Clinical trial NCT02727699
Conditions: Dementia, Alzheimer Type
Keywords: Dementia Alzheimer's Disease Xanamem UE2343 (Laboratory Code for Xanamem) Cortisol XanADu Actinogen 11β-HSD1 11-beta-Hydroxysteroid Dehydrogenase Type 1 Mild Alzheimer's Disease Cognitive Impairments emestedastat
Sponsor: Actinogen Medical
Start date: 2017-03-23; Completion date: 2019-03-15
Enrollment: 185 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This XanADu Phase II study in mild Alzheimer's Disease (AD) is to assess the safety, tolerability and efficacy of Xanamem in subjects with mild dementia due to Alzheimer's Disease. Subjects will be randomized to receive either 10mg once daily Xanamem or Placebo at a 1:1 ratio in a double-blinded fashion.

Detailed description:
This is a Phase II, randomised, multi-centre, double-blind, placebo-controlled proof-of-concept study to assess the safety, tolerability and efficacy of oral Xanamem once daily in adult subjects with mild dementia due to AD.

Based on Xanamem's mode of action on hippocampal function, amnestic symptoms may respond best, thus favouring the inclusion of mild dementia due to AD, with given evidence of disease progression. Subjects will be treated in a double-blind fashion, where both the investigators and subjects will be unaware of the treatment assignments, to minimise any subjective or unrecognised bias carried by the investigators and subjects. Placebo will be used as the comparator in this study.

It is planned to randomise approximately 174 subjects at approximately 25 study sites in three countries (Australia, United Kingdom, and United States), with the aim to enrol 7 to 10 subjects at each study site. Subject enrolment will be competitive but a cap of 20 subjects per study site is to be established to avoid any side effects. In case the sample composition at one study site is creating concerns, an enrolment stop can also occur at fewer than 20 subjects.

At study end, a total of 185 subjects were randomised into this study and received active treatment.

The data safety monitoring board (DSMB) will periodically meet for the review of accumulating safety study data and will also be involved in the interim analysis.

At the Baseline visit (Week 0), eligible subjects will be randomised on a 1:1 ratio to receive either Xanamem administered orally once daily (QD) for the treatment group or matching placebo for the placebo group. Subjects will return to the study site for visits at Week 4 and Week 8, End of Treatment (Week 12) and Follow-up (4 weeks post last dose of study drug) visits, at which study assessments will be performed.

Ad hoc telephone contact may also occur at any other time-point throughout the study, if deemed necessary by the investigator/study nurse, or if the subject wishes to report an Adverse Event (AE)

Subjects will be interviewed and examined at the study site at each visit and will complete a variety of questionnaires and routine safety evaluations.

Optional Pharmacodynamic (PD) sampling will be performed at specific visits. Subjects who do not provide consent for this optional sub-study will still be eligible for the main study.

The overall study duration for an individual subject will be 17 to 20 weeks, including a screening period of one to 4 weeks, a double-blind treatment period of 12 weeks, and a follow-up period of 4 weeks. The total duration of the study is expected to be 2 years.

Arms: arm 1: Oral Xanamem™ capsules 10mg, to be administered once daily arm 2: Matching placebo which is identical in appearance to the test product except that it contains no active ingredient, to be administered once daily
Interventions: intervention 1: Xanamem™ intervention 2: Placebo (for Xanamem™)
Intervention descriptions: intervention 1: Xanamem™ is formulated in green and cream coloured size 3, Coni-Snap shaped gelatin capsules as an excipient blend at a dose of 10mg. It contains active pharmaceutical ingredient of UE2343 intervention 2: Excipient blend capsules manufactured to mimic Xanamem™ capsules

Protocol documents:
SAP_002.pdf: 
 
 
CONFIDENTIAL 
Page 1 of 59 
 
 
 
 
Actinogen Medical 
Protocol Number: ACW0002 
 
 
 
 
XanADu: A Phase II, Double-Blind, 12-Week, Randomised, 
Placebo-Controlled Study to Assess the Safety, Tolerability and 
Efficacy of Xanamem™ in Subjects with Mild Dementia due to 
Alzheimer’s Disease (AD) 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
Version: Final V3.0 
 
Date: 22MAR2019 
 
 
 
 
 
 
 
 
 
ICON Study Number 3580/0001 






 
 
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REVISION HISTORY 
 
Date 
Version 
Description 
Author 
26Apr2016 
Draft V0.1 
Initial Draft 
Sunoj Chacko Varughese 
28FEB2017 
Draft V0.2 
Updated as per Amended protocol Amendment 
2; 24-Nov-2016 
Ramesh Vishwakarma 
06MAR2017 
Draft V0.3 
Updated as per Peer reviewer’s comments 
Ramesh Vishwakarma 
16MAR2017 
Draft V0.4 
Updated as per internal reviewer’s comments 
Ramesh Vishwakarma 
20MAR2017 
Final V 1.0 
Final 
HyeJung Ko 
28NOV2017 
Final V 2.0 
Updated as per Amended protocol Amendment 
4; 16-Oct-2017 
Prasanth Sasidharan 
05Jan2018 
Final V2.1 
Removed analysis on QTcB  
Prasanth Sasidharan 
19Feb2019 
Final V2.1 
Section 7.7.1 :  
1) Add impute ADCOMs score at week 
12/EOT for the placebo group for the 1st 
sensitivity analysis; 2) Any sites randomized 
subjects less than or equal to 10 will be pooled 
by country for the 2nd sensitivity model; 
3)Added two sensitivity analyses using 
multiple imputation method. 
DukHyun Kim 
19Feb2019 
Final V2.1 
Section 5.1 : 1) p-value decimal points from 
four to three; 2) Output minimum font size to 
change from nine to eight 
DukHyun Kim 
19Feb2019 
Final V2.1 
Section 7.11 (new) : adding subgroup analyses 
section 
DukHyun Kim 
19Feb2019 
Final V2.1 
Section 7.7.2.5 : adding sensitivity analysis 
having covariate of sites  
DukHyun Kim 
19Feb2019 
Final V2.1 
Section5.2 : Changing the definition of efficacy 
variable 
DukHyun Kim 
19Feb2019 
Final V2.1 
Section 7.7.1 : Adding the how to pool the site 
with few subjects. 
DukHyun Kim 
07Mar2019 
Final V2.1 
Added Section 7.12 Statistical Analysis Plan 
for Additional Analyses to be Conducted by 
McCloud Consulting Group After Database 
Lock 
Prasanth Sasidharan 
11Mar2019 
Final V2.1 
1.In section 7.3, update “major/minor” into” 
Key and Non-Key” per Peter’s comments   2.In 
section 7.11, add “if at least 25% of subjects 
are in both groups” for Baseline CDR Global 
score (0.5 vs 1.0) per Peter’s comments 
 
Jing Luo 
18Mar2019 
Final V2.1 
In section 7.7.1 (1)Update Repeat a) to g) for 
placebo group and combine both datasets 
into“Repeat a) to g) for placebo group and 
combine both datasets with the records from 
both groups with non-missing ADCOMs score 
at Week 12.”   (2)For resampling part, Update 
the SAS code.  (3) Add  “Under this approach 
we assume that patients with missing data in 
both treatment groups would have outcomes 
like a patient in the placebo group as soon they 
become missing.” And “Under this approach 
we assume that patients with missing data in 
Jing Luo 


 
 
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each treatment groups would have outcomes 
like a patient in that treatment group as soon 
they become missing.” Separately for the 2 
multiple imputation part. 
21Mar2019 
Final V2.1 
In section 7.7.1, update the description of 
“imputing missing Week 12/EOT data based on 
multiple imputation using both the Xanamem 
and placebo group” per MCG suggestion. 
Jing Luo 
22Mar2019 
Final V2.1 
In the abbreviation section, revert back MAR 
and add MNAR. 
Jing Luo 
22Mar2019 
Final V3.0 
Updated the version as 3.0 
Jing Luo 
 
 
 


 
 
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TABLE OF CONTENTS 
REVISION HISTORY.....................................................................................................................4 
TABLE OF CONTENTS .................................................................................................................6 
LIST OF ABBREVIATIONS ..........................................................................................................9 
1.0 
INTRODUCTION ................................................................................................................11 
2.0 
STUDY OBJECTIVES ........................................................................................................12 
3.0 
STUDY DESIGN .................................................................................................................13 
3.1 
Description of the Disease ..........................................................................................13 
3.2 
Study Design ...............................................................................................................13 
3.3 
Study Treatments and Assessments ............................................................................14 
3.4 
Randomisation and Blinding ......................................................................................14 
3.5 
Sample Size ................................................................................................................14 
4.0 
ENDPOINTS AND VARIABLES .......................................................................................15 
5.0 
STATISTICAL CONSIDERATIONS .................................................................................18 
5.1 
General Considerations ...............................................................................................18 
5.2 
Specification of Baseline Values ................................................................................19 
5.3 
Multiple Comparisons and Multiplicity......................................................................19 
6.0 
ANALYSIS POPULATION ................................................................................................20 
6.1 
Full Analysis Set (FAS) ..............................................................................................20 
6.2 
Per Protocol (PP) Analysis Set ...................................................................................20 
6.3 
Safety Analysis Set .....................................................................................................20 
6.4 
PK Set .........................................................................................................................20 
6.5 
PD Set .........................................................................................................................20 
7.0 
METHODS OF ANALYSES AND PRESENTATIONS ....................................................21 
7.1 
Subject Disposition .....................................................................................................21 
7.2 
Demographic and Baseline Characteristics ................................................................21 
7.3 
Protocol Deviations ....................................................................................................21 
7.4 
Medical History ..........................................................................................................22 
7.5 
Prior and Concomitant Medication .............................................................................22 
7.6 
Study Drug Treatment Duration of Exposure and Compliance ..................................22 
7.7 
Efficacy Endpoints and Analyses ...............................................................................22 
7.7.1 
Primary Efficacy Endpoints and Analyses ...................................................23 


 
 
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7.7.1.1 ADCOMs/ADAS-Cog v14 score ...................................................23 
7.7.2 
Secondary Efficacy Endpoints and Analyses ...............................................32 
7.7.2.1 Rey Auditory Verbal Learning Test (RAVLT) Score ...................32 
7.7.2.2 Clinical Dementia Rating scale - Sum of Boxes (CDR-SOB) 
Score ..............................................................................................32 
7.7.2.3 Mini-Mental Status Examination (MMSE) Score .........................32 
7.7.2.4 Neuropsychiatric Inventory (NPI) .................................................33 
7.7.2.5 Neuropsychological Test Batteries (NTB) – Executive 
Domain ...........................................................................................33 
7.8 
Safety Endpoints and Analyses ..................................................................................33 
7.8.1 
Adverse Events .............................................................................................34 
7.8.2 
Clinical Safety Laboratory Parameters.........................................................35 
7.8.3 
Electrocardiogram ........................................................................................36 
7.8.4 
Nerve Function Monitoring (NFM) .............................................................36 
7.8.4.1 Neuropathy Total Symptom Score (NTSS)-6 ................................36 
7.8.4.2 Toronto Clinical Neuropathy Score (TCNS) .................................37 
7.8.4.3 Neurography (SNAP, CMAP and NCV) .......................................37 
7.8.5 
Columbia Suicide Severity Rating Scale (CSSRS) ......................................37 
7.8.6 
Other Safety Endpoints and Analyses ..........................................................39 
7.9 
Pharmacokinetics (PK) /Pharmacodynamics (PD) Endpoints Analyses ....................39 
7.10 Other Exploratory Endpoints Analyses ......................................................................40 
7.10.1 
Metabolic Function ......................................................................................40 
7.11 Subgroup Analyses .....................................................................................................40 
8.0 
HANDLING OF MISSING VALUES ................................................................................41 
9.0 
INTERIM ANALYSIS ........................................................................................................42 
9.1 
Introduction .................................................................................................................42 
9.2 
Data Safety Monitoring Board (DSMB) .....................................................................43 
9.3 
Analysis Population for Interim Analysis ...................................................................43 
9.4 
Cutoff Data for Interim Analysis ................................................................................43 
9.5 
Endpoint for Interim Analysis ....................................................................................43 
10.0 CHANGES FROM ANALYSIS METHODS PLANNED IN THE PROTOCOL ..............44 
11.0 REFERENCES .....................................................................................................................45 


 
 
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12.0 APPENDIX ..........................................................................................................................46 
Appendix 1: Schedule of Activities .....................................................................................46 
Appendix 2: Classification of Visits Window ......................................................................49 
Appendix 3: Scoring Details of Efficacy Variables .............................................................50 
 
 
 


 
 
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LIST OF ABBREVIATIONS 
Abbreviation 
Term 
ACTH 
Adrenocorticotropic Hormone 
AD 
Alzheimer’s Disease 
ADAS-Cog v14 
Alzheimer's Disease Assessment Scale - Cognitive subscale, version 14 
ADCOMs 
AD COMposite Score 
AE 
Adverse Event  
AESI 
Adverse Event of Special Interest 
ALT 
Alanine Aminotransferase 
ANCOVA 
Analysis of covariance 
AST 
Aspartate Aminotransferase 
BMI 
Body Mass Index 
CDR 
Clinical Dementia Rating Scale 
CDR-SOB 
Clinical Dementia Rating scale - Sum of Boxes 
CFT 
Category Fluency Test 
CI 
Confidence Interval 
COWAT 
Controlled Word Association  Test 
CSSRS 
Columbia Suicide Severity Rating Scale 
DHEAS 
Dehydroepiandrosterone Sulfate 
DSMB 
Data Safety Monitoring Board 
eCRF 
Electronic Case Report Form 
ECG 
Electrocardiogram 
EOT 
End of Treatment 
FAS 
Full Analysis Set 
HbA1c 
Haemoglobin A1c 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
LS 
Least Squares (means) 
MAR 
Missing at Random 
MedDRA 
Medical Dictionary for Drug Regulatory Activities 
MMSE 
Mini-Mental Status Examination 
MNAR 
Missing not at Random 
N, n 
Number of subjects/subjects in a sample from a population or analysis group 
NCV 
Nerve Conduction Velocity 
NPI 
Neuropsychiatric Inventory 
NTB 
Neuropsychological Test Batteries 
PLS 
Partial Least Squares 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PP 
Per Protocol 
PT 
Preferred Term  
QD 
Once a day 
QTcF 
QT Time using the Fridericia’s Correction 
RAVLT 
Rey Auditory Verbal Learning Test 


 
 
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LIST OF ABBREVIATIONS 
Abbreviation 
Term 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SOC 
System Organ Class 
TEAE 
Treatment-emergent Adverse Event 
UK 
United Kingdom 
USA 
United States of America 
VIP 
Variable Importance of Projection 
VLDL 
Very Low-density lipoprotein 
WHO 
World Health Organization  
WOCBP 
Women of Childbearing Potential 
                
 
 
  
 


 
 
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1.0 
INTRODUCTION 
The purpose of this document is to provide further details about the statistical analysis methods, 
data derivations and data summaries to be employed in the study protocol ACW0002 [Universal 
Trial Number: U1111-1177-5932]: XanADu: A Phase II, Double-Blind, 12-Week, Randomised, 
Placebo-Controlled Study to Assess the Safety, Tolerability and Efficacy of Xanamem™ in 
Subjects with Mild Dementia due to Alzheimer’s Disease (AD). This statistical analysis plan 
(SAP) has been based on International Conference on Harmonisation (ICH) E3 and E9 
guidelines and in reference to protocol final Protocol Amendment 4 16Oct2017 and Annotated 
Case Report Form version 1.0: date 10-March-2017. The SAP covers statistical analysis, 
tabulations and listings of all data including efficacy and safety data.  
Any major deviations from the methods specified in this document and the protocol will be 
discussed and documented with revision history. 
 
 


 
 
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2.0 
STUDY OBJECTIVES  
Primary Objective 
The primary objective of the study is to evaluate the extent to which Xanamem™ improves 
performance from Baseline to End of Treatment (EOT) compared to placebo, as measured by 
changes in AD COMposite Scores (ADCOMs, composite data derived from Alzheimer's Disease 
Assessment Scales - Cognitive subscale version 14 [ADAS-Cog v14], Clinical Dementia Rating 
Scale - Sum of Boxes [CDR-SOB], and Mini-Mental Status Examination [MMSE]) and ADAS-
Cog v14 as primary endpoints in subjects with mild dementia due to probable AD.  
Secondary Objectives 
Secondary objectives of this study are to assess the extent to which Xanamem™ improve 
performance from Baseline to EOT compared to placebo, as measured by changes to: 
• Rey Auditory Verbal Learning Test (RAVLT) 
• CDR-SOB 
• MMSE 
• Neuropsychiatric Inventory (NPI) 
• Neuropsychological Test Batteries (NTB) – Executive Domain (Controlled Word 
Association Test [COWAT] and Category Fluency Test [CFT] 
 
 
 


 
 
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3.0 
STUDY DESIGN 
3.1 
Description of the Disease 
Alzheimer’s disease (AD) is emerging as one of the most important global public health issues to 
face modern humanity. With the ageing population and success of medical interventions in many 
other disease areas, the prevalence of AD is rapidly increasing. Data from the 2015 World 
Alzheimer’s Report estimates there are 47 million people globally affected by AD, with the 
number set to double every 20 years. The burden of the disease is global, with nearly 70% of the 
increase expected to be in middle and low income countries.   
In Australia, more than 342,800 people are living with dementia. Without a medical 
breakthrough, the number of people with dementia is expected to be almost 900,000 by 2050.  
Each week, there are more than 1,800 new cases of dementia in Australia, and approximately 
25,100 people with younger onset dementia (a diagnosis of dementia under the age of 65; 
including people as young as 30). The number of people with AD in the United Kingdom (UK) 
has increased since the late 1990s and is a major cause of morbidity and mortality. This increase 
has been associated primarily with an increasing incidence of elderly people and better case 
ascertainment. 
Of the 5.3 million Americans with AD, an estimated 5.1 million are aged 65 years and older, and 
approximately 200,000 are under the age of 65. The number of Americans with AD and other 
dementias will increase each year as the size and proportion of the population of the United 
States of America (USA) aged 65 years and older continues to increase. By 2025, the number of 
people aged 65 and older with AD is estimated to reach 7.1 million - a 40% increase from the 
5.1 million aged 65 and older affected in 2015.  By 2050, this number could triple to a projected 
13.8 million, barring the development of medical breakthroughs to prevent or cure the disease. 
3.2 
Study Design  
Study ACW0002 is a Phase II, randomised, multi-centre, double-blind, placebo-controlled proof-
of-concept study to assess the safety, tolerability and efficacy of oral Xanamem™ QD in adult 
subjects with mild dementia due to AD.  
A subject will be eligible for enrolment in the study if ALL of the inclusion and exclusion 
criteria met.  
After obtaining informed consent, the screening procedures will be performed at the screening 
visit as per the schedule of activities (Appendix 1). Protocol section 9.4.1 has detail description 
about the study procedures and assessments. It is planned to randomise approximately 
174 subjects at approximately 20 sites in the three countries (Australia, UK and USA), with the 
aim to enroll 7 to 10 subjects at each study site.  


 
 
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The overall study duration for an individual subject will be 17 to 20 weeks, including a screening 
period of one to four weeks, a double-blind treatment period of 12 weeks, and a follow-up period 
of four weeks. The total duration of the study is expected to be two years.  
Subjects may withdraw from the study at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator or sponsor for safety, behavioural, or 
administrative reasons. Subjects withdrawn from the study cannot be re-enrolled at a later time, 
regardless of the reason for withdrawal. This study may be terminated prematurely at any time 
by Actinogen Medical for medical, operational or ethical reasons at individual or all study sites. 
Study protocol will help to understand more about the study design.  
3.3 
Study Treatments and Assessments 
One capsule of Xanamem™, or the matching placebo, will be administered orally with 
approximately 200 mL of preferably warm water once a day (QD), preferably with food in the 
morning, to eligible subjects from Baseline (Week 0) to EOT (Week 12) for a total of 12 weeks. 
Subjects will attend the study site, in a fasted state, for a Baseline (Week 0) visit, Interim visits 
(Week 4 and Week 8) and EOT (Week 12) visit. Subjects should aim to take study drug at the 
same time each morning with food (30 minutes after the start of a standard meal) at the study site, 
and after all pre-dose blood samples have been taken. One Follow-up visit is planned. 
Throughout the study, subjects will be assessed for the study objectives as outlined in the 
schedule of activities (Appendix 1).  The visit window details are outlined in the Appendix 2. 
3.4 
Randomisation and Blinding  
This study is randomised, double-blind, placebo-controlled Phase II proof-of-concept study.  
There is a well-defined randomisation plan for subject’s randomisation and blinding. Detailed 
randomisation details will be document in the study randomisation plan. The randomisation 
codes will be computer-generated by ICON Biostatistics, and kept by a statistician independent 
from the project team. A copy will be provided to whoever performs the PK and PD assessments, 
when the Pharmacokinetic (PK) and Pharmacodynamic (PD) data are analysed, as well as to the 
DSMB (Data Safety Monitoring Board).  Randomisation codes will be generated in blocks 
stratified by site to ensure approximate balance between dose schemes (1:1) and balanced per 
site.  
3.5 
Sample Size  
Study is planned to randomise approximately 174 subjects (87 per treatment group) at 
approximately 20 study sites in three countries (Australia, UK, and USA), with the aim to enroll 
7 to 10 subjects at each study site.  
 
 


 
 
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4.0 
ENDPOINTS AND VARIABLES 
The primary as well as secondary and other endpoints and its variables are given below. 
  
Primary Efficacy Endpoints 
The primary efficacy endpoints of this study are:  
• Change from Baseline (Week 0) to Week 12/EOT in the ADCOMs (a composite data 
derived from Alzheimer's Disease Assessment Scales - Cognitive subscale version 14 
[ADAS-Cog v14], Clinical Dementia Rating Scale-Sum of Boxes [CDR-SOB], and Mini-
Mental Status Examination [MMSE])  
• Change from Baseline (Week 0) to Week 12/EOT in the ADAS-Cog v14 score  
Primary Efficacy Endpoints variables 
The following primary efficacy variables will be evaluated: 
• ADCOMs: a composite score based on ADAS-Cog v14, CDR-SOB and MMSE. 
• ADAS-Cog v14 
 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints of this study are:  
• Change from Baseline (Week 0) to Week 12/EOT of RAVLT score 
• Change from Baseline (Week 0) to Week 12/EOT of CDR-SOB score 
• Change from Baseline (Week 0) to Week 12/EOT of MMSE score 
• Change from Baseline (Week 0) to Week 12/EOT of NPI score 
• Change from Baseline (Week 0) to Week 12/EOT of NTB – Executive Domain score 
(COWAT and CFT) 
Secondary Efficacy Endpoints variables  
The following secondary efficacy variables will be evaluated: 
• RAVLT 
• CDR-SOB 
• MMSE 
• NPI 
• NTB – Executive Domain (COWAT and CFT) 


 
 
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ADCOMs-related assessments (ADAS-Cog v14, CDR-SOB and MMSE), RAVLT, NPI and 
NTB – Executive Domain will be performed at the Baseline (Week 0) and the EOT (Week 12) 
visits to minimise burden for rater and subject. 
MMSE and CDR-SOB will also be performed at Screening. 
Safety Endpoints 
The safety endpoints of this study are:  
• Change in clinical safety laboratory values from Baseline (Week 0) to EOT (Week 12) 
• Incidence of adverse events (AEs) 
• Change in electrocardiogram (ECG)  
• Change in Nerve Function monitoring (NFM) (including NTSS-6, TCNS and 
neurography (nerve conduction velocity and amplitude) of peripheral sensory and motor 
nerves) 
• Change in Columbia suicide severity rating scale (CSSRS) and the incidence of CSSRS 
related event 
• Abnormality in physical examination 
• Change in vital signs 
 
Safety Endpoint variables  
The following safety variables will be evaluated: 
• Clinical safety laboratory values for haematology, biochemistry and urinalysis 
• AEs, serious adverse events (SAEs), and adverse events of special interest (AESIs) 
• ECG 
• NFM 
• CSSRS 
• Physical examination 
• Vital signs 
 
Pharmacokinetics (PK) /Pharmacodynamics (PD) endpoints  
The following are the PK/ PD endpoints of this study:  
• PK assessment 
• Optional PD assessment 


 
 
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PK/PD Endpoints variables  
The following PK/PD variables will be evaluated 
• PK assessment : XanamemTM concentration 
• PD assessment: Adrenocorticotropic Hormone (ACTH), Dehydroepiandrosterone Sulfate 
(DHEAS), androstenedione and testosterone 
Other Exploratory Endpoints 
The other exploratory endpoints include:  
• Metabolic function 
Other Exploratory endpoints variables  
The following other exploratory endpoints variables will be evaluated 
• Metabolic function: lipids, blood pressure, glucose, hemoglobin A1c [HbA1c], body 
weight and body mass index [BMI] 
 
 
 


 
 
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5.0 
STATISTICAL CONSIDERATIONS 
5.1 
General Considerations 
Statistical analyses will be performed using SAS software, version 9.3 or higher. Formal 
hypothesis will be tested in this study and it will be explained in detail on following section.  
Continuous data will be summarized using number (n), mean, standard deviation (SD), minimum 
value, median, maximum value and, if appropriate, number of missing values.  Unless noted 
otherwise, summaries will be produced by visit (where applicable) and results will be presented 
overall and by treatment group. If more than one value is reported at a scheduled visit, the value 
collected closest to the intended visit date will be used. In the case of a tie, the latest version will 
be summarized. If there is more than one value reported at the same date, the average value of 
multiple values will be obtained. Where changes from Baseline are analysed, subjects will be 
included only if both a Baseline and at least one valid post-Baseline measurement are available.  
Categorical data will be summarized using number (n) and percentages. Percentages will be 
calculated based on the number of non-missing values (if result display by visit) otherwise it will 
be calculated based on the population count.  The number of missing values will be presented as 
a separate category with no percentage, if one or more subjects have missing data for the 
summary.  Otherwise, all categories will be presented (even if no subjects are counted in the 
category). Counts of zero in any category will be presented without percentage.  
Precision of summary statistics: 
• Integer – Sample size (n, N) and number of missing responses (if displayed). 
• One additional decimal place than reported/collected on the electronic Case Report Form 
(eCRF) – mean and  median 
• Two additional decimal places than reported/collected on the eCRF – standard deviation. 
• Same number of decimal places as reported/collected on the eCRF – minimum, 
maximum. 
• Percentages, CV – one decimal place. 
• P-values will be presented for three decimal points (i.e., 0.xxx).  
Precision of output display:  
• Report output will be generated using SAS (version 9.3 or higher) ODS RTF with no 
borders or framing around table elements.  
• Font – Courier New font with minimum of eight point font size 
• Margins – For USA, minimum of 3/4” bound edge margin and 3/8” other margins on 
8.5”x11” paper. 


 
 
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All data will be presented on listings in order of treatment group, subject, site [wherever defined], 
assessment date/time and assessment (in order collected on eCRF, unless specified otherwise). 
Dates will be presented in the format DDMMMYYYY. Times will be displayed in 24-hour clock 
format. Numbering of tables, figures and listings will follow ICH E3 guidelines.  
Unless noted otherwise, unscheduled measurements will be excluded from the descriptive 
statistical analysis. However, unscheduled measurements that were performed immediately after 
the scheduled measurement, in case of a previous measurement error (e.g. equipment failure), 
will not be excluded from the analysis. In these cases, the original erroneous measurement will 
be excluded from the analysis and the unscheduled visit substituted. All the unscheduled 
measurements will be included in the listing. 
5.2 
Specification of Baseline Values 
For efficacy variables: Baseline value is defined as the latest Week 0 observation prior to or on 
the date of the first dose of study drug. The exception is MMSE which is defined as the latest 
Screening or Week 0 observation prior to or on the date of the first dose of study drug. When 
MMSE results are analysed as part of the ADCOMs analysis, use of screening results are not 
allowed, in order to ensure that all Baseline values contributing to the ADCOMs refer to the 
same point in time.For safety endpoints: Baseline value is defined as the observation prior to or 
on the date of the first dose of study drug. 
5.3 
Multiple Comparisons and Multiplicity 
Multiplicity between both primary endpoints will be handled using an a priori hierarchical 
approach.  
 
 


 
 
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6.0 
ANALYSIS POPULATION 
The populations used for analysis will include Full Analysis Set (FAS), Per Protocol (PP) 
Analysis Set, Safety Analysis Set, PK Set and PD Set. The success of the primary efficacy 
endpoints will be evaluated based on the FAS; these primary efficacy endpoints will also be 
analyzed for the PP analysis set. The evaluation of secondary efficacy endpoints will be based on 
FAS and PP analysis set. The evaluation of safety endpoints will be based on safety analysis set. 
PK set and PD set will be used for PK and PD endpoints analysis.  
6.1 
Full Analysis Set (FAS)  
The FAS will consist of all subjects randomised who received at least one dose of study drug. 
Subjects will be analysed in the treatment group they were randomised to even if they received 
incorrect study drug. Where changes from Baseline are analysed, subjects will be included only 
if both a Baseline and at least one valid post-Baseline measurement are available. 
The FAS will be the primary analysis set for efficacy analyses. 
6.2 
Per Protocol (PP) Analysis Set 
 
PP analysis set is a subset of the FAS, and will consist of all randomised subjects for whom no 
key protocol violation is documented. The PP analysis set will provide supportive data for the 
efficacy analyses. 
Allocation of subjects to the PP analysis set will be performed before unblinding of the study. A 
list of all protocol violations will be documented in a separate file.  
6.3 
Safety Analysis Set 
The safety analysis set will consist of all subjects who received at least one dose of study drug.  
Subjects will be analysed according to the treatment they actually received. The safety analysis 
set will be the primary analysis set for safety analyses. 
6.4 
PK Set 
The PK set will consist of all subjects in the safety analysis set who has at least one post-dose PK 
assessment. PK analyses will be performed using the PK set. 
6.5 
PD Set 
The PD set will consist of all subjects in the safety analysis set who has at least one post-dose PD 
assessment. PD analyses will be performed using the PD set. 
 
 


 
 
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7.0 
METHODS OF ANALYSES AND PRESENTATIONS  
The following sub-sections would be considered for logical presentation of study data.  
7.1 
Subject Disposition 
The number of subjects screened, screen failure, randomised, treated, subjects in each analysis 
set, on-going status, study completion status, Follow-up details will be summarized. Subjects 
who discontinued/withdrawn from the study will be summarized with reason and listed by their 
primary reason. Subject allocation by study site will also be summarized. Inclusion/exclusion 
criteria evaluation will be listed. The denominator which is used for the percentage calculation 
will be mentioned in the table footnote.  This table will be summarized overall and by treatment 
group by using all subjects.   
7.2 
Demographic and Baseline Characteristics 
Demographic data and subject characteristics at Baseline will be summarized overall and by 
treatment group using descriptive summary statistics for FAS. The demographic and Baseline 
characteristics include age [continuous summary and categorical summary as Age <65 years, 
Age >=65 years], gender, race, pregnancy test result. Also Baseline characteristics results of 
height, weight, BMI will be summarized overall and by treatment group. All demographic and 
Baseline characteristics will be listed in full.   
7.3 
Protocol Deviations  
A protocol deviation is defined as any intentional or unintentional change to, or noncompliance 
with, the approved protocol procedures or requirements. Deviations may result in study 
termination of an investigator or investigational site or discontinue subjects from study. 
Examples of deviations include, but are not limited to: 
• Informed consent violation. 
• Inclusion/exclusion criteria not met. 
• Study procedures not followed. 
• Missed visit. 
• Visit outside study window. 
• Others like procedural deviations such as incorrect storage of study drug, failure to 
update the Internal Consent Form (ICF) when new risks become known etc… 
Protocol deviation will be identified by the project team prior to database lock. A summary of 
major protocol deviations will be provided overall and by treatment group. All protocol 
deviations (Key and Non-Key) will be listed. All randomised subjects will be included in the 
summary. 


 
 
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7.4 
Medical History 
All medical history will be coded using the latest version of Medical Dictionary for Regulatory 
Activities (MedDRA). The incidence of medical history abnormalities will be summarized using 
descriptive statistics by system organ class (SOC) and preferred term (PT). Subjects are counted 
only once in each PT and SOC category. Summary table will be sorted in alphabetical order by 
SOC and in decreasing frequency of PT based on total number of incidence within each SOC. 
Safety analysis set will be used for the analysis with actual treatment received for the summary. 
Medical history will also be displayed in patient listing. 
7.5 
Prior and Concomitant Medication 
Concomitant medication is defined as all medications still being taken by a subject at 
randomisation and which continue to be taken during the study.   
Prior medication is defined as all medications taken by a subject within 1 month prior to 
randomisation into the study. 
Prior and Concomitant medications will be classified using the latest version of World Health 
Organization Drug Dictionary (WHO drug). All prior/concomitant medication will be listed.  
7.6 
Study Drug Treatment Duration of Exposure and Compliance 
Treatment exposure and compliance will be assessed by maintaining adequate study drug 
dispensing records. Duration of exposure to study medication (weeks) and compliance (%) will 
be summarized descriptively.  
Duration of exposure = (Last treatment date – First treatment date) + 1. 
Treatment Compliance = (Number of study drug taken / number of study drug that should have 
been taken) x 100.  
Where, number of study drug taken = sum of (total number of capsule taken since last visit), and 
number of study drug that should have been taken= (date of last dose – date of first dose +1). 
Descriptive summary statistics will be used to summarize treatment duration of exposure and 
compliance. Also the compliance will be summarized categorically as number of subjects with a 
compliance < 80%, between 80% and 120% and > 120%. Safety analysis set will be used for the 
analysis with actual treatment received and presented by treatment group and overall. All study 
drug accountability data will be listed.  
7.7 
Efficacy Endpoints and Analyses 
The primary efficacy analysis will be based on both FAS and PP population. Sensitivity analyses 
with primary efficacy endpoints will be based on FAS population. The secondary efficacy 
analysis will be analysed in a descriptive summary statistics based on FAS and PP population. 
Descriptive summary statistics mentioned in section 5.1 will be performed for all data used 


 
 
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within the context of the efficacy analysis models. Summaries will be presented by visit and by 
treatment group. Comprehensive listings of all data will be presented.  
7.7.1 Primary Efficacy Endpoints and Analyses 
The objective of the primary efficacy analysis is the evaluation of the performance of 
Xanamem™ as compared to placebo for the change in the primary efficacy endpoints ADCOMs 
and ADAS-Cog v14 from Baseline (Week 0) to Week 12/EOT. The two primary efficacy 
endpoints will be evaluated in an a priori hierarchical fashion, where the results of the ADAS-
Cog v14 analysis will only be interpreted as confirmatory if superiority of Xanamem™ over 
placebo can be shown for the ADCOMs.  
7.7.1.1 
ADCOMs/ADAS-Cog v14 score 
ADCOMs, composite score (0 - 1.97) is derived from ADAS-Cog v14, CDR-SOB, and 
MMSE.ADAS-Cog v14 score is sum of all 14 items of ADAS-Cog v14. Scoring details for 
ADCOMs and ADAS-Cog v 14 score are given in Appendix 3. 
For analysis of the primary efficacy variables, analysis of covariance (ANCOVA) model will be 
used to assess the change in ADCOMs/ADAS-Cog v14 score from Baseline (Week 0) to 
Week 12/EOT. The ANCOVA model will include treatment group as fixed effects and the 
Baseline value as a covariate. 
The primary efficacy hypothesis is: 
Ho: μP ≤ μX 
H1: μP > μX, 
where μP and μX denote the change from Baseline (Week 0) to Week 12/EOT in ADCOMs and 
ADAS-Cog v14 for the placebo and Xanamem™ treatment groups, respectively. Both tests will 
be performed at a type I error rate of 0.05 one-sided, with a priori hierarchical handling of 
multiplicity, based on the least squares means (LS means) for Week 12/EOT. LS means from the 
ANCOVA will be used to derive 90% and 95% confidence intervals. The primary efficacy 
analysis will not replace missing Week 12/EOT. 
Unless otherwise specified, the ANCOVA will have the following characteristics: 
• All subjects in the FAS will be included in the primary efficacy analysis as long as there 
are both Baseline and valid post-Baseline measurements at Week 12/EOT available. 
• The response variable will be the change in ADCOMs score from Baseline (Week 0) to 
Week 12/EOT visit. Only post-Baseline measurements collected on the EOT will be 
considered response values.  
• The following covariate will be used in the models: 
o Baseline ADCOMs score 


 
 
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o Treatment group 
 
• The following SAS statements will be employed:  
proc mixed data=xxxx  ; 
 
class <treatment group>; 
 
model <  change ADCOMs score> = <baseline ADCOMs score>  
<treatment group> ; 
 
lsmeans <treatment group>/ diff cl alpha=0.05; 
 
lsmeans <treatment group>/ diff cl alpha=0.10; 
ods output lsmean=xxx diffs=xxx; 
run; 
Baseline ADCOMs score, as well as observed and change from Baseline values at post-Baseline 
visits, will be summarized descriptively. 
The analysis described above will be repeated for ADAS-Cog v14. Also analysis will be 
repeated on PP analysis set for supportive evidence. 
Whilst the European Medicines Agency discussion paper5 foresees the use of the linear models 
for sensitivity analyses, complementing different methods of primary analyses, the type and 
order of analyses in this study – ANCOVA as primary efficacy analysis and placebo-based 
imputation as sensitivity analysis – are chosen in a different fashion due to the following reasons: 
• The development stage this study is associated with, where the primary aim is to explore 
a possible therapeutic effect of Xanamem™; in conjunction with 
• The relatively short study duration, which can be expected to reduce the number of 
missing values in either treatment group and 
• The fact that the primary efficacy variables will only be assessed at Baseline (Week 0) 
and Week 12/EOT. 
Sensitivity analyses aim at assessing the robustness of the primary efficacy analysis. The 
following four analyses will be performed: 
1) An additional ANCOVA, imputing missing Week 12/EOT data based on resampling from the 
placebo subjects, taking Baseline values into account 
Process 
a) Select records from placebo group with non-missing ADCOMs score at Week 12 
b) Select records from Xanamem group with missing ADCOMs score at Week 12 


 
 
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c) Merge datasets from a) and b)  
(Total number of records in merged dataset = number of records in dataset a) * number of 
records in dataset b)) 
d) Using Baseline (placebo) and Baseline (Xanamem), calculate DIFF variable to find 
record in placebo group which has smallest in difference with Baseline in test group  
DIFF = abs (Baseline (Xanamem) – Baseline (placebo)) 
e) Calculate RANDNO variable with RANUNI function and select the smallest randno 
f) Select 1 record for each missing case in Xanamem group and impute ADCOMs score at 
Week 12 based on ADCOMs score at Week 12 in placebo group  
g) Calculate change from Baseline based on imputed ADCOMs score at Week 12 for 
Xanamem group  
h) Repeat a) to g) for placebo group and combine both datasets with the records from both 
groups with non-missing ADCOMs score at Week 12. 
i) Run proc ANCOVA specified above 
The following SAS statements will be employed:  
For Xanamem group: 
data placebo; 
set indata; 
if <treatment group> = Placebo and <VISIT> = Week 12 and AVAL <> missing; 
rename CHG=CHG_P BASE=BASE_P ID=ID_P AVAL=AVAL_P; 
run; 
 
data test; 
set indata; 
if <treatment group> = Test and <VISIT> = Week 12 and AVAL = missing; 
run; 
 
proc sql; 
create table outdata as 
select *from test, placebo ; 
quit; 
 


 
 
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proc sort data=outdata; 
by id id_p; 
run; 
 
data outdata1; 
set outdata; 
diff=abs(BASE – BASE_P); 
seed_no=ID * ID_P; 
randno=ranuni(seed_no);  
AVAL = AVAL_P; 
CHG=AVAL – BASE; 
run; 
 
proc sort data=outdata1 out=outdata2; 
by id diff randno; 
run; 
 
proc sort data=outdata2 nodupkey; 
by id; 
run; 
 
data outdata3; 
set outdata2; 
keep ID <treatment group> BASE AVAL CHG; 
run; 
         For placebo group, follow above process and keep the imputed data in outdata4. 
          
data nomissing; 
set indata; 
if aval^=missing; 
run; 
 


 
 
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data FINAL; 
set outdata3  outdata4  nomissing; 
run; 
 
where CHG= Change ADCOMs score from Baseline, BASE=baseline ADCOMs score and 
AVAL=ADCOMs score at Week 12/EOT. 
Run PROC MIXED procedure specified above with FINAL dataset. 
 
2) An additional ANCOVA, adding site as a factor. Sites will be pooled by country if 
randomized subjects will be less than or equal to 10.The following SAS statements will be 
employed:  
proc mixed data=xxxx  ; 
 
class <treatment group> <site>; 
 
model <  change ADCOMs score> = <baseline ADCOMs score>  
<treatment group> <site>; 
 
lsmeans <treatment group>/ diff cl alpha=0.05; 
ods output lsmean=xxx diffs=xxx; 
run; 
 
3) An additional ANCOVA, imputing missing Week 12/EOT data based on placebo-based 
multiple imputation with missing not at random (MNAR) assumption.  
Process 
Missing data at Week 12/EOT will be imputed using a regression model based on placebo-based 
imputation model. The imputation model will include the Baseline values and Week 12/EOT 
values. The imputation model for the missing observations in both the Xanamem group and the 
placebo group will be constructed from the observed data in the placebo group only. Under this 
approach we assume that patients with missing data in both treatment groups would have 
outcomes like a patient in the placebo group as soon they become missing. The imputation will 
be performed for 100 times and imputed datasets will be analysed using an ANCOVA model. 
Approximately 100 imputed datasets will be created and results from the analysis of each 
imputed dataset will be combined using Rubin’s method.  
 
• The following SAS statements will be employed:  


 
 
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proc mi data=xxxx nimpute=100 seed=3489876 out=yyyy; 
class < treatment group>; 
monotone  reg (<ADCOMs score at week 12/EOT>); 
mnar model(<ADCOMs score at week 12/EOT> /modelobs=(<treatment 
group>=’Placebo’)); 
var <baseline ADCOMs score> < ADCOMs score at week 12/EOT>; 
run; 
 
data zzzz; 
set yyyy; 
<change ADCOMs score> = <ADCOMSs score at week 12/EOT> –< baseline 
ADCOMs score>; 
run; 
 
* For 95% Confidence Interval; 
proc mixed data=zzzz; 
by _imputation_; 
class <treatment group>; 
model <change ADCOMs score>=<baseline ADCOMs score> <treatment 
group>; 
lsmeans <treatment group>/ diff cl alpha=0.05; 
ods output lsmeans=aaaa diffs=bbbb; 
run; 
 
** LSmeans; 
proc mianalyze parms(classvar=full)=aaaa; 
class <treatment group>; 
modelefficts <treatment group>; 
ods output parameterestimates=cccc; 
run; 
 
** Differences; 


 
 
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proc mianalyze parms(classvar=full)=bbbb; 
class <treatment group>; 
modeleffects <treatment group>; 
ods output parameterestimates=dddd; 
run; 
 
* For 90% Confidence Interval; 
proc mixed data=zzzz; 
by _imputation_; 
class <treatment group>; 
model <change ADCOMs score>=<baseline ADCOMs score> <treatment 
group>; 
lsmeans <treatment group>/ diff cl alpha=0.10; 
ods output lsmeans=aaaa2 diffs=bbbb2; 
run; 
 
** Differences; 
proc mianalyze params(classvar=full)=bbbb2; 
class <treatment group>; 
modeleffects <treatment group>; 
ods output parameterestimates=dddd2; 
run; 
 
The analysis described above will be repeated for ADAS-Cog v14. 
 
4) An additional ANCOVA, imputing missing Week 12/EOT data based on multiple imputation 
using both the Xanamem and placebo group with the missing at random (MAR) assumption.  
Process 
Missing data at Week 12/EOT will be imputed using a regression based imputation model. The 
imputation model will include Treatment Group, Baseline values and Week 12/EOT values. The 
imputation model for the missing observations in both the Xanamem group and the placebo 
group will be constructed from the complete-case observed data for patients in both the 
Xanamem group and the placebo group. Under this approach we assume that patients with 


 
 
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missing data in each treatment group would have outcomes like a complete-case patient in that 
treatment group, where a complete-case patient is one with no missing values for any of the 
variables in the imputation model. This is known as the complete-case missing values (CCMV) 
approach. By study design, all patients will have non-missing data for Baseline and Treatment 
Group. Therefore Week 12/EOT is the only variable in the imputation model which can possibly 
have missing values. Since there is only one possible missing data pattern for the ADCOMs 
analysis, an imputation model based on complete-case patients only (CCMV) is equivalent to an 
imputation model based on patients with any missing data pattern. For this reason, although 
CCMV is usually a MNAR approach, for the specific case of the ADCOMs analysis (and 
ADAS-Cog v14 analysis), it is equivalent to a MAR approach.  
The imputation will be performed 100 times and imputed datasets will be analysed using an 
ANCOVA model. Approximately 100 imputed datasets will be created and results from the 
analysis of each imputed dataset will be combined using Rubin’s method. 
 
• The following SAS statements will be employed:  
 
proc mi data=xxxx nimpute=100 seed=3489876 out=yyyy; 
class < treatment group>; 
monotone reg (<ADCOMs score at week 12/EOT>);  
mnar model(<ADCOMs score at week 12/EOT>/modelobs=ccmv); 
var <treatment group> <baseline ADCOMs score> < ADCOMs score at week 
12/EOT>; 
run; 
 
data zzzz; 
set yyyy; 
<change ADCOMs score> = <ADCOMSs score at week 12/EOT> – <baseline 
ADCOMs score>; 
run; 
 
* For 95% Confidence Interval; 
proc mixed data=yyyy; 
by _imputation_; 
class <treatment group>; 


 
 
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model<change ADCOMs score>=<baseline ADCOMs score> <treatment 
group>; 
lsmeans <treatment group>/ diff cl alpha=0.05;  
ods output lsmeans=aaaa diffs=bbbb; 
run; 
 
** LSmeans; 
proc mianalyze parms(classvar=full)=aaaa; 
class <treatment group>; 
modelefficts <treatment group>; 
ods output parameterestimates=cccc; 
run; 
 
** Differences; 
proc mianalyze parms(classvar=full)=bbbb; 
class <treatment group>; 
modeleffects <treatment group>; 
ods output parameterestimates=dddd; 
run; 
 
* For 90% Confidence Interval; 
proc mixed data=yyyy; 
by _imputation_; 
class <treatment group>; 
model<change ADCOMs score>=<baseline ADCOMs score> <treatment 
group>; 
lsmeans <treatment group>/ diff cl alpha=0.1;  
ods output lsmeans=aaaa2 diffs=bbbb2; 
run; 
 
** Differences; 
proc mianalyze parms(classvar=full)=bbbb2; 


 
 
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class <treatment group>; 
modeleffects <treatment group>; 
ods output parameterestimates=dddd2; 
run; 
 
The analysis described above will be repeated for ADAS-Cog v14. 
 
7.7.2 
Secondary Efficacy Endpoints and Analyses 
Secondary efficacy variables will be analysed in a descriptive manner. Summary statistics will be 
presented overall and by treatment group and an exploratory comparison will be performed 
between the two treatment groups. Analysis will be done for FAS and PP analysis set.  
7.7.2.1 
Rey Auditory Verbal Learning Test (RAVLT) Score 
RAVLT results of Recall List A [Total number of correct words], Recall List B [Number of 
correct words] and Final recall of List A scores [Number of correct words] will be analysed for 
each visit as actual values and change from Baseline. An exploratory ANCOVA will be 
performed on the change from Baseline (Week 0) to Week 12/EOT for comparison between the 
treatment groups, including treatment group as fixed effect, and the Baseline value as a covariate. 
The analysis described for primary efficacy analysis will be used for RAVLT data. Scoring 
details are given in Appendix 3.  
7.7.2.2 
Clinical Dementia Rating scale - Sum of Boxes (CDR-SOB) Score 
CDR-SOB score (0 – 18) is a sum of all six items of CDR-SOB. CDR-SOB score will be 
analysed for each visit as actual values and change from Baseline. An exploratory ANCOVA 
will be performed on the change from Baseline (Week 0) to Week 12/EOT for comparison 
between the treatment groups, including treatment group as fixed effect, and the Baseline value 
as a covariate. The analysis described for primary efficacy analysis will be used for CDR-SOB 
data. Scoring details are given in Appendix 3.  
7.7.2.3 
Mini-Mental Status Examination (MMSE) Score 
MMSE total score (0 - 30) is a sum of all 30 point questionnaire of MMSE. MMSE will be 
analysed for each visit as actual values and change from Baseline. An exploratory ANCOVA 
will be performed on the change from Baseline (Week 0) to Week 12/EOT for comparison 
between the treatment groups, including treatment group as fixed effect, and the Baseline value 
as a covariate. The analysis described for primary efficacy analysis will be used for MMSE data. 
Scoring details are given in Appendix 3.  


 
 
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7.7.2.4 
Neuropsychiatric Inventory (NPI) 
The NPI total score is calculated by multiplying the frequency and severity rates per domain 
(maximum score per domain is 12) and then calculating the total of all domains (total NPI-score 
minimum is 0 and maximum 144). Total distress score (0 – 60) will summarized descriptively. 
Scoring details are given in Appendix 3. 
Total NPI score, score by domain and total distress score will be analysed for baseline and last 
visit including change from Baseline. An exploratory ANCOVA will be performed on the 
change from Baseline (Week 0) to Week 12/EOT in the total NPI score for comparison between 
the treatment groups, including treatment group as fixed effect. Subgroup analyses will be 
performed for subjects with (score > 1) and without (score 0 to 1) symptoms at Baseline if 
warranted by the number of subjects in each treatment. The analysis described for primary 
efficacy analysis will be used for NPI data. 
7.7.2.5 
Neuropsychological Test Batteries (NTB) – Executive Domain 
Total NTB score is the sum of ‘Total correct response’ of Category Fluency Test (CFT) and 
‘Total number of correct words’ of Controlled Oral Word Association – Test (COWAT). Each 
score (‘Total correct response’ of CFT and ‘Total number of correct word’ of COWAT) will also 
be analysed. Those results will be analysed for Baseline and last visit including change from 
Baseline. An exploratory ANCOVA will be performed on the change from Baseline (Week 0) to 
Week 12/EOT in the NTB total score for comparison between the treatment groups, including 
treatment group as fixed effect, and the Baseline value as a covariate. In addition to the 
composite score, the change from Baseline (Week 0) to Week 12/EOT in independent 
components will be analysed with ANCOVA for COWAT and CFT - total correct responses 
score. The analysis described for primary efficacy analysis will be used for NTB- executive 
domain data. Sensitivity analysis with adding sites as covariate will be performed in FAS 
population. Site will be pooled as same to the primary efficacy endpoint. Scoring details are 
given in Appendix 3. 
7.8 
Safety Endpoints and Analyses 
All safety endpoints will be summarized for safety analysis set with actual treatment group 
received. The following are the safety endpoint variables that will be summarized.  
• Clinical safety laboratory values for haematology, biochemistry and urinalysis 
• AEs, SAEs, and AESIs 
• ECG 
• NFM 
o NTSS-6 
o TCNS 


 
 
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o NCV and amplitude of peripheral motor and sensory nerves 
• CSSRS 
• Physical examination 
• Vital signs 
7.8.1 
Adverse Events  
Any detrimental change in the subject’s condition collected from after signing the ICF and up to 
completion of the 4-week Follow-up period after the last administration of study drug, should be 
considered an AE. Any new SAEs occurring up to 60 days after the last administration of study 
drug should be reported.  
Treatment-emergent adverse events (TEAEs) are those AEs which worsen in severity on or after 
date of first administration of study drug or with onset date on or after first administration of 
study drug. 
AEs with missing start dates, but with stop dates either overlapping into the treatment period or 
missing, will be considered TEAEs. A TEAE with missing drug-relationship will be considered 
as related.  
All AEs will be coded by SOC and PT using the latest version of MedDRA. Incidences of 
TEAEs will be tabulated by SOC and PT. Incidences of TEAEs will also be presented by 
maximum severity, seriousness, AESI and drug-related. Subjects who are temporary or 
permanently discontinued from treatment and discontinued from study will be summarized by 
SOC and PT in a separate table. Subjects are counted only once in each SOC, and only once in 
each PT category.  
The following tables will be developed for summarizing AEs.  
• Overall summary of TEAEs: it includes number of TEAEs, subjects with any TEAE, 
subjects with any SAE, subjects with any severe TEAEs, subjects with any drug-related 
TEAEs, subjects with any AESI, subjects with TEAEs leading to temporary or 
permanently treatment discontinuation, subjects with TEAEs leading to study 
discontinuation. 
• Summary of TEAEs by SOC and PT 
• Summary of serious TEAEs by system organ class and preferred terms 
• Summary of TEAEs by system organ class, preferred terms and maximum severity 
• Summary of drug-related TEAEs by system organ class, preferred terms  
• Summary of Treatment-emergent AESI by system organ class and preferred terms 


 
 
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• Summary of TEAEs leading to temporary or permanent discontinuation of study drug by 
system organ class, preferred terms 
• Summary of TEAEs leading to study discontinuation by system organ class, preferred 
terms 
All AEs, AESI, SAEs and deaths will be listed.  
7.8.2 
Clinical Safety Laboratory Parameters 
Descriptive statistics for absolute value and absolute change from Baseline [only for continuous 
results parameters, otherwise display percentage change from Baseline] for protocol specified 
laboratory parameters of biochemistry, haematology and urinalysis will be presented for Baseline 
(Week 0) to EOT (Week 12) by treatment group and overall. International System of Units (SI 
units) will be used for the analysis. The abnormality in laboratory parameters will be 
summarized by treatment group. 
Values outside the normal range (N) will be categorized as H (above the normal range) or L 
(below the normal range) based on the reference range of the Safety Laboratories. Shift tables 
will be presented showing the number of subjects per treatment group with N, H or L at the 
Baseline (Week 0) to EOT (Week 12). Laboratory test results will be listed by including 
laboratory blood tests, which are to only be performed at screening and abnormal values outside 
normal ranges will be flagged.  
The following laboratory test parameters will be summarized:  
Laboratory Test 
Parameters 
Haematology  
Haemoglobin, Haematocrit, Platelet count, Red blood cell count, White 
blood cell count and differential, Basophils, Eosinophils, Monocytes, 
Neutrophils and Lymphocytes 
Biochemistry 
Alkaline Phosphatase, Alanine Aminotransferase (ALT), Aspartate 
Aminotransferase 
(AST), 
Gamma-glutamyl 
transpeptidase, 
Phosphorous, Potassium, Uric acid, Bilirubin (total), Protein (total), 
Creatinine, Follicle-stimulating hormone [Females only. To be taken 
only if there is clinical concern about the subject’s menopausal status], 
Human chorionic gonadotrophin [Pregnancy test on women of 
childbearing potential only] 
Urinalysis 
Urate crystals, phosphate crystals, bilirubin crystals, blood, clarity, 
colour, glucose, ketones, leukocytes, protein, squamous epithelial cells, 
trans. epithelial 
cells, triple phosphate crystals, Microscopic 
examination [Performed only if required, based on urinalysis results] 


 
 
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Metabolic indicators 
Glucose, fasting, Cholesterol, Triglycerides, High-density lipoprotein-
cholesterol, Low-density lipoprotein-cholesterol, HbA1c, Very Low-
density lipoprotein (VLDL) Cholesterol 
7.8.3 
Electrocardiogram 
Descriptive statistics for absolute value and absolute change from Baseline for protocol specified 
laboratory parameters of heart rate, RR, PR, QRS, and QT (uncorrected) and QTc (corrected) 
interval,  QTcF will be presented for scheduled visits by treatment group and overall.  
Shift tables will be presented for overall ECG result showing the number of subjects per 
treatment group with Normal, Abnormal without Clinical Significance, and Abnormal with 
Clinical Significance at the Baseline to post-dose scheduled visits.  
ECG data will be listed. 
7.8.4 
Nerve Function Monitoring (NFM) 
NFM consists of sensory testing (vibration and thermal perception), motor and sensory nerve 
neurography (amplitude and conduction velocity) and clinician-rated outcome in TCNS. The aim 
is to detect intra-subject worsening from before treatment as an indicator for neurotoxicity.  
Subject total “Before Treatment” status is calculated as the average of the Screening visit and 
Baseline visit data.  The tests will follow existing local standards and procedures, but should be 
run in a consistent fashion within a given site and subject to minimise intra-subject variability, 
e.g. constant skin temperature of the feet of at least 32ºC/90ºF, same assessor, same procedures, 
same chronological order of assessments and approximate same time of day.  Measurements will 
be taken twice for each assessed nerve in both the left and right extremity. Two measures for 
each test will be obtained and averaged.   
7.8.4.1 
Neuropathy Total Symptom Score (NTSS)-6  
The six questions of NTSS-6 should be completed as part of the assessment of subjects’ 
medical history; also asking for input from the caregiver to make sure no information is lost. 
Each item will also be graded for its frequency and intensity, adding up to a total score from ‘0’ 
to ‘21.96’ points (maximum score per symptom is 3.66). A total score of > 6 would exclude the 
subject from the study. 
Descriptive statistics for absolute value and absolute change from Baseline for total NTSS-6 
score and each score per symptom will be presented for screening, Baseline (Week 0),  Interim 
(Week 4), Interim (Week 8) EOT (Week 12) and Follow-up (4 weeks post last dose of study 
drug) visits by treatment group and overall. The subjects with total NTSS-6 score> 6 will also be 
summarized by treatment group and overall for screening, Baseline (Week 0), Interim (Week 4), 
Interim (Week 8) EOT (Week 12) and Follow-up (4 weeks post last dose of study drug) visits. 
NTSS-6 data will be listed. 


 
 
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7.8.4.2 
Toronto Clinical Neuropathy Score (TCNS)  
The neurological examination will cover all aspects of the Toronto Clinical Neuropathy 
Score (TCNS). Following TCNS data15 will be collected. 
Symptom scores (0-6) 
Reflex scores (0-8) 
Sensory test scores (0-5) 
Foot  
Pain 
Numbness 
Tingling 
Weakness 
Ataxia 
Upper-limb symptoms 
Knee reflex 
Ankle reflex 
Pinprick 
Temperature 
Light touch 
Vibration 
Positioin 
Symptom scores: present=1; absent=0. 
Reflex scores: absent=2; reduced=1, normal=0 for each side (right and left) 
Sensory test scores: abnormal (for any side, left or right)=1, normal=0 
The total TCNS score (0 – 19) is sum of all items of TCNS15. 
Descriptive statistics for absolute value and absolute change from Baseline for total TCNS score 
will be presented for screening, Baseline, Interim (Week 4), Interim (Week 8) EOT (Week 12) 
and Follow-up (4 weeks post last dose of study drug) visits by treatment group and overall.  The 
abnormal results for any sensory test from the TCNS will also be summarized by treatment 
group and overall for screening, Baseline (Week 0), Interim (Week 4), Interim (Week 8) EOT 
(Week 12) and Follow-up (4 weeks post last dose of study drug) visits.  TCNS data will be listed. 
7.8.4.3 
Neurography (SNAP, CMAP and NCV) 
Neurography (nerve conduction velocity and amplitude) of peripheral sensory and motor nerves 
will be tested. Measurements will be taken twice for each assessed nerve in both the left and 
right extremity. Two measures for each test will be obtained and averaged. Descriptive statistics 
for absolute value and absolute change from Baseline for neurography (SNAP, CMAP and NCV 
– sensory nerve and motor nerve assessment) data will be presented for screening, Baseline 
(Week 0), Interim (Week 4), Interim (Week 8), EOT (Week 12), Follow-up (4 weeks post last 
dose of study drug) by treatment group and overall. Neurography data will be listed.   
7.8.5 
Columbia Suicide Severity Rating Scale (CSSRS) 
The CSSRS is a measure of suicidal ideation and behaviour. The below mentioned endpoints 
will be summarized descriptively by visit [wherever applicable]. Total score for past 6 months 
[screening visit] will be the Baseline value14.  
CSSRS Endpoints 


 
 
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1. Suicidal Ideation Score (1 – 5): The maximum suicidal ideation category present at the 
assessment. Assign a score of 0 if no ideation is present. 
2. Suicidal ideation (yes, no): A “yes” answer at any time during treatment to any one of the 
suicidal ideation questions on the CSSRS. 
3. Suicidal behaviour (yes, no): A “yes” answer at any time during treatment to any one of 
the suicidal behaviour questions on the CSSRS. 
4. Suicidal ideation or behaviour (yes, no): A “yes” answer at any time during treatment to 
any one of the suicidal ideation and behaviour questions on the CSSRS. 
5. Treatment-emergent suicidal ideation compared to recent history (yes, no): An increase in 
the maximum suicidal ideation score during treatment from the maximum suicidal 
ideation category during a specific pre-treatment period (CSSRS scales taken during the 
specified pre-treatment period; excludes “lifetime” scores from the Baseline CSSRS scale 
or Baseline/Screening CSSRS scale). 
6. Treatment-emergent serious suicidal ideation compared to recent history (yes, no): An 
increase in the maximum suicidal ideation score to 4 or 5 on the CSSRS during treatment 
from not having serious suicidal ideation (scores of 0-3) during a specified pre-treatment 
period (CSSRS scales taken during the specified pre-treatment period; excludes “lifetime” 
scores from the Baseline CSSRS scale or Baseline/Screening CSSRS scale). 
7. Emergence of serious suicidal ideation compared to recent history (yes, no): An increase 
in the maximum suicidal ideation score to 4 or 5 on the CSSRS during treatment from no 
suicidal ideation (scores of 0) during a specified pre-treatment period (CSSRS scales 
taken during the specified pre-treatment period; excludes “lifetime” scores from the 
Baseline CSSRS scale or Baseline/Screening CSSRS scale). 
8. Improvement in suicidal ideation at a time point of interest compared to Baseline (yes, 
no): An improvement in this endpoint can be considered as a decrease in suicidal ideation 
score at the time point of interest (e.g., the last measurement during treatment) from the 
Baseline measurement (e.g., the measurement taken just prior to treatment).  
9. Emergence of suicidal behaviour compared to all prior history (yes, no): The occurrence 
of suicidal behaviour during treatment from not having suicidal behaviour prior to 
treatment (includes “lifetime” and/or “screening” scores from the Baseline CSSRS scale, 
Screening CSSRS scale, or Baseline/Screening CSSRS scale, and any “Since Last Visit” 
from the Since Last Visit CSSRS scales taken prior to treatment. 
Numbers of subjects with “yes” answer to each question for suicidal ideation and suicidal 
behaviour, and CSSRS endpoint 2 – 4 (Suicidal ideation, Suicidal behaviour, and Suicidal 
ideation or behaviour) will be summarized by treatment group and overall.  


 
 
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Number of subjects with events per CSSRS endpoint 5-9 (Treatment-emergent suicidal ideation 
compared to recent history, Treatment-emergent serious suicidal ideation compared to recent 
history, Emergence of serious suicidal ideation compared to recent history, Improvement in 
suicidal ideation at a time point of interest compared to Baseline and Emergence of suicidal 
behaviour compared to all prior history) will be summarized by treatment group and overall. 
Shift tables will be presented showing the number of subjects per treatment group with ‘No 
suicidal ideation or behaviour’, ‘Suicidal ideation’ or ‘Suicidal behaviour’ at the Baseline to 
post-treatment. Subjects with both ‘Suicidal ideation’ and ‘Suicidal behaviour’ are included in 
the ‘Suicidal behaviour’ category. 
Shift tables will be presented for Suicidal Ideation Score (CSSRS endpoint 1) showing the 
number of subjects per treatment group with maximum score 0 - 5 at the Baseline to post-
treatment. 
CSSRS data will be listed.   
7.8.6 
Other Safety Endpoints and Analyses 
Other safety endpoints of vital signs and physical examination data will be summarized or listed. 
Safety analysis set will be used for the analyses.   
Vital Signs 
Descriptive statistics for absolute value and absolute change from Baseline for protocol specified 
vital sign parameters of blood pressure, heart rate, respiratory rate and oral temperature will be 
presented for scheduled visits by treatment group and overall. Vital signs data will be listed.  
Physical Examination 
Physical examination data will be listed.  
7.9 
Pharmacokinetics (PK) /Pharmacodynamics (PD) Endpoints Analyses 
PK plasma and PD parameters will be assessed using the PK/ PD set, respectively.  
A separate Modelling and Simulation Analysis Plan will be prepared and results from the PK/PD 
modelling will be reported separately from the clinical study report.  
XanamemTM concentrations will be summarized descriptively by treatment group, visit and time 
point.  
PD parameters of ACTH, DHEAS, androstenedione and testosterone will be summarized for 
absolute values, change from baseline and % change from baseline.  
Sub-group analysis will be performed by gender for PK/PD data.  PK/PD data sampling details 
will be listed.  


 
 
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7.10 
Other Exploratory Endpoints Analyses 
The other exploratory endpoints will be summarized for safety analysis set with actual treatment 
group received. The following other endpoints will be summarized.    
• Metabolic function: lipids, blood pressure, glucose, HbA1c, body weight and BMI 
7.10.1 Metabolic Function 
Descriptive statistics for absolute value and absolute change from Baseline for protocol specified 
laboratory parameters of lipids [cholesterol, triglycerides, high-density lipoprotein-cholesterol, 
low-density lipoprotein-cholesterol, low-density lipoprotein-cholesterol], supine systolic and 
diastolic blood pressure, glucose, HbA1c, body weight, BMI will be presented for scheduled 
visits by treatment group and overall. International System of Units (SI units) will be used for the 
analysis.  
7.11 
Subgroup Analyses 
To explore the homogeneity of the treatment effect across relevant patient subsets, following 
subgroup analysis will be performed for efficacy endpoints as specified. 
• Baseline CDRGlobal score (0.5 vs 1.0) : all primary and secondary efficacy endpoints if 
at least 25% of subjects are in both groups. 
• Baseline HbA1c (lower 30% vs upper 30%) : co-primary efficacy endpoints 
• Baseline Glucose level (lower 30% vs upper 30%) : co-primary efficacy endpoints 
 
7.12 
Statistical Analysis Plan for Additional Analyses to be Conducted by McCloud 
Consulting Group After Database Lock 
Any additional analyses conducted after database lock performed by McCloud Consulting Group 
(MCG) will be specified in the document ‘MCG ACW002 XanADu Statistical Analysis Plan for 
Additional Analyses Conducted After Database Lock’. The analyses to be conducted by MCG 
may include, but are not limited to, analyses of cortisol data which will not be available until 
after the date of database lock, and additional subgroup analyses planned after reviewing the 
final unblinded study results. 
 
 
 
 


 
 
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8.0 
HANDLING OF MISSING VALUES 
In general, for all variables only the observed data from the patients will be used in the analysis.  
Missing Baseline data for the MMSE may be replaced by the Screening results only for the 
analysis of MMSE alone. When MMSE results are analysed as part of the ADCOMs analysis, 
such a replacement is not allowed, in order to ensure that all Baseline values contributing to the 
ADCOMs refer to the same point in time. 
No imputation of values for other missing data will be performed, unless specified, for e.g. 
sensitivity analysis for primary efficacy endpoints.  
Adverse events with missing causal drug relationship will be summarized as related.  
Missing safety data will not be replaced, except for AE and Concomitant Medication dates as 
described below. 
Adverse Event:  
If due to partial dates or times it is not possible to definitively conclude that an AE is not 
treatment emergent, then a conservative approach will be taken into account whereby it will be 
classified as a TEAE, e.g. if the first dose date is “13May” and the AE starts in “May”, then that 
AE will be classified as a TEAE, unless the AE stop date precludes this (i.e. the AE stop date is 
definitively prior to the first dose date).  
Some more imputation scenarios: 
If onset date is missing or partial, but stop date is prior to first dose date, then onset date 
is set to January 1st on the same year of stop date. 
If onset date is completely missing, onset date is set to date of first dose. 
If (year is present and month and day are missing) or (year and day are present and month 
is missing): 
If year = year of first dose, then set month and day to month and day of first dose 
If year < year of first dose, then set month and day to December 31st unless the 
calculation results in a negative time duration. 
If year > year of first dose, then set month and day to January 1st. 
If month and year are present and day is missing:  
If year = year of first dose and 
month = month of first dose then set day to day of first dose date  
month < month of first dose then set day to last day of month 
month > month of first dose then set day to first day of month 


 
 
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If year < year of first dose then set day to last day of month 
If year > year of first dose then set day to first day of month 
For all other cases, set onset date to date of first dose.  
Concomitant Medication Dates: 
Missing or partially missing medication date and prior or concomitant medication determination: 
If due to partial dates it is not possible to categorize a medication as prior or concomitant, then a 
conservative approach will be taken into account whereby it will be classified as such, e.g. if the 
first dose date is “13May” and another medication is started in “May”, then that medication will 
be classified as both prior and concomitant, unless the medication stop date precludes one of 
these classifications.  
Some more imputation scenarios: 
If start date is completely missing, start date will not be imputed. 
If (year is present and month and day are missing) or (year and day are present and month 
is missing), set month and day to January 1. 
If year and month are present and day is missing, set day to 1st day of month. 
If end date is completely missing, end date will not be imputed. 
If (year is present and month and day are missing) or (year and day are present and month 
is missing), set month and day to December 31. 
If year and month are present and day is missing, set day to last day of the month. 
  
9.0 
INTERIM ANALYSIS 
9.1 
Introduction 
One interim analysis is planned to be performed when approximately 50 subjects corresponding 
to FAS completed the study to make a decision on early discontinuation with efficacy on the 
basis of an analysis of covariance (ANCOVA) for the change in ADCOMs/ADAS-Cog v14 
score from Baseline (Week 0) to Week 12/EOT. To adjust the overall probability of type I errors 
to 0.05, the Haybittle-Peto approach will be used, thus setting the stopping boundary for the 
primary efficacy variables at a one-sided 0.001, leaving the full type I error rate of a one-sided 
0.05 for the final analysis. This interim efficacy analysis aims at providing additional 
information on the efficacy parameters to the DSMB, including both descriptive and inferential 
statistics. No study adaptations are planned based on these analyses. Should there be evidence of 
an overwhelming effect, the DSMB may recommend stopping early for success. 


 
 
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9.2 
Data Safety Monitoring Board (DSMB) 
A DSMB must be established to independently monitor safety and efficacy data as well as 
operation of the study. After each meeting, the DSMB will provide advice on whether the study 
should be continued, modified, or discontinued on the basis of the toxicities observed. The 
DSMB will also review the results of the interim analysis and determine whether these data meet 
the criteria for stopping the study early for efficacy. Detailed tasks of the DSMB will be 
described in a separate DSMB charter. 
9.3 
Analysis Population for Interim Analysis 
For efficacy endpoints, the FAS will be used for the interim analysis. 
For safety endpoints, the Safety Analysis Set will be used for the interim analysis. 
Each analysis set is defined in the section 6.0. 
9.4 
Cutoff Data for Interim Analysis 
Cutoff date will be the time point when approximately 50 subjects corresponding to FAS 
completed the study with the primary efficacy assessments at Week 12/EOT. All data available 
at the cutoff will be included in the interim analysis.  
9.5 
Endpoint for Interim Analysis 
The following endpoints will be analysed in this interim analysis:  
Efficacy; 
   Primary efficacy endpoints: 
• ADCOMS 
• ADAS-Cog 
   Secondary efficacy endpoints: 
• MMSE 
• CDR-SOB 
• RAVLT 
• NPI 
• NTB – Executive domain (COWAT and CFT) 
Safety; 
• Laboratory values 
• Incidence of AEs 
• NFM 


 
 
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PK/PD; 
• Plasma concentrations of Xanamem™ 
The details of analysis on efficacy, safety and PK/PD endpoints are presented under SAP section 
7.7 efficacy endpoints and analysis, 7.8 safety endpoints and analysis and 7.9 PK/PD endpoint 
analyses.  
10.0 CHANGES FROM ANALYSIS METHODS PLANNED IN THE PROTOCOL 
Not Applicable 
 
 


 
 
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11.0 REFERENCES 
1. World Alzheimer Report. Alzheimer's Disease International, 2015. 
2. https://fightdementia.org.au/about-us/media/key-facts-and-statistics. 
3. Lewis H, Beher D, Cookson N, et al. Quantification of Alzheimer pathology in ageing 
and dementia: age-related accumulation of amyloid-beta(42) peptide in vascular 
dementia. Neuropathol Appl Neurobiol. 2006 Apr; 32(2):103-18. 
4. 4. https://www.alz.org/facts/downloads/facts_figures_2015.pdf. 
5. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2014/10/ 
WC500176827.pdf. 
6. https://support.sas.com/resources/papers/proceedings14/SAS270-2014.pdf 
7. Wang J, et al. ADCOMS: a composite clinical outcome for prodromal Alzheimer’s 
disease trials. J Neurol Neurosurg Psychiatry 2016;0:1–7. doi:10.1136/jnnp-2015-312383 
8. Michael Schmid. Rey Auditory Verbal Learning Test. A Handbook, 1996. 
9. Richard C. Mohs, Ph.D. The Administration and Scoring Manual for the Alzheimer’s 
Disease Assessment Scale 1994 Revised Edition, Copyright © 1994 by Mount Sinai 
School of Medicine. A Publication of the Alzheimer’s Disease Cooperative Study (NIA 
2U19AG010483-22) 
10. Morris, J.C. (1993). The clinical dementia rating (CDR): Current version and scoring 
rules. Neurology, 43(11), 2412-2414. 
11. Folstein MF, Folstein SE, McHugh, PR. "Mini-mental state". A practical method for 
grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975; 12(3):189–
98. 
12. Kaufer DI, Cummings JL, Christine D, et al. Assessing the impact of neuropsychiatric 
symptoms in Alzheimer’s disease: the Neuropsychiatric Inventory Caregiver Distress 
Scale. J Am Geriatr Soc. 1998; 46(2):210-5. 
13. Neuropsychiatric Inventory (NPI), Comprehensive Assessment of Psychopathology in 
Patients with Dementia. Jeffrey L. Cummings, MD, UCLA Alzheimer's Disease Center, 
Reed Neurological Research Center, 710 Westwood Plaza, Los Angeles, California, USA 
90095-1769 
(telephone 
310/206-5238; 
FAX 
310/206-5287; 
e-mail 
jcummings@mednet.ucla.edu). 
14. http://cssrs.columbia.edu/wp-content/uploads/ScoringandDataAnalysisGuide-for-
Clinical-Trials.pdf. 
15. Vera Bril et.al. Validation of the Toronto Clinical Scoring System for Diabetic 
Polyneuropathy; Diabetes Care, Volume 25, Number 11, November 2002. 


 
 
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12.0 APPENDIX 
Appendix 1: Schedule of Activities 
Visit name 
Screening 
1 
Baseline 
1 
Interim 1 
Telephone 
Contact 14 
EOT 1,2 
Follow-
up 1 
Unscheduled 
Safety Visit 
15 
Visit time and variance 
Weeks -1 
to -4 
Week 0 
Week 4
± 
4 days 
Week 8
± 
4 days 
Ad hoc 
Week 12
± 4 days 
4 Weeks 
Post 
Last 
Dose of 
Study 
Drug 
± 4 days 
 
Informed consent (subject 
and caregiver) 
X 
 
 
 
 
 
 
 
Inclusion and exclusion 
criteria 
X 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
Prior/concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
MMSE (subject only) and 
CDR-SOB (subject and 
caregiver) 
X 
X 
 
 
 
X 
 
 
ADAS-Cog v14 (subject 
only), RAVLT (subject 
only), NTB (subject only) 
and NPI (caregiver only) 
 
X 
 
 
 
X 
 
 
NTSS-6 (subject and 
caregiver) 3 
X 
X 
X 
X 
X 
X 
X 
X 
CSSRS (subject and 
caregiver) 
X 
 
X 
X 
 
X 
X 
 
Physical and neurological 
examination (including 
TCNS), weight, vital signs 
4 
X 
X 
X 
X 
 
X 
X 
X 
NFM (including clinician-
rated outcome in TCNS) 5 
X 
X 
X 
X 
 
X 
X 
 
Height 
X 
 
 
 
 
 
 
 
BMI 
 
X 
 
 
 
X 
 
 
Brain MRI/CT 6 
X 
 
 
 
 
 
 
 
Randomisation 
 
X 
 
 
 
 
 
 
 PK blood sample 7 
 
X 
X 
X 
 
X 
 
X 
Safety laboratory sample 
(biochemistry, 
haematology and urine 
examination) 
X 
X 
X 
X 
 
X 
X 
 


 
 
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Visit name 
Screening 
1 
Baseline 
1 
Interim 1 
Telephone 
Contact 14 
EOT 1,2 
Follow-
up 1 
Unscheduled 
Safety Visit 
15 
Visit time and variance 
Weeks -1 
to -4 
Week 0 
Week 4
± 
4 days 
Week 8
± 
4 days 
Ad hoc 
Week 12
± 4 days 
4 Weeks 
Post 
Last 
Dose of 
Study 
Drug 
± 4 days 
 
Vitamin B12 
X 
 
 
 
 
 
 
 
Sample for metabolic 
function testing:  glucose 
and lipids, HbA1c 8 
 
X 
 
 
 
X 
 
 
Pregnancy test 9 
X 
X 
X 
X 
 
X 
X 
 
FSH test 10 
X 
 
 
 
 
 
 
 
Benzodiazepines screening 
11 
X 
 
 
 
 
 
 
 
Optional PD sample for 
adrenocorticotropic 
hormone, 
dehydroepiandrosterone 
sulfate, androstenedione 
and testosterone 12 
 
X 
X 
X 
 
X 
X 
 
ECG 
X 
X 13 
X 
X 
 
X 
X 
 
Daily Drug Intake Diary 
 
X 
X 
X 
 
X 
 
 
Drug dispense 
 
X 
X 
X 
 
 
 
 
Adverse event capture 
X 
X 
X 
X 
X 
X 
X 
X 
Drug accountability 
 
 
X 
X 
 
X 
 
 
IWRS 
X 
X 
X 
X 
 
 
 
 
Abbreviations:  ADAS-Cog v14=Alzheimer's Disease Assessment Scale-cognitive subscale; BMI=body mass index; 
CDR-SOB=Clinical Dementia Rating scale-Sum of Boxes; CSSRS=Columbia Suicide Severity Rating Scale; 
CT=computed tomography; ECG=electrocardiogram; EOT=End of Treatment; FSH=follicle-stimulating hormone; 
HbA1c=haemoglobin A1c; IWRS=Interactive Web Response System; MMSE=Mini-Mental Status Examination; 
MRI=magnetic resonance imaging; NFM=nerve function monitoring; NPI=Neuropsychiatric Inventory; 
NTB=Neuropsychological Test Batteries; NTSS=Neuropathy Total Symptom Score; RAVLT=Rey Auditory Verbal 
Learning Test; PD=pharmacodynamic; PK=pharmacokinetic; TCNS=Toronto Clinical Neuropathy Score.  
1 
Caregiver is required to be present at all visits (but not for all scales).  For details see Section 9.4.1 of protocol 
2 
Subjects terminating the study early will, if possible, undergo all assessments planned for the EOT (Week 12) 
visit. 
3 
The NTSS-6 should be completed with the help of site staff, also taking into consideration input from the 
caregiver. 
4 
Vital signs must include but not be limited to the measurement of orthostatic changes in heart rate and blood 
pressure.  For details see Section 12.6 of protocol.  Neurological examination will cover all aspects of the 
TCNS, which includes muscle strength/weakness in arms and legs, ataxia (gait, stance and finger-nose 
coordination), light touch (upper and lower extremity), pinprick (upper and lower extremity), position sense 
(toes and thumbs), reflexes (knee and ankle).  The neurological examination can be conducted ± 3 days of the 
scheduled protocol visit (for details see Section 12.5 of protocol.). 


 
 
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5 
NFM consists of sensory testing (vibration and thermal perception), motor and sensory nerve neurography 
(amplitude and conduction velocity) and clinician-rated outcome in TCNS.  The NFM can be conducted 
± 3 days of the scheduled protocol visit, except at the Screening visit where there is no limit and at the Baseline 
visit where it must be conducted within 3 days prior to the randomisation step.  Note: Subject-related outcome 
measure, NTSS-6, is part of NFM but listed separately.  For details see Section 12.7 of protocol. 
6 
A brain MRI/CT scan is only needed if no historic scan is available from within 12 months prior to Screening.  
A wider window may be accepted but requires written approval from the ICON Medical Monitor. 
7 
One PK sample will be taken 3 to 5 hours post-dose at the Baseline (Week 0) visit and two PK samples will be 
taken (at arrival on site [pre-dose] and 3 to 5 hours post-dose) at the Interim visits (Week 4 and Week 8).  One 
PK sample will be taken at the EOT (Week 12) visit.  NB:  The subject will not be dosed during the EOT visit.  
For details, see Section 9.4.1 of protocol.  The exact time-points of blood sampling for PK analysis and drug 
intake will be documented.  Between visits, subjects will record the exact times of study drug intake in the Drug 
Intake Diary.  The subject will be required to bring the diary to the Interim visits (Week 4 and Week 8) and 
EOT (Week 12) visit. 
8 
Taken from the blood sample at Baseline (Week 0), and EOT (Week 12) visits. 
9 
Women of childbearing potential only.  A serum pregnancy test will be performed at Screening and a urine 
pregnancy test at all subsequent clinic visits. 
10 Females only.  To be taken only if there is clinical concern about the subject’s menopausal status. 
11 Urine collected for the urinalysis sample will also be used to test for the presence of benzodiazepines at the 
Screening visit.  A second urine sample, prior to randomisation, will be needed if a benzodiazepine re-test is 
required. 
12 This sample should be collected as soon as possible after the subject arrives at the study site (pre-dose).  This 
could, if possible, be combined with other blood draws to minimise the burden for subjects.  For optimal results, 
the sample for androstenedione analysis should be taken between 6 am and 10 am. 
13 ECG at Baseline only required if Screening ECG was performed more than 2 weeks earlier.   
14 Ad hoc telephone contact may occur at any time-point throughout the study, if deemed necessary by the 
investigator/study nurse, or if the subject wishes to report an AE. 
15 If an SAE occurs in a subject, the subject will return to the site for a PK sample.  Additional procedures will be 
performed as indicated, for details see Section 12.1.1.3 of protocol). 
 
Note:  For each study visit, excluding the Screening visit, subjects will arrive at the study site having fasted for at 
least 10 hours.  Subjects should aim to take study drug at the same time each morning with food (30 minutes after 
the start of a standard meal) at the study site, and after all pre-dose blood samples have been taken. It is 
recommended that the subject visit the study site in the morning so that the fasted period will have been overnight.  
The investigator will record time of arrival and the hours fasted.  The investigator will take the appropriate blood 
samples from the subject, for various assessments, as indicated in the following sections.  After the blood draws, the 
subject will take food and a drink (to be provided either by the study site, or the subject).  About 30 minutes after 
the start of the meal, subjects will be administered study drug in the presence of appropriate site staff.  The exact 
time of dosing is to be recorded in the Drug Intake Diary. 
 
 


 
 
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Appendix 2: Classification of Visits Window 
Timing of assessment 
(days relative to Treatment a) 
Visit 
Visit Name to display 
for Analysis 
Study Day  
(Relative Day) a 
Weeks -1 to -4 
Screening 
Screening  
-28 ~ -1 
Week 0* 
Baseline 
Baseline (Week 0) 
1 
Week 4 (± 4 days) 
Interim 
Interim (Week 4) 
29 (25 – 33) 
Week 8 (± 4 days) 
Interim 
Interim (Week 8) 
57 (53 – 61) 
Week 12 (± 4 days) 
EOT 
EOT (Week 12) 
85 (81  - 89) 
4 Weeks Post Last Dose of 
Study Drug (± 4 days) 
Follow-up 
Follow-up (4 weeks 
post last dose of study 
drug) 
28 (24 ~ 32) days after 
last dose of study drug b 
* It also depends on Baseline definition of each variable.  
a. Day 1 is the day of first dose of treatment. 
b. calculate study day (relative day) based on last dose of study drug 
 
 


 
 
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Appendix 3: Scoring Details of Efficacy Variables 
Alzheimer's Disease COMposite Score (ADCOMs) 
ADCOMs score is composite score derived from ADAS-Cog v14, CDR-SOB, and MMSE.  
The resultant composite score, ADCOMS, is a weighted linear combination of the remaining 
individual scale items in the final fitted PLS model using the corresponding PLS coefficients as 
weighting factors see the table. The range of ADCOMS is between 0 and 1.97. Items making 
contributions to ADCOMS include 4 items of the ADAS-cog; two items of the MMSE, and all 
six items of the CDR-SOB. 
 
Items selected in the Wold’s PLS model and their corresponding PLS coefficients 7 
Scale 
Item name 
PLS coefficients 
ADAS-cog 
Delayed word recall 
0.008 
Orientation 
0.017 
Word recognition 
0.004 
Word finding difficulty 
0.016 
MMSE 
Orientation time 
0.042 
Drawing 
0.038 
CDR-SB 
Personal care 
0.054 
Community affairs 
0.109 
Home and hobbies 
0.089 
Judgment and problem solving 
0.069 
Memory 
0.059 
Orientation 
0.078 
ADAS-cog: Alzheimer’s Disease Assessment Scale–cognitive subscale; CDR-SB: Clinical 
Dementia Rating, sum of boxes; MMSE: Mini-Mental State Exam; PLS: partial least squares.  
 
 The ADCOMs score, which is rescaled decline, will be derived based on the coefficients and 
corresponding items selected from PLS regression in above table: 
 
ADCOMs score
= 0.008 ∗    − +  0.017
∗$%&''%& − +  0.004 ∗) &%'%& − 
+  0.016 ∗) +%&%& %++%,' − +  0.042
∗$%&''%& '%.//0 +  0.038 ∗%&//0 +  0.054
∗34&  56 −7 +  0.109 ∗5..,&%' ++%456 −7 
+  0.089 ∗9. & ℎ;;%456 −7 +  0.069 
∗<,.&' & =;. 4>%&56 −7 +  0.059
∗/. 56 −7 + 0.078 ∗$%&''%&56 −7  


 
 
CONFIDENTIAL 
Page 51 of 59 
 
It is careful to use the reversed score with regard to MMSE (maximum score for each item – 
MMSE score of each item). It means that for the derivation of ADCOMS score, (5- MMSE score 
of ‘Orientation time’) will be used for ‘Orientation time’ and (1-MMSE score for ‘Drawing’) 
will be used for ‘Drawing’. 
 
 


 
 
CONFIDENTIAL 
Page 52 of 59 
 
Rey Auditory Verbal Learning Test (RAVLT) 
The standard RAVLT format starts with a list of 15 words, which an examiner reads aloud at the 
rate of one per second. The participant’s task is to repeat all the words he or she can remember, 
in any order. This procedure is carried out a total of five times which can be used for the 
evaluation of incremental practice effects. Then the examiner presents a second list of 15 words, 
allowing the participant only one attempt at recall. Immediately following this, the participant is 
asked to remember as many words as possible from the first list8.  
 
The RAVLT test and its score details are given below:  
 
RAVLT 
 Scoring  
    Recall List A 
Total number of correct words 
    Recall List B 
Number of correct words 
    Final recall of List A 
Number of correct words 
  
 
 


 
 
CONFIDENTIAL 
Page 53 of 59 
 
Alzheimer’s Disease Assessment Scale - Cognitive Behaviour Section (ADAS-Cog v14)  
The ADAS-cog v149 includes the following 14 items, with a Total scoring range of 0 – 90.  
ADAS Cog Item 
Scoring Details 
Item 1 - Word Recall Task 
On this task, the participant is given three trials to learn a list of ten 
high-frequency, high imagery nouns. The ten words are printed in 
block letters on white cards.  
Scoring: 
The participant's score is the mean number of words not recalled 
across the three trials (maximum score = 10). 
The score should be calculated to two decimal places. 
If any of the three trials is not completed for any reason, then the task 
is considered incomplete and a missing data code must be assigned to 
the item score. 
Item 2 - Naming Objects and Fingers 
For this task, the participant is asked to name 12 randomly presented 
real objects, with high (flower, bed, whistle, pencil), medium (rattle, 
mask, scissors, comb) and low (wallet, harmonica, stethoscope, tongs) 
frequency values. The participant is also asked to name the fingers of 
his/her dominant hand. 
Scoring: 
0 = 0-2 items (objects and fingers) named incorrectly 
1 = 3-5 items (objects and fingers) named incorrectly 
2 = 6-8 items (objects and fingers) named incorrectly 
3 = 9-11 items (objects and fingers) named incorrectly 
4 = 12-14 items (objects and fingers) named incorrectly 
5 = 15-17 items (objects and fingers) named incorrectly 
Item 3 - Commands 
This task is designed to assess receptive speech. The participant is 
asked to carry out five separate commands with 1 to 5 steps per 
command. 
Scoring: 
0 = all commands correct 
1 = 1 command incorrect 
2 = 2 commands incorrect 
3 = 3 commands incorrect 
4 = 4 commands incorrect 
5 = all 5 commands incorrect 
Item 4 - Constructional Praxis 
This test assesses the participant's ability to copy four geometric 
forms ranging from a very simple one (circle) to a fairly difficult one 
(cube). 
Scoring: 
0 = all 4 drawings correct 
1 = 1 form drawn incorrectly 
2 = 2 forms drawn incorrectly 
3 = 3 forms drawn incorrectly 
4 = 4 forms drawn incorrectly (but one or more side/section of at least 
one shape drawn) 
5 = No figures drawn, no recognizable attempt at drawing any 
side/section of any figure 
Item 5 - Ideational Praxis 
This task is designed to determine whether the participant can perform 
a familiar but complex sequence of actions. 
Scoring: 
0 = all components performed correctly 
1 = failure to perform 1 component 


 
 
CONFIDENTIAL 
Page 54 of 59 
 
ADAS Cog Item 
Scoring Details 
2 = failure to perform 2 components 
3 = failure to perform 3 components 
4 = failure to perform 4 components 
5 = failure to perform 5 components 
Item 6 - Orientation 
In this task, the participant is asked 8 questions regarding his or her 
orientation to person, place and time. 
Scoring: One point is given for each incorrect response (maximum = 
8). 
Item 7 - Word Recognition Task 
On this task the participant is given one trial to learn a list of 12 
words.  
Scoring: 
There are 24 opportunities for error in the one trial of recognition, 
including the 12 learning (target) words and 12 distractor words. The 
participant could incorrectly identify a distracter word as one of the 
learning words they were just shown, or they could incorrectly say 
they were not shown a learning word. While all incorrect responses 
should be noted on the form by the tester (there are 0-24 errors 
possible in the trial), the maximum error score is 12. If the participant 
makes 13-24 errors, the score for the trial remains at 12. Dr. Mohs has 
stated that the maximum error score is 12 per trial as this is the 
average number of errors that would be made by a person guessing 
randomly.  
Item 8 - Language 
This item is a global rating of the quality of speech, i.e., lack of 
clarity, difficulty in making oneself understood with words.  
Scoring: 
0 = participant speaks clearly and/or is understandable 
1 = very mild: one instance of lack of understandability 
2 = mild: participant has difficulty less than 25% of the time 
3 = moderate: participant has difficulty 25-50% of the time 
4 = moderately severe: participant has difficulty more than 50% of the 
time 
5 = severe: one or two word utterances; fluent, but empty speech; 
mute 
Item 9 - Comprehension of spoken 
language 
This item evaluates the participant’s ability to understand spoken 
language.  
Scoring: 
0 = None: participant understands. 
1 = Very Mild: one or two instances of misunderstanding. 
2 = Mild: 3–5 instances of misunderstanding. 
3 = Moderate: requires several repetitions and rephrasings. 
4 = Moderately Severe: participant only occasionally responds 
correctly; i.e., yes-or-no questions. 
5 = Severe: participant rarely responds to questions appropriately; not 
due to poverty of speech. 
Item 10 - word finding difficulty 
Along with Spoken Language Ability, this item rates impairment in 
expressive speech, but it rates only word finding difficulty, whereas 
Spoken Language Ability is a more global rating of the extent to 
which the participant can communicate verbally.  
Scoring: 
0=no evidence of word finding difficulty in spontaneous speech 
1=very mild: 1 or 2 instances, not clinically significant 
2=mild: noticeable circumlocution or synonym substitution 
3=moderate: loss of words without compensation on occasion 


 
 
CONFIDENTIAL 
Page 55 of 59 
 
ADAS Cog Item 
Scoring Details 
4=moderately severe: frequent loss of words without compensation 
5=severe: nearly total loss of content of words; speech sounds empty; 
1-2 word utterances 
Item 11 - Remembering Test 
Instructions 
This item evaluates the participant’s ability to remember the 
instructions given for the Word Recognition task only. The score is 
based on the number of instruction repetitions only after the first two 
words. No other tasks or aspects of the ADAS-cog are considered 
when scoring this item. 
Scoring: 
0 = No reminders given in Word Recognition 
1 = very mild: reminded once 
2 = mild: reminded 2 times 
3 = moderate: reminded 3 or 4 times 
4 = moderately severe: reminded 5 or 6 times 
5 = severe: reminded 7 or more times 
Item 12 - Maze 
In this task, the participant is asked to find his or her way through a 
maze with a pencil, without hitting a dead end. The participant is told 
he or she may pause to make a decision. The task is halted after the 
participant makes two errors or 240 seconds has elapsed. An example 
maze is given for practice before the participant attempts the test 
maze. 
Scoring: 
The score is the time to completion or the time at which the 
participant made the second error (maximum time = 240 seconds).  
The score from the practice task is not included. The score is 
calculated only from the timed performance task. 
Item 13 - Number Cancellation 
In this task, the participant is asked to cross off as many target digits 
as possible in 45 seconds. 
Scoring: 
The score is the number of target items correctly crossed off in 45 
seconds, minus the number of incorrectly crossed off items, and 
minus the number of reminders given. 
The score from the practice task is not included. The score is 
calculated only from the timed performance task. 
Item 14 - Delayed Recall 
If added, this item adds 10 points to the possible total ADAS-cog 
score.  In this task, the participant is asked to recall the 10 words 
presented during the Word Recall task. There is one trial of recall. 
This task is administered following completion of the COMMANDS 
and CONSTRUCTIONAL PRAXIS items. 
Scoring: 
The score is the number of words not recalled (Maximum score = 10). 
Final 
Sum score of 14 items 
 
 
 
 
 
 
 


 
 
CONFIDENTIAL 
Page 56 of 59 
 
Clinical Dementia Rating Scale - Sum of Boxes (CDR-SOB) 
 
The CDR-SOB includes the following six items, with a Total scoring range of 0 – 18. Only 
caregiver/ informant details are to be collected 10.  
CDR 
Scoring 
Domain 1: Memory Questions 
Scoring (0, 0.5, 1, 2, 3) for replies of Informant 
Domain 2: Orientation 
Scoring (0, 0.5, 1, 2, 3) for replies of Informant 
Domain 3: Judgment and Problem Solving 
Scoring (0, 0.5, 1, 2, 3) for replies of Informant 
Domain 4: Community Affairs 
Scoring (0, 0.5, 1, 2, 3) for replies of Informant 
Domain 5: Home and Hobbies 
Scoring (0, 0.5, 1, 2, 3) for replies of Informant 
Domain 6: Personal Care 
Scoring (0, 1, 2, 3) for replies of Informant 
  
Total score = Sum of the Boxes 
 
 
 


 
 
CONFIDENTIAL 
Page 57 of 59 
 
Mini-Mental Status Examination (MMSE) 
The MMSE is a 30-point questionnaire that is used extensively in clinical and research settings 
to measure cognitive impairment11 and is commonly used in medicine and allied health to 
screen for dementia. It is also used to estimate the severity and progression of cognitive 
impairment and to follow the course of cognitive changes in an individual over time; thus 
making it an effective way to document a participant’s response to treatment. The total score 
range is 0 – 30.  
 
 
 
 


 
 
CONFIDENTIAL 
Page 58 of 59 
 
Neuropsychiatric Inventory (NPI) 
The NPI was constructed to survey neuropsychiatric disorders in demented patients12. NPI 
having 12 domains and For each domain, the relatives assess the frequency of the behaviour (4-
point scale), the severity of the symptom (3-point scale) and the emotional stress for the 
caregiver (6-point scale).  
The NPI total score is calculated by multiplying the frequency and severity rates per domain 
(maximum score per domain is 12) and then calculating the total of 10 domains [domain A to L]. 
(total NPI-score minimum is 0 and maximum 144). The 12 item score is being used. Total 
distress is sum of distress of 12 items of the NPI distress questions 13.  
NPI 
Scoring 
Domain A: Delusions 
Score of Frequency (1 - 4), Score of Severity (1 - 3), Distress (0-5) 
Domain B: Hallucinations 
Score of Frequency (1 - 4), Score of Severity (1 - 3), Distress (0-5) 
Domain C: Agitation / Aggression 
Score of Frequency (1 - 4), Score of Severity (1 - 3), Distress (0-5) 
Domain D: Depression/Dysphoria 
Score of Frequency (1 - 4), Score of Severity (1 - 3), Distress (0-5) 
Domain E: Anxiety 
Score of Frequency (1 - 4), Score of Severity (1 - 3), Distress (0-5) 
Domain F: Elation/Euphoria 
Score of Frequency (1 - 4), Score of Severity (1 - 3), Distress (0-5) 
Domain G: Apathy / Indifference 
Score of Frequency (1 - 4), Score of Severity (1 - 3), Distress (0-5) 
Domain H: Disinhibition 
Score of Frequency (1 - 4), Score of Severity (1 - 3), Distress (0-5) 
Domain I: Irritability / Lability 
Score of Frequency (1 - 4), Score of Severity (1 - 3), Distress (0-5) 
Domain J: Aberrant Motor Behavior 
Score of Frequency (1 - 4), Score of Severity (1 - 3), Distress (0-5) 
Domain K: Sleep 
Score of Frequency (1 - 4), Score of Severity (1 - 3), Distress (0-5) 
Domain L: Appetite and eating disorders 
Score of Frequency (1 - 4), Score of Severity (1 - 3), Distress (0-5) 
Frequency is rated as: 1 - Occasionally - less than once per week; 2 - Often - about once per week; 3 - Frequently - 
several times per week but less than every day; 4 - Very frequently - daily or essentially continuously present. 
Severity is rated as: 1 - Mild - produces little distress in the patient; 2 - Moderate - more disturbing to the patient but 
can be redirected by the caregiver; 3 - Severe - very disturbing to the patient and difficult to redirect. 
Distress is scored as: 0 - no distress; 1- minimal; 2 – mild; 3 – moderate; 4 - moderately severe; 5 - very severe or 
extreme 
 
 
 
 


 
 
CONFIDENTIAL 
Page 59 of 59 
 
Neuropsychological Test Battery (NTB) - Executive Domain (COWAT and CFT) 
NTB score is the sum of correct response of Category Fluency Test (CFT) and Controlled Oral Word Association – 
Test (COWAT).  The following scoring table will explain it very clearly.  
 
NTB (COWAT and CFT) 
Scoring 
    COWAT 
Total number of correct words 
    CFT 
Total correct responses 
Total incorrect responses 
Total intrusions 
    Total 
COWAT + CFT(Correct response) 
 
 

Prot_000.pdf: 
Actinogen Medical 
CONFIDENTIAL 
Protocol: XanADu 
 
 
Final Protocol Incorporating Non-Sub. Amendment 5
18-Jul-2018
Page 1 of 106
 
1 
TITLE PAGE 
 
 
AMENDED CLINICAL STUDY PROTOCOL 
XanADu:  A Phase II, Double-Blind, 12-Week, Randomised, Placebo-Controlled Study 
to Assess the Safety, Tolerability and Efficacy of Xanamem™ in Subjects with Mild 
Dementia due to Alzheimer’s Disease (AD) 
 
 
Protocol Number: 
ACW0002 
Project Name:  
XanADu 
Universal Trial Number: 
U1111-1177-5932 
Test Product: 
Xanamem™ (UE2343) 
Indication: 
Mild Dementia due to Alzheimer’s disease 
Sponsor: 
Actinogen Medical, Level 9, Suite 1, 68 Pitt 
 
Street, Sydney, New South Wales 2000, 
 
Australia 
Development Phase: 
Phase II 
Date of the Final Protocol: 
08-Mar-2016 
Version of the Final Protocol: 
Final Version 2 
Date of Protocol Amendment 1:  
08-Aug-2016 
Date of Protocol Amendment 2:  
24-Nov-2016 
Date of Protocol Amendment 3: 
27-Jan-2017 (United Kingdom only) 
Date of Protocol Amendment 4: 
16-Oct-2017 
Date of Non-Substantial Amendment 5: 
18-Jul-2018 
 
The confidential information in this document is provided to you as an investigator, potential 
investigator or consultant for review by you, your staff and applicable Independent Ethics 
Committee and/or Institutional Review Board.  It is understood that the information will not 
be disclosed to others without written authorisation from Actinogen Medical except to the 
extent necessary to obtain informed consent from those persons to whom the drug may be 
administered. 
 


Actinogen Medical
Protocol: XanADu
CONFIDENTIAL
SIGNATURtr PAGES
SPON$OR SIGNATURE PAGE
PROTOCOL TITLE; XanADu: A Phase IIu Doub,le-Blind, l2-Week, Randomised,
Placebo-Controlled Study to Assess the Safety, Tolerability and Efficacy of X*namem"M
in Subjects with Mild Dementia due to Alzheimer's Disease (AD)
PROTOCOTNUMBER: ACW0002
I have read and understood the protoeol entitled as above and confirrn that, to the best
of my knowledge, the protocol accurately describes the design and conduct of the study.
Aqtiposen Msdical
Vincent Ruffles
Vice President of Drug Development
Actinogen Medical
Date (daylmonth/year)
2b+tf,t ,tr ttr
Final Protocol Incorporating Non-Sub. Amendment 5
18-Jul-2018
Professor Alan Boyd, M
Sponsor's Responsible
Actinogen Medical
Page2 of 107




Actinogen Medical 
CONFIDENTIAL 
Protocol: XanADu 
 
 
Final Protocol Incorporating Non-Sub. Amendment 5
18-Jul-2018
Page 4 of 106
 
SIGNATURE OF INVESTIGATOR 
I have read the protocol entitled “A Phase II, Double-Blind, 12-Week, Randomised, 
Placebo-Controlled Study to Assess the Safety, Tolerability and Efficacy of Xanamem™ in 
Subjects with Mild Dementia due to Alzheimer’s Disease (AD)” and confirm that, to the best 
of my knowledge, the protocol accurately describes the design and conduct of the study. 
 
I agree to conduct the study outlined above in accordance with the terms and conditions of 
the protocol, International Conference on Harmonisation guidelines on Good Clinical 
Practice and with applicable regulatory requirements.  All information pertaining to the study 
shall be treated in a confidential manner. 
 
Changes to the protocol will only be implemented after written approval is received from 
Actinogen Medical and the Institutional Review Board or Independent Ethics Committee (as 
appropriate), with the exception of medical emergencies.   
I will ensure that study staff fully understand and follow the protocol. 
 
 
 
 
 
(Name, job title and institution) 
 
 
 
 
 
Date (day/month/year) 
 
 
 
 
 
 
 
 
 
(Signature) 
 
 
 
 
 


Actinogen Medical 
CONFIDENTIAL 
Protocol: XanADu 
 
 
Final Protocol Incorporating Non-Sub. Amendment 5
18-Jul-2018
Page 5 of 106
 
3 
GENERAL INFORMATION 
XanADu:  A Phase II, Double-Blind, 12-Week, Randomised, Placebo-Controlled Study to 
Assess the Safety, Tolerability and Efficacy of Xanamem™ in Subjects with Mild Dementia 
due to Alzheimer’s Disease (AD) 
Protocol No.: 
ACW0002 
Date of the Final Protocol: 
08-Mar-2016 
Date of Protocol Amendment 1: 
08-Aug-2016 
Date of Protocol Amendment 2: 
24-Nov-2016 
Date of Protocol Amendment 3: 
27-Jan-2017 (United Kingdom only) 
Date of Protocol Amendment 4: 
16-Oct-2017  
Date of Non-Sub. Protocol Amendment 5: 18-Jul-2018 
Sponsor: 
Actinogen Medical 
 
Level 9, Suite 1 
 
68 Pitt Street 
 
Sydney, New South Wales 2000 
 
Australia 
Clinical Research Organisation: 
ICON Clinical Research Pty Ltd  
 
Suite 201, Level 2 
 
2-4 Lyon Park Road 
 
North Ryde, New South Wales 2113 
 
Australia 
Sponsor’s Legal Representative in 
ICON Clinical Research UK Ltd 
the European Union: 
Concept House 6 
 
Stoneycroft Rise 
 
Chandlers Ford 
 
Eastleigh, Hampshire SO53 3LD 
 
United Kingdom 
Sponsor Signatory: 
Vincent Ruffles 
 
Vice President of Drug Development  
 
Actinogen Medical 
 
Level 9, Suite 1 
 
68 Pitt Street 
 
Sydney, New South Wales 2000 
 
Australia 
 
Tel No.:  +61 2 8964 7401 
 
Fax No.:  +61 2 8964 7588 


Actinogen Medical 
CONFIDENTIAL 
Protocol: XanADu 
 
 
Final Protocol Incorporating Non-Sub. Amendment 5
18-Jul-2018
Page 6 of 106
 
Sponsor Medical Expert: 
Professor Alan Boyd 
 
Sponsor’s Responsible Physician 
 
Actinogen Medical 
 
Level 9, Suite 1 
 
68 Pitt Street 
 
Sydney, New South Wales 2000 
 
Australia 
 
Tel No.:  +61 2 8964 7401 
 
Fax No.:  +61 2 8964 7588 
Central Clinical Laboratory: 
ICON Laboratory Services 
 
South County Business Park 
 
Leopardstown, Dublin 18 
 
Ireland 
Secondary Clinical Laboratory:                    Edinburgh Clinical Research Facility 
 
                                                Queen's Medical Research Institute 
 
                                                47 Little France Crescent 
                                                                       Edinburgh EH16 4TJ 
 
                                                Scotland UK 
 


Actinogen Medical 
CONFIDENTIAL 
Protocol: XanADu 
 
 
Final Protocol Incorporating Non-Sub. Amendment 5
18-Jul-2018
Page 7 of 106
 
4 
STUDY SYNOPSIS 
Name of Sponsor/Company: 
Actinogen Medical 
Individual Study 
Table Referring to Part of 
the Dossier: 
 
 
Volume: 
 
Page: 
(For National Authority Use 
Only) 
Name of Product: 
Xanamem™ 
Name of Active Ingredient: 
(5-(1H-Pyrazol-4-yl)thiophen-3-yl)(3-
hydroxy-3-(pyrimidin-2-yl)-8 
azabicyclo[3.2.1]octan-8-yl)methanone 
Title of Study: 
XanADu:  A Phase II, Double-Blind, 12-Week, Randomised, Placebo-Controlled Study to Assess the Safety, 
Tolerability and Efficacy of Xanamem™ in Subjects with Mild Dementia due to Alzheimer’s Disease (AD) 
Study Sites: 
It is planned that approximately 20 study sites will be initiated for this study in three countries (Australia, United 
Kingdom and United States of America). 
Publication(s): 
None. 
Planned Study Period: 
March 2017 to February 2019 (last subject last visit) 
Development Phase: 
Phase II 
Objectives: 
Primary Objective: 
The primary objective of the study is to evaluate the extent to which Xanamem™ improves performance from 
Baseline to end of treatment (EOT) compared to placebo, as measured by changes in AD COMposite Scores 
(ADCOMs, composite data derived from Alzheimer's Disease Assessment Scales - Cognitive subscale 
version 14 [ADAS-Cog v14], Clinical Dementia Rating Scale - Sum of Boxes [CDR-SOB], and Mini-Mental 
Status Examination [MMSE]) and ADAS-Cog v14 as primary endpoints in subjects with mild dementia due to 
probable AD. 
Secondary Objectives: 
Secondary objectives of this study are to assess the extent to which Xanamem™ improves performance from 
Baseline to EOT compared to placebo, as measured by changes to: 
 
Rey Auditory Verbal Learning Test (RAVLT) 
 
CDR-SOB 
 
MMSE 
 
Neuropsychiatric Inventory (NPI) 
 
Neuropsychological Test Batteries (NTB) – Executive Domain 
Methodology: 
This is a randomised, double-blind, placebo-controlled Phase II proof-of-concept study. 
Number of Subjects: 
It is planned that approximately 174 subjects will be enrolled to ensure that 156 subjects would complete the 
12-week double-blind study period (78 subjects in each treatment group).  A 10% drop-out rate is expected. 
Diagnosis and Main Criteria for Inclusion: 
1. Males and females aged 50 years or older at the time of informed consent.   
2. Female subjects: 
a) 
Post-menopausal women, defined as no menses for 12 months without an alternative medical cause.  
If there is any concern about the menopausal status of a prospective female subject, a 
follicle-stimulating hormone test (FSH) should be requested to confirm post-menopausal status.  
Post-menopausal women confirmed by FSH level > 40 mIU/mL, will be confirmed by central 
laboratory. 
b) 
Women of childbearing potential (WOCBP) must have a negative pregnancy test at Screening and 
Baseline, and be willing to use highly effective methods of contraception from the Screening visit


Actinogen Medical 
CONFIDENTIAL 
Protocol: XanADu 
 
 
Final Protocol Incorporating Non-Sub. Amendment 5
18-Jul-2018
Page 8 of 106
 
Name of Sponsor/Company: 
Actinogen Medical 
Individual Study 
Table Referring to Part of 
the Dossier: 
 
 
Volume: 
 
Page: 
(For National Authority Use 
Only) 
Name of Product: 
Xanamem™ 
Name of Active Ingredient: 
(5-(1H-Pyrazol-4-yl)thiophen-3-yl)(3-
hydroxy-3-(pyrimidin-2-yl)-8 
azabicyclo[3.2.1]octan-8-yl)methanone 
until 3 months after last dose of study drug.  The central laboratory will flag positive serum human 
chorionic gonadotropin as exclusionary at Screening (re-test of Screening if required).  In such cases, 
the site will perform a local urine pregnancy test at Baseline to determine if the subject can continue 
to randomisation. 
c) 
Are permanently sterile or have had a hysterectomy, bilateral salpingectomy or bilateral 
oophorectomy. 
d) 
Women must not be breastfeeding. 
3. Male Subjects: 
a) Who are sexually active, fertile men must use highly effective methods of contraception from Day 1 
until 3 months after last dose of study drug if their partners are WOBC. 
b) Who are permanently sterile or have had bilateral orchiectomy. 
4. Diagnosis of mild dementia due to probable AD with increased level of certainty (provided by evidence of 
clinical deterioration within the 6 months preceding Screening, as assessed by the investigator) as 
determined by the National Institute of Ageing and the Alzheimer’s Association workgroup.  Individual 
criteria will be included in the electronic case report form. 
5. Mild dementia due to probable AD with MMSE of 20 to 26 (inclusive). 
6. CDR Global Score of 0.5 to 1.0. 
7. A brain magnetic resonance imaging or computed tomography scan in the 12 months preceding Screening 
(a wider window may be accepted but requires written approval by the ICON Medical Monitor) that, in the 
investigator’s opinion, is consistent with AD as the principal aetiology of the dementia with no other 
clinically significant abnormality, e.g. another principal underlying aetiology of the subject’s dementia, or a 
lesion which could affect cognition e.g. a brain tumour or large stroke. 
8. On stable dose of acetylcholinesterase inhibitor (AChEI) and/or memantine (at least 3 months prior to 
Screening) OR treatment-naïve.  Initiating AChEIs or memantine during the study will not be permitted. 
9. Apart from a clinical diagnosis of mild dementia due to probable AD, the subject must be in good health as 
determined by the investigator, based on medical history and screening assessments. 
10. Has a consenting study partner who, in the investigator’s judgement, has frequent and sufficient contact 
with the subject to be able to provide accurate information as to the subject’s cognitive and functional 
abilities.  The study partner must be available to provide information to the investigator and study site staff 
about the subject and agrees to attend all study site visits in person for scale completion.  A study partner 
should be available for the duration of the study.  The measure of adequate availability will be at the 
investigator’s discretion. 
11. Must be willing and able to comply with the requirements of the protocol and must be available to complete 
the study. 
12. Must satisfy a medical examiner about their fitness to participate in the study. 
13. Must provide written informed consent to participate in the study.  
Exclusion Criteria 
1. Clinically significant abnormalities in vital signs (blood pressure, heart rate, respiration rate and oral 
temperature), as determined by the investigator. 
2. Clinically significant abnormal haematology, biochemistry and urine examination values, as determined by 
the investigator.  Additionally, abnormal liver and renal function and Vitamin B12 levels below lower 
threshold may impact cognitive function.  The following values will have an alert flag on the laboratory 
report and are specifically excluded:  
a) 
Vitamin B12 < 176 pg/mL 
b) 
Haemoglobin < 11 g/dL for females and < 12 g/dL for males 
c) 
Aspartate aminotransferase > 3 x upper limit of normal (ULN) 


Actinogen Medical 
CONFIDENTIAL 
Protocol: XanADu 
 
 
Final Protocol Incorporating Non-Sub. Amendment 5
18-Jul-2018
Page 9 of 106
 
Name of Sponsor/Company: 
Actinogen Medical 
Individual Study 
Table Referring to Part of 
the Dossier: 
 
 
Volume: 
 
Page: 
(For National Authority Use 
Only) 
Name of Product: 
Xanamem™ 
Name of Active Ingredient: 
(5-(1H-Pyrazol-4-yl)thiophen-3-yl)(3-
hydroxy-3-(pyrimidin-2-yl)-8 
azabicyclo[3.2.1]octan-8-yl)methanone 
d) 
Alanine aminotransferase > 3 x ULN 
e) 
Serum creatinine > 2 x ULN 
f) 
Urine benzodiazepines when positive:  One re-test will be allowed in cases where the subject’s intake 
of benzodiazepines is within the allowed dose.  Re-tests must be performed within 7 days of the last 
benzodiazepine dose prior to the Baseline visit.  A positive re-test for urine benzodiazepines is 
exclusionary. 
Re-testing of laboratory parameters that requires a confirmatory value within the screening period will be 
permitted in an effort to find all possible well-qualified subjects.  The most current result prior to 
randomisation is the value by which study inclusion will be assessed, as it represents the subject’s most 
current, clinical state.  Consultation with the ICON Medical Monitor (MM) is advised, to identify whether 
repeat testing of any particular parameter is acceptable and clinically relevant. 
3. Has had a significant systemic illness or infection within the past 4 weeks prior to randomisation, as 
determined by the investigator. 
4. Clinically significant neurological disease other than AD, such as (but not limited to) Parkinson’s disease, 
multi-infarct dementia, Huntington’s disease, normal pressure hydrocephalus, brain tumour, progressive 
supranuclear palsy, seizure disorder, subdural haematoma, multiple sclerosis or a history of significant head 
trauma followed by persistent neurologic defaults or known structural brain abnormalities. 
5. Subjects with clinical evidence of peripheral neuropathy or historical evidence of clinically significant 
nerve conduction abnormalities.  Clinical evidence of neuropathy is defined as: 
a) Inability to sense a stimulus even at the secondary (more proximal) skin area for pinprick,  light touch, 
and vibration or temperature at the foot, in at least one extremity (in case neurography measures are 
normal, the case will be discussed with the ICON MM to assess subject eligibility) 
b) 
Nerve conduction abnormalities beyond local normal values or inability to measure Sensory Nerve 
Action Potential or Compound Muscle Action Potential in the primary or a secondary (back-up) nerve 
c) 
Neuropathy Total Symptom Score (NTSS)-6 score > 6, but note that subjects are eligible even if they 
show: 
 
Missing reflexes of the Achilles tendon (ankle), but a positive patellar (knee) tendon reflex 
 
Missing ability to name toe or thumb position 
6. Has had a stroke within the year prior to randomisation, as determined by the investigator. 
7. Has a lifetime diagnosis of a major psychiatric disorder (other than dementia), based on the Diagnostic and 
Statistical Manual of Mental Disorders, 4th Edition criteria.  This includes but is not limited to 
schizophrenia, schizoaffective disorder, bipolar affective disorder, alcohol dependence syndrome or major 
depressive disorder. 
8. Has a history of disease directly related to the hypothalamus, the pituitary and/or the adrenal glands which 
affect the hypothalamic-pituitary-adrenal axis function. 
9. Has uncontrolled clinical conditions relating to glucose and lipid metabolism. 
10. Clinically significant electrocardiogram (ECG) abnormalities, including QTc interval > 450 msec, 
following ECG tracings at Screening.  A single repeat evaluation will be allowed if the investigator or 
designee has reason to believe the reading is faulty or to help assess the clinical significance of an 
abnormality.  Any other ECG abnormality that is seen as exclusionary will first be discussed with the ICON 
MM. 
11. Use of any prohibited medication. 
12. Participation in another clinical study of an investigational drug or device whereby the last drug/device 
administration is within 60 days of Screening. 
13. Inability to communicate well with the investigator (i.e. language problem, non-fluent English [as scales 
will be provided in English only], poor mental development or impaired cerebral function). 


Actinogen Medical 
CONFIDENTIAL 
Protocol: XanADu 
 
 
Final Protocol Incorporating Non-Sub. Amendment 5
18-Jul-2018
Page 10 of 106
 
Name of Sponsor/Company: 
Actinogen Medical 
Individual Study 
Table Referring to Part of 
the Dossier: 
 
 
Volume: 
 
Page: 
(For National Authority Use 
Only) 
Name of Product: 
Xanamem™ 
Name of Active Ingredient: 
(5-(1H-Pyrazol-4-yl)thiophen-3-yl)(3-
hydroxy-3-(pyrimidin-2-yl)-8 
azabicyclo[3.2.1]octan-8-yl)methanone 
14. Subject will undergo the tests, ADAS-Cog v14, CDR-SOB, MMSE, NTB (executive domain) and RAVLT 
at the indicated time-points to avoid uncontrolled learning effects.  Subjects who need to perform these tests 
externally to and in parallel with this study will be excluded. 
15. Subject has ingested any food or drink containing grapefruit, Seville oranges, star fruit, or derived products 
(e.g. fruit juice), for at least 3 days prior to the first administration of study drug.  Subjects must be willing 
to abstain from ingesting these foods and drinks throughout the study, as it may interfere with the activity of 
XanamemTM. 
Test Product, Dose and Mode of Administration: 
Oral Xanamem™ capsules, 10 mg administered once a day (QD). 
Dosing:  
At Week 0, eligible subjects will be randomised to 10 mg/matching placebo QD with a 1:1 allocation ratio. 
Reference Therapy, Dose and Duration of Administration: 
Matching placebo which is identical in appearance to the test product except that it contains no active 
ingredient. 
Duration of Treatment: 
Subjects should participate in the study for 17 to 20 weeks, including a treatment period of 12 weeks.   
Assessments: 
Efficacy 
 
ADAS-Cog v14 
 
RAVLT  
 
CDR-SOB 
 
MMSE 
 
NPI 
 
NTB – Executive Domain 
Safety 
 
Change in clinical safety laboratory values from Baseline (Week 0) to EOT (Week 12) 
 
Incidence of adverse events (AEs) 
 
ECG 
 
NTSS-6 
 
Neurological examination:  This will cover all aspects of the Toronto Clinical Neuropathy Score (TCNS): 
 Muscle strength/weakness in arms and legs 
 Ataxia (gait, stance and finger-nose coordination) 
 Light touch (upper and lower extremity) 
 Pinprick (upper and lower extremity) 
 Position sense (toes and thumbs) 
 Reflexes (knee and ankle) 
 
Nerve Function Monitoring (NFM):  This includes the abovementioned scales (NTSS-6 and TCNS), as well 
as neurography (nerve conduction velocity and amplitude) of peripheral sensory and motor nerves.  The 
NFM should follow existing local standards and procedures and should be run in a consistent fashion.  The 
test must be undertaken and reviewed by suitably qualified and experienced personnel.  
 
Columbia Suicide Severity Rating Scale (CSSRS) 
 
Physical examination 


Actinogen Medical 
CONFIDENTIAL 
Protocol: XanADu 
 
 
Final Protocol Incorporating Non-Sub. Amendment 5
18-Jul-2018
Page 11 of 106
 
Name of Sponsor/Company: 
Actinogen Medical 
Individual Study 
Table Referring to Part of 
the Dossier: 
 
 
Volume: 
 
Page: 
(For National Authority Use 
Only) 
Name of Product: 
Xanamem™ 
Name of Active Ingredient: 
(5-(1H-Pyrazol-4-yl)thiophen-3-yl)(3-
hydroxy-3-(pyrimidin-2-yl)-8 
azabicyclo[3.2.1]octan-8-yl)methanone 
 
Vital signs 
Ad hoc telephone contact may occur at any time-point throughout the study, if deemed necessary by the 
investigator/study nurse, or if the subject wishes to report an adverse event (AE). 
Pharmacokinetics/Pharmacodynamics 
 
Pharmacokinetic (PK) assessment:  PK blood samples will be taken from all enrolled subjects. 
 
Optional pharmacodynamic (PD) assessment:  PD blood samples will be taken from approximately 
50 subjects enrolled into the main study, who also volunteer to take part in the PD sub-study, unless a 
higher number is defined as a result of the analysis of the PD data, by the Data Safety Monitoring Board 
(DSMB).  Samples will be taken pre-dose from subjects in a fasted state, to evaluate the 
adrenocorticotropic hormone, dehydroepiandrosterone sulfate, androstenedione and testosterone at the 
Baseline (Week 0), Interim visits (Week 4 and Week 8), EOT (Week 12) and Follow-up (4 weeks post 
last dose of study drug) visits.  For optimal results, the sample for androstenedione analysis should be 
taken between 6 am and 10 am. 
Other Exploratory Assessments 
 
Metabolic function (lipids, blood pressure, glucose, haemoglobin A1c [HbA1c], body weight, body 
mass index [BMI]) analysis will be performed on all enrolled subjects. 
Statistical Methods: 
Analysis sets 
The safety analysis set will consist of all subjects who receive at least one dose of study drug.  Subjects will be 
analysed according to the treatment they actually received.  The safety analysis set will be the primary analysis 
set for safety analyses. 
The full analysis set (FAS) will consist of all subjects randomised who received at least one dose of study drug.  
Subjects will be analysed in the treatment group they were randomised to even if they received incorrect study 
drug.  Where changes from Baseline are analysed, subjects will be included only if both a Baseline and at least 
one valid post-Baseline measurement are available.  The FAS will be the primary analysis set for efficacy 
analyses. 
The per protocol (PP) analysis set is a subset of the FAS, and will consist of all randomised subjects for whom 
no key protocol violation is documented.  The PP analysis set will provide supportive data for the efficacy 
analyses.  Allocation of subjects to the PP analysis set will be performed before unblinding of the study. 
The PK set will consist of all subjects in the safety population who have at least one post-dose PK assessment.  
PK analyses will be performed using the PK set. 
The PD set will consist of all subjects in the safety population who have at least one post-dose PD assessment.  
PD analyses will be performed using the PD set. 
Statistical Analysis 
For analysis of the primary efficacy variables, an analysis of covariance (ANCOVA) model will be used to 
assess the change in ADCOMs/ADAS-Cog v14 score from Baseline (Week 0) to Week 12 (EOT).  Treatment 
group will be used as fixed effect and the baseline value as a covariate.  Least squares means from the 
ANCOVA model will be used to derive 90% and 95% confidence intervals.  The analysis described above will 
be repeated on the PP set for supportive evidence.  There will be no imputation of missing Week 12/EOT values 
in the primary efficacy analysis. 
Sensitivity analyses aim at assessing the robustness of the primary efficacy analysis.  The following two 
analyses will be performed: 
 
An additional ANCOVA, imputing missing Week 12/EOT data based on resampling from the placebo 
subjects, taking baseline values into account. 
 
An additional ANCOVA, adding site as a factor.  Sites contributing few subjects may be pooled.  Any 
decision on pooling sites will be undertaken before unblinding. 


Actinogen Medical 
CONFIDENTIAL 
Protocol: XanADu 
 
 
Final Protocol Incorporating Non-Sub. Amendment 5
18-Jul-2018
Page 12 of 106
 
Name of Sponsor/Company: 
Actinogen Medical 
Individual Study 
Table Referring to Part of 
the Dossier: 
 
 
Volume: 
 
Page: 
(For National Authority Use 
Only) 
Name of Product: 
Xanamem™ 
Name of Active Ingredient: 
(5-(1H-Pyrazol-4-yl)thiophen-3-yl)(3-
hydroxy-3-(pyrimidin-2-yl)-8 
azabicyclo[3.2.1]octan-8-yl)methanone 
For secondary efficacy variables, summary statistics according to the endpoints’ scale will be presented and 
treatment groups will be compared in an exploratory fashion. 
Safety variables will be analysed as follows: Clinical laboratory measurements, AEs, vital signs, physical 
examination and ECG data will be summarised following usual practice.  NFM and CSSRS variables will be 
presented using summary statistics according to each variable’s scale and treatment groups will be compared in 
an exploratory fashion.  Special attention will be directed at intra-subject changes over the course of the study. 
Interim Analysis 
There is one planned interim analysis after 50 completed subjects.  The following endpoints will be analysed in 
this interim analysis: 
Efficacy: 
 
ADAS-Cog 
 
MMSE 
 
CDR-SOB 
 
ADCOMS 
 
RAVLT 
 
NPI 
 
NTB – Executive domain (Controlled Word Association Test and Category Fluency Test) 
Safety: 
 
Laboratory values 
 
Incidence of AEs 
 
NFM 
PK/PD: 
 
Plasma concentrations of Xanamem™ 
This interim efficacy analysis aims at providing additional information on the efficacy parameters to the DSMB, 
including both descriptive and inferential statistics.  No study adaptations are planned based on these analyses.  
Should there be evidence of an overwhelming effect, the DSMB may recommend stopping early for success.  
For control of the type I error rate, the Haybittle-Peto approach will be used, thus setting the stopping boundary 
at a one-sided 0.001, leaving the full type I error rate of a one-sided 0.05 for the final analysis. 
Date of the Non-Substantial Amendment to Protocol:  18-Jul-18 
 


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Final Protocol Incorporating Non-Sub. Amendment 5
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5 
TABLE OF CONTENTS 
1 
TITLE PAGE ............................................................................................................ 1 
2 
SIGNATURE PAGES ............................................................................................... 2 
3 
GENERAL INFORMATION .................................................................................... 5 
4 
STUDY SYNOPSIS .................................................................................................. 7 
5 
TABLE OF CONTENTS ........................................................................................ 13 
5.1 
List of Tables .............................................................................................. 16 
5.2 
List of Appendices and Supplements .......................................................... 16 
6 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .............................. 17 
7 
INTRODUCTION ................................................................................................... 19 
7.1 
Background ................................................................................................ 19 
7.2 
Rationale .................................................................................................... 20 
8 
STUDY OBJECTIVES ........................................................................................... 22 
8.1 
Primary Objectives ..................................................................................... 22 
8.2 
Secondary Objectives ................................................................................. 22 
8.3 
Efficacy Assessments ................................................................................. 22 
8.4 
Safety Assessments ..................................................................................... 22 
8.5 
Pharmacokinetics/Pharmacodynamics ........................................................ 23 
8.6 
Other Exploratory Assessments .................................................................. 23 
9 
INVESTIGATIONAL PLAN .................................................................................. 24 
9.1 
Overall Study Design and Plan ................................................................... 24 
9.1.1 
Description ................................................................................................. 24 
9.2 
Discussion of Study Design ........................................................................ 24 
9.2.1 
Dose Rationale ........................................................................................... 26 
9.2.2 
Risk/Benefit and Ethical Assessment ........................................................ 26 
9.3 
Selection of Study Population ..................................................................... 27 
9.3.1 
Inclusion Criteria ....................................................................................... 27 
9.3.2 
Exclusion Criteria ...................................................................................... 28 
9.4 
Schedule of Assessments ............................................................................ 30 
9.4.1 
Study Procedures and Assessments ........................................................... 35 
9.4.1.1 
Screening Visit (Weeks -1 to -4) ................................................ 35 
9.4.1.2 
Baseline Visit (Week 0) ............................................................. 37 
9.4.1.3 
Interim Visit (Week 4) ............................................................... 39 
9.4.1.4 
Interim Visit (Week 8) ............................................................... 41 
9.4.1.5 
Telephone Contact (Ad Hoc)...................................................... 43 
9.4.1.6 
End of Treatment Visit (Week 12) ............................................. 43 
9.4.1.7 
Follow-up Visit (4 Weeks Post Last Dose of Study Drug ± 4 
Days) .......................................................................................... 45 
9.4.1.8 
Unscheduled Safety Visit ........................................................... 46 


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9.5 
Withdrawal of Subjects ............................................................................... 46 
9.6 
Early Termination ....................................................................................... 47 
10 
TREATMENT OF SUBJECTS ............................................................................... 49 
10.1 
Identity of Study Treatments ....................................................................... 49 
10.1.1 
Administration of Study Treatments .......................................................... 49 
10.2 
Study Treatment Packaging and Labelling .................................................. 49 
10.2.1 
Packaging ................................................................................................... 49 
10.2.2 
Labelling .................................................................................................... 49 
10.2.3 
Shipment and Storage ................................................................................ 50 
10.2.4 
Blinding and Randomisation of Study Treatment(s) ................................. 50 
10.3 
Procedure for Breaking the Randomisation Code ........................................ 51 
10.4 
Subject Compliance .................................................................................... 51 
10.5 
Study Treatment Accountability ................................................................. 52 
10.6 
Study Treatment Destruction ...................................................................... 52 
10.7 
Concomitant Medications and Therapy ....................................................... 52 
10.8 
Prohibited Medications ............................................................................... 52 
11 
ASSESSMENT OF EFFICACY .............................................................................. 55 
11.1 
Efficacy Variables ...................................................................................... 55 
11.1.1 
Efficacy Assessments ................................................................................ 55 
11.1.1.1 Alzheimer's Disease COMposite Score (ADCOMs) .................. 55 
11.1.1.2 Rey Auditory Verbal Learning Test (RAVLT) .......................... 55 
11.1.1.3 Alzheimer’s Disease Assessment Scale - Cognitive 
Behaviour Section (ADAS-Cog v14) ......................................... 56 
11.1.1.4 Clinical Dementia Rating Scale - Sum of Boxes 
(CDR-SOB) and Global (CDR Global) ...................................... 56 
11.1.1.5 Mini-Mental Status Examination (MMSE) ................................ 57 
11.1.1.6 Neuropsychiatric Inventory (NPI) .............................................. 57 
11.1.1.7 Neuropsychological Test Battery (NTB) - Executive 
Domain (COWAT and CFT) ...................................................... 57 
12 
ASSESSMENT OF SAFETY .................................................................................. 59 
12.1 
Adverse Events ........................................................................................... 59 
12.1.1 
Definitions ................................................................................................. 59 
12.1.1.1 Recording of Adverse Events ..................................................... 60 
12.1.1.2 Monitoring of Adverse Events ................................................... 61 
12.1.1.3 Reporting of Serious Adverse Events......................................... 62 
12.2 
Laboratory Assessments ............................................................................. 63 
12.3 
Electrocardiogram Assessments .................................................................. 64 
12.4 
Physical Examination ................................................................................. 64 
12.5 
Neurological Examination, Including Toronto Clinical Neuropathy Score .. 64 
12.6 
Vital Signs .................................................................................................. 65 


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12.7 
Nerve Function Monitoring......................................................................... 65 
12.7.1 
Reporting Abnormal Nerve Function Monitoring ..................................... 67 
12.8 
Neuropathy Total Symptom Score-6 ........................................................... 68 
12.9 
Columbia Suicide Severity Rating Scale ..................................................... 68 
13 
PHARMACOKINETIC AND PHARMACODYNAMIC ASSESSMENT ............... 69 
14 
OTHER EXPLORATORY ASSESSMENTS .......................................................... 71 
15 
STATISTICAL EVALUATION ............................................................................. 72 
15.1 
Sample Size and Power ............................................................................... 72 
15.2 
Statistical Methods ..................................................................................... 72 
15.2.1 
Statistical Analysis Sets ............................................................................. 72 
15.2.2 
Efficacy and Safety Variables .................................................................... 73 
15.2.2.1 Primary Efficacy Variables ........................................................ 73 
15.2.2.2 Secondary Efficacy Variables .................................................... 73 
15.2.2.3 Safety Variables ......................................................................... 73 
15.2.2.4 PK and PD Variables .................................................................. 74 
15.2.2.5 Other Exploratory Variables ...................................................... 74 
15.2.3 
Methods of Statistical Analyses ................................................................. 74 
15.2.3.1 General Principles ...................................................................... 74 
15.2.3.2 Missing Data............................................................................... 74 
15.2.3.3 Demographic and Baseline Characteristics ................................ 74 
15.2.3.4 Subject Disposition..................................................................... 74 
15.2.3.5 Evaluation of Primary Efficacy Variables .................................. 75 
15.2.3.6 Evaluation of Secondary Efficacy Variables .............................. 76 
15.2.3.7 Evaluation of Safety Variables ................................................... 76 
15.2.3.8 PK/PD Modelling ....................................................................... 77 
15.2.3.9 Evaluation of Exploratory Variables .......................................... 77 
15.2.3.10 Compliance and Exposure .......................................................... 78 
15.2.3.11 Interim Analysis ......................................................................... 78 
15.2.4 
Data Safety Monitoring Board ................................................................... 79 
15.2.4.1 Data Safety Monitoring Board Nerve Function Monitoring 
Sub-committee............................................................................ 79 
16 
DIRECT ACCESS TO SOURCE DATA/NOTES ................................................... 81 
17 
QUALITY CONTROL AND QUALITY ASSURANCE ........................................ 82 
17.1 
Conduct of the Study .................................................................................. 82 
17.2 
Study Initiation and Monitoring .................................................................. 82 
18 
ETHICS .................................................................................................................. 84 
18.1 
Independent Ethics Committee/Institutional Review Board ......................... 84 
18.2 
Written Informed Consent .......................................................................... 84 


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19 
DATA HANDLING AND RECORD KEEPING .................................................... 86 
19.1 
Case Report Forms/Source Data Handling .................................................. 86 
19.2 
Retention of Essential Documents ............................................................... 86 
20 
FINANCING AND INSURANCE .......................................................................... 87 
21 
PUBLICATION POLICY ....................................................................................... 88 
22 
REFERENCE LIST ................................................................................................. 89 
23 
APPENDICES ........................................................................................................ 92 
 
5.1 
List of Tables 
Table 1 
Schedule of Assessments ................................................................................ 31 
Table 2 
Ingredients of Xanamem™ and Matching Placebo Capsules, Using a 
Representative Dose of 10 mg (% w/w) .......................................................... 49 
Table 3  
Primary and Secondary Skin Area to Test the Sensory Quality ....................... 65 
Table 4 
NFM Requirements ........................................................................................ 67 
 
5.2 
List of Appendices and Supplements 
Appendix I 
World Medical Association Declaration of Helsinki, version of 1996 (the 
version referenced by the Food and Drug Administration and European 
Commission)  
Appendix II 
Per Protocol Laboratory Evaluations 
Appendix III Prohibited Medication - Brand Names per Country 
Appendix IV Contraception 


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6 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
AA 
Alzheimer’s Association 
AChEI 
Acetylcholinesterase inhibitor 
ACTH 
Adrenocorticotropic Hormone 
AD 
Alzheimer’s disease 
ADAS-Cog v14 
Alzheimer's Disease Assessment Scale - Cognitive subscale, 
version 14 
ADCOMs 
AD COMposite Score 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ANCOVA 
Analysis of covariance 
AUC0-24hr 
Area under the plasma concentration-time curve from 0 to 24 hours 
BMI 
Body mass index 
CDR 
Clinical Dementia Rating scale 
CDR-SOB 
Clinical Dementia Rating scale - Sum of Boxes 
CFT 
Category Fluency Test 
Cmax 
Maximum concentration 
CMAP 
Compound Muscle Action Potential 
Cmin 
Minimum concentration 
CNS 
Central nervous system 
COWAT 
Controlled Word Association Test 
CSF 
Cerebrospinal fluid 
CSSRS 
Columbia Suicide Severity Rating Scale 
CT 
Computed tomography 
CYP3A4 
Cytochrome P450 3A4 
DHEAS 
Dehydroepiandrosterone sulfate 
DSMB 
Data Safety Monitoring Board 
eCRF 
Electronic case report form 
ECG 
Electrocardiogram 
EOT 
End of Treatment 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
FSH 
Follicle-stimulating hormone 
GCP 
Good clinical practice 
HbA1c 
Haemoglobin A1c 
11β-HSD1 
1β-hydroxysteroid dehydrogenase Type 1 
IC50 
Inhibitory concentration of 50% 
ICF 
Informed consent form 


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ICH 
International Conference on Harmonisation 
IEC 
Independent ethics committee 
IMP 
Investigational medicinal product 
IRB 
Institutional review board 
IWRS 
Interactive Web Response System 
LS 
Least squares (means) 
MAD 
Multiple Ascending Dose 
MedDRA 
Medical Dictionary for Regulatory Activities 
MM 
Medical Monitor 
MMSE 
Mini-Mental Status Examination 
MRI 
Magnetic resonance imaging 
NCV 
Nerve conduction velocity 
NFM 
Nerve Function Monitoring 
NIA 
National Institute of Ageing 
NPI 
Neuropsychiatric Inventory 
NTB 
Neuropsychological Test Batteries 
NTSS 
Neuropathy Total Symptom Score 
pCOA 
Pre-dementia Clinical Outcome Assessments 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PP 
Per protocol 
PV 
Pharmacovigilance 
QD 
Once a day 
QTcB 
QT time using the Bazett’s correction 
QTcF 
QT time using the Fridericia’s correction 
RAVLT 
Rey Auditory Verbal Learning Test 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SNAP 
Sensory Nerve Action Potential 
SOP 
Standard operating procedure 
TEAE 
Treatment-emergent adverse event 
TCNS 
Toronto Clinical Neuropathy Score 
UK 
United Kingdom 
ULN 
Upper limit of normal 
USA 
United States of America 
WOCBP 
Women of childbearing potential 
 


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7 
INTRODUCTION 
7.1 
Background 
Alzheimer’s disease (AD) is emerging as one of the most important global public health 
issues to face modern humanity.  With the ageing population and success of medical 
interventions in many other disease areas, the prevalence of AD is rapidly increasing.  Data 
from the 2015 World Alzheimer’s Report1 estimates there are 47 million people globally 
affected by AD, with the number set to double every 20 years.  The burden of the disease is 
global, with nearly 70% of the increase expected to be in middle and low income countries.   
In Australia, more than 342,800 people are living with dementia.  Without a medical 
breakthrough, the number of people with dementia is expected to be almost 900,000 by 2050.  
Each week, there are more than 1,800 new cases of dementia in Australia, and approximately 
25,100 people with younger onset dementia (a diagnosis of dementia under the age of 65; 
including people as young as 302).  The number of people with AD in the United Kingdom 
(UK) has increased since the late 1990s and is a major cause of morbidity and mortality.  This 
increase has been associated primarily with an increasing incidence of elderly people3 and 
better case ascertainment. 
Of the 5.3 million Americans with AD, an estimated 5.1 million are aged 65 years and older, 
and approximately 200,000 are under the age of 65.  The number of Americans with AD and 
other dementias will increase each year as the size and proportion of the population of the 
United States of America (USA) aged 65 years and older continues to increase.  By 2025, the 
number of people aged 65 and older with AD is estimated to reach 7.1 million - a 40% 
increase from the 5.1 million aged 65 and older affected in 2015.  By 2050, this number could 
triple to a projected 13.8 million, barring the development of medical breakthroughs to 
prevent or cure the disease4. 
The cost of treating AD is approaching one trillion dollars and if dementia care was a country 
it would be the 18th largest economy.  AD is one of the leading causes of death in the 
developed world, and in Australia is second only to ischemic heart disease.  Compounding 
this societal burden is the relative limited benefit provided by the currently available 
treatment options.  None of the four registered drugs (donepezil, rivastigmine, galantamine 
and memantine, which are available in a number of different formulations), provide much 
more than short-term symptomatic benefit, and significantly, none are disease-modifying.  
The AD community desperately needs new alternative treatment options, and ideally, drugs 
with a disease-modifying potential.   
The Food and Drug Administration (FDA) in the USA has recently updated draft guidelines 
for the treatment of AD.  However, despite the FDA encouraging the development of new 
agents to be tested clinically in patients with early symptoms of the disease5, 99.6% of the 
244 agents tested from 2002 to 2012 failed to achieve their primary endpoints6.  Only one 
drug tested during that period, the N-methyl-D-aspartate-receptor antagonist memantine, was 
approved, and then only for the treatment of moderate to severe AD.  Therefore, there is a 


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high medical need for alternative therapies, and particularly those with the potential for 
disease modification. 
The pre-clinical evidence to date would indicate that Xanamem™ could be an effective 
symptomatic and disease-modifying treatment for mild AD.  This XanADu Phase II study in 
mild AD is a proof-of-concept study, designed to demonstrate the efficacy and safety of 
Xanamem™ in mild AD. 
7.2 
Rationale 
The steroid-converting enzyme, 11β-hydroxysteroid dehydrogenase Type 1 (11β-HSD1), is 
found predominantly in the liver, adipose and brain.  It catalyses the reduction of inert 
cortisone to the active glucocorticoid hormone, cortisol.  There is comprehensive evidence 
from studies in rodents and in humans that regulation of cortisol levels via inhibition of 
11β-HSD1 provides a therapeutic strategy to treat metabolic diseases such as Type 2 diabetes 
and central nervous system (CNS) conditions such as cognitive impairment and AD7,8,9,10,11. 
In the brain, 11β-HSD1 is highly expressed in regions such as the hippocampus, frontal 
cortex and cerebellum.  These regions are important for cognition and the hippocampus, in 
particular, has high expression of glucocorticoid receptors.  There is substantial evidence that 
elevated glucocorticoid levels contribute to cognitive dysfunction, are neurotoxic and may 
contribute to AD12,13,14,15. 
For example: 
 In vivo, in rats, corticosterone administration causes regression of hippocampal neuronal 
dendrites16. 
 In primates, long-term (1 year) implantation of cortisol pellets in the hippocampus causes 
shrinkage and dendritic atrophy13.  11β-HSD1 knock-out mice are protected against 
glucocorticoid-associated, age-related cognitive dysfunction on two different genetic 
backgrounds17,18. 
 
Long-term 
potentiation 
(the 
probable 
cellular/synaptic 
electrophysiological basis of memory) is enhanced in hippocampal slices from these 
mice. 
 In three separate and independent studies pharmacological inhibition of 11β-HSD1 leads 
to improvements in cognition in wild-type aged and young rodents and in the 
Tg2576 model of AD9,10,11. 
 In rodent models of AD, corticosterone is elevated, whilst treatment with glucocorticoids 
has been shown to elevate Aβ15. 
 Studies from the University of Edinburgh found that the 11β-HSD1 enzyme amplified 
glucocorticoid production in target tissues (such as adipose and the hippocampus).  
Overexpression of the gene in adipose resulted in obesity whilst genetic deletion of the 
gene protected against age-related memory impairment, leading to the hypothesis that 
inhibitors of 11β-HSD1 could have the potential to treat metabolic disease and cognitive 
impairment by safely reducing glucocorticoid levels in these target tissues.  The original 
proof-of-concept studies in humans at the University of Edinburgh utilised the prototype, 
non-selective, 11β-HSD1 inhibitor carbenoloxone, which significantly improved 


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cognition in healthy elderly men and in subjects with Type 2 diabetes by significantly 
(p<0.01) improving verbal fluency and memory at 4 to 6 weeks compared to placebo19. 
Reducing glucocorticoid action in the CNS has therefore emerged as an important therapeutic 
goal in the treatment of age-associated cognitive impairment and AD. 
Xanamem™ (former designation UE2343) is a new investigational medicinal product, under 
development for the treatment of mild AD with the potential for both symptomatic and 
disease-modifying effects.  Xanamem™ displays high potency and selectivity for human 
11β-HSD1 when compared to related hydroxysteroid dehydrogenase enzymes and receptors.  
Based on pre-clinical data from rodent models of AD and age-related cognitive impairment it 
is anticipated that Xanamem™ will have a beneficial effect on the cognitive decline 
associated with AD.  Additionally, pre-clinical data also indicate that treatment may slow the 
progression of β-amyloid plaque deposition in the brain. 
Two Phase I studies (RD 656/25368 [a Single Ascending Dose study] and ACW0001 
[a Multiple Ascending Dose, Fed-Fasted and CNS study]) in 88 healthy volunteers 
established the pharmacokinetic (PK) and pharmacodynamic (PD) parameters of Xanamem™ 
and concluded that the drug was safe and well tolerated in doses from 2 to 35 mg twice daily, 
and that it should preferably be taken with food.  The presence of the drug in the 
cerebrospinal fluid (CSF) confirmed that it crosses the blood brain barrier.  PK/PD modelling 
of the CSF to plasma ratios obtained in the multiple ascending dose study were used to select 
the optimum dose regimen for this Phase II study in mild AD.   
This Phase II study will assess the safety, tolerability and efficacy of oral Xanamem™ for 
12 weeks in male and female subjects aged 50 years and older with mild dementia due to AD.  
This study will be conducted in compliance with the protocol, International Conference on 
Harmonisation (ICH) guidelines on Good Clinical Practice (GCP) and applicable local 
regulatory requirements and laws. 
In this study design, subjects will be randomised to receive either 10 mg once a day (QD) 
XanamemTM or matching placebo for a 12-week period.   
To support the selection of this dose, PK modelling was conducted based on the Multiple 
Ascending Dose (MAD) study results obtained from human volunteers, when 10, 20 and 
35 mg of XanamemTM was administered twice daily for 10 days.  From this modelling, 
predicted PK values in plasma for maximum concentration (Cmax), minimum concentration 
(Cmin) and area under the plasma concentration-time curve from 0 to 24 hours (AUC0-24hr) and 
for CSF Cmax, Cmin were estimated at steady state for 10, 20 and 30 mg XanamemTM 
administered QD.  This modelling confirmed that any of these doses would achieve 
consistent Xanamem CSF levels above the inhibitory concentration of 50% (IC50) (the 
optimal target threshold) for the 11β-HSD1 enzyme. 
More information can be found in the Investigator’s Brochure20. 


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8 
STUDY OBJECTIVES 
8.1 
Primary Objectives 
The primary objective of the study is to evaluate the extent to which Xanamem™ improves 
performance from Baseline to end of treatment (EOT) compared to placebo, as measured by 
changes in AD COMposite Scores (ADCOMs, composite data derived from Alzheimer's 
Disease Assessment Scales - Cognitive subscale version 14 [ADAS-Cog v14], Clinical 
Dementia Rating Scale - Sum of Boxes [CDR-SOB], and Mini-Mental Status Examination 
[MMSE]) and ADAS-Cog v14 as primary endpoints in subjects with mild dementia due to 
probable AD. 
8.2 
Secondary Objectives 
Secondary objectives of this study are to assess the extent to which Xanamem™ will improve 
performance from Baseline to EOT compared to placebo, as measured by changes to: 
 Rey Auditory Verbal Learning Test (RAVLT) 
 CDR-SOB 
 MMSE 
 Neuropsychiatric Inventory (NPI) 
 Neuropsychological Test Batteries (NTB) – Executive Domain 
8.3 
Efficacy Assessments 
See Section 11.1 for details of the efficacy assessments. 
 ADAS-Cog v14 
 RAVLT 
 CDR-SOB 
 MMSE 
 NPI 
 NTB – Executive Domain (Controlled Word Association Test [COWAT] and Category 
Fluency Test [CFT]) 
ADCOMs-related assessments (ADAS-Cog v14, CDR-SOB and MMSE), RAVLT, NPI and 
NTB – Executive Domain, will be performed at the Baseline (Week 0) and the EOT 
(Week 12) visits to minimise burden for rater and subject. 
MMSE and CDR-SOB will also be performed at Screening. 
8.4 
Safety Assessments 
 Change in clinical safety laboratory values from Baseline (Week 0) to EOT (Week 12) 
 Incidence of adverse events (AEs) 


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 Electrocardiogram (ECG) (study sites’ local equipment will be used and ECG will be 
read locally by an appropriately qualified and experienced ECG reader; the same 
equipment should be used throughout the study at that study site) 
 Neuropathy Total Symptom Score (NTSS)-6: The six questions of NTSS-6 should be 
completed as part of the assessment of subjects’ medical history, also asking for input 
from the caregiver to make sure no information is lost.  Each item will also be graded for 
its frequency and intensity, adding up to a total score from “0” to “21.96” points.  A total 
score of > 6 would exclude the subject from the study. 
 The neurological examination will cover all aspects of the Toronto Clinical Neuropathy 
Score (TCNS).  See Section 12.5 for details of this examination. 
 Nerve Function Monitoring (NFM).  See Section 12.7 for details of NFM. 
 Columbia Suicide Severity Rating Scale (CSSRS) 
 Physical Examination 
 Vital signs 
All evaluations will be performed as detailed in the Schedule of Assessments (Table 1).  Ad 
hoc telephone contact may occur at any time-point throughout the study, if deemed necessary 
by the investigator/study nurse, or if the subject wishes to report an adverse event (AE). 
8.5 
Pharmacokinetics/Pharmacodynamics 
 PK assessment:  PK blood samples will be taken from all enrolled subjects. 
 Optional PD assessment:  PD blood samples will be taken from approximately 
50 subjects enrolled into the main study who also volunteer to take part in the PD 
sub-study, unless a higher number is defined as a result of the analysis of the PD data, by 
the Data Safety Monitoring Board (DSMB).  Samples will be taken pre-dose from 
subjects in a fasted state, to evaluate the adrenocorticotropic hormone (ACTH), 
dehydroepiandrosterone sulfate (DHEAS), androstenedione and testosterone at the 
Baseline (Week 0) visit, Interim visits (Week 4 and Week 8), EOT (Week 12) and 
Follow-up (4 weeks post last dose of study drug) visits.  For optimal results, the sample 
for androstenedione analysis should be taken between 6 am and 10 am. 
Note:  results of the PK and PD (biomarkers) analyses will not be disclosed to study sites to 
avoid unintended subject treatment unblinding (for further details refer to the XanADu 
Laboratory Manual). 
8.6 
Other Exploratory Assessments 
 Metabolic function (lipids, blood pressure, glucose, haemoglobin A1c [HbA1c], body 
weight, body mass index [BMI]) analysis will be performed on all enrolled subjects. 


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9 
INVESTIGATIONAL PLAN 
9.1 
Overall Study Design and Plan 
9.1.1 
Description 
This 
is 
a 
Phase II, 
randomised, 
multi-centre, 
double-blind, 
placebo-controlled 
proof-of-concept study to assess the safety, tolerability and efficacy of oral Xanamem™ QD 
in adult subjects with mild dementia due to AD. 
It is planned to randomise approximately 174 subjects at approximately 20 study sites in three 
countries (Australia, UK, and USA), with the aim to enrol 7 to 10 subjects at each study site.  
Subject enrolment will be competitive but a cap of 20 subjects per study site is to be 
established to avoid any site effects.  In case data quality at one study site is creating concerns, 
an enrolment stop can also occur at fewer than 20 subjects.   
The DSMB will periodically meet for the review of accumulating safety study data and will 
also be involved in the interim efficacy analysis (see Section 15.2.4 for details). 
At the Baseline visit (Week 0), eligible subjects will be randomised on a 1:1 ratio to receive 
either Xanamem™ administered orally, QD (treatment group) or matching placebo (placebo 
group).  Subjects will return to the study site for the Interim visits (Week 4 and Week 8), 
EOT (Week 12) and Follow-up (4 weeks post last dose of study drug) visits, at which study 
assessments, as detailed in Table 1 (Schedule of Assessments), will be performed.  For 
further details on the dosing and treatment of subjects, refer to Section 10. 
Ad hoc telephone contact may occur at any time-point throughout the study, if deemed 
necessary by the investigator/study nurse, or if the subject wishes to report an AE. 
Subjects will be interviewed and examined at the study site at each visit, and will complete a 
variety of questionnaires and routine safety evaluations.   
Selected subjects will undergo additional PD sampling at specific visits after providing 
appropriate informed consent.  Subjects who do not provide consent for this optional 
assessment, will still be eligible for the main study. 
The overall study duration for an individual subject will be 17 to 20 weeks, including a 
screening period of 1 to 4 weeks, a double-blind treatment period of 12 weeks, and a 
follow-up period of 4 weeks.  The total duration of the study is expected to be approximately 
2 years (last subject last visit). 
9.2 
Discussion of Study Design 
This study is designed to investigate the safety, tolerability and efficacy of Xanamem™ in 
subjects with mild dementia due to AD. 
Based on Xanamem™’s mode of action on the hippocampal function, amnestic symptoms 
may respond best, thus favouring the inclusion of mild dementia due to AD, with given 
evidence of disease progression.  Subjects will be treated in a double-blind fashion, where 
both the investigators and subjects will be unaware of the treatment assignments, to minimise 
any subjective or unrecognised bias carried by the investigators and subjects.  Placebo will be 


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used as the comparator in this study.  In this study, Xanamem™ will be administered in 
conjunction with current standard therapy (see Sections 9.3.1 and 9.3.2). 
Recognising that no animal toxicology reproductive or development studies have been 
performed with Xanamem™ as yet, women of childbearing potential (WOCBP) who have a 
positive pregnancy test at Screening and/or Baseline, or those who are not willing to use 
highly effective methods of contraception or who are not permanently sterile or have not had 
a hysterectomy, bilateral salpingectomy or bilateral oophorectomy, will be excluded from the 
study. 
Subjects should aim to take the study drug at the same time each morning with meals (i.e. not 
in fasted condition) due to an approximately 25% higher bioavailability observed when taken 
in a fed state.  Drug intake when fasted has no safety concern and will not be treated as a 
protocol deviation. 
A variety of scales will be employed in this study for the assessment of efficacy.  ADCOMs 
(composite data derived from ADAS-Cog v14, CDR-SOB and MMSE) are used to determine 
the primary efficacy endpoint as these scales have a higher sensitivity for domains affected 
by early AD and episodic memory problems than other scales21.  ADAS-Cog will be a 
co-primary endpoint since this is the most established and widely validated scale.  RAVLT is 
used to determine the most important secondary efficacy endpoint as this scale has the 
highest expected sensitivity for change in episodic memory, which is the most probable target 
of Xanamem™ effects.  Although many scales will be employed during this study, subjects 
will not complete all of them at every visit.  This is to ensure no learning effect between two 
adjacent visits, to reduce the total number of assessments, to minimise burden for raters and 
subjects and thus increase study compliance and to allow more focus on critical parameters. 
Sparse PK blood samples will be taken from all subjects who participate in the main study.  
The PK samples will be taken pre-dose and between 3 and 5 hours post-dose (as required per 
Table 1), i.e. the time interval during which peak concentrations were observed in the Phase I 
studies.  In addition, a PK sample will be collected from each subject in whom a serious AE 
(SAE) occurs, noting the time of the last dose of study drug administered relative to the time 
at which the PK sample was collected. 
PD blood samples will be collected from a sub-group of approximately 50 subjects (unless a 
higher number is defined as a result of the DSMB analysis of the PD data).  The PD sampling 
in this study will complement the previously reported Phase I data, in which most of the 
subjects were male and only a small number of subjects were aged 50 years or older.  If, after 
evaluation of the PD data by the DSMB, it is considered that an insufficient number of 
subjects are on active drug, further PD data will be collected.   
NFM, including vibration detection threshold, thermal (cold and warm) detection, and nerve 
conduction, is required to rule out any impact of Xanamem™ on nerve conduction in an 
elderly population, and to exclude long-term neurotoxic effects.  Subjects with clinically 
symptomatic peripheral nerve damage at the Screening visit (e.g. polyneuropathy) will be 
excluded from the study to avoid confusion with the Xanamem™ safety profile. 


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Other efficacy/safety endpoints used in this study are well-established and well-accepted 
measurements for AD studies. 
Interim visits are scheduled at Week 4 and Week 8 to allow the observation of potential 
adverse reactions. 
9.2.1 
Dose Rationale 
In this study design, subjects will be randomised to receive either 10 mg QD XanamemTM or 
matching placebo for a 12-week period. 
To support the selection of this dose, PK modelling was conducted based on the MAD study 
results obtained from human volunteers, when 10, 20 and 35 mg of XanamemTM was 
administered twice daily for 10 days.  From this modelling, predicted PK values in plasma for 
Cmax, Cmin and AUC0-24hr and for CSF Cmax, Cmin were estimated at steady state for 10, 20 and 
30 mg XanamemTM administered QD.  This modelling confirmed that any of these doses 
would achieve consistent Xanamem CSF levels above the IC50 (the optimal target threshold) 
for the 11β-HSD1 enzyme. 
More information on the dose recommendation can be found in the Investigator’s Brochure20. 
9.2.2 
Risk/Benefit and Ethical Assessment 
Xanamem™’s mechanism of action suggests a main role on hippocampal function, which 
may improve amnestic symptoms that are the main symptoms in subjects of mild AD.  
Furthermore, Xanamem™ may slow the progression of amyloid plaque deposition in the 
brain.  Therefore, Xanamem™ has the potential for both symptomatic and disease-modifying 
effects in subject with mild AD. 
Xanamem™ is an inhibitor of the 11β-HSD1 enzyme.  Compounds which inhibit 11β-HSD1 
are intended to affect the intracellular cortisone-cortisol balance, resulting in altered 
glucocorticoid action.  It is therefore expected that AEs seen following the administration of 
Xanamem™ may be related to effects on glucose and fatty acid metabolism, or loss of 
suppression of innate immunity.  In addition, inhibition of 11β-HSD1 results in enhanced 
cortisol clearance and potentially a compensatory increase in ACTH and cortisol secretion to 
maintain normal cortisol levels.  As a result, ACTH-dependent secretion of adrenal androgens 
may be increased. 
To date, Xanamem™ has an acceptable safety profile:  in the MAD study22, all 
treatment-emergent AEs (TEAEs) were either mild or moderate in intensity.  A total of 
6/24 (25.0%) subjects reported at least one TEAE possibly related to study drug, whilst all 
the other TEAEs were reported as unrelated or unlikely to be related to study drug. 
Of the five TEAEs considered to be moderate in intensity, one event of diarrhoea (20 mg 
UE2343) and one event of headache (35 mg UE2343) were considered as possibly related to 
study drug.  The other moderate TEAEs were all unrelated or unlikely to be related to study 
drug.  The laboratory parameters were within normal range and no clinically significant 
abnormalities were recorded.  In the subsequent fed-fasted study22 in 12 subjects, the most 
commonly reported TEAE by preferred term was “Abnormal dreams”, with a total of 


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five events reported by 5/12 (41.7%) subjects.  These were considered possibly related to 
study drug (two events under fed conditions, one under fasted conditions and two across both 
the fed and fasted period), all mild in intensity and resolved. 
Overall, there were no clinically significant abnormalities noted in nerve conduction studies 
for any of the subjects in the MAD cohorts. 
Post-study, a total of six subjects experienced QT time increases of > 30 msec from Baseline 
using the Bazett’s correction (QTcB).  QTcB increases of > 60 msec were reported on 
one subject in the placebo group (change from Baseline to Day 10 [4 hours post-dose]) and 
one subject in the 20 mg Xanamem™ group (change from Baseline to post-study). 
The potential benefits of Xanamem™ are therefore considered to outweigh the potential risks.   
Close monitoring of safety, including potential effect on metabolic and nerve function, will 
be conducted throughout this study. 
9.3 
Selection of Study Population 
9.3.1 
Inclusion Criteria 
A subject will be eligible for enrolment in the study if ALL of the following criteria apply: 
1. Males and females aged 50 years or older at the time of informed consent. 
2. Female subjects: 
a) Post-menopausal women, defined as no menses for 12 months without an alternative 
medical cause.  If there is any concern about the menopausal status of a prospective 
female subject, a follicle-stimulating hormone (FSH) test should be requested to 
confirm post-menopausal status.  Post-menopausal women confirmed by FSH level 
> 40 mIU/mL, will be confirmed by central laboratory. 
b) WOCBP must have a negative pregnancy test at Screening and Baseline, and be 
willing to use highly effective methods of contraception from the Screening visit until 
3 months after last dose of study drug.  The central laboratory will flag positive serum 
human chorionic gonadotropin as exclusionary at Screening (re-test of Screening if 
required).  In such cases, the site will perform a local urine pregnancy test at Baseline 
to determine if the subject can continue to randomisation (see Appendix IV for more 
information). 
c)  Are permanently sterile or have had a hysterectomy, bilateral salpingectomy or 
bilateral oophorectomy. 
d) Women must not be breastfeeding. 
3. Male subjects: 
a) Who are sexually active, fertile men must use highly effective methods of 
contraception from Day 1 until 3 months after last dose of study drug if their 
partners are WOCBP (see Appendix IV for more information).  
b) Who are permanently sterile or have had bilateral orchiectomy. 


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4. Diagnosis of mild dementia due to probable AD with increased level of certainty 
(provided by evidence of clinical deterioration within the 6 months preceding Screening, 
as assessed by the investigator) as determined by the National Institute of Ageing (NIA) 
and the Alzheimer’s Association (AA) workgroup, detailed in Section 4.1 and 4.2.123.  
Individual criteria will be included in the electronic case report form (eCRF). 
5. Mild dementia due to probable AD with MMSE of 20 to 26 (inclusive). 
6. CDR Global Score of 0.5 to 1.0. 
7. A brain magnetic resonance imaging (MRI) or computed tomography (CT) scan in the 
12 months preceding Screening (a wider window may be accepted but requires written 
approval by the ICON Medical Monitor [MM]) that, in the investigator’s opinion, is 
consistent with AD as the principal aetiology of the dementia with no other clinically 
significant abnormality, e.g. another principal underlying aetiology of the subject’s 
dementia, or a lesion which could affect cognition e.g. a brain tumour or large stroke. 
8. On stable dose of acetylcholinesterase inhibitor (AChEI) and/or memantine (at least 
3 months prior to Screening) OR treatment-naïve.  Initiating AChEIs or memantine 
during the study will not be permitted. 
9. Apart from a clinical diagnosis of mild dementia due to probable AD, the subject must be 
in good health as determined by the investigator, based on medical history and screening 
assessments. 
10. Has a consenting study partner who, in the investigator’s judgement, has frequent and 
sufficient contact with the subject to be able to provide accurate information as to the 
subject’s cognitive and functional abilities.  The study partner must be available to 
provide information to the investigator and study site staff about the subject and agrees to 
attend all study site visits in person for scale completion.  A study partner should be 
available for the duration of the study.  The measure of adequate availability will be at the 
investigator’s discretion. 
11. Must be willing and able to comply with the requirements of the protocol and must be 
available to complete the study. 
12. Must satisfy a medical examiner about their fitness to participate in the study. 
13. Must provide written informed consent to participate in the study. 
9.3.2 
Exclusion Criteria 
A subject will NOT be eligible for this study if ANY of the following criteria apply: 
1. Clinically significant abnormalities in vital signs (blood pressure, heart rate, respiration 
rate and oral temperature), as determined by the investigator. 
2. Clinically significant abnormal haematology, biochemistry and urine examination values, 
as determined by the investigator.  Additionally. abnormal liver and renal function and 
Vitamin B12 levels below lower threshold may impact cognitive function.  The following 
values will have an alert flag on the laboratory report and are specifically excluded:  


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a) Vitamin B12 < 176 pg/mL 
b) Haemoglobin < 11 g/dL for females and < 12 g/dL for males 
c) Aspartate aminotransferase > 3 x upper limit of normal (ULN) 
d) Alanine aminotransferase > 3 x ULN 
e) Serum creatinine > 2 x ULN 
f) Urine benzodiazepines when positive:  One re-test will be allowed in cases where the 
subject’s intake of benzodiazepines is within the allowed dose.  Re-tests must be 
performed within 7 days of the last benzodiazepine dose prior to the Baseline visit.  A 
positive re-test for urine benzodiazepines is exclusionary. 
Re-testing of laboratory parameters that requires a confirmatory value within the 
screening period will be permitted in an effort to find all possible well-qualified subjects.  
The most current result prior to randomisation is the value by which study inclusion will 
be assessed, as it represents the subject’s most current, clinical state.  Consultation with 
the ICON MM is advised, to identify whether repeat testing of any particular parameter is 
acceptable and clinically relevant. 
3. Has had a significant systemic illness or infection within the past 4 weeks prior to 
randomisation, as determined by the investigator. 
4. Clinically significant neurological disease other than AD, such as (but not limited to) 
Parkinson’s disease, multi-infarct dementia, Huntington’s disease, normal pressure 
hydrocephalus, brain tumour, progressive supranuclear palsy, seizure disorder, subdural 
haematoma, multiple sclerosis or a history of significant head trauma followed by 
persistent neurologic defaults or known structural brain abnormalities. 
5. Subjects with clinical evidence of peripheral neuropathy or historical evidence of 
clinically significant nerve conduction abnormalities.  Clinical evidence of neuropathy is 
defined as: 
a) Inability to sense a stimulus even at the secondary (more proximal) skin area for 
pinprick, light touch, and vibration or temperature at the foot, in at least one extremity 
(in case neurography measures are normal, the case will be discussed with the ICON 
MM to assess subject eligility) 
b) Nerve conduction abnormalities beyond local normal values or inability to measure 
SNAP or CMAP in the primary or a secondary (back-up) nerve 
c) NTSS-6 score > 6, but note that subjects are eligible even if they show: 
 
Missing reflexes of the Achilles tendon (ankle), but a positive patellar (knee) 
tendon reflex 
 
Missing ability to name toe or thumb position 
6. Has had a stroke within the year prior to randomisation, as determined by the investigator. 
7. Has a lifetime diagnosis of a major psychiatric disorder (other than dementia), based on 
the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition criteria.  This 


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includes but is not limited to schizophrenia, schizoaffective disorder, bipolar affective 
disorder, alcohol dependence syndrome or major depressive disorder. 
8. Has a history of disease directly related to the hypothalamus, the pituitary and/or the 
adrenal glands which affect the hypothalamic-pituitary-adrenal axis function. 
9. Has uncontrolled clinical conditions relating to glucose and lipid metabolism. 
10. Clinically significant ECG abnormalities, including QTc interval > 450 msec, following 
ECG tracings at Screening.  A single repeat evaluation will be allowed if the investigator 
or designee has reason to believe the reading is faulty or to help assess the clinical 
significance of an abnormality.  Any other ECG abnormality that is seen as exclusionary 
will first be discussed with the ICON MM. 
11. Use of any prohibited medication (see Section 10.8 for details). 
12. Participation in another clinical study of an investigational drug or device whereby the 
last drug/device administration is within 60 days of Screening. 
13. Inability to communicate well with the investigator (i.e. language problem, non-fluent 
English [as scales will be provided in English only], poor mental development or 
impaired cerebral function). 
14. Subject will undergo the tests, ADAS-Cog v14, CDR-SOB, MMSE, NTB (executive 
domain) and RAVLT at the indicated time-points to avoid uncontrolled learning effects.  
Subjects who need to perform these tests externally to and in parallel with this study will 
be excluded. 
15. Subject has ingested any food or drink containing grapefruit, Seville oranges, star fruit, or 
derived products (e.g. fruit juice), for at least 3 days prior to the first administration of 
study drug.  Subjects must be willing to abstain from ingesting these foods and drinks 
throughout the study, as it may interfere with the activity of Xanamem™. 
9.4 
Schedule of Assessments 
The Schedule of Assessments is presented in Table 1. 


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Table 1 Schedule of Assessments 
Visit name 
Screening 1 
Baseline 1 
Interim 1 
Telephone 
Contact 14 
EOT 1,2 
Follow-up 1 
Unscheduled 
Safety Visit 15 
Visit time and variance 
Weeks -1 to 
-4 
Week 0 
Week 4 
± 4 days 
Week 8
± 4 days 
Ad hoc 
Week 12 
± 4 days 
4 Weeks 
Post Last 
Dose of 
Study Drug
± 4 days 
 
Informed consent (subject and caregiver) 
X 
 
 
 
 
 
 
 
Inclusion and exclusion criteria 
X 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
Prior/concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
MMSE (subject only) and CDR-SOB (subject 
and caregiver) 
X 
X 
 
 
 
X 
 
 
ADAS-Cog v14 (subject only), RAVLT 
(subject only), NTB (subject only) and NPI 
(caregiver only) 
 
X 
 
 
 
X 
 
 
NTSS-6 (subject and caregiver) 3 
X 
X 
X 
X 
X 
X 
X 
X 
CSSRS (subject and caregiver) 
X 
 
X 
X 
 
X 
X 
 
Physical and neurological examination 
(including TCNS), weight, vital signs 4 
X 
X 
X 
X 
 
X 
X 
X 
NFM (including clinician-rated outcome in 
TCNS) 5 
X 
X 
X 
X 
 
X 
X 
 
Height 
X 
 
 
 
 
 
 
 
BMI 
 
X 
 
 
 
X 
 
 
Brain MRI/CT 6 
X 
 
 
 
 
 
 
 
Randomisation 
 
X 
 
 
 
 
 
 


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Visit name 
Screening 1 
Baseline 1 
Interim 1 
Telephone 
Contact 14 
EOT 1,2 
Follow-up 1 
Unscheduled 
Safety Visit 15 
Visit time and variance 
Weeks -1 to 
-4 
Week 0 
Week 4 
± 4 days 
Week 8
± 4 days 
Ad hoc 
Week 12 
± 4 days 
4 Weeks 
Post Last 
Dose of 
Study Drug
± 4 days 
 
 PK blood sample 7, 15 
 
X 
X 
X 
 
X 
 
X 
Safety laboratory sample (biochemistry, 
haematology and urine examination) 
X 
X 
X 
X 
 
X 
X 
 
Vitamin B12 
X 
 
 
 
 
 
 
 
Sample for metabolic function testing:  glucose 
and lipids, HbA1c 8 
 
X 
 
 
 
X 
 
 
Pregnancy test 9 
X 
X 
X 
X 
 
X 
X 
 
FSH test 10 
X 
 
 
 
 
 
 
 
Benzodiazepines screening 11 
X 
 
 
 
 
 
 
 
Optional PD sample for adrenocorticotropic 
hormone, dehydroepiandrosterone sulfate, 
androstenedione and testosterone 12 
 
X 
X 
X 
 
X 
X 
 
ECG 
X 
X 13 
X 
X 
 
X 
X 
 
Daily Drug Intake Diary 
 
X 
X 
X 
 
X 
 
 
Drug dispense 
 
X 
X 
X 
 
 
 
 
Adverse event capture 
X 
X 
X 
X 
X 
X 
X 
X 
Drug accountability 
 
 
X 
X 
 
X 
 
 
IWRS 
X 
X 
X 
X 
 
 
 
 
Abbreviations:  ADAS-Cog v14=Alzheimer's Disease Assessment Scale-cognitive subscale; BMI=body mass index; CDR-SOB=Clinical Dementia Rating scale-Sum of 
Boxes; CSSRS=Columbia Suicide Severity Rating Scale; CT=computed tomography; ECG=electrocardiogram; EOT=End of Treatment; FSH=follicle-stimulating hormone; 
HbA1c=haemoglobin A1c; IWRS=Interactive Web Response System; MMSE=Mini-Mental Status Examination; MRI=magnetic resonance imaging; NFM=nerve function 


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monitoring; NPI=Neuropsychiatric Inventory; NTB=Neuropsychological Test Batteries; NTSS=Neuropathy Total Symptom Score; RAVLT=Rey Auditory Verbal Learning 
Test; PD=pharmacodynamic; PK=pharmacokinetic; TCNS=Toronto Clinical Neuropathy Score.  
1 
Caregiver is required to be present at all visits (but not for all scales).  For details see Section 9.4.1. 
2 
Subjects terminating the study early will, if possible, undergo all assessments planned for the EOT (Week 12) visit. 
3 
The NTSS-6 should be completed with the help of site staff, also taking into consideration input from the caregiver. 
4 
Vital signs must include but not be limited to the measurement of orthostatic changes in heart rate and blood pressure.  For details see Section 12.6  Neurological 
examination will cover all aspects of the TCNS, which includes muscle strength/weakness in arms and legs, ataxia (gait, stance and finger-nose coordination), light touch 
(upper and lower extremity), pinprick (upper and lower extremity), position sense (toes and thumbs), reflexes (knee and ankle).  The neurological examination can be 
conducted ± 3 days of the scheduled protocol visit (for details see Section 12.5). 
5 
NFM consists of sensory testing (vibration and thermal perception), motor and sensory nerve neurography (amplitude and conduction velocity) and clinician-rated 
outcome in TCNS.  The NFM can be conducted ± 3 days of the scheduled protocol visit, except at the Screening visit where there is no limit and at the Baseline visit 
where it must be conducted within 3 days prior to the randomisation step.  Note: Subject-related outcome measure, NTSS-6, is part of NFM but listed separately.  For 
details see Section 12.7. 
6 
A brain MRI/CT scan is only needed if no historic scan is available from within 12 months prior to Screening.  A wider window may be accepted but requires written 
approval from the ICON Medical Monitor. 
7 
One PK sample will be taken 3 to 5 hours post-dose at the Baseline (Week 0) visit and two PK samples will be taken (at arrival on site [pre-dose] and 3 to 5 hours 
post-dose) at the Interim visits (Week 4 and Week 8).  One PK sample will be taken at the EOT (Week 12) visit.  NB:  The subject will not be dosed during the EOT 
visit.  For details, see Section 9.4.1.  The exact time-points of blood sampling for PK analysis and drug intake will be documented.  Between visits, subjects will record 
the exact times of study drug intake in the Drug Intake Diary.  The subject will be required to bring the diary to the Interim visits (Week 4 and Week 8) and EOT 
(Week 12) visit. 
8 
Taken from the blood sample at Baseline (Week 0), and EOT (Week 12) visits. 
9 
Women of childbearing potential only.  A serum pregnancy test will be performed at Screening and a urine pregnancy test at all subsequent clinic visits. 
10 Females only.  To be taken only if there is clinical concern about the subject’s menopausal status. 
11 Urine collected for the urinalysis sample will also be used to test for the presence of benzodiazepines at the Screening visit.  A second urine sample, prior to 
randomisation, will be needed if a benzodiazepine re-test is required. 
12 This sample should be collected as soon as possible after the subject arrives at the study site (pre-dose).  This could, if possible, be combined with other blood draws to 
minimise the burden for subjects.  For optimal results, the sample for androstenedione analysis should be taken between 6 am and 10 am. 
13 ECG at Baseline only required if Screening ECG was performed more than 2 weeks earlier.   
14 Ad hoc telephone contact may occur at any time-point throughout the study, if deemed necessary by the investigator/study nurse, or if the subject wishes to report an AE. 
If an SAE occurs in a subject, the subject will return to the site for a PK sample.  Additional procedures will be performed as indicated, for details see Section 12.1.1.3).  
15  Cortisol will be measured using the existing PK blood samples taken at Baseline (Week 0), Week 4, Week 8, and Week 12.  
Note:  For each study visit, excluding the Screening visit, subjects will arrive at the study site having fasted for at least 10 hours.  Subjects should aim to take study drug at 
the same time each morning with food (30 minutes after the start of a standard meal) at the study site, and after all pre-dose blood samples have been taken.  It is 
recommended that the subject visit the study site in the morning so that the fasted period will have been overnight.  The investigator will record time of arrival and the hours 
fasted.  The investigator will take the appropriate blood samples from the subject, for various assessments, as indicated in the following sections.  After the blood draws, the 


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subject will take food and a drink (to be provided either by the study site, or the subject).  About 30 minutes after the start of the meal, subjects will be administered study 
drug in the presence of appropriate site staff.  The exact time of dosing is to be recorded in the Drug Intake Diary. 


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9.4.1 
Study Procedures and Assessments 
For each study visit (except the Screening visit), subjects will arrive at the study site having 
fasted for at least 10 hours.  It is recommended that the subject visit the study site in the 
morning so that the fasted period will have been overnight.  The investigator will record the 
time of arrival and the hours fasted.  The investigator will take the appropriate blood samples 
from the subject, for various assessments, as indicated in the following sections.  After the 
blood draws for the Baseline visit, Interim visits (Week 4 and Week 8) and EOT (Week 12) 
visit, the subject will take food and a drink (to be provided either by the study site or the 
subject).  About 30 minutes after the start of the meal, subjects will be administered study 
drug in the presence of the investigator.  The exact time of dosing is to be recorded in the 
Drug Intake Diary (which forms part of the Subject Visit-by-Visit Guide).  
9.4.1.1 
Screening Visit (Weeks -1 to -4) 
Subjects are to undergo a Screening visit at least 7 days, but no more than 28 days, prior to 
the planned Baseline visit (Week 0).  Study sites may perform the Screening procedures at 
any time point within the Screening window.  The subjects will spend approximately half a 
day at the study site.  The screening period should be at least 1 week in duration to have a 
homogeneous sample regarding subject learning effects whilst performing the cognitive tests. 
During the Screening visit, subjects will be screened at the study site to confirm their 
eligibility for participation in the study.  The investigator or sub-investigator will discuss with 
each subject the nature of the study, its requirements, and its restrictions.  Written informed 
consent must be obtained prior to the conduct of any protocol-specific procedures. 
Subjects who do not randomise within 28 days of screening will be screen failed.  The 
screening period may be extended to 31 days if the only outstanding eligibility criterion is the 
NFM assessment.  Re-screening may be allowed once, after approval by the ICON MM.  
Subjects who are re-screened after 30 days (from date screen failure was confirmed), must be 
re-consented with a new screening number, and repeat the screening assessments.  For 
subjects re-screened within 30 days (from date screen failure was confirmed), only 
assessments with results that would exclude the subject will need to be repeated. 
Screening procedures and assessments are as follows: 
The chronological order of the assessments below should be followed. 
1. Obtain written informed consent from the subject and subject’s caregiver in accordance 
with local regulations, including those for the sub-population PD assessment. 
2. Register screening of the subject using the ICON Interactive Web Response System 
(IWRS). 
3. Review subject eligibility (inclusion and exclusion criteria).  Any questions regarding 
subject eligibility can be addressed to the ICON MM. 
4. Document demographics. 
5. Document medical history and prior and concomitant medications. 


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6. Complete screening scales (MMSE [subject only], CDR-SOB [subject and caregiver] and 
CSSRS [subject and caregiver]): 
o 
The neuropsychological testing (MMSE and CDR-SOB) should be performed 
during the same period of the day at the Screening, Baseline (Week 0) and EOT 
(Week 12) visits to minimise a confounding impact of fluctuations in vigilance. 
Once the above assessments have been performed, the following can be performed in the 
order most convenient to the investigator/study site staff: 
7. Physical examination (including height and weight), neurological examination  and vital 
signs measurement (blood pressure, heart rate, respiration rate and oral temperature).  The 
neurological examination shall cover all aspects of the TCNS: 
o 
Muscle strength/weakness in arms and legs 
o 
Ataxia (gait, stance and finger-nose coordination) 
o 
Light touch (upper and lower extremity) 
o 
Pinprick (upper and lower extremity) 
o 
Position sense (toes and thumbs) 
o 
Reflexes (knee and ankle) 
The thresholds for “Normal=0” for all Sensory Test Scores are set as follows:  Subject 
can discriminate any of these qualities (pinprick, temperature, light touch, vibration, 
position sense) at least at the secondary (more proximal) region to test that quality (see 
Table 3 for primary and secondary skin-areas). 
8. NTSS-6 (subject and caregiver): The six questions of NTSS-6 should be completed as 
part of the assessment of subjects’ medical history, also asking for input from the 
caregiver to make sure no information is lost.  Each item will also be graded for its 
frequency and intensity, adding up to a total score from “0” to “21.96” points.  A total 
score of > 6 would exclude the subject from the study. 
9. NFM:  for details see Section 12.7.  Two measures for each test will be obtained and 
averaged.  The test must be undertaken and reviewed by suitably qualified and 
experienced personnel.  The following tests will be performed:  
o 
Vibration detection threshold 
o 
Thermal (cold and warm) detection   
o 
Nerve conduction (velocity and amplitude) 
o 
Sensory nerve - Sural nerve or back-up nerves (Ulnar nerve or Median nerve) 
SNAP and NCV 
o 
Motor nerve - Peroneal nerve or back-up nerve (Tibial nerve) CMAP and 
NCV 
For quality control measures, the results of neurography of one subject per study site will 
be reviewed by a member of the DSMB Nerve Function Monitoring sub-committee.  The 


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study site will complete a Neurography Screening Quality Control Form and send it to the 
ICON MM (STUDY-MA-DL-3580-0001@iconplc.com).  The study site may, however, 
proceed with subject randomisation if all eligibility criteria are fulfilled. 
10. Laboratory sampling: 
o 
A blood sample will be taken for haematology and biochemistry, pregnancy test 
(WOCBP only) and Vitamin B12.  If there is clinical concern about a female 
subject’s menopausal status, FSH will be measured. 
o 
Safety laboratory urine sampling.  Note:  the urine sample can be collected from the 
subject at any time whilst at the study site, whenever he/she visits the toilet. 
11. Urine screen for benzodiazepines.  This sample will be taken from the urine sample 
collected above. 
12. ECG (local ECG equipment with ECG to be read locally by an appropriately qualified 
and experienced ECG reader at the study site). 
13. Brain MRI or CT scan, if applicable.  This is only needed if no historic scan is available 
from within 12 months prior to Screening. 
Before the subject leaves the study site, the following final procedures should be completed: 
14. Record AEs (including SAEs) that may have occurred after informed consent was 
obtained. 
15. Remind the subject to attend the Baseline (Week 0) visit in a fasted state. 
16. Schedule the Baseline (Week 0) visit.   
17. Remind the caregiver that he/she is required to be present at all visits (but not for all 
scales). 
9.4.1.2 
Baseline Visit (Week 0) 
Eligible subjects will return to the study site for the Baseline (Week 0) visit, in a fasted state.  
Subjects must continue to satisfy inclusion/exclusion criteria in order to be eligible for 
randomisation.  The subjects will attend the study site from the morning until approximately 
mid-afternoon. 
Baseline procedures and assessments should be conducted in chronological order as follows: 
1. Re-review subject eligibility (inclusion and exclusion) criteria to ensure that the subject 
continues to be eligible for inclusion into the study. 
2. Laboratory sampling: 
o 
A blood sample will be taken for haematology and biochemistry, including 
metabolic function testing (HbA1c, glucose and lipids). 
o 
Urine will be collected.  Note:  the urine sample can be collected from the subject at 
any time whilst at the study site, whenever he/she visits the toilet.  A urine 
pregnancy test (WOCBP only) will be performed from this sample at the site.  


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o 
An additional blood sample will be taken 3 to 5 hours post-dose for PK analysis.  
The exact times of sampling plus the exact time of study drug intake on this day 
must be documented. 
For those subjects who have volunteered for the optional PD sub-study: 
o 
An optional blood sample will be taken for PD analysis, i.e. ACTH, DHEAS, 
androstenedione and testosterone.  This sample will be taken from approximately 
50 subjects enrolled into the main study, who also volunteer to take part in this 
sub-study.  For optimal results, the sample for androstenedione analysis should be 
taken between 6 am and 10 am. 
3. Ensure the subject has breakfast after the laboratory sampling.  The subject will take 
study drug 30 minutes after the start of breakfast and study site staff will document the 
exact time of study drug intake. 
4. ECG (only required in case Screening was performed more than 2 weeks earlier).  
Confirm that the QTc is still acceptable for inclusion. 
5. Perform physical and neurological examination and vital signs measurement (blood 
pressure, heart rate, respiration rate and oral temperature).  The neurological examination 
can be conductedwithin 3 days prior to the scheduled protocol visit.  Assess weight for 
calculation of BMI.  Complete TCNS in the course of the neurological examination, as 
well as NTSS-6 (with input from the caregiver) to ensure the subject did not develop new 
signs or symptoms of neuropathy which would exclude him/her from further 
participation. 
6. Review concomitant medication. 
7. NFM:  for details see Section 12.7.  Perform the assessment at the area the subject could 
detect the sensory stimulus during the Screening visit.  Two measures for each test will be 
obtained and averaged.  Both extremities will be assessed.  The test must be undertaken 
and reviewed by suitably qualified and experienced personnel.  The NFM can be 
conducted within 3 days prior to the scheduled protocol visit, but must be prior to the 
randomisation step.  Even in case Screening and Baseline are scheduled within 1 week, a 
second NFM assessment is required. 
Example: Subject was able to detect a vibration threshold at the medial malleolus at 2/8, 
perform the vibration threshold testing again at the medial malleolus.  Where subjects 
can no longer detect vibration at the medial malleolus (but at patella with a threshold of 
4/8), this would still reflect a worsening and may disqualify the subject from further 
participation. 
The following tests will be performed:  
o 
Vibration detection threshold 
o 
Thermal (cold and warm) detection   
o 
Nerve conduction (velocity and amplitude) 


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o 
Sensory nerve - Sural nerve or back-up nerves (Ulnar nerve or Median nerve) 
SNAP and NCV 
o 
Motor nerve - Peroneal nerve or back-up nerve (Tibial nerve) CMAP and 
NCV 
If any of these NFM tests show a deterioration from the “Before Treatment” status 
(calculated as the average of the Screening visit and Baseline visit data), please contact 
the ICON MM (STUDY-MA-DL-3580-0001@iconplc.com) within 24 hours of becoming 
aware of the deterioration, to define follow-up activities and assess whether the subject 
must be withdrawn from study. 
8. Randomise the subject visit using ICON IWRS, dispense study drug and provide the 
subject with a Subject Visit-by-Visit Guide (which also contains the Drug Intake Diary). 
Note:  the first dose of study drug must be taken in the presence of the investigator/study 
site staff, to ensure compliance, and enable the subject to open the drug container and 
make an entry into the Drug Intake Diary. 
9. Assess AEs. 
10. Complete scales (MMSE [subject only] and CDR-SOB [subject and caregiver]). 
11. Neuropsychological scales (ADAS-Cog v14 [subject only], RAVLT [subject only], NTB 
[subject only], and NPI [caregiver only]): 
o 
The neuropsychological testing should be performed during the same period of the 
day at the Screening, Baseline (Week 0) and EOT (Week 12) visits to minimise a 
confounding impact of fluctuations in vigilance. 
12. Before leaving the study site, the 3 to 5 hour post-dose PK sample (as described in No. 2 
above), should be drawn. 
13. Remind the subject to document the time of study drug intake each day and to attend the 
Interim (Week 4) visit in a fasted state.  
14. Schedule the Interim (Week 4) visit. 
9.4.1.3 
Interim Visit (Week 4) 
Subjects will attend the study site for the Interim (Week 4 ± 4 days) visit, in a fasted state.  
The subjects will attend the study site from the morning until approximately mid-afternoon. 
The proposed chronology of events for the interim procedures and assessments are as follows: 
1. Laboratory sampling: 
o 
A blood sample will be taken for haematology and biochemistry. 
o 
Urine will be collected.  Note:  the urine sample can be collected from the subject 
at any time whilst at the study site, whenever he/she visits the toilet.  A urine 
pregnancy test (WOCBP only) will be performed from this sample at the site. 


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o 
A blood sample will be taken pre-dose for PK analysis (only if the subject can 
provide the date and time of the last dose of study drug).  A second blood sample 
will be taken 3 to 5 hours post-dose for PK analysis.  The exact times of sampling 
plus the exact time of study drug intake on this day must be documented. 
For those subjects who have volunteered for the optional PD sub-study: 
o 
An optional blood sample will be taken for PD analysis, i.e. ACTH, DHEAS, 
androstenedione and testosterone.  This sample will be taken from approximately 
50 subjects enrolled into the main study, who also volunteer to take part in the 
sub-study.  For optimal results, the sample for androstenedione analysis should be 
taken between 6 am and 10 am. 
2. Register the subject visit using ICON IWRS and dispense study drug. 
3. Allow the subject to have breakfast after the laboratory sampling.  The subject will take 
study drug 30 minutes after the start of breakfast and study site staff will document the 
exact time of study drug intake. 
4. Perform physical and neurological examination and vital signs measurement (blood 
pressure, heart rate, respiration rate, weight and oral temperature).  The neurological 
examination can be conducted ± 3 days of the scheduled protocol visit.  Complete TCNS 
in the course of the neurological examination, as well as NTSS-6 (with input from the 
caregiver) to ensure the subject did not develop new signs or symptoms of neuropathy. 
5. Review concomitant medications. 
6. CSSRS (subject and caregiver). 
7. ECG (local ECG equipment with ECG to be read locally by an appropriately qualified 
and experienced ECG reader at the study site).  The same equipment as for Baseline ECG 
should be used, to avoid errors in calculating QTc. 
8. NFM - for details see Section 12.7.  Peform the assessment at the area the subject could 
detect the sensory stimulus during the Baseline visit.  Two measures for each test will be 
obtained and averaged.  Both extremities will be assessed.  The test must be undertaken 
and reviewed by suitably qualified and experienced personnel.  The NFM can be 
conducted ± 3 days of the scheduled protocol visit.  The following tests will be 
performed:  
o 
Vibration detection threshold 
o 
Thermal (cold and warm) detection   
o 
Nerve conduction (velocity and amplitude) 
o 
Sensory nerve - Sural nerve or back-up nerves (Ulnar nerve or Median nerve) 
SNAP and NCV 
o 
Motor nerve - Peroneal nerve or back-up nerve (Tibial nerve) CMAP and 
NCV 


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If any of these NFM tests show a deterioration from the “Before Treatment” status 
(calculated as the average of the Screening visit and Baseline visit data), please contact 
ICON MM (STUDY-MA-DL-3580-0001@iconplc.com) to define follow-up activities 
and assess whether the subject must be withdrawn from study. 
9. Record AEs.  AEs of special interest (AESIs) (worsening of NFM [calculated as the 
average of the Screening visit and Baseline visit data] or prolongation of QTc) must be 
treated as SAEs and notified to ICON Pharmacovigilance (PV) within 24 hours (see 
Section 12.1.1).  ICON PV or ICON MM will then contact the study site to explain the 
required next steps for further evaluation. 
10. Perform study drug accountability and review Drug Intake Diary for completion 
compliance. 
11. Schedule the second Interim (Week 8) visit. 
12. Remind the subject to document the time of study drug intake on each day and to attend 
the Interim (Week 8) visit in a fasted state. 
13. Remind the caregiver that he/she is required to be present at all visits (but not for all 
scales). 
14. Before leaving the study site, the second PK sample (3 to 5 hours post-dose; as described 
in No. 1 above), should be drawn. 
9.4.1.4 
Interim Visit (Week 8) 
Subjects will attend the study site for the Interim (Week 8 ± 4 days) visit, in a fasted state.  
The subjects will attend the study site from the morning until approximately mid-afternoon. 
The proposed chronology of events for the interim procedures and assessments are as follows: 
1. Laboratory sampling: 
o 
A blood sample will be taken for haematology and biochemistry. 
o 
Urine will be collected.  Note:  the urine sample can be collected from the subject 
at any time whilst at the study site, whenever he/she visits the toilet.  A urine 
pregnancy test (WOCBP only) will be performed from this sample at the site. 
o 
A blood sample will be taken pre-dose for PK analysis (only if the subject can 
provide the date and time of the last dose of study drug).  A second blood sample 
will be taken 3 to 5 hours post-dose for PK analysis.  The exact times of sampling 
plus the exact time of study drug intake on this day must be documented. 
For those subjects who have volunteered for the optional PD sub-study: 
o 
An optional blood sample will be taken for PD analysis, i.e. ACTH, DHEAS, 
androstenedione and testosterone.  This sample will be taken from approximately 
50 subjects enrolled into the main study, who also volunteer to take part in the 
sub-study.  For optimal results, the sample for androstenedione analysis should be 
taken between 6 am and 10 am. 


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2. Register the subject visit using ICON IWRS and dispense study drug. 
3. Allow the subject to have breakfast after the laboratory sampling.  The subject will take 
study drug 30 minutes after the start of breakfast and study site staff will document the 
exact time of study drug intake. 
4. Perform physical and neurological examination and vital signs measurement (blood 
pressure, heart rate, respiration rate, weight and oral temperature).  The neurological 
examination can be conducted ± 3 days of the scheduled protocol visit.  Complete TCNS 
in the course of the neurological examination, as well as NTSS-6 (with input from the 
caregiver) to ensure the subject did not develop new signs or symptoms of neuropathy.  
5. Review concomitant medications. 
6. CSSRS (subject and caregiver). 
7. ECG (local ECG equipment with ECG to be read locally by an appropriately qualified 
and experienced ECG reader at the study site).  The same equipment as for Baseline ECG 
should be used, to avoid errors in calculating QTc. 
8. NFM - for details see Section 12.7.  Perform the assessment at the area the subject could 
detect the sensory stimulus during the Week 4 visit.  Two measures for each test will be 
obtained and averaged.  Both extremities will be assessed.  The test must be undertaken 
and reviewed by suitably qualified and experienced personnel.  The NFM can be 
conducted ± 3 days of the scheduled protocol visit.  The following tests will be 
performed:  
o 
Vibration detection threshold 
o 
Thermal (cold and warm) detection   
o 
Nerve conduction (velocity and amplitude) 
o 
Sensory nerve - Sural nerve or back-up nerves (Ulnar nerve or Median nerve) 
SNAP and NCV 
o 
Motor nerve - Peroneal nerve or back-up nerve (Tibial nerve) CMAP and 
NCV 
If any of these NFM tests show a deterioration from the “Before Treatment” status 
(calculated as the average of the Screening visit and Baseline visit data), please contact 
ICON MM (STUDY-MA-DL-3580-0001@iconplc.com) to define follow-up activities 
and assess whether the subject must be withdrawn from study. 
9. Record AEs.  AESIs (worsening of NFM [calculated as the average of the Screening visit 
and Baseline visit data] or prolongation of QTc) must be treated as SAEs and notified to 
ICON PV within 24 hours (see Section 12.1.1).  ICON PV or ICON MM will then 
contact the study site to explain the required next steps for further evaluation. 
10. Perform study drug accountability and review Drug Intake Diary for completion 
compliance. 


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11. Schedule the EOT (Week 12) visit. 
12. Remind the subject to document the time of study drug intake on each day and to attend 
the EOT (Week 12) visit in a fasted state. 
13. Remind the caregiver that he/she is required to be present at all visits (but not for all 
scales). 
14. Before leaving the study site, the second PK sample (3 to 5 hours post-dose; as described 
in No. 1 above), should be drawn. 
9.4.1.5 
Telephone Contact (Ad Hoc) 
Subjects can telephone the study sites at any time during the study in order to report an AE.  
At this contact, site staff will be required to: 
1. Question the subject about any new/updates on AEs. 
2. Question the subject to determine any changes to concomitant medications. 
3. Complete NTSS-6 (with input from the caregiver) to ensure the subject did not develop 
new signs or symptoms of neuropathy. 
4. Remind the subject of the date of next visit, if applicable. 
5. Remind the subject to document the exact time of study drug intake each day. 
6. Remind the caregiver that he/she is required to be present at all visits (but not for all 
scales). 
9.4.1.6 
End of Treatment Visit (Week 12) 
Subjects will attend the study site for the EOT (Week 12 ± 4 days) visit, in a fasted state.  The 
subjects will attend the study site from the morning until approximately mid-afternoon.  This 
is also an early termination visit for subjects who withdraw prior to Week 12. 
Proposed chronology of events for the EOT procedures and assessments are as follows: 
1. Laboratory sampling: 
o 
A blood sample will be taken for haematology and biochemistry, including 
metabolic function testing (HbA1c, glucose and lipids). 
o 
Urine will be collected.  Note:  the urine sample can be collected from the subject 
at any time whilst at the study site, whenever he/she visits the toilet.  A urine 
pregnancy test (WOCBP only) will be performed from this sample at the site. 
o 
A blood sample will be taken for PK analysis (only if the subject can provide the 
date and time of the last dose of study drug).  The exact time of sampling must be 
documented. 
For those subjects who have volunteered for the optional PD sub-study: 
o 
An optional blood sample will be taken for PD analysis, i.e. ACTH, DHEAS, 
androstenedione and testosterone for PD analysis.  This sample will be taken from 
approximately 50 subjects enrolled into the main study, who also volunteer to take 


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part in the sub-study.  For optimal results, the sample for androstenedione analysis 
should be taken between 6 am and 10 am. 
2. Allow the subject to have breakfast after the laboratory sampling.   
3. Perform physical and neurological examination and vital signs measurement (blood 
pressure, heart rate, respiration rate, weight and oral temperature).  The neurological 
examination can be conducted ± 3 days of the scheduled protocol visit.  Complete TCNS 
in the course of the neurological examination, as well as NTSS-6 (with input from the 
caregiver) to ensure the subject did not develop new signs or symptoms of neuropathy.  
4. NFM - for details see Section 12.7.  Perform the assessment at the area the subject could 
detect the sensory stimulus during the Week 8 visit.  Two measures for each test will be 
obtained and averaged.  Both extremities will be assessed.  The test must be undertaken 
and reviewed by suitably qualified and experienced personnel.  The NFM can be 
conducted ± 3 days of the scheduled protocol visit.  The following tests will be 
performed:  
o 
Vibration detection threshold 
o 
Thermal (cold and warm) detection 
o 
Nerve conduction (velocity and amplitude) 
o 
Sensory nerve - Sural nerve or back-up nerves (Ulnar nerve or Median nerve) 
SNAP and NCV 
o 
Motor nerve - Peroneal nerve or back-up nerve (Tibial nerve) CMAP and 
NCV 
If any of these tests show a deterioration from the “Before Treatment” status (calculated 
as the average of the Screening visit and Baseline visit data), please contact ICON MM 
(STUDY-MA-DL-3580-0001@iconplc.com) to define the follow-up activities and assess 
whether the subject must be withdrawn from study. 
5. Review concomitant medications. 
6. Neuropsychological scales (ADAS-Cog v14 [subject only], CDR-SOB [subject and 
caregiver], MMSE [subject only], RAVLT [subject only], NTB [subject only], NPI 
[caregiver only] and CSSRS [subject and caregiver]): 
o 
The neuropsychological testing should be performed during the same period of the 
day at the Screening, Baseline (Week 0) and EOT (Week 12) visits to minimise a 
confounding impact of fluctuations in vigilance 
7. ECG (local ECG equipment with ECG to be read locally by an appropriately qualified 
and experienced ECG reader at study site).  The same equipment as for Baseline ECG 
should be used, to avoid errors in calculating QTc. 
8. Record AEs.  AESIs (worsening of NFM [calculated as the average of the Screening visit 
and Baseline visit data] or prolongation of QTc) must be treated as SAEs and notified to 


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ICON PV within 24 hours (see Section 12.1.1).  ICON PV or ICON MM will then 
contact the study site to explain the required next steps for further evaluation. 
9. Perform study drug accountability and review Drug Intake Diary for completion 
compliance. 
9.4.1.7 
Follow-up Visit (4 Weeks Post Last Dose of Study Drug ± 4 Days) 
Subjects who complete the 12-week double-blind treatment period, or subjects who 
terminated early, will attend a Follow-up (4 weeks post last dose of study drug ± 4 days) visit 
for safety purposes, in a fasted state.  The subjects will spend the morning at the study site. 
Follow-up procedures and assessments are as follows: 
1. Laboratory sampling: 
o 
A blood sample will be taken for haematology and biochemistry. 
o 
Urine will be collected.  Note:  the urine sample can be collected from the subject 
at any time whilst at the study site, whenever he/she visits the toilet.  A urine 
pregnancy test (WOCBP only) will be performed from this sample at the site. 
For those subjects who have volunteered for the optional PD sub-study: 
o 
An optional blood sample will be taken for PD analysis, i.e. ACTH, DHEAS, 
androstenedione and testosterone.  This sample will be taken from approximately 
50 subjects enrolled into the main study, who also volunteer to take part in the 
sub-study.  For optimal results, the sample for androstenedione analysis should be 
taken between 6 am and 10 am. 
2. Perform physical and neurological examination and vital signs measurement (blood 
pressure, heart rate, respiration rate, weight and oral temperature).  The neurological 
examination can be conducted ±  3days of the scheduled protocol visit.  Complete TCNS 
in the course of the neurological examination, as well as NTSS-6 (with input from the 
caregiver) to ensure the subject did not develop new signs or symptoms of neuropathy. 
3. NFM - for details see Section 12.7.  Perform the assessment at the area the subject could 
detect the sensory stimulus during the Week 12 visit.  Two measures for each test will be 
obtained and averaged.  Both extremities will be assessed.  The test must be undertaken 
and reviewed by suitably qualified and experienced personnel.  The NFM can be 
conducted ± 3 days of the scheduled protocol visit.  The following tests will be 
performed:  
o 
Vibration detection threshold 
o 
Thermal (cold and warm) detection   
o 
Nerve conduction (velocity and amplitude) 
o 
Sensory nerve - Sural nerve or back-up nerves (Ulnar nerve or Median nerve) 
SNAP and NCV 


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o 
Motor nerve - Peroneal nerve or back-up nerve (Tibial nerve) CMAP and 
NCV 
If any of these tests show a deterioration from the “Before Treatment” status (calculated 
as the average of the Screening visit and Baseline visit data), please contact ICON MM 
(STUDY-MA-DL-3580-0001@iconplc.com) to define the follow-up activities. 
4. Review concomitant medications. 
5. Complete the CSSRS (subject and caregiver). 
6. ECG (local ECG equipment with ECG to be read locally by an appropriately qualified 
and experienced ECG reader at the study site).  The same equipment as for Baseline ECG 
should be used, to avoid errors in calculating QTc. 
7. Record AEs.  AESIs (worsening of NFM [calculated as the average of the Screening visit 
and Baseline visit data] or prolongation of QTc) must be treated as SAEs and notified to 
ICON PV within 24 hours (see Section 12.1.1).  ICON PV or ICON MM will then 
contact the study site to define follow-up activities and to assess whether the subject must 
be withdrawn from study.  
9.4.1.8 
Unscheduled Safety Visit 
If an SAE occurs in a subject, the subject will return to the site for a PK sample, as close as 
possible to SAE onset.  Procedures and assessments are as follows: 
1. Review concomitant medications. 
2. A blood sample will be taken for PK analysis.  The exact date and time of sampling must 
be documented. 
3. Review the Drug Intake Diary for completion compliance and for the date and time of the 
last dose of study drug prior to the PK sample. 
4. Perform physical and neurological examination and vital signs measurement (blood 
pressure, heart rate, respiration rate, weight and oral temperature).  The neurological 
examination can be conducted ± 1 day of the scheduled protocol visit.  Complete TCNS 
in the course of the neurological examination, as well as NTSS-6 (with input from the 
caregiver) to ensure the subject did not develop new signs or symptoms of neuropathy.  
5. Record AEs.  AESIs (worsening of NFM [calculated as the average of the Screening visit 
and Baseline visit data] or prolongation of QTc) must be treated as SAEs and notified to 
ICON PV within 24 hours (see Section 12.1.1).  ICON PV or ICON MM will then 
contact the study site to define follow-up activities and to assess whether the subject must 
be withdrawn from study.  
9.5 
Withdrawal of Subjects 
Subjects may withdraw from the study at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator or sponsor for safety, behavioural, 
or administrative reasons.  The decision to withdraw consent and discontinue participation in 
the study will not prejudice the subject’s future medical treatment in any way.  If a subject 


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does not return for a scheduled visit, every effort will be made to contact the subject.  In any 
circumstance, every effort will be made to document subject outcome, if possible.  The 
investigator should inquire about the reason for withdrawal, and request the subject to return 
for the EOT (Week 12) visit, if applicable, and follow-up with the subject regarding any 
unresolved AEs (for details see Section 12.1.1.1).  The investigator or sub-investigator will 
be responsible for reporting subject withdrawal to Actinogen Medical/ICON.  Subjects 
withdrawn from the study cannot be re-enrolled at a later time, regardless of the reason for 
withdrawal. 
If a subject consents to undertake additional and optional study procedures/assessments but 
withdraws consent for doing so at a later visit, he/she will be retained in the study for the 
routine study procedures/assessments.  If a subject withdraws from the study, and also 
withdraws consent for disclosure of future information, no additional data should be 
collected.  Actinogen Medical/ICON may retain and continue to use any data collected before 
such withdrawal of consent. 
Subjects shall be withdrawn during the course of the study when subject well-being is at risk, 
including but not limited to: 
 Subject needs to take a prohibited medication.  In case medication from the list of drugs 
potentially prolonging QTc (Appendix III) is introduced, the most appropriate approach 
will be discussed upfront with the ICON MM since the subject may not need to be 
withdrawn in all cases, e.g. in situations where the new drug is only provided temporarily, 
or in low doses, or in situations where baseline QTc was in the lower range of normal. 
 ECG indicates a QTc level above a threshold of 480 msec at the Interim (Week 4 and 
Week 8) visits or an increase in QTc from Baseline > 60 msec (for details see 
Section 12.3).  In this case, it should be reported as an AESI, within 24 hours. 
 Subject develops signs or symptoms of peripheral neuropathy in any two tests of NFM, 
confirmed by the DSMB Nerve Function Monitoring sub-committee. 
 The subject is unable to tolerate their prescribed study drug per protocol. 
 Subject has evidence of drug-induced liver injury or any other drug-induced injury (such 
as thrombocytopenia), detected in ongoing safety monitoring of laboratory results. 
 Subject is confirmed to be pregnant. 
9.6 
Early Termination 
This study may be terminated prematurely at any time by Actinogen Medical for medical, 
operational or ethical reasons at individual or all study sites. 
If the study is prematurely terminated or discontinued, Actinogen Medical/ICON will 
promptly notify the investigator, institutions and all competent regulatory authorities in 
writing outlining the reasons for the termination.  The investigator or Actinogen 
Medical/ICON will promptly inform the Independent Ethics Committee/Independent 
Regulatory Board (IEC/IRB).  After notification, the investigator must contact all 


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participating subjects and the hospital pharmacies (if applicable) within a reasonable time 
period and inform them of the premature termination/discontinuation of the study. 
As directed by Actinogen Medical/ICON, all study materials, except documents needed for 
archiving requirements, will be collected and all eCRFs completed to the greatest extent 
possible.  The study monitor will ensure that any outstanding data clarification issues and 
queries are resolved, and that all study records at the study site are complete. 


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10 
TREATMENT OF SUBJECTS 
10.1 
Identity of Study Treatments 
10.1.1 
Administration of Study Treatments 
One capsule of Xanamem™, or the matching placebo, will be administered orally with 
approximately 200 mL of preferably warm water QD, preferably with food in the morning, to 
eligible subjects from Baseline (Week 0) to EOT (Week 12) for a total of 12 weeks. 
Subjects will attend the study site, in a fasted state, for a Baseline (Week 0) visit, Interim 
visits (Week 4 and Week 8) and EOT (Week 12) visit.  Subjects should aim to take study 
drug at the same time each morning with food (30 minutes after the start of a standard meal) 
at the study site, and after all pre-dose blood samples have been taken.   
Xanamem™ is formulated in green and cream-coloured size 3, Coni-Snap shaped gelatin 
capsules as an excipient blend at a dose of 10 mg (see Table 2).  The dose of XanamenTM will 
be 10 mg administered orally, QD.   
Table 2 
Ingredients of Xanamem™ and Matching Placebo Capsules, Using a 
Representative Dose of 10 mg (% w/w) 
Component 
Function 
Placebo 
10 mg 
UE2343 
Active pharmaceutical 
ingredient 
0 
5.26 
Lactose 
Diluent 
95.0 
89.74 
Croscarmellose sodium 
Disintegrant 
4.0 
4.00 
Talc 
Glidant 
0.5 
0.05 
Magnesium stearate 
Lubricant 
0.5 
0.05 
Note:  The formulations shown are based on % w/w with a nominal capsule fill weight of 190 mg. 
10.2 
Study Treatment Packaging and Labelling 
10.2.1 
Packaging 
Xanamem™ will be provided in 35 mL high-density polyethylene bottles with child-resistant 
closure push down lids and an induction seal.  Each bottle will contain 32 capsules and 
subjects will receive three bottles each (one bottle dispensed at the Baseline [Week 0] visit 
and one bottle dispensed at each of the Interim [Week 4 and Week 8] visits). 
The drug product and matching placebo will be manufactured by Pharmaceutical Packaging 
Professionals Pty Ltd.  All supplies will be provided in consistent packaging with consistent 
labelling to maintain the study blind.  Further information relating to the study drug is 
available to the investigator(s) in the Investigator Brochure20. 
10.2.2 
Labelling 
Xanamem™ and placebo capsules will be packaged and labelled according to current ICH 
Good Manufacturing Practice and GCP guidelines and national legal requirements. 


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10.2.3 
Shipment and Storage 
The study drug will be supplied to study sites (initial and re-supply) by external providers on 
behalf of Actinogen Medical.  The IWRS supports the study drug supply process.  The 
recipient at the study site must check the study drug for completeness, correct bottle numbers, 
any loss or damage and confirm receipt.  The study drug will be stored between 15 and 25ºC 
(59 to 77ºF), separately from normal hospital or practice inventories, in a locked facility with 
access limited to the investigator and authorised personnel.  The investigator must ensure that 
the study drug is dispensed only to subjects enrolled in the study according to this study 
protocol. 
Current stability data supports storage of the Xanamem™ and placebo capsules between 15 
and 25ºC (59 to 77ºF).  See drug label for further details. 
10.2.4 
Blinding and Randomisation of Study Treatment(s) 
A double-blind design is employed so that both the investigators and the subjects will be 
unaware of the treatment assignment during the whole study. 
After written informed consent is obtained from an eligible subject, a 6-digit subject 
number will be assigned to this subject.  The first digit will denote the country, followed by 
the study site number and a subject sequence number.  This number will be created and 
allocated by the IWRS, when the subject first enters the system at Screening.  The first 
subject screened at a study site will be assigned the number 001; the second will be assigned 
the number 002, and so on.  For example, Subject 204001 will be the first subject screened at 
study Site 04 in Country 2.  Subjects will be identified during the whole study only by their 
assigned subject number. 
The randomisation codes will be computer-generated by ICON Biostatistics, and kept by a 
statistician independent from the project team.  A copy will be provided to whomever 
performs the PK and PD assessments, when the PK and PD data are analysed, as well as to 
the DSMB.  Randomisation codes will be generated in blocks stratified by site to ensure 
approximate balance between dose schemes (1:1) and balanced per site.  Randomisation 
codes will be assigned sequentially as subjects become eligible for randomisation. 
Subjects who are eligible for randomisation will be assigned a unique 3-digit randomisation 
number at the Baseline (Week 0) visit by IWRS.  This randomisation number identifies 
which treatment will be allocated to the subject.  Subjects who withdraw after randomisation 
are not to be replaced and their randomisation number will not be re-used. 
To ensure blinding, the study drug (Xanamem™ capsules) and the matching placebo have the 
same shape and size.  Subjects will receive one capsule of Xanamem™ or one capsule of 
matching placebo capsule QD during the double-blind treatment period.  Labels on the study 
drug containers will not identify treatment a subject is randomised to.  Traceability of the 
treatment is ensured by the study drug number. 
The 4-digit bottle number will identify study drug packs and will be detailed on the study 
drug label.  


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Dispensing of study drug will be coordinated by IWRS.  The system will assign a bottle 
number corresponding to the randomisation arm. 
10.3 
Procedure for Breaking the Randomisation Code 
The study site investigator and appropriate ICON project team members will be authorised to 
access the Emergency Unblinding functionality within the IWRS.  The system will require 
the user to enter an authorisation key number to complete the emergency unblinding 
transaction.  The exact description of the treatment assigned to the individual subject then 
will be accessible.  Emergency unblinding can thus be made for any subject without affecting 
the double-blind nature of the study.  Subject treatment information may only be accessed in 
the event of an emergency and out of necessity to know the identity of the allocated study 
drug in order to institute appropriate therapeutic management.   
Should a situation arise where unblinding is urgently required (i.e. knowledge of treatment 
code is required to adequately manage a life-threatening situation), the investigator at that 
study site may perform immediate unblinding through IWRS.  If time allows, the investigator 
may contact the ICON MM prior to unblinding the individual subject to discuss the rationale 
for emergency unblinding. 
In the event that emergency unblinding is performed, the investigator can view and must print 
the blinded confirmation document from IWRS.  The investigator must record on the 
confirmation document printout the reason for the emergency unblinding, and sign the 
document.  The confirmation document must then to be kept in a safe place until the end of 
the study.  Once a randomisation code has been broken for a subject, he/she must be 
withdrawn from 
the 
study.  The investigator must inform the ICON MM 
(STUDY-MA-DL-3580-0001@iconplc.com) in writing within 24 hours. 
10.4 
Subject Compliance 
After dispensing study drug (Xanamem™ or placebo) to subjects at Baseline (Week 0), 
investigators will follow up with subjects on their compliance to study drug.  This first dose 
of study drug must be taken in the presence of the investigator/study site staff, to enable 
compliance and ensure the subject is capable to open the drug container and make an entry in 
the Drug Intake Diary. 
Study drug accountability will be performed and documented by study site staff at the Interim 
visits (Week 4 and Week 8) and EOT (Week 12) visit.  Subject compliance to treatment will 
be calculated as follows: 
Treatment Compliance = (Number of study drug taken –number of study drug that should 
have been taken). 
Any non-compliance will be documented, and explained in the source documents and the 
eCRF. 
An 80% treatment compliance will still be acceptable as per protocol. 


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10.5 
Study Treatment Accountability 
Records will be maintained supporting the delivery of study drug(s) to the study sites, the 
inventory at the study sites, the use by each subject and the return to the study drug vendor or 
local on-site destruction. 
These records will include dates, quantities, batch numbers, expiry dates and the unique code 
numbers assigned to the study drug and to the study subjects. 
The investigator will be responsible for ensuring that the records adequately document that 
the subjects were provided the doses specified in the protocol and that all study drug received 
from the study drug vendor is reconciled.  All study drug accountability records for study 
drug must be readily available for inspection by the study monitor and/or auditor, and open to 
regulatory inspection at any time. 
10.6 
Study Treatment Destruction 
Any unused or partially used study drug or empty containers must not be destroyed until the 
study drug accountability documentation has been checked and specific permission for 
destruction has been given by the ICON study monitor.  Any destruction of study drug must 
be documented and filed.  Drug destruction may be performed on site, however, this must be 
discussed with the ICON study monitor before proceeding. 
10.7 
Concomitant Medications and Therapy 
Medications that are considered necessary for the subject’s safety and well-being may be 
given during the course of the study at the discretion of the investigator and must be recorded 
in the appropriate sections of the eCRF. 
All medications taken by a subject within 1 month prior to Screening are regarded as prior 
medication and must be documented as such in the eCRF. 
All medications still being taken by a subject at randomisation and which continue to be 
taken during the study are regarded as concomitant medication and must be documented as 
such in the eCRF. 
10.8 
Prohibited Medications 
Details of prohibited medications are as follows (see Appendix III for a list of potential 
prohibited medications, including the brand names [please note this list is not exhaustive and 
serves as a guide to prohibited medications with brand names included and must be used in 
conjunction with the details of prohibited medications detailed below]): 
 Initiating AChEIs or memantine during the study will not be permitted. 
 Changes in medication or doses of psychotropics (or other medication that may have an 
impact on cognition such as anticholinergic medication) within 4 weeks prior to 
Screening and/or throughout the course of the study are not permitted. 
 Regular intake of benzodiazepines may cause cognitive decline24.  Use of sedative drugs 
(specifically benzodiazepines, barbiturates and other anxiolytics) more than twice in 
a week or three times in a month in the past 6 months prior to Screening, or positive at 


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Screening will result in a subject being excluded from the study.  The subject will be 
asked by site staff about their use of benzodiazepines.  If the subject responds with “No 
use”, but subsequent benzodiazepine screening is positive, the subject will be excluded.  
If the subject responds with “Regularly”, the subject will be excluded.  If the subject 
responds with “Only rarely” (i.e. maximum of twice a week), the site staff should enquire 
when the last dose of benzodiazepines had been taken.  One urine benzodiazepine 
screening re-test will be allowed in cases where the subject’s intake of benzodiazepine is 
within the allowed dose and re-test is performed within 7 days of last benzodiazepine 
dose and prior to the Baseline visit.  Positive re-test for urine benzodiazepines is 
exclusionary.  If the re-test result is negative, the subject can remain in the study. 
 Marked adrenal suppression occurs with high doses of inhaled corticosteroid above 
1.5 mg/day 
(0.75 mg/day 
for 
fluticasone 
propionate)25. 
 
Thus, 
inhaled 
glucocorticosteroids (e.g. prednisone equivalent) > 1 g per day, and any oral steroid 
preparations, are prohibited within 2 weeks prior to Baseline (Week 0) and/or throughout 
the course of the study.   
 Several studies have shown the potential for hypothalamic-pituitary-adrenal axis 
suppression 
from 
potent 
topical 
corticosteroids26. 
 
Thus, 
topical 
glucocorticosteroids > 50 g per week are prohibited during the study and within 2 weeks 
prior to Baseline (Week 0) and/or throughout the course of the study. 
 Due to Xanamem™ being mainly metabolised by cytochrome P450 3A4 (CYP3A4), the 
following drugs which inhibit this isoenzyme must not be administered within 2 weeks 
prior to Baseline (Week 0) and/or throughout the course of the study:  boceprevir, 
clarithromycin, 
erythromycine, 
indinavir, 
itraconazole, 
ketoconazole, 
nelfinavir, 
posaconazol, ritonavir, voriconazole, nefazodone. 
 The following drugs strongly inducing CYP3A4 are prohibited within 2 weeks prior to 
Baseline (Week 0) and/or throughout the course of the study:  carbamazepine, 
phenobarbital, phenytoin, primidone, rifampicin, St Johns Wort. 
 Drugs known to prolong the QTc interval (including quinidine and nuedexta) may be 
provided with caution after the Screening visit.  In case such medication is introduced, the 
most appropriate approach will be discussed upfront with the ICON MM since the subject 
may not need to be withdrawn in all cases, e.g. in situations where the new drug is only 
provided temporarily, or in low doses, or in situations where baseline QTc was in the 
lower range of normal. 
 Vitamin B12 and Omega 3 (including specifically Souvenaid) are allowed if at stable 
doses for 3 months prior to Baseline. 
 Drugs that are known to cause peripheral neuropathy are not permitted within 6 months 
prior to Screening and/or throughout the course of the study.  Known drugs included:   
o Arsenic, colchicine and gold 
o Cardiovascular drugs:  amiodarone, hydralazine, perhexiline  


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o Anti-cancer drugs:  cisplatin, docetaxel, paclitaxel, suramin, vincristine  
o Anti-infectives:  chloroquine, isoniazid, metronidazole, nitrofurantoin, thalidomide 
o Autoimmune disease drugs:  etanercept, infliximab, leflunomide  
o Dermatologicals:  dapsone 
o Anti-convulsants:  phenytoin  
o Anti-alcohol drugs:  disulfiram  
o Anti-human immunodeficiency virus (HIV) drugs:  didanosine, stavudine, zalcitabine 


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11 
ASSESSMENT OF EFFICACY 
11.1 
Efficacy Variables 
Efficacy variables include the following: 
 ADAS-Cog v14 
 RAVLT 
 CDR-SOB 
 MMSE 
 NPI 
 NTB – Executive Domain (COWAT and CFT) 
11.1.1 
Efficacy Assessments 
Examples of all the scales used in this study and the NIA and AA criteria, together with 
instructions on how to use these scales are provided in the “XanADu Scale Binder” which 
includes the scale and scoring instructions.  A short description of these scales and the 
rationale as to why these were selected are provided in the following sections. 
11.1.1.1 
Alzheimer's Disease COMposite Score (ADCOMs) 
The FDA published draft guidance on developing drugs for early stage AD in 2013, called for 
outcome measures that assess both cognitive and functional domains that are clinically 
meaningful to individuals and caregivers5.  The pre-dementia Clinical Outcome Assessments 
(pCOA) Team, in alliance with the Clinical Outcomes Working Group in Alzheimer's 
Disease Neuroimaging Initiative Private Partners Scientific Board, has worked over the past 
few years to harmonise industry efforts to develop composite outcome measures that would 
provide more sensitive clinical measures in the earlier, mild cognitive impairment, stages of 
the disease.  After consideration of the various composites in development, the team selected 
the ADCOMs as the prototype clinical composite outcome assessment tool to be advanced 
through the regulatory qualification process.  ADCOMs consists of a weighted combination 
of items from commonly used outcome scales; ADAS-Cog v14, MMSE and CDR-SOB have 
been identified through an unbiased statistical approach to be most sensitive in individuals 
with amnestic mild cognitive impairment and prodromal AD.  In 2013, the Coalition Against 
Major Diseases submitted formal letters of intent to both the FDA and European Medicines 
Agency.  Both agencies accepted the pCOA project into their qualification procedures; 
however, both stressed the need to demonstrate the clinical meaningfulness of the 
composite21. 
11.1.1.2 
Rey Auditory Verbal Learning Test (RAVLT) 
Originally developed in the 1940s, the RAVLT has evolved over the years, and several 
variations of the test have emerged.  The standard RAVLT format starts with a list of 
15 words, which an examiner reads aloud at the rate of one per second.  The participant’s task 
is to repeat all the words he or she can remember, in any order.  This procedure is carried out 


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a total of five times which can be used for the evaluation of incremental practice effects.  The 
examiner then presents a second list of 15 words, allowing the participant only one attempt at 
recall.  Immediately following this, the participant is asked to remember as many words as 
possible from the first list.  The RAVLT has proven useful in evaluating various functions of 
verbal learning and memory, including proactive and retroactive inhibition, retention, 
encoding versus retrieval, and the subjective organisation of learning material.  Since the test 
is brief, straightforward, easy to understand, and appropriate for both children and adults 
(ages 7 through 89), it has gained widespread acceptance27.  The enumerated functions 
represent various processes of auditory learning and (explicit) episodic (long-term) memory 
which are known to be associated with hippocampal functions and represent a core area of 
changes in early stages of AD.   
11.1.1.3 
Alzheimer’s Disease Assessment Scale - Cognitive Behaviour Section 
(ADAS-Cog v14) 
The ADAS-Cog was developed in the early 1980s in response to the then-perceived lack of 
appropriate instruments available to test the efficacy of AD drug treatments.  It aims to assess 
the “severity of dysfunction and research in subjects with AD”28.  Since its inception, the 
ADAS-Cog has been used in over 127 AD clinical studies and, although developed 
specifically for AD, it has frequently been used in non-AD populations, including mild 
cognitive impairment29.  The original ADAS-Cog measures cognitive performance by 
combining ratings of 11 components (Word Recall, Word Recognition, Constructional 
Praxis, Orientation, Naming Objects and Fingers, Commands, Ideational Praxis, 
Remembering Test Instruction, Spoken Language, Word Finding, Comprehension) 
representing six broad areas of cognition:  memory, language, ability to orientate oneself to 
time, place and person, construction of simple designs, and planning and performing simple 
behaviours in pursuit of a basic, predefined goal.  The ADAS-Cog with 11 items is scored 
from 0 to 70.  The ADAS-Cog v14 was designed to assess cognitive impairment in 
individuals with early AD.  A version of the digit cancellation task was reliable and sensitive 
to a broad range of dementia severity.  Performance on the word learning task with delayed 
recall and a subset of the mazes task were impaired even in mild AD.  As such, these tasks 
were felt to be useful in studies involving mild or at-risk subjects, as they provide a useful 
addition to the 11-item version of the ADAS30.  Three items (delayed word recall, 
attention/visual search task, and maze solution) have been added to the ADAS-Cog v11 to 
assess the participant’s attention and concentration. 
This 14-item instrument will be referred to as the ADAS-Cog v14.  Total scores of 
ADAS-Cog 14 range from 0 to 90, with higher scores indicating greater disease severity. 
11.1.1.4 
Clinical Dementia Rating Scale - Sum of Boxes (CDR-SOB) and Global (CDR 
Global) 
The Washington University CDR is a global assessment instrument that yields global and 
SOB scores, with the global score regularly used in clinical and research settings to stage 
dementia severity31.  The CDR-SOB score has been considered a more detailed quantitative 
general index than the global score and provides more information than the global CDR score 


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in participants with mild dementia32.  CDR Global results are relevant for subject eligibility 
and thus will also be performed at the Screening visit. 
The CDR is obtained through semi-structured interviews of patients and informants, and 
cognitive functioning is rated in six domains of functioning: memory, orientation, judgement 
and problem solving, community affairs, home and hobbies, and personal care.  Each domain 
is rated on a five-point scale of functioning as follows: 0, no impairment; 0.5, questionable 
impairment; 1, mild impairment; 2, moderate impairment; and 3, severe impairment. 
The global CDR score is computed via an algorithm33.  CDR Global score is calculated using 
the Washington University online algorithm34. 
The CDR-SOB is based on summing each of the domain box scores, with scores ranging 
from 0-18. 
11.1.1.5 
Mini-Mental Status Examination (MMSE) 
The MMSE is a 30-point questionnaire that is used extensively in clinical and research 
settings to measure cognitive impairment35 and is commonly used in medicine and allied 
health to screen for dementia.  It is also used to estimate the severity and progression of 
cognitive impairment and to follow the course of cognitive changes in an individual over 
time; thus making it an effective way to document a participant’s response to treatment.  For 
this study, MMSE results are relevant for subject eligibility and thus will also be performed at 
the Screening visit. 
11.1.1.6 
Neuropsychiatric Inventory (NPI) 
The NPI was constructed to survey neuropsychiatric disorders in demented patients36.  
Compared to many older scales, the NPI comprises a wide range of neuropsychiatric 
symptoms.  Furthermore, the NPI uses screening and in-depth questions, which simulates a 
clinical interview, allowing it to be conducted relatively quickly and easily.  An additional 
advantage of this instrument is that the same interview can optionally register emotional 
stress of caregivers37.  The purpose of the interview and questionnaire are explained, one 
screening question per behaviour domain is asked, after which approximately seven in-depth 
questions are then possible.  For each domain, the relatives assess the frequency of the 
behaviour (4-point scale), the severity of the symptom (3-point scale) and the emotional 
stress for the caregiver (6-point scale).  The NPI total score is calculated by multiplying the 
frequency and severity rates per domain (maximum score per domain is 12) and then 
calculating the total of all domains (total NPI-score minimum is 0 and maximum 144).  
During this study, NPI will only be assessed at the Baseline (Week 0) and EOT visits 
(Week 12) to minimise burden for rater and subject and thus allowing more focus on primary 
parameters. 
11.1.1.7 
Neuropsychological Test Battery (NTB) - Executive Domain (COWAT and 
CFT) 
The NTB is composed of a group of established cognitive performance tests that were chosen 
from existing, well known cognitive test batteries (e.g. Wechsler Memory Test) and known 
for their good reliability and sensitivity in early AD.  The NTB measures various distinct 


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features of (episodic) memory and executive functions38.  Since memory performance, 
especially features of episodic (long-term) memory, will already be assessed by other 
above-mentioned cognitive scales, only the NTB tests which are known measures of 
executive function features were selected for the current study.  These include word 
association, category fluency tasks and digit span tasks; a combined cognitive (specifically 
executive function) performance score will be calculated through z-transformations of the 
raw scores obtained in the individual tests.  The psychometric properties of the NTB suggest 
it to be particularly suitable for the evaluation of drug effects in participants with a mild 
severity of AD.  During this study, NTB – Executive Domain will only be assessed at the 
Baseline (Week 0) and EOT visits (Week 12) to minimise burden for rater and subject and 
thus allowing more focus on primary parameters. 


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12 
ASSESSMENT OF SAFETY 
Safety variables include the following: 
 Change in clinical safety laboratory values from Baseline (Week 0) to EOT (Week 12) 
(for details see Section 12.2) 
 Incidence of AEs (for details see Section 12.1.1.1) 
 ECG (for details see Section 12.3) 
 NTSS-6 (for details see Section 12.8) 
 Neurological examination:  This will cover all aspects of the TCNS (for details see 
Section 12.5) 
 NFM:  This includes the abovementioned scales (NTSS-6 and TCNS), as well as 
neurography (nerve conduction velocity and amplitude) of peripheral sensory and motor 
nerves.  The NFM should follow existing local standards and procedures and should be 
run in a consistent fashion.  The test must be undertaken and reviewed by suitably 
qualified and experienced personnel.  For details see Section 12.7. 
 CSSRS (for details see Section 12.9) 
 Physical examination (for details see Section 12.4) 
 Vital signs (for details see Section 12.6) 
Ad hoc telephone contact may occur at any time-point throughout the study, if deemed 
necessary by the investigator/study nurse, or if the subject wishes to report an AE.  The 
timing and frequency of safety assessments are described in Section 9.4 and Section 9.4.1. 
12.1 
Adverse Events  
12.1.1 
Definitions 
The definitions for AEs and SAEs are given below.  It is of the utmost importance that all 
staff involved in the study are familiar with the content of this section.  The principal 
investigator is responsible for ensuring this. 
Adverse Event 
An AE is defined as any untoward medical occurrence in a subject administered a 
pharmaceutical product, and which does not necessarily have a causal relationship with this 
treatment.  An AE can therefore be any unfavourable and unintended sign, symptom or 
disease temporally associated with the use of an investigational medicinal product (IMP), 
whether or not related to the IMP. 
Adverse Event of Special Interest 
An AESI is an AE of scientific and medical concern specific to the sponsor’s product for 
which ongoing monitoring and rapid communication by the investigator to ICON could be 
appropriate. Such an event might require further investigation in order to characterize and 
understand it.  These include worsening of NFM qualifying as a potential safety signal (see 


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Section 12.7), and prolongation of QTc above the threshold of 480 msec or a change from 
Baseline > 60 msec.  An AESI will be reported similar to an SAE (see below).  ICON PV or 
ICON MM will contact the study site reporting the AESI to discuss the required additional 
examinations of the affected subject. 
Serious Adverse Event 
An SAE is defined as, but is not limited to, one that: 
 Results in death 
 Is life-threatening 
 Requires subject hospitalisation or prolongs existing hospitalisation 
 Results in persistent or significant disability/incapacity 
 Is a congenital anomaly/birth defect 
 Is an important medical event* 
*Important medical events that may not result in death, be life-threatening or require 
hospitalisation may be considered a serious adverse drug experience, when based on 
appropriate medical judgement.  They may jeopardise the subject or the subject may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition.  This 
also includes AESIs. 
Where an SAE is reported, a PK sample should be collected, noting both the time at which 
the last dose of study drug was administered and the time at which the PK sample was 
collected (see Section 9.4.1.8). 
12.1.1.1 
Recording of Adverse Events 
For the purposes of this study, any detrimental change in the subject’s condition, after signing 
the informed consent form (ICF) and up to completion of the 4-week follow-up period after 
the last administration of study drug, should be considered an AE.  At each study visit the 
investigator (or delegate) will determine whether any AEs have occurred.  If known, the 
medical diagnosis of an AE should be recorded in preference to the listing of signs and 
symptoms.  All AEs are to be recorded on the “adverse event” pages in the subjects’ eCRF. 
AEs and SAEs will be recorded from signing informed consent and at each study visit up to 
the end of the follow-up period at 4 weeks post last dose of study drug. 
If, at any time after the Follow-up (4 weeks post last dose of study drug) visit, an investigator 
is made aware of an SAE that can be reasonably related to study drug, he/she should 
promptly notify Actinogen Medical/ICON. 
The investigator will assess the intensity of AEs based on the following definitions: 
 Mild (awareness of sign or symptom, but easily tolerated) 
 Moderate (discomfort sufficient to cause interference with normal activities) 
 Severe (incapacitating, with inability to perform normal activities) 


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It is important to distinguish between serious and severe AEs.  Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Section 12.1.1.3. 
An AE of severe intensity need not necessarily be considered serious.  For example, nausea 
that persists for several hours may be considered severe nausea but not an SAE.  On the other 
hand, a stroke that results in only a limited degree of disability may be considered a mild 
stroke but would be an SAE. 
For an AE to be a suspected drug-related event, there should be at least a reasonable 
possibility of a causal relationship between the study drug and the AE. 
12.1.1.2 
Monitoring of Adverse Events 
All ongoing AEs should be followed up for 30 days after the last administration of study 
drug, with the exception of any ongoing study drug-related AEs, which should be followed 
until resolution, unless in the investigator's opinion, the AE is unlikely to resolve due to the 
subject’s underlying disease.  Any new SAEs occurring up to 60 days after the last 
administration of study drug should be reported to Actinogen Medical/ICON according to 
Section 12.1.1.3. 
Abnormal Laboratory Values/Vital Signs/Electrocardiograms 
Laboratory/vital signs/ECG abnormalities should be reported as AEs if any one of the 
following criteria are met: 
 Any criterion for an SAE is fulfilled 
 The laboratory/vital signs/ECG abnormality causes the subject to discontinue from the 
study treatment 
 The laboratory/vital signs/ECG abnormality causes the subject to interrupt the study 
treatment 
 The laboratory/vital signs/ECG abnormality causes the subject to modify the dose of 
study treatment 
 The investigator believes that the abnormality should be reported as an AE, especially 
when the investigator requested a confirmatory test which confirmed the initial value 
 If laboratory/vital signs/ECG abnormality is associated with clinical signs and symptoms, 
the sign or symptom should be reported as an AE and the associated laboratory result or 
vital sign or ECG reading should be considered additional information that must be 
collected on the relevant eCRF 
Deaths 
Should a death occur within the study period or within 60 days after the last administration of 
study drug, both an AE form and an SAE form should be completed, detailing the AE that 
resulted in the death (note that death is an outcome, not an event).  The SAE must be reported 
as detailed in Section 12.1.1.3.  The report should contain a comment regarding the 
co-involvement of progression of disease, if appropriate, and should assign main and 
contributory causes of death. 


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Overdose 
There is no antidote available for Xanamem™.  Any overdose needs to be managed 
according to standard of care and reported as an AE. 
Pregnancy 
In the very unlikely event that pregnancy occurs, the following should be noted:  pregnancy 
itself is not regarded as an AE unless there is a suspicion that the study drug may have 
interfered with the effectiveness of a contraceptive medication.  However, the outcome of all 
pregnancies (spontaneous miscarriage, elective termination, normal birth or congenital 
abnormality) must be followed up and documented even after the subject has been withdrawn 
from the study. 
All reports of congenital abnormalities/birth defects are SAEs.  Spontaneous miscarriages 
should also be reported and handled as SAEs.  Elective abortions without complications 
should not be handled as AEs.  All outcomes of pregnancy must be reported to Actinogen 
Medical/ICON on a pregnancy outcomes report form. 
12.1.1.3 
Reporting of Serious Adverse Events 
Investigators and other study site personnel must inform the appropriate ICON 
representatives of any SAEs and AESIs that occur (whether or not attributable to the study 
drug) in the course of the study, within 24 hours of when he/she becomes aware of it. 
When an SAE or AESI is discovered by the site or is identified by an ICON clinical research 
associate during site visits, SAEs or AESI will be entered by the site members into the eCRF, 
which contains specific questions for events regarded as serious.  ICON PV will receive the 
alert through automated e-mail notification. 
In case of technical problems in transmitting the SAE through the eCRF within the 24-hour 
timeline, the investigator/site representative shall complete the SAE form and fax or e-mail 
to: 
For Australia: 
Fax No.: +6565657939 
Tel No.: +6568960378 (business hours) 
 
+6565339503 (out of hours) 
E-mail: 
icon-safety-centralreceipt@iconplc.com 
For the UK: 
Fax No.: +44 (0)208 100 5005 
Tel No.: +44 (0)1628 496 300 
E-mail: 
icon-safety-centralreceipt@iconplc.com 
For the USA: 
Fax No.: +1 215 616 3096 
Tel No.: +1 888 723 9952 
E-mail: 
icon-mads@iconplc.com 


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If the site staff calls ICON PV to report an SAE, the caller will be prompted to provide the 
following information, as available: 
 Study name, sponsor name, protocol number 
 Reporter’s name, investigator’s name and telephone number 
 Site number, subject’s study number and subject’s initials 
 SAE term, start and stop dates of the event 
 Relationship to each IMP, action taken in regard to IMP, and subject outcome 
The ICON representative will work with the investigator to compile all the necessary 
information and ensure that the appropriate sponsor representative receives a report within 
1 day (24 hours) for all fatal and life-threatening cases and within 5 days for all other SAEs 
and AESIs. 
Follow-up information on SAEs and AESIs must also be reported by the investigator by 
entering this updated information into the eCRF within the same time frames. 
If a non-serious AE becomes serious, this and other relevant follow-up information must also 
be provided to ICON within 24 hours as described above.  The following variables will be 
recorded for each AE:  verbatim/AE description, time and date for AE start and stop, 
maximum intensity, seriousness, causality rating, whether or not the AE caused the subject to 
discontinue, and the outcome. 
All SAEs and AESIs must be reported, whether or not considered causally related to the 
study drug or to the study procedure(s).  All SAEs and AESIs will be recorded in the eCRF.  
Prompt notification of SAEs to ICON PV, as described above, is essential so that regulatory 
requirements and ethical obligations to the subjects involved in the study can be met.  The 
investigator is responsible for informing the Ethics Committee of the SAE as per local 
requirements. 
12.2 
Laboratory Assessments 
Information on the volume of blood to be sampled during the study for assessing laboratory 
parameters will be available in the laboratory manual.  All blood samples will be collected, 
prepared and transferred according to the instructions provided by the central laboratory.  The 
central laboratory will provide the study sites with the appropriate material prior to the study 
start. 
Blood and urine samples will be collected for protocol clinical laboratory evaluations 
according to Table 1.  The laboratory evaluations performed during the study are presented in 
Appendix II. 
Additional laboratory safety evaluations will be performed at other times, if judged to be 
clinically appropriate, or if the ongoing review of the data suggests a more detailed 
assessment of laboratory safety evaluations is required.  Any changes to the scheduled times 
of laboratory safety tests will be agreed with ICON/Actinogen Medical and documented.  The 
investigator will perform a clinical assessment of all laboratory safety data. 


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Further details of the required activities and schedule for laboratory assessments can be found 
in the separate study specific laboratory manuals (or equivalent). 
12.3 
Electrocardiogram Assessments 
Local equipment will be used.  Subjects must be resting quietly in a supine position or in the 
most recumbent position possible for at least 5 minutes before the ECG is obtained.  Where 
available, an auto-created assessment report should be printed and added to the source 
documents, otherwise, a manual assessment of the ECG must be documented.  The following 
ECG parameters will be recorded:  heart rate, RR, PR, QRS, and QT (uncorrected) and QTc 
(corrected) intervals.  QTc will be calculated based on locally available algorithms.  QTc will 
be calculated using the Fridericia correction.  Bazett’s correction overcorrects at elevated 
heart rates and under corrects at heart rates below 60 bpm.  Fridericia’s correction is more 
accurate than Bazett’s correction in subjects with such altered heart rates.  If the study site 
has no access to the Fridericia correction, the raw data will be shared with the ICON MM 
(STUDY-MA-DL-3580-0001@iconplc.com) and Data Management to calculate QTc 
accordingly.  The investigator or designee is responsible for reviewing the ECGs to assess 
whether they are normal or abnormal.  ECG assessment will include physician interpretation 
of the tracings, e.g. rhythm, presence of arrhythmia or conduction defects, morphology, any 
evidence of myocardial infarction, or ST segment, T-wave, and U-wave abnormalities, and 
over-reading of any incorrect machine interpretations.  Abnormal ECGs will be assessed for 
clinical significance.  A single repeat evaluation will be allowed if the investigator or 
designee has reason to believe the reading is faulty or to help assess the clinical significance 
of an abnormality.  Any other ECG abnormality that is seen as exclusionary will first be 
discussed with the ICON MM (e.g. a marked prolongation of QT/QTc interval after repeated 
demonstration of a QTc interval > 450 ms, history of additional risk factors for Torsade Des 
Pointes, use of concomitant medications that prolong the QT/QTc interval). 
For any ECG that the investigator considers clinically significant, the investigator will: 
 Repeat the ECG 
 Perform follow-up ECG(s) if any significant abnormalities are detected to document 
resolution and as clinically indicated 
 Record as an AE any ECG that (1) is confirmed and the investigator considers clinically 
significant, or (2) requires a subject to be discontinued from the study, or (3) requires a 
subject to receive treatment. 
12.4 
Physical Examination 
A standard physical examination is sufficient, assessing all core body functions.   
12.5 
Neurological Examination, Including Toronto Clinical Neuropathy Score 
A basic, manual neurological examination will include all items of TCNS: 
o 
Muscle strength/weakness in arms and legs 
o 
Ataxia (gait, stance and finger-nose coordination) 


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o 
Light touch (upper and lower extremity) 
o 
Pinprick (upper and lower extremity) 
o 
Position sense (toes and thumbs) 
o 
Reflexes (knee and ankle) 
The thresholds for “Normal=0” for all Sensory Test Scores are set as follows:  Subject can 
discriminate any of these qualities (pinprick, temperature, light touch, vibration, position 
sense) at least at the secondary (more proximal) region to test that quality (seeError! 
Reference source not found. Table 3 for primary and secondary skin-areas). 
Table 3  Primary and Secondary Skin Area to Test the Sensory Quality 
Sensory quality 
Distal (primary) area 
Proximal (secondary) area 
1. Pinprick 
Plantar area of foot 
Ankle 
2. Temperature 
Plantar area of foot 
None 
3. Light touch 
Plantar area of foot 
Ankle 
4. Vibration 
Medial malleolus 
Patella 
5. Position 
Big toe 
Thumb 
 
12.6 
Vital Signs 
The following vital signs will be recorded during this study (this must include but not be 
limited to the measurement of orthostatic changes in heart rate and blood pressure): 
 Heart rate (beats per minute [bpm]) 
 Blood pressure (supine, according to Riva-Rocci’s method, plus orthostatic change in 
blood pressure; pathologic orthostatic changes are defined as:  Decrease of ≥ 15 mmHg 
diastolic last supine to first standing or decrease ≥ 20 mmHg systolic last supine to first 
standing or increase of pulse ≥ 20 bpm) 
 Body temperature (Celsius or Fahrenheit) 
 Height (Baseline only; feet or cm) 
 Weight (pounds or kg) 
12.7 
Nerve Function Monitoring 
NFM consists of sensory testing (vibration and thermal perception), motor and sensory nerve 
neurography (amplitude and conduction velocity) and clinician-rated outcome in TCNS.  
Subject-related outcome measure, NTSS-6, is part of NFM, and is discussed in Section 12.8. 
The aim is to detect intra-subject worsening from before treatment as an indicator for 
neurotoxicity.  Subject total “Before Treatment” status is calculated as the average of the 
Screening visit and Baseline visit data.  The tests will follow existing local standards and 
procedures, but should be run in a consistent fashion within a given site and subject to 
minimise intra-subject variability, e.g. constant skin temperature of the feet of at least 


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32ºC/90ºF, same assessor, same procedures, same chronological order of assessments, same 
time of day.  Measurements will be taken twice for each assessed nerve in both the left and 
right extremity.  The NFM can be conducted ± 3 days of the scheduled protocol visit, except 
at the Baseline visit, where it must be conducted within 3 days prior to the randomisation 
step. 
The following tests will be performed: 
 Vibration detection threshold:  Note that vibration is also part of the TCNS.  This test will 
be performed with a Rydel–Seiffer graded tuning fork (64 Hz, 8/8 scale) that is placed 
over a bony prominence (medial malleolus) of each foot and left there until the subject 
can no longer feel any vibration.  Threshold will be determined as a disappearance 
threshold with two stimuli repetitions of each foot. 
Subjects with the ability to define a threshold within two assessments (even if at 1/8) will 
be graded “Normal=0” in TCNS.  If the subject cannot discriminate such a threshold at 
the medial malleolus (most distal point to measure), the same exercise will be repeated 
with the tuning fork placed over the patella. 
 Thermal (cold and warm) detection (qualitative) at both legs, at the lateral mid-dorsum of 
the feet; using the Minnesota Thermal Discs with Copper (C; felt as colder) and polyvinyl 
(P; felt as warmer than copper) at room termperature.  Sites open to enrolment under this 
amendment that do not have access to Minnesota Thermal Discs, will continue to conduct 
thermal detection via cold and warm vials, as per the following:  Thermal (cold and 
warm) detection (qualitative) at both legs, using one vial filled with ice water and one 
filled with warm water.  This assessment will also be included in the scoring of TCNS.  
The subject will be asked (with eyes closed) whether it feels warm or cold when one of 
these vials is touching his/her feet.  The number of correct answers out of 10 attempts 
(five with warm and five with cold in a random order) will define the threshold. Where 
subjects have less than five correct answers, the same test will be repeated in an area in 
the middle of the lower leg, up to the knee. If the subject can detect at least 6/10 correctly, 
the subject will be scored “0” (normal) in TCNS. 
This assessment will also be included in the scoring of TCNS.  Each disc is placed in 
random order for about 2 seconds over the lateral dorsum of each foot.  The subject will 
be asked (with eyes closed) whether a disc feels warmer or colder (realtive to each other).  
The two discs will be positioned in random order (C then P; or P then C) 10 times at each 
foot.  After testing the first foot, the same procedure will be performed on the other side. 
1. If 9 or 10 pair tests at each side are identified correctly:  the subject is eligible. 
2. If 8 or less pairs are correctly named as “warmer” or “colder” at any foot:  exclude the 
subject. 
If the subject can detect at least 9 of /10 pairs correctly, the subject will be scored “0” 
(normal) in TCNS. 
 Nerve conduction:  Local equipment, procedures and normal values will be used.  The 
measures will be obtained twice for each assessed nerve.  For the second measure, all 


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electrodes need to be placed again.  Preferably, surface electrodes will be used.  It is 
recommended to measure in the following order: Sural No 1 – Peroneal No 1 – Sural 
No 2 – Peroneal No 2, to ensure independent measures. 
 Sensory - Sural nerve:  In case the Sural nerve is not measurable for SNAP,  the Ulnar 
nerve or Median nerve will be used for sensory neurography as “back-up” nerves.  SNAP 
amplitude will be assessed Baseline-to-peak.  The number of repetitions will be according 
to local standards.  NCV will be calculated according to local standards. 
 Motor - Peroneal nerve:  Only if the Peroneal nerve is not measurable for CMAP, the 
Tibial nerve motor component will be used as back-up.  CMAP amplitude will be 
measured peak-to-peak.  The number of repetitions will be according to local standards.  
NCV will be calculated according to local standards. 
The NFM should follow existing local standards and procedures and should be run in a 
consistent fashion.  Please see Table 4 for a summary of the NFM assessments and personnel 
involved: 
Table 4 
NFM Requirements 
Outcome 
Test 
Conducted by 
Frequency 
Protocol reference 
Clinician-rated 
Toronto Clinical 
Neuropathy Score 
(TCNS) 
Certified 
neurologist or a 
physician who has 
received 
appropriate training 
from a neurologist 
Every visit, except 
ad hoc or 
unscheduled safety 
visits, i.e. maximum 
6 times 
Section 12.5 
Sensory testing 
Vibration detection 
threshold 
Section 12.7 
Thermal detection 
Neurography 
Motor and sensory 
nerve (amplitude 
and conduction 
velocity) 
Individual trained in 
these techniques, 
which may include 
(but is not limited 
to) a neurologist, 
neurophysiologist 
or neurophysiology 
assistant 
Subject-rated 
Neuropathy Total 
Symptom Score-6 
(NTSS-6) 
Health care 
professional, e.g. 
study nurse, study 
coordinator 
Every visit, 
including ad hoc 
and unscheduled 
safety visits, i.e. 
approximately 
6 times 
Sections 12.7 and 
12.8 
12.7.1 
Reporting Abnormal Nerve Function Monitoring 
If the investigator observes any worsening of NFM assessments compared to the subject’s 
status prior to administration of study drug (subject total Before Treatment status is 
calculated as the average of the Screening visit and Baseline visit data), they will complete a 
checklist with a set of additional standard questions that may explain the observation, and 
inform the ICON MM (STUDY-MA-DL-3580-0001@iconplc.com).  The subject will 
continue to receive study drug. 


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The ICON MM will review the data for this subject within 1 business day and decide whether 
the event fulfils the criteria of a potential nerve safety signal (i.e. at least two related NFM 
parameters affected AND no other plausible explanation available).  If classified as a 
potential nerve safety signal, this will be escalated to the DSMB Nerve Function Monitoring 
sub-committee, as per communication flow and according to timelines detailed in the DSMB 
Charter.  If the event does not fulfil the criteria, the site is informed and the case is closed. 
One member of the DSMB Nerve Function Monitoring sub-committee will review the 
package (in an unblinded fashion) and conclude within two business days whether the finding 
is: 
 a) Confirmed:  If Confirmed, the ICON MM is informed and will initiate a stop of dosing 
of the subject.  The case is also escalated to the full DSMB to decide whether the study 
can progress as planned. 
 b) Not confirmed:  If Not confirmed, the DSMB Nerve Function Monitoring sub-
committee needs to instruct the site, in a blinded manner (via the ICON MM), what 
additional measures are needed, e.g. to repeat the neurography, include other nerves in the 
assessment, etc. 
 c) Artefact/existing event:  If classified as an artefact/existing event, the case is closed and 
the subject will continue in the study as planned. 
12.8 
Neuropathy Total Symptom Score-6 
The six questions of NTSS-6 should be completed as part of the assessment of subjects’ 
medical history, also asking for input from the caregiver to make sure no information is lost.  
Each item will also be graded for its frequency and intensity, adding up to a total score from 
“0” to “21.96” points.  A total score of > 6 would exclude the subject from the study. 
12.9 
Columbia Suicide Severity Rating Scale 
The CSSRS was initially designed to assess suicidal ideation and behaviour in clinical 
studies39.  Psychometric analysis of data on adolescents indicated that a lifetime history of 
worst-point suicidal ideation including either suicidal intent or intent with a plan, predicts a 
future risk of an actual attempt that is four times as great as the risk associated with a history 
of current suicidal ideation including a desire to be dead or increased general ratings of 
depression.  The CSSRS demonstrated good convergent and divergent validity with other 
multi-informant suicidal ideation and behaviour scales and had high sensitivity and 
specificity for suicidal behaviour classifications compared with another behaviour scale and 
an independent suicide evaluation board. 
The CSSRS is frequently asked for or recommended by various international agencies such 
as the FDA or World Health Organisation.  The CSSRS has been administered numerous 
times and has exhibited excellent feasibility – no mental health training is required to 
administer it. 


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13 
PHARMACOKINETIC AND PHARMACODYNAMIC ASSESSMENT 
PK and PD assessments will include: 
 PK assessment.  PK results are blinded and will not be provided to the sites or the 
subjects. 
o Each participating subject will provide one blood sample between 3 to 5 hours 
post-dose at the Baseline (Week 0) visit and two blood samples (pre- and post-dose) 
at each of the Interim visits (Week 4 and Week 8) and one sample at the EOT 
(Week 12) visit.  The first sample is a trough sample and will be taken on arrival at 
the study site, from subjects in a fasted state, before dosing.  The second sample will 
be taken between 3 to 5 hours post-dose, around the time anticipated peak 
concentrations occur.  The exact time of sampling, plus the exact time of study drug 
intake on that day and the previous day, and the time of food intake must be 
documented. 
o The study site shall remind participating study subjects to write down the exact 
time-point when study drug was taken each day, in the Drug Intake Diary, between all 
study visits up to the EOT (Week 12) visit. 
o Subjects who cannot provide a documented time-point for study drug intake for the 
24 hours prior to the visit will not undergo PK sampling.  They will be reminded to 
properly document the time of study drug intake for the next visit.  Another attempt 
for PK sampling will then be made. 
o PK blood samples will be analysed for concentrations of Xanamem™ by a validated 
liquid chromatography–mass spectrometry method.  Data collection and standard 
curve regression will be performed using Analyst® software from AB Sciex.  Only 
active treatment samples will be analysed.  It should be noted that the randomisation 
code will be provided to ICON Bioanalytical Laboratory to exclude placebo samples 
for PK analysis.  In no case will this code list be made known to the study 
investigators or the monitors.  Xanamem™ concentrations will not be disclosed to the 
study site due to the unblinding potential.  After the database lock and unblinding of 
the study, the PK data will be delivered within ICON for PK analysis. 
o PK blood samples will be analysed for cortisol levels by the secondary clinical 
laboratory in a blinded fashion.  
 Optional PD assessment.  Samples for the determination of ACTH, DHEAS, 
androstenedione and testosterone will be taken from a sub-population of approximately 
50 subjects enrolled into the main study, who also volunteer to take part in the PD 
sub-study, unless a higher number is defined as a result of the analysis of the data from 
those subjects, by the DSMB.  Subjects who cannot provide a PK sample will not 
undergo PD sampling.  Another attempt for PD sampling will be made at the next visit.  
The 
objective 
of 
this 
is 
to 
assess 
the 
impact 
of 
XanamenTM 
on 
the 
hypothalamic-pituitary-adrenal axis.  The sample must be taken pre-dose (as early as 
possible in the morning).  For optimal results, the sample for androstenedione analysis 


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should be taken between 6 am and 10 am.  PD results are blinded and will not be 
provided to the sites or the subjects; results will not be disclosed to study sites to avoid 
unintended subject treatment unblinding. 


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14 
OTHER EXPLORATORY ASSESSMENTS 
Other exploratory assessments will include: 
 Metabolic function (lipids, blood pressure, glucose, HbA1c, body weight and BMI) 
analysis will be performed on all enrolled subjects. 
The timing and frequency of this assessment is described in Section 9.4 and Section 9.4.1. 


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15 
STATISTICAL EVALUATION 
15.1 
Sample Size and Power 
The sample size calculation is based on ADAS-Cog v14 rather than ADCOMs as prior 
information on the treatment effect to be anticipated in the ADCOMs scale is very limited.  
The sample size at a one-sided type I error rate of 5% and a power of 80% for detecting a 
difference of 2 points in the change from Baseline between the treatment groups is 
78 subjects per arm, if the standard deviation of the change from Baseline is 5 points.  It is 
planned to include ADAS-Cog v14 into the confirmatory testing stream by the use of a 
hierarchical testing procedure, such that no adjustment of the type 1 error rate is necessary. 
As a drop-out rate of approximately 10% is assumed, the number of subjects randomised 
should be increased to approximately 174 (87 per treatment group). 
Regarding NFM, the sample size of 156 subjects (approximately 78 subjects per treatment 
group) is sufficient to ensure that any untoward effects with a true proportion of at least 3% 
are observed in at least one subject within a treatment group with a probability of 
approximately 90%.  An untoward effect with a true proportion of 5% or higher will be 
detected with a probability of > 98% in a sample of 78 subjects. 
The study is planned to enrol 7 to 10 subjects at each study site. 
15.2 
Statistical Methods 
15.2.1 
Statistical Analysis Sets 
Safety Analysis Set 
The safety analysis set will consist of all subjects who received at least one dose of study 
drug.  Subjects will be analysed according to the treatment they actually received. 
The safety analysis set will be the primary analysis set for safety analyses. 
Full Analysis Set 
The full analysis set (FAS) will consist of all subjects randomised who received at least one 
dose of study drug.  Subjects will be analysed in the treatment group they were randomised to 
even if they received incorrect study drug.  Where changes from Baseline are analysed, 
subjects will be included only if both a Baseline and at least one valid post-Baseline 
measurement are available. 
The FAS will be the primary analysis set for efficacy analyses. 
Per Protocol Analysis Set 
The per protocol (PP) analysis set is a subset of the FAS, and will consist of all randomised 
subjects for whom no key protocol violation is documented (refer to the applicable ICON 
standard operating procedure [SOP]).  The PP analysis set will provide supportive data for 
the efficacy analyses. 
Allocation of subjects to the PP analysis set will be performed before unblinding of the study. 


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PK Set 
The PK set will consist of all subjects in the safety population who have at least one 
post-dose PK assessment.  PK analyses will be performed using the PK set. 
PD Set 
The PD set will consist of all subjects in the safety population who have at least one 
post-dose PD assessment.  PD analyses will be performed using the PD set. 
15.2.2 
Efficacy and Safety Variables 
15.2.2.1 
Primary Efficacy Variables 
The primary objective of this study will be evaluated using two primary efficacy variables. 
The first primary efficacy variable is the change from Baseline (Week 0) to Week 12/EOT in 
the ADCOMs, a composite score based on ADAS-Cog v14, CDR-SOB and MMSE. 
The second primary efficacy variable is the change from Baseline (Week 0) to Week 12/EOT 
in the ADAS-Cog v14. 
Multiplicity between both primary endpoints will be handled using an a priori hierarchical 
approach, such that the results for the ADAS-Cog v14 will only be interpreted in a 
confirmatory fashion if results for the ADCOMs allowed a rejection of the null hypothesis.   
15.2.2.2 
Secondary Efficacy Variables 
The following secondary efficacy variables will be evaluated: 
 RAVLT 
 CDR -SOB 
 MMSE 
 NPI 
 NTB – Executive Domain (COWAT and CFT) 
15.2.2.3 
Safety Variables 
The following safety variables will be evaluated: 
 Clinical safety laboratory values 
 AEs, SAEs and AESIs 
 ECG 
 NFM: 
o NTSS-6 
o TCNS 
o NCV and amplitude of peripheral motor and sensory nerves 
 CSSRS 


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 Physical examination 
 Vital signs 
15.2.2.4 
PK and PD Variables 
 PK assessment 
 PD assessment:  ACTH, DHEAS, androstenedione and testosterone 
15.2.2.5 
Other Exploratory Variables 
 Metabolic function:  lipids, blood pressure, glucose, HbA1c, body weight and BMI 
15.2.3 
Methods of Statistical Analyses 
15.2.3.1 
General Principles 
The aim of the primary efficacy analysis is the evaluation of the performance of Xanamem™ 
as compared to placebo for the change in the primary efficacy endpoints ADCOMs and 
ADAS-Cog v14 from Baseline to Week 12/EOT.  The two primary efficacy variables will be 
evaluated in an a priori hierarchical fashion, where the results of the ADAS-Cog v14 analysis 
will only be interpreted as confirmatory if superiority of Xanamem™ over placebo can be 
shown for the ADCOMs. 
The aim of the secondary efficacy analyses is to provide general results regarding the 
performance of Xanamem™ as compared to placebo in subjects with mild dementia due to 
AD. 
A statistical analysis plan (SAP) will be prepared and finalised before study data are 
unblinded.  A separate Modelling and Simulation Analysis Plan will be prepared for PK data. 
15.2.3.2 
Missing Data 
For efficacy variables where the change from baseline is analysed, no imputation for missing 
values will be performed, i.e. the analysis will be based on “Observed Cases”, except where 
otherwise specified. 
Treatment of missing items for the individual scores will be described in the SAP. 
Missing Baseline data for the MMSE may be replaced by the Screening results only for the 
analysis of MMSE alone.  When MMSE results are analysed as part of the ADCOMs 
analysis, such a replacement is not allowed, in order to ensure that all Baseline values 
contributing to the ADCOMs refer to the same point in time. 
Other replacement of missing values is not foreseen. 
15.2.3.3 
Demographic and Baseline Characteristics 
Demographic and Baseline characteristics will be analysed in a descriptive fashion and 
results will be presented overall and by treatment group. 
15.2.3.4 
Subject Disposition 
The following will be summarised (overall and by treatment group where applicable): 


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 Subjects screened 
 Subjects randomised 
 Subjects treated 
 Subjects in each analysis set 
 Subjects completing the study/withdrawing early (including withdrawal reason) 
 Subject allocation by study site 
15.2.3.5 
Evaluation of Primary Efficacy Variables 
For analysis of the primary efficacy variables, an analysis of covariance (ANCOVA) model 
will be used to assess the change in ADCOMs/ADAS-Cog v14 score from Baseline (Week 0) 
to Week 12/EOT.  Treatment group will be used as fixed effect and the baseline value as a 
covariate.  For both primary efficacy variables, the following hypotheses will be tested: 
H0:  μP ≤ µX vs. H1:  μP > µX, 
where μP and μX denote the change from Baseline to Week 12/EOT in ADCOMs and 
ADAS-Cog v14 for the placebo and Xanamem™ treatment groups, respectively.  Both tests 
will be performed at a type I error rate of 0.05 one-sided, with a priori hierarchical handling 
of multiplicity, as described above, based on the least squares means (LS means) for the 
change from Baseline to Week 12/EOT.  LS means from the ANCOVA will be used to derive 
90% and 95% confidence intervals.  The primary efficacy analysis will not replace missing 
Week 12/EOT. 
The analysis described above will be repeated on the PP set for supportive evidence. 
Sensitivity analyses aim at assessing the robustness of the primary efficacy analysis.  The 
following two analyses will be performed: 
 An additional ANCOVA, imputing missing Week 12/EOT data based on resampling from 
the placebo subjects, taking baseline values into account 
 An additional ANCOVA, adding site as a factor.  Sites contributing few subjects may be 
pooled.  Any decision on pooling sites will be undertaken before unblinding. 
Whilst the European Medicines Agency discussion paper40 foresees the use of the linear 
models for sensitivity analyses, complementing different methods of primary analyses, the 
type and order of analyses in this study – ANCOVA as primary efficacy analysis and 
placebo-based imputation as sensitivity analysis – are chosen in a different fashion due to the 
following reasons: 
 The development stage this study is associated with, where the primary aim is to explore 
a possible therapeutic effect of Xanamem™; in conjunction with 
 The relatively short study duration which can be expected to reduce the number of 
missing values in either treatment group and 
 The fact that the primary efficacy variables will only be assessed at Baseline and 
Week 12/EOT. 


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15.2.3.6 
Evaluation of Secondary Efficacy Variables 
Secondary efficacy variables will be analysed in a descriptive manner.  Summary statistics 
will be presented overall and by treatment group, and an exploratory comparison will be 
performed between the two treatment groups. 
RAVLT:  Results will be described for each visit as actual values and change from Baseline.  
An exploratory ANCOVA will be performed on the change from Baseline to Week 12/EOT 
for comparison between the treatment groups, including treatment group as fixed effect, and 
the baseline value as a covariate. 
CDR-SOB:  Results will be described for each visit as actual values and change from 
Baseline.  An exploratory ANCOVA will be performed on the change from Baseline to 
Week 12/EOT for comparison between the treatment groups, including treatment group as 
fixed effect and the baseline value as a covariate. 
MMSE:  Results will be described for each visit as actual values and change from Baseline.  
An exploratory ANCOVA will be performed on the change from Baseline to Week 12/EOT 
for comparison between the treatment groups, including treatment group as fixed effect and 
the baseline value as a covariate. 
NPI:  Results will be described by domain for Baseline and last visit.  An exploratory 
ANCOVA will be performed on the change from Baseline to Week 12/EOT for comparison 
between the treatment groups, including treatment group as fixed effect.  Sub-group analyses 
will be performed for subjects with (score > 1) and without (score 0 to 1) symptoms at 
Baseline if warranted by the number of subjects in each treatment group and sub-group. 
NTB – Executive Domain (COWAT and CFT):  Results will be described for Baseline and 
last visit.  An exploratory ANCOVA will be performed on the change from Baseline to 
Week 12/EOT for comparison between the treatment groups, including treatment group as 
fixed effect, and the baseline value as a covariate.  In addition to the composite score, 
independent components will be analysed. 
15.2.3.7 
Evaluation of Safety Variables 
Clinical safety laboratory data:  clinical safety laboratory data will be presented by treatment 
group and overall.  For each visit, the actual result and the change from Baseline will be 
presented.  Count and shift tables for values outside the normal ranges will be presented as 
appropriate.  In addition, individual listings will be provided for subjects with at least one 
value outside the normal range for a given laboratory parameter. 
AEs:  TEAEs will be described using descriptive statistics, and coded according to the 
Medical Dictionary for Regulatory Activities (MedDRA) system organ class and MedDRA 
preferred term, by treatment group and overall for the following categories: 
 All TEAEs 
 Treatment-emergent AESI 
 Treatment-emergent SAEs 


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 TEAEs by severity 
 Drug-related TEAEs 
 TEAEs leading to temporary or permanent discontinuation of study drug 
 TEAEs leading to study discontinuation 
ECG:  The results for the ECG will be presented by treatment group and overall.  For each 
visit, the actual results and the change from Baseline will be presented. 
CSSRS:  Suicidal ideation, suicidal behaviour and self-injurious behaviour without suicidal 
intent, as well as suicide-related TEAEs based on the CSSRS during treatment, will be 
tabulated by treatment group and overall.  Shift tables by treatment group will be prepared for 
changes in CSSRS categories from Baseline to during treatment, as well as for the maximum 
suicidal ideation score.  In addition, individual listings will be provided for subjects with at 
least one occurrence of suicidal ideation, suicidal behaviour or self-injurious behaviour 
without suicidal intent at any time under treatment. 
Vital signs:  The results for vital signs will be presented by treatment group and overall.  For 
each visit, the actual results and the change from Baseline will be presented. 
Physical examination:  Abnormal results will be presented by individual listings. 
NFM data will be analysed in the safety data set.  Variables will be presented using summary 
statistics according to each variable’s scale and treatment groups will be compared in an 
exploratory fashion.  Special attention will be directed at intra-subject changes over the 
course of the study.  Count tables will be provided by treatment group and overall for 
subjects with a) an NTSS-6 > 6 and b) abnormal results for any sensory test from the TCNS.  
For each visit, the actual results and the change from status before study drug treatment will 
be presented. 
15.2.3.8 
PK/PD Modelling 
Nonlinear mixed effects modelling will be utilised to develop a population PK model for 
Xanamem™ plasma concentrations.  From this, exposure metrics will be derived which may 
be used subsequently to explore exposure-response relationships with selected exposure and 
efficacy/safety endpoints. 
A separate Modelling and Simulation Analysis Plan will be prepared and results from the 
PK/PD modelling will be reported separately from the clinical study report. 
15.2.3.9 
Evaluation of Exploratory Variables 
Exploratory variables will be analysed by treatment group and overall using descriptive 
statistics for categorical and continuous data, as applicable.  For continuous data, the change 
from Baseline will be analysed in addition to the actual visit values; for categorical data, shift 
tables will be presented as appropriate. 


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15.2.3.10 Compliance and Exposure 
Exposure will be analysed by calculating the number of days with exposure to study drug.  
Results will be presented overall and by treatment group. 
Compliance will be analysed by calculating the ratio between the actual intake of study drug 
as documented by dispensed and returned study drug and the expected intake of study drug 
according to the treatment schedule.  The percentage compliance will be described overall 
and by treatment group, and the number of subjects with a compliance < 80%, between 80% 
and 120% and > 120% will be presented by treatment group and overall. 
15.2.3.11 Interim Analysis 
There is one planned interim analysis after 50 completed subjects.  The following endpoints 
will be analysed in this interim analysis: 
Efficacy: 
 ADAS-Cog 
 MMSE 
 CDR-SOB 
 ADCOMS 
 RAVLT 
 NPI 
 NTB – Executive domain (COWAT and CFT) 
Safety: 
 Laboratory values 
 Incidence of AEs 
 NFM 
PK/PD: 
 Plasma concentrations of Xanamem™ 
Evaluation of efficacy evaluables will be conducted as described in Sections 15.2.3.5 and 
15.2.3.6.  For control of the type I error rate, the Haybittle-Peto approach will be used, thus 
setting the stopping boundary for the primary efficacy variables at a one-sided 0.001, leaving 
the full type I error rate of a one-sided 0.05 for the final analysis.  Full details of the interim 
efficacy analysis will be specified in the SAP. 
This interim efficacy analysis aims at providing additional information on the efficacy 
parameters to the DSMB, including both descriptive and inferential statistics.  No study 
adaptations are planned based on these analyses.  Should there be evidence of an 
overwhelming effect, the DSMB may recommend stopping early for success.  Further details 
will be available in the DSMB Charter. 


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15.2.4 
Data Safety Monitoring Board 
A 
DSMB 
consisting 
of 
two 
sponsor-independent 
clinical 
experts 
and 
one 
sponsor-independent statistical expert will be established.  The DSMB will periodically meet 
for the review of accumulating study data, including safety (AE and laboratory data), PD data 
and NFM data, and will also be involved in the interim efficacy analysis. 
The DSMB will have access to unblinded data. 
The DSMB will make recommendations for the remaining part of the study (further details 
will be provided in the DSMB Charter).  The DSMB may recommend to continue with the 
study as planned, stop the study for early safety reasons, or judge if the dose is in any way 
problematic for this subject population and determine if dose modification is needed.   
The DSMB will submit its recommendations in writing to Actinogen Medical who are 
responsible for responding to the recommendations of the DSMB and taking appropriate 
action.  The investigators will only be informed by Actinogen Medical/ICON if the study is 
stopped or if additional PD subjects need to be enrolled.  The DSMB may choose to make 
additional evaluations at any time if they feel this is warranted from a safety point of view. 
The DSMB will also review unblinded PD data, available at the time of the interim analysis, 
of the subjects enrolled into the main study, who also volunteer to take part in the sub-study, 
to determine whether enough samples were collected from subjects on active drug.  The PD 
sampling in this study will complement the previously reported Phase I data, in which most 
of the subjects were male and only a small number of subjects were aged 50 years or older. 
The interim efficacy analysis aims at providing additional information on the efficacy 
parameters to the DSMB.  No study adaptations are planned based on these analyses.  Should 
there be evidence of an overwhelming effect, the DSMB may recommend stopping early for 
success.  For control of the type I error rate, the Haybittle-Peto approach will be used, thus 
setting the stopping boundary at a one-sided 0.001, leaving the full type I error rate of a 
one-sided 0.05 for the final analysis. 
The DSMB will act according to its own written SOP described in a charter and will prepare 
written minutes of its meetings.  The Charter of the DSMB will be stored in the Trial Master 
File.  The DSMB will maintain records of its meetings and these will become part of the 
study file when the study is complete. 
In order not to disseminate unblinded data and to ensure that all staff involved in the conduct 
and final analysis of the study remain blind to the data, only the members of the DSMB, the 
DSMB Nerve Function Monitoring sub-committee and the unblinded DSMB statistician will 
have access to these data. 
15.2.4.1 
Data Safety Monitoring Board Nerve Function Monitoring Sub-committee 
The DSMB Nerve Function Monitoring sub-committee consists of two experts in 
neurophysiology, one of which will be the DSMB Chairperson.  The unblinded NFM data 
will be primarily reviewed by the DSMB Nerve Function Monitoring sub-committee.  When 


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there is a confirmed nerve safety signal, this is escalated to the DSMB for consideration and 
recommendations for the study.  Further details will be provided in the DSMB Charter. 
For quality control measures, the results of neurography of one subject per study site will be 
reviewed by a member of the DSMB Nerve Function Monitoring sub-committee.  The study 
site will complete a Neurography Screening Quality Control Form and send it to the ICON 
MM.  The study site may, however, proceed with subject randomisation if all eligibility 
criteria are fulfilled. 


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16 
DIRECT ACCESS TO SOURCE DATA/NOTES 
The investigator/study site will provide direct access to source data/documents for 
study-related monitoring, audits, IEC/IRB review and regulatory inspection. 


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17 
QUALITY CONTROL AND QUALITY ASSURANCE 
17.1 
Conduct of the Study 
ICON shall implement and maintain quality control and quality assurance procedures with 
written SOPs to ensure that the study is conducted and data are generated, documented and 
reported in compliance with the protocol, ICH GCP and applicable regulatory requirements. 
This study will be conducted in accordance with the provisions of the Declaration of Helsinki 
(October 1996), and in accordance with USA FDA regulations (CFR, Sections 312.50 and 
312.56), with ICH GCP (CPMP/ICH 135/95) (applicable to clinical studies run in the 
European Union and Australia) and the National Statement on Ethical Conduct in Human 
Research (2007) - Updated May 2015 (applicable to clinical studies run in Australia). 
The investigator may not deviate from the protocol without a formal protocol amendment 
having been established and approved by an appropriate IEC/IRB, except when necessary to 
eliminate immediate hazards to the subject or when the change(s) involve(s) only logistical or 
administrative aspects of the study.  In the event of such deviations from the protocol, the 
implemented deviation or change and the reason(s) for it, should be submitted to: 
 Actinogen Medical/ICON for agreement 
 The IEC/IRB for review and approval or favourable opinion (if required) 
 The applicable competent regulatory authority (if required) 
At the earliest opportunity, the investigator (or delegate) must inform Actinogen 
Medical/ICON about any notable protocol deviations and explain any deviation from the 
approved study protocol in the eCRF and/or in the Protocol Deviation Log, if applicable. 
Any deviations may result in the subject being withdrawn from the study and render that 
subject non-evaluable. 
17.2 
Study Initiation and Monitoring 
Before the start of the study, the ICON study monitor will visit the study site to ensure 
adequacy of the facilities and to discuss responsibilities regarding study protocol adherence 
with the investigator and other personnel involved in the study. 
The investigator may not recruit subjects into the study until such time that a visit has been 
made by an ICON study monitor to conduct a detailed review of the protocol, eCRF and 
study supplies (Site Initiation Visit).  In addition, the investigator may not enrol any subjects 
into the study before written approval or a favourable opinion from the IEC/IRB for 
conducting the study has been received. 
The investigator will permit the ICON study monitor access to review study data as 
frequently as deemed necessary to ensure that data are being recorded in an adequate manner 
and that protocol adherence is satisfactory (on-site monitoring visits).  These data include 
records of tests performed as a requirement for participating in the study as well as other 
medical records required to confirm subject eligibility for the study and to confirm 
information contained in the eCRF.  During on-site monitoring visits, the ICON study 


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monitor will require access to the Investigator Site File to ensure completeness and 
correctness of all documentation required for the study.  The date on which the ICON study 
monitor (or delegate) visits the study site will be recorded in the Site Visit Log (or 
equivalent).  During monitoring visits, the study site’s coordinator (if applicable) and the 
investigator should be available, the source documentation should be accessible, and a 
suitable environment should be provided for the ICON study monitor to review study-related 
documentation. 
The investigator, as part of his/her responsibilities, is expected to co-operate with the sponsor 
and ICON in ensuring that the study adheres to ICH GCP requirements and applicable 
regulatory requirements.  The investigator (or delegate) should record all data generated in 
the eCRF in a timely manner, so that the data is available for off-site monitoring and review. 


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18 
ETHICS 
18.1 
Independent Ethics Committee/Institutional Review Board 
Prior to the start of the study, the investigator is responsible for ensuring that the protocol and 
consent form have been reviewed and approved by a relevant regulatory authorities and 
IEC/IRB.  The IEC/IRB shall be appropriately constituted and perform its functions in 
accordance with the FDA, ICH GCP and local requirements, as applicable. 
The applicable regulatory authorities and IEC/IRB shall approve all protocol amendments 
(except for logistical or administrative changes), written informed consent documents and 
document updates, subject recruitment procedures (e.g. advertisements), written information 
to be provided to the subjects, Investigator Brochure, available safety information, 
information about payment and compensation available to subjects, the investigator's 
curriculum vitae and/or other evidence of qualifications and any other documents requested 
by the IEC/IRB and Regulatory Authority (Competent Authority), as applicable. 
18.2 
Written Informed Consent 
A Subject Information Sheet and ICF will be prepared by Actinogen Medical/ICON in 
accordance with the provisions of ICH GCP and local legal requirements.  The subject 
caregiver information sheet and ICF will be prepared by ICON in accordance with the 
provisions of ICH GCP and local legal requirements.  This may be included in the study 
Subject Information Sheet and ICF or be a separate document as determined by local 
requirements and is referred to as the Caregiver Information and Consent form for the 
purpose of this protocol.  The caregiver must separately give informed consent for his/her 
own participation in the study. 
Before undergoing Screening procedures for possible enrolment into the study, the subject 
and subject’s caregiver must be informed about the nature, scope, and possible consequences 
of the study.  This information must be given orally to the subject and subject’s caregiver by 
a physician or medically qualified person (according to applicable regulatory requirements) 
who is well informed about the nature, scope, and possible consequences of the study.  
Written information about the study will also be provided in the Subject Information Sheet 
and Caregiver Information and Consent form.  The date on which this oral and written 
information on the study was provided to the subject and subject’s caregiver, and by whom it 
was provided, must be documented in the subject’s medical records. 
The subject and subject’s caregiver must be given ample time and opportunity to inquire 
about details of the study and to consider participation in the study.  If, after reading the 
Subject Information Sheet, ICF and Caregiver Information and Consent form, consent is 
given to participate in the study, then the ICF must be signed and personally dated by the 
subject and the person conducting the informed consent discussion.  If the subject cannot 
provide written informed consent, the subject’s legal guardian or other representative, 
accordingly to local regulations as appropriate, must provide written informed consent prior 
to beginning screening activities.  Even if unable to provide written informed consent, the 
subject must assent verbally to participating in the study and the subject’s medical records 


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should note this assent (according to local regulations as appropriate).  The subject and 
subject’s caregiver will be provided with a copy of the signed ICF.  The original signed ICF 
will be filed with the subject’s records. 
The Subject Information Sheet, ICF and Caregiver Information and Consent form must be 
approved by the IEC/IRB before they can be used in the study. 
The Subject Information Sheet, ICF and Caregiver Information and Consent form must be 
revised whenever important new information becomes available that may be relevant to the 
subject’s and subject’s caregiver consent.  Any revision of these documents must be approved 
by the IEC/IRB before they can be used in the study.  The subject and subject’s caregiver 
must be informed in a timely manner if new information becomes available that may be 
relevant to their willingness to continue participation in the study.  The communication of 
this information should be documented appropriately. 
Subjects will sign a separate section of the ICF or a separate ICF (depending on local legal 
requirements) for the optional assessment of PD sampling.  Subjects who do not sign the 
respective ICF or section of ICF, will still be able to take part in the main study. 


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19 
DATA HANDLING AND RECORD KEEPING 
19.1 
Case Report Forms/Source Data Handling 
The investigator shall be provided with standardised eCRFs and shall ensure that all data 
from subject visits are promptly entered into the eCRFs in accordance with the specific 
instructions given.  The investigator must electronically sign subjects’ eCRF to verify the 
integrity of the data recorded. 
The investigator must maintain source documents, such as laboratory reports, ECGs, 
consultation reports, and complete medical history and physical examination reports. 
19.2 
Retention of Essential Documents 
The investigator/institution should maintain the study documents as specified in the ICH 
guidelines on GCP and as required by the applicable regulatory requirements.  The 
investigator/institution should take measures to prevent accidental or premature destruction of 
these documents. 
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or until at least 2 years have elapsed since the formal 
discontinuation of clinical development of the study drug.  These documents should be 
retained for a longer period, however, if required by the applicable regulatory requirements or 
by an agreement with Actinogen Medical.  It is the responsibility of Actinogen Medical to 
inform the investigator/institution as to when these documents no longer need to be retained. 


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20 
FINANCING AND INSURANCE 
Clinical Trial Insurance will be addressed in a separate agreement and will be maintained by 
Actinogen Medical. 


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21 
PUBLICATION POLICY 
Actinogen Medical shall retain the ownership of all data.  Actinogen Medical/ICON will 
provide the relevant study protocol information in a public database (ClinicalTrials.gov) at 
commencement of the study.  When the study is complete, ICON shall arrange the analysis 
and tabulation of data.  A clinical study report shall then be prepared by ICON, which may be 
used by Actinogen Medical for publication, presentation at scientific meetings, or submission 
to IEC/IRB and regulatory authorities in accordance with applicable requirements, or as 
otherwise required.  All proposed publications based on this study are subject to approval by 
Actinogen Medical. 


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22 
REFERENCE LIST 
1. World Alzheimer Report.  Alzheimer's Disease International, 2015. 
2. https://fightdementia.org.au/about-us/media/key-facts-and-statistics. 
3. Lewis H, Beher D, Cookson N, et al.  Quantification of Alzheimer pathology in ageing 
and dementia:  age-related accumulation of amyloid-beta(42) peptide in vascular 
dementia.  Neuropathol Appl Neurobiol. 2006 Apr; 32(2):103-18. 
4. https://www.alz.org/facts/downloads/facts_figures_2015.pdf. 
5. Food and Drug Administration (2013) Draft Guidance for Industry.  Alzheimer’s disease:  
Developing drugs for the treatment of early stage disease.  Accessed 2-24-2013. 
6. Ousset PJ, Cummings J, Delrieu J, et al.  Is Alzheimer’s disease drug development broken?  
What must be improved.  J Prev Alz Dis.  2014; 1:40-5. 
7. Hermanowski-Vosatka A, Balkovec JM, Cheng K, et al. 11β-HSD1 inhibition ameliorates 
metabolic syndrome and prevents progression of atherosclerosis in mice.  J Exp Med. 
2005 Aug 15; 202(4):517-27. 
8. Lloyd DJ, Helmering J, Cordover D, et al.  Antidiabetic effects of 11β‐HSD1 inhibition in 
a mouse model of combined diabetes, dyslipidaemia and atherosclerosis.  Diabetes Obes 
Metab.  2009; 11(7): 688-99. 
9. Sooy K, Webster SP, Noble J, et al.  Partial deficiency or short-term inhibition of 
11β-hydroxysteroid dehydrogenase type 1 improves cognitive function in aging mice.  
J Neurosci. 2010 Oct 13; 30(41):13867-72. 
10. Mohler EG, Browman KE, Roderwald VA, et al.  Acute inhibition of 11β-hydroxysteroid 
dehydrogenase type-1 improves memory in rodent models of cognition.  J Neurosci. 
2011 Apr 6; 31(14):5406-13. 
11. Sooy K, Noble J, McBride A, et al.  Cognitive and Disease-Modifying Effects of 
11β-Hydroxysteroid Dehydrogenase Type 1 Inhibition in Male Tg2576 Mice, a Model of 
Alzheimer's Disease.  Endocrinology.  2015; 156(12):4592-603. 
12. Lupien SJ, de Leon M, De Santi S.  Cortisol levels during human aging predict 
hippocampal atrophy and memory deficits.  Nat Neurosci.  1998; 1(1):69-73. 
13. Sapolsky RM, Uno H, Rebert CS, et al.  Hippocampal damage associated with prolonged 
glucocorticoid exposure in primates.  J Neurosci.  1990 Sep; 10(9):2897-902. 
14. Csernansky, JG, Dong, H, Fagan AM, et al.  Plasma cortisol and progression of dementia 
in subjects with Alzheimer-type dementia.  Am J Psychiatry. 2006; 163(12):2164-9. 
15. Green KN, Billings LM, Roozendaal, et al.  Glucocorticoids increase amyloid-β and tau 
pathology in a mouse model of Alzheimer’s disease.  J Neurosci. 2006; 
30;26(35):9047-56. 


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16. Woolley CS, Gould E, McEwen BS, et al.  Exposure to excess glucocorticoids alters 
dendritic morphology of adult hippocampal pyramidal neurons.  Brain Res. 1990; 
29;531(1-2):225-31. 
17. Yau JL, McNair KM, Noble J, et al.  Enhanced hippocampal long-term potentiation and 
spatial learning in aged 11β-hydroxysteroid dehydrogenase type 1 knock-out mice.  
J Neurosci. 2007 Sep 26; 27(39):10487-96. 
18. Yau JL, Noble J, Kenyon J, et al.  Lack of tissue glucocorticoid reactivation in 
11β-hydroxysteroid dehydrogenase type 1 knock-out mice ameliorates age-related 
learning impairments.  Proc Natl Acad Sci U S A. 2001; 98(8):4716-21. 
19. Sandeep TC, Yau JL, MacLullich AM, et al. 11β-hydroxysteroid dehydrogenase 
inhibition improves cognitive function in healthy elderly men and type 2 diabetics.  Proc 
Natl Acad Sci U S A.  2004 Apr 27; 101(17):6734-9. 
20. Investigator’s Brochure.  Version 8, dated 13 October 2017. 
21. Stephenson D, Brumfield M, Romero K, et al.  Alzheimer’s and Parkinson’s Diseases 
Face Common Challenges in Therapeutic Development:  Role of the Precompetitive 
Consortium, Coalition Against Major Diseases.  J Alzheimers Dis Parkinsonism.  2015; 
5:183. 
22. Clinical Study Report.  ACW0001.  A Phase I Double-Blind, Randomised, 
Placebo-Controlled, Multiple Ascending Dose Study to Assess the Safety, Tolerability, 
Pharmacokinetics and Pharmacodynamics of UE2343 in Healthy Subjects.  Date of Final 
Clinical Study Report: 18 September 2015. 
23. McKhann GM, Knopman DS, Chertkow H, et al.  The diagnosis of dementia due to 
Alzheimer’s disease: Recommendations from the National Institute on Aging and the 
Alzheimer’s Association workgroup.  Alzheimers Dement 2011; 7(3):263-9. 
24. Billioti de Gage S, Moride Y, Ducruet T, et al.  Benzodiazepine use and risk of 
Alzheimer’s disease: case-control study.  BMJ 2014; 349. 
25. Lipworth BJ.  Systemic Adverse Effects of Inhaled Corticosteroid Therapy:  A 
Systematic Review and Meta analysis, Arch Intern Med.  1999; 159(9):941-55. 
26. Robertson DB and Maibach HI.  Adverse systemic effects of TCS in:  H.I.G.I.  Maibach, 
C. Surber [Eds.] TCS.  Karger, Basel; 1992; 163-9. 
27. Michael Schmid.  Rey Auditory Verbal Learning Test.  A Handbook, 1996. 
28. Mohs RC, Rosen WG, Davis KL.  The Alzheimer’s Disease Assessment Scale:  An 
instrument for assessing treatment efficacy.  Psychopharmacol Bull.  1983; 19(3):448-50. 
29. Farlow MR, He Y, Tekin S, et al.  Impact of ApoE in mild cognitive impairment.  
Neurology.  2004; 63(10):1898-901. 
30. Mohs RC, Knopman D, Petersen RC, et al.  Development of cognitive instruments for use 
in clinical trials of antidementia drugs:  additions to the Alzheimer's Disease Assessment 


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Scale that broaden its scope.  The Alzheimer's Disease Cooperative Study.  Alzheimer 
Dis Assoc Disord.  1997; 11 Suppl 2:S13-21. 
31. Hughes CP, Berg L, Danziger WL, et al.  A new clinical scale for the staging of dementia.  
Br J Psychiatry. 1982; 140(6):566–72. 
32. Lynch CA, Walsh C, Blanco, A et al.  The clinical dementia rating sum of box score in 
mild dementia.  Dement Geriatr Cogn Disord. 2006; 21(1):40–3. 
33. Morris, J.C.  The clinical dementia rating (CDR): Current version and scoring rules. 
Neurology. 1993; 43(11),2412-14. 
34. http://biostat.wustl.edu/ adrc/cdrpgm/index.html. 
35. Folstein MF, Folstein SE, McHugh, PR. "Mini-mental state".  A practical method for 
grading the cognitive state of patients for the clinician.  J Psychiatr Res.  1975; 
12(3):189–98. 
36. Kaufer DI, Cummings JL, Christine D, et al.  Assessing the impact of neuropsychiatric 
symptoms in Alzheimer’s disease:  the Neuropsychiatric Inventory Caregiver Distress 
Scale.  J Am Geriatr Soc.  1998; 46(2):210-5. 
37. Cummings JL, Mega M, Gray K, et al.  The Neuropsychiatric Inventory:  comprehensive 
assessment of psychopathology in dementia.  Neurology.  1994; 44(12):2308-14. 
38. Harrison J, Minassian SL, Jenkins L, et al.  A Neuropsychological Test Battery for Use in 
Alzheimer Disease Clinical Trials.  Arch. Neurol.  2007; 64(9):1323-9. 
39. Posner K, Brown GK, Stanley B, et al.  The Columbia-Suicide Severity Rating Scale:  
initial validity and internal consistency findings from three multisite studies with 
adolescents and adults.  Am J Psychiatry.  2011 Dec; 168(12):1266-77. 
40. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2014/10/
WC500176827.pdf. 
 


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23 
APPENDICES 
Appendix I 
World Medical Association Declaration of Helsinki, version of 1996 (the 
version referenced by FDA and European Commission) 
 
 


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October 1996  
17.C 
 
 
Original: English 
 
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI 
 
Recommendations guiding physicians 
in biomedical research involving human subjects 
 
Adopted by the 18th World Medical Assembly  
Helsinki, Finland, June 1964 
 
and amended by the 
29th World Medical Assembly, Tokyo, Japan, October 1975 
35th World Medical Assembly, Venice, Italy, October 1983  
41st World Medical Assembly, Hong Kong, September 1989 
and the 
48th General Assembly,Somerset West, Republic of South Africa, October 1996 
 
 


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INTRODUCTION 
 
It is the mission of the physician to safeguard the health of the people. His or her knowledge 
and conscience are dedicated to the fulfillment of this mission. 
 
The Declaration of Geneva of the World Medical Association binds the physician with the 
words, "The Health of my patient will be my first consideration," and the International Code 
of Medical Ethics declares that, "A physician shall act only in the patient's interest when 
providing medical care which might have the effect of weakening the physical and mental 
condition of the patient." 
 
The purpose of biomedical research involving human subjects must be to improve 
diagnostic, therapeutic and prophylactic procedures and the understanding of the aetiology 
and pathogenesis of disease. 
 
In current medical practice most diagnostic,  therapeutic or prophylactic  procedures involve 
hazards. This applies especially to biomedical research. 
 
Medical progress is based on research which ultimately must rest in part on 
experimentation involving human subjects. 
 
In the field of biomedical research a fundamental distinction must be recognized between 
medical research in which the aim is essentially diagnostic or therapeutic for a patient, and 
medical research, the essential object of which is purely scientific and without implying 
direct diagnostic or therapeutic value to the person subjected to the research. 
 
Special caution must be exercised in the conduct of research which may affect the 
environment, and the welfare of animals used for research must be respected. 
 
Because it is essential that the results of laboratory experiments be applied to human 
beings to further scientific knowledge and to help suffering humanity,  the  World Medical 
Association has prepared the following recommendations as a guide to every physician in 
biomedical research involving human subjects. They should be kept under review in the 
future. It must be stressed that the standards as drafted are only a guide to physicians all 
over the world. Physicians are not relieved from criminal, civil and ethical responsibilities 
under the laws of their own countries. 
 
 
I. 
BASIC PRINCIPLES 
 
1. Biomedical research involving human subjects must conform to generally 
accepted scientific principles and should be based  on  adequately 
performed laboratory and animal experimentation and on a thorough 
knowledge of the scientific literature. 
 
2. The design and performance of each experimental procedure involving 
human subjects should be clearly formulated in an experimental protocol 
which should be transmitted for consideration, comment and guidance to a 
specially appointed committee independent of the investigator and the 
sponsor provided that this independent committee is in conformity with the 
laws and regulations of the country in which the research experiment is 
performed. 
 
3. Biomedical research involving human subjects should be conducted only by 
scientifically qualified persons and under the supervision of a clinically 
competent medical person. The responsibility for the human subject must 
always  rest  with  a  medically  qualified  person  and  never  rest  on  the 
subject of the research, even though the subject has given his or  her 
consent. 
 


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4. Biomedical research involving human subjects cannot legitimately be carried 
out unless the importance of the objective is in proportion to the inherent risk 
to the subject. 
 
5. Every biomedical research project involving human subjects should be 
preceded by careful assessment of predictable risks in comparison with 
foreseable benefits to the subject or to others. Concern for the interests of 
the subject must always prevail over the interests of  science  and society. 
 
6. The right of the research subject to safeguard his or her integrity must 
always be respected. Every precaution should be taken to respect the 
privacy of the subject and to minimize the impact of the study on the 
subject's physical and mental integrity and on the personality of the subject. 
 
7. Physicians should abstain from engaging in research projects involving 
human subjects unless they are satisfied that the hazards involved are 
believed to be predictable. Physicians should cease any investigation if the 
hazards are found to outweigh the potential benefits. 
 
8. In publication of the results of his or her research, the physician is obliged to 
preserve the accuracy of the results. Reports of experimentation not in 
accordance with the principles laid down in this Declaration should not be 
accepted for publication. 
 
9. In any research on human beings, each potential subject must be 
adequately informed of the aims, methods, anticipated benefits and potential 
hazards of the study and the discomfort it may entail. He or she should be 
informed that he or she is at liberty to abstain from participation in the study 
and that he or she is free to withdraw his or her consent to participation at 
any time. The physician should then obtain the subject's freely-given 
informed consent, preferably in writing. 
 
10. When obtaining informed consent for the research project the physician 
should be particularly cautious if the subject is in a dependent relationship to 
him or her or may consent under duress. In that case the informed consent 
should be obtained by a physician who is not engaged in the investigation 
and who is completely independent of this official relationship. 
 
11. In case of legal incompetence, informed consent should be obtained from 
the legal guardian in accordance with national legislation. Where physical or 
mental incapacity makes it impossible to obtain informed consent, or when 
the subject is a minor, permission from the responsible relative replaces that 
of the subject in accordance with national legislation. 
 
Whenever the minor child is in fact able to give a consent, the minor's 
consent must be obtained in addition to the consent of the minor's legal 
guardian. 
 
12. The research protocol should always contain a statement of the ethical 
considerations involved and should indicate that the principles enunciated in 
the present Declaration are complied with. 
 
 
 


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II. 
MEDICAL RESEARCH COMBINED WITH PROFESSIONAL CARE (Clinical 
Research) 
 
1. In the treatment of the sick person, the physician must be free to use a new 
diagnostic and therapeutic measure, if  in  his  or  her  judgement  it offers 
hope of saving life, reestablishing health or alleviating suffering. 
 
2. The potential benefits, hazards and discomfort of a new method should be 
weighed against the advantages of the best current diagnostic and 
therapeutic methods. 
 
3. In any medical study, every patient - including those of a control group, if 
any - should be assured of the best proven diagnostic and therapeutic 
method. This does not exclude the use of inert placebo in studies where no 
proven diagnostic or therapeutic method exists. 
 
4. The refusal of the patient to participate in a study must never interfere with 
the physician-patient relationship. 
 
5. If the physician considers it essential not to obtain informed consent, the 
specific reasons for this proposal should be stated in the experimental 
protocol for transmission to the independent committee (I, 2). 
 
6. The physician can combine medical research with professional care, the 
objective being the acquisition of new medical knowledge, only  to  the 
extent that medical research is justified by its potential diagnostic or 
therapeutic value for the patient. 
 
 
III. 
NON-THERAPEUTIC 
BIOMEDICAL RESEARCH 
INVOLVING 
HUMAN 
SUBJECTS (Non-Clinical Biomedical Research) 
 
1. In the purely scientific application of medical research carried out on a 
human being, it is the duty of the physician to remain the protector of the life 
and health of that person on whom biomedical  research  is  being carried 
out. 
 
2. The subject should be volunteers - either healthy persons or patients for 
whom the experimental design is not related to the patient's illness. 
 
3. The investigator or the investigating team should discontinue the research if 
in his/her or their judgement it may, if continued, be harmful to the individual. 
 
4. In research on man, the interest of science and society should never take 
precedence over considerations related to the wellbeing of the subject. 
 
 
 
 
 
 
 


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Appendix II 
Per Protocol Laboratory Evaluations 
 
Haematology: 
Haemoglobin 
Haematocrit 
Platelet count 
Red blood cell count  
White blood cell count and differential 
 
Basophils  
Eosinophils  
Monocytes  
Neutrophils 
Lymphocytes 
Biochemistry: 
Alkaline phosphatase 
Aspartate aminotransferase 
Alanine aminotransferase 
Gamma-glutamyl transpeptidase 
Phosphorous 
Potassium 
Glucose, fasting 
Uric acid  
Bilirubin (total)                                                        
 
Cholesterol 
Triglycerides 
High-density lipoprotein-cholesterol  
Low-density lipoprotein-cholesterol  
Protein (total) 
Creatinine & Creatinine Clearance 
Follicle-stimulating hormone 1  
Human chorionic gonadotrophin 2  
Urinalysis: 
Urate crystals, phosphate crystals, bilirubin crystals, blood, clarity, colour, glucose, ketones, 
leukocytes, protein, squamous epithelial cells, trans. epithelial cells, triple phosphate crystals 
Microscopic examination 3 
Other: 
HbA1c 
VLDL Cholesterol  
ACTH 
Androstenedione                                                     
XanamemTM  
 
DHEAS  
Total testosterone 
Vitamin B12  
Cortisol 4 
Drugs of abuse screen: 
Urine benzodiazepines (Screening visit, unless a re-test is required.  If a re-test is required this 
must be performed prior to randomisation.) 
1. 
Females only.  To be taken only if there is clinical concern about the subject’s menopausal status. 
2. 
Pregnancy test on women of childbearing potential only. 
3. 
Performed only if required, based on urinalysis results. 
4.     Performed using the PK blood samples.   
 


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Appendix III Prohibited Medication - Brand Names per Country 
 
 


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 Appendix III 
Prohibited Medication 
 
6 months prior to Screening (and throughout the study) 
Sedative drugs (specifically benzodiazepines, barbiturates and other anxiolytics) more than twice 
in 1 week or 3 times in 1 month. 
This also includes sedative (anticholinergic) anti-incontinence drugs: 
Oxybutynin 
Ditropan, Gelnique, Oxytrol, Cystrin, Kentera, Lyrinel, 
Oxytrol 
probantheline/propantheline 
Pro-Banthine 
solifenacin 
Vesicare, Vesomni 
trospium 
Sanctura, Flotros, Regurin, Uraplex 
 
Sedative (and anticholinergic) Antihistamines: 
chlorpheniramine/chlorphenamine 
maleate 
Chlor-trimeton,  Efidac,  Kloromin,  Phenetron,  Teldrin, 
Piriton 
cyproheptadine 
Periactin 
diphenhydramine 
Benadryl, Beldin, Belix, Benylin, Nytol 
hydroxyzine 
Atarax, Vistaril, Orgatrax, Ucerax 
 
Sedative (anticholinergic) antidepressants are not allowed at any dose. NOTE: Major Depression 
is an Exclusion criterion: 
Amitriptyline,  amoxapine,  clomipramine,  desipramine,  doxepin,  imipramine,  nortriptyline, 
paroxetine 
  
 
 


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Medicines that are known to cause peripheral neuropathy: 
 
Arsenic , Colchicine, Gold 
Cardiovascular drugs 
Amiodarone, Hydralazine, Perhexiline 
Anti-cancer drugs 
Cisplatin, Docetaxel, Paclitaxel, Suramin, Vincristine 
Anti-infectives 
Chloroquine,  Isoniazid,  Metronidazole,  Nitrofurantoin, 
Thalidomide 
Anti-human immunodeficiency virus 
(HIV) drugs 
Didanosine, Stavudine, Zalcitabine 
Autoimmune disease drugs 
Etanercept, Infliximab, Leflunomide 
Dermatologicals 
Dapsone 
Anti-convulsants 
Phenytoin 
Anti-alcohol drugs 
Disulfiram 
 
4 weeks prior to Screening 
Changes in medication or doses of psychotropics (antidementive drugs) 
 
2 weeks prior to Baseline (and throughout the study) 
Inhaled glucocorticosteroids (e.g. 
prednisone 
equivalent) 
> 1 g per 
day, 
topical 
glucocorticosteroids > 50 g per week, and any oral steroid preparations 
 
Inhaled glucocorticosteroids 
budesonide 
Budelin, Easyhaler, Pulmicort, Symbicort 
flunisolide 
Aerobid, Aerospan 
fluticasone 
Advair, Flovent, Flixotide, Seretide, Breo Ellipta 
ciclesonide 
Alvesco 
mometasone 
Asmanex 
beclomethasone 
Beclovent, Qvar, Fostair, Vanceril 


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Topical glucocorticosteroids 
Hydrocortisone 
Dermacort, Epicort, Egocort, Sigmacort 
Triamcinolone 
Kenacort 
Fluticasone 
Cutivate 
Clobetasol 
Dermovate, Clobex, ClobaDerm, Temovate 
Betamethasone 
Betnovate, Diprosone, Diprolene, Celestone 
Halobetasol 
Ultravate 
 
Drugs known to inhibit or induce CYP3A4 as listed below: 
Erythromycin 
E.E.S., Robimycin, EMycin, Erymax, Ery-Tab, Eryc
Ranbaxy, Erypar, Eryped, Erythrocin Stearate Filmtab,
Erythrocot, 
E-Base, 
Erythroped, 
Ilosone 
MY-E,
Pediamycin, Zineryt, Abboticin, Abboticin-ES, Erycin, 
PCE Dispertab, Stiemycine, Acnasol, Tiloryth 
Clarithromycin 
Biaxin, Prevpac, Clarac, Clarithro, Kalixocin, Klacid 
Indinavir 
Crixivan 
Itraconazole 
Lozanoc, Sporanox, Onmel, 
Ketoconazole 
Ketozole, Daktarin, Nizoral, Extina, Xolegel 
Ritonavir 
Kaletra, Norvir, Technivie, Viekira Pak 
Rifampicin 
Rifadin, Rifater, Rifinah, Rimactane, Rimstar, Rimycin, 
Rifamate 
St. John's Wort 
Various, including OTC 
Vandetanib 
Caprelsa 
Voriconazole 
Vfend, Vttack 
Further listed in protocol but either rarely used or anyway not relevant since the underlying 
disease (e.g. epilepsy) is usually an exclusion criterion: boceprevir, nelfinavir, posaconazol, 
nefazodone, carbamazepine, phenytoin, primidone. 
 


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Prohibited during to the study 
Initiating AChEIs or memantine 
Changes in medication or doses of psychotropics (or other medication that may have an 
impact on cognition), such as any anticholinergic drug, including antidepressants (see above), 
and antipsychotics (chlorpromazine, clozapine, olanzapine, thioridazine). 
NOTE that psychiatric diseases that may impact cognition and memory are an Exclusion 
Criterion. 
 
Allowed when stable 3 months prior to Baseline prior and during to the study 
Vitamin B12 and Omega 3 (including specifically Souvenaid) 
 
Allowed during to the study, but requiring upfront discussion with ICON Medical Monitor 
Drugs that may prolong QTc 
Antiarrhythmics 
Amiodarone 
Cordarone, Pacerone, Nexterone, Aratac , Rithmik 
Disopyramide 
Norpace, Rythmodan 
Dofetilide 
Tikosyn 
Dronedarone 
Multaq 
Flecainide 
Tambocor, Almarytm, Apocard, Ecrinal, Flecaine, 
Flecatab 
Ibutilide 
Corvert 
Procainamide 
Pronestyl, Procan 
Quinidine 
Quinaglute  Duraquin,  Quinact,  Quinidex,  Cin-Quin, 
Quinora, Nuedexta 
Sotalol 
Betapace, Sotalex, Sotacor, Cardol, Solavert, Sotab 
 Anesthetic 
Propofol 
Diprivan, Propoven, Anesia, Fresefol , Provive 
Sevoflurane 
Ulane, Sojourn, Sevorane 
 


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Antibiotic 
Azithromycin 
Zithromax, Zmax, Azith, Zitrocin 
Ciprofloxacin 
Cipro, Cipro-XR, Neofloxin, C-Flox, Ciprol, CIFRAN , 
Ciproxin, Loxip, Roflo 
Grepafloxacin 
Raxar 
Levofloxacin 
Levaquin, Tavanic 
Moxifloxacin 
Avelox, Avalox, Avelon 
Antidepressants 
Citalopram 
Celexa, Cipramil, Celapram, Celica, Ciazil, Cipramil, 
Citadrl, Dralopram, Lopacit, Talam 
Escitalopram 
Cipralex, Lexapro, Nexito, Seroplex, Elicea, Lexamil,
Lexam, Esitalo, Cilopam-S escilupin, escital, escitalup,
Escicor, Esipram, Loxalate 
Antifungal 
Fluconazole 
Diflucan, Trican, Dizole, Fluzole, Ozole 
Pentamidine 
Pentam 
 Phosphodiesterase 3 inhibitor 
Anagrelide 
Agrylin, Xagrid 
Cilostazol 
Pletal 
 
 
 


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Appendix IV Contraception 
 
 


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 Appendix IV - Contraception 
 
1. Definitions 
 
Definition of women of childbearing potential and of fertile men 
 
For the purpose of this study, a woman is considered of childbearing potential 
(WOCBP), i.e. fertile, following menarche and until becoming post-menopausal 
unless 
permanently 
sterile. 
Permanent 
sterilization 
methods 
include 
hysterectomy, bilateral salpingectomy and bilateral oophorectomy. 
 
A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. A high follicle stimulating hormone (FSH) level in 
the postmenopausal range may be used to confirm a post-menopausal state in 
women not using hormonal contraception or hormonal replacement therapy. 
However in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient. 
 
For the purpose of this study, a man is considered fertile after puberty unless 
permanently sterile by bilateral orchiectomy. 
 
 
2. Birth control methods 
 
Birth control methods which may be considered as highly effective 
 
For the purpose of this study, methods that can achieve a failure rate of less than 
1% per year when used consistently and correctly are considered as highly 
effective birth control methods. Such methods include: 
 
 
combined (estrogen- and progesterone-containing) hormonal contraception 
associated with inhibition of ovulation1: 
o oral 
o intravaginal 
o transdermal 
 
progesterone-only  hormonal  contraception  associated  with  inhibition  of 
ovulation1: 
o oral 
o injectable 
o implantable2 
 intrauterine device (IUD)2 
 
intrauterine hormone-releasing system (IUS)2 
 
bilateral tubal occlusion2 
 
vasectomized partner2,3 
 
sexual abstinence4 
 
 


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Birth control methods which may not be considered as highly effective 
 
Birth control methods that result in a failure rate of more than 1% per year 
include: 
 
 
progesterone-only oral hormonal contraception, where inhibition of 
ovulation is not the primary mode of action 
 
male or female condom with or without spermicide5 
 
cap, diaphragm or sponge with spermicide5 
 
Birth control methods which are considered unacceptable in clinical trials 
 
 
Periodic abstinence (calendar, symptothermal, post-ovulation methods), 
withdrawal 
(coitus 
interruptus), 
spermicides 
only, 
and 
lactational 
amenorrhoea method (LAM) are not acceptable methods of contraception. 
Female condom and male condom should not be used together. 
 
 
 
Footnotes: 
 
1 Hormonal contraception may be susceptible to interaction with the IMP, which 
may reduce the efficacy of the contraception method. 
 
2 Contraception methods that in the context of this study are considered to have 
low user dependency. 
 
3 Vasectomized partner is a highly effective birth control method provided that 
partner is the sole sexual partner of the WOCBP trial participant and that the 
vasectomized partner has received medical assessment of the surgical success. 
 
4 In the context of this study, sexual abstinence is considered a highly effective 
method only if defined as refraining from heterosexual intercourse during the 
entire period of risk associated with the study treatments. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the clinical trial and 
the preferred and usual lifestyle of the subject. 
 
5 A combination of male condom with either cap, diaphragm or sponge with 
spermicide (double barrier methods) are also considered acceptable, but not 
highly effective, birth control methods