.  Al ka hest,  I nc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
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C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 5 7  of 9 9   
 
1 7  
A P P E N DI C E S  
 
T he ne ur oc o g niti ve a n d m ot or assess me nts , as well as assess me nts of acti vities i n dail y li vi n g  i n t his secti o n a n d 
ass ociate d i nf or mati o n are pr o vi de d as E X A M P L E S O N L Y . T he act ual assess me nts, relate d s o urce d oc u me nts, 
a n d i nstr ucti o ns f or a d mi nistrati o n a n d sc ori n g are i ncl u de d i n a rater refere nce ma n ual or e q ui vale nt . 
 
 


 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
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C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 5 8  of 9 9   
 
1 7. 1   M O V E M E N T DI S O R D E R S O CI E T Y ’S U NI FI E D P A R KI N S O N ’S DI S E A S E R A TI N G 
S C A L E  
 
T he M D S -U P D R S ( Fa h n 1 9 8 7 , G oetz 2 0 0 8 ) was de vel o pe d as a n eff ort t o i nc or p orate ele me nts fr o m e xisti n g 
scales t o pr o vi de a c o m pre he nsi ve b ut efficie nt a n d fle xi ble mea ns t o m o nit or P D -relate d disa bilit y a n d 
i m pair me nt. T he M D S -U P D R S has f o ur c o m p o ne nts ( Part 1 , Me ntati o n, Be ha vi or, a n d M o o d; Part 2 , Acti vities of 
Dail y Li v i n g; Part 3 , M ot or; Part 4 , C o m plicati o ns). F or  Parts  1 -3 , the rati n g f or eac h ite m is fr o m 0 ( n or mal) t o 4 
(se vere). T he t otal sc ore f or eac h Part is o bta ine d fr o m t he s u m of t he c orres p o n di n g ite m sc ores . T he esti mate d 
ti me f or c o m pleti o n of Parts 1 -3  is 2 0-3 0 mi n utes . I n Part 4 m, t he rater uses hist orical a n d o bjecti ve i nf or mati o n t o 
assess t w o m ot or c o m plicati o ns, d ys ki nesias, a n d m ot or fl uct uati o ns t hat i ncl u de off -me dical state d yst o nia.  
 
U nifie d P ar ki ns o n’s Dise ase R ati n g Sc ale ( U P D R S)  P art s 1 -4  
 
P art 1 . Acti vities of D ail y L i vi n g 
 
I ntellect u al I m p air me nt 
0 = N or mal.  
1 = Mil d . C o nsiste nt f or getf ul ness wit h partial rec ollecti o n of e ve nts a n d n o ot her diffic ulties.  
2 = M o derate  me m or y l oss, wit h dis orie ntati o n a n d m o derate diffic ult y ha n dli n g c o m ple x pr o ble ms . Mil d b ut 
defi nite i m pair me nt of f u ncti o n at h o me wit h nee d of occasi o nal pr o m pti n g.   
3 = Se vere  me m or y l oss wit h dis orie ntati o n f or ti me a n d ofte n t o place . Se vere i m pair me nt i n ha n dli n g pr o ble ms.  
4 = Se vere me m or y l oss wit h orie ntati o n preser ve d t o pers o n o nl y . U na ble t o ma ke j u d ge me nts or s ol ve pr o ble ms . 
Re q uires m uc h hel p wit h pers o nal care . Ca n n ot be left al o ne at all.  
 
T h o u g ht Dis or der ( D ue t o de me nti a or dr u g i nt o xic ati o n.)  
0 = N o ne . 
1 = Vi vi d drea mi n g.  
2 = “ Be ni g n” hall uci nati o ns wit h i nsi g ht retai ne d.   
3 = Occasi o nal t o fre q ue nt hall uci nati o ns or del usi o ns; wit h o ut i nsi g ht; c o ul d i nterfere wi t h dail y acti vities. 
4 = Persiste nt hall uci nati o ns, del usi o ns, or fl ori d ps yc h osis . N ot a ble t o care f or self.  
 
De pressi o n  
0 = N o ne.  
1 = Peri o ds of sa d ness or g uilt greater t ha n n or mal, ne ver s ustai ne d f or da ys or wee ks.  
2  = S ustai ne d de pressi o n ( 1 wee k or  m ore).   
3 = S ustai ne d de pressi o n wit h ve getati ve s y m pt o ms (i ns o m nia, a n ore xia, wei g ht l oss, l oss of i nterest).  
4 = S ustai ne d de pressi o n wit h ve getati ve s y m pt o ms a n d s uici dal t h o u g hts or i nte nt.  
 
M oti v ati o n/i niti ati ve  
0 = N or mal.  
1 = Less asserti ve t ha n us ual; m ore passi ve.  
2  = L oss of i nitiati ve or disi nterest i n electi ve ( n o nr o uti ne) acti vities.   
3 = L oss of i nitiati ve or disi nterest i n da y t o da y (r o uti ne) acti vities.  
4 = Wit h dra w n, c o m plete l oss of m oti vati o n.  
 
 
P art 2 . Acti vities of D a il y L i vi n g 
 
S peec h  
0 = N or mal.  
1 = Mil dl y affecte d. N o diffic ult y bei n g u n derst o o d.  
2 = M o deratel y affecte d. S o meti mes as ke d t o re peat state me nts.  


 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
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C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 5 9  of 9 9   
 
3 = Se verel y affecte d. Fre q ue ntl y as ke d t o re peat state me nts.  
4 = U ni ntelli gi ble m ost of t he ti me.  
  
S ali v ati o n  
0 = N or mal.  
1 = Sli g ht b ut defi nite e xcess of sali va i n m o ut h; ma y ha ve ni g htti me dr o oli n g.  
2 = M o deratel y e xcessi ve sali va; ma y ha ve mi ni mal dr o oli n g.  
3 = Mar ke d e xcess of sali va wit h s o me dr o oli n g.  
4 = Mar ke d dr o oli n g, re q uires c o nsta nt tiss ue or ha n d kerc hief.  
 
S w all o wi n g  
0 = N or mal.  
1 = Rare c h o ki n g.  
2 = Occasi o nal c h o ki n g.  
3 = Re q uires s oft f o o d.  
4 = Re q uires N G t u be or gastr ot o m y fee di n g.  
 
H a n d writi n g  
0 = N or mal.  
1 = Sli g htl y sl o w or s mall.  
2 = M o deratel y sl o w or s mall; all w or ds are le gi ble.  
3 = Se verel y affecte d; n ot all w or ds are le gi ble.  
4 = T he maj orit y of w or ds are n ot le gi ble.  
 
C utti n g F o o d a n d H a n dli n g U te nsils 
0 = N or mal.  
1 = S o me w hat sl o w a n d cl u ms y, b ut n o hel p nee de d.  
2 = Ca n c ut m ost f o o ds, alt h o u g h cl u ms y a n d sl o w; s o me hel p nee de d.  
3 = F o o d m ust be c ut b y s o me o ne b ut ca n still fee d sl o wl y.  
4 = Nee ds t o be fe d.  
 
Dressi n g  
0 = N or mal.  
1 = S o me w hat sl o w, b ut n o hel p nee de d.  
2 = Occasi o nal assista nce wit h b utt o ni n g, gett i n g ar ms i n slee ves.  
3 = C o nsi dera ble hel p re q uire d b ut ca n d o s o me t hi n gs al o ne.  
4 = Hel pless.  
 
 
H y gie ne  
0 = N or mal.  
1 = S o me w hat sl o w, b ut n o hel p nee de d.  
2 = Nee ds hel p t o s h o wer or bat he; or ver y sl o w i n h y gie nic care.  
3 = Re q uires assista nce f or was hi n g, br us hi n g teet h, c o m bi n g hair, g oi n g t o bat hr o o m.  
4 = F ole y cat heter or ot her mec ha nical ai ds.  
 
T ur ni n g i n B e d a n d A dj usti n g B e d C l ot hes 
0 = N or mal.  
1 = S o me w hat sl o w a n d cl u ms y, b ut n o hel p nee de d.  
2 = Ca n t ur n al o ne o r a dj ust s heets, b ut wit h great diffic ult y.  
3 = Ca n i nitiate, b ut n ot t ur n or a dj ust s heets al o ne.  
4 = Hel pless.  


 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
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C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 6 0  of 9 9   
 
  
F alli n g ( U nrel ate d t o F reezi n g)  
0 = N o ne.  
1 = Rare falli n g.  
2 = Occasi o nall y falls, less t ha n o nce per da y.  
3 = Falls a n a vera ge of o nce dail y.  
4 = Falls m ore t ha n o nce dail y.  
 
Freezi n g W he n W al ki n g  
0 = N o ne.  
1 = Rare freezi n g w he n wal ki n g; ma y ha ve start  hesitati o n.  
2 = Occasi o nal freezi n g w he n wal ki n g.  
3 = Fre q ue nt freezi n g. Occasi o nall y falls fr o m freezi n g.  
4 = Fre q ue nt falls fr o m freezi n g.  
 
W al ki n g  
0 = N or mal.  
1 = Mil d diffic ult y. Ma y n ot s wi n g ar ms or ma y te n d t o dra g le g.  
2 = M o derate diffic ult y b ut re q uires little or n o assista nce.  
3 = Se vere dist ur ba nce of wal ki n g, re q uiri n g assista nce.  
4 = Ca n n ot wal k at all, e ve n wit h assista nce.  
 
Tre m or ( S y m pt o m atic co m pl ai nt of tre m or i n a n y p art of b o d y.)  
0 = A bse nt.  
1 = Sli g ht a n d i nfre q ue ntl y prese nt.  
2 = M o derate; b ot hers o me t o patie nt.  
3 = Se vere; i nterferes wit h ma n y acti vities.  
4 = Mar ke d; i nterferes wit h m ost acti vities.  
 
 
Se ns or y C o m pl ai nts R el ate d t o P ar ki ns o nis m  
0 = N o ne.  
1 = Occasi o nall y has n u m b ness, ti n gli n g, or mil d ac hi n g.  
2 = Fre q ue ntl y has n u m b ness, ti n gli n g, or ac hi n g; n ot distressi n g.  
3 = Fre q ue nt pai nf ul se nsati o ns.  
4 = E xcr uciati n g pai n.  
 
P art 3 . M ot or E x a mi n ati o n  
 
S peec h  
0 = N or mal.  
1 = Sli g ht l oss of e x pressi o n, dicti o n a n d/ or v ol u me.  
2 = M o n ot o ne, sl urre d b ut u n dersta n da ble; m o deratel y i m paire d.  
3 = Mar ke d  i m pair me nt, diffic ult t o u n dersta n d. 
4 = U ni ntelli gi ble.  
 
F aci al E x pressi o n  
0 = N or mal.  
1 = Mi ni mal h y p o mi mia, c o ul d be n or mal  “ P o ker Face .” 
2 = Sli g ht b ut defi nitel y a b n or mal di mi n uti o n of facial e x pressi o n  
3 = M o derate h y p o mi mia; li ps parte d s o me of t he ti me.  
4 = Mas ke d or fi xe d facies wit h se vere or c o m plete l oss of facial e x pressi o n; li ps parte d 1/ 4 i nc h or m ore. ( hea d, 
u p per a n d l o wer e xt re mities) 


 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
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C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 6 1  of 9 9   
 
  
Tre m or at R est 
0 = A bse nt.  
1 = Sli g ht a n d i nfre q ue ntl y prese nt.  
2 = Mil d i n a m plit u de a n d persiste nt. Or m o derate i n a m plit u de, b ut o nl y i nter mitte ntl y prese nt.  
3 = M o derate i n a m plit u de a n d prese nt m ost of t he ti me.  
4 = Mar ke d i n a m plit u de a n d prese nt m ost of t he ti me.  
 
Acti o n or P ost ur al T re m or of H a n ds  
0 = A bse nt.  
1 = Sli g ht; prese nt wit h acti o n.  
2 = M o derate i n a m plit u de, prese nt wit h acti o n.  
3 = M o derate i n a m plit u de wit h p ost ure h ol di n g as well as acti o n.  
4 = Mar ke d i n a m plit u de; i nterfe res wit h fee di n g. 
 
Ri gi dit y ( J u d ge d o n p assi ve m o ve me nt of m aj or joi nts wit h p atie nt rel a xe d i n sitti n g p ositi o n. c o g w heeli n g 
t o be ig n ore d.)  
0 = A bse nt.  
1 = Sli g ht or detecta ble o nl y w he n acti vate d b y mirr or or ot her m o ve me nts.  
2 = Mil d t o m o derate.  
3 = Mar ke d, b ut f ull ra n ge of m oti o n easil y ac hie ve d.  
4 = Se vere, ra n ge of m oti o n ac hie ve d wit h diffic ult y.  
 
Fi n ger T a ps ( P atie nt ta ps th u m b wit h in de x fi n ger i n ra pi d successi o n.)  
0 = N or mal.  
1 = Mil d sl o wi n g a n d/ or re d ucti o n i n a m plit u de.  
2 = M o deratel y i m paire d. Defi nite a n d earl y fati g ui n g. Ma y ha ve occasi o nal arrests i n m o ve me nt.  
3 = Se verel y i m paire d. Fre q ue nt hesitati o n i n i nitiati n g m o ve me nts or arrests i n o n g oi n g m o ve me nt.  
4 = Ca n barel y perf or m t he tas k.  
 
H a n d m o ve me nts ( P atie nt o pe ns a n d cl oses h a n ds i n ra pi d  s uccessi o n.)  
0 = N or mal.  
1 = Mil d sl o wi n g a n d/ or re d ucti o n i n a m plit u de. 
2 = M o deratel y i m paire d. Defi nite a n d earl y fati g ui n g. Ma y ha ve occasi o nal arrests i n m o ve me nt.  
3 = Se verel y i m paire d. Fre q ue nt hesitati o n i n i nitiati n g m o ve me nts or arrests i n o n g oi n g m o ve me nt.  
4 = Ca n barel y perf or m t he tas k.  
 
R a pi d Alter n ati n g M o ve me nts o f H a n ds (P r o n ati o n-s u pi n ati o n m o ve me nts o f h a n ds, vertic all y a n d 
h oriz o nt all y, wit h a s l ar ge a n a m plit u de a s p ossi ble, b ot h h a n ds si m ult a ne o usl y.) 
0 = N or mal.  
1 = Mil d sl o wi n g a n d/ or re d ucti o n i n a m plit u de.  
2 = M o deratel y i m paire d. Defi nite a n d earl y fati g ui n g. Ma y ha ve occasi o nal arrests i n m o ve me nt.  
3 = Se verel y i m paire d. Fre q ue nt hesitati o n i n i nitiati n g m o ve me nts or arrests i n o n g oi n g m o ve me nt.  
4 = Ca n barel y perf or m t he tas k.  
 
Le g A gilit y ( P atie nt t a ps heel o n the gr o u n d in r a pi d s uccessi o n pic ki n g u p e ntire le g . A m plit u de s h o ul d be 
at le ast 3 i nc hes.)  
0 = N or mal.  
1 = Mil d sl o wi n g a n d/ or re d ucti o n i n a m plit u de.  
2 = M o deratel y i m paire d. Defi nite a n d earl y fati g ui n g. Ma y ha ve occasi o nal arrests i n m o ve me nt.  
3 = Se verel y i m paire d. Fre q ue nt hesitati o n i n i nitiati n g m o ve me nts or arrests i n o n g oi n g m o ve me nt.  
4 = Ca n barel y perf or m t he tas k.  


 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
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C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 6 2  of 9 9   
 
  
Arisi n g fr o m C h air ( P atie nt atte m pts to rise fr o m a  str ai g ht-b ac ke d c h air, wit h ar ms f ol de d acr oss c hest.)  
0 = N or mal.  
1 = Sl o w; or ma y nee d m ore t ha n o ne atte m pt.  
2 = P us hes self u p fr o m ar ms of seat.  
3 = Te n ds t o fall bac k a n d ma y ha ve t o tr y m ore t ha n o ne ti me b ut ca n get u p wit h o ut hel p.  
4 = U na ble t o arise wit h o ut hel p.  
 
P ost ure  
0 = N or mal erect.  
1 = N ot q ui te erect, sli g htl y st o o pe d p ost ure; c o ul d be n or mal f or ol der pers o n. 
2 = M o deratel y st o o pe d p ost ure, defi nitel y a b n or mal; ca n be sli g htl y lea ni n g t o o ne si de.  
3 = Se verel y st o o pe d p ost ure wit h k y p h osis; ca n be m o deratel y lea ni n g t o o ne si de.  
4 = Mar ke d f le xi o n wit h e xtre me a b n or malit y of p ost ure. 
 
G ait  
0 = N or mal.  
1 = Wal ks sl o wl y, ma y s h uffle wit h s h ort ste ps, b ut n o festi nati o n ( haste ni n g ste ps) or pr o p ulsi o n.  
2 = Wal ks wit h diffic ult y b ut re q uires little or n o assista nce; ma y ha ve s o me festi nati o n, s h ort ste ps, or pr o p ulsi o n. 
3 = Se vere dist ur ba nce of gait, re q uiri n g assista nce.  
4 = Ca n n ot wal k at all, e ve n wit h assista nce.  
 
P ost ur al S t a bilit y (R es p o nse t o s u d de n, str o n g p osteri or dis pl ace me nt pr o d uce d b y p ull o n s h o ul ders w hile 
p atie nt  erect wit h e yes o pe n a n d feet sli g htl y a p art. P atie nt is pre p are d.)  
0 = N or mal.  
1 = Retr o p ulsi o n b ut rec o vers u nai de d.  
2 = A bse nce of p ost ural res p o nse; w o ul d fall if n ot ca u g ht b y e xa mi ner.  
3 = Ver y u nsta ble, te n ds t o l ose bala nce s p o nta ne o usl y.  
4 = U na ble t o sta n d wit h o ut assista nce.  
 
B o d y B r a d y ki nesi a a n d H y p o ki nesi a ( C o m bi ni n g sl o w ness, hesit a nc y, decre ase d ar m  s wi n g, s m all 
a m plit u de, a n d p o vert y of m o ve me nt i n ge ner al.)  
0 = N o ne.  
1 = Mi ni mal sl o w ness, gi vi n g m o ve me nt a deli berate c haracter; c o ul d be n or mal f or s o me pers o ns. P ossi bl y 
re d uce d a m plit u de. 
2 = Mil d de gree of sl o w ness a n d p o vert y of m o ve me nt w hic h is defi nitel y a b n or mal. Alter nati vel y, s o me re d uce d 
a m plit u de. 
3 = M o derate sl o w ness, p o vert y or s mall a m plit u de of m o ve me nt.  
4 = Mar ke d sl o w ness, p o vert y or s mall a m plit u de of m o ve me nt.  
 
P art 4 . M ot or C o m plic ati o ns  
 
Ti me S pe nt wit h D ys ki nesi as  
0 = N or mal: N o  d ys ki nesias . 
1 = Sli g ht:  2 5 % of wa ki n g da y.  
2 = Mil d: 2 6 -5 0 % of wa ki n g da y.  
3 = M o derate : 5 1-7 5 % of wa ki n g da y.  
4 = Se vere: > 7 5 % of wa ki n g da y.  
 
F u ncti o n al I m p act of D ys ki nesi as  
0 = N or mal: N o  d ys ki nesias or n o i m pact b y d ys ki nesias o n acti vities or s ocial i nteracti o ns . 
1 = Sli g ht: D ys ki nesias i m pact a fe w acti vities, b ut patie nt is a ble t o perf or m all acti vities a n d partici pate i n all  


 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 6 3  of 9 9   
 
s ocial i nteracti o ns d uri n g d ys ki netic peri o ds. 
2 = Mil d: D ys ki nesias i m pact ma n y acti vities, b ut patie nt us uall y perf or ms all acti vities a n d partici pates i n all 
s ocial i nteracti o ns d uri n g d ys ki netic peri o ds. 
3 = M o derate : D ys ki nesias i m pact ma n y acti vities t o t he p oi nt t hat patie nt us uall y d oes n ot perf or m s o me acti vities 
or partici pate i n s o me s ocial acti vities d uri n g d ys ki netic e pis o des . 
4 = Se vere: D ys ki nesias i m pact f u ncti o n t o t he p oi nt t hat t he patie nt us uall y d oes n ot perf or m m ost acti vities or 
partici pate i n m ost s ocial i nteracti o ns d uri n g d ys ki netic e pis o des . 
 
Ti me S pe nt i n t he Off St ate  
0 = N or mal: N o  Off ti me . 
1 = Sli g ht:  2 5 % of wa ki n g da y.  
2 = Mil d: 2 6 -5 0 % of wa ki n g da y.  
3 = M o derate : 5 1-7 5 % of wa ki n g da y.  
4 = Se vere: > 7 5 % of wa ki n g da y.  
 
F u ncti o n al I m p act of Fl uct u ati o ns  
0 = N or mal: N o  fl uct uati o ns or n o i m pact b y fl uct uati o ns o n acti vities or s ocial i nteracti o ns. 
1 = S li g ht: Fl uct uati o ns i m pact o n a fe w acti vities, b ut d uri n g Off state, patie nt is a ble t o perf or m all acti vities a n d 
partici pate i n all s ocial i nteracti o ns t hat t y picall y occ ur i n t he O n state.  
2 = Mil d: Fl uct uati o ns i m pact ma n y acti vities, b ut d uri n g Off s tate, patie nt us uall y perf or ms all acti vities a n d 
partici pates i n all s ocial i nteracti o ns t hat t y picall y occ ur i n t he O n state.  
3 = M o derate : Fl uct uati o ns i m pact o n t he perf or ma nce of acti vities d uri n g t he Off state t o t he p oi nt t hat patie nt 
us uall y d oes n ot perf or m s o me acti vities or partici pate i n s o me s ocial i nteracti o ns t hat are perf or me d d uri n g 
O n peri o ds.  
4 = Se vere: Fl uct uati o ns i m pact o n f u ncti o n t o t he p oi nt t hat, d uri n g Off, t he patie nt us uall y d oes n ot perf or m m ost 
acti vities or partici pate i n m o st s ocial i nteracti o ns t hat are perf or me d d uri n g O n peri o ds. 
 
C o m ple xit y of M ot or Fl uct u ati o ns  
0 = N or mal: N o  m ot or fl uct uati o ns . 
1 = Sli g ht: Off ti mes are pre dicta ble all or al m ost all of t he ti me ( > 7 5 %). 
2 = Mil d: Off ti mes are pre dicta ble m ost of t he ti me ( 5 1 -7 5 %) . 
3 = M o derate : Off ti mes are pre dicta ble s o me of t he ti me ( 2 6 -5 0 % ). 
4 = Se vere: Off e pis o des are rarel y pre dica ble ( < 2 5 % ). 
 
P ai nf ul Off St ate D yst o ni a  
0 = N or mal: N o  d yst o nia or n o Off ti me . 
1 = Sli g ht:  2 5 % of ti me i n Off state.  
2 = Mil d: 2 6 -5 0 % of ti me i n Off state.  
3 = M o derate : 5 1-7 5 % of ti me i n Off state.  
4 = Se vere: > 7 5 % of ti me i n Off state.  
 
 


 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
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C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 6 4  of 9 9   
 
1 7. 2  M O N T R E A L C O G NI TI V E A S S E S S M E N T  
 
T he M o C A ( Nasre d di ne 2 0 0 5 ) is a c o m m o nl y use d scree ni n g test easil y a d mi nistere d b y n o n-s pecialist staff. It 
assesses t he d o mai ns of atte nti o n a n d c o nce ntrati o n, e xec uti ve f u ncti o ns, me m or y, la n g ua ge, vis u oc o nstr ucti o nal 
s kills, c o nce pt ual t hi n ki n g, calc ulati o ns, a n d orie ntati o n. T he t otal p ossi ble sc ore is 3 0 p oi nts wit h a sc ore of 2 6 or 
m ore c o nsi dere d n or mal .  
 
 
 
 
 


 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
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C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 6 5  of 9 9   
 
1 7. 3   S C H W A B A N D E N G L A N D A C TI VI TI E S O F D AI L Y LI VI N G  
 
T he S E -A D L e val uate s patie nts’ perce pti o n of gl o bal f u ncti o nal ca pacit y a n d de pe n de nce ( Sc h wa b 1 9 6 8 ). Sc ori n g 
is e x presse d i n ter ms of perce nta ge, i n 1 0 ste ps fr o m 1 0 0 t o 0 ( 1 0 0 %, n or mal stat us; 0 %, be dri d de n wit h ve getati ve 
d ysf u ncti o n), s o t hat t he l o wer t he sc ore, t he w orse t he f u ncti o nal stat us. T he rati n g is ma de b y a n 
o bser ver/ pr ofessi o nal.  
 
Sc h w a b A n d E n gl a n d Acti vities o f D ail y Li vi n g Sc ale 
 
1 0 0 % = C o m pletel y i n de pe n de nt. A ble t o d o all c h ores wit h o ut sl o w ness, diffic ult y or i m pair me nt. Esse ntiall y 
n or mal. U na ware of a n y diffic ult y.  
9 0 % = C o m pletel y i n de pe n de nt. A ble t o d o all c h ores wit h s o me de gree of sl o w ness, diffic ult y a n d i m pair me nt. 
Mi g ht ta ke t wice as l o n g. Be gi n ni n g t o be a ware of diffic ult y.  
8 0 % = C o m pletel y i n de pe n de nt i n m ost c h ores. Ta kes t wice as l o n g. C o nsci o us of diffic ult y a n d sl o w ness. 7 0 % = 
N ot c o m pletel y i n de pe n de nt. M ore diffic ult y wit h s o me c h ores. T hree t o f o ur ti mes as l o n g i n s o me. M ust 
s pe n d a lar ge part of t he da y wit h c h ores. 
6 0 % = S o me de pe n de nc y. Ca n d o m ost c h ores, b ut e xcee di n gl y sl o wl y a n d wit h m uc h eff ort. Err ors; s o me 
i m p ossi ble. 
5 0 % = M ore de pe n de nt. Hel p wit h half, sl o wer, etc. Diffic ult y wit h e ver yt hi n g. 4 0 % = Ver y de pe n de nt. Ca n assist 
wit h all c h ores, b ut fe w al o ne.  
3 0 % = Wit h eff ort, n o w a n d t he n d oes a fe w c h ores al o ne or be gi ns al o ne. M uc h hel p nee de d. 2 0 % = N ot hi n g 
al o ne. Ca n be a sli g ht hel p wit h s o me c h ores. Se vere i n vali d.  
1 0 % = T otall y de pe n de nt, hel pless. C o m plete i n vali d.  
0 %   = Ve getati ve f u ncti o ns s uc h as  s wall o wi n g, bla d der a n d b o wel f u ncti o ns are n ot f u ncti o ni n g. Be dri d de n. 
 
 


 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
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C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 6 6  of 9 9   
 
1 7. 4   C LI NI C A L I M P R E S SI O N O F S E V E RI T Y I N D E X –  P A R KI N S O N ’S DI S E A S E  
 
T he CI SI -P D is a se verit y i n de x f or me d b y f o ur ite ms ( m ot or si g ns, disa bilit y, m ot or c o m plicati o ns a n d c o g niti ve 
stat us), rate d 0 ( n ot at all) t o si x ( ver y se vere or se verel y disa ble d). A t otal sc ore is calc ulate d b y s u m mi n g t he ite m 
sc ores. T he scale is c o m plete d b y a cli nicia n at t he ti me of assess me nt . It ta kes a fe w sec o n ds t o c o m plete o nce t he 
state of t he patie nt is k n o w n ( Marti nez -Marti n 2 0 0 6 ). 
 
Cli nic al I m pressi o n of Se verit y I n de x ( CI SI -P D)  
 M ot or Si g ns  
0  
N or mal  
1  
Ver y mil d  
2  
Mil d  
3  
Mil d t o m o derate  
4  
M o derate  
5  
Se vere  
6  
Ver y se vere  
Dis a bilit y  
0  
N or mal  
1  
Mi ni mal sl o w ness a n d/ or cl u msi ness  
2  
Sl o w ness a n d/ or cl u msi ness. N o li mitati o ns  
3  
Li mitati o n f or de ma n di n g acti vities  
D oes n ot nee d hel p, or r arel y, f or b asic acti vities of d ail y li vi n g ( A D L)  
4  
Li mitati o n t o perf or m basic A D L Hel p is re q uire d f or s o me ba sic A D L 
5  
Great li mitati o n t o perf or m basic A D L Hel p is re q uire d f or m ost or all basic A D L  
6  
Se verel y disa ble d; hel pless C o m plete assista nce nee de d  
M ot or C o m plic ati o ns ( d ys ki nesi a a n d fl uct u ati o ns)  
0  
N ot at all  
1  
Ver y mil d  
2  
Mil d  
3  
Mil d t o m o derate  
4  
M o der ate 
5  
Se vere  
6  
Ver y se vere  
C o g niti ve St at us  
0  
N or mal  
1  
Mi ni mal c o g niti ve pr o ble ms  
2  
Mil d c o g niti ve pr o ble ms. N o li mitati o ns  
3  
Mil d t o m o derate c o g niti ve pr o ble ms. Li mitati o ns f or de ma n di n g acti vities. D oes n ot nee d hel p, or rarel y, 
f or basic acti vities 
4  
M o derate c o g niti ve pr o ble ms. Li mitati o ns f or basic acti vities. Hel p is nee de d f or s o me basic acti vities  
5  
Se vere c o g niti ve pr o ble ms. Ma n y li mitati o ns f or basic acti vities. Hel p is nee de d f or m ost or all basic A D L  
6  
Se verel y disa ble d; hel pless.  C o m plete a n d c o nti n ue d assista nce nee de d  
 
Sc ore  
M ot or si g ns  
 
 
 
 
 
_ _ _ _ _  
Dis a bilit y  
 
 
 
 
 
_ _ _ _ _  
M ot or C o m plic ati o ns    
 
 
 
_ _ _ _ _   
C o g niti ve St at us  
  
 
 
 
_ _ _ _ _  
CI SI -P D T ot al sc ore ( S u m of t he f o ur ite ms ( 0 -2 4)):  _ _ _ _ _  
 
  
 
 


 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
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C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 6 7  of 9 9   
 
1 7. 5   P A R KI N S O N ’S DI S E A S E Q U A LI T Y O F LI F E Q U E S TI O N N AI R E -3 9  
 
T he P D Q -3 9 is a self -a d mi nistere d q uesti o n naire of 3 9 q uesti o ns relati n g t o 8 ke y areas of healt h a n d dail y 
acti vities, i ncl u di n g b ot h m ot or a n d n o n -m ot or s y m pt o ms ( Pet o 1 9 9 8 ). T he ei g ht di me nsi o ns i ncl u de: m o bilit y, 
acti vities of dail y li vi n g, e m oti o nal well -bei n g, sti g ma, s ocial s u p p ort, c o g niti o ns, c o m m u nicati o n, a n d b o dil y 
disc o mf ort . It is sc ore d o n a scale of 0-1 0 0 wit h l o wer sc ores i n dicati n g better healt h a n d hi g h sc ores  i n dicati n g 
m ore se vere s y m pt o ms .  
 
P ar ki ns o n’s Dise ase Q u ali t y of Life Q uesti o n n aire-3 9  
 
 
 


 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
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C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 6 8  of 9 9   
 
 
 


 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
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C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 6 9  of 9 9   
 
 
 


 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 7 0  of 9 9   
 
 
 


 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
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C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 7 1  of 9 9   
 
 
 
 


 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
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C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 7 2  of 9 9   
 
1 7. 6  S H E E H A N S UI CI D A LI T Y T R A C KI N G S C A L E  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Re pri nte d wit h per missi o n fr o m S hee ha n 2 0 1 4 . 


 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
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C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 7 3  of 9 9   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Re pri nte d wit h per missi o n fr o m S hee ha n 2 0 1 4 . 


 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 7 4  of 9 9   
 
 
1 7. 7   M O V E M E N T DI S O R D E R S O CI E T Y ’S P A R KI N S O N ’S DI S E A S E C RI T E RI A  
 
 
 
 
 
Pr o vi de d f or use i n cli nical trial d oc u me ntati o n i n P ost u ma 2 0 1 5 . 


 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 7 5  of 9 9   
 
1 7. 8   H A U S E R 3 -D A Y P A TI E N T DI A R Y  
 
T he Ha user patie nt diar y (Ha user  2 0 0 0 ) was de v el o pe d t o assess f u ncti o nal stat us o ver a peri o d of ti me i n patie nts 
wit h m ot or fl uct uati o ns a n d d ys ki nesia. It is a self -c o m plete d refere nce diar y desi g ne d t o se parate d ys ki nesia t hat 
ha d a n e gati ve i m pact o n patie nt -defi ne d f u ncti o nal stat us fr o m d ys ki nesia t hat di d n ot. Wit h t his diar y, t he effect 
of a n i nter ve nti o n ca n be e x presse d as t he c ha n ge i n off -me dicati o n ti me a n d t he c ha n ge i n o n -me dicati o n ti me 
wit h tr o u bles o me d ys ki nesia ( ba d ti m e). T he s u m ca n be use d as a n o utc o me varia ble a n d c o m pare d t o baseli ne or 
acr oss gr o u ps.   
 
 
 
 
Re pri nte d wit h per missi o n fr o m Ha user 2 0 0 0 . 


 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
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C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 7 6  of 9 9   
 
1 7. 9  M O DI FI C A TI O N O F DI E T I N R E N A L DI S E A S E  F O R M U L A  
Gl o mer ular filtrati o n rate ( G F R) ma y be esti mate d base d o n t he M D R D  f or m ula:  
 
W he n ser u m creati ni ne is i n m g/ d L (c o n ve nti o nal u nits), t he G F R ma y be esti mate d base d o n t he 
f oll o wi n g M D R D f or m ula: 
G F R ( m L/ mi n/ 1. 7 3 m 2) = 1 8 6 × (ser u m creati ni ne)– 1. 1 5 4 × ( A ge) – 0. 2 0 3 × ( 0. 7 4 2 if fe male) × ( 1. 2 1 0 if 
Africa n A merica n)  
 
W he n ser u m creati ni ne i s i n μ m ol/ L ( SI u nits), t he G F R ma y be esti mate d base d o n t he f oll o wi n g 
M D R D f or m ula:  
G F R ( m L/ mi n/ 1. 7 3 m 2) = 1 8 6 × (ser u m creati ni ne/ 8 8. 4)– 1. 1 5 4 × ( A ge [ years])– 0. 2 0 3 × ( 0. 7 4 2 if fe male) × 
( 1. 2 1 0 if Africa n A merica n)  
 
 
 
 
 
 




 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
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C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 7 8  of 9 9   
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
  
 
1 7. 1 1  C LI NI C A L E V A L U A TI O N O F LI V E R I N J U R Y  
 
1 7. 1 1 . 1 I N T R O D U C TI O N 
 
Alterati o ns of li ver la b orat or y para meters,
 are t o be 
f urt her e val uate d usi n g t he pr oce d ures descri be d bel o w. 


 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 7 9  of 9 9   
 
 
 
1 7. 1 1 . 2 P R O C E D U R E S  
Re peat t he f oll o wi n g la b orat or y tests: A L T, A S T, a n d bilir u bi n (t otal a n d direct) - wit hi n 4 8 t o 7 2 h o urs a n d 
pr o vi de a d diti o nal bl o o d sa m ple t o t he ce ntral la b orat or y f or a ut o mat ic refle x testi n g of t he bel o w liste d 
la b orat or y para meters. O nl y i n cases i n w hic h t he ce ntral la b orat or y is n ot i m me diatel y a vaila ble (e. g., if t he 
l o gistics are s uc h t hat t he s u bject´s re peat s peci me n w o ul d n ot reac h t he ce ntral la b orat or y i n a reas o na ble 
ti mefra me), A L T, A S T, a n d bilir u bi n (t otal a n d direct) will be e val uate d b y t he l ocal la b orat or y a n d res ults 
will be ma de a vaila ble t o t he i n vesti gat or a n d t o Al ka hest as s o o n as p ossi ble. If A L T a n d/ or A S T > 3 -f ol d 
U L N c o m bi ne d wit h a n ele vati o n of t ot al bilir u bi n > 2 -f ol d U L N are c o nfir me d, res ults of t he la b orat or y 
para meters descri be d bel o w m ust be ma de a vaila ble t o t he i n vesti gat or a n d t o Al ka hest as s o o n as p ossi ble.  
I n a d diti o n, t he f oll o wi n g s h o ul d be re p orte d i n t he C R F: 
•  
Detaile d hist or y of c urre nt s y m pt o ms a n d c o nc urre nt dia g n oses a n d me dical hist or y acc or di n g t o t he 
DI LI C hec klist pr o vi de d i n t he I S F . 
•  
Hist or y of c o nc o mita nt dr u g use (i ncl u di n g n o n -prescri pti o n me dicati o ns, her bal a n d dietar y 
s u p ple me nt pre parati o ns), alc o h ol use, recreati o nal dr u g use, a n d s pecial diets acc or di n g t o t he DI LI 
C hec klist pr o vi de d i n t he I S F . 
•  
Hist or y of e x p os ure t o e n vir o n me ntal c he mical a ge nts (c o nsi der h o me a n d w or k place e x p os ure) 
acc or di n g t o t he DI LI C hec klist pr o vi de d i n t he I S F . 
 
1 7. 1 1 .2. 1  Cli nic al C he mistr y  
•  
O btai n a n al kali ne p h os p hatase, al b u mi n, pr ot hr o m bi n ti me  or I N R, creati ni ne ki nase ( C K), creati ni ne 
ki nase M B test ( C K -M B,) cer ul o plas mi n, α -1 a ntitr y psi n, tra nsferri n a m ylase, li pase, gl uc ose, 
c h olester ol, tri gl yceri des . 
 
1 7. 1 1 . 2. 2  Se r ol o g y 
•  
O btai n a he patitis A (a nti -i m m u n o gl o b uli n M [I g M], a nti -I G M), he patitis B ( he patitis B a nti ge n, a nti-
H Bs, D N A), he patitis C (a nti -he patitis C vir us [H C V ]), ri b o n ucleic aci d ( R N A) if a nti-H C V p ositi ve), 
he patitis D (a nti -I g M, a nti-i m m u n o gl o b uli n G [Ig G ]), he patitis E (a nti -he patitis E vir us [H E V ]), a nti-
H E V I g M, R N A if a nti -H E V I g M p ositi ve), a nti -s m o ot h m uscle a nti b o d y (titer), a nti-n uclear 
a nti b o d y (titer), a nti -li ver-ki d ne y micr os o mes ( L K M) a nti b o d y, a nti mit oc h o n drial a nti b o d y, E pstei n 
Barr vir us ( vasc ularize d c o m p osite all otra ns pla ntati o n [V C A ] I g G, V C A I g M), c yt o me gal o vir us 
(I g G, I g M), her pes si m ple x vir us (I g G, I g M), varicella (I g G, I g M), par v o vir us (I g G, I g M), 
t o x o plas m osis (I g G, I g M). 
 
1 7. 1 1 . 2. 3  H or m o nes  
•  
T h yr oi d -sti m ulati n g h or m o ne. 
 
1 7. 1 1 . 2. 4  He m at ol o g y  
•  
T hr o m b oc ytes, 
. 
 
1 7. 1 1 . 2. 5  Ultr as o u n d  


 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 8 0  of 9 9   
 
•  
Pr o vi de a n a b d o mi nal ultras o u n d t o r ule o ut biliar y tract, pa ncreatic, or i ntra he patic pat h ol o g y ( e. g., 
bile d uct st o nes or ne o plas m) . 
 
1 7. 1 1 . 2. 6 O bser v ati o n/ Re pe at Testi n g 
•  
I nitiate cl ose obser vati o n of s u bjects b y re peat testi n g of A L T, A S T, a n d t otal bilir u bi n ( wit h 
fracti o nati o n b y t otal a n d direct) at least wee kl y u ntil t he la b orat or y A L T a n d/ or A S T a b n or malities 
sta bilize or ret ur n t o n or mal, t he n acc or di n g t o t he pr ot oc ol. De pe n di n g o n  f urt her la b orat or y c ha n ges, 
a d diti o nal para meters i de ntifie d e. g., b y refle x testi n g will be f oll o we d u p base d o n me dical j u d g me nt 
a n d G C P. 
 


 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 8 1  of 9 9   
 
1 7. 1 2  P H A R M A C O KI N E TI C, BI O M A R K E R, P H A R M A C O G E N O MI C , A N D F A C S 
S A M P LI N G  
 
1 7. 1 2 . 1 T A B L E O F P H A R M A C O KI N E TI C, BI O M A R K E R, P H A R M A C O G E N O MI C , a n d F A C S 
S A M P LI N G  
 
Visit  
Ti me P oi nt  
Ti me f or 
D at a b ase 
Set u p  
P K  
Bl o o d  
E xtr a Bi o m ar ker Ali q u ot fr o m 
P K Bl o o d S a m ple  
P G X 
Bl o o d  
F A C S & 
C B C  
2  
Pri or t o ( i.e., wit hi n 1 5 mi n 
bef ore st u d y a ge nt 
a d mi nistrati o n) 
 
-0: 1 5 h  
 
X  
 
X  
 
X  
 
X  
0: 0 0  
0: 0 0 h  
St u d y a ge nt a d mi nistrati o n  
 
1: 0 0 ± 1 5  mi n utes  
1: 0 0 h  
X  
X  
 
X  
2: 0 0 ± 3 0  mi n utes  ( o pti o nal) 
2: 0 0 h  
X  
 
 
 
3  
-0 0: 1 5 mi n ( i.e., wit hi n 1 5 mi n 
bef ore st u d y a ge nt 
a d mi nistrati o n) 
 
 
 
X  
 
 
 
4  
-0 0: 1 5 mi n ( i.e., wit hi n 1 5 mi n 
bef ore st u d y a ge nt 
a d mi nistrati o n) 
 
 
 
X  
 
 
 
 
0: 0 0  
0: 0 0 h 
St u d y a ge nt a d mi nistrati o n  
1: 0 0 ± 1 5  mi n utes  ( o pti o nal) 
1: 0 0 h 
X  
 
 
 
2: 0 0 ± 3 0  mi n utes  ( o pti o nal) 
2: 0 0 h 
X  
 
 
 
5  
-0 0: 1 5 mi n ( i.e., wit hi n 1 5 mi n 
bef ore st u d y a ge nt 
a d mi nistrati o n) 
 
 
 
X  
 
 
 
 
6 
( E O T) 
-0 0: 1 5 mi n ( i.e., wit hi n 1 5 mi n 
bef ore st u d y a ge nt 
a d mi nistrati o n) 
 
 
X  
 
X  
 
 
X  
0: 0 0  
0: 0 0 h 
St u d y a ge nt a d mi nistrati o n  
1: 0 0 ± 1 5  mi n utes  ( o pti o nal) 
1: 0 0 h 
X  
 
 
 
2: 0 0 ± 3 0  mi n utes  ( o pti o nal) 
2: 0 0 h 
X  
 
 
 
7  
A n y ti me d uri n g visit –  
prefera bl y at t he e n d of all visit 
pr oce d ures  
 
 
 
X  
 
X  
 
 
 
1 7. 1 3  P H A R M A C O KI N E TI C M E A S U R E S A N D E V A L U A TI O N  
 
1 7 . 13 . 1 TI MI N G O F P H A R M A C O KI N E TI C B L O O D S A M P LI N G  
F or t he ti me sc he d ules of p har mac o ki netic bl o o d sa m ples, please refer t o  Secti o n 1 7. 1 2 . 1.  


 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 8 2  of 9 9   
 
 
1 7. 1 3 . 2 P H A R M A C O KI N E TI C S A M P L E H A N D LI N G A N D S HI P M E N T  
Met h o ds of p har mac o ki netic sa m ple c ollecti o n are descri be d i n  Secti o n 7. 2. 2. 1 . 2. F urt her i nstr ucti o ns f or 
sa m pli n g pr oce d ures, a n d f or ha n dli n g, st ora ge a n d s hi p me nt of t he sa m ples will be pr o vi de d i n t he 
La b orat or y  Ma n ual i n t he I S F .  
 
1 7. 1 3 . 3 P H A R M A C O KI N E TI C D A T A E V A L U A TI O N  
F or p har mac o ki netic a nal ysis a n d dis pla ys, c o nce ntrati o ns will be prese nte d i n t he sa me f or mat as re p orte d i n 
t he bi oa nal ytical re p ort. O nl y c o nce ntrati o ns wit hi n t he vali date d c o nce ntrati o n ra n ge a n d act ual sa m pli n g 
ti mes will be use d f or t he calc ulati o n of p har mac o ki netic para meters. 
 
1 7. 1 3 . 4 H A N D LI N G O F MI S SI N G BI O A N A L Y TI C A L D A T A  
I n t he n o nc o m part me ntal a nal ysis, c o nce ntrati o n data i de ntifie d wit h N O S, N O R, a n d N O A will n ot be 
c o nsi dere d. B L Q a n d N O P val ues i n t he la g p has e will be set t o zer o . T he la g p hase is defi ne d as t he peri o d 
bet wee n ti me zer o a n d t he first ti me p oi nt wit h a c o nce ntrati o n a b o ve t he q ua ntificati o n li mit. All ot her B L Q 
a n d/ or N O P val ues of t he pr ofile will be i g n ore d . E ver y eff ort will be ma de t o i ncl u d e all c o nce ntrati o n data 
i n a n a nal ysis. If n ot p ossi ble, a case t o case decisi o n is re q uire d w het her t he val ue s h o ul d be e xcl u de d. 
Descri pti ve statistics of c o nce ntrati o ns will be calc ulate d o nl y w he n at least 2/ 3 of t he i n di vi d uals ha ve 
c o nce ntrati o ns wi t hi n t he vali date d c o nce ntrati o n ra n ge. T he o verall sa m ple size t o deci de w het her t he ' 2/ 3' 
r ule is f ulfille d will be base d o n t he t otal n u m ber of sa m ples i nte n de d t o be dra w n f or t hat ti me p oi nt (i.e., 
B L Q, N O R, N O S, N O A, N O P are i ncl u de d) . Descri pti ve st atistics of para meters are calc ulate d o nl y w he n at 
least 2/ 3 of t he i n di vi d ual para meter esti mates of a certai n para meter are a vaila ble. 
 
 


 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 8 3  of 9 9   
 
1 8  
R E VI SI O N HI S T O R Y  
1 8. 1  S U M M A R Y O F C H A N G E S  
 
P r ot oc ol V ersi o n 4. 0  d ate d 2 2 M A Y 2 0 2 0  
Re pl aces: Pr ot oc ol V ersi o n 3 .1  d ate d 0 6 J A N 2 0 2 0  
 
T he f oll o wi n g ta ble descri bes c ha n g es fr o m V ersi o n 3. 1  ( date d 0 6J A N 2 0 2 0 ) wit h j ustificati o ns 
pr o vi de d.  
 
Secti o n  
Descri pti o n  
J ustific ati o n  
T hr o u g h o ut  
Pr ot oc ol versi o n u p date.  
Previ o usly re a d :  V 3 .1 _ 0 6J A N 2 0 2 0  
 
N o w re a ds: V 4. 0 _ 2 2 M A Y 2 0 2 0  
Versi o n c o ntr ol. 
T hr o u g h o ut  
Mi n or gra m mar, c o nte nt, a n d st yle u p dates.  
Mi n or c o nte nt u p dates f or 
clarit y/acc urac y /st yle of c o nte nt.  
Ta ble of 
C o nte nts  
Mi n or c o nte nt u p dates.  
Mi n or u p dates re q uire d t o reflect 
re vise d c o nte nt. 
P r ot oc ol 
S u m mar y, 
Sc he matic of 
St u d y Desi g n, 
4 . 1, 5. 3 
S u bject d urati o n is 1 8 wee ks  w hic h i ncl u des  
S cree ni n g (-1 4 t o -7  da ys pri or t o Baseli ne ), 
treat me nt ( 1 2 wee ks), a n d 4  wee k s of f oll o w-u p.  
C o nte nt re vise d f or acc urac y.  
Pr ot oc ol 
S u m mar y, 3, 
4. 2. 3, 7. 1. 1. 3, 
7. 1. 1. 3. 8 
(re m o ve d 
secti o n –  
s u bse q ue nt 
secti o ns 
re n u m bere d), 
7. 3, 1 5, 1 6. 1  
T he Ze n o wal k wa y assess me nt was  re m o ve d fr o m t he 
trial.  
T he Ze n o wal k wa y was n ot 
a vaila ble at a n y partici pati n g st u d y 
sites. 
5. 1  
•  
U p date d I ncl usi o n Criteri o n # 8 : 
o  Previ o usly re a d : “If o n a nti de pressa nt 
me dicati o ns, m ust be o n sta ble d osa ge f or 
at least 8 wee ks pri or t o e nr oll me nt. ” 
o  N o w re a ds: “If o n a nti de pressa nt 
me dicati o ns or ne ur ole ptic me dicati o ns, 
m ust be o n sta ble d osa ge f or at least 8 
wee ks pri or t o e nr oll me nt. ” 
 
Re m o ve d  
as a pr o hi bite d 
me dicati o n a n d i ncl u de d g ui da nce 
f or sta ble d osa ge of all ne ur ole ptic 
me dicati o ns 8 wee ks p ri or t o 
e nr oll me nt. 


 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 8 4  of 9 9   
 
5. 2  
•  
U p date d E xcl usi o n Criteri o n # 3 : 
o  Previ o usly re a d : “
 
 
 
 
 
 
o  N o w re a ds: “ 
 
 
 
 
 
 
 
•  
U p date d E xcl usi o n Criteri o n # 4 : 
o  
 
 
 
 
  
 
 
 
 
 
 
 
 
•  
U p da te d E xcl usi o n Criteri o n #5 : 
o  
 
 
 
 
 
  
 
 
 
 
 
•  
E xcl usi o n Criteri o n # 6  re m o ve d: 
o  
 
 
 
 
 
 
 
 
 
•  
E xcl usi o n Criteri o n # 7  re m o ve d: 
o  
 
 
 
E xcl usi o n re vise d t o pr o vi de 
narr o wer wi n d o w of pr o hi bite d 
me dicati o n  usa ge . 
 
 
 
 
 
 
 
 
 
 
 
U p date d e xcl usi o n  base d o n fi n di n gs 
fr o m a cli nical dr u g -dr u g i nteracti o n 
st u d y. 
 
 
 
 
 
 
 
 
 
 
U p date d e xcl usi o n  base d o n 
fi n di n gs fr o m a cli nical dr u g -dr u g 
i nteracti o n st u d y. 
 
 
 
 
 
 
 
 
Re m o ve d e xcl usi o n  base d o n 
fi n di n gs fr o m a cli nical dr u g -dr u g 
i nteracti o n st u d y. 
 
 
 
 
 
 
 
Re m o ve d e xcl usi o n  base d o n 
fi n di n gs fr o m a cli nical dr u g -dr u g 
i nteracti o n st u d y. 
 


 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 8 5  of 9 9   
 
 
 
 
•  
   E xcl usi o n Criteri o n # 8  re m o ve d: 
o  
 
 
 
 
 
 
•  
U p date d E xcl usi o n Criteri o n # 6 ( pre vi o us l y # 9): 
o  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
•  
U p date d E xcl usi o n Criteri o n # 8 ( pre vi o usl y # 1 1 ): 
o  
 
  
 
 
 
 
•  
Pre vi o us E xcl usi o n Criteri a # 1 0 a n d # 1 2 -# 2 0  
re n u m bere d t o #7 a n d # 9 -# 1 7 , res pecti vel y, a n d 
a p pr o priate cr oss -refere nce were a d de d. 
 
 
 
Re m o ve d e xcl usi o n  base d o n 
fi n di n gs fr o m a cli nical dr u g -dr u g 
i nteracti o n st u d y. 
 
 
 
 
U p date d e xcl usi o n  base d o n 
fi n di n gs fr o m a cli nical dr u g -dr u g 
i nteracti o n st u d y. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Re m o ve d  
as a pr o hi bite d 
me dicati o n a n d i ncl u de d g ui da nce 
f or sta ble d osa ge of all ne ur ole ptic 
me dicati o ns 8 wee ks pri or t o 
e nr oll me nt. 
 
Re vise d n u m beri n g f or clarit y.  
 
 
 
7. 2. 2. 1 , 7. 3, 
1 5, 1 7. 1 2  
A d diti o nal o pti o nal P K e val uati o ns were a d de d at Visit 2 
(o pti o nal P K at + 2 h o urs)  a n d Visits 4 a n d 6 ( o pti o nal P K  
sa m ples at + 1 h o ur a n d + 2 h o urs).  
N e w ( o pti o nal) sa m ple c ollecti o ns 
a n d a nal yses  were a d de d t o i m pr o ve  
P K e val uati o n . 
7. 3, 1 5  
Te xt was m o difie d f or clarit y relate d t o or der of 
assess me nts. 
Clarificati o n of t he or der ( or lac k of 
s pecifie d or der) f or partic ular 
assess me nts. 
7. 5, 1 5, 1 7. 1 0  
C o nte nt u p dates ma de t o e ns ure all re visi o ns i n t he 
E xcl usi o n Criteria relate d t o pr o hi bite d me dicati o ns  a n d 
s u bsta nces, as well as preca uti o ns  a n d m o nit ori n g , were 
c orrectl y i ncl u de d/ descri be d. 
U p date d c o nte nt  base d o n fi n di n gs 
fr o m a cli nical dr u g -dr u g i nteracti o n 
st u d y. 
 


 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 8 6  of 9 9   
 
 
P r ot oc ol V ersi o n 3. 1  d ate d 0 6 J A N 2 0 2 0  
Re pl aces: Pr ot oc ol V ersi o n 3 . 0 d ate d 0 2 D E C 2 0 1 9  
 
T he f oll o wi n g ta ble descri bes c ha n g es fr o m V ersi o n 3. 0  ( date d 0 2 D E C 2 0 1 9) wit h j ustificati o ns 
pr o vi de d.  
 
 
Pr ot oc ol V ersi o n 3. 0  d ate d 0 2 D E C 2 0 1 9  
Re pl aces: Pr ot oc ol V ersi o n 2. 0 d ate d 2 4 J U L 2 0 1 9  
 
T he f oll o wi n g ta ble descri bes c ha n g es fr o m V ersi o n 3. 0  ( date d 0 2 D E C 2 0 1 9) wit h j ustificati o ns 
pr o vi de d.  
 
1 3. 3, 1 5 , 
1 7. 1 0  
C o nte nt a d de d re: fle xi bilit y f or wi n d o w e xte nsi o ns a n d 
misse d pr ot oc ol assess me nts relate d t o C O VI D -1 9.  A n y 
de viati o n t o t he pr ot oc ol t o re d uce t he ris k of C O VI D -1 9 
will be ca pt ure d as a “ Pr ot oc ol De viati o n relate d t o 
C O VI D -1 9” t o cate g orize t he a ntici pate d i ncrease i n 
pr ot oc ol de via ti o ns d ue t o t he pa n de mic.  T hese meas ures 
are te m p orar y, a n d will be re peale d as s o o n as t he 
sit uati o n (e. g., g o ver n me ntal r ules, be nefit/ris k assess me nt 
f or t he trial, etc.) all o ws.   
Ne w c o nte nt t o acc o u nt f or p ote ntial 
pr ot oc ol de viati o ns relate d t o 
C O VI D -1 9.  
Secti o n  
Descri pti o n  
J ustific ati o n  
T hr o u g h o ut  
Pr ot oc ol versi o n u p date.  
Previ o usly re a d :  V 3 . 0_ 0 2 D E C 2 0 1 9  
 
N o w re a ds : V 3 .1 _ 0 6 J A N 2 0 2 0 
Versi o n c o ntr ol. 
T hr o u g h o ut  
Mi n or gra m mar, c o nte nt, a n d st yle u p dates.  
Mi n or c o nte nt u p dates f or 
clarit y/acc urac y /st yle of c o nte nt.  
Ta ble of 
C o nte nts  
Mi n or c o nte nt u p dates. 
Mi n or u p dates re q uire d t o reflect 
re vise d c o nte nt. 
5. 1  
T he c o ntrace pti ve met h o d “se x ual a bsti ne nce” has 
bee n re m o ve d fr o m I ncl usi o n Criteri o n #1 0  as it is 
n ot c o nsi dere d a hi g hl y effecti ve c o ntrace pti ve 
met h o d  wit h o ut s u p ple me ntati o n.  
C o n te nt re visi o n f or ali g n me nt wit h 
re g ulat or y g ui da nce re gar di n g 
hi g hl y effecti ve met h o ds of 
c o ntrace pti o n. 
8. 4. 2. 1  
Pr ot oc ol pre vi o usl y i n dicate d t hat a n S A E Re p ort 
F or m a n d S A E f oll o w -u p i nf or mati o n c o ul d be se nt  
t o 
 wit hi n 2 4 h o urs  of recei pt of 
i nf or mati o n b y t he i n vesti gati o nal site. T he 
la n g ua ge has bee n a me n de d t o i n dicate t hat t hese 
ite ms m ust be se nt i m me diatel y ( wit h o ut c ul pa ble 
dela y), b ut n o later t ha n 2 4 h o urs of recei pt of 
i nf or mati o n b y t he i n vesti gati o nal site. 
C o nte nt re vi si o n t o pr o vi de clarit y 
of ur ge nc y of re p orti n g of S A E 
Re p ort F or ms a n d f oll o w -u p 
i nf or mati o n. 
Secti o n  
Descri pti o n  
J ustific ati o n  
T hr o u g h o ut  
Pr ot oc ol versi o n u p date.  
Previ o usly re a d :  V 2. 0 _ 2 4 J U L2 0 1 9  
 
N o w re a ds : V 3 . 0_ 0 2 D E C 2 0 1 9  
Versi o n c o ntr ol. 
Ta ble of 
Mi n or c o nte nt u p dates.  
Mi n or u p dates re q uire d t o reflect 


 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 8 7  of 9 9   
 
C o nte nts  
re vise d c o nte nt. 
List of 
A b bre viati o ns  
Delete d  T B ; re vise d I R B defi niti o n, a d de d C P K 
(creati ne p h os p h o ki nase) a n d C R P ( C-reacti ve 
pr otei n).  
Mi n or u p dates re q uire d f or acc urac y 
a n d t o reflect re vise d c o nte nt. 
P r ot ocol 
S u m mar y, 
4. 2. 3 , 1 6. 1 
U p dates t o e x pl orat or y e n d p oi nt i n last b ullet:  
Previ o usly re a d :  
Pr ot oc ol S u m mar y: “ I n c o nse nti n g s u bjects ( o pti o nal): 
c ha n ges i n fecal mar kers of i ntesti nal i nfla m mati o n 
(cal pr otecti n a n d lact oferri n) a n d per mea bilit y (al p ha-1 
a ntitr y psi n a n d z o n uli n). ” 
Secti o n 4. 2. 3: “ I n c o nse nti n g s u bjects ( o pti o nal): 
c han ges i n fecal mar kers of i ntesti nal i nfla m mati o n 
(cal pr otecti n a n d lact oferri n) a n d per mea bilit y (al p ha-1 
a ntitr y psi n a n d z o n uli n ) (Sc h wiertz 2 0 1 8 ).” 
 
N o w re a ds:  
Pr ot oc ol S u m mar y: “ I n c o nse nti n g s u bjects 
( o pti o nal): c haracterizati o n of t he c o m p ositi o n a n d 
f u ncti o n of t he fecal g ut micr o bi o me.” 
Secti o n 4. 2. 3:  “ I n c o nse nti n g s u bjects ( o pti o nal): 
c haracterizati o n of t he c o m p ositi o n a n d f u ncti o n of 
t he fecal g ut micr o bi o me (S c h wiertz 2 0 1 8 , Si n g h 
2 0 1 9 ).” 
C o nte nt re vise d t o pr o vi de 
a d diti o nal fle xi bilit y i n e val uati o n of 
micr o bi o me; rece nt s u p p orti n g 
refere nce a d de d ( Si n g h 2 0 1 9). 
4. 1 , 7. 3. 1. 1, 
1 5  
C ha n ge d scree ni n g peri o d wi n d o w fr o m “ Da y -1 0 
t hr o u g h Da y -7” t o “ Da y -1 4 t hr o u g h Da y -7”  
 
Re vise d  t o all o w m ore ti me f or sites 
t o sc he d ule s u bjects. 
5 . 1 
•  I ncl usi o n Criteri o n # 1 0 : 
Previ o usly re a d:  
•  Fe male s u bjects m ust n ot be pre g na nt or 
breastfee di n g. W o me n  a n d me n  of c hil d beari n g 
p ote ntial ( W O C B P) m ust ha ve a ne gati ve 
pre g na nc y test at Scree ni n g. W O C B P a n d me n 
m ust a gree t o use hi g hl y effecti ve c o ntrace pti o n 
(Cli nical Trial Facilitati o n Gr o u p 2 0 1 4 ) pri or t o 
st u d y e ntr y. A w o ma n is c o nsi dere d of 
c hil d beari n g p ote ntial f oll o wi n g me narc he a n d 
u ntil bec o mi n g p ost me n o pa usal ( n o me nses f or at 
least 2 years wit h o ut a n alter nati ve ca use). S h o ul d 
a w o ma n bec o me pre g na nt or s us pect s he is 
pre g na nt w hile s he or her part ner is parti ci pati n g i n 
t he st u d y, s he s h o ul d i nf or m her treati n g p h ysicia n 
i m me diatel y. Male s u bjects m ust be willi n g t o use 
a barrier met h o d c o ntrace pti o n w hile partici pati n g 
i n t he st u d y.  
N o w re a ds:  
•  Fe male s u bjects m ust n ot be pre g na nt or 
breastfee di n g. W o me n of c hil d beari n g p ote ntial 
( W O C B P) m ust ha ve a ne gati ve pre g na nc y test at 
Scree ni n g. W O C B P m ust a gree t o use hi g hl y 
effecti ve c o ntrace pti o n w hic h i ncl u des c o m bi ne d 
(estr o ge n a n d pr o gest o ge n c o ntai ni n g) h or m o nal 
c o ntrace pti o n ass ociate d wit h i n hi biti o n of 
Pr o vi de d a d diti o nal details 
re gar di n g hi g hl y effecti ve 
c o ntrace pti o n . 


 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 8 8  of 9 9   
 
o v ulat i o n ( oral, i ntra va gi nal, tra ns der mal), 
pr o gest o ge n -o nl y h or m o nal c o ntrace pti o n 
ass ociate d wit h i n hi biti o n of o v ulati o n ( oral, 
i njecta ble, i m pla nta ble), i ntra uteri ne de vice, 
i ntra uteri ne h or m o ne-releasi n g s yste m, bilateral 
t u bal occl usi o n, vasect o mize d partner, or se x ual 
a bsti ne nce ( Cli nical Trial Facilitati o n Gr o u p 2 0 1 4 ) 
pri or t o st u d y e ntr y. A w o ma n is c o nsi dere d of 
c hil d beari n g p ote ntial f oll o wi n g me narc he a n d 
u ntil bec o mi n g p ost me n o pa usal ( n o me nses f or at 
least 2 years wit h o ut a n alter nati ve ca use). S h o ul d 
a w o ma n bec o me pre g na nt or s us pect s he is 
pre g na nt w hile s he or her part ner is partici pati n g i n 
t he st u d y, s he s h o ul d i nf or m her treati n g p h ysicia n 
i m me diatel y. Male s u bjects m ust be willi n g t o use 
a barrie r met h o d c o ntrace pti o n. 
5. 2  
•  
U p date d E xcl usi o n Criteri o n  # 2 t o re m o ve 
t u berc ul osis testi n g ( b y Q ua nti F E R O N testi n g) at 
scree ni n g. 
 
•  
U p date d E xcl usi o n Criteri o n # 4:  
o  
 
 
 
 
 
 
 
 
 
 
 
•  
U p date d E xcl usi o n Crit eri o n # 5: 
o  
 
 
 
 
 
 
 
 
 
 
 
•  
U p date d E xcl usi o n Criteri o n # 6:  
o  
 
 
 
 
 
 
 
 
 
 
Delete d t u berc ul osis testi n g at 
scree ni n g si nce it is n ot re q uire d. 
 
 
C o nte nt re vise d t o pr o vi de cr oss -
refere nce t o listi n g of pr o hi bite d 
me dicati o ns  a n d s u bsta nces. 
 
 
 
 
 
 
 
 
C o nte nt re vise d t o clarif y p ote ntial 
dr u g i nteracti o ns  wit h cr oss -
refere nce t o listi n g of pr o hi bite d 
me dicati o ns  a n d s u bsta nces. 
 
 
 
 
 
 
 
C o nt e nt re vise d t o clarif y p ote ntial 
dr u g i nteracti o ns  wit h cr oss -
refere nce t o listi n g of pr o hi bite d 
me dicati o ns  a n d s u bsta nces. 
 
 
 
 
 
 


 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 8 9  of 9 9   
 
 
 
 
 
 
 
 
•  
U p date d E xcl usi o n Criteri o n # 7:  
o  
 
 
 
 
 
 
 
 
 
 
 
•  
   A d de d E xcl usi o n Criteri o n # 8:  
o  
 
 
 
 
 
 
•  
Pre vi o us E xcl usi o n Criteri a # 8 -# 1 9 re n u m bere d t o 
# 9 -# 2 0  a n d a p pr o priate cr oss -refere nce were 
a d de d . 
  
 
 
 
 
 
 
 
C o nte nt re vise d t o clarif y p ote ntial 
dr u g i nteracti o ns  wit h  cr oss-
refere nce t o list of pr o hi bite d 
me dicati o ns  a n d s u bsta nces. 
 
 
 
 
 
 
 
Criteria re n u m bere d d ue t o a d diti o n 
of E xcl usi o n Criteri o n # 8  a n d cr oss -
refere nce t o list of pr o hi bite d 
me dicati o ns  a n d s u bsta nces was 
a d de d. 
 
 
 
Criteria re n u m bere d d ue t o a d diti o n 
of E xcl usi o n Criteri o n # 8 a n d cr oss -
refere nce t o list of pr o hi bite d 
me dicati o ns a n d s u bsta nces were 
a d de d, as a p p ro priate.  
 
7. 1. 1. 2. 7  
•  
Re m o ve d Ser ol o g y testi n g f or T B fr o m Bl o o d a n d 
Uri ne C ollecti o n f or La b orat or y E val ua ti o ns 
 
•  
A d de d t he f oll o wi n g e xa mi nati o ns t o C he mistr y: 
creati ne p h os p h o ki nase ( C P K), c h olester ol (t otal), 
a n d C-reacti ve pr otei n. 
P ositi ve scree ni n g f or T B is  n o 
l o n ger a n E x cl usi o n C riterio n . 
 
A d diti o n of la b orat or y tests f or 
re q uire d m o nit ori n g.  
7. 5  
C o nte nt u p dates ma de t o e ns ure all pr o hi bite d me dicati o ns  
a n d s u bsta nces , per t he re vise d E xcl usi o n Criteria, were 
descri be d . 
C o nte nt re vise d t o clarif y a d diti o nal  
pr o hi bite d me dicati o ns a n d 
s u bsta nces. 
 
8. 4. 2. 1  
S A E Re p orti n g I nf or mati o n: 
Previ o usly re a d :  
•  
“ All S A Es occ urri n g d uri n g t he st u d y s h o ul d be 
re p orte d i m me diatel y. 
•  
T he S A E Re p ort F or m a n d rele va nt s o urce 
d oc u me nts, if a p plica ble, m ust be c o m plete d 
a n d e maile d t o
wit hi n 
2 4 h o urs of o bser vati o n or l ear ni n g of t he e ve nt.  
•  
F oll o w -u p i nf or mati o n m ust be se nt t o t he C R O 
wit hi n 2 4 h o urs of recei pt of i nf or mati o n b y t he 
Ti mefra me f or Re p orti n g S A Es 
ha ve bee n u p date d t o clarif y c o ntact 
i nf or mati o n. 


 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 9 0  of 9 9   
 
 
Pr ot oc ol V ersi o n 2. 0  d ate d 2 4 J U L 2 0 1 9  
Re pl aces: Pr ot oc ol V ersi o n 1. 2  d ate d 1 7 M A Y 2 0 1 9  
 
T he f oll o wi n g ta ble descri bes c ha n g es fr o m V ersi o n 1.2  ( date d 1 7 M A Y 2 0 1 9) wit h j ustificati o ns 
pr o vi de d.  
 
i n vesti gati o nal site.” 
 
N o w re a ds:  
•  
“T he S A E Re p ort F or m a n d rele va nt s o urce 
d oc u me nts, if a p plica ble, m ust be c o m plete d a n d 
n otifie d, fa xe d, or e maile d t o  
 wit hi n 
2 4 h o urs of o bser vati o n or lear ni n g of t he e ve nt.  
o  
 
 
 
 
 
 
 
 
 
 
•  
F oll o w -u p i nf or mati o n m ust be se nt t o  
 
wit hi n 2 4 h o urs of recei pt of i nf or mati o n b y t he 
i n vesti gati o nal site.” 
 
8. 4. 2. 2  
S A E Re p orti n g I nf or mati o n:  
Previ o usly re a d : “T he S A E Re p ort F or m m ust be 
c o m plete d a n d e maile d t o
 
acc or di n g t o t he ti mefra mes s pecifie d i n  Secti o n 
8. 4. 2. 1 .” 
 
N o w re a ds : “T he S A E Re p ort F or m m ust be c o m plete d 
a n d fa xe d or e maile d t o  
 acc or di n g t o t he 
ti mefra mes s pecifie d i n Secti o n 8. 4. 2. 1 .” 
Re vise d si nce t he S A E re p orti n g 
i nf or mati o n was u p date d. 
1 7. 1 0, 
1 7. 1 0. 1  
C o nte nt a n d ta ble u p date d wit h e x pa n de d list of 
pr o hi bite d me dicati o ns a n d s u bsta nces d ue t o 
re vise d E xcl usi o n Criteria (see Secti o n 5. 2  re visi o ns 
descri be d a b o ve). 
C o nte nt  re vise d t o clarif y a d diti o nal 
pr o hi bite d me dicati o ns a n d 
s u bsta nces. 
 
1 7. 1 0. 2  
Ta ble a d de d wit h e x pa n de d list of pr o hi bite d 
me dicati o ns a n d s u bsta nces d ue t o re vise d 
E xcl usi o n Criteria (see Secti o n 5. 2  re visi o ns 
descri be d a b o ve ). 
C o nte nt de vel o pe d  t o clarif y 
a d diti o nal pr o hi bite d me dicati o ns 
a n d s u bsta nces.  
 
Secti o n  
Descri pti o n  
J ustific ati o n  
T hr o u g h o ut  
Pr ot oc ol versi o n u p date.  
Previ o usly re a d : V 1. 2 _ 1 7 M A Y 2 0 1 9  
 
N o w re a ds : V 2 . 0_ 2 4 J U L2 0 1 9  
Versi o n c o ntr ol. 
T hr o u g h o ut  
Mi n or gra m mar a n d c o nte nt u p dates.  
Mi n or gra m mar/c o nte nt u p dates f or 


 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 9 1  of 9 9   
 
clarit y/acc urac y of c o nte nt.  
Ta ble of 
C o nte nts  
Mi n or c o nte nt u p dates.  
Mi n or u p dates re q uire d t o reflect 
re vise d c o nte nt. 
List of 
A b bre viati o ns  
A d de d H B V , mI T T, a n d T B 
U p date d a b bre viati o ns t o i ncl u de 
He patitis B v ir us ( H BV) , M o difie d 
i nte nt-t o-treat ( mI T T), a n d 
T u berc ul osis  ( T B).  
Pr ot oc ol 
S u m mar y, 5 . 1 
C ha n ge d a ge ra n ge i ncl usi o n criteri o n fr o m “ 4 0 t o 
8 0 years of a ge” t o “ 5 0 t o 8 0 year s of a ge”  
Eff ort t o r e d uce n u m ber of W O C B P 
partici pati n g  i n t he st u d y t o re d uce 
pr o ba bilit y of pre g na n c y d uri n g t he 
trial. 
Pr ot oc ol 
S u m mar y, 4. 1  
N u m ber of Sites:  
Previ o usly re a d : “A p pr o xi matel y 1 0  i n t he U nite d 
States ( U S) a n d u p t o 1 0 i n Ger ma n y ” 
 
N o w re a ds : “A p pr o xi matel y 3 0 sites are pla n ne d 
gl o ball y ” 
E x pa n di n g ge o gra p hic ra n ge t o 
s u p p ort ti mel y recr uit me nt a n d 
a d diti o nal ge o gra p hic 
re prese ntati o n.   
5. 1  
U p date d I ncl usi o n Criteri o n # 1 0  f oll o ws: 
Previ o usly  re a d: 
•  
Fe male s u bjects m ust n ot be 
pre g na nt or breastfee di n g. 
W o me n of c hil d beari n g p ote ntial 
( W O C B P) m ust ha ve a ne gati ve 
pre g na nc y test at Scree ni n g. 
W O C B P a n d me n m ust a gree t o 
use hi g hl y effecti ve 
c o ntrace pti o n ( Cli nical Trial 
Facilitati o n Gr o u p 2 0 1 4 ) pri or t o 
st u d y e ntr y. Birt h c o ntr ol 
me t h o ds c o nsi dere d acce pta ble 
f or t his st u d y i ncl u de d o u ble-
barrier met h o ds; h or m o nal 
c o ntrace pti ves t hat are i njecte d, 
i m pla nte d, or ta ke n orall y; or a n 
i ntra uteri ne de vice. A w o ma n is 
c o nsi dere d of c hil d beari n g 
p ote ntial f oll o wi n g me narc he 
a n d u ntil bec o mi n g 
p ost me n o pa usal ( n o me nses f or 
at least 2 years wit h o ut a n 
alter nati ve ca use). S h o ul d a 
w o ma n bec o me pre g na nt or 
s us pect s he is pre g na nt w hile s he 
or her part ner is partici pati n g i n 
t he st u d y, s he s h o ul d i nf or m her 
treati n g p h ysicia n i m me diatel y. 
N o w  re ads:  
•  
Fe male s u bjects m ust n ot be 
pre g na nt or breastfee di n g. 
W o me n of c hil d beari n g p ote ntial 
( W O C B P) m ust ha ve a ne gati ve 
pre g na nc y test at Scree ni n g. 
Ali g n me nt w it h Cli nical T rial 
F acilitati o n G r o u p rec o m me n dati ons  
o n use of c o ntrace pti ve s i n cli nical 
trials. 


 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 9 2  of 9 9   
 
W O C B P a n d me n m ust a gree t o 
use hi g hl y effecti ve 
c o ntrace pti o n (Cli nical Trial 
Facilitati o n Gr o u p 2 0 1 4 ) pri or t o 
st u d y e ntr y. A w o ma n is 
c o nsi dere d of c hil d beari n g 
p ote ntial f oll o wi n g me narc he 
a n d u ntil bec o mi n g 
p ost me n o pa usal ( n o me nses f or 
at least 2 years wit h o ut a n 
alter nati ve ca use). S h o ul d a 
w o ma n bec o me pre g n a nt or 
s us pect s he is pre g na nt w hile s he 
or her part ner is partici pati n g i n 
t he st u d y, s he s h o ul d i nf or m her 
treati n g p h ysicia n i m me diatel y. 
Male s u bjects m ust be willi n g t o 
use a barrier met h o d 
c o ntrace pti o n w hile partici pati n g 
i n t he st u d y. 
  
5. 2  
U p date d E xcl usi o n Criteria as f oll o ws:  
 
•  E xcl usi o n Criteri o n # 2 , b ullet 5, re m o ve d: 
 
 
 
•  E xcl usi o n Criteri o n # 2 , b ullet 6 ( pre vi o usl y b ullet 7): 
Previ o usly re a d:  
•  He patic i m pair me nt.  
N o w re a ds:  
•  C urre nt, acti ve li ver disease: > 3 -f ol d ele vati o n of 
li ver e nz y mes (ala ni ne a mi n otra nsferase [ A L T] 
a n d as partate a mi n otra nsferase [ A S T] o ver u p per 
li mit of n or mal). 
 
•  E xcl usi o n Criteri o n # 2, b ullet 7 ( pre vi o usl y b ullet 8): 
Previ o usly  re a d: 
•  U nc o ntr olle d s yste mic h y perte nsi o n .  
N o w  re a ds: 
•  U nc o ntr olle d hi g h bl o o d press ure (s yst olic bl o o d 
press ure of 1 6 0 m m H g or hi g her a n d/ or diast olic 
bl o o d press ure of 1 0 0 m m H g or hi g her) des pite 
a de q uate treat me nt d uri n g t he 3 m o nt hs pri or t o 
d osi n g.  
 
•  E xcl usi o n Criteri o n # 4 : 
Previ o usly re a d:  
•  
 
 
  
N o w re a ds:  
 
 
E xcl usi o n was a carr y o ver fr o m 
earlier p hase st u d y. Warfari n a n d 
fact or Xa a ntic oa g ula nts a d de d t o 
E xcl usi o n Criteri o n # 4  as t hese are 
C Y P 3 A 4/ 5 a n d/ or P -g p s u bstrates 
t hat ha ve a narr o w t hera pe utic 
i n de x; als o clarifies t hat 
acet ylsalic ylic aci d is n ot p r o hi bite d. 
 
 
C riteri o n clarifie d wit h a d diti o nal 
descri pti ve c o nte nt  t o ai d 
i n vesti gat ors i n deter mi ni n g 
eli gi bilit y.   
 
 
 
 
 
C riteri o n clarifie d wit h a d diti o nal 
descri pti ve c o nte nt  t o ai d 
i n vesti gat ors i n deter mi ni n g 
eli gi bilit y.   
   
 
 
 
 
 


 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 9 3  of 9 9   
 
•  
 
  
 
•  E xcl usi o n Criteri o n # 7 : 
Previ o usly re a d:  
•  
 
 
  
N o w re a ds:  
•  
 
 
  
 
C riteri o n clarifie d wit h a d diti o nal 
descri pti ve c o nte nt/e xa m ple s t o ai d 
i n vesti gat ors i n deter mi ni n g 
eli gi bilit y. 
 
 
 
 
 
 
Criteri o n clarifie d t o i ncl u de  
 
t o sta n dar dize 
wit h rec o m me n dati o ns i n t he 
I n vesti gat or’s Br oc h ure.   
 
5. 4. 2  
A d de d la n g ua ge t o clarif y t hat s u bjects w h o ha ve 
wit h dra w n d ue t o a d verse dr u g e ve nts or a d verse 
reacti o ns base d o n st u d y pr oce d ures will n ot be re place d.  
Pr o vi de clarificati o n ar o u n d 
ha n dli n g of partici pa nt wit h dra wal 
a n d s u bject re place me nt. 
7. 1. 1. 1. 9, 
7. 3. 2. 1, 
7. 3. 3. 2, 
7. 3. 4. 1  
A d de d / defi ne d A d mi nistrati o n of d o pa mi ner gic 
me dicati o n as a st u d y pr oce d ure  a n d u p date d la n g ua ge i n 
t he St u d y Sc he d ule secti o ns fr o m “ C o m me nce o n-
me dicati o n state” t o “ A d mi nistrati o n of d o pa mi ner gic 
me dicati o n”  
Ali g n wit h S c he d ule of E ve nts a n d 
pr o vi de clarificati o n ar o u n d t he 
a d mi nistrati o n of d o pa mi ner gic 
me dicati o n.  
7. 1. 1. 2. 7  
A d de d Ser ol o g y testi n g f or H B V, H C V, HI V, a n d T B t o 
Bl o o d a n d Uri ne C ollecti o n f or La b orat or y E val uati o ns  
P ositi ve scree ni n g f or H B V, H C V, 
HI V, a n d / or T B is a n E x cl usi o n 
C riterio n , b ut was missi n g fr o m t he 
la b orat or y e val uati o ns.  A d de d 
detail  t o clarif y t hese assess me nts  
wil l be perf or me d at Scree ni n g. 
7. 3. 7  
A d de d defi niti o n f or e n d of trial/e n d of st u d y.  
Clarif y defi niti o n e n d of trial/e n d of 
st u d y (last patie nt last visit) vs e n d 
of treat me nt (eac h s u bject’s last 
visit) . 
7. 5  
C o nte nt u p dates ma de t o e ns ure t hat all pr o hi bite d 
me dicati o ns, per t he E xcl usi o n Criteria, were descri be d . 
F urt her clarificati o n of all pr o hi bite d 
me dicati o ns  a n d ali g n me nt wit h 
I n vesti gat or’s Br oc h ure. 
8. 1. 1  
M o dificati o n of A E defi niti o n t o re m o ve la n g u a ge t hat 
i n dicate d w orse ni n g of P D s y m pt o ms  is n ot a n A E. 
Ali g n me nt  t o l ocal la w a n d E U r ules 
( 2 0 1 1/ C/ 1 7 2/ 0 1/ E C, C T-3) 
re gar di n g defi niti o n of A E as it 
pertai n s t o worse ni n g of a pre -
e xisti n g ill ness.  
1 0. 6. 3  
A d de d a d diti o nal detail o n u n bli n di n g pr oce d ures 
i ncl u di n g h o w t o pr ocee d if t he we b -base d ra n d o mizati o n 
s yste m is n ot a vaila ble.  
P r o vi de a d diti o nal details o n 
u n bli n d pr oce d ures  
1 7. 9  
M o difie d M D R D f or m ula t o i ncl u de t w o f or m ulas.  
O ne is use d w he n  ser u m creati ni ne  res ults are 
pr o vi de d i n SI u n its  ( μ m ol/ L)  a n d t he sec o n d w he n  
ser u m creati ni ne are pr o vi de d i n c o n ve nti o nal u nits  
( m g/ d L).   
Pr o vi de clarificati o n o n w hic h 
M D R D f or m ula t o use base d o n 
u nits of ser u m creati ni ne  res ults.   
1 7. 1 0  
I ntr o d uct or y c o nte nt a n d T a ble 1 7. 1 0. 1 u p date d t o 
i ncl u de m o derate as well as str o n g C Y P 3 A 4/ 5 
a n d/ or P-g p i n hi bit ors a n d i n d ucers.  
U p date d c o nte nt f or sta n dar dizati o n 
wit h I n vesti gat or’s Br oc h ure  


 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 9 4  of 9 9   
 
 
Pr ot oc ol V ersi o n 1. 2  d ate d 1 7 M A Y 2 0 1 9  
Re pl aces: Pr ot oc ol V ersi o n 1. 1  d ate d 1 8 A P R 2 0 1 9  
 
T he f oll o wi n g ta ble descri bes c ha n g es fr o m V ersi o n 1. 1  ( date d 1 8 A P R 2 0 1 9) wit h j ustificati o ns 
pr o vi de d.  
 
Secti o n  
Descri pti o n  
J ustific ati o n  
C o ver pa ge  
A d diti o n of E u dr aC T N o.  
 
U p date A ut h orize d Re prese ntati ve fr o m J o nas 
Ha n nesta d t o Est her Ra w ner  
Re q uire d f or Ger ma n y . 
 
I nter nal pers o n nel c ha n ge  of 
res p o nsi bilities. 
T hr o u g h o ut  
Pr ot oc ol versi o n u p date.  
Previ o usly re a d : V 1. 1 _ 1 8 A P R 2 0 1 9  
 
N o w re a ds : V 1. 2 _ 1 7 M A Y 2 0 1 9  
Versi o n c o ntr ol.  
T hr o u g h o ut  
Mi n or gra m mar a n d c o nte nt u p dates.  
Mi n or gra m mar/c o nte nt u p dates f or 
clarit y/acc urac y of c o nte nt.  
Ta ble of 
C o nte nts  
Mi n or c o nte nt u p dates.  
Mi n or u p dates re q uire d t o reflect 
re vise d c o nte nt. 
List of 
A b bre viati o ns  
E M A/ E ur o pea n Me dici nes A ge nc y a n d b.i. d. /t wice 
per da y a d de d t o list of a b bre viati o ns.  
Missi n g a b bre viati o n/ defi niti o n s 
a d de d. 
State me nt of 
C o m plia nce  
A d de d E M A/ E ur o pea n Me dici nes A ge nc y t o 
c o nte nt i n b ullets 3 a n d 5.  
A d de d per re g ulat or y re q uire me nts 
f or a gl o bal st u d y wit h E ur o pea n 
sites. 
Pr ot oc ol 
S u m mar y, 4. 1  
N u m ber of Sites:  
Previ o usly re a d : “A p pr o xi matel y 1 5 i n t he U nite d 
States ( U S) a n d u p t o 1 0 i n Ger ma n y ” 
 
N o w re a ds : “A p pr o xi matel y 1 0  i n t he U nite d States 
( U S) a n d u p t o 1 0 i n Ger ma n y” 
Pr o p ose d n u m ber of sites i n t he U S 
re d uce d. 
Pr ot oc ol 
S u m mar y , 
4. 2. 2  
Sec o n dar y E n d p oi nt a d de d:  
•  Ha user 3 -Da y Patie nt Diar y . 
A d diti o n of sec o n dar y e n d p oi nt t o 
meas ure c ha n ges i n o n/ off ti me . 
Pr ot oc ol 
S u m mar y , 
4. 2. 3  
E x pl orat or y E n d p oi nt a d de d:   
•  I n c o nse nti n g s u bjects ( o pti o nal): c ha n ges i n fecal 
mar kers of i ntesti nal i nfla m mati o n (cal pr otecti n a n d 
lact oferri n) a n d per mea bilit y (al p ha-1 a ntitr y psi n a n d 
z o n uli n). 
O pti o nal fecal sa m ple a d de d f or 
assess me nt of micr o bi o me.  
2. 2  
A d diti o nal details o n d ose selecti o n a d de d.  
Pr o vi de a d diti o nal  p har mac o ki netic 
data a n d  j ustificati o n f or d ose 
selecti o n. 
2. 2  
C o nte nt a d de d re: o pti o nal fecal sa m ple  f or 
assess me nt of micr o bi o me : 
“I n a d diti o n, a n o pti o nal assess me nt  will be 
c o n d ucte d i n c o nse nti n g s u bjects t o e val uate 
p ote ntial micr o bi o me c ha n ges as assesse d b y fecal 
mar kers of i ntesti nal i nfla m mati o n (cal pr otecti n a n d 
lact oferri n) a n d per mea bilit y (al p ha-1 a ntitr y psi n 
a n d z o n uli n) at scree ni n g a n d f oll o wi n g treat me n t 
(Sc h wiertz 2 0 1 8 ).”  
A d de d descri pti ve c o nte nt re: 
o pti o nal fecal sa m ple f or assess me nt 
of micr o bi o me.  


 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 9 5  of 9 9   
 
3  
C o nte nt a d de d: re: o pti o nal fecal sa m ple f or assess me nt of 
micr o bi o me:  
“I n c o nse nti n g s u bjects, fecal sa m ples will be o btai ne d at 
scree ni n g a n d f oll o wi n g treat me nt t o assess p ote ntial 
micr o bi o me c ha n ges. “  
A d de d descri pti ve c o nte nt re: 
o pti o nal fecal sa m ple f or assess me nt 
of micr o bi o me.  
4. 1  
C o nte nt re vise d re: o pti o nal fecal sa m ple f or assess me nt 
of micr o bi o me:  
Previ o usly re a d:  
“ D uri n g t he scree ni n g peri o d ( Da y -1 0 t hr o u g h Da y -7), 
s u bjects will u n der g o all scree ni n g assess me nts t o assess 
eli gi bilit y. ” 
N o w re a ds:  
“D uri n g t he scree ni n g peri o d ( Da y -1 0 t hr o u g h Da y -7), 
s u bjects will u n der g o all scree ni n g assess me nts t o assess 
eli gi bilit y. I n c o nse nti n g s u bjects, fecal sa m ples will als o 
be c ollecte d at scree ni n g f or micr o bi o me assess me nt. ” 
A d de d descri pti ve c o nte nt re: 
o pti o nal fecal sa m ple f or assess me nt 
of micr o bi o me.  
 
 
 
 
 
 
 
5. 2  
U p date d  e xcl usi o n criteria # 2 t o i ncl u de t he f oll o wi n g:  
“ P ositi ve scree ni n g test res ult f or he patitis B, he patitis C, 
h u ma n i m m u n o deficie nc y vir us ( HI V), or t u berc ul osis ( b y 
Q ua nti F E R O N testi n g) .” 
A d de d f or a d diti o nal safet y a n d per 
re g ulat or y re q uire me nts f or a gl o bal 
st u d y wit h E ur o pea n sites. 
6. 2  
B ullet c o nte nt delete d:  
•     A vaila bilit y of a si g ne d F D A F or m(s) 1 5 7 2 a n d 
Fi na ncial Discl os ure F or m(s) f or t he pri nci pal 
i n vesti gat or a n d site s u b-i n vesti gat or(s) 
 
B ullet c o nte nt re vise d:  
Previ o usly re a d:  
•  A p pr o val of t he st u d y pr ot oc ol a n d inf or me d co nse nt 
b y t he I R B or I E C.  
 
N o w re a ds:  
•  A p pr o val of t he st u d y pr ot oc ol a n d inf or me d 
co nse nt (s) b y t he I R B or I E C.  
 
Previ o usly re a d:  
•  A p pr o val/ n otificati o n of t he a p pr o priate re g ulat or y 
a ut h orit y . 
 
N o w re a ds:  
•  A p pr o val/ n otificati o n of t he a p pr o priate re g ulat or y 
a ut h orit y (ies). 
 
C o nte nt is n ot a p plica ble t o all 
gl o bal sites; re m o ve d per re g ulat or y 
re q uest.  
 
 
C o nte nt re vise d t o reflect p ote ntial 
( o pti o nal) c o nse nt f or partici pati o n 
i n micr o bi o me assess me nt.  
 
 
 
 
 
 
C o nte nt re vise d t o reflect a d diti o n 
of E M A  as a  re g ulat or y a ut h orit y 
t hr o u g h o ut. 
7. 1. 1. 3  
C o nte nt re vise d:  
Previ o usly re a d:  
“Pr oce d ures t o assess efficac y i ncl u de m ot or a n d 
c o g niti ve f u ncti o n testi n g  a n d assess me nt of acti vities of 
dail y li vi n g . ” 
 
N o w re a ds:  
“Pr oce d ures t o assess efficac y i ncl u de m ot or a n d 
c o g niti ve f u ncti o n testi n g , assess me nt of acti vities of dail y 
C o nte nt a d de d re: fecal sa m ple 
a d de d assess me nt of micr o bi o me.  


 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 9 6  of 9 9   
 
li vi n g, a n d, i n c o nse nti n g s u bjects, micr o bi o me 
assess me nt . ” 
 
Assess me nt s a d de d: 
“ 1 0. Fecal mar kers of i ntesti nal i nfla m mati o n a n d 
per mea bilit y  ( o pti o nal).”   
“ 1 1. Ha user 3 -Da y Patie nt Diar y.”  
7. 1. 1. 3. 1 0  
C o nte nt a d de d re: assess me nt of micr o bi o me:  
“7. 1. 1. 3. 1 0  
Fecal Mar kers of I ntesti nal I nfla m mati o n 
a n d Per mea bilit y 
I ntesti nal i nfla m mati o n a n d i ncrease i ntesti nal 
per mea bilit y ( b ot h p ossi bl y f uele d b y d ys bi osis) ha ve 
bee n i m plicate d i n t he m ultifact orial pat h o ge nesis of P D 
(Sc h wiertz 2 0 1 8 ). I n c o nse nti n g s u bjects, fecal sa m ples 
will be c ollecte d at scree ni n g a n d at e n d of treat me nt  a n d 
sa m ples will be flas h fr oze n f or assess me nt. F ull 
i nf or mati o n as t o pr oce d ure f or c ollecti o n a n d pr ocessi n g 
of sa m ples will be i ncl u de d i n t he I S F. ”   
A d de d descri pti ve c o nte nt re: 
o pti o nal fecal sa m ple f or assess me nt 
of micr o bi o me.  
7. 1. 1. 3, 
7. 1. 1. 3. 1 1 , 
7. 3. 1. 1, 
7. 3. 2. 1 , 
7. 3. 3. 1, 
7. 3. 3. 2  
Descri pti o n a n d assess me nt f or  Ha user 3 -Da y  Diar y a d de d  
T he 3 -Da y Ha user Diar y assess me nt 
was a d de d t o o btai n i nf or mati o n 
re gar di n g p ote ntial f u ncti o nal 
i m pr o ve me nt a n d/ or decreases o n 
off -ti me.  
7. 3. 1 . 1, 
7. 3. 3. 2  
O pti o nal fecal sa m ple a d de d.  
O pti o nal fecal sa m ple c ollect i o n 
a d de d f or assess me nt of 
micr o bi o me.  
7. 5  
A d diti o nal details o n pr o hi bite d me dicati o ns, treat me nts, 
a n d me dicati o ns a d de d.  
Pr o vi de clarificati o n o n pr o hi bite d 
oral s u p ple me nts.  
8. 4. 2. 1 , 
8. 5  
E M A a d de d t o c o nte nt. 
A d de d per re g ulat or y re q uire me nts 
f or a gl o bal st u d y wit h E ur o pea n 
sites. 
1 0. 3  
E val ua ble defi niti o n a d de d a n d clarificati o n t o 
mI T T/ E val ua ble set a d de d  
A d diti o n o f e val ua ble defi niti o n. 
1 3. 1. 1  
Previ o usly re a d:  “S u b -i n vesti gat ors as liste d o n F or m 
F D A 1 5 7 2, or ot her a ut h orize d st u d y pers o n nel are 
eli gi ble t o si g n f or t he i n vesti gat or, e xce pt w here t he 
i n vesti gat or’s si g nat ure is s pecificall y re q uire d.” 
 
N o w re a ds:  “S u b -i n vesti gat ors or ot her a ut h orize d st u d y 
pers o n nel are eli gi ble t o si g n f or t he i n vesti gat or, e xce pt 
w here t he  i n vesti gat or’s si g nat ure is s pecificall y 
re q uire d.” 
C o nte nt is n ot a p plica ble t o all 
gl o bal sites; re m o ve d per re g ulat or y 
re q uest. 
1 5  
Ha user 3 -Da y Patie nt Diar y a d de d t o pr o vi de 
q uesti o n naire at V 1 a n d V 5 a n d f or c ollecti o n of t he 
q uesti o n naire at V 2 a n d V 6  
 
O pti o nal c o nse nt f or fecal sa m ple a n d fecal sa m ple 
c ollecti o n (at scree ni n g [ V 2] a n d Visit 6 / E O T).  
A d diti o n of sec o n dar y e n d p oi nt t o 
meas ur e c ha n ges i n o n/ off ti me.  
 
 
 
O pti o nal fecal sa m ple c o nse nt a n d 
c ollecti o n a d de d f or assess me nt of 
micr o bi o me.  
1 6. 1 , 1 6. 2 
F ull refere nce s f or A L K 4 2 9 0 -1 0 1, Ha user 2 0 0, Ha user 
Ne w  refere nces a d de d t o list. 


 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 9 7  of 9 9   
 
 
 
Pr ot oc ol V ersi o n 1. 1 d ate d 1 8 A P R 2 0 1 9  
Re pl aces: Pr ot oc ol V ersi o n 1. 0 d ate d 1 0 J A N 2 0 1 9  
 
T he f oll o wi n g ta ble descri bes c ha n g es fr o m V ersi o n 1. 0 ( date d 1 0J A N 2 0 1 9) wit h j ustificati o ns 
pr o vi de d.  
 
2 0 0 4, Sc h wiertz 2 0 1 8 , a d de d t o list. 
F ull refere nce f or Ha user et all ( 2 0 0 0, 2 0 0 4)  a d de d t o list. 
 
 
 
1 7. 8  
I nserti o n of ne w A p pe n di x f or Ha user 3-Da y Diar y . 
S u bse q ue nt a p pe n dices, 1 7. 8 t hr o u g h 1 7. 1 2, se q ue ntiall y 
re n u m bere d t hr o u g h o ut pr ot oc ol. 
A d diti o n of A p pe n di x f or 3 -Da y 
Ha user Diar y . 
Secti o n  
Descri pti o n  
J ustific ati o n  
T hr o u g h o ut  
Pr ot oc ol versi o n u p da te.  
Previ o usly re a d : V 1. 0 _ 1 0J A N 2 0 1 9  
 
N o w re a ds : V 1. 1 _ 1 8 A P R 2 0 1 9  
Versi o n c o ntr ol.  
T hr o u g h o ut  
Mi n or gra m mar a n d c o nte nt u p dates.  
Mi n or gra m mar/c o nte nt u p dates f or 
clarit y/acc urac y of c o nte nt.  
Ta ble of 
C o nte nts  
Mi n or c o nte nt u p dates.  
Mi n or u p dates re q uire d t o reflect 
re vise d c o nte nt. 
List of 
A b bre viati o ns  
 w A M D / Wet a ge-relate d mac ular de ge nerati o n 
a d de d t o list of a b bre viati o ns.  
Missi n g a b bre viati o n / defi niti o n 
a d de d. 
Pr ot oc ol 
S u m mar y,  
4. 1  
N u m ber of Sites:  
Previ o usly re a d : “ A p pr o xi matel y 2 0 i n t he U nite d 
States ( U S) ” 
 
N o w re a ds : “A p pr o xi matel y 1 5 i n t he U nite d States ( U S) 
a n d u p t o 1 0 i n Ger ma n y ” 
N u m ber of site s i n U S re d uce d a n d 
u p t o 1 0 sites i n Ger ma n y a d de d.  
2. 3. 1  
Se nte nce re gar di n g trials:  
Previ o usly re a d : “ I n o ur o n g oi n g  E ur o pea n st u dies 
i n treat me nt-naï ve a n d refract or y s u bjects wit h 
w A M D …”  
 
N o w re a ds : “I n o ur rece ntl y c o m plete d E ur o pea n st u dies 
i n treat me nt-naï ve a n d refract or y s u bjects wit h 
w A M D …”  
C o nte nt u p date d t o i n dicate t hat 
st u dies i n w A M D ha ve bee n 
c o m plete d.  
5. 1, 5. 2  
Pre vi o us I ncl usi o n Criteria # 9 re m o ve d a n d i ncl u de d as 
E xcl usi o n Criteria # 8.  
 
 
 
C urre nt I ncl usi o n Criteria # 1 0:  
Previ o usly re a d:  “ … pri or t o st u d y e ntr y. A w o ma n is 
c o nsi dere d of c hil d beari n g p ote ntial f oll o wi n g me narc he 
a n d u ntil bec o mi n g p ost me n o pa usal ( n o me nses f or at 
least 2 years wit h o ut a n alter nati ve ca use). S h o ul d a 
w o ma n bec o me pre g na nt or s us pect s he is pre g na nt w hile 
s he or her part ner is partici pati n g i n t he st u d y, s he s h o ul d 
Re nal f u ncti o n re q uire me nts were 
pre vi o usl y s plit bet wee n 
I ncl usi o n/ E xcl usi o n Criteria, b ut are 
n o w c o m bi ne d t o pre ve nt c o nf usi o n.  
 
C o nte nt u p date d t o reflect gl o bal 
re g ulat or y re q uire me nts.  
 
 
 
 
 


 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 9 8  of 9 9   
 
i nf or m her treati n g p h ysicia n i m me diatel y.” 
 
N o w re a ds:  “ … pri or t o st u d y e ntr y. Birt h c o ntr ol met h o ds 
c o nsi dere d acce pta ble f or t his st u d y i ncl u de d o u ble -
barrier met h o ds; h or m o nal c o ntrace pti ves t hat are 
i njecte d, i m pla nte d, or ta ke n orall y; or a n i ntra uteri ne 
de vice. A w o ma n is c o nsi dere d of c hil d beari n g p ote ntial 
f oll o wi n g me narc he a n d u ntil bec o mi n g p ost me n o pa usal 
( n o me nses f or at least 2 years wit h o ut a n alter nati ve 
ca use). S h o ul d a w o ma n bec o me pre g na nt or s us pect s he 
is pre g na nt w hile s he or her part ner is partici pati n g i n t he 
st u d y, s he s h o ul d i nf or m her treati n g p h ysicia n 
i m me diatel y.” 
 
B ullet s 2  a n d 9 u p date d i n E xcl usi o n Criteria # 2  
Previ o usly re a d:  “
 
  
 
N o w re a ds : “
 
  
 
Previ o usly re a d:  “P ositi ve scree ni n g f or  he patitis B, 
he patitis C, or h u ma n i m m u n o def icie nc y vir us ( HI V)” 
 
N o w re a ds: “K n o w n i nfecti o n wit h he patitis B, he patitis 
C, or h u ma n i m m u n o deficie nc y vir us ( HI V).” 
 
E xcl usi o n Criteria # 8:  
Previ o usly re a d : “ …
 
 
 
N o w re a ds:  “ …
 
 
 
B ullet 3 a d de d t o c urre nt E xcl usi o n Criteria # 1 1:  
“I ncl usi o n of v ul nera ble pers o ns b y l ocal re g ulati o n ( e. g., 
i m pris o ne d or i nstit uti o nalize d).” 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C larificati o n of e xcl usi o n criteria 
a n d p u nct uati o n a d de d.  
 
 
 
 
 
 
 
 
 
 
 
 
C larificati o n of e xcl usi o n criteria. 
 
 
 
 
 
 
C o nte nt u p date d t o reflect gl o bal 
re g ulat or y re q uire me nts. 
 
5. 4. 1, 1 2. 3. 2, 
1 2. 5  
C o nte nt relate d t o “s u bject’s le gall y a ut h orize d 
re prese ntati ve” re m o ve d. 
S u bject s m ust be a ble t o pr o vi de 
c o nse nt; a s u bject’s le gall y 
a ut h orize d re prese ntati ves will n ot 
be all o we d t o pr o vi de c o nse nt 
a n d/ or ma ke decisi o ns o n be half of 
t he s u bject. 
7. 1. 1. 1, 
7. 1. 1. 1. 1, 
7. 3. 1, 1 5  
“ H oe h n a n d Ya hr” assess me nt c ha n ge d t o “ m o difie d 
H oe h n a n d Ya hr” assess me nt .  
C o nte nt u p date d t o reflect acc urate 
ter mi n ol o g y f or assess me nt. 
7. 1. 1. 1. 6  
C o nte nt re gar di n g t he ne ur ol o gical e xa m: 
Previ o usly re a d:  “T he ne ur ol o gical e xa m will i ncl u de 
cra nial ner ves ( vis ual fiel ds, f u n d osc o pic e xa m, p u pillar y 
li g ht refle x, e xtra oc ular m uscles, facial se nsati o n a n d 
s y m metr y, palate a n d t o n g ue, a n d hea d t ur ni n g a n d 
C o nte nt a d de d t o pr o vi de 
clarificati o n o n c o m p o ne nts of t he 
ne ur ol o gical e xa m.  


 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 9 9  of 9 9   
 
 
s h o ulder s hr u g); m uscle stre n gt h, t o ne, a n d b ul k; refle xes 
( bice ps, trice ps, k nees, a n kles, a n d pla ntar); c o or di nati o n 
(fi n ger-t o-n ose, heel -k nee -s hi n); se ns or y f u ncti o n (li g ht 
t o uc h a n d pi n pric k); a n d gait. ”   
 
N o w re a ds:   “T he ne ur ol o gical e xa m will i ncl u de  cra nial 
ner ves ( vis ual fiel ds, f u n d osc o pic e xa m, p u pillar y li g ht 
refle x, e xtra oc ular m uscles, facial se nsati o n a n d 
s y m metr y, palate a n d t o n g ue, a n d hea d t ur ni n g a n d 
s h o ul der s hr u g); m uscle stre n gt h, t o ne, b ul k, a n d 
a b n or mal m o ve me nts ; refle xes ( bice ps, trice ps, k nees, 
a n kles, a n d pla ntar); c o or di nati o n (fi n ger -t o-n ose, heel -
k nee -s hi n); se ns or y f u ncti o n (li g ht t o uc h, pi n pric k , a n d 
vi brati o n ); a n d gait.”   
7. 3. 3. 2  
S u b -b ullet # 2 u n d er “ Assess me nts t o be c o n d ucte d i n t he 
o n -me dicati o n state”:  
Previ o usly re a d :“ M o C A ” 
 
N o w re a ds : “M o C A ( Visit 6 O nl y )” 
C o nte nt u p date d t o reflect t hat 
M o C A will be c o n d ucte d a t Visit 6 
o nl y , rat her t ha n at Visit 4 a n d Visit 
6  as n ote d i n t he pre vi o us versi o n . 
1 5  
M o C A at Visit 4 re m o ve d.  
Assess me nt was n ot re q uire d at 
Visit 4.  
1 6. 1  
F ull refere nce f or At ha u da et al 2 0 1 7 a d de d t o list.  
Missi n g refere nce a d de d t o list.