Conditions: Psychosis Dementia Aggression Agitation Alzheimer Dementia
Keywords: Psychotic Disorders
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 81
Healthy volunteers: no

Brief summary:
A ten-week study to assess MP-101 in Dementia-Related Psychosis and/or Agitation and Aggression

Detailed description:

Arms:
arm 1: Week 0:

Participants received 20 milligrams (mg) MP-101 orally QD (1 x 20-mg caps) and 2 placebo caps.

Week 1:

Participants received 40 mg MP-101 orally QD (2 x 20-mg caps) and 1 placebo caps.

Week 2 through Week 9:

Participants received 60 mg MP-101 orally QD (3 x 20-mg caps ). arm 2: Participants received 3 capsules (caps) of placebo orally once daily (QD) during Week 0, Week 1, and Week 2 through Week 9.

Interventions: intervention 1: MP-101 intervention 2: Placebo
Intervention descriptions: intervention 1: Capsules intervention 2: Capsules

Protocol document:
Prot_000.pdf: 
 
Protocol MP-101-01(b) 
Tolerability, Pharmacokinetics, and Efficacy of MP-101 in the Treatment of Patients with 
Dementia-Related Psychosis and/or Agitation and Aggression 
 
NCT03044249 
Approval Date: 13Feb2018 


MP-101-01(b) Clinical Protocol 
Page 1 
MP-101 
Protocol MP-101-01(b) 
Tolerability, Pharmacokinetics, and Efficacy of MP-101 in the 
Treatment of Patients with Dementia-Related Psychosis 
and/or Agitation and Aggression   
Confidential Information 
The information contained in this document is confidential and is intended for the use of 
clinical investigators.  It is the property of Mediti Pharma, Inc. and should not be copied by 
or distributed to persons not involved in the clinical investigation of MP-101, unless such 
persons are bound by a confidentiality agreement with Mediti Pharma, Inc. 
Note to Regulatory Authorities:  This document may contain protected personal data 
and/or commercially confidential information exempt from public disclosure.  Mediti 
Pharma, Inc. requests consultation regarding release/redaction prior to any public release.  
In the United States, this document is subject to Freedom of Information Act (FOIA) 
Exemption 4 and may not be reproduced or otherwise disseminated without the written 
approval of Mediti Pharma, Inc. 
MP-101 
A Phase 2, double-blind, randomized, parallel, 10-week study of MP-101 (1 MP-101 dose 
arm), compared with placebo in patients with dementia-related psychosis and/or agitation 
and aggression.  The starting dose will be 20 mg per day, with titration to a target dose of 
60 mg per day. 
Mediti Pharma, Inc. 
Montreal, Quebec, H3B 3X3, Canadá 
Protocol Approval Date: December 19, 2016 
Protocol Amendment (a) Approval Date:  February 24, 2017 
Protocol Amendment (b) Approval Date:  February 13, 2018 
 
 
 


MP-101-01(b) Clinical Protocol 
Page 2 
MP-101 
Table of Contents 
Tolerability, Pharmacokinetics, and Efficacy of MP-101 in the 
Treatment of Patients with Dementia-Related Psychosis 
and/or Agitation and Aggression  
Section 
Page 
1. 
Synopsis ...................................................................................................................................8 
2. 
Schedule of Activities ............................................................................................................11 
3. 
Introduction ...........................................................................................................................13 
4. 
Objectives and Endpoints ......................................................................................................16 
4.1. 
Primary Objective and Endpoint ......................................................................................16 
4.2. 
Secondary Objectives and Endpoints ...............................................................................16 
4.3. 
Exploratory Objectives and Endpoints .............................................................................16 
5. 
Study Design .........................................................................................................................17 
5.1. 
Overall Design ..................................................................................................................17 
5.2. 
Number of Participants .....................................................................................................17 
5.3. 
End of Study Definition....................................................................................................18 
5.4. 
Scientific Rationale for Study Design ..............................................................................18 
5.5. 
Justification for Dose ........................................................................................................18 
6. 
Study Population ...................................................................................................................20 
6.1. 
Inclusion Criteria ..............................................................................................................20 
6.2. 
Exclusion Criteria .............................................................................................................22 
6.3. 
Lifestyle and/or Dietary Requirements ............................................................................23 
6.4. 
Screen Failures .................................................................................................................23 
7. 
Treatment ...............................................................................................................................24 
7.1. 
Treatment Administration ................................................................................................24 
7.1.1. 
Packaging and Labeling ...........................................................................................24 
7.2. 
Method of Treatment Assignment ....................................................................................25 
7.2.1. 
Timing of Dose Administration ...............................................................................25 
7.3. 
Blinding ............................................................................................................................25 
7.4. 
Dose Titration ...................................................................................................................26 
7.5. 
Preparation/Handling/Storage/Accountability .................................................................27 
7.6. 
Treatment Compliance .....................................................................................................27 
7.7. 
Concomitant Therapy .......................................................................................................27 
7.8. 
Treatment after the End of the Study ...............................................................................28 
8. 
Discontinuation Criteria ........................................................................................................29 


MP-101-01(b) Clinical Protocol 
Page 3 
MP-101 
8.1. 
Discontinuation from Study Treatment ............................................................................29 
8.1.1. 
Permanent Discontinuation from Study Treatment .................................................29 
8.1.2. 
Discontinuation of Inadvertently Enrolled Patients .................................................30 
8.2. 
Discontinuation from the Study ........................................................................................30 
8.3. 
Patients Lost to Follow-up................................................................................................30 
9. 
Study Assessments and Procedures .......................................................................................31 
9.1. 
Efficacy Assessments .......................................................................................................31 
9.1.1. 
Primary Efficacy Assessment ..................................................................................31 
9.1.2. 
Secondary Efficacy Assessments .............................................................................31 
9.1.3. 
Exploratory Efficacy Assessments ...........................................................................32 
9.2. 
Adverse Events .................................................................................................................32 
9.2.1. 
Serious Adverse Events ...........................................................................................33 
9.2.1.1. 
Suspected Unexpected Serious Adverse Reactions ...........................................34 
9.2.2. 
Complaint Handling .................................................................................................34 
9.3. 
Treatment of Overdose .....................................................................................................34 
9.4. 
Safety ................................................................................................................................34 
9.4.1. 
Physical and Neurological Examination ..................................................................34 
9.4.2. 
Vital Signs ................................................................................................................35 
9.4.3. 
Electrocardiograms ..................................................................................................35 
9.4.4. 
Laboratory Tests ......................................................................................................36 
9.4.5. 
Other Tests ...............................................................................................................36 
9.4.5.1. 
Columbia Suicide Severity Rating Scale ...........................................................36 
9.4.6. 
Safety Monitoring ....................................................................................................36 
9.5. 
Pharmacokinetics ..............................................................................................................37 
9.5.1. 
Pharmacokinetic Sampling ......................................................................................37 
9.5.2. 
Bioassay ...................................................................................................................38 
9.6. 
Genetics ............................................................................................................................38 
9.6.1. 
Apolipoprotein E and HTR2A Genotyping .............................................................38 
9.6.2. 
Whole Blood Sample for Pharmacogenetic Research .............................................38 
9.7. 
Biomarkers .......................................................................................................................39 
10. Statistical Considerations and Data Analysis ........................................................................40 
10.1. Sample Size Determination ..............................................................................................40 
10.2. Populations for Analyses ..................................................................................................40 
10.3. Statistical Analyses ...........................................................................................................40 
10.3.1. 
General Statistical Considerations ...........................................................................40 
10.3.2. 
Treatment Group Comparability ..............................................................................41 
10.3.2.1. 
Patient Disposition .............................................................................................41 
10.3.2.2. 
Patient Characteristics ........................................................................................41 


MP-101-01(b) Clinical Protocol 
Page 4 
MP-101 
10.3.2.3. 
Concomitant Therapy .........................................................................................41 
10.3.2.4. 
Treatment Compliance .......................................................................................41 
10.3.3. 
Efficacy Analyses ....................................................................................................41 
10.3.3.1. 
Primary Analyses ...............................................................................................41 
10.3.3.2. 
Secondary Analyses ...........................................................................................42 
10.3.3.3. 
Exploratory Analyses .........................................................................................42 
10.3.4. 
Safety Analyses ........................................................................................................42 
10.3.4.1. 
Adverse Events ...................................................................................................42 
10.3.4.2. 
Other Evaluations of Safety ...............................................................................43 
10.3.5. 
Pharmacokinetic Analyses .......................................................................................43 
10.3.6. 
Other Analyses .........................................................................................................43 
10.3.6.1. 
Pharmacogenetics Exploratory Analyses ...........................................................43 
10.3.7. 
Interim Analyses ......................................................................................................43 
11. References .............................................................................................................................44 
 
 


MP-101-01(b) Clinical Protocol 
Page 5 
MP-101 
List of Tables 
Table 
Page 
Table 7.1. 
Treatment Regimens ..................................................................................24 
Table 7.2. 
List of Excluded Concomitant Medications ..............................................28 
Table 9.1. 
Plasma Pharmacokinetic Sampling Scheme ..............................................37 
 
 
 


MP-101-01(b) Clinical Protocol 
Page 6 
MP-101 
List of Figures 
Figure 
Page 
Figure 5.1. 
Illustration of study design for protocol MP-101-01. ................................17 
Figure 7.1. 
Dose titration schedule for protocol MP-101-01. ......................................26 
 
 
 


MP-101-01(b) Clinical Protocol 
Page 7 
MP-101 
List of Appendices 
Appendix 
Page 
Appendix 1. 
Abbreviations and Definitions ...................................................................48 
Appendix 2. 
Clinical Laboratory Tests ...........................................................................52 
Appendix 3. 
Study Governance, Regulatory and Ethical Considerations ......................53 
Appendix 4. 
Hepatic Monitoring Tests for Treatment-Emergent Abnormality .............56 
Appendix 5. 
Timed Up and Go Test ...............................................................................57 
Appendix 6. 
Protocol Amendment MP-101-01(b) Summary [Tolerability, 
Pharmacokinetics, and Efficacy of MP-101 in the Treatment of 
Psychosis in Patients with Alzheimer’s Disease] ......................................58 


MP-101-01(b) Clinical Protocol 
Page 8 
MP-101 
1. Synopsis 
Title of Study: 
Tolerability, Pharmacokinetics, and Efficacy of MP-101 in the Treatment of Patients with Dementia-Related 
Psychosis and/or Agitation and Aggression 
Rationale: 
MP-101 (formerly known as LY2979165 ammonium monohydrate) is the alanine prodrug of LY2812223, a 
selective orthosteric metabotropic glutamate (mGlu) 2 receptor agonist.  Study MP-101-01 is a Phase 2, multicenter, 
double-blind, randomized, parallel, 10-week study of MP-101 (1 MP-101 dose arm), compared to placebo in 
patients with dementia-related psychosis and/or agitation and aggression.  
There are currently no approved therapies for the treatment of dementia-related psychosis and/or agitation and 
aggression.  Antipsychotics are commonly prescribed off-label despite an association with increased risk of cerebral 
vascular adverse events such as stroke, increased all-cause mortality, as well as more rapid progression to severe 
dementia. 
Metabotropic glutamate 2 receptors are localized in presynaptic terminals throughout the cortex and limbic brain 
structures.  Activation of mGlu2 receptors suppresses excessive presynaptic release of glutamate; this excessive 
release may contribute to the development of psychosis.  Administration of MP-101 produces potent preclinical 
antipsychotic, anti-stress, and analgesic effects. 
The objectives of Study MP-101-01 are to assess the tolerability, pharmacokinetics (PK), and efficacy of MP-101 in 
patients with dementia-related psychosis and/or agitation and aggression. 
Objectives and Endpoints: 
Primary Objective and Endpoint 
• 
To test the hypothesis that oral administration of once daily (QD) MP-101 will improve psychotic 
symptoms and/or agitation and aggression in patients with dementia when compared to placebo 
o 
Endpoint:  Change from baseline to 10-week treatment endpoint in the Neuropsychiatric Inventory 
(NPI)-Psychosis subscale (combination of 2 items:  hallucinations and delusions) and/or in the 
agitation/aggression domain. 
Secondary Objectives and Endpoints 
• 
To assess whether MP-101 is superior to placebo in the following: neuropsychiatric disturbances, caregiver 
distress, anxiety  
o 
Endpoints:  Change from baseline to 10-week treatment endpoint in the following: Clinical Global 
Impression of Improvement (CGI-I); NPI Total Score; NPI-Core Total  (combination of 3 items: 
hallucinations, delusions, and agitation/aggression); NPI Caregiver Distress; NPI domain of  anxiety;  
• 
To determine if MP-101 is safe and tolerable in patients with dementia-related psychosis and/or agitation 
and aggression 
o 
Endpoints:  Treatment-emergent adverse events (TEAEs); Unified Parkinson’s Disease Rating Scale 
Part III 
• 
To assess the PK of MP-101 and its primary active metabolite, LY2812223, in patients with 
dementia-related psychosis and/or agitation and aggression 


MP-101-01(b) Clinical Protocol 
Page 9 
MP-101 
o 
Endpoint:  Plasma PK data 
Exploratory Objectives and Endpoints 
• 
To assess whether MP-101 is superior to placebo in changes in patient behavior and caregiver burden 
o 
Endpoints:  Change from baseline to 10-week treatment endpoint in the following: NPI domains of 
depression/dysphoria, elation/euphoria, apathy/indifference, disinhibition, irritability/lability, 
aberrant motor behavior, sleep and nighttime behavior disorders, and appetite and eating disorders; 
Mini-Mental State Examination (MMSE); Zarit Burden Interview-22 (ZBI-22) 
• 
To explore the effect of 5-hydroxytryptamine serotonin 2A receptor (HTR2A) and apolipoprotein E 
(APOE) genotypes on response to treatment 
o 
Endpoints:  HTR2A single nucleotide polymorphism (SNP) rs7330461 genotype data; HTR2A SNP 
rs6313 (102T/C) genotype data; APOE genotype data 
• 
To explore exposure-response relationships with efficacy and safety clinical endpoints as needed 
o 
Endpoints:  Efficacy and safety clinical endpoints, as needed 
Summary of Study Design: 
Study MP-101-01 is a Phase 2, multicenter, double-blind, 1:1 randomized, parallel, 10-week study of MP-101 
(1 MP-101 dose arm) compared to placebo in patients with dementia-related psychosis and/or agitation and 
aggression.  All patients will be randomized to receive either placebo or MP-101.  Randomization will be stratified 
by MMSE score and estimated glomerular filtration rate value. 
Treatment Arms: 
Patients will be randomized to the MP-101arm or the placebo arm at Visit 2 (Week 0).  Patients in the MP-101 arm 
will begin dosing at 20 mg QD of study drug.  If in the opinion of the investigator, the patient cannot tolerate the 
initial 20-mg QD dose of study drug (administered for the first week of dosing and assessed at or before Visit 3 
[Week 1]) the patient will be discontinued from the study.  Study drug intolerance will be determined by the 
investigator and includes TEAEs of special interest identified from prior studies, e.g., dizziness, nausea, and 
vomiting. 
At Visit 3 (Week 1), the dose of MP-101 (or equivalent placebo) will be increased to 40 mg.  If intolerance is 
reported at a dose of 40 mg between Visit 3 (Week 1) and Visit 4 (Week 2), the patient will be discontinued from 
the study. 
At Visit 4 (Week 2), the dose of MP-101 (or equivalent placebo) will be increased to 60 mg.  If intolerance is 
reported at a dose of 60 mg between Visits 4 (Week 2) and Visit 5 (Week 4), the patient will be asked to return for 
an unscheduled visit for down-titration to 40 mg.  Patients down-titrated to 40 mg prior to Visit 5 (Week 4) will 
remain at this dose for the remainder of the study.  
At Visit 5 (Week 4), the dose of MP-101 (or equivalent placebo) will be maintained at 60 mg.  If intolerance is 
reported at a dose of 60 mg at Visit 5 (Week 4), the patient will be down-titrated to 40 mg and will remain at this 
dose for the remainder of the study.  If intolerance is reported at a dose of either 40 mg or 60 mg beyond Visit 5 
(Week 4) the subject will be discontinued from the study. 
In order to maintain blinding, patients randomized to the placebo arm will undergo the identical up-titration 
procedures, with similar down-titration rules as described above. 


MP-101-01(b) Clinical Protocol 
Page 10 
MP-101 
Number of Patients: 
Approximately 100 patients will be enrolled to obtain approximately 80 patients in the Evaluable population. 
Statistical Analysis: 
The primary treatment effect will be measured as the difference in the percentage of patients with a response on 
either the NPI-Psychosis or Agitation/Aggression subscales at the end of the treatment period. A patient with a 30% 
improvement from baseline on a subscale will be considered a responder for that subscale. A patient with a 
psychosis diagnosis at screening will be considered an overall responder with a response on the NPI-Psychosis 
subscale, a patient with a diagnosis of agitation/aggression at screening will be considered an overall responder with 
a response on the NPI-Agitation/Aggression subscale, and a patient with both diagnoses will be considered an 
overall responder with a response on either subscale. The primary analysis will use a one-sided Fisher’s exact test 
with a 5% type 1 error rate.  The primary population for analysis will include all randomized patients who take at 
least 1 dose of double-blind study treatment and complete Visit 5 (Week 4) with NPI efficacy data (i.e., the 
Evaluable population). 
The primary analyses will be performed with patients grouped by treatment arm (i.e., MP-101 or placebo) regardless 
of their final dose level. 


MP-101-01(b) Clinical Protocol 
Page 11 
MP-101 
2. Schedule of Activities 
Schedule of Activities for Protocol MP-101-01 
 
Screen 
Treatment Period (10 Weeks) 
Follow-
up 
 
 
ET 
Visit Number 
V1 
V2 
V3a 
V4 
V5 
V6 
V7a 
V8 
V9 
Week 
-1 to -5 
0 
1 
2 
4 
6 
8 
10 
11 
Days from Randomization (target) 
-1 to-35 
0 
7 
14 
28 
42 
56 
70 
77 
Visit Window (± days from target) 
 
 
 
2 
2 
2 
 
2 
2 
Study site visit 
x 
x 
 
x 
x 
x 
 
x 
x 
x 
Informed Consent 
(before any procedures/tests) 
x 
 
 
 
 
 
 
 
 
 
Clinical Assessments 
Demographics, height 
x 
 
 
 
 
 
 
 
 
 
Weight 
x 
x 
 
x 
x 
x 
 
x 
x 
x 
Vital signs (BP and pulse) 
x 
x 
 
x 
x 
x 
 
x 
x 
x 
Medical history and physical exam 
x 
 
 
 
 
 
 
 
 
 
Neurological exams 
x 
x 
 
 
 
 
 
x 
 
x 
TUG (if applicable) 
x 
x 
 
x 
x 
x 
 
x 
x 
 
Concomitant medications 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Inclusion/exclusion review 
x 
xb 
 
 
 
 
 
 
 
 
Hepatitis B surface antigen, 
Hepatitis C antibody, HIV 
x 
 
 
 
 
 
 
 
 
 
Randomization 
 
x 
 
 
 
 
 
 
 
 
Investigational product dispensing 
 
x 
 
x 
x 
x 
 
 
 
 
Dose administration at site 
 
x 
 
x 
x 
 
 
 
 
 
Investigational product 
accountability 
 
 
 
x 
x 
x 
 
x 
 
x 
Symptom directed physical exam 
 
x 
 
x 
x 
x 
 
x 
x 
x 
Habits (alcohol, caffeine, nicotine, 
tobacco) 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
Safety Measures 
Adverse event assessment 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
C–SSRSc 
x 
x 
 
x 
x 
x 
 
x 
x 
x 
Single 12-lead ECG 
x 
x 
 
x 
x 
 
 
x 
x 
x 
Efficacy and Outcome Measures 
NPI 
xb 
xb 
 
x 
x 
x 
 
x 
x 
x 
CGI-S 
 
x 
 
 
 
 
 
 
 
 
CGI-I 
 
 
 
 
x 
 
 
x 
x 
x 
ZBI-22  
 
x 
 
 
x 
 
 
x 
 
 
MMSE 
x 
x 
 
 
x 
 
 
x 
 
x 
UPDRS Part III 
 
x 
 
 
x 
 
 
x 
x 
x 
Laboratory Samples 
Clinical chemistry and hematology 
x 
x 
 
x 
 
x 
 
x 
 
x 
Urinalysis 
x 
x 
 
 
 
 
 
x 
 
x 
Plasma sample collection for PK 
analysis (see Table 9.1) 
 
 
 
x 
x 
x 
 
x 
 
x 
Plasma and serum collection for 
biomarker research 
 
x 
 
 
 
x 
 
x 
 
x 
Blood for epigenetic research 
 
x 
 
 
 
x 
 
x 
 
x 
Blood for assessment of APOE and  
HTR2A SNPsd 
 
x 
 
 
 
 
 
 
 
 
Blood for pharmacogenetic researchd 
 
x 
 
 
 
 
 
 
 
 


MP-101-01(b) Clinical Protocol 
Page 12 
MP-101 
Study Schedule Protocol MP-101-01 (continued) 
Abbreviations:  APOE = apolipoprotein E; BP = blood pressure; CGI-I=Clinical Global Impressions of Improvement; 
CGI-S=Clinical Global Impressions of Severity; C-SSRS= Columbia Suicide Severity Rating Scale; ECG = 
electrocardiogram; ET = early termination; HIV = human immunodeficiency virus; HTR2A = 5-hydroxytryptamine serotonin 
2A receptor; MMSE = Mini-Mental State Examination;  NPI = Neuropsychiatric Inventory; PK = pharmacokinetic, SNP = 
single nucleotide polymorphism; TUG = Timed Up and Go test; UPDRS = Unified Parkinson’s Disease Rating Scale; V = 
visit; Zarit Burden Interview-22= ZBI-22.  
a 
Phone call. 
b Patients must have at least one of the following at Visit 1 (screening) and Visit 2 (Week 0): 
o 
an NPI score of ≥4 on either delusions or hallucinations individual items  
o 
an NPI score of ≥6 on the Psychosis Subscale (combined delusions and hallucinations)  
o 
an NPI score of ≥4 on agitation/aggression domain 
c 
During screening, the “Lifetime/Recent-Clinical” version of the C-SSRS will be used.  The “Since Last Visit-Clinical” 
version will be used for all subsequent assessments. 
d Samples should be collected at V2, if possible, but may be collected at an alternate visit if they cannot be collected at V2. 
 


MP-101-01(b) Clinical Protocol 
Page 13 
MP-101 
3. Introduction 
MP-101 (formerly known as LY2979165 ammonium monohydrate) is the alanine prodrug of 
LY2812223, a selective orthosteric metabotropic glutamate (mGlu) 2 receptor agonist.  The 
objectives of Study MP-101-01 are to assess the tolerability, pharmacokinetics (PK), and 
efficacy of MP-101 in the treatment of patients with dementia-related psychosis and 
agitation/aggression. 
Dementia is characterized by multiple cognitive deficits severe enough to interfere with daily 
functioning and affects approximately 6.5% of people over the age of 65 (Matthews et al. 2013) 
Dementia can be caused by numerous neurodegenerative disorders including (but not limited to) 
Alzheimer’s disease (AD), dementia with Lewy bodies (DLB) and frontotemporal dementia 
(FTD). While cognitive impairment is the hallmark symptom of dementia, behavioral and 
psychological disturbances are almost invariably present at some point during the illness 
(Steinberg et al. 2008; Lyketsos et al. 2002) Among the most disturbing and burdensome of these 
symptoms are psychosis (hallucinations and delusions) as well as aggression and agitation 
(Rocca et al. 2010).  These types of neuropsychiatric symptoms are among the most complex, 
stressful, and costly aspects of care and lead to poor health outcomes, including excess 
morbidity, mortality, hospital stays, and early placement in a nursing home (Kales et al. 2015; 
Wancata et al. 2003).  There are currently no approved therapies for dementia-related psychosis 
or agitation/aggression.  Antipsychotics are commonly prescribed off-label despite an association 
with increased risk of cerebral vascular adverse events (AEs) such as stroke, increased all-cause 
mortality (Wooltorton 2002, 2004; Hermann et al. 2004; Smith and Beier 2004), as well as more 
rapid progression to severe dementia (Schneider et al. 2006). 
Metabotropic glutamate receptors are plasma-membrane-associated, G-protein-coupled proteins 
that modulate neuronal excitability function via presynaptic, postsynaptic, and glial mechanisms.  
There are currently 8 members of the mGlu receptor family (mGlu1-mGlu8) that vary in their 
primary sequence, tissue localization, agonist/antagonist pharmacology, and signal transduction 
pathways (Conn and Pin 1997).  The mGlu2 and mGlu3 receptors are heavily distributed within 
cortical and limbic structures of the brain (e.g., prefrontal cortex, hippocampus, and amygdala) 
and localize predominantly on presynaptic nerve terminals (Tamaru et al. 2001).  Activation of 
mGlu2/3 receptors by glutamate, or by other exogenous agonists, leads to the inhibition of 
synaptic glutamate release, thereby dampening downstream postsynaptic excitation.  The 
mGlu2/3 receptor agonists are effective in animal models associated with hyper-glutamatergic 
tone (e.g., states associated with psychosis and stress/anxiety).  Acute intraperitoneal 
administration of MP-101 produces potent antipsychotic, anti-stress, and analgesic effects in the 
rat.  These effects are consistent with the known preclinical behavioral attributes of mGlu2/3 
receptor agonists which have been tested in patients and have demonstrated clinical efficacy in 
schizophrenia and generalized anxiety disorder (Patil et al. 2007; Dunayevich et al. 2008).  
Additionally, MP-101 produces an mGlu2-dependent antidepressant-like effect in the mouse 
forced swim assay; potency and efficacy are comparable to that observed with the antidepressant 
imipramine. 


MP-101-01(b) Clinical Protocol 
Page 14 
MP-101 
Pimavanserin is a 5-hydroxytryptamine (serotonin) 2A (5-HT2A/HTR2A) receptor antagonist 
which has demonstrated efficacy in the treatment of psychosis in Parkinson’s disease patients 
(Cummings et al. 2014) and has advanced to a Phase 3 study for dementia-related psychosis.  
Significant neuroanatomical overlap exists between mGlu2(3) and 5-HT2A receptors and strong 
pharmacological evidence supports interactions along key neural pathways (Marek et al. 2000).  
In rodent models, MP-101 has similar clinical effects to pimavanserin, providing further support 
for study of MP-101 for the treatment of patients with dementia-related psychosis. 
As of December 2016, MP-101 has been administered to 116 healthy male subjects as single and 
multiple oral doses for up to 14 days in 3 clinical studies.  These studies included: 1) a single-
ascending dose (SAD) study in the 20- to 150-mg dose range (Study I4S-EW-HHCA [HHCA]), 
2) a multiple-ascending dose (MAD) study in the 20 to 400 mg once daily (QD) dose range 
(Study I4S-EW-HHCB [HHCB]) and 3) a pharmacodynamic (PD) biomarker study evaluating 
the effect of single doses of MP-101 on the ketamine-induced magnetic resonance imaging 
(MRI) signal (Study I4S-EW-HHCC [HHCC]).  The SAD study included a food effect 
evaluation and cerebrospinal fluid (CSF) sampling, and the MAD study included CSF sampling.  
In the MAD study, after multiple QD dosing of MP-101 in the 20- to 400-mg dose range, 
conversion of MP-101 to its active metabolite, LY2812223, was extensive; plasma exposure to 
MP-101 was generally <1% that of LY2812223.  Plasma LY2812223 exposure at steady-state 
was dose proportional over the 20- to 400-mg dose range, and showed minimal accumulation in 
the 20-mg QD cohort.  In plasma, the LY2812223 time of maximum concentration (tmax) at 
steady-state was approximately 4 hours, and terminal half-life (t1/2) was approximately 11 hours, 
with the majority of drug eliminated within 24 hours.  After administration of single 20- to 
150-mg MP-101 doses, the mean urine recovery of LY2812223 in the first 24 hours postdose 
ranged from 44% to 62%, suggesting renal excretion is a major elimination pathway for 
LY2812223 (Study HHCA).  After multiple QD dosing at 150 mg, CSF exposure to LY2812223 
was achieved in all subjects by 7 hours postdose on Day 14 and ranged from 38 nM to 141 nM 
(Study HHCB). 
The most common AEs reported in the 3 clinical studies were (in order of decreasing frequency):  
dizziness, vomiting, nausea, tiredness, and headache.  In the MAD study, vomiting appeared to 
be a “first-dose” effect for most subjects (1 subject also had an episode of vomiting on Day 2, 
which did not recur with continued dosing).  Nausea also tended to occur during the first 3 days 
of dosing, whereas dizziness tended to be reported later during dosing and at higher MP-101 
doses (150 and 250 mg), but nausea did not persist with ongoing dosing.  There were no 
significant changes in vital signs (blood pressure [BP] and heart rate), electrocardiograms 
(ECGs; including corrected QT interval [QTc]), and safety laboratory tests (biochemistry, 
hematology, and urinalysis) in subjects receiving MP-101. 
To date, there have been no adverse drug reactions associated with administration of MP-101 in 
healthy subjects, for which AEs were mild (summarized above).  In an elderly patient population 
with dementia-related psychosis and agitation/aggression, the mild AEs reported in healthy 
subjects may present a greater safety concern.  Adverse events include reports of dizziness which 
could lead to gait instability and falls in an elderly dementia population.  The risk for gait 


MP-101-01(b) Clinical Protocol 
Page 15 
MP-101 
instability will be assessed for ambulatory patients throughout Study MP-101-01 with the Timed 
Up and Go (TUG) test.  Similarly, transient vomiting, unrelated to the dose, was reported in 
healthy subjects in the SAD and MAD studies.  There is a greater risk of dehydration or 
aspiration in dementia patients.  To improve patient safety, MP-101 exposure will be reduced in 
Study MP-101-01 (60-mg maximal dose in dementia patients vs. 400-mg QD dose in healthy 
subjects). 
More detailed information about the known and expected benefits, risks, serious adverse events 
(SAEs), and reasonably anticipated AEs of MP-101 can be found in the Investigator’s Brochure 
(IB). 


MP-101-01(b) Clinical Protocol 
Page 16 
MP-101 
4. Objectives and Endpoints 
4.1. Primary Objective and Endpoint 
• To test the hypothesis that oral administration of QD MP-101 will improve psychotic 
symptoms and/or agitation/aggression in patients with dementia when compared to 
placebo 
o Endpoint:  Change from baseline to 10-week treatment endpoint in the 
Neuropsychiatric Inventory (NPI)-Psychosis subscale (combination of 2 items:  
hallucinations and delusions) and/or in the agitation/aggression domain.  
4.2. Secondary Objectives and Endpoints 
Secondary objectives and endpoints in patients with dementia-related psychosis and/or 
agitation and aggression are as follows: 
• To assess whether MP-101 is superior to placebo in the following:  neuropsychiatric 
disturbances, caregiver distress, and anxiety 
o Endpoints:  Change from baseline to 10-week treatment endpoint in the 
following: Clinical Global Impression of Improvement (CGI-I); NPI Total Score; 
NPI-Core Total  (combination of 3 items: hallucinations, delusions, and 
agitation/aggression); NPI Caregiver Distress (NPI-D) and NPI domains of 
anxiety 
• To determine if MP-101 is safe and tolerable  
o Endpoints:  Treatment-emergent adverse events (TEAEs); Unified Parkinson’s 
Disease Rating Scale (UPDRS) Part III 
• To assess the PK of MP-101 and its primary active metabolite, LY2812223 
o Endpoint:  Plasma PK data 
4.3. Exploratory Objectives and Endpoints 
• To assess whether MP-101 is superior to placebo in changes in patient behavior and 
caregiver burden 
o Endpoints:  Change from baseline to 10-week treatment endpoint in the following: 
NPI domains of depression/dysphoria, elation/euphoria, apathy/indifference, 
disinhibition, irritability/lability, aberrant motor behavior, sleep and nighttime 
behavior disorders, and appetite and eating disorders; Mini-Mental State 
Examination (MMSE); Zarit Burden Interview-22 (ZBI-22) 
• To explore the effect of HTR2A and apolipoprotein E (APOE) genotypes on response to 
treatment 
o Endpoints:  HTR2A single nucleotide polymorphism (SNP) rs7330461 genotype 
data; HTR2A SNP rs6313 (102T/C) genotype data; APOE genotype data 
• To explore exposure-response relationships with efficacy and safety clinical endpoints as 
needed 
o Endpoints:  Efficacy and safety clinical endpoints, as needed 


MP-101-01(b) Clinical Protocol 
Page 17 
MP-101 
5. Study Design 
5.1. Overall Design 
Study MP-101-01 is a Phase 2, multicenter, double-blind, randomized, parallel, placebo-
controlled, 10-week study of MP-101, consisting of screening, treatment, and follow-up periods, 
in patients with dementia-related psychosis and/or agitation and aggression.   All patients will be 
randomized 1:1 to receive either placebo or MP-101. 
Figure 5.1. Illustrates the study design 
 
 
Abbreviations:  CGI-I=Clinical Global Impressions of Improvement; CGI-S=Clinical Global Impressions of 
Severity; C-SSRS = Columbia Suicide Severity Rating Scale; MMSE = Mini-Mental State Examination; NPI = 
Neuropsychiatric Inventory; PK = pharmacokinetic; UPDRS = Unified Parkinson’s Disease Rating Scale; 
ZBI-22 = Zarit Burden Interview-22. 
Figure 5.1. 
Illustration of study design for protocol MP-101-01. 
5.2. Number of Participants 
Approximately 100 patients will be enrolled to obtain approximately 80 patients in the Evaluable 
population (see Section 10.2). 


MP-101-01(b) Clinical Protocol 
Page 18 
MP-101 
5.3. End of Study Definition 
End of the study is the date of the last visit or last scheduled procedure shown in the Schedule of 
Activities (Section 2) for the last patient. 
5.4. Scientific Rationale for Study Design 
The primary objective of this study is to test the hypothesis that MP-101, when administered at a 
target dose of 60 mg QD, will improve psychotic symptoms and/or agitation and aggression in 
patients with dementia when compared to placebo. 
A randomized, double-blind, placebo-controlled design will be utilized in this study.  
Randomization minimizes systematic bias in the selection and assignment of patients to study 
therapy and provides justification for inferential statistical methods to be used on data from this 
study.  Strategies to minimize placebo response include 1:1 randomization, blinding, and 
centralized rater training.  Using an appropriate concurrent placebo arm enables direct statistical 
estimation of benefits and harms due to study therapy and minimizes bias in the assessment and 
interpretation of observed treatment effects.  The details regarding dose selection are described in 
Section 5.5. 
5.5. Justification for Dose 
The MP-101 oral dose range of 20 to 60 mg QD was selected based on current in vitro, 
preclinical, and clinical PK and PD data.  The dose titration scheme of 20 mg QD for the first 
week and 40 mg QD for the second week, with a final titration to 60 mg QD on the third week, is 
intended to minimize nausea and vomiting. 
Pharmacokinetic data from 3 previous clinical studies of MP-101 (SAD and MAD studies in 
healthy subjects [Studies HHCA and HHCB], and a biomarker study of ketamine-induced 
pharmacological magnetic resonance imaging [phMRI] signal in healthy male subjects [Study 
HHCC]), were used to simulate LY2812223 CSF exposure levels.  In all prior clinical studies in 
healthy subjects, MP-101 doses up to 400 mg QD for 14 days were generally well tolerated. 
A dose of 60 mg demonstrated target engagement (phMRI study) and was predicted to achieve a 
range of LY2812223 CSF concentrations (median maximum observed drug concentration [Cmax] 
approximately 30 nM, 90% confidence interval [CI]:  10 nM to 80 nM) that would exceed the 
mGlu2 cyclic adenosine monophosphate (cAMP) half maximal effective concentration (EC50) of 
5.6 nM for 24 hours, and the mGlu2 cAMP concentration for maximum achievable response 
concentration (EC100) of approximately 50 nM for at least 10 hours, in healthy subjects with 
normal renal function (Eli Lilly and Company, data on file).  In the CSF sampling cohort in 
Study HHCB, CSF exposure to LY2812223 at steady-state was achieved in all subjects at 
approximately 7 hours postdose, and ranged from 38 nM to 141 nM. 
This study population includes patients with impaired renal function (lower estimated glomerular 
filtration rate [eGFR] limit = 45 ml/min/1.73m2).  In a patient with an eGFR of 
45 ml/min/1.73m2, the mean predicted plasma LY2812223 Cmax at steady-state for a 60 mg QD 
MP-101 dosing regimen is approximately 3600 nM (90% CI: 2800 nM to 4800 nM).  These 


MP-101-01(b) Clinical Protocol 
Page 19 
MP-101 
values are lower than those observed at steady-state for a 400 mg QD dose in Study HHCB 
(geometric mean LY2812223 Cmax during a dosing interval at steady-state:  10900 nM; 90% CI: 
7880 nM to 15600 nM); where MP-101 doses up to 400 mg were well tolerated.  Concentrations 
in CSF may be expected to be higher for this population as well, in a manner consistent with the 
plasma concentrations.  These estimations assume that MP-101 and LY2812223 are primarily 
renally eliminated in this patient population, and that LY2812223 exposure is dose proportional. 
Based on these data, a 60-mg dose would be expected to provide efficacious CSF exposures in 
this population, in addition to adequate safety to be able to test this dose in Phase 2 studies. 


MP-101-01(b) Clinical Protocol 
Page 20 
MP-101 
6. Study Population 
Eligibility of patients for study enrollment will be determined following screening, which will 
include a full medical history, physical examination, clinical laboratory testing, and an ECG. 
Enrollment must be within 35 days of screening. 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, are not permitted. 
6.1. Inclusion Criteria 
Patients are eligible for inclusion in the study only if they meet all of the following criteria at 
screening: 
Type of Patient – Patient and Disease Characteristics 
[1] 
Males or females (of non-childbearing potential) ≥50 years of age 
Note:  Females of non-childbearing potential are defined as women ≥60 years 
of age, postmenopausal women ≥50 and <60 years of age who have had 
a cessation of menses for at least 12 months, or women who are 
congenitally or surgically sterile (i.e., have had a hysterectomy or 
bilateral oophorectomy or tubal ligation). 
To confirm postmenopausal status for women ≥50 and <60 years of age 
who have had a cessation of menses for at least 12 months, follicle 
stimulating hormone levels will be assessed and must be ≥40 mIU/mL. 
Note:  Males must agree to use 2 forms of highly effective birth control (see 
below) with female partners of childbearing potential while enrolled in 
the study, and for at least 28 days following the last dose of 
investigational product. 
The following birth control methods are considered highly effective: 
• Oral, injectable, or implanted hormonal contraceptives 
• Condom with a spermicidal foam, gel, film, cream, or suppository 
• Occlusive cap (diaphragm or cervical/vault caps) with a spermicidal 
foam, gel, film, cream, or suppository 
• Intrauterine device 
• Intrauterine system (e.g.,, progestin-releasing coil) 
• Vasectomized male (with appropriate postvasectomy documentation 
of the absence of sperm in the ejaculate). 
[2] 
Ambulatory (with or without walking device) with a stable gait as assessed with a 
TUG test (Okumiya et al. 1998; Nordin et al. 2006) that must be completed in 


MP-101-01(b) Clinical Protocol 
Page 21 
MP-101 
≤30 seconds.  The test may be repeated once with instruction. Patients in wheelchairs 
are also eligible and do not need to complete the TUG test. 
[3] 
 Have an MMSE score of 10 to 24. 
 
[4] 
Meets clinical criteria for one of the following disorders: dementia associated with 
Parkinson's disease, dementia with Lewy bodies, possible or probable Alzheimer's 
disease, frontotemporal degeneration spectrum disorders, vascular dementia. 
 
[5] 
Must be able to communicate verbally. 
[6] 
At Visit 1 (screening) and Visit 2 (Week 0) have at least ONE of the following: 
o an NPI score of ≥4 on either delusions or hallucinations individual items  
o an NPI score of ≥6 on the Psychosis Subscale (combined delusions and 
hallucinations)  
o an NPI score of ≥4 on agitation/aggression domain 
[7] 
Have a reliable caregiver to accompany the patient to all study visits.  This caregiver 
must provide written informed consent to participate and be in frequent contact with 
the patient (defined as spending at least 4 hours/day at least 4 days/week with the 
patient and who is knowledgeable about the patient’s daytime and nighttime 
behaviors).  The caregiver must be able to communicate with site personnel, and in the 
opinion of the investigator, must understand the written protocol-specified 
questionnaires.  If a caregiver cannot continue, one replacement caregiver will be 
allowed if the above criterion is met. 
[8] 
Must be on a stable dose of cholinesterase inhibitor and/or memantine, if applicable.  
[9] 
If taking antipsychotic drugs or any drug intended to treat psychosis, must be on a 
stable treatment regimen for ≥1 month prior to the baseline visit (Visit 2). Note:  If the 
patient has recently stopped taking antipsychotic drugs or any drug intended to treat 
psychosis, he or she must have discontinued treatment at least 4 weeks before Visit 1 
(screening). 
[10] Have venous access sufficient to allow for blood sampling per the protocol. 
[11] Have clinical laboratory test results within normal reference range for the population or 
investigative site, or results with acceptable deviations that are judged to be not 
clinically significant by the investigator. 
[12] Are capable of participating in all study assessments in the opinion of the investigator. 
Informed Consent 
[13] Are able and willing to provide consent (patients and caregivers). 


MP-101-01(b) Clinical Protocol 
Page 22 
MP-101 
6.2. Exclusion Criteria 
Patients will be excluded from participating in the study if they meet any of the following 
criteria: 
Diagnostic Assessments 
[14] Have a history of significant psychotic disorders (including, schizophrenia, delusional 
disorder, substance abuse psychosis that lasted over 6 months, major depressive 
disorder or bipolar disorder with psychotic episodes). 
[15] 
Has a history of ischemic stroke within the last 12 months or any evidence of 
hemorrhagic stroke.  
Medical Conditions 
[16] Have renal impairment as defined by eGFR <45 ml/min/1.73m2 using the Chronic 
Kidney Disease Epidemiology Collaboration Cystatin C Equation (Grubb et al. 2010; 
Peralta et al. 2011; Inker et al. 2012). 
[17] Have significant cardiovascular, respiratory, gastrointestinal, renal, hematologic, or 
oncologic comorbidities that could impact patient safety and study participation over 
10 weeks. 
[18] Have a history of seizures (other than remote history of childhood febrile seizure) or 
other condition that would place the patient at increased risk of seizures.  Patients 
taking anticonvulsants for seizure control are also excluded. 
[19] Are, in the investigator’s judgment, at risk for suicide, including patients who have 
answered ‘yes’ to either Question 4 (Active Suicidal Ideation with Some Intent to Act, 
Without Specific Plan) or Question 5 (Active Suicidal Ideation with Specific Plan and 
Intent) on the Suicidal Ideation portion of the Columbia Suicide Severity Rating Scale 
(C-SSRS), or answered ‘yes’ to any of the suicide-related behaviors (actual attempt, 
interrupted attempt, aborted attempt, preparatory act or behavior) on the Suicidal 
Behavior portion of the C-SSRS; and the ideation or behavior occurred within a month 
of Visit 1 (screening). 
[20] Have a Fridericia’s corrected QT interval (QTcF) >450 ms (males) or 470 ms (females) 
at Visit 1 (screening). 
 
 


MP-101-01(b) Clinical Protocol 
Page 23 
MP-101 
Prior/Concurrent Clinical Trial Experience 
[21] Are currently enrolled in any other clinical trial involving an investigational product or 
any other type of medical research judged not to be scientifically or medically 
compatible with this study. 
[22] Have participated, within the last 30 days, in a clinical trial involving an investigational 
product.  If the previous investigational product has a long half-life, 3 months or 
5 half-lives (whichever is longer) must have passed. 
Other Exclusions 
[23] Are investigator site personnel directly affiliated with this study and/or their immediate 
families.  Immediate family is defined as a spouse, parent, child, step-child or sibling, 
whether biological or legally adopted. 
[24] Are Mediti Pharma, Inc. or Eli Lilly and Company employees or immediate family 
members of employees; or are employees of any third-party involved in the study who 
require exclusion of their employees.  This pertains to both caregivers and patients. 
[25] In the opinion of the investigator or sponsor, are unsuitable for inclusion in the study. 
6.3. Lifestyle and/or Dietary Requirements 
Throughout the study, patients may undergo medical assessments and review of compliance with 
requirements before continuing in the study. 
Study participants should be instructed not to donate blood or blood products during the study or 
for 8 weeks following the study. 
6.4. Screen Failures 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
re-screened 1 time with sponsor approval.  The time period from screen fail to rescreen will be 
determined by the investigator.  If rescreening is performed, a new informed consent form (ICF) 
must be signed, and the patient will be assigned a new identification number.  Additionally, all 
screening procedures must be conducted at rescreen to ensure all eligibility criteria are met. 
At screening and throughout the study, procedure/lab retests may be conducted at the discretion 
of the investigator and do not constitute a rescreen. 


MP-101-01(b) Clinical Protocol 
Page 24 
MP-101 
7. Treatment 
7.1. Treatment Administration 
This study compares 60-mg MP-101 versus matching placebo administered orally QD for 
10 weeks.  Table 7.1 shows the treatment regimens. 
Three capsules of 20-mg MP-101 and/or placebo will be ingested with 240 mL of room 
temperature water with the patient in an upright position.  Doses should be administered at 
approximately the same time in the morning each day.  For all visits that include PK sampling, 
the approximate start and stop times of food consumption prior to dosing and up to 4 hours 
postdose will be recorded as detailed in Section 9.5.1. 
Table 7.1. 
Treatment Regimens 
Treatment Arm 
Dose 
Week 0 
Week 1 
Week 2 through Week 9 
MP-101 
20-mg MP-101 QD 
(1 × 20-mg caps and 
2 placebo caps) 
40-mg MP-101 QD 
(2 × 20-mg caps and 
1 placebo cap) 
60-mg MP-101 QDa 
(3 × 20-mg caps) 
Placebo 
Placebo QD 
(3 placebo caps) 
Placebo QD 
(3 placebo caps) 
Placebo QD 
(3 placebo caps) 
Abbreviations:  caps = capsule; QD = once daily; TEAE= treatment-emergent adverse event. 
a Refer to Figure 7.1 for the dose titration schedule. 
The investigator or designee is responsible for: 
• explanation of the correct use of the investigational product(s) to the 
patient/caregiver/site personnel, 
• verification that instructions are followed properly, 
• maintenance of accurate records of investigational product receipt, dispensing and 
collection, and 
• return of all unused and used medication to Mediti Pharma, Inc. or its designee at the end 
of the study. 
Note:  In some cases, sites may destroy the material if, during the investigative site selection, the 
evaluator has verified and documented that the site has appropriate facilities and written 
procedures to dispose of clinical trial materials. 
7.1.1. Packaging and Labeling 
The specific dose strength of the drug product (DP), MP-101 DP, corresponds to the free acid 
equivalent (i.e., 20-mg MP-101 DP is equivalent to 20-mg LY2979165 free acid equivalent). 
MP-101 will be provided in a wallet design (blister pack) containing blister strips.  Each wallet 
will contain 9 rows of 3 capsules each.  Placebo capsules that look identical to MP-101 capsules, 
but contain no active ingredient, will also be provided. 


MP-101-01(b) Clinical Protocol 
Page 25 
MP-101 
Clinical trial materials will be labeled according to the country’s regulatory requirements. 
7.2. Method of Treatment Assignment 
Patients who meet all criteria for enrollment will be randomized in a 1:1 ratio (MP-101:placebo) 
to double-blind treatment at Visit 2 (Week 0).  Assignment to treatment arms will be determined 
by a computer-generated random sequence using an interactive web-response system (IWRS).  
The IWRS will be used to assign blister packs containing double-blind investigational product to 
each patient.  Blister packs will be dispensed at Visits 2, 4, 5, and 6,  (Weeks 0, 2, 4, and 6, 
respectively).  During the patient’s visit, the site will access the IWRS for the correct blister pack 
numbers to dispense.   
Randomization will be stratified by baseline MMSE score and eGFR value: 
• MMSE < 16 or MMSE > 16 
• eGFR <60 or eGFR > 60 
7.2.1. Timing of Dose Administration 
The dose will be administered at approximately the same time in the morning each day.  Patients 
will record the actual time of each dose of study drug and the time of food consumption before 
and after each dose; this information will be collected. 
7.3. Blinding 
Blinding will be maintained throughout the conduct of the trial until all data are verified to an 
acceptable level of quality and locked. 
Select individuals may gain access to unblinded data prior to the final database lock to initiate 
the final population PK model development.  The individuals and unblinded data will be 
specified in the unblinding plan section of the Statistical Analysis Plan (SAP) or a separate 
unblinding plan document. 
If, in the opinion of the investigator or the Mediti Pharma, Inc. clinical research physician (CRP) 
or designee, unblinding of patients is necessary for the management of adverse or other clinically 
relevant events, the patients’ treatment code will be made available.  
Emergency unblinding for AEs may be performed through the IWRS, which may supplement or 
take the place of emergency codes generated by a computer drug-labeling system.  This option 
may be used ONLY if the patient’s well-being requires knowledge of the patient’s treatment 
assignment.  All unblinding events are recorded and reported by the IWRS. 
If an investigator, site personnel performing assessments, or patient is unblinded, the patient 
must be discontinued from the study.  In cases where there are ethical reasons to have the patient 
remain in the study, the investigator must obtain specific approval from a Mediti Pharma, Inc. or 
designated CRP for the patient to continue in the study. 
In case of an emergency, the investigator has the sole responsibility for determining if unblinding 
of a patient’s treatment assignment is warranted.  Patient safety is the primary consideration in 


MP-101-01(b) Clinical Protocol 
Page 26 
MP-101 
making such a determination.  If the investigator decides that unblinding is warranted, the 
investigator should make every effort to contact the Mediti Pharma, Inc. CRP prior to 
unblinding, unless a delay compromises patient safety.  If a patient’s treatment assignment is 
unblinded, Mediti Pharma, Inc. must be notified immediately. 
Upon completion of the study, all codes must be returned to Mediti Pharma, Inc. or its designee. 
7.4. Dose Titration 
Figure 7.1 illustrates the dose titration schedule. 
 
Figure 7.1. 
Dose titration schedule for protocol MP-101-01. 
At Visit 2 (Week 0), patients will be randomized to the MP-101 arm or the placebo arm.  All 
patients will start at a dose of 20 mg or equivalent placebo (Figure 7.1).  If intolerance is reported 
at a dose of 20 mg between Visit 2 (Week 0) and Visit 3 (Week 1), the patient will be 
discontinued from the study.  Intolerance is defined as the inability to tolerate TEAEs such as 
dizziness, nausea, and vomiting, which in the opinion of the investigator are possibly related to 
MP-101. 
At Visit 3 (Week 1), the dose of MP-101 (or equivalent placebo) will be increased to 40 mg.  If 
intolerance is reported at a dose of 40 mg between Visit 3 (Week 1) and Visit 4 (Week 2), the 
patient will be discontinued from the study. 
At Visit 4 (Week 2), the dose of MP-101 (or equivalent placebo) will be increased to 60 mg.  If 
intolerance is reported at a dose of 60 mg between Visits 4 (Week 2) and 5 (Week 4), the patient 
will be asked to return for an unscheduled visit for down-titration to 40 mg.  Patients down-
titrated to 40 mg prior to Visit 5 (Week 4) will remain at this dose for the remainder of the study.  


MP-101-01(b) Clinical Protocol 
Page 27 
MP-101 
At Visit 5 (Week 4), the dose of MP-101 (or equivalent placebo) will be maintained at 60 mg.  If 
intolerance is reported at a dose of 60 mg at Visit 5 (Week 4), the patient will be down-titrated to 
40 mg and will remain at this dose for the remainder of the study.  If intolerance is reported at a 
dose of either 40 mg or 60 mg beyond Visit 5 (Week 4), the subject will be discontinued from 
the study. 
7.5. Preparation/Handling/Storage/Accountability 
Only participants enrolled in the study or their designated caregivers may receive investigational 
product and only authorized site staff may supply study treatment.  All study treatments should 
be stored in an environmentally controlled and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff. 
The investigator, institution, or head of the medical institution (where applicable) is responsible 
for study treatment accountability, reconciliation, and record maintenance (such as receipt, 
reconciliation and final disposition records).  A Mediti Pharma, Inc. delegate (e.g., site monitor) 
will conduct an accountability assessment. 
7.6. Treatment Compliance 
Patient compliance with investigational product will be assessed at each visit.  Compliance will 
be assessed by direct questioning and documentation of returned capsules.  Patient compliance 
with study drug will also be recorded in the patient diary.   
Patients who are noncompliant will be discontinued from the study.  A patient will be considered 
noncompliant if he or she misses more than 5 consecutive days of investigational product at 
60 mg, or more than 10 cumulative days of investigational product at 60 mg during the study.  
Similarly, a patient will be considered noncompliant if he or she is judged by the investigator to 
have intentionally or repeatedly taken more than the prescribed amount of medication. 
7.7. Concomitant Therapy 
Patients on stable concomitant medication at the time of study entry (e.g., AChEIs) should 
continue their regular, unchanged dose throughout the study.  Any medication used during the 
course of the study must be documented.  A list of Excluded Concomitant Medications is 
presented in Table 7.2.  Questions concerning the excluded medications should be directed to the 
sponsor.  Use of any of the listed medications would result in either a screen fail (see 
Section 6.2) or discontinuation from the study. 
Patients with worsening psychosis or agitation/aggression requiring rescue therapy will be 
withdrawn from the study. 


MP-101-01(b) Clinical Protocol 
Page 28 
MP-101 
Table 7.2. 
List of Excluded Concomitant Medications 
Drug Class 
Opioids, tramadol, ketorolac except occasional use as needed 
Antiemetics (except occasional use as needed metoclopramide, domperidone, other dopamine receptor 
blockers) 
Antihistamines (except occasional use as needed) 
Hydroxyzine (except occasional use as needed) 
Hypnotics 
Lithium 
Psychostimulants (modafanil) 
Skeletal muscle relaxants (except occasional use as needed) 
 
7.8. Treatment after the End of the Study 
MP-101 will not be made available to patients after conclusion of the study. 


MP-101-01(b) Clinical Protocol 
Page 29 
MP-101 
8. Discontinuation Criteria 
8.1. Discontinuation from Study Treatment 
8.1.1. Permanent Discontinuation from Study Treatment 
Discontinuation of dosing for abnormal liver tests should be considered by the investigator when 
a patient meets 1 of the following conditions, after consultation with the Sponsor designated 
medical monitor: 
• alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >8 × upper limit of 
normal (ULN) 
• alanine aminotransferase or AST >5 × ULN for more than 2 weeks 
• alanine aminotransferase or AST >3 × ULN and total bilirubin level (TBL) >2 × ULN or 
prothrombin time >1.5 × ULN 
• alanine aminotransferase or AST >3 × ULN with the appearance of fatigue, nausea, 
vomiting, right upper-quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%) 
• alkaline phosphatase (ALP) >3 × ULN 
• alkaline phosphatase >2.5 × ULN and TBL >2 × ULN 
• alkaline phosphatase >2.5 × ULN with the appearance of fatigue, nausea, vomiting, right-
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%) 
In addition, patients will be discontinued from the investigational product in the following 
circumstances: 
• the occurrence of worsening psychosis and/or agitation or aggression requiring rescue 
therapy 
• the occurrence of an SAE that in the opinion of the investigator would preclude the 
patient from continuing in the study 
• the occurrence of a clinically significant event, which is defined as a moderate (Grade 2) 
AE, laboratory result, ECG finding, or vital sign change based on the Common 
Terminology Criteria for Adverse Events v4.03 (CTCAE) or most current version, that in 
the opinion of the investigator would preclude the patient from continuing in the study.  
Clinically significant events of special interest include vomiting or “dizziness” associated 
with balance and gait instability as assessed for ambulatory patients using the TUG test 
For patients who discontinue the investigational product early, sites will make every reasonable 
effort to ensure that patients have procedures performed as shown in the Schedule of Activities 
(Section 2). 


MP-101-01(b) Clinical Protocol 
Page 30 
MP-101 
8.1.2. Discontinuation of Inadvertently Enrolled Patients 
If the sponsor or investigator identifies a patient who did not meet enrollment criteria and was 
inadvertently enrolled, a discussion must occur between the Mediti Pharma, Inc. CRP or 
designee and the investigator to determine if the patient may continue in the study.  If both agree 
it is medically appropriate to continue, the investigator must obtain documented approval from 
the Mediti Pharma, Inc. CRP or designee to allow the inadvertently enrolled patient to continue 
in the study with or without treatment with investigational product. 
8.2. Discontinuation from the Study 
Patients may be discontinued in the following circumstances: 
• enrollment in any other clinical trial involving an investigational product or enrollment in 
any other type of medical research judged not to be scientifically or medically compatible 
with this study 
• participation in the study needs to be stopped for medical, safety, regulatory, or other 
reasons consistent with applicable laws, regulations, and good clinical practice (GCP) 
• investigator decision 
o the investigator decides that the patient should be discontinued from the study 
o if the patient, for any reason, requires treatment with another therapeutic agent 
that is intended for the treatment of psychosis, discontinuation from the study 
occurs prior to introduction of the new agent 
• patient decision 
o the patient and/or caretaker requests patient withdrawal 
• sponsor decision 
If a patient discontinues the study early, the site will make every reasonable effort to have the 
patient return for an early termination visit to have end-of-study procedures performed as shown 
in the Schedule of Activities (Section 2).  If the patient does not return, this will not be 
considered a protocol deviation. 
8.3. Patients Lost to Follow-up 
A patient will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site.  Site personnel are expected to make 
diligent attempts to contact patients who fail to return for scheduled visits or were otherwise 
unable to be followed up by the site. 


MP-101-01(b) Clinical Protocol 
Page 31 
MP-101 
9. Study Assessments and Procedures 
Section 2 lists the Schedule of Activities, detailing the study procedures and their timing. 
Appendix 2 lists the laboratory tests that will be performed for this study. 
Unless otherwise stated in subsections below, all samples collected for specified laboratory tests 
will be destroyed within 60 days of receipt of confirmed test results.  Certain samples may be 
retained for a longer period, if necessary, to comply with applicable laws, regulations, or 
laboratory certification standards. 
Investigators must document their timely review of each laboratory safety report. 
9.1. Efficacy Assessments 
9.1.1. Primary Efficacy Assessment 
The primary endpoint is the response on the NPI-Psychosis subscale items of delusions and 
hallucinations and/or the agitation/aggression domain. 
Neuropsychiatric Inventory (NPI; Cummings et al. 1994). 
The NPI is a tool for assessing psychopathology in patients with brain disorders (i.e., AD and 
other dementias).  Information is obtained from an informed caregiver who is familiar with the 
patient’s behavior.  Ten behavioral and 2 neurovegetative areas are included in the NPI: 
delusions, hallucinations, agitation/aggression, depression/dysphoria, anxiety, elation/euphoria, 
apathy/indifference, disinhibition, irritability/lability, aberrant motor behavior, sleep and 
nighttime behavior disorders and appetite and eating disorders.  An initial question assesses the 
10 items and 2 neurovegetative evaluations of the scale.  If the answer to the initial question is 
‘no’, no further questions are pursued.  If the answer is ‘yes’, sub questions are asked; ratings of 
the frequency and severity of the behavior(s) are determined by the caregiver according to the 
criteria provided with each behavior.  Distress induced in the caregiver by each behavior is also 
rated.  Therefore, a total of 4 scores are computed for each behavior type:  frequency, severity, 
total (frequency × severity), and caregiver distress (Cummings 2009). 
9.1.2. Secondary Efficacy Assessments 
The secondary endpoints are listed below. 
Clinical Global Impression of Improvement (CGI-I; Guy et al. 1976) 
 
The CGI-I is a 7-point scale that requires the clinician to assess how much the patient’s illness 
has improved or worsened relative to baseline (Visit 2).  The scale ranges from 1 (very much 
improved) to 7 (very much worse). 
 
Neuropsychiatric Inventory (NPI; Cummings et al. 1994) 
Neuropsychiatric disturbances, caregiver distress, and other key parameters of patient behavior 
in this study will be measured using the NPI total score, the NPI Domains of anxiety, sleep and 


MP-101-01(b) Clinical Protocol 
Page 32 
MP-101 
nighttime behavior disorders, and the NPI Caregiver Distress (NPI-D) score.  A detailed 
description of NPI scoring can be found in Section 9.1.1. 
Mini-Mental State Examination (MMSE; Folstein et al. 1975) 
The MMSE is a brief assessment used to assess cognitive function.  The assessment is a simple, 
30-question, pen-and-paper test that evaluates attention, orientation, memory, registration, recall, 
calculation, language, and the ability to draw a complex polygon (Arevalo-Rodriguez et al. 
2015).  The range for the total MMSE score is 0 to 30, with lower scores indicating greater 
impairment. 
Unified Parkinson’s disease Rating Scale Part III (UPDRS; Fahn, 1987) 
Part III of the UPDRS is an investigator-scored scale used to assess the motor symptoms of 
patients with Parkinson's disease.  The investigator indicates if the patient is receiving 
medication for treating Parkinson's disease symptoms (specifically levodopa, and the time since 
the last dose) and the patient’s clinical response to the medication.  The investigator rates the 
patient on 14 items based on observation or the performance of a task the patient performs (even 
in the context of any comorbidities) on a 5-point scale.  The scores range from 0 to 4, with higher 
scores indicate greater impairment. 
9.1.3. Exploratory Efficacy Assessments 
The exploratory endpoints are listed below. 
Neuropsychiatric Inventory (NPI; Cummings et al. 1994) 
Changes in patient behavior as measured by the following NPI domains: depression/dysphoria; 
elation/euphoria, apathy/indifference, disinhibition, irritability/liability, aberrant motor behavior, 
and appetite and eating disorders.  A detailed description of NPI scoring can be found in 
Section 9.1.1. 
Zarit Burden Interview-22 (ZBI-22; Zarit et al. 1980) 
Changes in caregiver burden will be assessed using the Zarit Burden Interview-22 (ZBI-22).  The 
ZBI-22 is a 22-point scale used to assess caregiver burden in the dementia patient population 
(Zarit et al. 1980). Each of the 22 items is rated on a scale of 0 to 4, where 0 = never, 1 = rarely, 
2 = sometimes, 3 = frequently, 4 = nearly always. The total score of the ZBI-22 is the sum of 
those 22 items. 
9.2. Adverse Events 
Investigators are responsible for monitoring the safety of patients who have entered this study 
and for notifying Mediti Pharma, Inc. or its designee to any event that is deemed clinically 
significant, even if this event may be considered an unanticipated benefit to the patients. 
The investigator is responsible for the appropriate medical care of patients during the study. 
The investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious or otherwise medically important, considered related to the investigational 
product or the study, or that caused the patients to discontinue the investigational product before 
completing the study.  The patients should be followed until the event resolves, stabilizes with 


MP-101-01(b) Clinical Protocol 
Page 33 
MP-101 
appropriate diagnostic evaluation, or is reasonably explained.  The frequency of follow-up 
evaluations of the AE is left to the discretion of the investigator. 
After the ICF is signed, study site personnel will record, via CRF, the occurrence and nature of 
each patient’s preexisting conditions, including clinically significant signs and symptoms of the 
disease under treatment in the study.  Additionally, site personnel will record any change in the 
condition(s) and the occurrence and nature of any AEs. 
The investigator will interpret and document whether or not an AE has a reasonable possibility 
of being related to study treatment, or a study procedure, taking into account the disease, 
concomitant treatment, and pathologies. 
A “reasonable possibility” means that there is a cause and effect relationship between the 
investigational product, study device and/or study procedure and the AE. 
The investigator answers yes/no when making this assessment. 
Planned surgeries should not be reported as AEs unless the underlying medical condition has 
worsened during the course of the study. 
If a patient’s investigational product is discontinued as a result of an AE, study site personnel 
must report this to Mediti Pharma, Inc. or its designee via CRF or designated data transmission 
methods, clarifying, if possible, the circumstances leading to discontinuation of treatment. 
9.2.1. Serious Adverse Events 
An SAE is any AE from this study that results in 1 of the following outcomes: 
• death 
• initial or prolonged inpatient hospitalization 
• considered life-threatening 
• persistent or significant disability/incapacity 
• congenital anomaly/birth defect 
• considered significant by the investigator for any other reason:  important medical events 
that may not result in death, be life-threatening, or require hospitalization may be 
considered serious based on best medical judgment 
Study site personnel must alert Mediti Pharma, Inc., or its designee, of any SAE within 24 hours 
of investigator awareness of the event via a sponsor-approved method.  If alerts are issued via 
telephone, they are to be immediately followed with official notification on study-specific SAE 
forms.  This 24-hour notification requirement refers to the initial SAE information and all 
follow-up SAE information. 
As with AEs, SAE reporting begins after the patient has signed informed consent. 


MP-101-01(b) Clinical Protocol 
Page 34 
MP-101 
Investigators are not obligated to actively seek AEs or SAEs in patients once they have 
discontinued from and/or completed the study (the patient summary CRF has been completed).  
However, if the investigator learns of any SAE, including a death, at any time after a patient has 
been discharged from the study, and he/she considers the event reasonably possibly related to the 
study treatment or study participation, the investigator must promptly notify Mediti Pharma, Inc. 
or its designee. 
Pregnancy (maternal or paternal exposure to investigational product) does not meet the definition 
of an AE.  However, to fulfill regulatory requirements any pregnancy should be reported 
following the SAE process to collect data on the outcome for both mother and fetus. 
9.2.1.1. Suspected Unexpected Serious Adverse Reactions  
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the IB and that the investigator identifies as related to investigational product or procedure.  
United States 21 CFR 312.32 and European Union Clinical Trial Directive 2001/20/EC and the 
associated detailed guidances or national regulatory requirements in participating countries 
require the reporting of SUSARs.  Mediti Pharma, Inc. has procedures that will be followed for 
the recording and expedited reporting of SUSARs that are consistent with global regulations and 
the associated detailed guidances. 
9.2.2. Complaint Handling 
Mediti Pharma, Inc. collects product complaints on investigational products and drug delivery 
systems used in clinical trials in order to ensure the safety of study participants, monitor quality, 
and facilitate process and product improvements. 
Patients should be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the investigational product so that the situation can be assessed. 
9.3. Treatment of Overdose 
Patients receiving more than 60 mg/day of MP-101 (or placebo) will be noted in the CRF.  It is 
not expected that doses of up to 400 mg/day will result in any TEAEs or SAEs in patients based 
on prior studies in healthy subjects.  Patients who receive more than 60 mg/day will be 
monitored for side effects and treated appropriately for emergent symptoms (e.g., hydration or 
inpatient monitoring when appropriate).  There are no specific antidotes for MP-101.  Significant 
misdosing or TEAEs related to misdosing may result in discontinuation from the study, but will 
remain at the discretion of the investigator after consultation with the Mediti Pharma, Inc. CRP 
or designee.  Patients with SAEs related to misdosing or overdose will be discontinued from the 
study. 
9.4. Safety 
9.4.1. Physical and Neurological Examination 
Physical and neurological examinations will be conducted according to the Schedule of 
Activities (Section 2) and as clinically indicated. 


MP-101-01(b) Clinical Protocol 
Page 35 
MP-101 
Body weight and height will be recorded.  Physical examinations will include assessment of 
general appearance, skin, head and neck, lymph nodes, thyroid, abdomen (bowel sounds and 
liver and spleen palpation), back (costovertebral angle tenderness), and musculoskeletal, 
cardiovascular, and respiratory systems.  Neurological examinations will include assessment of 
mental status, cranial nerves, muscle strength, tone, and bulk, motor and sensory systems, muscle 
stretch reflexes, coordination, and balance and gait.  Gait and balance will be assessed with the 
TUG test (Appendix 5) for ambulatory patients.  The physical and neurological examination will 
be performed by a physician, nurse practitioner, or physician’s assistant holding appropriate 
delegation. 
If a clinically meaningful change is noted during the study, an additional full neurological 
examination will be performed as soon as possible, along with any other medical follow-up 
deemed necessary by the investigator. 
Any clinically significant change from baseline (Visit 2 [Week 0]) on follow-up physical and 
neurological examinations should be reported to Mediti Pharma, Inc. or its designee as an AE via 
CRF. 
9.4.2. Vital Signs 
For each patient, vital signs measurements should be conducted according to the Schedule of 
Activities (Section 2) and the provided study-specific recommendations  
Blood pressure and pulse rate should be measured after at least 5 minutes in the supine position. 
Orthostatic BP measurements are to be obtained if the patient complains of orthostatic 
lightheadedness.  Blood pressure will be obtained with the patient supine for 5 minutes and then 
after 3 minutes standing.  Additional vital signs may be measured during each study period if 
warranted and agreed upon between the sponsor and investigator. 
Any clinically significant findings from vital signs measurement that result in a diagnosis and 
that occur after the patient receives the first dose of study treatment should be reported to Mediti 
Pharma, Inc. or its designee as an AE via CRF. 
9.4.3. Electrocardiograms 
For each patient, a single 12-lead digital ECG will be collected according to the Schedule of 
Activities (Section 2) and the provided study-specific recommendations. 
Electrocardiograms should be recorded before collecting any blood for safety or PK tests, when 
possible.  Patients must be supine for approximately 5 to 10 minutes before ECG collection and 
remain supine but awake during ECG collection.  Electrocardiograms may be obtained at 
additional times, when deemed clinically necessary.  All ECGs recorded should be stored at the 
investigational site.  
Electrocardiograms will be interpreted by a qualified physician (the investigator or qualified 
designee) at the site as soon after the time of ECG collection as possible, and ideally while the 


MP-101-01(b) Clinical Protocol 
Page 36 
MP-101 
patient is still present, to determine whether the patient meets entry criteria at the relevant visit(s) 
and for immediate patient management, should any clinically relevant findings be identified. 
If a clinically significant finding is identified (including, but not limited to, changes in QTcF 
from baseline) after enrollment, the investigator will determine if the patient can continue in the 
study.  The investigator or qualified designee is responsible for determining if any change in 
patient management is needed, and must document his/her review of the ECG printed at the time 
of collection.  Any new clinically relevant finding should be reported as an AE. 
Any clinically significant findings from ECGs that result in a diagnosis and that occur after the 
patient receives the first dose of the investigational product, should be reported to Mediti 
Pharma, Inc., or its designee, as an AE via CRF. 
9.4.4. Laboratory Tests 
For each patient, laboratory tests detailed in Appendix 2 should be conducted according to the 
Schedule of Activities (Section 2) and the study-specific laboratory manual. 
Any clinically significant findings from laboratory tests that result in a diagnosis and that occur 
after the patient receives the first dose of investigational product should be reported to Mediti 
Pharma, Inc. or its designee as an AE via CRF. 
9.4.5. Other Tests 
9.4.5.1. Columbia Suicide Severity Rating Scale 
Consistent with US Food and Drug Administration (FDA) regulatory guidance (FDA [WWW]), 
any occurrence of suicide-related thoughts and behaviors will be assessed as indicated in the 
Schedule of Activities (Section 2) using the C-SSRS, a scale that captures the occurrence, 
severity, and frequency of suicide-related thoughts and behaviors during the corresponding 
assessment period.  The scale includes suggested questions to elicit the type of information 
needed to determine if a suicide-related thought or behavior occurred. 
Terms captured by the use of the C-SSRS can be mapped to Columbia Classification Algorithm 
for Suicide Assessment (Posner et al. 2007) to facilitate future pooling of data. 
The first time the scale is administered in this study, the C-SSRS “Lifetime/Recent-Clinical” 
version will be used, and the findings will constitute the baseline assessment.  The “Since Last 
Visit-Clinical” version will be used for all subsequent assessments.  If a suicide-related thought 
or behavior is identified at any time during the study, a thorough evaluation will be performed by 
a study physician, and appropriate medical care will be provided.  If, based on administration of 
the C-SSRS, it is determined that suicide-related behaviors have occurred, then the additional 
information will be collected to allow for a more complete assessment of these behaviors. 
9.4.6. Safety Monitoring 
The Mediti Pharma, Inc. CRP or designee, and Chorus will monitor safety data throughout the 
course of the study.  Chorus will oversee the formal and periodic safety reviews conducted 
during the study. 


MP-101-01(b) Clinical Protocol 
Page 37 
MP-101 
These safety reviews include the review of SAEs within time frames mandated by company 
procedures, as well as the review of evolving aggregate safety data within the study by 
appropriate methods.  This review will include the assessment of: 
• trends in safety data 
• adverse events including monitoring of vomiting or dizziness associated with balance and 
gait instability as assessed using the TUG test 
If a patient experiences elevated ALT ≥3 × ULN, ALP ≥2 × ULN, or TBL ≥2 × ULN, clinical 
and laboratory monitoring should be initiated by the investigator and continue until resolution 
with further treatment as clinically indicated.  To ensure patient safety and comply with 
regulatory guidance, the investigator is to consult with the Mediti Pharma, Inc. CRP or designee 
regarding collection of specific recommended clinical information and follow-up laboratory tests 
(see Appendix 4). 
In the event that safety monitoring uncovers an issue that needs to be addressed by unblinding at 
the group level, only members of the Assessment Committee (see Section 10.3.7) can conduct 
additional analyses of the safety data.  Furthermore, the entire study may be stopped in the event 
of safety concerns over drug related adverse events. 
9.5. Pharmacokinetics 
9.5.1. Pharmacokinetic Sampling 
At the visits and times specified in the Schedule of Activities (Section 2), venous blood samples 
will be collected from all patients, for a total of 5 scheduled samples per patient, to determine the 
plasma concentrations of MP-101, and its primary active metabolite LY2812223.  The sparse 
sampling scheme in Table 9.1 will be used. 
Table 9.1. 
Plasma Pharmacokinetic Sampling Scheme 
Week 
Visit 
Sample Collection Time Intervals 
2 
4 
4 to 8 hours postdose 
4 
5 
Predose and 0 to 2 hours postdose 
6 
6 
8 to 12 hours postdose 
10 
8 
2 to 4 hours postdose 
The actual sample collection date and time (24-hour clock time) must be recorded, as well as the 
date and time of the 2 most recent doses.  If a patient discontinues early, a sample should be 
taken at the early termination visit, if possible. 
Samples are to be collected at specific time intervals relative to dose administration; therefore, 
visits that include timed PK testing (Visits 4, 5, 6, and 8 [Weeks 2, 4,  6, and 10, respectively]) 
must be scheduled relative to the patient’s dosing schedule.  During Visit 5 (Week 4), the first 
PK sample will be taken predose; the dose will be administered and another PK sample will be 
taken up to 2 hours postdose.  For all visits that include PK sampling, the approximate start and 
stop times of food consumption prior to dosing and up to 4 hours postdose will be recorded. 


MP-101-01(b) Clinical Protocol 
Page 38 
MP-101 
Additional PK samples may be collected at additional time points during the study if warranted 
and agreed upon between both the investigator and sponsor. 
Instructions for the collection and handling of blood samples will be provided by the sponsor. 
9.5.2. Bioassay 
Human plasma samples will be analyzed for MP-101 and LY2812223 using a validated liquid 
chromatography-tandem mass spectrometry method at a laboratory approved by the sponsor.  
Samples will be collected from all patients, but only samples from patients taking MP-101 are 
planned to be assayed. 
Bioanalytical samples collected to measure investigational product concentrations will be 
retained for a maximum of 2 years following last patient visit for the study.  During this time, 
samples remaining after the bioanalyses may be used for exploratory analyses such as 
metabolism and/or protein binding work. 
Drug concentration information that may unblind the study will not be reported to investigative 
sites or blinded personnel until the study has been unblinded. 
9.6. Genetics 
9.6.1. Apolipoprotein E and HTR2A Genotyping 
Apolipoprotein E and HTR2A genotyping is a mandatory part of this study, unless country-
specific laws or regulations prohibit this type of testing.  Blood sampling for APOE and HTR2A 
genotyping will be performed as shown in the Schedule of Activities (Section 2).  Sample 
processing and handling instructions will be provided by the sponsor.  Neither patients nor 
investigators will receive the genotype results unless there is a country-specific law or regulation 
that requires notification of the results.  Failure to collect samples for APOE and HTR2A will 
not be considered a protocol violation if country-specific regulations prohibit the testing of 
genetic material or transportation of such material outside of the country. 
9.6.2. Whole Blood Sample for Pharmacogenetic Research 
A whole blood sample (approximately 10 mL) will be collected for pharmacogenetic analysis as 
specified in the Schedule of Activities (Section 2), where local regulations allow.  Sample 
processing and handling instructions will be provided by the sponsor.  Samples will not be used 
to conduct unspecified disease or population genetic research, either now or in the future.  
Samples will be used to investigate variable response to MP-101 and to investigate genetic 
variants thought to play a role in AD.  Assessment of variable response may include evaluation 
of AEs or differences in efficacy.  All samples will be coded with the patient number.  These 
samples and any data generated can be linked back to the patient only by the investigative site 
personnel. 
Samples will be retained for a maximum of 15 years after the last patient visit, or for a shorter 
period if local regulations and/or ethical review boards (ERBs)/investigational review boards 
(IRBs) impose shorter time limits, for the study at a facility selected by Mediti Pharma, Inc. or its 


MP-101-01(b) Clinical Protocol 
Page 39 
MP-101 
designee.  This retention period enables use of new technologies, response to regulatory 
questions, and investigation of variable response that may not be observed until later in the 
development of MP-101 or after MP-101 is commercially available. 
Molecular technologies are expected to improve during the 15-year storage period and therefore 
cannot be specifically named.  However, existing approaches include whole genome or exome 
sequencing, genome-wide association studies, multiplex assays, and candidate gene studies.  
Regardless of technology utilized, data generated will be used only for the specific research 
scope described in this section.  
9.7. Biomarkers 
Biomarker research is performed to address questions of relevance to drug disposition, target 
engagement, PD, mechanism of action, variability of patient response (including safety), and 
clinical outcome.  Sample collection is incorporated into clinical studies to enable examination of 
these questions through measurement of biomolecules including DNA, RNA, proteins, lipids, 
and other cellular elements. 
Plasma, serum, and whole blood samples for epigenetic analyses will be collected for 
non-pharmacogenetic biomarker research at the times specified in the Schedule of Activities 
(Section 2), where local regulations allow.  Sample processing and handling instructions will be 
provided by the sponsor. 
Samples will be used for research on the drug target, disease process, variable response to 
MP-101, pathways associated with psychosis in AD, mechanism of action of MP-101, and/or 
research method, or for validating diagnostic tools or assay(s) related to psychosis in AD. 
All samples will be coded with the patient number.  These samples and any data generated can 
be linked back to the patient only by the investigative site personnel. 
Samples will be retained for a maximum of 15 years after the last patient visit, or for a shorter 
period if local regulations and/or ERBs/IRBs impose shorter time limits, at a facility selected by 
Mediti Pharma, Inc. or its designee.  This retention period enables use of new technologies, 
response to regulatory questions, and investigation of variable response that may not be observed 
until later in the development of MP-101 or after MP-101 becomes commercially available. 


MP-101-01(b) Clinical Protocol 
Page 40 
MP-101 
10. Statistical Considerations and Data Analysis 
10.1. Sample Size Determination 
Approximately 100 patients will be enrolled to enable approximately 80 evaluable patients to 
complete the study through at least Visit 5 (Week 4).  The sample size was chosen so that there is 
at least an 80% chance the trial will show a statistically significant improvement in the response 
rate on the NPI-Psychosis scale (hallucinations plus delusions scores) and/or on the 
NPI-agitation/aggression domain in patients treated with MP-101 compared to placebo. This 
assumes a true response rate of 65% in the MP-101 treatment group versus 35% in the placebo 
treatment group, using a one-sided Fisher’s exact test with a 5% type 1 error rate.   
10.2. Populations for Analyses 
For the purposes of analysis, the following populations are defined: 
Population 
Description 
Randomized 
All patients who sign informed consent and are randomized. 
Safety 
All randomized patients who take at least 1 dose of double-blind study 
treatment.  In the event of a treatment error, patients will be analyzed according 
to the treatment they actually received. 
Intent-to-Treat 
All randomized patients who take at least 1 dose of double-blind study 
treatment and have at least 1 postbaseline efficacy assessment.  In the event of 
a treatment error, patients will be analyzed according to the treatment to which 
they were randomized. 
Evaluable 
All patients in the Intent-to-Treat population who complete at least Visit 5 
(Week 4) with NPI efficacy data. Specifically, patients with a diagnosis of 
psychosis must have at least one psychosis sub-scale score at Visit 5 or later 
and patients with a diagnosis of agitation/aggression must have at least one 
agitation/aggression sub-scale score at Visit 5 or later. 
10.3. Statistical Analyses 
10.3.1. General Statistical Considerations 
Statistical analysis of this study will be the responsibility of Mediti Pharma, Inc. or its designee. 
Details of the summarization and analysis of the clinical trial data will be described in the SAP, 
which will be finalized prior to database lock. 
The primary analyses will be performed with patients grouped by treatment arm (i.e., MP-101 or 
placebo) regardless of their final dose level. 
The sample size was calculated assuming a 20% drop-out of patients in each arm, and assuming 
that early withdrawal is not influenced by the treatment effect.  Secondary and supportive 
analyses may be performed to explore the effect of early withdrawal on the primary endpoint. 


MP-101-01(b) Clinical Protocol 
Page 41 
MP-101 
Pharmacokinetic analyses will be conducted on data from all patients on MP-101.  Safety 
analyses will be conducted for all treated patients, whether or not they completed all protocol 
requirements. 
Additional exploratory analyses of the data will be conducted as deemed appropriate.   
A change to the data analysis methods described in the protocol will require an amendment only 
if it changes a principal feature of the protocol.  Any other change to the data analysis methods 
described in the protocol or SAP, and the justification for making the change, will be described 
in the clinical study report. 
10.3.2. Treatment Group Comparability 
10.3.2.1. Patient Disposition 
A detailed description of patient disposition will be provided at the end of the study.   
10.3.2.2. Patient Characteristics 
Patient’s baseline age, sex, race, height, body weight, body mass index, MMSE score, other 
baseline efficacy measures, previous exposure to antipsychotic treatment, and eGFR value will 
be recorded.  Baseline and demographic characteristics will be summarized using descriptive 
statistics by treatment arm and overall. 
10.3.2.3. Concomitant Therapy 
Approved medications will be permitted in this study as described in Section 7.7.  Patients who 
begin such treatments during the study will be summarized. 
10.3.2.4. Treatment Compliance 
The proportion of patients who are significantly noncompliant, as noted in Section 7.6, may be 
summarized. 
10.3.3. Efficacy Analyses 
10.3.3.1. Primary Analyses 
The primary objective of this study will be assessed in the Evaluable population by analyzing 
NPI response rates. Response will be defined using two NPI endpoints: 1) the psychosis domain 
score, calculated as the sum of the delusions and hallucinations domain scores, and 2) the 
aggression/agitation domain score. Each domain score is the product of the severity and 
frequency ratings.  
A patient with a 30% improvement from baseline on a subscale will be considered a responder 
for that subscale. At baseline, patients will be given a diagnosis of psychosis and/or 
agitation/aggression. A patient with a psychosis diagnosis will be considered an overall 
responder with a response on the psychosis subscale, a patient with a diagnosis of 
aggression/agitation will be considered an overall responder with a response on the 
aggression/agitation subscale, and a patient with both diagnoses will be considered an overall 
responder with a response on either subscale. 


MP-101-01(b) Clinical Protocol 
Page 42 
MP-101 
The primary analysis will use a one-sided Fisher’s exact test with a 5% type 1 error rate. 
10.3.3.2. Secondary Analyses 
Secondary efficacy outcomes include CGI-I; NPI Total Score; NPI-Core Total (combination of 3 
items: hallucinations, delusions, and agitation/aggression); NPI Caregiver Distress; NPI domain 
of anxiety. 
The delusions, hallucinations, and aggression/agitation domain scores will be added together to 
form a Core Total score. A patient with a 30% improvement from baseline will be considered a 
responder on the Core Total score. The treatment groups will be compared using a one-sided 
Fisher’s exact test. 
The psychosis and aggression/agitation domain scores, and the Core Total score, will be 
analyzed as continuous measures. 
The change from baseline for quantitative endpoints will be analyzed using repeated measures 
mixed models assuming data are missing at random, with covariates for baseline and the 
stratification factors. 
The CGI-I scores will be analyzed using Cochran-Mantel-Haenszel tests, stratifying by the 
randomization strata, and using modified Ridit scores (i.e. van Elteren tests).  
Details of the analyses of secondary efficacy outcomes will be specified in the SAP. 
10.3.3.3. Exploratory Analyses 
The exploratory efficacy objectives to determine whether MP-101 is superior to placebo in 
patient behavior and caregiver burden. Changes in patient behavior will be assessed using NPI 
domains of depression/dysphoria, elation/euphoria, apathy/indifference, disinhibition, 
irritability/lability, aberrant motor behavior, sleep and nighttime behavior disorders, and appetite 
and eating disorders; MMSE.   
The ZBI-22 is being utilized to assess caregiver burden. 
The exposure-response relationships between efficacy and safety endpoints may also be 
explored, as needed. 
Details of the analyses of exploratory efficacy outcomes will be specified in the SAP 
10.3.4. Safety Analyses 
10.3.4.1. Adverse Events 
All investigational product and protocol procedure AEs will be listed, and if the frequency of 
events allows, safety data will be summarized using descriptive methodology. 
The incidence of symptoms for each treatment will be presented by severity and by association 
with investigational product as perceived by the investigator.  Symptoms reported to occur prior 
to enrollment will be distinguished from those reported as new or increased in severity during the 
study.  Each symptom will be classified by the most suitable term from the most current version 
of Medical Dictionary for Regulatory Activities (MedDRA). 


MP-101-01(b) Clinical Protocol 
Page 43 
MP-101 
The number of investigational product-related SAEs will be reported. 
10.3.4.2. Other Evaluations of Safety 
Other safety parameters that will be assessed include physical/neurological examinations, safety 
clinical laboratory parameters, vital signs, and ECG parameters.  The parameters will be listed 
and summarized using standard descriptive statistics.  Additional analysis will be performed if 
warranted upon review of the data. 
10.3.5. Pharmacokinetic Analyses 
MP-101 and LY2812223 concentrations will be summarized by treatment and time postdose 
using summary statistics (number, mean, standard deviation, coefficient of variation [CV], 
minimum, median, maximum, geometric mean, and geometric CV). 
For the final analysis, the PK of LY2812223 will be characterized using population PK methods; 
the effect of renal function on PK will be evaluated.  Data from this study may be pooled with 
data from previous studies.  The relationship of LY2812223 concentrations with efficacy and/or 
safety measures may be explored.  The population PK or PK/PD analyses will be performed 
separately and reported in a population PK report.  Other analyses may be performed as needed. 
10.3.6. Other Analyses 
10.3.6.1. Pharmacogenetics Exploratory Analyses 
To explore the effect of genotype on the response to MP-101 in dementia patients, genotype data 
for HTR2A SNP rs7330461, HTR2A SNP rs6313 (102T/C), APOE, and other genotypes may be 
analyzed.  The analysis methods may be detailed in the SAP. 
10.3.7. Interim Analyses 
An interim analysis is planned for this trial which will occur after approximately 20 patients have 
completed Visit 5 (Week 4) to evaluate safety and LY2812223 PK.  A second interim analysis 
may be performed to evaluate the futility of finding differences in the efficacy endpoints between 
treatment groups. All interim analysis details, including unblinding plans and stopping rules for 
the futility analysis, will be documented in the Assessment Committee Charter. 
Study sites will receive information about interim results ONLY if they need to know for the 
safety of their patients. 


MP-101-01(b) Clinical Protocol 
Page 44 
MP-101 
11. References 
Arevalo-Rodriguez I, Smailagic N, Roque I Figuls M, Ciapponi A, Sanchez-Perez E, Giannakou 
A, Pedraza OL, Bonfill Cosp X, Cullum S. Mini-Mental State Examination (MMSE) for the 
detection of Alzheimer's disease and other dementias in people with mild cognitive 
impairment (MCI). Cochrane Database Syst Rev. 2015;5(3):CD010783. 
Bateman RJ, Xiong C, Benzinger TL, Fagan AM, Goate A, Fox NC, Marcus DS, Cairns NJ, Xie 
X, Blazey TM, Holtzman DM, Santacruz A, Buckles V, Oliver A, Moulder K, Aisen PS, 
Ghetti B, Klunk WE, McDade E, Martins RN, Masters CL, Mayeux R, Ringman JM, Rossor 
MN, Schofield PR, Sperling RA, Salloway S, Morris JC; Dominantly Inherited Alzheimer 
Network. Clinical and biomarker changes in dominantly inherited Alzheimer's disease 
[published correction appears in N Engl J Med. 2012;367(8):780]. N Engl J Med 
2012;367(9):795-804. 
Conn PJ, Pin JP. Pharmacology and functions of metabotropic glutamate receptors. Annu Rev 
Pharmacol Toxicol. 1997;37:205-237. 
Cummings JL, Mega M, Gray K, Rosenberg-Thompson S, Carusi DA, Gornbein J. The 
Neuropsychiatric Inventory: comprehensive assessment of psychopathology in dementia. 
Neurology. 1994;44(12):2308-2314. 
Cummings JL. Neuropsychiatric Inventory. Comprehensive assessment of psychopathology in 
patients with dementia. David Geffen School of Medicine at UCLA. Los Angeles, CA. 2009. 
Cummings J, Isaacson S, Mills R, Williams H, Chi-Burris K, Corbett A, Dhall R, Ballard C. 
Pimavanserin for patients with Parkinson's disease psychosis: a randomised, placebo-
controlled phase 3 trial [published correction appears in Lancet. 2014;384(9937):28]. Lancet. 
2014;383(9916):533-540. 
Drevets WC, Rubin EH. Psychotic symptoms and the longitudinal course of senile dementia of 
the Alzheimer type. Biol Psychiatry. 1989;25(1):39-48. 
Dunayevich E, Erickson J, Levine L, Landbloom R, Schoepp DD, Tollefson GD. Efficacy and 
tolerability of an mGlu2/3 agonist in the treatment of generalized anxiety disorder [published 
correction appears in Neuropsychopharmacology. 2008;33(10):2549]. 
Neuropsychopharmacology. 2008;33(7):1603-1610. 
Fahn S, Elton R, UPDRS program members. Unified Parkinson’s disease rating scale. In: Fahn 
S, Marsden C, Goldstein M, Calne D, eds. Recent developments in Parkinson’s disease. 
Florham Park, NJ: Macmillan. Healthcare Information; 1987:153-16. 
[FDA] Food and Drug Administration. Guidance for Industry Suicidal Ideation and Behavior: 
Prospective Assessment of Occurrence in Clinical Trials. August 2012. Available at: 
http://www.fda.gov/downloads/Drugs/.../Guidances/UCM225130.pdf. Published August 2012. 
Accessed November 3, 2016. 
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):189-198. 


MP-101-01(b) Clinical Protocol 
Page 45 
MP-101 
Grubb A, Blirup-Jensen S, Lindström V, Schmidt C, Althaus H, Zegers I; IFCC Working Group 
on Standardisation of Cystatin C (WG-SCC). First certified reference material for cystatin C in 
human serum ERM-DA471/IFCC. Clin Chem Lab Med. 2010;48(11):1619-1621. 
Guy W. ECDEU Assessment Manual for Psychopharmacology. Rockville, MD: US Department 
of Health, Education, and Welfare Public Health Service Alcohol, Drug Abuse, and Mental 
Health Administration; 1976. 
Herrmann N, Mamdani M, Lanctot KL. Atypical antipsychotics and risk of cerebrovascular 
accidents. Am J Psychiatry. 2004;161(6):1113-1115. 
Inker LA, Schmid CH, Tighiouart H, Eckfeldt JH, Feldman HI, Greene T, Kusek JW, Manzi J, 
Van Lente F, Zhang YL, Coresh J, Levey AS; CKD-EPI Investigators [published corrections 
appear in N Engl J Med. 2012;367(7):681 and N Engl J Med. 2012;367(21):2060]. Estimating 
glomerular filtration rate from serum creatinine and cystatin C. N Engl J Med. 2012;367(1):20-
29. 
Kales HC, Gitlin LN, Lyketsos CG. Assessment and management of behavioral and 
psychological symptoms of dementia. BMJ. 2015;350: h369 
Levy ML, Cummings JL, Fairbanks LA, Bravi D, Calvani M, Carta A. Longitudinal assessment 
of symptoms of depression, agitation, and psychosis in 181 patients with Alzheimer's disease. 
Am J Psychiatry. 1996;153(11):1438-1443. 
Lopez OL, Wisniewski SR, Becker JT, Boller F, DeKosky ST. Psychiatric medication and 
abnormal behavior as predictors of progression in probable Alzheimer disease. Arch Neurol. 
1999;56(10):1266-1272. 
Lyketsos CG, Lopez O, Jones B, et al. Prevalence of Neuropsychiatric Symptoms in Dementia 
and Mild Cognitive Impairment Results From the Cardiovascular Health Study. JAMA. 
2002;288(12):1475-1483 
Marek GJ, Wright RA, Schoepp DD, Monn JA, Aghajanian GK. Physiological antagonism 
between 5-hydroxytryptamine(2A) and group II metabotropic glutamate receptors in prefrontal 
cortex. J Pharmacol Exp Ther. 2000;292(1):76-87. 
Matthews FE, Arthur A, Barnes LE, Bond J, Jagger C, Robinson L, et al. A two-decade 
comparison of prevalence of dementia in individuals aged 65 years and older from three 
geographical areas of England: results of the Cognitive Function and Ageing Study I and II. 
The Lancet. 2013; 382(9902):1405-1412. 
Nordin E, Rosendahl E, Lundin-Olsson L. Timed “Up & Go” test: reliability in older people 
dependent in activities of daily living--focus on cognitive state. Phys Ther. 2006;86(5):646-
655. 
Okumiya K, Matsubayashi K, Nakamura T, Fujisawa M, Osaki Y, Doi Y, Ozawa T. The timed 
“up & go” test is a useful predictor of falls in community-dwelling older people. J Am Geriatr 
Soc. 1998;46(7):928-930. 
Patil ST, Zhang L, Martenyi F, Lowe SL, Jackson KA, Andreev BV, Avedisova AS, Bardenstein 
LM, Gurovich IY, Morozova MA, Mosolov SN, Neznanov NG, Reznik AM, Smulevich AB, 
Tochilov VA, Johnson BG, Monn JA, Schoepp DD. Activation of mGlu2/3 receptors as a new 


MP-101-01(b) Clinical Protocol 
Page 46 
MP-101 
approach to treat schizophrenia: a randomized Phase 2 clinical trial [published correction 
appears in Nat Med. 2007;13(10):1264]. Nat Med. 2007;13(9):1102-1107. 
Paulsen JS, Salmon DP, Thal LJ, Romero R, Weisstein-Jenkins C, Galasko D, Hofstetter CR, 
Thomas R, Grant I, Jeste DV. Incidence of and risk factors for hallucinations and delusions in 
patients with probable AD. Neurology. 2000a;54(10):1965-1971. 
Paulsen JS, Ready RE, Stout JC, Salmon DP, Thal LJ, Grant I, Jeste DV. Neurobehaviors and 
psychotic symptoms in Alzheimer's disease. J Int Neuropsychol Soc. 200b0;6(7):815-820. 
Peralta CA, Shlipak MG, Judd S, Cushman M, McClellan W, Zakai NA, Safford MM, Zhang X, 
Muntner P, Warnock D. Detection of chronic kidney disease with creatinine, cystatin C, and 
urine albumin-to-creatinine ratio and association with progression to end-stage renal disease 
and mortality. JAMA. 2011;305(15):1545-1552. 
Posner K, Oquendo MA, Gould M, Stanley B, Davies M. Columbia Classification Algorithm of 
Suicide Assessment (C-CASA):  classification of suicidal events in the FDA's pediatric 
suicidal risk analysis of antidepressants. Am J Psychiatry. 2007;164(7):1035-1043. 
Robert P, Ferris S, Gauthier S, Ihl R, Winblad B, Tennigkeit F. Review of Alzheimer's disease 
scales: is there a need for a new multi-domain scale for therapy evaluation in medical practice? 
Alzheimers Res Ther. 2010;2(4):24. 
Rocca P, Leotta D, Liffredo C, Mingrone C, Sigaudo M, Capellero B, et al. Neuropsychiatric 
symptoms underlying caregiver stress and insight in Alzheimer's disease. Dement Geriatr 
Cogn Disord. 2010;30(1):57-63. 
Ropacki SA, Jeste DV. Epidemiology of and risk factors for psychosis of Alzheimer's disease: a 
review of 55 studies published from 1990 to 2003. Am J Psychiatry. 2005;162(11):2022-2030. 
Schneider LS, Dagerman K, Insel PS. Efficacy and adverse effects of atypical antipsychotics for 
dementia: meta-analysis of randomized, placebo-controlled trials. Am J Geriatr Psych. 
2006;14(3):191-210. 
Smith DA, Beier MT. Association between risperidone treatment and cerebrovascular adverse 
events: examining the evidence and postulating hypotheses for an underlying mechanism. J 
Am Med Dir Assoc. 2004;5(2):129-132. 
Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, Fagan AM, Iwatsubo T, Jack CR Jr, 
Kaye J, Montine TJ, Park DC, Reiman EM, Rowe CC, Siemers E, Stern Y, Yaffe K, Carrillo 
MC, Thies B, Morrison-Bogorad M, Wagster MV, Phelps CH. Toward defining the preclinical 
stages of Alzheimer's disease: recommendations from the National Institute on Aging-
Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. 
Alzheimers Dement. 2011;7(3):280-292. 
Steinberg M, Shao H, Zandi P, Lyketsos CG, Welsh-Bohmer KA, Norton MC, et al. Point and 
5-year period prevalence of neuropsychiatric symptoms in dementia: the Cache County Study. 
Int J Geriatr Psychiatry. 2008;23(2): 170–177. 
Stern Y, Mayeux R, Sano M, Hauser WA, Bush T. Predictors of disease course in patients with 
probable Alzheimer's disease. Neurology. 198t7;37(10):1649-1653. 


MP-101-01(b) Clinical Protocol 
Page 47 
MP-101 
Tamaru Y, Nomura S, Mizuno N, Shigemoto R. Distribution of metabotropic glutamate receptor 
mGluR3 in the mouse CNS: differential location relative to pre- and postsynaptic sites. 
Neuroscience. 2001;106(3):481-503. 
Villemagne VL, Burnham S, Bourgeat P, Brown B, Ellis KA, Salvado O, Szoeke C, Macaulay 
SL, Martins R, Maruff P, Ames D, Rowe CC, Masters CL; Australian Imaging Biomarkers 
and Lifestyle (AIBL) Research Group. Amyloid β deposition, neurodegeneration, and 
cognitive decline in sporadic Alzheimer's disease: a prospective cohort study. Lancet Neurol. 
2013;12(4):357-367. 
Wancata J, Windhaber J, Krautgartner M, Alexandrowicz R. The consequences of non-cognitive 
symptoms of dementia in medical hospital departments. Int J Psychiatry Med. 2003;33(3):257-
71. 
Wooltorton E. Risperidone (Risperdal): increased rate of cerebrovascular events in dementia 
trials. CMAJ. 2002;167(11):1269-1270. 
Wooltorton E. Olanzapine (Zyprexa): increased incidence of cerebrovascular events in dementia 
trials. CMAJ. 2004;170(9):1395. 
Zarit SH, Reever KE, Bach-Peterson J. Relatives of the impaired elderly; correlates of feelings of 
burden. The Gerontologist. 1980;20(6):649-655. 


MP-101-01(b) Clinical Protocol 
Page 48 
MP-101 
Appendix 1. 
Abbreviations and Definitions 
Term 
Definition 
5-HT2A/HTR2A 
5-hydroxytryptamine (serotonin) 2A (receptor) 
AChEI 
acetylcholinesterase inhibitors 
AD 
Alzheimer’s disease 
ADL 
Activity of Daily Living 
AE 
adverse event:  Any untoward medical occurrence in a patient or clinical investigation 
patient administered a pharmaceutical product that does not necessarily have a causal 
relationship with this treatment.  An adverse event can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or not 
related to the medicinal (investigational) product. 
APOE 
apolipoprotein E 
AST 
aspartate aminotransferase 
BP 
blood pressure 
bpm 
beats per minute 
cAMP 
cyclic adenosine monophosphate 
CGI-I 
Clinical Global Impression of Improvement 
CGI-S 
Clinical Global Impression of Severity 
CI 
confidence interval 
CKD EPI 
Chronic Kidney Disease Epidemiology Collaboration 
Cmax 
maximum observed drug concentration 
CRF 
case report form 
CRP 
clinical research physician:  Individual responsible for the medical conduct of the study.  
Responsibilities of the CRP may be performed by a physician, global safety physician, or 
other medical officer. 
CSF 
cerebrospinal fluid 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CT 
computed tomography 


MP-101-01(b) Clinical Protocol 
Page 49 
MP-101 
CTCAE 
Common Terminology Criteria for Adverse Events 
complaint 
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system. 
CV 
coefficient of variation 
DSM-V 
Diagnostic and Statistical Manual of Mental Disorders-Fifth Edition 
DP 
drug product 
EC50 
half maximal effective concentration 
EC100 
maximum achievable response concentration 
ECG 
Electrocardiogram 
ERB 
ethical review board 
eGFR 
estimated glomerular filtration rate 
enroll 
The act of assigning a patient to a treatment.  Patients who are enrolled in the trial are those 
who have been assigned to a treatment. 
enter 
Patients entered into a trial are those who sign the informed consent form directly or 
through their legally acceptable representatives. 
FDA 
US Food and Drug Administration 
GCP 
good clinical practice 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
interim analysis 
An interim analysis is an analysis of clinical study data, separated into treatment groups, 
that is conducted before the final reporting database is created/locked. 
investigational 
product 
A pharmaceutical form of an active ingredient or placebo being tested or used as a reference 
in a clinical trial, including products already on the market when used or assembled 
(formulated or packaged) in a way different from the authorized form, or marketed products 
used for an unauthorized indication, or marketed products used to gain further information 
about the authorized form. 
IRB 
investigational review board 
IWRS 
interactive web-response system 
mGlu 
metabotropic glutamate 
MAD 
multiple-ascending dose 


MP-101-01(b) Clinical Protocol 
Page 50 
MP-101 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMSE 
Mini-Mental State Exam 
MRI 
magnetic resonance imaging 
NPI 
Neuropsychiatric Inventory 
NPI-D 
Neuropsychiatric Inventory-Caregiver Distress 
PD 
Pharmacodynamics 
phMRI 
pharmacological magnetic resonance imaging 
PK 
Pharmacokinetic 
PPS 
per-protocol set:  The set of data generated by the subset of patients/who sufficiently 
complied with the protocol to ensure that these data would be likely to exhibit the effects of 
treatment, according to the underlying scientific model. 
QD 
quaque die (once daily) 
QTc 
corrected QT interval 
QTcF 
Fridericia’s corrected QT interval 
SAD 
single-ascending dose 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
screen 
The act of determining if an individual meets minimum requirements to become part of a 
pool of potential candidates for participation in a clinical study.  
SNP 
single nucleotide polymorphism 
SUSAR 
suspected unexpected serious adverse reaction 
t1/2 
terminal half-life 
TEAE 
treatment-emergent adverse event:  An untoward medical occurrence that emerges during a 
defined treatment period, having been absent pretreatment, or worsens relative to the 
pretreatment state, which and does not necessarily have to have a causal relationship with 
this treatment. 
tmax 
time of maximum concentration 
TUG 
Timed Up and Go 
ULN 
upper limit of normal 
UPDRS 
Unified Parkinson’s Disease Rating Scale 


MP-101-01(b) Clinical Protocol 
Page 51 
MP-101 
ZBI-22 
Zarit Burden Interview-22 
 


MP-101-01(b) Clinical Protocol 
Page 52 
MP-101 
Appendix 2. 
Clinical Laboratory Tests 
Laboratory Tests 
Clinical Chemistrya,b 
Serum Concentrations of: 
Sodium 
Potassium 
Total bilirubin 
Direct bilirubin 
Alkaline phosphatase 
Alanine aminotransferase (ALT) 
Aspartate aminotransferase (AST) 
Blood urea nitrogen (BUN) 
Creatininec 
Uric acid 
Calcium 
Glucose 
Albumin 
Total Protein 
Creatine kinase (CK) 
Cystatin-C 
Complete Blood Count with differential 
Urine dipstickd 
Serology a,b 
Hepatitis C Antibody 
HIV 
Hepatitis B Surface Antigen 
Other Testsa 
FSHe 
Pharmacokinetica 
MP-101 and LY2812223 plasma concentrations  
Abbreviations:  CKD-EPI= Chronic Kidney Disease Epidemiology Collaboration; FSH = follicle stimulating 
hormone; HIV = human immunodeficiency virus. 
a Assayed by sponsor-designated laboratory 
b Unscheduled or repeat blood chemistry, hematology, and urinalysis panels may be performed at the discretion of 
the investigator, as needed. 
c Estimated glomerular filtration rate will be calculated using serum creatinine values and the CKD-EPI Cystatin C 
Equation (Grubb et al. 2010; Peralta et al. 2011; Inker et al. 2012). 
d Microscopic examination of sediment performed only if abnormalities are noted on the routine urinalysis. 
e To confirm postmenopausal status for women ≥50 and <60 years of age who have had a cessation of menses, an 
FSH test will be performed. Non-childbearing potential is defined as an FSH ≥40 mIU/mL and a cessation of 
menses for at least 12 months. 


MP-101-01(b) Clinical Protocol 
Page 53 
MP-101 
Appendix 3. 
Study Governance, Regulatory and Ethical 
Considerations 
Informed Consent 
The investigator is responsible for: 
• ensuring that the patient understands the potential risks and benefits of participating in 
the study. 
• ensuring that informed consent is given by each patient or legal representative.  This 
includes obtaining the appropriate signatures and dates on the informed consent form 
(ICF) prior to the performance of any protocol procedures and prior to the administration 
of investigational product. 
• answering any questions the patient may have throughout the study and sharing in a 
timely manner any new information that may be relevant to the patient’s willingness to 
continue his or her participation in the trial. 
Ethical Review 
The investigator or appropriate local representative must give assurance that the ethical review 
board (ERB) was properly constituted and convened as required by International Conference on 
Harmonisation (ICH) guidelines and other applicable laws and regulations. 
Documentation of ERB approval of the protocol and the ICF must be provided to Mediti Pharma, 
Inc. before the study may begin at the investigative site(s).  Mediti Pharma, Inc. or its 
representatives must approve the ICF before it is used at the investigative site(s).  All ICFs must 
be compliant with the ICH guideline on good clinical practice (GCP). 
The study site’s ERB(s) should be provided with the following: 
• the current Investigator’s Brochure (IB) and updates during the course of the study 
• ICF 
• relevant curricula vitae 
Regulatory Considerations 
This study will be conducted in accordance with: 
1) consensus ethics principles derived from international ethics guidelines, 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences International Ethical Guidelines  
2) applicable ICH GCP Guidelines  
3) applicable laws and regulations 
Some of the obligations of the sponsor will be assigned to a third party organization. 


MP-101-01(b) Clinical Protocol 
Page 54 
MP-101 
Protocol Signatures 
The sponsor’s responsible medical officer will approve the protocol, confirming that, to the best 
of his or her knowledge, the protocol accurately describes the planned design and conduct of the 
study.   
After reading the protocol, each principal investigator will sign the protocol signature page and 
send a copy of the signed page to a Mediti Pharma, Inc. representative. 
Final Report Signature 
The sponsor will select a qualified investigator from among participating investigators to serve 
as the final report coordinating investigator.  If this investigator is unable to fulfill this function, 
another investigator will be chosen by the sponsor. 
The sponsor’s responsible medical officer and statistician will sign/approve the final clinical 
study report for this study, confirming that, to the best of his or her knowledge, the report 
accurately describes the conduct and results of the study. 
Data Quality Assurance 
To ensure accurate, complete, and reliable data, Mediti Pharma, Inc. or its representatives will do 
the following: 
• provide instructional material to the study sites, as appropriate. 
• provide training to instruct the investigators and study coordinators.  This training will 
give instruction on the protocol, the completion of the case report forms (CRFs), and 
study procedures. 
• make periodic visits to the study site. 
• be available for consultation and stay in contact with the study site personnel by mail, 
telephone, and/or fax. 
• review and evaluate CRF data and/or use standard computer edits to detect errors in data 
collection. 
• conduct a quality review of the database. 
In addition, Mediti Pharma, Inc. or its representatives will periodically check a sample of the 
patient data recorded against source documents at the study site.  The study may be audited by 
Mediti Pharma, Inc. and/or regulatory agencies at any time.  Investigators will be given notice 
before an audit occurs. 
The investigator will keep records of all original source data.  This might include laboratory 
tests, medical records, or clinical notes.  If requested, the investigator will provide the sponsor, 
applicable regulatory agencies, and applicable ERBs with direct access to the original source 
documents. 


MP-101-01(b) Clinical Protocol 
Page 55 
MP-101 
Data Collection Tools/Source Data 
An electronic data capture system will be used in this study.  The site must define and retain all 
source records and must maintain a record of any data where source data are directly entered into 
the data capture system. 
Study and Site Closure 
Discontinuation of Study Sites 
Study site participation may be discontinued if Mediti Pharma, Inc. or its designee, the 
investigator, or the ERB of the study site judges it necessary for medical, safety, regulatory, or 
other reasons consistent with applicable laws, regulations, and GCP. 
Discontinuation of the Study 
The study will be discontinued if Mediti Pharma, Inc. or its designee judges it necessary for 
medical, safety, regulatory, or other reasons consistent with applicable laws, regulations, and 
GCP. 
 


MP-101-01(b) Clinical Protocol 
Page 56 
MP-101 
Appendix 4. 
Hepatic Monitoring Tests for Treatment-
Emergent Abnormality 
Selected tests may be obtained in the event of a treatment-emergent hepatic abnormality and may 
be required in follow-up with patients in consultation with Mediti Pharma, Inc. or its designee 
clinical research physician. 
Hepatic Monitoring Tests 
Hepatic Hematologya 
Haptoglobina 
Hemoglobin 
 
Hematocrit 
Hepatic Coagulationa 
RBC 
Prothrombin Time 
WBC 
Prothrombin Time, INR 
Neutrophils, segmented 
 
Lymphocytes 
Hepatic Serologiesa,b 
Monocytes 
Hepatitis A antibody, total 
Eosinophils 
Hepatitis A antibody, IgM 
Basophils 
Hepatitis B surface antigen 
Platelets 
Hepatitis B surface antibody 
 
Hepatitis B Core antibody 
Hepatic Chemistrya 
Hepatitis C antibody 
Total bilirubin 
Hepatitis E antibody, IgG 
Conjugated bilirubin 
Hepatitis E antibody, IgM 
Alkaline phosphatase 
 
ALT 
Anti-nuclear antibodya 
AST 
 
GGT 
CPK  
Anti-smooth muscle antibody (or anti-actin 
antibody)a 
Abbreviations:  ALT = alanine aminotransferase; AST = aspartate aminotransferase; CPK = creatinine 
phosphokinase; GGT = gamma-glutamyl transferase; Ig = immunoglobulin; INR = international normalized 
ratio; RBC = red blood cells; WBC = white blood cells. 
a Assayed by Mediti Pharma, Inc.-designated or local laboratory. 
b Reflex/confirmation dependent on regulatory requirements and/or testing availability 


MP-101-01(b) Clinical Protocol 
Page 57 
MP-101 
Appendix 5. 
Timed Up and Go Test 
Name:___________________________ MR: ______________________ Date:________  
1. 
Equipment:  arm chair, tape measure, tape, stop watch.  
2. 
Begin the test with the subject sitting correctly (hips all of the way to the back of the seat) 
in a chair with arm rests.  The chair should be stable and positioned such that it will not 
move when the subject moves from sit to stand.  The subject is allowed to use the arm 
rests during the sit – stand and stand – sit movements.  
3. 
Place a piece of tape or other marker on the floor 3 meters away from the chair so that it 
is easily seen by the subject.  
4. 
Instructions: “On the word GO you will stand up, walk to the line on the floor, turn 
around and walk back to the chair and sit down.  Walk at your regular pace.” 
5. 
Start timing on the word “GO” and stop timing when the subject is seated again correctly 
in the chair with their back resting on the back of the chair. 
6. 
The subject wears their regular footwear, may use any gait aid that they normally use 
during ambulation, but may not be assisted by another person.  There is no time limit.  
They may stop and rest (but not sit down) if they need to. 
7. 
Normal healthy elderly usually complete the task in 10 seconds or less.  Very frail or 
weak elderly with poor mobility may take 2 minutes or more. 
8. 
The subject should be given a practice trial that is not timed before testing. 
9. 
Results correlate with gait speed, balance, functional level, the ability to go out, and can 
follow change over time. 
Normative Reference Values by Age 
Age Group 
Time in Seconds (95% Confidence Interval) 
60 – 69 years 
8.1 (7.1 – 9.0)  
70 – 79 years  
9.2 (8.2 – 10.2)  
80 – 99 years  
11.3 (10.0 – 12.7)  
 
Cut-off Values Predictive of Falls by 
Group 
Time in Seconds 
Community dwelling frail older adults 
>14 associated with high fall risk 
Postoperative hip fracture patients at 
time of discharge 
>24 predictive of falls within 6 months after hip 
fracture 
Frail older adults  
>30 predictive of requiring assistive device for 
ambulation and being dependent in ADLs 
 
 
 


MP-101-01(b) Clinical Protocol 
Page 58 
MP-101 
Appendix 6. 
Protocol Amendment MP-101-01(b) 
Summary [Tolerability, Pharmacokinetics, and Efficacy 
of MP-101 in the Treatment of Psychosis in Patients with 
Alzheimer’s Disease] 
Overview 
Protocol MP-101-01 [Tolerability, Pharmacokinetics, and Efficacy of MP-101 in the Treatment 
of Psychosis in Patients with Alzheimer’s Disease] has been amended.  The new protocol is 
indicated by amendment (b) and will be used to conduct the study in place of any preceding 
version of the protocol. 
The revisions to the protocol detailed below are being implemented to maximize the potential of 
MP-101 reaching future patients in this difficult-to-treat population. Dementia can be caused by 
numerous neurodegenerative disorders including (but not limited to) Alzheimer’s disease (AD); 
therefore, to expand patient eligibility, this protocol amendment includes patients with all 
neurodegeneration-related dementias including Alzheimer’s disease, Lewy body dementia, 
Parkinson’s disease dementia, and frontotemporal dementia.  
While cognitive impairment is the hallmark symptom of dementia, behavioral and psychological 
disturbances are almost invariably present at some point during the illness (Steinberg et al. 2008; 
Lyketsos et al. 2002). Among the most disturbing and burdensome of these symptoms are 
psychosis (hallucinations and delusions) as well as aggression and agitation. Therefore again, in 
an effort to expand the patient population, these additional measures are being included in the 
protocol amendment. 
Additionally, an attempt to minimize caregiver and patient burden with the revised protocol has 
been made by reducing the number of study visits, scales performed at each visit, and excluded 
concomitant medications.   
The overall changes made to this protocol are as follows. 
Note: Deletions have been identified by strikethroughs or grayed out for figures. Additions 
have been identified by the use of underscore. Additional/instructional text is in italics. 
 
 


MP-101-01(b) Clinical Protocol 
Page 59 
MP-101 
Revised Protocol Sections 
Study Title: 
Tolerability, Pharmacokinetics, and Efficacy of MP-101 in the Treatment of Patients with 
Dementia-Related Psychosis and/or Agitation and Aggression in Patients with Alzheimer’s 
Disease 
The change in study indication was updated at all relevant places/sections in the protocol. 
 
All edits made to the main body were applied to the synopsis section as well. 
 
Section 2. 
Schedule of Activities 
Following efficacy assessment schedule was revised: Mini-Mental State Examination (MMSE) 
Visit 6 (Week 6) assessment was removed.  
Following efficacy assessments were removed:  Cohen Mansfield Agitation Inventory (CMAI), 
Alzheimer’s Disease Cooperative Study Activities of Daily Living (ADCS ADL), Alzheimer’s 
Disease Cooperative Study Clinical Global Impression of Change (ADSC CGIC). 
Following efficacy assessments were added: Clinical Global Impression of Improvement (CGI-I) 
at Visits 5, 8, 9 and ET; Zarit Burden Inverview-22 (ZBI-22) at Visits 2, 5, and 8.  
Visit 7 (Week 8) was changed from a site visit to a telephone call, thus cancelling all of the on-
site scales and procedures previously associated with that visit. The Visit 7 PK sample draw was 
moved to Visit 8 (Week 10). 
Footnote ‘b’ meant for Inclusion/Exclusion Criteria Review activity was updated as below: 
b 
Patients must have at least one of the following at Visit 1 (screening) and Visit 2 
(Week 0) an NPI score of ≥4 on either individual item (delusions or hallucinations) or ≥6 on 
Psychosis Subscale (combined delusions and hallucinations) at Alternatively, pVisit 1 
(screening) and Visit 2 (Week 0): 
• an NPI score of ≥4 on either delusions or hallucinations individual items  
• an NPI score of ≥6 on the Psychosis Subscale (combined delusions and hallucinations)  
• an NPI score of ≥4 on agitation/aggression domain 
Section 3. 
Introduction 
Introduction section was updated to reflect the change in study indication from Alzheimer’s 
disease and psychosis to dementia-related psychosis and agitation/aggression. 
Section 4. 
Objectives and Endpoints 
4.1. 
Primary Objective and Endpoint 


MP-101-01(b) Clinical Protocol 
Page 60 
MP-101 
• To test the hypothesis that oral administration of QD MP-101 will improve psychotic 
symptoms and/or agitation/aggression in patients with dementia AD when compared to 
placebo 
o Endpoint:  Change from baseline to 10-week treatment endpoint in the 
Neuropsychiatric Inventory (NPI)-Psychosis subscale (combination of 2 items:  
hallucinations and delusions)  and/or in the agitation/aggression domain.  
(combination of 2 items:  hallucinations and delusions).  
4.2. 
Secondary Objectives and Endpoints 
Secondary objectives and endpoints in patients with dementia related psychosis and/or agitation 
and aggression are as follows: 
• To assess whether MP-101 is superior to placebo in the following: overall psychosis, 
neuropsychiatric disturbances, caregiver distress, and anxiety, agitation/aggression, and 
function 
o Endpoints:  Change from baseline to 10-week treatment endpoint in the 
following: Clinical Global Impression of ImprovementSeverity (CGI-IS); NPI 
Total Score; NPI-Core Total (combination of 3 items: hallucinations, delusions, 
and agitation/aggression); NPI Caregiver Distress (NPI-D); and NPI domains of 
anxiety and agitation/aggression; Alzheimer’s Disease Cooperative Study-
Activities of Daily Living Inventory (ADCS-ADL); and Cohen-Mansfield 
Agitation Inventory (CMAI) 
• To determine if MP-101 is safe and tolerable in AD patients with psychosis 
o Endpoints:  Treatment-emergent adverse events (TEAEs); Unified Parkinson’s 
Disease Rating Scale (UPDRS) Part III 
• To assess the PK of MP-101 and its primary active metabolite, LY2812223 
o Endpoint:  Plasma PK data 
4.3. 
Exploratory Objectives and Endpoints 
• To assess whether MP-101 is superior to placebo in changes in patient behavior and 
caregiver burden 
o Endpoints:  Change from baseline to 10-week treatment endpoint in the 
following: Alzheimer’s Disease Cooperative Study-Clinical Global Impression of 
Change (ADCS-CGIC); NPI domains of depression/dysphoria, elation/euphoria, 
apathy/indifference, disinhibition, irritability/lability, aberrant motor behavior, 
sleep and nighttime behavior disorders, and appetite and eating disorders; Mini-
Mental State Examination (MMSE); Zarit Burden Interview-22 (ZBI-22) 
• To explore the effect of HTR2A and apolipoprotein E (APOE) genotypes on response to 
treatment 


MP-101-01(b) Clinical Protocol 
Page 61 
MP-101 
o Endpoints:  HTR2A single nucleotide polymorphism (SNP) rs7330461 genotype 
data; HTR2A SNP rs6313 (102T/C) genotype data; APOE genotype data 
• To explore exposure-response relationships with efficacy and safety clinical endpoints as 
needed 
o Endpoints:  Efficacy and safety clinical endpoints, as needed 
Section 5. 
Study Design 
5.1. 
Overall Design 
Study MP-101-01 is a Phase 2, multicenter, double-blind, randomized, parallel, placebo-
controlled, 10-week study of MP-101, consisting of screening, treatment, and follow-up periods, 
in AD patients with dementia related psychosis and/or agitation and aggression. with psychosis.  
All patients will be randomized 1:1 to receive either placebo or MP-101. 
Figure 5.1. Illustrates the study design.
Abbreviations: AD = Alzheimer’s disease; CGI-I = Clinical Global Impression of Improvement/Severity; 
CGI-S = Clinical Global Impression of Severity; C-SSRS= Columbia Suicide Severity Rating Scale; MMSE= Mini-
Mental State Examination; NPI-P = Neuropsychiatric Inventory-Psychosis; PK = pharmacokinetic; UPDRS=Unified 
Parkinson’s Disease Rating Scale; Zarit Burden Interview-22. 
Figure 5.1. 
Illustration of study design for protocol MP-101-01. 


MP-101-01(b) Clinical Protocol 
Page 62 
MP-101 
5.2. 
Number of Participants 
Approximately 200100 patients will be enrolled to obtained approximately 16080 patients in the 
Evaluable population. 
 
Section 6. 
Study Population 
6.1. 
Inclusion Criteria 
Type of Patient – Patient and Disease Characteristics 
[2] 
Ambulatory (with or without walking device) with a stable gait as assessed with a TUG 
test (Okumiya et al. 1998; Nordin et al. 2006) that must be completed in ≤30 seconds.  
The test may be repeated once with instruction.  Patients in wheelchairs are also eligible 
and do not need to complete the TUG test. 
 [3] 
probable AD based on the National Institute on Aging-Alzheimer’s Association criteria 
(McKhann et al, 2011) and  
[4] 
Meets clinical criteria for one of the following disorders: dementia associated with 
Parkinson’s disease, dementia with Lewy bodies, possible or probable Alzheimer’s 
disease, frontotemporal degeneration spectrum disorders, vascular dementia 
[5] 
Must be able to communicate verbally. 
[4] 
Have psychotic symptoms that developed following the diagnosis of probable AD.  The 
psychotic symptoms must include visual and/or auditory hallucinations, and/or delusions. 
[5] 
At Visit 1 (screening) and Visit 2 (Week 0) have at least ONE of the following: 
o Have an NPI score of ≥4 on either delusions or hallucinations individual items 
(delusions or hallucinations)  
o an NPI score of ≥6 on the Psychosis Subscale (combined delusions and 
hallucinations)  
 
at Visit 1 (screening) and Visit 2 (Week 0) 
  
or 
• Have an NPI score of ≥4 on agitation/aggression domainat Visit 1 (screening) and 
Visit 2 (Week 0). 
[7] 
Have had an MRI or a computed tomography (CT) scan concurrent with or following the 
diagnosis of probable AD, to exclude prior stroke or structural brain disease. 
[8] 
Must be on a stable dose of cholinesterase inhibitor and/or memantine, if applicable. 


MP-101-01(b) Clinical Protocol 
Page 63 
MP-101 
[9] 
Are receiving acetylcholinesterase inhibitors (AChEIs) on a stable doses for  ≥13 months 
prior to the baseline visit and during the study or, in the opinion of the investigator is will 
be likely to remain on a stable treatment regimen for 6 months.  Patients not being treated 
with AChEIs are also eligible for study enrollment.  If taking antipsychotic drugs or any 
drug intended to treat psychosis, must be on a stable treatment regimen for ≥1 month 
prior to the baseline visit (Visit 2). Note:  If athe patient has recently stopped taking 
antipsychotic drugs or any drugs intended to treat psychosis, he or she must have 
discontinued treatment at least 4 weeks before Visit 1 (screening).  Patients receiving 
memantine therapy are eligible for study enrollment if there is a washout of memantine 
treatment (minimum 7 half-lives; approximately 28 days) during the screening period and 
prior to randomization; such patients must also meet all other eligibility criteria for study 
entry. 
6.2. 
Exclusion Criteria 
Diagnostic Assessments 
[14] 
Have a history of significant psychotic disorders prior to or simultaneous with the 
probable diagnosis of AD (including, but not limited to, schizophrenia, delusional 
disorder, substance abuse psychosis that lasted over 6 months, major depressive disorder, 
or bipolar disorder with psychotic episodes). 
[15] 
Had a history of ischemic stroke within the last 12 months or any evidence of 
hemorrhagic stroke. 
[16] 
Have an MRI or CT scan (on file since the onset of symptoms of AD) that is inconsistent 
with a probable diagnosis of AD. 
[17] 
Meets National Institute of Neutological Disorders and Stroke/Association International 
pour la Recherche et l’Eseignement en Neuroscience criteria for vascular dementia 
(Pohjasvaara et al. 200).  Meets Diagnostic and Statistical Manual of Mental Disorder-
Fifth Edition (DSM-V) criteria for delirium. 
Mental Conditions 
[19] 
Have psychosis from non-AD-associated etiologies (e.g., substance abuse or a diagnosis 
of psychosis prior to the development of AD). 
[24] 
Uses any antipsychotics or any other drug intended to treat psychosis after Visit 1 
(screening).  If the patient is taking the medication prior to study entry, there must be a 
washout period equal to a minimum of 5 half-lives of that medication prior to Visit 2 
(Week 0).  If the half-life of a medication is unknown (e.g., herbal products), then the 
patient should have a 28-day medication washout. 
 


MP-101-01(b) Clinical Protocol 
Page 64 
MP-101 
Section 7. 
Treatment 
7.2 
Method of Treatment Assignment 
Patients who meet all criteria for enrollment will be randomized in a 1:1 ratio (MP-101:placebo) 
to double-blind treatment at Visit 2 (Week 0).  Assignment to treatment arms will be determined 
by a computer-generated random sequence using an interactive web-response system (IWRS).  
The IWRS will be used to assign blister packs containing double-blind investigational product to 
each patient.  Two bBlister packs (1 for every 2 weeks between visits) will be dispensed at Visits 
2, 4, 5, and 6 and 7 (Weeks 0, 2, 4, and 6, and 8, respectively).  During the patient’s visit, the site 
will access the IWRS for the correct blister pack numbers to dispense. 
7.7 
Concomitant Therapy 
Patients with worsening psychosis or agitation/aggression requiring rescue therapy will be 
withdrawn from the study. 
Table 7.2. 
List of Excluded Medications 
Drug Class 
Analgesics (Opioids, tramadol, ketorolac except occasional use us as needed 
Antiemetics (except occasional use as needed metoclopramide, domperidone, other dopamine receptor 
blockers) 
Antihistamines (except occasional use as needed) bromophenerapine, chlorpheneramine, diphenhydramine) 
Anxiolytics (except lorazepam) 
Buspirone 
Corticosteroids (oral) 
Dopamine agonists 
Eldepryl, selegeline hydrochloride 
Fluorocortisol 
Gastrointestinal antispasmodics (belladonna, dicyclomine, hyoscyamine) 
Herbal supplements with CNS activity 
Including, but not limited to, Ginkgo Biloba, St. John’s Wort, Kava, ephedrine, cycloserine, glycine, 
pregnenolone 
Hydroxyzine (except occasional use as needed) 
Hypnotics 
Lithium 
Psychostimulants (modafanil) 
Rimonabant 
Reserpine 
Skeletal muscle relaxants (except occasional use as neededbaclofen, carpisopradol) 
Sleeping medications (zolpiden, chloral hydrate) 
Steroids (parenteral) 
Triptans 
 
Section 8. 
Discontinuation Criteria 
8.1. 
Discontinuation from Study Treatment 


MP-101-01(b) Clinical Protocol 
Page 65 
MP-101 
8.1.1. Permanent Discontinuation from Study Treatment 
In addition, patients will be discontinued from the investigational product in the following 
circumstances: 
• the occurrence of worsening psychosis and/or agitation or aggression requiring rescue 
therapy 
Section 9. 
Study Assessments and Procedures 
9.1.1. Primary Efficacy Assessment 
The primary endpoint is the response on the NPI-Psychosis subscale items of delusions and 
hallucinations and/or the agitation/aggression domain. 
9.1.2. Secondary Efficacy Assessment 
Following secondary endpoints were removed: Clinical Global Impression of Severity; Cohen 
Mansfield Agitation Inventory (CMAI); Alzheimer’s Disease Cooperative Study-Activities of 
Daily Living Inventory (ADCS-ADL). 
The following endpoint was added: 
Clinical Global Impression of Improvement (CGI-I; Guy et al. 1976) 
The CGI-I is a 7-point scale that requires the clinician to assess how much the patient’s illness 
has improved or worsened relative to baseline (Visit 2).  The scale ranges from 1 (very much 
improved) to 7 (very much worse). 
9.3. 
Exploratory Efficacy Assessment 
Following exploratory endpoint was removed: Alzheimer’s Disease Cooperative Study-Clinical 
Global Impression of Change (ADCS-CGIC). 
The following endpoint was added: 
Zarit Burden Interview-22 (ZBI-22; Zarit et al. 1980) 
Changes in caregiver burden will be assessed using the Zarit Burden Interview-22 (ZBI-22).  The 
ZBI-22 is a 22-point scale used to assess caregiver burden in the dementia patient population 
(Zari et al. 1980). Each of the 22 items is rated on a scale of 0 to 4, where 0 = never, 1 = rarely, 2 
= sometimes, 3 = frequently, 4 = nearly always. The total score of the ZBI-22 is the sum of those 
22 items. 
 
9.5.1 Pharmacokinetic Sampling 
PK sample collection scheduled at Week 8 (Visit 7) was moved to Week 10, Visit 8 (2 to 4 hours 
postdose). 
Section 10. 
Statistical Considerations and Data Analysis 
10.1. Sample Size Determination 


MP-101-01(b) Clinical Protocol 
Page 66 
MP-101 
Approximately 200100 patients will be enrolled to enable approximately 16080 evaluable 
patients to complete the study through at least Visit 5 (Week 4).  The sample size was chosen so 
that there is at least a 76 80% chance the trial will show a 65% or greater Bayesian posterior 
probability of at least a 1 point improvementstatistically significant improvement in the response 
rate on the NPI-Psychosis scale (hallucinations plus delusions scores) and/or on the NPI 
agitation/aggression domain in patients treated with MP-101 compared to placebo at 10 weeks 
after the start of treatment..  This assumes a true response rate of 65% in the MP-101 treatment 
group versus 35% in the placebo treatment group, using a one-sided Fisher’s exact test with a 5% 
type 1 error rate.  The operating characteristics of this analysis were studied through simulations, 
with non-informative priors for the parameters of the underlying assumed normal distribution of 
the scores. 
10.2. Population Analysis 
Population 
Description 
Evaluable 
All patients in the Intent-to-Treat population who complete at least Visit 5 
(Week 4) with NPI efficacy data. Specifically, patients with a diagnosis of 
psychosis must have at least one psychosis sub-scale score at Visit 5 or later 
and patients with a diagnosis of agitation/aggression must have at least one 
agitation/aggression sub-scale score at Visit 5 or later. 
All patients in the Intent-to-Treat population who complete Visit 5 (Week 4) 
with NPI efficacy data. 
10.3.3. Efficacy Analyses 
10.3.3.1. 
Primary Analyses 
The primary objective of this study will be assessed in the Evaluable population by analyzing the 
change from baseline to the 10-week treatment endpoint of the combined hallucinations and 
delusions scores from the NPI-Psychosis subscale NPI response rates. Response will be defined 
using two NPI endpoints: 1) the psychosis domain score, calculated as the sum of the delusions 
and hallucinations domain scores, and 2) the aggression/agitation domain score. Each domain 
score is the product of the severity and frequency ratings.  
A patient with a 30% improvement from baseline on a subscale will be considered a responder 
for that subscale. At baseline, patients will be given a diagnosis of psychosis and/or 
agitation/aggression. A patient with a psychosis diagnosis will be considered an overall 
responder with a response on the psychosis subscale, a patient with a diagnosis of 
aggression/agitation will be considered an overall responder with a response on the 
aggression/agitation subscale, and a patient with both diagnoses will be considered an overall 
responder with a response on either subscale. 
The primary analysis will use a one-sided Fisher’s exact test with a 5% type 1 error rate. 
The change from baseline to the 10-week time point (Visit 8 [Week 10]) will be estimated using 
repeated measures mixed models assuming data are missing at random, with covariates for 
baseline and the stratification factors.  The Bayesian posterior probability that the mean change 
from baseline MP-101 score is better than the mean change from baseline placebo score by at 


MP-101-01(b) Clinical Protocol 
Page 67 
MP-101 
least 1 point will be calculated.  Non-informative priors for the parameters of the normal 
distribution will be used. 
The precise analysis methods will be detailed in the SAP, which will be completed prior to 
database lock. 
10.3.3.2. 
Secondary Analyses 
The secondary efficacy endpoints will be assessed by analyzing the change from baseline to the 
10-week time point using analysis methods appropriate to the type of measurement. These 
Ssecondary efficacy outcomes include  CGI-IS; NPI Total Score; NPI-Core Total (combination 
of 3 items: hallucinations, delusions, and agitation/aggression); NPI Caregiver Distress-D; NPI 
domain of anxiety, agitation/aggression, and sleep and nighttime behavior disorders; CMAI; 
MMSE; ADCS-ADL; and the UPDRS, Part III. 
The delusions, hallucinations, and aggression/agitation domain scores will be added together to 
form a Core Total score. A patient with a 30% improvement from baseline will be considered a 
responder on the Core Total score. The treatment groups will be compared using a one-sided 
Fisher’s exact test. 
The psychosis and aggression/agitation domain scores, and the Core Total score, will be 
analyzed as continuous measures. 
The change from baseline for quantitative endpoints will be analyzed using repeated measures 
mixed models assuming data are missing at random, with covariates for baseline and the 
stratification factors. 
The CGI-I scores will be analyzed using Cochran-Mantel-Haenszel tests, stratifying by the 
randomization strata, and using modified Ridit scores (i.e. van Elteren tests).  
10.3.3.3. 
Exploratory Analyses 
The exploratory efficacy objectives to determine whether MP-101 is superior to placebo in 
patient behavior and caregiver burden. Changes in patient behavior will be assessed using 
ADCS-CGIC and NPI domains of depression/dysphoria, elation/euphoria, apathy/indifference, 
disinhibition, irritability/lability, aberrant motor behavior, sleep and nighttime behavior 
disorders, and appetite and eating disorders; MMSE. The analysis methods for the exploratory 
efficacy analyses will be detailed in the SAP. 
The ZBI-22 is being utilized to assess caregiver burden. 
The exposure-response relationships between efficacy and safety endpoints may also be 
explored, as needed, as detailed in the SAP. 
Details of the analyses of exploratory efficacy outcomes will be detailed in the SAP. 
10.3.6. Other Analyses 
10.3.6.1. 
Pharmacogenetics Exploratory Analyses 


MP-101-01(b) Clinical Protocol 
Page 68 
MP-101 
To explore the effect of genotype on the response to MP-101 in AD dementia patients with 
psychosis, genotype data for HTR2A SNP rs7330461, HTR2A SNP rs6313 (102T/C), APOE, 
and other genotypes may be analyzed.  The analysis methods may be detailed in the SAP. 
10.3.7.  
Interim Analysis 
An interim analysis is planned for this trial which will occur after approximately 20 patients have 
completed Visit 5 (Week 4) to evaluate PK and safety.  A second interim analysis may be 
performed to evaluate the futility of finding differences in the efficacy endpoints between 
treatment groups. All interim analysis details, including unblinding, plans and stopping rules for 
the futility analysis, will be documented in the Assessment Committee Charter. 
Section 11. 
References 
List of references was updated in line with the edits made in the main body text. 

SAP_001.pdf: 
 
Statistical Analysis Plan MP-101-01(b) 
Tolerability, Pharmacokinetics, and Efficacy of MP-101 in the Treatment of Patients with 
Dementia-Related Psychosis and/or Agitation and Aggression 
 
NCT03044249 
Approval Date: 20Nov2018 


 
MP-101-01(b) Statistical 
Analysis Plan Version 1 Final.docx 
Electronic Signature Page 
 
 
PPD


 
MP-101-01(b) Statistical 
Analysis Plan Version 1 Final.docx 
EMB Statistical Solutions, LLC 
Confidential and Proprietary 
Effective Date 
Statistical Analysis Plan v1 Final 
Page 2 of 26 
20NOV2018 
 
Please use 11pt Calibri (black) text. 
 
 
 
Statistical Analysis Plan 
MP-101-01(b) 
Tolerability, Pharmacokinetics, and Efficacy of MP-101 in 
the Treatment of Patients with Dementia-Related Psychosis 
and/or Agitation and Aggression 
 
Version 1 Final 
Effective Date: 20 NOV 2018 
 
Prepared for 
Mediti Pharma, Inc. 
Montreal, Quebec, H3B 3X3, Canada 
 
 
 
 
 
 
 
 
 
Prepared by 


Sponsor 
Compound: 
Protocol: 
 
 
 
 
EMB Statistical Solutions, LLC 
Confidential and Proprietary 
Effective Date 
Statistical Analysis Plan v1.1 
Page 3 of 26 
DDMONYYYY 
 
EMB Statistical Solutions, LLC 
55 Corporate Woods 
9300 West 110th Street, Suite 550 
Overland Park, Kansas  66210 


Mediti Pharma, Inc. 
Compound: MP-101 
 
Protocol: MP-101-01(b) 
 
 
EMB Statistical Solutions, LLC 
Confidential and Proprietary 
Effective Date 
Statistical Analysis Plan v1 Final 
Page 4 of 26 
20NOV2018 
 
Table of Contents 
Description 
Page 
ABBREVIATIONS/DEFINITIONS .............................................................................. 6 
1. 
Introduction and Objectives ................................................................................ 7 
1.1. 
Introduction .......................................................................................................... 7 
1.2. 
Study Objectives and Endpoints ......................................................................... 7 
1.3. 
Definition of NPI Response and Core Total Response ...................................... 8 
1.4. 
Sample Size Determination .................................................................................. 9 
2. 
General Statistical Methodology and Conventions ........................................... 9 
2.1. 
General Considerations........................................................................................ 9 
2.2. 
Randomization and Unblinding Plan ............................................................... 10 
2.3. 
Analysis Populations .......................................................................................... 11 
2.4. 
Treatment Groups .............................................................................................. 11 
2.5. 
Definition of Baseline Assessments ................................................................... 12 
2.6. 
Definition of Study Visit ..................................................................................... 12 
2.7. 
Handling of Dropouts and Missing Data .......................................................... 12 
2.8. 
Adjustment for Multiplicity .............................................................................. 13 
2.9. 
Adjustment for Multiple Centers ...................................................................... 13 
2.10. Adjustment for Covariates ................................................................................ 13 
2.11. Subgroup Analyses ............................................................................................. 13 
2.12. Coding of Concomitant Medications and Adverse Events ............................. 14 
2.13. Computation of Questionnaire Scores .............................................................. 14 


Mediti Pharma, Inc. 
Compound: MP-101 
 
Protocol: MP-101-01(b) 
 
 
EMB Statistical Solutions, LLC 
Confidential and Proprietary 
Effective Date 
Statistical Analysis Plan v1 Final 
Page 5 of 26 
20NOV2018 
3. 
Interim Analyses ................................................................................................. 15 
4. 
Patient Characteristics ....................................................................................... 16 
4.1. 
Patient Disposition .............................................................................................. 16 
4.2. 
Protocol Violations ............................................................................................. 16 
4.3. 
Demographics and Baseline Assessments......................................................... 16 
4.4. 
Concomitant Medications .................................................................................. 16 
5. 
Efficacy Analyses ................................................................................................ 17 
5.1. 
Primary Analysis ................................................................................................ 17 
5.2. 
Secondary Analyses ............................................................................................ 17 
5.3. 
Exploratory Analyses ......................................................................................... 18 
6. 
Safety Analyses ................................................................................................... 18 
6.1. 
Study Medication Exposure and Treatment Compliance .............................. 18 
6.2. 
Adverse Events .................................................................................................... 19 
6.3. 
Clinical Laboratory Analyses ............................................................................ 20 
6.4. 
Vital Signs and Weight ....................................................................................... 21 
6.5. 
Electrocardiograms ............................................................................................ 21 
6.6. 
Other Safety Analyses ........................................................................................ 21 
7. 
Pharmacokinetic Analyses ................................................................................. 21 
8. 
Reporting Conventions ...................................................................................... 23 
9. 
Schedule of Assessments .................................................................................... 24 
References ....................................................................................................................... 26 
 
 
 


Mediti Pharma, Inc. 
Compound: MP-101 
 
Protocol: MP-101-01(b) 
 
 
EMB Statistical Solutions, LLC 
Confidential and Proprietary 
Effective Date 
Statistical Analysis Plan v1 Final 
Page 6 of 26 
20NOV2018 
ABBREVIATIONS/DEFINITIONS 
Abbreviation 
Definition 
AE 
Adverse Event 
CRP 
Clinical Research Physician 
CSR 
Clinical Study Report 
C–SSRS 
Columbia Classification Algorithm for Suicide Assessment 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
Interim Analysis 
An interim analysis is an analysis of clinical study data, separated into treatment 
groups, that is conducted before the final reporting database is created/locked 
ITT 
Intent-to-Treat 
IWRS 
Interactive Web-Response System 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMSE 
Mini-Mental State Exam 
NPI 
Neuropsychiatric Inventory 
PK 
Pharmacokinetics 
PT 
Preferred Term 
QD 
Once daily  (quaque die) 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SOC 
System Organ Class 
TEAE 
Treatment Emergent Adverse Event 
TUG 
Timed Up and Go 
UPDRS Part III 
Unified Parkinson’s Disease Rating Scale, Part III 
WHODD 
World Health Organization Drug Dictionary 
ZBI-22 
Zarit Burden Interview - 22 
 
 
 


Mediti Pharma, Inc. 
Compound: MP-101 
 
Protocol: MP-101-01(b) 
 
 
EMB Statistical Solutions, LLC 
Confidential and Proprietary 
Effective Date 
Statistical Analysis Plan v1 Final 
Page 7 of 26 
20NOV2018 
1. 
INTRODUCTION AND OBJECTIVES 
1.1. 
Introduction 
Study MP-101-01(b) is a Phase 2, multicenter, double-blind, 1:1 randomized, parallel, placebo-controlled, 
10-week study of MP-101, consisting of screening, treatment, and follow-up periods, in patients with 
dementia-related psychosis and/or agitation and aggression.  
This statistical analysis plan (SAP) describes the analysis variables and statistical procedures that will be 
used to analyze and report the results from Protocol MP-101-01(b), which was approved on 13 February 
2017.  
Some of the analyses detailed here may be more explicit or in some aspects different from those stated in 
the protocol. In case of differences, this SAP supersedes the statistical sections in the protocol.  
Changes to the protocol that impact the design, the data collected, or the statistical methods and that occur 
after the finalization of this SAP may require amendment of the approved SAP. Similarly, changes to the 
planned analysis variables and/or statistical methods described in the approved SAP may also require 
amendment of the SAP. 
The formats for the tables, listings, and figures described in this SAP are provided in a companion 
document. Changes to the formats of these reports that are decided after the finalization of the SAP will 
not require an amendment. In addition, any additional supportive or exploratory analyses requested after 
SAP approval will not require amendment of the SAP. These additional analyses will be described in the 
clinical study report (CSR).  
See the study protocol for details about the study design, procedures, and schedule of assessments and see 
the electronic case report form (eCRF) for details about variables collected and their possible values. 
The time and events schedule for this study is provided in Section 9. 
EMB Statistical Solutions will have responsibility for performing these analyses. 
1.2. 
Study Objectives and Endpoints 
Table 1 shows the objectives and endpoints of the study. 
Table 1. Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
To test the hypothesis that oral administration of 
once daily (QD) MP-101 will improve psychotic 
symptoms and/or agitation and aggression in 
patients with dementia when compared to 
Change from baseline to 10-week treatment endpoint 
in the Neuropsychiatric Inventory (NPI)-Psychosis 
subscale (combination of 2 items: hallucinations and 
delusions) and/or in the agitation/aggression domain.  


Mediti Pharma, Inc. 
Compound: MP-101 
 
Protocol: MP-101-01(b) 
 
 
EMB Statistical Solutions, LLC 
Confidential and Proprietary 
Effective Date 
Statistical Analysis Plan v1 Final 
Page 8 of 26 
20NOV2018 
Objectives 
Endpoints 
placebo. 
Secondary 
To assess whether MP-101 is superior to 
placebo in the following: neuropsychiatric 
disturbances, caregiver distress, and anxiety. 
Change from baseline to 10-week treatment endpoint 
in the following: Clinical Global Impression of 
Improvement (CGI-I); NPI Total Score; NPI-Core 
Total (combination of 3 items: hallucinations, 
delusions, and agitation/aggression); NPI Caregiver 
Distress; NPI domain of anxiety. 
To determine if MP-101 is safe and tolerable. 
Treatment-emergent adverse events (TEAES); Unified 
Parkinson’s Disease Rating Scale (UPDRS) Part III. 
To assess the PK of MP-101 and its primary 
active metabolite, LY2812223. 
Plasma PK concentrations. 
Exploratory 
To assess whether MP-101 is superior to 
placebo in changes in patient behavior and care-
giver burden. 
Change from baseline to 10-week treatment endpoint 
in the following: NPI domains of 
depression/dysphoria, elation/euphoria, 
apathy/indifference, disinhibition, irritability/lability, 
aberrant motor behavior, sleep and nighttime behavior 
disorders, and appetite and eating disorders; Mini-
Mental State Examination (MMSE); Zarit Burden 
Interview-22 (ZBI-22). 
To explore the effect of HTR2A and ApoE 
genotypes on response to treatment. 
5-hydroxytryptamine serotonin 2A receptor (HTR2A) 
single nucleotide polymorphism (SNP) rs7330461 
genotype data; HTR2A SNP rs6313 (102T/C) 
genotype data; ApoE genotype data. 
To explore exposure-response relationships with 
efficacy and safety clinical endpoints, as 
needed. 
Efficacy and safety clinical endpoints, as needed. 
1.3. 
Definition of NPI Response and Core Total Response 
NPI response will be defined using two NPI endpoints: 1) the psychosis domain score, calculated as the 
sum of the delusions and hallucinations domain scores, and 2) the aggression/agitation domain score. 
Each domain score is the product of the severity and frequency ratings.  


Mediti Pharma, Inc. 
Compound: MP-101 
 
Protocol: MP-101-01(b) 
 
 
EMB Statistical Solutions, LLC 
Confidential and Proprietary 
Effective Date 
Statistical Analysis Plan v1 Final 
Page 9 of 26 
20NOV2018 
A patient with a 30% improvement from baseline on a subscale will be considered a responder for that 
subscale. At baseline, patients will be given a diagnosis of psychosis and/or agitation/aggression. A 
patient with a psychosis diagnosis will be considered an overall responder with a response on the 
psychosis subscale, a patient with a diagnosis of aggression/agitation will be considered an overall 
responder with a response on the aggression/agitation subscale, and a patient with both diagnoses will be 
considered an overall responder with a response on either subscale. 
The delusions, hallucinations, and aggression/agitation domain scores will be added together to form a 
Core Total score. A patient with a 30% improvement from baseline will be considered a responder on the 
Core Total score. 
1.4. 
Sample Size Determination 
Approximately 100 patients will be enrolled to enable approximately 80 evaluable patients to complete 
the study through at least Visit 5 (Week 4).  
The primary analysis will use a one-sided Fisher’s exact test with a 5% type 1 error rate. 
If the NPI response rate in MP-101 treated patients is 30% greater than in placebo treated patients (65% 
vs 35%), with 40 evaluable patients per treatment group there is at least an 80% chance (i.e. Power) that 
MP-101 will demonstrate superiority to placebo. 
The sample size was calculated assuming an expected 20% drop-out rate of patients in each arm prior to 
Week 4, so that 100 patients are planned to be enrolled to arrive at 40 patients/arm (N=80) in the 
Evaluable population.  
2. 
GENERAL STATISTICAL METHODOLOGY AND CONVENTIONS 
2.1. 
General Considerations 
All computations for statistical analyses will be performed using SAS® software, Version 9.4 or later. All 
SAS programs used in the production of statistical summary outputs will be validated with independent 
programming prior to finalization. In addition, all program outputs will be independently reviewed. The 
validation process will be used to confirm that all data manipulations and calculations were accurately 
done. Once validation is complete, a senior statistical reviewer will perform a final review of the 
documents to ensure the accuracy and consistency with this plan and consistency within tables. Upon 
completion of validation and quality review procedures, all documentation will be collected and filed by 
the project statistician or designee. 
Before implementation of parametric methods of analysis, the distribution of analysis variables will be 
examined to determine if model assumptions are satisfied. Transformations or nonparametric methods of 
analysis may be used if warranted. However, in some cases, nonparametric analysis may be the initially 
proposed method due to the expected distribution of response. Whenever alternative methods of analysis 
are required, the description of the new method along with the rationale for its use will be documented in 
the Clinical Study Report (CSR). 


Mediti Pharma, Inc. 
Compound: MP-101 
 
Protocol: MP-101-01(b) 
 
 
EMB Statistical Solutions, LLC 
Confidential and Proprietary 
Effective Date 
Statistical Analysis Plan v1 Final 
Page 10 of 26 
20NOV2018 
Data listings will be sorted by treatment group, investigative site, and patient identification number, and 
patients will be identified in the listings by the investigator number concatenated with the patient number.  
Some patients were enrolled under protocol MP-101-01(a). These patients completed the Cohen-
Mansfield Agitation Inventory questionnaire, Alzheimer’s Disease Cooperative Study - Activities of 
Daily Living Inventory, and Alzheimer’s Disease Cooperative Study - Clinical Global Impression of 
Change. These questionnaires were removed from MP-101-01(b). Data from these questionnaires will not 
be included in tables, listings, or figures but SDTM/AdAM datasets will be created. For the remaining 
instruments, assessments were discontinued at some visits. Data collected at these visits will be included 
in listings, but summary tables will only include the scheduled assessments under the current protocol. 
2.2. 
Randomization and Unblinding Plan 
Cenduit LLC will be responsible for the system that randomly assigns study treatments to patients. 
Assignment to treatment arms will be determined by a computer-generated random sequence using an 
interactive web-response system (IWRS). Randomization will be stratified by baseline MMSE score and 
eGFR value: 
 
MMSE < 16 or MMSE ≥ 16 
 
eGFR < 60 or eGFR ≥ 60 
Members of the Assessment Committee and unblinded teams will gain access to unblinded data, prior to 
the final database lock, in order to perform the interim analyses. Information that may unblind the study 
during the analyses will not be reported to study sites or blinded study team members (including Mediti 
Pharma, Inc. personnel) until the study and all data management activities have been completed at the end 
of the trial, unless there is information study sites need to know for the safety of their patients. Members 
of the Assessment Committee or unblinded teams will not disseminate any information derived from its 
privileged access to the data without the prior written approval of Mediti Pharma, Inc. 
The investigator may determine that unblinding of a patient’s treatment assignment during the trial is 
warranted for medical management of the patient. However, if it is decided that unblinding is warranted, 
every effort should be made to contact the Chorus clinical research physician (CRP) prior to unblinding a 
patient’s treatment assignment unless this could delay emergency treatment of the patient. If a patient’s 
treatment assignment is unblinded for the investigator, Chorus must be notified immediately and the 
patient must be discontinued from the study, unless the investigator obtains specific approval from the 
Chorus CRP for the study participant to continue in the study. Emergency unblinding to the investigator 
for adverse events may be performed through the IWRS, which may supplement or take the place of 
emergency codes generated by a computer drug-labeling system. This option may be used ONLY if the 
patient’s ultimate well-being requires knowledge of the patient’s treatment assignment.  
Analyses will not include patient’s data collected after the time of unblinding. Sensitivity analyses that 
include these data may be performed depending on how much of this data there is.  
Cenduit LLC is responsible for making the randomization file available to the unblinded interim analysis 
team at EMB Statistical Solutions. After the last patient completes the study and all data management 


Mediti Pharma, Inc. 
Compound: MP-101 
 
Protocol: MP-101-01(b) 
 
 
EMB Statistical Solutions, LLC 
Confidential and Proprietary 
Effective Date 
Statistical Analysis Plan v1 Final 
Page 11 of 26 
20NOV2018 
data activities have been completed – data entered, coding completed, and all queries resolved – the 
Chorus Asset Manager or designee and Study Statistician will approve the unblinded interim analysis 
reporting team at EMB Statistical Solutions to release the randomization schedule. 
A list of individuals who become unblinded prior to study completion will be maintained by the 
Assessment Committee chairperson, the Asset Manager, and/or the unblinded statistician at EMB 
Statistical Solutions and will be placed in the final Study Trial Master Files.  
2.3. 
Analysis Populations 
The analysis populations are described in Table 3. 
Table 3. Analysis Populations 
Population 
Description 
Randomized 
All randomized patients who sign informed consent. 
Safety 
All randomized patients who take at least 1 dose of double-blind study treatment. In 
the event of a treatment error, patients will be analyzed according to the treatment 
they actually received. 
Intent-to-Treat 
(ITT) 
All randomized patients who take at least 1 dose of double-blind study treatment and 
have at least one post-baseline efficacy assessment. In the event of a treatment error, 
patients will be analyzed according to the treatment to which they were randomized. 
Evaluable 
All patients in the Intent-to-Treat population who complete at least Visit 5 (Week 4) 
with NPI efficacy scores. Specifically, patients with a diagnosis of psychosis must 
have at least one psychosis sub-scale score at Visit 5 or later and patients with a 
diagnosis of agitation/aggression must have at least one agitation/aggression sub-scale 
score at Visit 5 or later. 
2.4. 
Treatment Groups 
The primary analyses will be performed with patients grouped by treatment arm (i.e. MP-101 or placebo) 
regardless of their final dose level. 
Patients will be randomized to the MP-101 or placebo arm at Visit 2 (Week 0). Patients in the MP-101 
arm will begin dosing at 20 mg once daily (QD) of study drug. If in the opinion of the investigator the 
patient cannot tolerate the initial 20-mg QD dose of study drug (administered for the first week of dosing 
and assessed at or before Visit 3 [Week 1]), the patient will be discontinued from the study. Study drug 
intolerance will be determined by the investigator and includes treatment-emergent adverse events 
(TEAEs) of special interest identified from prior studies, e.g. dizziness, nausea, and vomiting. 
At Visit 3 (Week 1), the dose of MP-101 (or equivalent placebo) will be increased to 40 mg. If 
intolerance is reported at a dose of 40 mg between Visit 3 (Week 1) and Visit 4 (Week 2), the patient will 
be discontinued from the study. 


Mediti Pharma, Inc. 
Compound: MP-101 
 
Protocol: MP-101-01(b) 
 
 
EMB Statistical Solutions, LLC 
Confidential and Proprietary 
Effective Date 
Statistical Analysis Plan v1 Final 
Page 12 of 26 
20NOV2018 
At Visit 4 (Week 2), the dose of MP-101 (or equivalent placebo) will be increased to 60 mg. If 
intolerance is reported at a dose of 60 mg between Visits 4 (Week 2) and Visit 5 (Week 4), the patient 
will be asked to return for an unscheduled visit for down-titration to 40 mg. Patients down-titrated to 40 
mg prior to Visit 5 (Week 4) will remain at this dose for the remainder of the study.  
At Visit 5 (Week 4), the dose of MP-101 (or equivalent placebo) will be maintained at 60 mg. If 
intolerance is reported at a dose of 60 mg at Visit 5 (Week 4), the patient will be down-titrated to 40 mg 
and will remain at this dose for the remainder of the study. If intolerance is reported at a dose of either 40 
mg or 60 mg beyond Visit 5 (Week 4) the patient will be discontinued from the study. 
2.5. 
Definition of Baseline Assessments 
Day 0 (Week 0) is defined in this study as the day of Visit 2. The last assessment made before the first 
dose of study drug will be defined as the Baseline assessment. This should include all assessments made 
on or before Day 0. Adverse events that occurred on Day 0 will be assumed to be treatment-emergent, 
unless the eCRF records that the event started prior to the first dose of study drug. 
2.6. 
Definition of Study Visit 
Patient data will be analyzed according to the nominal visit collected in the eCRF. Unscheduled visits at 
which safety data is collected (e.g. labs and ECGs) may result in clinically significant findings or 
withdrawal, which will be included in adverse event and/or disposition summaries. 
2.7. 
Handling of Dropouts and Missing Data 
Dates 
Imputation of missing or partial dates is not expected, but if a complete date is required for calculations, 
the following algorithms will be applied:  
 
For the start date:  
- If year, month, and day are missing then use the minimum of the patient's first visit date or the 
consent date.  
- If either only month or month and day are missing then use January 1.  
- If only day is missing, impute the first day of the month.  
 
For the end date:  
- If year, month, and day are missing then use the patient's last visit date.  
- If either only month or month and day are missing then use December 31.  
- If only day is missing then use the last day of the month.  
- Do not expand the record past the patient's last visit.  


Mediti Pharma, Inc. 
Compound: MP-101 
 
Protocol: MP-101-01(b) 
 
 
EMB Statistical Solutions, LLC 
Confidential and Proprietary 
Effective Date 
Statistical Analysis Plan v1 Final 
Page 13 of 26 
20NOV2018 
The original missing or partial date, the imputed complete date, and the indicator variable that indicates 
which dates were imputed will be retained in the database. 
NPI Response 
Patients whose response to treatment cannot be determined due to missing data (including early 
withdrawal) will be considered non-responders.  
2.8. 
Adjustment for Multiplicity 
There are no planned adjustments for multiple efficacy endpoints or analyses. 
2.9. 
Adjustment for Multiple Centers 
Differences between study centers will be not be incorporated into the statistical analyses for this study. 
There are no plans to analyze data within centers. 
2.10. Adjustment for Covariates 
Where possible, analyses will adjust for the baseline value of the endpoint and by the four baseline 
randomization strata, i.e.:  
 
MMSE < 16, eGFR < 60  
 
MMSE < 16, eGFR ≥ 60 
 
MMSE ≥ 16, eGFR < 60 
 
MMSE ≥ 16, eGFR ≥ 60 
2.11. Subgroup Analyses 
Subgroup analyses based on diagnosis (i.e. Psychosis and Agitation/aggression) at baseline will be 
performed for the NPI response rate. Other subgroup analyses may be performed. For purposes of 
analysis, a patient’s baseline NPI scores will be used for diagnosis.  
Specifically, a patient will be included in the Psychosis subgroup if at least ONE of the following is true 
at baseline: 
 
NPI score of ≥ 4 on either delusions or hallucinations individual items 
 
NPI score of ≥ 6 on the Psychosis Subscale (combined delusions and hallucinations) 
A patient will be included in the Agitation/aggression subgroup if the following is true at baseline: 
 
NPI score of ≥ 4 on agitation/aggression domain 
A patient can be in both subgroups. 


Mediti Pharma, Inc. 
Compound: MP-101 
 
Protocol: MP-101-01(b) 
 
 
EMB Statistical Solutions, LLC 
Confidential and Proprietary 
Effective Date 
Statistical Analysis Plan v1 Final 
Page 14 of 26 
20NOV2018 
2.12. Coding of Concomitant Medications and Adverse Events 
Adverse events (AEs) will be coded using the Medical Dictionary for Regulatory Activities (MedDRA), 
and concomitant medications will be coded using the World Health Organization Drug Dictionary 
(WHODD). The versions of the dictionaries used for reporting will be provided in the CSR. 
2.13. Computation of Questionnaire Scores 
Neuropsychiatric Inventory (Cummings et al. 1994) 
Ten behavioral and 2 neurovegetative areas (i.e. domains) are included in the NPI: delusions, 
hallucinations, agitation/aggression, depression/dysphoria, anxiety, elation/euphoria, apathy/indifference, 
disinhibition, irritability/lability, aberrant motor behavior, sleep and nighttime behavior disorders and 
appetite and eating disorders. An initial question assesses the 10 items and 2 neurovegetative evaluations 
of the scale. If the answer to the initial question is ‘no’, no further questions are pursued. If the answer is 
‘yes’, sub questions are asked; ratings of the frequency and severity of the behavior(s) are determined by 
the caregiver according to the criteria provided with each behavior. Distress induced in the caregiver by 
each behavior is also rated. Therefore, a total of 3 scores are recorded for each behavior type: frequency, 
severity, and caregiver distress. A domain score will be computed as the product of the frequency and 
severity scores. A domain score will only be computed if the frequency and severity scores are non-
missing. 
The psychosis domain score will be calculated as the sum of the delusions and hallucinations domain 
scores. If either domain score is missing, the psychosis domain score will be set to missing.  
The 10-item Total score will be calculated as the sum of all individual NPI domain scores, except for the 
sleep and appetite domains. If any individual domain score is missing, the Total score will be set to 
missing. 
Clinical Global Impression of Improvement (Guy, 1976) 
The CGI-I is a 7-point scale that requires the clinician to assess how much the patient’s illness has 
improved or worsened relative to baseline (Visit 2). The scale ranges from 1=very much improved to 
7=very much worse. 
Mini-Mental State Examination (Folstein et al., 1975) 
The MMSE is a simple, 30-question, pen-and-paper test that evaluates attention, orientation, memory, 
registration, recall, calculation, language, and the ability to draw a complex polygon. The range for the 
total MMSE score (i.e. the total number of correctly answered items) is 0 to 30, with lower scores 
indicating greater impairment. If any individual item is missing, the MMSE score will be set to missing. 
Unified Parkinson’s Disease Rating Scale Part III (Fahn, 1987) 
Part III of the UPDRS is an investigator-scored scale used to assess the motor symptoms of patients with 
Parkinson's disease. The investigator rates the patient on 14 items based on observation or the 
performance of a task the patient performs (even in the context of any comorbidities) on a 5-point scale. 


Mediti Pharma, Inc. 
Compound: MP-101 
 
Protocol: MP-101-01(b) 
 
 
EMB Statistical Solutions, LLC 
Confidential and Proprietary 
Effective Date 
Statistical Analysis Plan v1 Final 
Page 15 of 26 
20NOV2018 
The scores range from 0 to 4, with higher scores indicate greater impairment. The total UPDRS score will 
be calculated as the sum of all items. If any individual item is missing, the UPDRS score will be set to 
missing. 
Note that patients who enrolled under protocol MP-101-01(a) were to complete the UPDRS at baseline, at 
Weeks 2 and 10, the follow-up visit, and (possibly) at the early termination visit. For protocol MP-101-
01(b), the Week 2 visit was moved to Week 4. For purposes of analysis, the Week 2 and Week 4 data will 
be summarized together as “Week 2/4”. 
Zarit Burden Interview-22 (Zarit et al., 1980) 
Changes in caregiver burden will be assessed using the Zarit Burden Interview-22 (ZBI-22). The ZBI-22 
is a 22-point scale used to assess caregiver burden in the dementia patient population. Each of the 22 
items is rated on a scale of 0 to 4, where 0 = never, 1 = rarely, 2 = sometimes, 3 = frequently, 4 = nearly 
always. The total score of the ZBI-22 is the sum of these 22 items. 
Columbia Suicide Severity Rating Scale 
Any occurrence of suicide-related thoughts and behaviors will be assessed using the C-SSRS, a scale that 
captures the occurrence, severity, and frequency of suicide-related thoughts and behaviors during the 
corresponding assessment period. The scale includes suggested questions to elicit the type of information 
needed to determine if a suicide-related thought or behavior occurred. 
The first time the scale is administered in this study, the C-SSRS “Lifetime/Recent-Clinical” version will 
be used, and the findings will constitute the baseline assessment. The “Since Last Visit-Clinical” version 
will be used for all subsequent assessments. If a suicide-related thought or behavior is identified at any 
time during the study, a thorough evaluation will be performed by a study physician, and appropriate 
medical care will be provided. If, based on administration of the C-SSRS, it is determined that suicide-
related behaviors have occurred, the additional information will be collected to allow for a more complete 
assessment of these behaviors. 
Only listings will be created from the individual C-SSRS items. 
3. 
INTERIM ANALYSES 
An interim analysis of safety and PK data will be performed after approximately 20 patients have 
completed Visit 5 (Week 4). In order to minimize the operational and statistical bias that result from 
performing an interim analysis, the interim analysis for this study will be conducted under the auspices of 
an Assessment Committee (AC). The purpose of the AC is to advise the Sponsor regarding the continuing 
safety of study participants and the ongoing scientific validity and integrity of the trial. 
No statistical tests will be performed on the data from the interim safety/PK analysis, and no adjustments 
will be made to the final analysis because of the interim safety/PK analysis.  
Displays used the in the interim safety/PK analysis will be a subset of those used in the final analysis 
(except for one PK figure), so that the description of the display will be included in this SAP.  


Mediti Pharma, Inc. 
Compound: MP-101 
 
Protocol: MP-101-01(b) 
 
 
EMB Statistical Solutions, LLC 
Confidential and Proprietary 
Effective Date 
Statistical Analysis Plan v1 Final 
Page 16 of 26 
20NOV2018 
A second interim analysis may be performed to evaluate the futility of finding differences in the NPI 
response rates between treatment groups.  
All interim analysis details, including unblinding plans and stopping rules for the futility analysis, will be 
documented in the AC Charter.  
4. 
PATIENT CHARACTERISTICS 
4.1. 
Patient Disposition 
The disposition of all randomized patients will be presented. The number of patients will be presented by 
population, by randomization strata, and by last scheduled visit previous to withdrawal. In addition, the 
reason for study discontinuation will be tabulated for the overall population and by treatment group using 
the list of reasons provided in the eCRF. 
4.2. 
Protocol Violations 
A list of protocol violations that could potentially impact the analysis of the study will be determined 
during the conduct of the study by study team members who are blinded to study treatment being 
received. These will be presented in a listing.  
4.3. 
Demographics and Baseline Assessments 
Patient’s baseline age, gender, race, height, body weight, body mass index, MMSE score, other baseline 
efficacy measures, initial disease history and pre-existing conditions, and eGFR values will be 
summarized using descriptive statistics by treatment arm and overall. These summaries will be based on 
the Safety population. Patients who are missing measurements of the baseline variable being analyzed 
will not be included in the summary for that variable. 
A summary will be made by age categorized as 50-64, 65-84, and 85 or older. 
Results of examinations of Hepatitis B surface antigen, Hepatitis C antibody, and HIV results, and 
substance use will be included in listings. 
Patient height and weight will be collected prior to randomization. Both variables will be reported in 
metric units (height in cm and weight in kg) and will be summarized as continuous variables along with 
Body Mass Index (in kg/m2).  
No statistical testing will be performed for comparisons of baseline characteristics. 
4.4. 
Concomitant Medications 
Concomitant medications will be defined as medications taken on or after the date of the first dose of 
study treatment. This includes all medications initially taken prior to the date of first dose of study 
treatment but with a stop date that is either missing or after the date of first dose of study treatment. Those 
medications where the stop date is documented as prior to the date of first dose of study treatment will be 
classified as prior medications. The prior medications will not be included in any summary reports. 


Mediti Pharma, Inc. 
Compound: MP-101 
 
Protocol: MP-101-01(b) 
 
 
EMB Statistical Solutions, LLC 
Confidential and Proprietary 
Effective Date 
Statistical Analysis Plan v1 Final 
Page 17 of 26 
20NOV2018 
The percent of patients who receive each concomitant medication, based on the WHODD preferred drug 
name, will be tabulated. By-patient listings of all concomitant medications that includes WHODD 
preferred drug names will be prepared. 
5. 
EFFICACY ANALYSES 
5.1. 
Primary Analysis 
The primary analysis of the NPI response rate will use a one-sided Fisher’s exact test with a 5% type 1 
error rate. The lower 95% confidence limit of the difference in NPI response rates (MP-101 minus 
Placebo) will be calculated using an exact unconditional confidence interval. 
Supporting Analyses 
A supporting analysis of the NPI response endpoint will be performed using a Cochran-Mantel-Haenszel 
test, stratifying by the randomization strata.  
5.2. 
Secondary Analyses 
Summary statistics of all domains of the NPI will be computed for the observed and change from baseline 
values in the Evaluable and ITT populations. Summaries of other secondary endpoints will be computed 
for the observed and change from baseline values in the Evaluable population.  
Supporting analyses of the secondary endpoints may be performed stratifying by randomization strata if 
there are sufficient numbers of patients within each strata. 
Quantitative Endpoints 
The quantitative secondary efficacy endpoints will be assessed by analyzing the change from baseline to 
the 10-week time point in the Evaluable population using PROC MIXED to model the difference in the 
Week 10 change from baseline score between treatment groups and to handle missing assessments. The 
change from baseline to each scheduled post-baseline visit will be estimated using repeated measures 
mixed models assuming data are missing at random, with covariates for baseline and visit. The lower 95% 
confidence limit of the difference in mean scores at Week 10 (MP-101 minus Placebo) will be estimated 
from the mixed model. The effects of baseline domain scores and treatment will be allowed to vary across 
visits. The following SAS code will be used, for assessments at Weeks 2, 4, 6, and 10. For patients who 
withdraw prior to Week 10, NPI data from the early termination visit will be used as the next visit’s 
assessment; for example, if a patient’s last scheduled assessment is at Week 4, the early termination data 
will be included in the analysis as Week 6. 
proc mixed; 
  class visit treatment patient; 
  model psychosis=visit*baseline visit*treatment / s; 
  repeated visit / type=vc subject=patient; 
  random patient; 
  estimate ‘Trt Effect, week 10’ visit*treatment 0 0 0 0 0 0 1 -1/cl alpha=.10; 
run; 


Mediti Pharma, Inc. 
Compound: MP-101 
 
Protocol: MP-101-01(b) 
 
 
EMB Statistical Solutions, LLC 
Confidential and Proprietary 
Effective Date 
Statistical Analysis Plan v1 Final 
Page 18 of 26 
20NOV2018 
In addition, plots of each least squares mean domain score (± standard error) for the psychosis, delusions, 
hallucinations, agitation/aggression, and total scores by scheduled visit will be created.  
Ordinal Endpoints 
The Core Total Score response rate will be analyzed using a one-sided Fisher’s Exact test. The lower 95% 
confidence limit of the difference in Core Total Score response rates (MP-101 minus Placebo) will be will 
be calculated using an exact unconditional confidence interval. The CGI-I will be analyzed using 
Cochran-Mantel-Haenszel tests using modified Ridit scores (i.e. van Elteren tests).  
5.3. 
Exploratory Analyses 
The exploratory efficacy objectives to determine whether MP-101 is superior to placebo in patient 
behavior and caregiver burden will be assessed using the same methods as the secondary endpoints. 
The effect of HTR2A and ApoE genotypes on response to treatment, and the exposure-response 
relationships between efficacy and safety endpoints, may also be explored, as needed. If performed, these 
analyses will be described in the CSR. 
6. 
SAFETY ANALYSES 
All analyses of safety including the extent of exposure to study medication will be performed using the 
Safety population. 
6.1. 
Study Medication Exposure and Treatment Compliance 
Extent of Exposure 
Patient exposure to study drug will be summarized by the duration of dose administration, the cumulative 
total dose while in the trial, and the maximum dose taken. 
Study drug is administered on site at each visit the dose level is changed, except Visit 2. The last dose 
will be assumed to have been administered on the day before each drug accountability visit. Therefore, 
duration of dosing will be calculated as the numbers of days (inclusive) between the first day study drug 
was taken and the last day study drug was taken. Missing start or end dates will not be imputed. 
MP-101 will be provided in a wallet design (blister pack) containing blister strips. Blister packs will be 
dispensed at Visits 2, 4, 5, and 6 (Weeks 0, 2, 4, and 6, respectively). Each wallet will contain 9 rows of 3 
capsules each. For the 20mg active dose, each row contains 1 capsule of active drug and 2 placebo 
capsules. For the 40mg active dose, each row contains 2 capsules of active drug and 1 placebo capsule. 
For the 60mg active dose, each row contains 3 capsules of active drug. For patients in the placebo arm, all 
capsules contain placebo. 
The number of capsules taken will be assumed to be 27 times the number of kits dispensed minus the 
number of capsules returned. For patients while on the 20mg and 40mg dose levels, it will not be possible 
to know how many active drug capsules were consumed if only partial doses were taken. Therefore, the 
cumulative total dose taken will be approximated as: 


Mediti Pharma, Inc. 
Compound: MP-101 
 
Protocol: MP-101-01(b) 
 
 
EMB Statistical Solutions, LLC 
Confidential and Proprietary 
Effective Date 
Statistical Analysis Plan v1 Final 
Page 19 of 26 
20NOV2018 
20*(1/3)*(number of capsules taken while at the 20mg dose level) +  
40*(2/3)*(number of capsules taken while at the 40mg dose level) +  
60*(number of capsules taken while at the 60mg dose level) 
Treatment Compliance 
Patient compliance with investigational product will be assessed at each visit by direct questioning and 
documentation of returned capsules. The number of days where a complete dose was not taken will be 
recorded and the total number of completed doses missed for each patients will be summarized along with 
extent of exposure. 
Patients who are noncompliant should be discontinued from the study. The number of patients who were 
withdrawn from the trial for significant non-compliance will be included in the summary of patient status. 
6.2. 
Adverse Events 
Investigators will monitor the safety of patients and will be responsible for their medical care during the 
study. The investigator will interpret and document clinically significant signs and symptoms along with 
any change in conditions and will indicate whether each event is serious or otherwise medically 
important, considered related to the study medication, or if it caused the patient to discontinue the study 
medication before completing the study. The patient will be followed until the event resolves, stabilizes 
with appropriate diagnostic evaluation, or is reasonably explained.  
No statistical testing will be performed for comparisons of AEs. 
Summaries of AEs will include the number of patients with at least one AE for each treatment group. 
When reporting by system organ class (SOC) and preferred term (PT), the reports will present the SOC in 
alphabetical order; while PTs within the SOC will be presented in order of overall decreasing frequency 
of occurrence in the MP-101 treatment group. A patient with multiple AEs (different PTs) coded to the 
same SOC will be counted only once for that SOC, but will be counted each time for different PTs within 
that SOC. A patient with separate events of the same PT (different start/stop dates) will be counted only 
once in the frequency tables for that PT. 
Treatment-Emergent Adverse Events 
Treatment-emergent adverse events (TEAE) include all adverse events that emerge or worsen after taking 
the first dose of study drug. TEAEs will be summarized for each treatment group by SOC and PT, and by 
PT in order of decreasing frequency of MP-101 preferred term. 
Serious Adverse Events 
Treatment-Emergent SAEs will be summarized for each treatment arm by SOC and PT. These reports 
will also include the total number of SAE for each SOC and PT.  


Mediti Pharma, Inc. 
Compound: MP-101 
 
Protocol: MP-101-01(b) 
 
 
EMB Statistical Solutions, LLC 
Confidential and Proprietary 
Effective Date 
Statistical Analysis Plan v1 Final 
Page 20 of 26 
20NOV2018 
Treatment-Emergent Adverse Events Resulting in Death 
If there are any TEAEs that result in death, a listing of all deaths will be provided. In addition, a summary 
table may also be created by PT in order of decreasing frequency of MP-101 preferred term. 
Treatment-Emergent Adverse Events Leading to Study Discontinuation 
TEAEs for which the action taken with medication is ‘Drug Withdrawal’ will be identified as TEAEs that 
lead to study discontinuation. The TEAEs that lead to study drug discontinuation will be summarized for 
each treatment group by SOC and PT for the Safety population. A by-patient listing of the TEAEs that 
lead to study drug discontinuation will also be provided. 
Treatment-Related Treatment-Emergent Adverse Events 
Every AE will be assessed by the investigator for its relationship to the randomly assigned study 
medication. The subset of TEAEs considered by the investigator as either possibly, probably, or definitely 
related to study treatment will be summarized as drug-related TEAEs by SOC and PT. 
Treatment-Emergent Adverse Events by Maximal Severity 
Every AE will be graded by the investigator as mild, moderate, or severe, so for each patient the greatest 
severity observed can be obtained by comparing the severity of all of a patient’s TEAEs that share the 
same SOC or PT. A table of TEAEs by maximal severity will be prepared for each treatment arm by SOC 
and PT.  
Treatment-Emergent (Not Including Serious) Adverse Events 
The most common non-serious TEAEs will be summarized. All PT that occur in at least 5% of the Safety 
Population patients in any treatment group, when not counting the serious TEAEs, will be tabulated by 
SOC and PT for each treatment group. These reports will also present the total number of TEAEs for each 
SOC and PT. 
Treatment-Emergent Adverse Events of Special Interest 
The TEAEs of special interest – with preferred terms grouped in the categories of dizziness, nausea, and 
vomiting – will be identified prior to unblinding and summarized. This summary will also present the 
total number of TEAEs for each category and PT.  
6.3. 
Clinical Laboratory Analyses 
At each time point, the change from baseline will be derived for each numeric laboratory parameter. 
Descriptive statistics for the value of each parameter at each time point and the change from baseline for 
each parameter at each post-dose time point will be provided by treatment group. A 95% confidence 
interval for the change from baseline will be computed for each treatment group using a large-sample T-
statistic approximation; the Normality assumption will not be checked. 
The number of patients discontinued due to abnormal liver laboratory assessments will be summarized. 


Mediti Pharma, Inc. 
Compound: MP-101 
 
Protocol: MP-101-01(b) 
 
 
EMB Statistical Solutions, LLC 
Confidential and Proprietary 
Effective Date 
Statistical Analysis Plan v1 Final 
Page 21 of 26 
20NOV2018 
6.4. 
Vital Signs and Weight 
At each time point, the change from baseline will be derived for each numeric vital sign parameter. 
Descriptive statistics for the value of each parameter at each time point and the change from baseline for 
each parameter at each post-dose time point will be provided by treatment group. 
6.5. 
Electrocardiograms 
At each time point, the change from baseline will be derived for each numeric ECG parameter. 
Descriptive statistics for the value of each parameter at each time point and the change from baseline for 
each parameter at each post-dose time point will be provided by treatment group. 
The number (percent) of patients who have an extreme QTcF value at any time while on treatment will be 
tabulated by treatment group. Extreme QTcF values will be determined using the following criteria:  
 
QTcF  ≥ 500 msec 
 
QTcF  ≥ 550 msec 
 
Change from baseline in QTcF ≥ 30 msec 
 
Change from baseline in QTcF ≥ 60 msec. 
All on-treatment values, including unscheduled assessments, will be considered. 
6.6. 
Other Safety Analyses 
Gait and balance will be assessed with the Timed Up and Go (TUG) test. At each time point, the change 
from baseline will be derived for the time to perform the task. Descriptive statistics for the value at each 
time point and the change from baseline at each post-dose time point will be provided by treatment group. 
The number of patients with any post-baseline clinically significant results of physical or neurological 
exams will be summarized. Any data captured by the C-SSRS will be included in by-patient listings. 
7. 
PHARMACOKINETIC ANALYSES 
At the visits specified in the Schedule of Activities (Section 9), venous blood samples will be collected 
from all patients, for a total of 5 scheduled samples per patient, to determine the plasma concentrations of 
MP-101 and its primary active metabolite LY2812223. The sparse sampling scheme in Table 2 will be 
used. The scheduled time for the 2 to 4 hour assessment was changed from Week 8 to Week 10 in 
Amendment b of the protocol. The concentration data will be summarized according to the time interval, 
ignoring differences in week or visit collected.  


Mediti Pharma, Inc. 
Compound: MP-101 
 
Protocol: MP-101-01(b) 
 
 
EMB Statistical Solutions, LLC 
Confidential and Proprietary 
Effective Date 
Statistical Analysis Plan v1 Final 
Page 22 of 26 
20NOV2018 
Table 2: Plasma Pharmacokinetic Sampling Scheme 
Week 
Visit 
Sample Collection Time Intervals 
2 
4 
4 to 8 hours post-dose 
4 
5 
Pre-dose and 0 to 2 hours post-dose 
6 
6 
8 to 12 hours post-dose 
8/10 
7/8 
2 to 4 hours post-dose 
The actual sample collection date and time (24-hour clock time) must be recorded, as well as the actual 
date and time of the 2 most recent doses. If a patient discontinues early, a sample should be taken at the 
early termination visit, if possible. Additional PK samples may be collected at additional time points 
during the study. 
In the case of unscheduled PK samples or samples taken at the early termination visit, the actual time 
from the last dose to the PK sample will be calculated and the concentration assigned to the appropriate 
time interval. 
The plasma concentrations of MP-101 and LY2812223 will be summarized using descriptive statistics: n, 
mean, standard deviation, coefficient of variation, minimum, median, maximum, geometric mean, and 
geometric coefficient of variation. In addition, the following figures will be created: 
1) Plots of individual QTcF absolute values (y-axis) versus plasma drug concentrations (x-axis). 
Separate figures for MP-101 concentrations and LY2812223 concentrations. 
Different symbols will be used to denote the dose level the patients were on at the time of the PK 
assessment. The least-squares regression line of QTcF versus concentration will be added to the 
plot, by dose level if there are a sufficient number of patients at more than one dose level. All 
data points will be included in a single plot. 
2) Plots of individual change from baseline QTcF values (y-axis) versus plasma drug concentrations 
(x-axis). Separate figures for MP-101 and LY2812223 concentrations. Different symbols will be 
used to denote the dose level the patients were on at the time of the PK assessment. A least-
squares regression line of QTcF versus concentration will be added to the plot, by dose level if 
there are a sufficient number of patients at more than one dose level. All data points will be 
included in a single plot. This plot will be similar to the plot of absolute QTcF values versus 
concentration.  
3) Plots of individual screening eGFR values (y-axis) versus individual average of dose normalized 
plasma drug concentrations (x-axis). Separate figures for MP-101 and LY2812223 
concentrations. For each patient, all concentrations will be dose normalized and averaged; that is, 
the concentration will be divided by the dose the patient was on at the time of the assessment, and 
all the dose-normalized concentrations will be averaged. This resulting average concentration 
value will be plotted; all data points will be included in a single plot.  
4)  [For the safety interim analysis only.] Plot of individual plasma drug concentrations (y-axis) as a 
function of time from last dose (x-axis). Separate figures for MP-101 and LY2812223 
concentrations. All dose groups overlaid and uniquely labelled. 


Mediti Pharma, Inc. 
Compound: MP-101 
 
Protocol: MP-101-01(b) 
 
 
EMB Statistical Solutions, LLC 
Confidential and Proprietary 
Effective Date 
Statistical Analysis Plan v1 Final 
Page 23 of 26 
20NOV2018 
a. For the interim analysis, there should be 3 assessments for each patient, which will be 
plotted at the following mid-points of the nominal time intervals: 0 = Visit 5/pre-dose 
values, 1 = Visit 5/0-2hr post-dose value, 6 = Visit 4/4-8hr post-dose value. All 
assessments from all patients will be included on the same figure, but the patients will not 
be differentiated. Different symbols will be used to denote the dose level the patients 
were on at the time of the PK assessment. 
b. For the final analysis, the data will be evaluated using population PK/PD modeling 
techniques, by a vendor approved by the Sponsor.  Data from this study may be 
combined with data from previous studies to develop the model. 
8. 
REPORTING CONVENTIONS 
The following conventions will be applied to all data presentations and analyses:  
 
Continuous variables will generally be summarized by the number of patients, mean, standard 
deviation, median, minimum, and maximum.  
 
Categorical variables will be summarized by the number and percentage of patients within each 
category. 
 
All mean and median values will be formatted to one more decimal place than the measured value. 
 
Standard deviation values will be formatted to two more decimal places than the measured value. 
 
Minimum and maximum values will be presented with the same number of decimal places as the 
measured value. 
 
The number and percent of responses will be presented in the form XX (XX %), where the percentage 
is in parentheses. Percentages will be rounded to the nearest percent. In the case of a frequency of 
zero, the frequency and percentage will be presented as 0 rather than 0 (0%). 
 
All summary tables will include the analysis population sample size (i.e. number of patients) in each 
treatment group. 
 
Date variables will be formatted as ddMMMYY for presentation. 
For PK data, the geometric coefficient of variation will be calculated assuming the data follow a log-
Normal distribution. That is, let X = concentration.  
If Y = log[X] has a Normal distribution with  
E[Y] = μ and Var[Y] = σ2,  
then X has a log-Normal distribution with  
E[X] = exp[μ + .5*σ2] = exp[μ]*exp[.5*σ2]  


Mediti Pharma, Inc. 
Compound: MP-101 
 
Protocol: MP-101-01(b) 
 
 
EMB Statistical Solutions, LLC 
Confidential and Proprietary 
Effective Date 
Statistical Analysis Plan v1 Final 
Page 24 of 26 
20NOV2018 
and  
Var[X] = exp[2μ + 2*σ2] – exp[2μ + σ2] = exp[2μ]*exp[σ2]*(exp[σ2] – 1) 
so 
SD[X] =exp[μ]*exp[.5*σ2]*sqrt(exp[σ2] – 1) 
Therefore, CV[X] = SD[X]/E[X] = sqrt(exp[σ2] – 1). The log-transformed concentration values will be 
computed and the coefficient of variation calculated using the sample variance.  
 
 
9. 
SCHEDULE OF ASSESSMENTS 
 
Screen 
Treatment Period (10 Weeks) 
Follow-
up 
 
 
ET 
Visit Number 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
Week 
-1 to -5 
0 
1 
2 
4 
6 
8 
10 
11 
Days from Randomization (target) 
-1 to-35 
0 
7 
14 
28 
42 
56 
70 
77 
Visit Window (± days from target) 
 
 
 
2 
2 
2 
 
2 
2 
Study site visit 
x 
x 
 
x 
x 
x 
 
x 
x 
x 
Informed Consent 
(before any procedures/tests) 
x 
 
 
 
 
 
 
 
 
 
Clinical Assessments 
Demographics, height 
x 
 
 
 
 
 
 
 
 
 
Weight 
x 
x 
 
x 
x 
x 
 
x 
x 
x 
Vital signs (BP and pulse) 
x 
x 
 
x 
x 
x 
 
x 
x 
x 
Medical history and physical exam 
x 
 
 
 
 
 
 
 
 
 
Neurological exams 
x 
x 
 
 
 
 
 
x 
 
x 
TUG (if applicable) 
x 
x 
 
x 
x 
x 
 
x 
x 
 
Concomitant medications 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Inclusion/exclusion review 
x 
x 
 
 
 
 
 
 
 
 
Hepatitis B surface antigen, 
Hepatitis C antibody, HIV 
x 
 
 
 
 
 
 
 
 
 
Randomization 
 
x 
 
 
 
 
 
 
 
 
Investigational product dispensing 
 
x 
 
x 
x 
x 
 
 
 
 
Dose administration at site 
 
x 
 
x 
x 
 
 
 
 
 
Investigational product 
accountability 
 
 
 
x 
x 
x 
 
x 
 
x 
Symptom directed physical exam 
 
x 
 
x 
x 
x 
 
x 
x 
x 
Habits (alcohol, caffeine, nicotine, 
tobacco) 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
Safety Measures 
Adverse event assessment 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
C–SSRS 
x 
x 
 
x 
x 
x 
 
x 
x 
x 
Single 12-lead ECG 
x 
x 
 
x 
x 
 
 
x 
x 
x 
Efficacy and Outcome Measures 
NPI 
x 
x 
 
x 
x 
x 
 
x 
x 
x 
CGI-S 
 
x 
 
 
 
 
 
 
 
 


Mediti Pharma, Inc. 
Compound: MP-101 
 
Protocol: MP-101-01(b) 
 
 
EMB Statistical Solutions, LLC 
Confidential and Proprietary 
Effective Date 
Statistical Analysis Plan v1 Final 
Page 25 of 26 
20NOV2018 
 
Screen 
Treatment Period (10 Weeks) 
Follow-
up 
 
 
ET 
Visit Number 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
Week 
-1 to -5 
0 
1 
2 
4 
6 
8 
10 
11 
Days from Randomization (target) 
-1 to-35 
0 
7 
14 
28 
42 
56 
70 
77 
Visit Window (± days from target) 
 
 
 
2 
2 
2 
 
2 
2 
CGI-I 
 
 
 
 
x 
 
 
x 
x 
x 
ZBI-22  
 
x 
 
 
x 
 
 
x 
 
 
MMSE 
x 
x 
 
 
x 
 
 
x 
 
x 
UPDRS Part III 
 
x 
 
 
x 
 
 
x 
x 
x 
Laboratory Samples 
Clinical chemistry and hematology 
x 
x 
 
x 
 
x 
 
x 
 
x 
Urinalysis 
x 
x 
 
 
 
 
 
x 
 
x 
Plasma sample collection for PK 
analysis 
 
 
 
x 
x 
x 
 
x 
 
x 
Plasma and serum collection for 
biomarker research 
 
x 
 
 
 
x 
 
x 
 
x 
Blood for epigenetic research 
 
x 
 
 
 
x 
 
x 
 
x 
Blood for assessment of APOE and  
HTR2A SNPs 
 
x 
 
 
 
 
 
 
 
 
Blood for pharmacogenetic research 
 
x 
 
 
 
 
 
 
 
 
See protocol for footnotes. 


Mediti Pharma, Inc. 
Compound: MP-101 
 
Protocol: MP-101-01(b) 
 
 
EMB Statistical Solutions, LLC 
Confidential and Proprietary 
Effective Date 
Statistical Analysis Plan v1 Final 
Page 26 of 26 
20NOV2018 
References 
Cummings JL, Mega M, Gray K, Rosenberg-Thompson S, Carusi DA, Gornbein J. The Neuropsychiatric 
Inventory: comprehensive assessment of psychopathology in dementia. Neurology. 1994; 
44(12):2308-2314. 
Fahn S, Elton R, UPDRS program members. Unified Parkinson’s disease rating scale. In: Fahn S, 
Marsden C, Goldstein M, Calne D, eds. Recent developments in Parkinson’s disease. Florham 
Park, NJ: Macmillan. Healthcare Information. 1987; 153-16. 
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):189-198. 
Guy W. ECDEU Assessment Manual for Psychopharmacology. Rockville, MD: US Department of 
Health, Education, and Welfare Public Health Service Alcohol, Drug Abuse, and Mental Health 
Administration. 1976. 
Zarit SH, Reever KE, Bach-Peterson J. Relatives of the impaired elderly; correlates of feelings of burden. 
The Gerontologist. 1980; 20(6):649-655.