Phase II, Double Blind, Randomized, Placebo Controlled, Parallel Group, Trial to Explore Efficacy, Safety and Pharmacokinetics of CPL500036 (PDE10A Inhibitor) in Patients With an Acute Exacerbation of Schizophrenia
Phase: PHASE2
Conditions: Schizophrenia
Sponsor: Celon Pharma SA

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Clinical Study Protocol 
Phase II, Double-blind, Randomized, Placebo-controlled, 
Parallel-group, Trial to Explore Efficacy, Safety and 
Pharmacokinetics of CPL500036 (PDE10A inhibitor) in Patients 
With an Acute Exacerbation of Schizophrenia 
 
Sponsor: 
Celon Pharma S.A. 
Ogrodowa 2A Str. 
05-
 
Poland 
Sponsor Study Number: 
02PDE2019 
EudraCT Number: 
2020-002316-51 
IMP Name: 
CPL500036 
Development Phase: 
Phase II 
Version (Date) of Final Protocol: 
version 4.0 (16 May 2024) 
 
This clinical study will be conducted in accordance with the International Council for Harmonisation Tripartite 
Guideline for Good Clinical Practice (GCP) E6(R2), the protocol and with other applicable regulatory requirements. 
Confidentiality Statement 
This document contains confidential information of Celon Pharma.  Do not copy or distribute without written 
permission from the Sponsor. 

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SIGNATURE PAGE 
Declaration of Sponsor 
I have read and understood the protocol version 4.0, dated 16th May 2024, specified below, 
and agree on the contents. 
Protocol Title: Phase II, Double-blind, Randomized, Placebo-controlled, Parallel-group, Trial to 
Explore Efficacy, Safety and Pharmacokinetics of CPL500036 (PDE10A inhibitor) in Patients 
With an Acute Exacerbation of Schizophrenia. 
This clinical study protocol was subjected to critical review.  The information it contains is 
consistent with current knowledge of the risks and benefits of the investigational medicinal 
product, as well as with the moral, ethical and scientific principles governing clinical research as 
set out in the guidelines on Good Clinical Practice applicable to this clinical study. 
Sponsor Signatory 
 
 
 
 
 
 
 

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SIGNATURE PAGE 
Declaration of the Investigator 
I have read and understood the protocol version 4.0, dated 16th May 2024, specified below, 
and agree on the contents1 
Protocol Title: Phase II, Double-blind, Randomized, Placebo-controlled, Parallel-group, Trial to 
Explore Efficacy, Safety and Pharmacokinetics of CPL500036 (PDE10A inhibitor) in Patients 
With an Acute Exacerbation of Schizophrenia. 
This clinical study protocol was subjected to critical review and has been released by the Sponsor.  
The information it contains is consistent with current risk and benefit evaluation of the 
investigational medicinal product, as well as with the moral, ethical and scientific principles 
governing clinical research as set out in the guidelines on Good Clinical Practice applicable to this 
clinical study. 
I have read all pages of this clinical study protocol, version 4.0, dated 16th May 2024 and confirm 
that it contains all the information required to conduct this study.  I agree to conduct the study as 
detailed in the protocol and comply with all the terms and conditions set out therein.  I confirm 
that I is to conduct the study in accordance with the provisions of the Declaration of Helsinki.  I 
will also ensure that Investigator(s) and other relevant members of my staff have access to copies 
of this protocol and the Declaration of Helsinki to enable them to work in accordance with the 
provisions of the documents and standard operating procedures of designated CRO company.  
Furthermore, current ICH-GCP, and local regulations is to be followed. 
I acknowledge that all data included in the clinical study protocol are confidential.  Copying, 
disclosing and publishing without assent of Sponsor is prohibited. 
Investigator Signatory 
 
 

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SIGNATURE PAGE 
Declaration of Statistician 
I have read and understood the protocol version 4.0, dated 16th May 2024, specified below, 
and agree on the contents. 
Protocol Title: Phase II, Double-blind, Randomized, Placebo-controlled, Parallel-group, Trial to 
Explore Efficacy, Safety and Pharmacokinetics of CPL500036 (PDE10A inhibitor) in Patients 
With an Acute Exacerbation of Schizophrenia. 
 
Statistician Signatory 
 
 
 
 
 

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LIST OF STUDY STAFF/ RESPONSIBLE PARTIES 
Sponsor 
 
Sponsor Project Management 
Study Coordinator 
CRO Project Management 
Serious Adverse Event Reporting 

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Medical Monitor 
 
Bioanalytical Laboratory 
Biostatistics 
Funding 

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AMENDMENT 7  Protocol v. 3.3 dated 22 November 2023
 Protocol v. 4.0 dated 16 May 2024 
Applicable Section 
Description of Change(s) 
Rationale: The introductions of amendments in statistical parts without any substantial amendments  
1.1. Protocol Synopsis, Statistical 
Methods 
The following text has been changed:  
Data Presentation/Descriptive Statistics: 
Analysis Sets: 
 
Full Analysis Set (FAS): All patients randomized to either 
CPL500036 or placebo  based on planned treatment regimen 
irrespective of their compliance to the planned course of 
treatment (intent-to-treat principle). 
 
Per Protocol (PP) Set: Patients from the FAS who completed the 
Treatment Period (Day 28) on study treatment without a major 
protocol deviation.  Protocol deviations will be determined prior 
to unblinding. 
 
Safety Set (SS): All patients who received at least 1 dose of 
study treatment (either CPL500036 or placebo). 
 
Pharmacokinetic Set (PS):  All subjects in the safety set with at 
least 1 evaluable PK parameter. evaluable and without any 
major protocol deviation thought to interfere with the 
absorption, distribution, metabolism, and excretion of 
CPL500036. 
 
Pharmacokinetic Set for parameter calculation (PSPC): All 
subjects in the safety set with extensive PK sampling that have 
at least 1 PK parameter evaluable and without any major 
protocol deviation thought to interfere with the absorption, 
distribution, metabolism, and excretion of CPL500036. 
The FAS will be the primary analysis set used for all efficacy 
analyses and the PP analysis set will be used for supportive analyses 
of the primary and select secondary efficacy endpoints.  Patients will 
be included in the treatment group they were randomized to.  The SS 
will be used for all safety analyses and patients will be included in 
the treatment group based on the treatment they actually received.   
 
Primary Efficacy Analysis: 
The null hypothesis is that there is no difference in the primary 
endpoint between either dose group compared to placebo, versus the 
alternative hypothesis, that at least 1 dose group is significantly 
different, using a 2-sided 10% significance level.  The primary 
endpoint will be analysed using a mixed effect repeated measures 
model (MRMM), with treatment, and time point, clinical site and 
interaction between clinical site and timepoint as fixed effects and 
baseline score as a covariate.  If there will be many clinical sites 
with few subjects, they can be pooled into bigger groups. Subject 
will be treated as a random effect, with an unstructured covariance 
structure to account for the correlation among repeated 
measurements.  If the model does not converge, another covariance 
structure, (e.g., AR(1), CS, etc.) will be explored.  Missing data will 

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be assumed to be missing at random.  A sensitivity analysis will be 
conducted whereby missing data is imputed using multiple 
imputation.  The primary analysis will compare each dose group with 
placebo, based on estimated marginal means (aka least square 
means, LS-means) from the model without adjustment for 
multiplicity.  As a secondary analysis of the primary endpoint a 
comparison of both treatment groups pooled, compared to placebo 
will also be made. 
 
Secondary Efficacy Analyses: 
All secondary endpoints will be analysed without adjustment for 
multiplicity.  The secondary endpoints, which are continuous, will 
be analysed using the same approach as described for the primary 
endpoint.  Missing data will be assumed to be missing at random.  At 
each time point, the LS-means will be reported (by treatment group 
and for the treatment difference for each dose group, compared to 
placebo).  The secondary endpoints which are binary (i.e., 
responder/non-responder) will be analysed at each time point using 
a Logistic regression model with treatment and clinical site (or 
country if there will be many clinical sites) as a fixed effect and 
baseline score as a covariate.  If a patient is missing data in order to 
derive their response at a given time point, the missing data will be 
imputed using multiple imputation for continuous endpoints and 
non-responser imputation for binary endpoints prior to the 
analysis. 
10.1.3. Analysis population 
The following text has been changed:  
 
Full Analysis Set (FAS): All patients randomized to either 
CPL500036 or placebo  based on planned treatment regimen 
irrespective of their compliance to the planned course of 
treatment (intent-to-treat principle). 
 
Per Protocol (PP) Set: Patients from the FAS who completed the 
Treatment Period (Day 28) on study treatment without a major 
protocol deviation.  Protocol deviations will be determined prior 
to unblinding. 
 
Safety Set (SS): All patients who received at least 1 dose of 
study treatment (either CPL500036 or placebo). 
 
Pharmacokinetic Set (PS):  All subjects in the safety set with at 
least 1 evaluable PK parameter. evaluable and without any 
major protocol deviation thought to interfere with the 
absorption, distribution, metabolism, and excretion of 
CPL500036. 
 
Pharmacokinetic Set for parameter calculation (PSPC): All 
subjects in the safety set with extensive PK sampling that have 
at least 1 PK parameter evaluable and without any major 
protocol deviation thought to interfere with the absorption, 
distribution, metabolism, and excretion of CPL500036. 
The FAS will be the primary analysis set used for all efficacy 
analyses and the PP analysis set will be used for supportive analyses 
of the primary and select secondary efficacy endpoints.  Patients will 
be included in the treatment group they were randomized to.  The SS 
will be used for all safety analyses and patients will be included in 
the treatment group based on the treatment they actually received.   

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10.3. Primary Efficacy Analysis 
The following text has been changed:  
The null hypothesis is that there is no difference in the primary 
endpoint between either dose group compared to placebo, versus the 
alternative hypothesis, that at least 1 dose group is significantly 
different, using a 2-sided 10% significance level.  The primary 
endpoint will be analysed using a mixed effect repeated measures 
model (MRMM), with treatment, and time point, clinical site and 
interaction between clinical site and timepoint as fixed effects and 
baseline score as a covariate.  If there will be many clinical sites 
with few subjects, they can be pooled into bigger groups. Subject 
will be treated as a random effect, with an unstructured covariance 
structure to account for the correlation among repeated 
measurements.  If the model does not converge, another covariance 
structure, (e.g., AR(1), CS, etc.) will be explored.  Missing data will 
be assumed to be missing at random.  A sensitivity analysis will be 
conducted whereby missing data is imputed using multiple 
imputation.  The primary analysis will compare each dose group with 
placebo, based on estimated marginal means (aka least square 
means, LS-means) from the model. 
10.4. Secondary Efficacy 
Analysis 
The following text has been changed:  
Secondary Efficacy Analyses: 
All secondary endpoints will be analysed without adjustment for 
multiplicity.  The secondary endpoints, which are continuous, will 
be analysed using the same approach as described for the primary 
endpoint.  Missing data will be assumed to be missing at random.  At 
each time point, the LS-means will be reported (by treatment group 
and for the treatment difference for each dose group, compared to 
placebo).  The secondary endpoints which are binary (i.e., 
responder/non-responder) will be analysed at each time point using 
a Logistic regression model with treatment and clinical site (or 
country if there will be many clinical sites) as a fixed effect and 
baseline score as a covariate.  In sensitivity analysis, if a patient is 
missing data in order to derive their response at a given time point, 
the missing data will be imputed using multiple imputation for 
continuous endpoints and non-responder imputation for binary 
endpoints prior to the analysis. 
10.8. Demographic and 
Anthropometric Information and 
Baseline Characteristics 
The following text has been changed:  
Demographic and anthropometric variables (age, sex, ethnicity, race, 
height, weight and BMI) will be listed by subject.  Demographic 
characteristics (age, sex, ethnicity and race) and anthropometric 
characteristics (height, weight and BMI) will be summarized by 
treatment and for all subjects in the safety analysis set FAS, SS, PP 
and PSPC populations.  The denominator for percentages will be 

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the number of subjects in the safety analysis set given analysis set 
for each treatment or for all subjects as applicable. 
Medical history data will be listed by subject including visit, 
description of the disease/procedure, MedDRA SOC, MedDRA 
preferred term, start date, and stop date (or ongoing if applicable), as 
well as summarized by treatment group and overall for full 
analysis set 
10.9. Prior and Concomitant 
Medication and Drug 
Administration 
The following text has been changed:  
Prior medications are those that started and stopped prior to the first 
dose of IMP.  Concomitant medications are those taken after first 
dosing (including medications that started prior to dosing and 
continued after). 
Prior and concomitant medication will be classified using the ATC 
codes contained in Register of Medicinal Products Approved for 
Marketing on the territory of the Republic of Poland and listed 
by subject and will include the following information: reported 
name, preferred term, ATC level 2 (therapeutic subgroup) and 4 
(chemical subgroup), the route of administration, dose, frequency, 
start date/time, duration and indication. Summary of prior and 
concomitant medications will be provided as a count and 
frequency for ATC level 2 and 4. 
Prior and concomitant medication will be coded according to the 
World Health Organization Drug Dictionary (WHO-DD) latest 
version. 
Drug administration dates and times will be listed for each subject. 
10.11.1. Adverse Events 
The following text has been changed: 
All AEs will be listed.  The number and percent of subjects 
experiencing an event will be tabulated for each SOC and preferred 
term.  The AEs will also be tabulated according to intensity and 
causality. An overview table presenting the incidence of AE will 
be presented. All tables will be prepared separately by number 
of patients and number of events. 
Serious AE will be listed separately. 
10.11.2. Clinical Laboratory Test 
The following text has been changed: 
Individual data listings of laboratory results will be presented for 
each subject.  Flags will be attached to values outside of the 
assessment.  Clinically significant laboratory test abnormalities that 
were considered AEs by the Investigator will be presented in the AE 
listings. 

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Clinical laboratory tests (observed values) as well as change from 
baseline and categorization of results will be summarized 
descriptively in tabular format.  Shift tables will be presented for 
selected laboratory parameters. 
10.11.3. Vital Signs 
The following text has been changed: 
Individual data listings of vital signs (observed and change from 
baseline) will be presented for each subject.  Individual clinically 
significant vital signs findings that were considered AEs by the 
Investigator will be presented in the AE listings. 
Observed values as well as change from baseline data will be 
summarized descriptively in tabular 
10.11.4. Standard 12-lead 
Electrocardiogram 
The following text has been changed: 
Standard 12-lead ECG data (observed and change from baseline) will 
be listed for each subject and time point.  Observed values will be 
summarized descriptively in tabular format.  Change from baseline 
will be summarized descriptively for QTc data all parameters.  A 
categorical QTc analysis will also be performed as well as shift 
tables. 
10.15. Timing of analysis 
The following point has been added: 
Baseline characteristics and efficacy analyses will be performed 
after the last subject completes a 28-day treatment period. All 
data until the Day 28 visit  will be verified and locked before the 
unblinding. A safety analysis will be performed after all the data, 
including follow-up visits will be completed, verified and whole 
database will be locked. 
The points numeration was updated. 

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SUMMARY LIST OF CHANGES 
AMENDMENT 6  Protocol v. 3.2 dated 01 September 2022
 Protocol v. 3.3 dated 22 November 
2023 
Applicable Section 
Description of Change(s) 
List of study stuff / responsible 
parties 
The Medical Monitor has been changed. 
 
 

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AMENDMENT 5  Protocol v. 3.1 dated 14 July 2021
 Protocol v. 3.2 dated 01 September 2022 
Applicable Section 
Description of Change(s) 
List of study stuff / responsible 
parties 
Due to the change of the CRO company, the corresponding data has 
been updated. Additionally, the Statistical Part Consultant and 
Medical Monitor have been changed. 
 
 
 

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AMENDMENT 4  Protocol v. 3.0 dated 03 March 2021 
 Protocol v. 3.1 dated 14 July 2021 
Applicable Section 
Description of Change(s) 
Rationale: Addition of Day 0 to the Study Schedule 
1.1. Protocol synopsis, Study 
design 
 The following text has been modified:  
(
) Patients that fulfil all the inclusion criteria and none of the 
exclusion criteria will immediately be admitted to the Clinical Unit 
and enter a Medication Washout Period of up to 7 days (Day -7 to 
Day -1) before the start of the 28-day Treatment Period 
randomization on Day 0.  The duration of the Medication Washout 
Period may be shorter or omitted for non-medicated patients.  
1.1. Protocol synopsis, Study 
Population, 
The following text has been added: 
NOTE: Investigators should ensure that all study enrollment criteria 
have been met at screening and on Day -1.  If a patient status after 
screening changes at baseline (Day -1) such that the study patient no 
longer meets all eligibility criteria, then the patient should be excluded 
from participation in the study (such patient is to be considered as 
screen failure). It should be remembered that all baseline 
procedures must be performed on Day -1, but final patient 
qualification should be made when all results are available, before 
randomization on Day 0.  
1.2. Schema, Study Overview 
The Figure 1 was updated. 
1.3. Schedule of Assessments, 
Time Points and Window 
Allowance 
The Table 1 was updated. 
1.3. Schedule of Assessments, 
Footnotes for Table 1 
The following text has been modified:  
 
 
4.1 Overview 
The following text has been modified:  
Patients that fulfil all the inclusion criteria and none of the 
exclusion criteria will immediately be admitted to the Clinical Unit 
and enter a Medication Washout Period of up to 7 days (Day -7 to 
Day -1) before the start of the 28-day Treatment Period 
randomization on Day 0.  The duration of the Medication Washout 
Period may be shorter or omitted for non-medicated patients.  
5. Study population 
The following text has been added: 
NOTE: Investigators should ensure that all study enrollment criteria 
have been met at screening and on Day -1.  If a patient status after 

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screening changes at baseline (Day -1) such that the study patient no 
longer meets all eligibility criteria, then the patient should be excluded 
from participation in the study (such patient is to be considered as 
screen failure). It should be remembered that all baseline 
procedures must be performed on Day -1, but final patient 
qualification should be made when all results are available, before 
randomization on Day 0.  
6.4.2. Randomization Numbers 
The following text has been modified:  
Prior to dosing, on Day 0 -1, subjects will be assigned a 
randomization number in accordance with the randomization code 
generated by eCRF platform. 
 
8.7. Hospitalization 
The following text has been modified:  
Patients are to be hospitalized after the screening qualification for 
washout period of up to 7 days (if necessary) before the start of the 
28-day Treatment Period randomization on Day 0. Patients are to 
be hospitalized during the treatment period (Day 1 to Day 28).  On 
Day 29 patients may be discharged from the clinical centre based on 
local standards of care if the patient is in stable condition under the 
 
9.2. Baseline (Day -1) 
The following text has been modified:  
exclusion are met.  If a patient status after screening changes at 
Baseline (Day -1) such that the study patient no longer meets all 
eligibility criteria, then the patient should be excluded from 
participation in the study (such patient is to be considered as screen 
failure). It should be remembered that all baseline procedures 
must be performed on Day -1, but final patient qualification 
should be made when all results are available, before 
randomization on Day 0. 
For a patient meeting all of the inclusion and none of the exclusion 
criteria the randomization procedure is to be performed.  
9.3. Day 0 
The following text has been added:  
qualification to the study based on all baseline results  this is the 
case, when not all baseline results (especially laboratory values) 
are to be available on Day -1. 
For a patient meeting all of the inclusion and none of the exclusion 
criteria the randomization procedure is to be performed.  
Rationale: Shortening the duration of Screening Period 

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1.1. Protocol synopsis, Study 
design 
The following text has been modified:  
For the Screening Period, patients will undergo screening 
assessments from Day -11 -10 to Day -8 in multiple settings (i.e., 
emergency departments, outpatient clinics, etc.) 
 
1.2. Schema, Study Overview 
The Figure 1 was updated. 
1.3. Schedule of Assessments, 
Time Points and Window 
Allowance 
The Table 1 was updated. 
1.3. Schedule of Assessments, 
Footnotes for Table 1 
 
 
 
 
 
 
 
 
 
 
4.1. Overview 
The following text has been modified:  
For the Screening Period, patients will undergo screening 
assessments from Day -11 -10 to Day -8 in multiple settings (i.e., 
emergency departments, outpatient clinics, etc.) 
 

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4.5. Study Duration 
The following text has been modified:  
The duration of participation for each subject will be approximately 
8 weeks.  The estimated study duration includes: 
1. Screening Period: Up to 11 10 days. 
2. Treatment Period: Days 1 to 28. 
3. Follow-up Period: 7 to 14 days after the post-last dose of IMP 
(Day 28)  Days 35 to 42.  
8.3.4. Vital Signs 
The following text has been modified:  
Respiratory rate (breaths per minute), body temperature 
, 3-
positional blood pressure (systolic and diastolic [mmHg]) and pulse 
(beats per minute [bpm]) (after 3 minutes lying down; after 3 minute 
sitting, immediately upon standing; and after 3 minutes standing) will 
be taken taken once at Screening (Day -11 -10 to -2); once at Baseline 
(Day -1); thrice on Day 1, Days 2-6 (each day), Day 7, 14, 21 and 28: 
pre-
before or after 1h 45 minutes and 9h post-dose; once during the 
follow-
 
8.3.5. Standard 12-lead 
Electrocardiograms 
The following text has been modified:  
The ECGs will be performed once, pre-dose 
administration) at all scheduled visits when IMP is administered. 
 
Once at Screening (Days -11 -10 to -2) and at Baseline (Day -1), 
 
On Days 7, 14, 21 and 28: pre-dose, 
 
On Follow-up Visits (Days 35 to 42).  
8.3.6. Physical Examination 
The following text has been modified:  
Physical examinations will be performed at the time points detailed 
in the Schedule of Assessments (Table 1)  and as detailed below: 
 
at Screening (Days -11 -10 to -2) and at Baseline (Day -1), 
 
On Day 28; not earlier than 5h post-dose, 
 
On Follow-up Visits (Days 35 to 42).  
8.3.9 Additional Safety Variables 
The following text has been modified:  
Neurological, ophthalmological, and dermatological examinations 
will be performed at the time points detailed in the Schedule of 
Assessments (Table 1) and as detailed below: 
Neurological examinations: 
 
At Screening (Days -11 -10 to -2) and at Baseline (Day -1), 
 
On Days 7, 14, 21 and 28; not earlier than 5h post-dose, 

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On Follow-up Visits (Days 35 to 42). 
Ophthalmological examinations: 
 
At Screening (Days -11 -10 to -2) and at Baseline (Day -1), 
 
On Day 28 not earlier than 5h post-dose. 
Dermatological examinations: 
 
At Screening (Days -11 -10 to -2) and at Baseline (Day -1), 
 
On Day 28; not earlier than 5h post-dose.  
8.5.1. Positive and Negative 
Syndrome Scale 
The following text has been modified:  
Screening (Day -11 -10 to -2); once at Baseline (Day -1); on Days 1, 
7, 14, 21 and 28 when start of ratings is to be within 5 minutes before 
or after 2h post-dose (it will be performed before any other scale)  
8.5.2. Clinical Global Impression 
Scale - Severity 
The following text has been modified:  
-S) will be performed once at 
Screening (Days -11 -10 to 2), once at baseline (Day -1); on Days 7, 
14, 21 and 28 when start of ratings is to be within 5 minutes before or 
after 2h post-dose (after PANSS)
 
9.1. Screening 
The following text has been modified:  
-11 -10 to 
Day  8 in multiple settings (i.e. emergency departments, outpatient 
 
Rationale: Addition of clarification note regarding Concomitant Treatment 
5.4.3. Prior and Concomitant 
Treatments 
The following text has been added:  
Precaution should be exercised in patients using concomitant 
treatment with agents being BCRP (Breast Cancer Resistance 
Protein) substrates (e.g. ezetimibe, pravastatin, rosuvastatin), as 
the Investigational Product may inhibit the BCRP. As per Table 
9, the dose of these drugs should be stable within 1 month prior 
confusions related to the cha
laboratory results should be discussed with the Medical 
 
 
 
 
 

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AMENDMENT 3  Protocol v. 2.1 dated 21 December 2020
 Protocol v. 3.0 dated 03 March 2021 
Applicable Section 
Description of Change(s) 
Rationale: Extension of explanation without any substantial amendments (in accordance with the 
Hungarian Regulatory Authority recommendation). 
2.5. Risk-benefit Assessments 
The following text has been added:  
patients with schizophrenia 
although effective are not perfect as they might be associated 
* The use of treatment with new 
mechanism of action may exert some risks, which, based on 
available information, was recognized and the study was design 
to minimize it. 
tolerability and PK of 2 doses of CPL500036, compared to 
placebo in patients with an acute exacerbation of schizophrenia. 
* Patients at imminent risk of suicide or injury to self, 
others, or property or participants who within the past year 
prior to screening have attempted suicide will be excluded from 
the study and risk of potential suicide ideations occurrence will 
be assess
 
*full  text available in 2.5 section 
4.2. Scientific Rationale for the 
Study Design 
The following text has been added:  
s the recommendations provided in the 
Guideline on clinical investigation of medicinal products, 
including depot 
(EMA/CHMP/40072/2010 Rev. 1, 30). 
Extrapyramidal 
symptoms (EPS) are potential adverse events that according to 
guideline are to be monitored during the studies in schizophrenia 
patients, which was addressed by using ESRS scale for EPS 
 
*full text available in 4.2 section 
Rationale: Minor errors were noted  
5.4.1. Dietary and Fluid 
Restrictions 
The following text has been modified:  
Dosing Day: Dosing during treatment period will take place after an 
overnight fast of at least 10 hours.  Water intake will be allowed up to 
1 hour before dosing and from 2 1 hours after dosing (excluding 
amount of water allowed for IMP administration). 
5.4.3. Prior and Concomitant 
Treatments 
The following text has been modified:  
antipsychotic within one treatment cycle prior to Day 1 1 month 

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(30 days) prior to Screening. or have used The using of mianserin, 
mirtazapine, nefazadone, cyproheptadine, or fluvoxamine within 1 
month (30 days) prior to the Day -1 before Screening is not 
recommended.  
11.5. Informed Consent 
The following text has been modified:  
As part of the informed consent procedure, the Investigator must 
explain orally and in writing the nature, duration and purpose of the 
study and the action of the drug in such a manner that the subject is 
aware of the potential risks, inconveniences or AEs that may occur.  
The subject should be informed that he/she is free to withdraw from 
the study at any time.  Subjects will receive all information that is 
required by federal local regulations and ICH guidelines.   
Throughout the protocol 
Minor grammatical, formatting, or spelling changes were made. 
Rationale: The additional clarification was added 
5.4.3. Prior and Concomitant 
Treatments 
The following text has been added:  
conditions can be taken consistently with the current 
recommendations, but at least 1 hour interval between 
concomitant medication and IMP administration must be 
 
6.8. Blinding and Breaking the 
Blind 
The following text has been modified:  
should not may be broken except only in from 
medical emergency (where knowledge of the study drug administered 
would affect the treatment of the emergency).  The decision to break 
the blind will be made on a case-by-case basis, at the discretion of the 
Investigator, and if possible, in collaboration with the Sponsor and/or 
 
6.9. Treatment of Overdose 
The following text has been added:  
of excessive pharmacological effects or overdose. 
conditions will be constantly monitored by Investigator.  Each 
case of overdose will be reported immediately to the Sponsor. The 
Investigator should follow-up and document the course and the 
outcome of each overdose even if the subject was withdrawn from 
the clinical study or if the clinical study has finished and if the 
patient agrees. Any SAE that occurs due to overdose must be 
recorded on the Serious Adverse Event Report Form and must be 
reported by Investigator to the Sponsor within 24 hours of 
 
7.1. Study Stopping Rules 
The following text has been added:  

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aware of conditions or events that suggest a possible hazard to 
subjects if the clinical study continues, then the clinical study may be 
terminated after appropriate consultation among the involved parties. 
If the investigator considers, that the continuation of the study is 
-benefit 
considerations have changed, the Investigator may decide the 
termination of the study for this subject without the 
consent/consulting Sponsor.  The clinical study may be terminated 
 
7.1.1.1. Safety Criteria 
The following text has been added:  
An individual subject is to be withdrawn from the study if: 
suspected to interfere with the study medication in the opinion 
of the Investigator or designee  
7.2. Subject Withdrawal and 
Replacement 
The following text has been added:  
IMP administration or before completion the study, may be replaced 
by another qualifying alternate only in case if total number of subjects 
in a given study arm who would complete the study would be 
insufficient and there are no safety concerns. The subject 
replacement is defined as recruiting additional patient, but it 
should be remembered that results from all randomized patients 
will be analyzed according to the population set definitions 
 
11.8 Confidentiality Data 
protection 
The following text has been modified:  
Subjects will be specified on study documents by their subject 
number, initial or birth date, not by name, or by subject number and 
birth year only, if required and to comply with local data 
protection regulations.  Documents that identify the subject (e.g., the 
 
Rationale: The section was adjusted to clarify and specify allowed concomitant medication usage 
(in accordance with the Hungarian Regulatory Authority recommendations). 
5.4.3. Prior and Concomitant 
Treatments 
The following text has been modified: 
In addition, benzatropine/biperiden may be administered for 
treatment of extrapyramidal side effects and propranolol may be 
administered for treatment of akathisia.  Lorazepam, zolpidem, 
benzatropine/biperiden and propranolol are allowed according to the 
instructions outlined in Table 5 below.  Within the daily and weekly 
limits 
shown 
in 
Table 
5, 
lorazepam, 
zolpidem, 
benzatropine/biperiden, and propranolol are permitted upon the 
Investigator or designee decision and are NOT allowed on a PRN 
(as needed) basis; each and every administration must be 

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considered and approved by the Investigator prior to 
administration. 
dose of lorazepam, zolpidem, benzatropine/biperiden, or 
propranolol (exceeding the limits given in Table 5), it must be 
recorded as Serious Adverse Event (SAE). 
The adverse event (AE) associated with the need for lorazepam, 
zolpidem, benzatropine/biperiden, or propranolol should be recorded 
on the AE eCRF.  The amount and timing of each lorazepam, 
zolpidem, benzatropine/biperiden, or propranolol administration 
should be recorded for each patient in the eCRF.  
5.4.3. Prior and Concomitant 
Treatments 
The table 5 was modified, as follows: 
-determine of weekly limits  
-akathisia treatment update 
13.Appendices 
The table 9 was modified, as follows: 
-update according to section 5.4.3. 
Rationale: Deletion of the confusing record without any substantial changes in statistics 
10.3. Primary Efficacy Analysis 
The following text has been modified:  
endpoint between either dose group compared to placebo, versus the 
alternative hypothesis, that at least 1 dose group is significantly 
different, using a 2-sided 10% significance level.  The primary 
endpoint will be analysed using a mixed effect repeated measures 
model (MRMM), with treatment and timepoint as fixed effects and 
baseline score as a covariate.  Subject will be treated as a random 
effect, with an unstructured covariance structure to account for the 
correlation among repeated measurements.  If the model does not 
converge, another covariance structure, (e.g., AR(1), CS, etc.) will be 
explored.  Missing data will be assumed to be missing at random.  A 
sensitivity analysis will be conducted whereby missing data is 
imputed using multiple imputation.  The primary analysis will 
compare each dose group with placebo. without adjustment for 
multiplicity.  As a secondary analysis of the primary endpoint a 
comparison of both treatment groups pooled, compared to 
placebo will also be made.  
Rationale: Addition of new references (due to extension of explanation in section 2.5. and in section 4.2.) 
12. Reference List 
The following references were added: 
Kinon, B. J., Potts, A. J., & Watson, S. B. (2011). Placebo 
response in clinical trials with schizophrenia patients. 
Current opinion in psychiatry, 24(2), 107-113. 

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29. Oliveira, I. R. D., Nunes, P. M., Coutinho, D. M., & Sena, E. 
P. D. (2009). Review of the efficacy of placebo in comparative 
clinical trials between typical and atypical antipsychotics. 
Brazilian Journal of Psychiatry, 31(1), 52-56. 
30. 
including 
depot 
preparations 
in 
the 
treatment 
of 
 
 
 

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AMENDMENT 2  Protocol v. 2.0 dated 28 August 2020 
 Protocol v. 2.1 dated 21 December 
2020 
Applicable Section 
Description of Change(s) 
Rationale: Minor errors were noted  
1.1. Protocol synopsis, Study 
population, Inclusion criteria 
The following text has been modified:  
6. A female is eligible to participate if she is not pregnant (negative 
pregnancy serum test at Screening and Day -1), not breastfeeding, 
and at least 1 of the following conditions applies:
 
5.2. Inclusion criteria 
The following text has been modified:  
6. A female is eligible to participate if she is not pregnant (negative 
pregnancy serum test at Screening and Day -1), not breastfeeding, 
and at least 1 of the following conditions applies:
 
1.1. Protocol synopsis, Study 
population, Exclusion criteria 
The following text has been modified:  
6. The patient has a moderate or severe substance use disorder 
(meeting more than 5 4 diagnostic criteria of DSM-5 either currently 
or within the last 6 months) for alcohol or other substances of abuse 
except nicotine or caffeine  
5.3. Exclusion criteria 
The following text has been modified:  
6. The patient has a moderate or severe substance use disorder 
(meeting more than 5 4 diagnostic criteria of DSM-5 either currently 
or within the last 6 months) for alcohol or other substances of abuse 
except nicotine or caffeine  
Rationale: Clarifying note was added 
1.1. Protocol synopsis, Criteria 
for evaluation 
Blood samples for PK 
analysis will be collected at the following time points for extensive 
PK sampling (approximately 30% of patients): 
 
Day 1 and Day 7 (steady state): pre-dose and 0.5, 1, 1.5, 2, 4, 8, 
12, and 24* hours post-dose. 
 
Days 2 to 6: pre-dose* and around 2 hours post-dose. 
 
Day 28: pre-dose and around 2 hours post-dose. 
*please note  the sample 24 hours post-dose on Day 1 it is the same sample 
as pre-dose on Day 2.  
1.3. Schedule of Assessments, 
Footnotes for Table 1 
 
 
 
*please note  the sample 24 hours post-dose on Day 1 it is the same sample 
as pre-dose on Day 2.  

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8.4.1. Blood sample collection 
Blood samples for PK 
analysis will be collected at the following time points for extensive 
PK sampling (approximately 30% of patients): 
 
Day 1 and Day 7 (steady state): pre-dose and 0.5, 1, 1.5, 2, 4, 8, 
12, and 24* hours post-dose. 
 
Days 2 to 6: pre-dose* and around 2 hours post-dose. 
 
Day 28: pre-dose and around 2 hours post-dose. 
*please note  the sample 24 hours post-dose on Day 1 it is the same sample 
as pre-dose on Day 2.  
 
 
 

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AMENDMENT 1  Protocol v. 1.0 dated 29 May 2020 
 Protocol v. 2.0 dated 28 August 2020 
Applicable Section 
Description of Change(s) 
Rationale: change of dose after Regulatory Authority recommendations. 
1.1. Protocol synopsis, Study 
Design 
The 
The study will be conducted 
at multiple clinical units.  Approximately 165 patients will be 
randomized at a 1:1:1 ratio to receive 20 mg CPL500036, 40 60 mg 
 
1.1. Protocol synopsis, Study 
Design 
patients will be dosed with 20 mg CPL500036, 40 60 mg CPL500036 
or placebo once daily for 28 consecutive days (Day 1 to Day 28).  
Patients will remain in-house for the duration of the Treatment 
 
4.1 Study design, Overview 
at multiple clinical units.  Approximately 165 patients will be 
randomized at a 1:1:1 ratio to receive 20 mg CPL500036, 40 60 mg 
 
Additionally, the following text has been modified on the same page: 
CPL500036, 40 60  mg CPL500036 or placebo once daily for 28 
consecutive days (Day 1 to Day 28).  Patients will remain in-house 
 
4.3. Justification for Dose 
subjects were divided into four cohorts. During the fourteen days, 
every cohort took other doses of the IMP: 3 mg, 10 mg, 30 mg and 60 
mg. All doses were tolerated well by subjects and were generally safe. 
Even at the highest dose, the IMP cause only the transient adverse 
events assessed as mild or moderate. For this reason, the Sponsor 
decided to administer two doses in the Phase II: 20 mg and 40 60 mg. 
Further details can be found in the IB [23
 
6.6 Dosing 
-blind 
manner, every patient will take the same number of capsules. 
Depending on the dose (20 mg or 40 60 mg) and the type of product 
(PG20 or placebo) intended for patient, he/she will take: 
- 4 6 capsules of PG20: 40 60 mg, 
- 2 capsules of PG20 and 2 4 capsules of placebo: 20 mg, 
- 4 6 
 

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6.7. Compliance, IMP 
accountability 
trained, qualified personnel designated by the Investigator.  A hand 
and mouth check will be performed after dosing to ensure the subjects 
have swallowed the dose administered.  The date and time of dosing 
will be documented on each dosing day.  Comments will be recorded 
if there are any deviations from the planned dosing procedures. A 
single dose is to be considered as a compliant when all 4 6 capsules 
are administered and administration is without any emesis occurring 
within 2h after IMP administration.  A patient is to be considered as 
compliant with dosing regimen when at least 80 % of the doses are 
 
Rationale: Minor errors were noted 
Throughout the protocol 
Minor grammatical, formatting, or spelling changes were made. 

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TABLE OF CONTENTS 
SIGNATURE PAGE ...................................................................................................................... 2
SIGNATURE PAGE ...................................................................................................................... 3
SIGNATURE PAGE ...................................................................................................................... 4
LIST OF STUDY STAFF/ RESPONSIBLE PARTIES ................................................................. 5
SUMMARY LIST OF CHANGES ................................................................................................ 8
List of Tables ................................................................................................................... 34
List of Figures .................................................................................................................. 34
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ................................................. 35
1.
PROTOCOL SUMMARY............................................................................................... 38
1.1.
Protocol Synopsis ............................................................................................... 38
1.2.
Schema ............................................................................................................... 46
1.3.
Schedule of Assessments, Time Points and Window Allowance ...................... 46
2.
INTRODUCTION ........................................................................................................... 51
2.1.
Background......................................................................................................... 51
2.2.
Summary of Findings from Non-clinical Studies with Potential Clinical 
Relevance ........................................................................................................... 53
2.2.1.
In Vivo Behavioural Studies  Antipsychotic Effects ..................................... 53
2.2.2.
In Vivo Behavioural Studies  Pro-cognitive Effects ..................................... 55
2.2.3.
In Vivo Behavioural Studies 
 Effects on Negative Symptoms of 
Schizophrenia ................................................................................................. 56
2.2.4.
Toxicology ...................................................................................................... 57
2.3.
Summary of Findings from Previous Clinical Studies ....................................... 57
2.4.
Rationale for the Clinical Study ......................................................................... 59
2.5.
Risk-benefit Assessment .................................................................................... 60
3.
STUDY OBJECTIVES AND ENDPOINTS................................................................... 63
3.1.
Primary Objective ............................................................................................... 63
3.2.
Secondary Objectives ......................................................................................... 63
3.3.
Endpoints ............................................................................................................ 63
3.3.1.
Efficacy ........................................................................................................... 63
3.3.2.
Safety .............................................................................................................. 64
3.3.3.
Pharmacokinetics ............................................................................................ 65
4.
STUDY DESIGN ............................................................................................................ 66
4.1.
Overview ............................................................................................................ 66
4.2.
Scientific Rationale for the Study Design .......................................................... 67
4.3.
Justification for Dose .......................................................................................... 67
4.4.
Order of Assessments ......................................................................................... 67
4.5.
Study Duration.................................................................................................... 68

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4.6.
End of the Study ................................................................................................. 68
4.7.
Study Completion ............................................................................................... 68
4.8.
Early Termination ............................................................................................... 68
5.
STUDY POPULATION .................................................................................................. 69
5.1.
Number of Subjects ............................................................................................ 69
5.2.
Inclusion Criteria ................................................................................................ 69
5.3.
Exclusion Criteria ............................................................................................... 70
5.4.
Restrictions ......................................................................................................... 72
5.4.1.
Dietary and Fluid Restrictions ........................................................................ 72
5.4.2.
Lifestyle Considerations ................................................................................. 73
5.4.3.
Prior and Concomitant Treatments ................................................................. 73
5.4.4.
Contraception Rules ........................................................................................ 76
6.
INVESTIGATIONAL MEDICINAL PRODUCT .......................................................... 77
6.1.
Study Agent ........................................................................................................ 77
6.1.1.
Physico-chemical characteristics .................................................................... 77
6.1.2.
Formulation ..................................................................................................... 77
6.2.
Identity of the Investigational Medicinal Products ............................................ 78
6.3.
Supply, Packaging, Labelling and Storage ......................................................... 78
6.4.
Subject Identification and Randomization ......................................................... 79
6.4.1.
Screening Numbers ......................................................................................... 79
6.4.2.
Randomization Numbers ................................................................................ 79
6.5.
Administration of Investigational Medicinal Products....................................... 79
6.6.
Dosing................................................................................................................. 79
6.7.
Compliance, IMP accountability ........................................................................ 80
6.8.
Blinding and Breaking the Blind ........................................................................ 80
6.9.
Treatment of Overdose ....................................................................................... 81
7.
DISCONTINUATION .................................................................................................... 82
7.1.
Study Stopping Rules ......................................................................................... 82
7.1.1.
Stopping Rules ................................................................................................ 82
7.2.
Subject Withdrawal and Replacement ................................................................ 83
8.
STUDY ASSESSMENTS AND PROCEDURES........................................................... 86
8.1.
Eligibility Screening ........................................................................................... 86
8.2.
Medical History, Demographic and Other Baseline Information ...................... 86
8.3.
Safety Variables.................................................................................................. 86
8.3.1.
Adverse Events ............................................................................................... 86
8.3.2.
Clinical Laboratory Assessments .................................................................... 92
8.3.3.
Alcohol test ..................................................................................................... 94
8.3.4.
Vital Signs ...................................................................................................... 94
8.3.5.
Standard 12-lead Electrocardiograms ............................................................. 94
8.3.6.
Physical Examinations .................................................................................... 95
8.3.7.
Extrapyramidal Side Effects ........................................................................... 95

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8.3.8.
Columbia Suicide Severity Rating Scale ........................................................ 95
8.3.9.
Additional Safety Variables ............................................................................ 96
8.4.
Pharmacokinetics Variables ............................................................................... 96
8.4.1.
Blood Sample Collection ................................................................................ 96
8.5.
Efficacy Variables .............................................................................................. 97
8.5.1.
Positive and Negative Syndrome Scale .......................................................... 97
8.5.2.
Clinical Global Impression Scale - Severity ................................................... 98
8.5.3.
Clinical Global Impression Scale - Improvement ........................................... 98
8.5.4.
Brief Assessment of Cognition in Schizophrenia ........................................... 98
8.6.
Total Amount of Blood ...................................................................................... 99
8.7.
Hospitalization .................................................................................................... 99
9.
STUDY SCHEDULE .................................................................................................... 100
9.1.
Screening .......................................................................................................... 100
9.2.
Baseline (Day -1) .............................................................................................. 101
9.3.
Day 0 ................................................................................................................ 101
9.4.
Day 1 ................................................................................................................ 101
9.5.
Days 2 to 6 ........................................................................................................ 102
9.6.
Day 7 ................................................................................................................ 103
9.7.
Days 8 to 13 ...................................................................................................... 103
9.8.
Day 14 .............................................................................................................. 104
9.9.
Days 15 to 20 .................................................................................................... 104
9.10.
Day 21 .............................................................................................................. 105
9.11.
Days 22 to 27 .................................................................................................... 105
9.12.
Day 28 .............................................................................................................. 106
9.13.
Day 29 .............................................................................................................. 106
9.14.
Follow-up visits ................................................................................................ 107
10.
STATISTICAL CONSIDERATIONS .......................................................................... 108
10.1.
Study Population .............................................................................................. 108
10.1.1.
Disposition of Subjects ................................................................................. 108
10.1.2.
Protocol Deviations ...................................................................................... 108
10.1.3.
Analysis population ...................................................................................... 108
10.2.
Evaluation of Efficacy ...................................................................................... 109
10.3.
Primary Efficacy Analysis ................................................................................ 109
10.4.
Secondary Efficacy Analyses ........................................................................... 109
10.5.
General Considerations .................................................................................... 110
10.6.
Protocol Deviations .......................................................................................... 110
10.7.
Subject Disposition ........................................................................................... 110
10.8.
Demographic and Anthropometric Information and Baseline Characteristics. 110
10.9.
Prior and Concomitant Medication and Drug Administration ......................... 111
10.10. Exposure ........................................................................................................... 111

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10.11. Safety Analyses ................................................................................................ 111
10.11.1. Adverse Events ............................................................................................. 111
10.11.2. Clinical Laboratory Tests.............................................................................. 111
10.11.3. Vital Signs .................................................................................................... 112
10.11.4. Standard 12-lead Electrocardiogram ............................................................ 112
10.11.5. Physical Examination ................................................................................... 112
10.11.6. Other Safety Variables .................................................................................. 112
10.12. Pharmacokinetics Analyses .............................................................................. 112
10.13. Pharmacokinetics/Pharmacodynamics Analyses.............................................. 113
10.14. Interim Analyses ............................................................................................... 113
10.15. Determination of Sample Size .......................................................................... 113
11.
ETHICAL, LEGAL AND ADMINISTRATIVE ASPECTS ........................................ 114
11.1.
Data Quality Assurance .................................................................................... 114
11.2.
Data collection and Access to Source Data/Documents ................................... 115
11.3.
Archiving Study Documents ............................................................................ 115
11.4.
Good Clinical Practice ...................................................................................... 116
11.5.
Informed Consent ............................................................................................. 116
11.6.
Insurance and Compensation for Injury ........................................................... 116
11.7.
Protocol Approval and Amendment(s) ............................................................. 117
11.8.
Confidentiality Data Protection ........................................................................ 117
11.9.
Publication Policy ............................................................................................. 117
12.
REFERENCE LIST ....................................................................................................... 119
13.
APPENDICES ............................................................................................................... 122
 
 
 

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List of Tables 
Table 1
Schedule of Assessments ......................................................................................... 47
Table 2
The minimal effective doses (MED) and all tested doses of CPL500036 
administered to rats in behavioral tests assessing potential antipsychotic effects ... 54
Table 3
The minimal effective doses (MED) and all tested doses of CPL500036 
administered to rats in behavioral tests assessing potential procognitive effects .... 56
Table 4
The minimal effective doses (MED) and all tested doses of CPL500036 
administered to rats in behavioral tests assessing effects on negative symptoms.... 57
Table 5
Restrictions on the Use of Lorazepam, Zolpidem, Benzatropine/Biperiden, and 
Propranolol during the Study ................................................................................... 75
Table 6
The composition of powder filled into gelatin capsule. ........................................... 78
Table 7
Assessment of Relationship of Adverse Events to Investigational Product ............ 89
Table 8
Clinical Laboratory Assessments ............................................................................. 93
Table 9. Drugs Allowed (Y) and Not Allowed (N) as Concomitant Medications ......................... 1
 
 
List of Figures 
Figure 1
Study Overview ........................................................................................................ 46
 

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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Definition 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
API 
Active pharmaceutical ingredient 
APO 
Apomorphine 
ASST 
Attentional set shifting task 
AST 
Aspartate aminotransferase 
AUC0-24 
Area under the concentration-time curve from time zero to 24 hours 
BACS 
Brief Assessment of Cognition in Schizophrenia 
BMI 
Body mass index 
BP 
Blood pressure 
bpm 
Beats per minute 
b.w. 
Body weight 
cAMP 
cyclic adenosine monophosphate 
CAR 
Conditioned Avoidance Response 
CGI-I 
Clinical Global Impression Scale - Improvement 
CGI-S 
Clinical Global Impression Scale- Severity 
cGMP 
cyclic guanosine monophosphate 
CL/F 
Apparent clearance 
Cmax 
Maximum observed concentration 
CRF 
Case report form 
CRO 
Contract research organization 
CSP 
Clinical study protocol 
CSR 
Clinical study report 
C-SSRS 
Columbia Suicide Severity Rating Scale 
Ctrough 
Observed trough concentrations 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, 5th Edition 
ECG 
Electrocardiogram 
eCRF 
electronic case report form 

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ED 
Extra-dimensional 
EDC 
Electronic data capture 
EPS 
Extrapyramidal side effects 
ESRS 
Extrapyramidal Symptom Rating Scale 
FAS 
Full Analysis Set 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
HBsAg 
Hepatitis B surface antigen 
HIV 
Human immunodeficiency virus 
HR 
Heart rate 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IgM 
Immunoglobulin M 
IMP 
Investigational medicinal product 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRMM 
Mixed effect repeated measures model 
MSN 
Medium spiny neurons 
NOAEL 
No-observed-adverse-effect-level 
NOR 
Novel object recognition test 
PANSS 
Positive and Negative Syndrome Scale 
PCP 
Phencyclidine 
PD 
Pharmacodynamics 
PDE10A 
Phosphodiesterase 10A 
PK 
Pharmacokinetics 
PP 
Per Protocol Set 
PPI 
Pre-pulse inhibition of the acoustic startle response 
PRN 
As needed 
PS 
Pharmacokinetic Set 
QTcF 
QT 
 

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SAE 
Serious adverse event 
SCID-5-CT 
Structured Clinical Interview for DSM-5 Clinical Trial Version 
SD 
Standard deviation 
SID 
Subject identification 
SOC 
System organ class 
SOP 
Standard operating procedure 
SS 
Safety Set 
SUSAR 
Suspected unexpected serious adverse reaction 
t  
Apparent terminal elimination half-life 
tmax 
Time corresponding to occurrence of Cmax 
ULN 
Upper limit of normal 
Vz/F 
Apparent volume of distribution during terminal phase 

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1. 
PROTOCOL SUMMARY 
1.1. 
Protocol Synopsis 
Protocol Title 
Phase II, Double-blind, Randomized, Placebo-controlled, Parallel-group, Trial 
to Explore Efficacy, Safety and Pharmacokinetics of CPL500036 (PDE10A 
inhibitor) in Patients with an Acute Exacerbation of Schizophrenia 
Study Numbers 
Sponsor Protocol No.: 02PDE2019 
Development Phase 
Phase II 
Sponsor 
Celon Pharma S.A. 
Study Centers 
This study will be conducted at multiple clinical units. 
Study Objectives 
Primary Objective: 
Efficacy: 
 
To determine if CPL500036 administered for 28 days can attenuate the 
positive symptoms associated with schizophrenia. 
Secondary Objectives: 
Efficacy: 
 
To determine if CPL500036 administered for 28 days can attenuate the 
negative symptoms associated with schizophrenia. 
 
To determine if CPL500036 administered for 28 days results in overall 
clinical improvement as assessed by the Clinical Global Impression 
Scale - Improvement (CGI-I). 
 
To determine if CPL500036 administered for 28 days results in overall 
clinical improvement as assessed by the Positive and Negative Symptom 
Scale (PANSS). 
Safety: 
 
To assess the safety and tolerability of CPL500036 administered for 
28 days. 
Pharmacokinetics: 
 
To assess the pharmacokinetic (PK) profile of CPL500036 administered 
for 28 days. 
Study Design 
This is a double-blind, randomized, placebo controlled, parallel group, dose 
ranging study to explore the efficacy, safety, tolerability and PK of 2 different 
doses of CPL500036 (phosphodiesterase 10A [PDE10A] inhibitor) in patients 
with an acute exacerbation of schizophrenia when administered for 28 days. 
The study will be conducted at multiple clinical units.  Approximately 
165 patients will be randomized at a 1:1:1 ratio to receive 20 mg CPL500036, 
40 mg CPL500036 or placebo.   
The study will comprise of a Screening Period (that will include a prior 
Medication Washout Period), a Treatment Period and a Follow-up Period. 
For the Screening Period, patients will undergo screening assessments from 
Day -10 to Day -8 in multiple settings (i.e., emergency departments, outpatient 
clinics, etc.).  Rolling admission will be employed in this study.  Patients that 
fulfil all the inclusion criteria and none of the exclusion criteria will 
immediately be admitted to the Clinical Unit and enter a Medication Washout 
Period of up to 7 days (Day -7 to Day -1) before the randomization on Day 0.  
The duration of the Medication Washout Period may be shorter or omitted for 
non-medicated patients. 

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During the Treatment Period, patients will be dosed with 20 mg CPL500036, 
40 mg CPL500036 or placebo once daily for 28 consecutive days (Day 1 to 
Day 28).  Patients will remain in-house for the duration of the Treatment 
Period. 
Approximately 30% of the patients (17 patients in each of the 3 treatment 
groups) will undergo extensive PK sampling during the Treatment Period, and 
the remaining 70% of the patients will only undergo sparse PK sampling. 
On Day 29, the patients may resume anti-psychotics treatment.  The 
Investigator will continue to monitor the patient for safety and clinical 
stability.  Patients will be discharged from the Clinical Unit based on local 
standards of care if the patient is in a stable condition under the regular 
medication(s). 
After discharge from the Clinical Unit, patients will return to the Clinical Unit 
for 2 once weekly Follow-
 
 1) days after the last 
dose of the investigational medicinal product (IMP) (Day 35 and Day 42). 
Patients that withdraw or are withdrawn from the study will attend an early 
termination visit at the Clinical Unit and 2 safety Follow-up V
 1) and 
 1) days after the last dose of IMP. 
Investigational Medicinal Product 
CPL500036 will be supplied by the Sponsor as PG20 product capsules with 
10 mg of CPL500036 as an active pharmaceutical ingredient (API), in blister 
packs. 
The matching placebo will be supplied by the Sponsor as capsules matching 
the PG20 product capsules, in blister packs. 
Number of Subjects 
Approximately 165 patients. 
Study Population 
Inclusion Criteria: 
Patients eligible for inclusion in this study have to fulfil all of the following 
criteria: 
1. The patient has a primary diagnosis of schizophrenia (Diagnostic and 
Statistical Manual of Mental Disorders, 5th Edition [DSM-5], 295.90) 
confirmed by clinical interview (Structured Clinical Interview for DSM-5 
Clinical Trial Version [SCID-5-CT]).  The participant's initial diagnosis 
2 years before Screening. 
2. Male or female patient aged 18 to 65, inclusive, at Screening. 
3. The patient's psychotic symptoms were exacerbated within 2 months 
(60 days) prior to Screening (e.g., aggravated delusion). 
4. The patient has a score of 5 (moderate severe) or higher in 3 or more items 
of the following PANSS items at Screening and Day -1: delusions (P1), 
conceptual disorganization (P2), hallucinations (P3), suspiciousness (P6), 
and unusual thought content (G9). 
5. The patient has a PANSS Total Score of 80 or higher during Screening 
and on Day -1.  
6. A female is eligible to participate if she is not pregnant (negative 
pregnancy test at Screening and Day -1), not breastfeeding, and at least 1 
of the following conditions applies: 
a) Not a woman of childbearing potential (a woman is considered to be 
of non-childbearing potential if she is post-menopausal for at least 
12 months or is surgically sterile [hysterectomy, bilateral 
oophorectomy, tubal ligation]). 

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b) Woman of childbearing potential, who agree to use contraceptive 
methods during the Treatment Period and for at least 28 days after 
the last dose of the study drug. 
The following are acceptable contraceptive methods: bilateral tubal 
occlusion, male sterilization, established proper use of hormonal 
contraceptives that inhibit ovulation, hormone-releasing intrauterine 
devices and copper intrauterine devices, male or female condom with 
spermicide; and cap, diaphragm, or sponge with spermicide. 
7. Male patients must agree to use a barrier method of contraceptive 
(condom + spermicide gel) for at least 90 days after the last dose of the 
study drug. 
8. The patient has a Clinical Global Impression Scale- Severity of Illness 
Scale (CGI-S) of 4 or greater at Screening and Day -1. 
9. The patient is able to and agrees to remain off prior antipsychotic 
medication and all excluded medications as outlined in the protocol for 
the duration of the Treatment Period. 
10. The patient is able to sign informed consent after receiving information 
about the trial. 
11. The patient has the ability and willingness to comply with the 
requirements and restrictions of the study protocol. 
Exclusion Criteria: 
Patients eligible for inclusion in this study must not fulfil any of the following 
criteria: 
1. The patient has a decrease in the PANSS Total Score by 20 percent (%) 
or more at Baseline (Day -1) compared with the Total Score at Screening 
([PANSS Total Score at Screening - PANSS Total Score at 
Baseline]/[PANSS Total Score at Screening- 
 20%).  
2. Patient participated in another interventional clinical study with an IMP 
during the last 30 days or 5 half-lives, whichever is longer, prior to the 
first dose of study drug. 
3. The patient has uncontrolled, hypertension, hypotension, clinically 
significant neurologic, cardiovascular, pulmonary, hepatic, renal, 
metabolic, gastrointestinal, or endocrine disease or other abnormality 
(other than the disease being studied), which may impact the ability of the 
patient to participate or potentially confound the study results. 
4. The patient has a history of severe head injury, traumatic brain injury, 
myocardial infarction or stroke. 
5. The patient has a positive urine drug result (illicit, illegal or without valid 
prescription or medical need) at Screening. 
6. The patient has a moderate or severe substance use disorder (meeting 
more than 4 diagnostic criteria of DSM-5 either currently or within the 
last 6 months) for alcohol or other substances of abuse except nicotine or 
caffeine. 
7. If female, the patient is pregnant (a positive pregnancy test at Screening 
or Day -1) or lactating or intending to become pregnant or intending to 
donate ova, before or during the course of the study or within 12 weeks 
after the last dose. 
8. The patient has a history of or known personality disorder or other 
psychiatric disorder that, in the opinion of the Investigator, would 
interfere with participation in the study. 

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9. The patient has a history of neuroleptic malignant syndrome, water 
intoxication, or paralytic ileus or other conditions that may interfere with 
absorption of study drug. 
10. The patient is considered by the Investigator to be at imminent risk of 
suicide or injury to self, others, or property or participants who within the 
past year prior to Screening have attempted suicide or have positive 
answers on item 4 or 5 on the C-SSRS at Screening or on Day -1. 
11. 
movement disorder that may interfere with the interpretation of study 
results. 
12. The patient has any existing or previous history of cancer that has been in 
remission for less than 5 years prior to Screening. 
Note: this criterion does not include those participants with basal cell, 
stage I squamous cell skin cancer or in situ cervical cancer. 
13. The patient has newly diagnosed diabetes or requires insulin for their 
treatment; diabetic patients that have had changes to their diabetic 
treatment regimen within 30 days prior to Screening or diabetic patients 
that have been hospitalized for their diabetes and/or diabetes related 
conditions in the past year prior to Screening. 
14. The patient has long QT syndrome or is under treatment with Class 1A 
(e.g., quinidine, procainamide) or Class 3 (e.g., amiodarone, sotalol) 
anti-arrhythmic drugs. 
15. The patients with acute or chronic hepatitis B or C infection (positive test 
for hepatitis B surface antigen; positive hepatitis C antibody), known 
human immunodeficiency virus (HIV) infection, or other acute or 
ongoing clinically significant viral or bacterial infections.. 
16. The patient has received any depot preparation (sustained-release 
formulation) of antipsychotic drugs within 1 month (30 days) prior to 
Screening. 
17. The patient is considered to be treatment resistant.  Treatment resistance 
is defined as prior non-response to 2 courses of treatment with anti-
psychotics of different chemical classes for at least 4 weeks each at doses 
considered to be effective. 
18. The patient has received monoamine oxidase (MAO) inhibitors or 
fluoxetine within 1 month (30 days) before Screening. 
19. The patient has received electroconvulsive therapy within 6 months 
(180 days) before Screening. 
20. The patient has 1 or more laboratory values outside the normal range that 
are considered by the Investigator to be clinically significant at Screening; 
or has any of the following at Screening: 
 
A serum creatinine value > 1.5 times the upper limit of 
normal (ULN). 
 
A total serum total bilirubin value > 1.5*ULN. 
 
A serum alanine aminotransferase (ALT) or aspartate 
aminotransferase (AST) value > 2*ULN. 
NOTE: Investigators should ensure that all study enrollment criteria have 
been met at screening and on Day -1.  If a patient status after screening changes 
at baseline (Day -1) such that the study patient no longer meets all eligibility 
criteria, then the patient should be excluded from participation in the study 
(such patient is to be considered as screen failure). It should be remembered 

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that all baseline procedures must be performed on Day -1, but final patient 
qualification should be made when all results are available, before 
randomization on Day 0. 
 
 
 

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Criteria for Evaluation 
Efficacy: 
Primary Endpoint: 
 
Change from baseline in PANSS positive subscale at Week 4. 
Secondary Endpoints: 
 
Change from baseline in PANSS positive subscale at Week 1, 2 and 3 
[Time Frame: Weeks 1, 2, and 3]. 
 
Change from baseline in PANSS Total Score at Weeks 1, 2, 3, 4 [Time 
Frame: Weeks 1, 2, 3, and 4]. 
 
Change from Baseline in PANSS Subscales Using the Marder 5 factor 
Model at Weeks 1, 2, 3, and 4 [Time Frame: Weeks 1, 2, 3, and 4]. 
 
Change from Baseline in PANSS Negative Subscales at Weeks 1, 2, 3 and 
4 [Time Frame: Weeks 1, 2, 3, 4]. 
 
Change from Baseline in PANSS general psychopathology Subscale at 
Weeks 1, 2, 3 and 4 [Time Frame: Weeks 1, 2, 3, 4]. 
 
Percentage of Clinical Responders Based on the PANSS Total Score.  A 
Frame: Weeks 1, 2, 3, 4]. 
 
Change from Baseline in Clinical Global Impression Severity (CGI-S) 
Score at Weeks 1, 2, 3, and 4 [Time Frame: Weeks 1, 2, 3, 4]. 
 
Clinical Global Impression Scale Improvement (CGI-I) Score at Weeks 
1, 2, 3, 4 [Time Frame: Weeks 1, 2, 3, 4]. 
 
Percentage of Responders Based on CGI-I Ratings Score at weeks 1, 2, 3, 
4. 
[Time Frame: Weeks 1, 2, 3, 4].  
 
Change from Baseline in Brief Assessment of Cognition in Schizophrenia 
(BACS) Score at Weeks 2 and 4 [Time Frame: Weeks 2 and 4]. 
Safety: 
Secondary Endpoints: 
 
Physical, 
neurological, 
ophthalmological, 
and 
dermatological 
examination findings. 
 
Adverse event assessments. 
 
Hematologic, clinical chemistry, coagulation and urinalysis results. 
 
Electrocardiogram (ECG) results. 
 
  
Pharmacokinetics: 
Secondary Endpoints: 
The data permitting the following plasma PK parameters will be evaluated 
after single and multiple dose administration for the extensive and sparse PK 
sampling group: 
 
Maximum observed concentration (Cmax) 
 
Time corresponding to occurrence of Cmax (tmax) 
 
AUC from time zero to 24 hours (AUC0-24) 
 
Apparent terminal elimination half-life (t1/2) 
 
Apparent clearance (CL/F) 
 
Apparent volume of distribution during terminal phase (Vz/F) 
 
Concentration immediately prior to dosing (Ctrough).  This parameter will 
only be calculated during the multiple dose administration. 

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Blood samples for PK analysis will be collected at the following time points 
for extensive PK sampling (approximately 30% of patients): 
 
Day 1 and Day 7 (steady state): pre-dose and 0.5, 1, 1.5, 2, 4, 8, 12, and 
24* hours post-dose. 
 
Days 2 to 6: pre-dose* and around 2 hours post-dose. 
 
Day 28: pre-dose and around 2 hours post-dose. 
*please note  the sample 24 hours post-dose on Day 1 it is the same sample as pre-
dose on Day 2. 
Blood samples for PK analysis will be collected at the following time points 
for sparse PK sampling (approximately 70% of the patients): 
 
Day 1 and Day 7 (steady state): pre-dose and 1, 2, 4 and 8 hours post-dose. 
 
Day 28: pre-dose and around 2 hours post-dose. 
Statistical Methods 
Sample Size Considerations: 
This proof of concept study is powered to rule out an effect size of 0.5 or 
greater for the primary endpoint.  With 50 patients per group, the study has 
80% power to detect an effect size of 0.5 or greater for 1 of the 2 dose groups, 
compared to placebo, given a 2-sample t-test, and a 2-sided 10% significance 
level.  Each dose will be compared to placebo, without adjustment for 
multiplicity so the type-I error will be slightly inflated, however, as this is a 
proof of concept study, the slight inflation is acceptable.  Assuming an 
approximately 10% of patients may drop out, approximately 165 patients will 
be randomized (55 patients per group). 
Data Presentation/Descriptive Statistics: 
Analysis Sets: 
 
Full Analysis Set (FAS): All patients randomized to either CPL500036 or 
placebo  based on planned treatment regimen irrespective of their 
compliance to the planned course of treatment (intent-to-treat principle). 
 
Per Protocol (PP) Set: Patients from the FAS who completed the 
Treatment Period (Day 28) on study treatment without a major protocol 
deviation.  Protocol deviations will be determined prior to unblinding. 
 
Safety Set (SS): All patients who received at least 1 dose of study 
treatment (either CPL500036 or placebo). 
 
Pharmacokinetic Set (PS):  All subjects in the safety set with at least 1 
evaluable PK parameter. 
 
Pharmacokinetic Set for parameter calculation (PSPC): All subjects in the 
safety set with extensive PK sampling that have at least 1 PK parameter 
evaluable and without any major protocol deviation thought to interfere 
with the absorption, distribution, metabolism, and excretion of 
CPL500036. 
The FAS will be the primary analysis set used for all efficacy analyses and the 
PP analysis set will be used for supportive analyses of the primary and 
secondary efficacy endpoints.  Patients will be included in the treatment group 
they were randomized to.  The SS will be used for all safety analyses and 
patients will be included in the treatment group based on the treatment they 
actually received.   
Evaluation of Efficacy: 
Descriptive statistics will be displayed to provide an overview of the study 
results.  For categorical variables, the number and percentage of subjects in 
each category will be presented.  The denominator for percentages will be 
based on the number of subjects appropriate for the purpose of analysis for the 

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respective treatment group.  For continuous variables, descriptive statistics 
will include number of subjects (n), mean, standard deviation (SD), median, 
minimum, and maximum.  For all analyses data from all centres will be pooled. 
Primary Efficacy Analysis: 
The null hypothesis is that there is no difference in the primary endpoint 
between either dose group compared to placebo, versus the alternative 
hypothesis, that at least 1 dose group is significantly different, using a 2-sided 
10% significance level.  The primary endpoint will be analysed using a mixed 
effect repeated measures model (MRMM), with treatment, time point, clinical 
site and interaction between clinical site and timepoint as fixed effects and 
baseline score as a covariate.  If there will be many clinical sites with few 
subjects, they can be pooled into bigger groups. Subject will be treated as a 
random effect, with an unstructured covariance structure to account for the 
correlation among repeated measurements.  If the model does not converge, 
another covariance structure, (e.g., AR(1), CS, etc.) will be explored.  Missing 
data will be assumed to be missing at random.  A sensitivity analysis will be 
conducted whereby missing data is imputed using multiple imputation.  The 
primary analysis will compare each dose group with placebo, based on 
estimated marginal means (aka least square means, LS-means) from the model 
without adjustment for multiplicity.  As a secondary analysis of the primary 
endpoint a comparison of both treatment groups pooled, compared to placebo 
will also be made. 
Secondary Efficacy Analyses: 
All secondary endpoints will be analysed without adjustment for multiplicity.  
The secondary endpoints, which are continuous, will be analysed using the 
same approach as described for the primary endpoint.  Missing data will be 
assumed to be missing at random.  At each time point, the LS-means will be 
reported (by treatment group and for the treatment difference for each dose 
group, compared to placebo).  The secondary endpoints which are binary (i.e., 
responder/non-responder) will be analysed at each time point using a Logistic 
regression model with treatment and clinical site (or country if there will be 
many clinical sites) as a fixed effect and baseline score as a covariate.  If a 
patient is missing data in order to derive their response at a given time point, 
the missing data will be imputed using multiple imputation for continuous 
endpoints and non-responser imputation for binary endpoints prior to the 
analysis. 
Pharmacokinetic and PK/PD Analyses: 
Evaluation of Pharmacokinetics CPL500036 plasma concentrations will be 
listed and summarized descriptively and graphically by time point and 
treatment group. 
Pharmacokinetic parameters of CPL500036 will be listed and summarized. 
Pharmacokinetic/PD data will also be displayed graphically as appropriate.  
Safety Analyses: 
Evaluation of Safety endpoints will be summarized descriptively by treatment 
group and visit for the Safety Population. 
 

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1.2. 
Schema 
The study design is presented in Figure 1. 
Figure 1 
Study Overview 
 
Screening Period and Washout Period 
Treatment Period 
Follow-up Visit 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed  
Consent 
Baseline  
 
Randomization 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Discharge 
 
 
 
 
 
 
 
 
 
 
 
 
DOSING 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day -10 to -2 
Day-1 
 
 
Day 0 
 
 
Day 1 
To Day 28 
 
Day 29 
 
7 days  
 1 day) 
and 14 days  
 1 day) 
post-last 
dose of IMP 
 
IMP = investigational medicinal product 
 
 
1.3. 
Schedule of Assessments, Time Points and Window Allowance 
Details on procedures and timing of assessments are presented in Table 1.   
 

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Table 1 
Schedule of Assessments 
 
Screening 
Period a 
and 
Washout 
Period b 
Baseline 
and 
Washout b 
Randomizationb 
Treatment Period 
Study Week 
 
 
 
Week 1 
Week 2 
Week 3 
Wee
Study Day 
-10 to -2 
-1 
0 
1 
2 to 6 
7 
8 to 13 
14 
15 to 20 
21 
22 to 27
Study Plan 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
X 
X 
 
 
 
 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 Alcohol test and 
urinary drug screen  
X 
X 
 
 
 
 
 
 
 
 
 
Viral serology 
X 
 
 
 
 
 
 
 
 
 
 
Weight and height 
X 
X 
 
 
 
 
 
 
 
 
 
IMP 
Administration: 
 
 
 
 
 
 
 
 
 
 
 
Medication Washout 
X 
X 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
CPL500036/Placebo 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Resumption of 
anti-psychotics 
 
 
 
 
 
 
 
 
 
 
 
Safety and 
Tolerability: 
 
 
 
 
 
 
 
 
 
 
 
Adverse event 
questioning 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 

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Screening 
Period a 
and 
Washout 
Period b 
Baseline 
and 
Washout b 
Randomizationb 
Treatment Period 
Study Week 
 
 
 
Week 1 
Week 2 
Week 3 
Wee
Study Day 
-10 to -2 
-1 
0 
1 
2 to 6 
7 
8 to 13 
14 
15 to 20 
21 
22 to 27
Study Plan 
 
 
 
 
 
 
 
 
 
 
 
ESRS monitoring d 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
Prior/concomitant 
medication 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
C-SSRSe 
X 
X 
 
 
 
 
X 
 
 
 
Blood pressure, 
pulse and respiratory 
rate (supine) and 
body temperature f 
X 
X 
 
X 
X 
X 
 
X 
 
X 
 
12-lead safety ECG g 
X 
X 
 
 
X 
 
X 
 
X 
 
Clinical laboratory 
evaluations (clinical 
chemistry, 
hematology, 
coagulation and 
urinalysis) 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
Physical examination 
X 
X 
 
 
 
 
 
 
 
 
 
Neurological 
examination 
X 
X 
 
 
 
Xh 
 
Xh 
 
Xh 
 
Ophthalmological 
examination 
X 
 
 
 
 
 
 
 
 
 
 
Dermatological 
examination 
X 
 
 
 
 
 
 
 
 
 
 

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Screening 
Period a 
and 
Washout 
Period b 
Baseline 
and 
Washout b 
Randomizationb 
Treatment Period 
Study Week 
 
 
 
Week 1 
Week 2 
Week 3 
Wee
Study Day 
-10 to -2 
-1 
0 
1 
2 to 6 
7 
8 to 13 
14 
15 to 20 
21 
22 to 27
Study Plan 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy testing 
X 
(serum) 
X 
(urine) 
 
 
 
 
 
 
 
 
 
Efficacy 
 
 
 
 
 
 
 
 
 
 
 
PANSS 
X 
X 
 
X i 
 
X i 
 
X i 
 
X i 
 
CGI-S 
X 
X 
 
 
X i 
 
X i 
 
X i 
 
CGI-I 
 
 
X i 
 
X i 
 
X i 
 
BACS 
 
X 
 
 
 
 
X i 
 
 
 
Pharmacokinetics 
 
 
 
 
 
 
 
 
 
 
 
Extensive PK blood 
sample collection 
 
 
 
X j 
X k 
X j 
 
 
 
 
 
Sparse PK blood 
sample collection 
 
 
 
X l 
 
X l 
 
 
 
 
 
BACS: Brief Assessment of Cognition in Schizophrenia; C-SSRS: Columbia Suicide Severity Rating Scale; ECG: Electrocardi
Symptom Rating Scale; CGI-I: Clinical Global Impression Scale - Improvement; CGI-S: Clinical Global Impression Scale - 
Medicinal Product; PANSS: Positive and Negative Syndrome Scale; PK: Pharmacokinetic(s). 
a) 
 
b) 
 
 
c) 

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d) 
 
e) 
f) 
g) 
 
h) 
i) 
 
 
 
j) 
 
k) 
 
*please note  the sample 24 hours post-dose on Day 1 it is the same sample as pre-dose on Day 2. 
l) 
 
 
m) 
 
 

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2. 
INTRODUCTION 
2.1. 
Background 
Phosphodiesterase 10A (PDE10A) is an enzyme belonging to the 
consisting of 11 members [1].  PDE10A possesses several splice variants not differing in the 
catalytic domain [2].  PDE10A is expressed highly specific in the striatum [3], in particular in 
medium spiny neurons (MSNs).  MSNs compose about 90% of the striatum and are characterized 
by expression of either dopamine receptors D1 or D2 that allow to group them in 2 different 
projection circuits.  MSNs expressing D1 receptors project to substantia nigra and constitute 
striatonigral (direct) pathway.  MSNs characterized by D2 expression project to globus pallidus 
and comprise striatopallidal (indirect) pathway.  These 2 pathways have contrary action on the 
transmission enabling to regulate various functions involved in control of motor movement, 
cognitive processes, emotions and learning [4]. 
PDE10A hydrolyses both cyclic adenosine monophosphate (cAMP) and cyclic guanosine 
monophosphate (cGMP)  cyclic nucleotides that are secondary messengers in many types of cells 
[1].  cAMP and cGMP in MSNs may trigger various molecular events including phosphorylation 
of the Protein Kinase A (PKA), Protein Kinase G (PKG), exchange proteins directly activated by 
cAMP (Epacs) and cyclic nucleotide-gated ion channels (CNG) [5].  Downstream signalling 
includes phosphorylation and activation of proteins that are highly expressed in MSNs  in 
particular: dopamine and cyclic AMP-regulated phospho- protein (DARPP-32)  as well activation 
of MAPK/ERK pathway.  Thus, inhibition of the PDE10A may modulate the MSNs action in an 
efficient way.  Inhibition of PDE10A in the stratopallidal circuit leads to diminishing of the D2 
activation signalling in contrast to the direct circuit, where stratonigral inhibition of the PDE10A 
result in mimicking the D1 signalling [6].  Balance between these 2 circuits plays essential function 
in controlling motor and executive functions [7].  It is postulated that modulation of both circuits 
by inhibition of PDE10A may lead not only to treating the positive symptoms, but also to 
improving negative or cognitive dysfunctions in schizophrenia [8].  These effects have been shown 
in several preclinical models by use of various PDE10A inhibitors [9; 10; 11; 12]. 
CPL500036 is a novel, PDE10A inhibitor characterized by high in vitro potency and selectivity.  
CPL500036 has good oral bioavailability and blood-brain-barrier penetration in rats.  Several 
behavioural studies have confirmed its antipsychotic and pro-cognitive action in rats.  Ex vivo 
studies have confirmed dose dependent phosphorylation of proteins dependent on cyclic 
nucleotides concentrations.  Based on the preclinical studies the compound has been selected as a 
good clinical candidate for the treatment of schizophrenia and psychotic disorders. 

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The compound CPL500036 was initially developed as a hydrochloride salt.  This form was used 
for preclinical studies including non-good laboratory practice (non-GLP) toxicity studies for 
determination of maximum tolerated dose and no-observed-adverse-effect-level (NOAEL) dose 
during 14-day toxicity study in rats and dogs.  However, due to instability of the salt caused by 
release of the hydrochloride and constituently changing water content, free form of the compound 
was selected for remaining toxicity studies in GLP standard - 28-days administration study in rats 
and dogs.   
The final product PG20 that was used in phase I clinical trial contains CPL500036 in free form as 
an active pharmaceutical ingredient (API) with excipients: copovidone, crospovidone, mannitol.  
Final product differs from the product (formulation) used in toxicity studies.  To compare both 
formulations bridging PK studies in rats and dogs were performed.  In both species the 
formulations presented a comparable PK profile with minimal higher exposition for the final 
product (30% higher exposition based on AUC(0-t) for the doses around determined NOAELs). 
was designed 
predominantly for the treatment of psychotic disorders like schizophrenia.  There are also some 
a beneficial effect 
for a patient suffering from Levodopa-
 
 
Schizophrenia is a mental disorder seriously impairing the ability to think logically, establish 
relationships with people and functioning in society [13].  This disease affects about 1% of the 
population with the onset of morbidity at the age of 20 to 30 years.  It is characterized by many 
symptoms, which in each patient can develop in a completely different direction and occur with 
various intensities.  For this reason, it could be diagnosed even after several years of illness [14].  
The risk of developing schizophrenia is closely related to the individual possibilities of coping 
with stress and emotions.  In the development of the disease, the importance of genetic background 
was found.  Schizophrenics revealed morphological changes in the structure of the brain, 
abnormalities in size, distribution and the mutual connection of neurons in the brain.  
Schizophrenia is characterized by the presence of positive symptoms (auditory hallucinations, 
delusions, hallucinations) and negative symptoms (concentration disorders, apathy, social 
withdrawal, impoverishment of vocabulary and hypomimia) [15].  The exact causes of 
schizophrenia are still under investigation, however, the leading hypotheses base on the high or 
low abundance of specific neurotransmitters: dopamine and glutamate, respectively [16].  
Therefore, psychotic episodes may be controlled, and in many cases prevented, by treatment with 
dopamine D2 receptor antagonists.  These antipsychotic agents represent the first and only line of 

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pharmacotherapy for the treatment of schizophrenia and have significantly reduced the burden of 
this illness on patients and society.  However, the use of anti-psychotics can be associated with 
severe, mechanism-related motor side effects, and 10% to 30% of patients receive little or no 
benefit from D2 receptor antagonists [13].  Although newer, atypical agents with mixed 
pharmacology have an improved safety profile with respect to motor side effects, many of them 
are associated with metabolic effects that can result in serious de novo medical problems.  
Moreover, there is a consensus that neither typical nor atypical agents treat the debilitating negative 
and cognitive symptoms of schizophrenia in the sufficient degree. 
2.2. 
Summary of Findings from Non-clinical Studies with Potential Clinical Relevance 
The purpose of the in vivo studies presented below was the examination of the CPL500036 effects 
on the positive, negative and cognitive schizophrenia symptoms in various pharmacological rat 
models. 
2.2.1. 
In Vivo Behavioural Studies  Antipsychotic Effects 
To assessed CPL500036 potential antipsychotic effects three in vivo behavioural studies were 
performed: 
Conditioned Avoidance Response: 
The Conditioned Avoidance Response (CAR) test allows to identify drugs having particular 
tranquillizing properties that are specifically effective against psychotic symptoms [17]. 
Inhibition of induced hyperlocomotion using phencyclidine and apomorphine models: 
In this study CPL500036 was evaluated as an antipsychotic agent in a pharmacological model of 
psychosis  phencyclidine (PCP) and apomorphine (APO) induced hyperlocomotion paradigm.  In 
humans, PCP and APO are known to produce a syndrome of behavioral effects which have many 
characteristics in common with schizophrenia [18].  Therefore, antagonism of PCP and APO 
effects might be evidence for antipsychotic efficacy of a compound. 

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Pre-pulse inhibition of the acoustic startle response: 
Pre-pulse inhibition of the acoustic startle response (PPI).  PPI is a neurological phenomenon in 
which a weaker pre-stimulus (pre-pulse) inhibits the reaction of an organism to a subsequent strong 
startling stimulus (pulse).  On a loud acoustic stimulus, normal rats (and humans) display a startle 
response [19].  The presentation of a pre-pulse stimulus reduces startle.  Compounds that model 
certain aspects of psychoses reverse this reduction; this effect can be normalized by many 
anti-psychotics. 
Different doses of CPL500036 was tested.  Minimal effective doses achieved at mentioned studies 
as well as all tested doses are summarized in Table 2. 
Table 2 
The minimal effective doses (MED) and all tested doses of CPL500036 
administered to rats in behavioral tests assessing potential antipsychotic effects 
Test 
Species 
Tested doses 
[mg/kg b.w.] 
MED 
[mg/kg b.w.] 
Antipsychotic effect 
Conditioned 
avoidance response 
(CAR) 
Rat 
0.1 
0.2 
0.2 
0.3 
Inhibition of 
phencyclidine 
induced 
hyperlocomotion 
(PCP- induced HA) 
Rat 
0.1 
0.1 
0.3 
1 
3 
10 
Inhibition of 
apomorphine 
induced 
hyperlocomotion 
Rat 
0.3 
0.6 
0.6 
Prepulse inhibition 
of the acoustic 
startle response 
(PPI) 
Rat 
0.1 
0.3 
0.3 
b.w. = body weight 
The results of presented behavioral studies in rats suggest antipsychotic-like activity of 
CPL500036 compound from 0.1 mg/kg body weight. 

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2.2.2. 
In Vivo Behavioural Studies  Pro-cognitive Effects 
To assessed CPL500036 potential pro-cognitive effects three in vivo behavioral studies were 
performed: 
Novel object recognition: 
For evaluation of pro-cognitive effect of CPL500036, the novel object recognition test (NOR) was 
performed.  The NOR task is very useful to study working memory and is evaluated by the 
differences in the exploration time of novel and familiar objects.  Normal rats show reduced 
exploration of the novel object at short time; compounds that disturb learning (PCP, ketamine, 
scopolamine) produce lack of object discrimination.  Conversely, normal rats show similar 
exploration of the known and novel objects at long; pro-cognitive compounds like PDE10A 
inhibitors may reduce the exploration of the familiar object. 
Attentional set shifting task: 
The attentional set shifting task (ASST) was developed as a measure of attention and cognitive 
flexibility in rats [20].  The ability to learn simple rules remains intact, deficits in learning to 
modify a response when the rules have changed are found in patients suffering from a variety of 
neuropsychiatric disorders such as schizophrenia. 
In ASST paradigm, rats must select a bowl containing a food reward based on the ability to 
discriminate the odours or the media covering the bait.  The ASST requires rats to initially learn a 
- dimensional 
(ED) shift stage, the essential phase of the task, animals must switch their attention to a previously 
irrelevant stimulus dimension and, for example, discriminate between the odours and not between 
the media covering the bait.  The animal's performance at the ED stage is considered an index of 
cognitive flexibility. 
Five-choice serial reaction time task: 
Executive functions, such as attention and inhibitory control, are affected in many psychiatric 
disorders, e.g. schizophrenia, attention-deficit hyperactivity disorder (ADHD) and substance abuse 
disorders.  The 5-choice serial reaction time task (5-CSRTT) for rats, in which the animals have 
to respond to a brief stimulus presented pseudo-randomly in 1 of 5 holes in order to obtain a food 
reward and which measures aspects of visuospatial sustained and divided attention, as well as a 
form of impulsive action 
 [21]. 

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Different doses of CPL500036 was tested.  Minimal effective doses achieved at mentioned studies 
as well as all tested doses are summarized in Table 3. 
Table 3 
The minimal effective doses (MED) and all tested doses of CPL500036 
administered to rats in behavioral tests assessing potential procognitive effects 
Test 
Species 
Tested doses 
[mg/kg b.w.] 
MED 
[mg/kg b.w.] 
Procognitive effect 
Novel object 
recognition test 
(NOR) 
Rat 
0.03 
0.1 
0.1 
0.3 
Attentional set 
shifting task 
(ASST) 
Rat 
0.01 
0.03 
0.03 
0.1 
Five-choice serial 
reaction time task 
(5-CSRTT) 
Rat 
0.03 
0.1 
0.1 
b.w. = body weight 
The results of presented behavioral studies in rats suggest pro-cognitive effect of CPL500036 
compound from 0.03 mg/kg body weight. 
2.2.3. 
In Vivo Behavioural Studies  Effects on Negative Symptoms of Schizophrenia 
To assessed CPL500036 potential effects on negative symptoms one in vivo behavioural study was 
performed: 
Social interaction test: 
Social interactions are a fundamental and adaptive component of the biology of numerous species.  
Social recognition is critical for the structure and stability of the networks and relationships that 
define societies.  Specifically, perturbations in social functioning such as social withdrawal and 
asociality that represent key items of a cluster of negative symptoms of schizophrenia may be 
modelled using the social interaction test (SIT) [22]. 
Different doses of CPL500036 was tested.  Minimal effective dose was not achieved at mentioned 
study.  All tested doses are summarized in Table 4. 

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Table 4 
The minimal effective doses (MED) and all tested doses of CPL500036 
administered to rats in behavioral tests assessing effects on negative symptoms 
Test 
Species 
Tested doses 
[mg/kg b.w.] 
MED 
[mg/kg b.w.] 
Negative symptoms 
Social interaction 
test (SIT) 
Rat 
0.1 
ND 
0.3 
0.6 
b.w. = body weight; ND = not determined 
CPL500036 at tested doses did not improve the negative-like symptoms of schizophrenia as 
assessed in a model based on N-Methyl-D-aspartate (NMDA) receptor antagonist induced social 
withdrawal. 
23]. 
2.2.4. 
Toxicology 
2.3. 
Summary of Findings from Previous Clinical Studies 

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2.4. 
Rationale for the Clinical Study 

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2.5. 
Risk-benefit Assessment 
Current antipsychotics used in patients with schizophrenia although effective are not perfect as 
they might be associated with different side effects. The development of new, effective therapy 
with improved safety profile would be a beneficial treatment options for schizophrenia patients. 
The PDE10 inhibitors, based on several preclinical models, may represent a new approach for 
treatment of psychosis. The use of treatment with new mechanism of action may exert some risks, 
which, based on available information, was recognized and the study was design to minimize it. 
In a similar phase 2, randomized, placebo-controlled study, the efficacy and safety of a selective 
PDE10A inhibitor (TAK-063) in patients with an acute exacerbation of schizophrenia were 
evaluated [25].  In this study, no clinically relevant or consistent differences were observed 
between study drug and placebo groups for hematologic, renal, or hepatic lab test results, vital 
signs, or ECG.  Most subjects reported AEs that were mild or moderate in severity, and the AEs 
reported in this study were generally consistent with the previously conducted phase 1 studies [26, 
27
-063) group were akathisia (placebo: 
4.9%; IMP: 13.3%), somnolence (placebo: 2.5%; IMP: 12.0%), dyspepsia (placebo: 7.4%; IMP: 
10.8%), headache (placebo: 11.1%; IMP: 7.2%), nausea (placebo: 6.2%; IMP: 6.0%), dystonia 
(placebo: 1.2%; IMP: 6.0%), and decreased appetite (placebo: 1.2%; IMP: 6.0%).  None of the 
serious adverse event (SAE) was considered related to study drug.  The investigated PDE10A 
inhibitor did not result in any deaths, and most AEs were mild or moderate in severity and did not 
result in the specific study discontinuation [26, 27]. 
Phase I study results in healthy volunteers showed that CPL500036 compound is generally safe 
and well tolerated. Potential risks associated with use of CPL500036 based on most frequently AE 
occurrence in phase I study, assessed as related or possible related with IMP: 
 
Drowsiness/somnolence
 
Feeling calm
 
Headache
 
Sensation of cold
 
ensation of hot/heat.
The intensity of observed AEs was classified as mild or moderate. All the  AEs were transient 
and their frequency decreased after Day 3 of administration (in multiple dosing). The most 

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frequent AE were drowsiness and somnolence (more than 50% all AEs reported in PART B). 
Details can be found in the IB [23]. 
This phase II study is to evaluate the efficacy, safety and tolerability and PK of 2 doses of 
CPL500036, compared to placebo in patients with an acute exacerbation of schizophrenia.  
Preclinical results available for CPL500036 compound shows antipsychotic-like properties of the 
compound.  The potential attenuation of positive symptoms associated with schizophrenia, in 
patients receiving the IMP, will be evaluated.  Treatment efficacy will be tested with potential 
improvements at the higher doses.  Placebo patients will not receive active treatment so should not 
experience health benefits.  However, patient receiving placebo may show improvement, called 
the placebo effect, since higher placebo response is observed in patients with schizophrenia clinical 
studies in the last decades [30]
-063, PDE10 inhibitor, 
mentioned above, percentages of responders were approximately 43% or 29% of patients receiving 
placebo, based on PANSS or CGI-I score, respectively [25]. 
The use of placebo in clinical studies with schizophrenia patients raise some ethical concerns.  
Guideline on clinical investigation of medicinal products, including 
depot preparations in the treatment of schizophrenia (EMA/CHMP/40072/2010 Rev. 1, 30).  the 
use of placebo control is considered necessary 
place the benefits of using a placebo arm will generally override any ethical reservations in short 
term controlled efficacy trials .  Placebo control group is required by many regulators because of 
its importance in helping to identify safety signals in clinical trial [28]. Placebo-controlled trails 
are usually consider the gold standard method to prove efficacy and safety of new drugs, including 
antypsychotics [29].  An apparent paradox occurs in placebo-controlled studies.  Using placebo 
challenges the ethical aspects but the use of placebo in drug development may actually serve to 
reduce the overall number of patients who are exposed to ineffective treatments because those 
studies require smaller sample size to detect a significant difference [28].  Thus, due to relative 
small number of patients included in randomized, placebo studies, consequently the number of 
non-responders are small. Studies involving placebo in psychosis are short in duration (maximum 
of eight weeks) and based on the evidence available, the conventional antipsychotics are associated 
with only a small effect when administered this short, with the larger effect in long-term studies 
[29]. Moreover, psychotic patients in placebo-controlled studies are usually hospitalized, under 
constant supervision.  They receive medications to control anxiety, agitation and insomnia and 
treatment may be discontinued if ineffective.  Due to this some may argue that hospitalized 
itself may largely contribute with recovery [29]. 

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The 02PDE2019 study is considered a short term study with up to 7 days of medication washout 
period and 28-day treatment phase.  The CPL500036 compound will be used in monotherapy , so 
other antipsychotic treatments will be discontinued, what is in line with the EMA  guidelines which 
consequences of these exclusions for generalizability of the trial results.  Therefore other 
antipsychotic drugs should be discontinued 
[30].  The protocol has been designed to 
minimize the risk to all research participants.  This study will be performed in controlled settings, 
all patients will be hospitalized to assure patients safety.  Subjects will be monitored to detect AEs 
during the study and followed appropriately to ensure resolution of AEs. 
To manage potential side effects and symptoms that may occur, allowed treatments are described.  
During the study lorazepam may be administered for anxiety/agitation or to aid sleep.  To manage 
insomnia from z-drugs, use of zolpidem is allowed in the study.  To treat extrapyramidal side 
effects and akathisia benzatropine/biperiden and propanolol are permitted, respectively.  The daily 
and weekly limits of those medications that can be used, on a PRN (as needed) basis are provided 
(rules for medication administration in Section 5.4.3).  If a patient  condition will require to 
exceed the specified dose, it must be recorded as Serious Adverse Event. 
During the whole study all the patients will be closely observed by the Investigator or appointed 
staff members to assure maximal safety.  Safety is to be ensured by performing clinical 
assessments/ evaluations and clinical laboratory measurements/ evaluations.  This includes i.a. 
monitoring of vital signs with 3-positional blood pressure and pulse measurements, ECG 
measurements and extrapyramidal side effects monitoring using Extrapyramidal Symptom 
Rating Scale (ESRS) assessments.  Patients at imminent risk of suicide or injury to self, others, 
or property or participants who within the past year prior to screening have attempted suicide 
will be excluded from the study and risk of potential suicide ideations occurrence will be 
assessed during the study. 
 

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3. 
STUDY OBJECTIVES AND ENDPOINTS 
3.1. 
Primary Objective 
Efficacy: 
 To determine if CPL500036 administered for 28 days can attenuate the positive symptoms 
associated with schizophrenia. 
3.2. 
Secondary Objectives 
Efficacy: 
 To determine if CPL500036 administered for 28 days can attenuate the negative symptoms 
associated with schizophrenia. 
 To determine if CPL500036 administered for 28 days results in overall clinical improvement 
as assessed by the Clinical Global Impression Scale - Improvement (CGI-I). 
 To determine if CPL500036 administered for 28 days results in overall clinical improvement 
as assessed by the Positive and Negative Symptom Scale (PANSS). 
Safety: 
 To assess the safety and tolerability of CPL500036 administered for 28 days. 
Pharmacokinetics: 
 To assess the pharmacokinetic (PK) profile of CPL500036 administered for 28 days. 
3.3. 
Endpoints 
3.3.1. 
Efficacy 
Primary Endpoint: 
 Change from baseline in PANSS positive subscale at Week 4. 
Secondary Endpoints: 
 Change from baseline in PANSS positive subscale at Week 1, 2 and 3 [Time Frame: Weeks 1, 
2, and 3]. 
 Change from baseline in PANSS Total Score at Weeks 1, 2, 3, 4 [Time Frame: Weeks 1, 2, 3, 
and 4]. 

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 Change from Baseline in PANSS Subscales Using the Marder 5-factor Model at Weeks 1, 2, 
3, and 4 [Time Frame: Weeks 1, 2, 3, and 4]. 
 Change from Baseline in PANSS Negative Subscales at Weeks 1, 2, 3 and 4 [Time Frame: 
Weeks 1, 2, 3, 4]. 
 Change from Baseline in PANSS general psychopathology Subscale at Weeks 1, 2, 3 and 4 
[Time Frame: Weeks 1, 2, 3, 4]. 
 Percentage of Clinical Responders Based on the PANSS Total Score.  A clinical responder is 
 30% decrease from baseline, [Time Frame: Weeks 1, 2, 3, 4]. 
 Change from Baseline in Clinical Global Impression - Severity (CGI-S) Score at Weeks 1, 2, 
3, and 4 [Time Frame: Weeks 1, 2, 3, 4]. 
 Clinical Global Impression Scale - Improvement (CGI-I) Score at Weeks 1, 2, 3, 4 [Time 
Frame: Weeks 1, 2, 3, 4]. 
 Percentage of Responders Based on CGI-I Ratings Score at weeks 1, 2, 3, 4. A responder is 
 [Time Frame: Weeks 1, 2, 
3, 4]. 
 Change from Baseline in Brief Assessment of Cognition in Schizophrenia (BACS) Score at 
Weeks 2 and 4 [Time Frame: Weeks 2 and 4]. 
3.3.2. 
Safety 
Secondary Endpoints: 
 Physical, neurological, ophthalmological, and dermatological examination findings. 
 Adverse event assessments. 
 Hematologic, clinical chemistry, coagulation and urinalysis results. 
 Electrocardiogram (ECG) results. 
 Extrapyramidal side effects monitoring using the Extrapyramidal Symptom Rating Scale 
(ESRS). 

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3.3.3. 
Pharmacokinetics 
Secondary Endpoints: 
The data permitting the following plasma PK parameters will be evaluated after single and multiple 
dose administration for the extensive and sparse PK sampling groups: 
 Maximum observed concentration (Cmax) 
 Time corresponding to occurrence of Cmax (tmax) 
 AUC from time zero to 24 hours (AUC0-24) 
 Apparent terminal elimination half-life (t1/2) 
 Apparent clearance (CL/F) 
 Apparent volume of distribution during terminal phase (Vz/F) 
 Concentration immediately prior to dosing (Ctrough).  This parameter will only be calculated 
during the multiple dose administration. 

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4. 
STUDY DESIGN 
4.1. 
Overview 
This is a double-blind, randomized, placebo controlled, parallel group, dose ranging study to 
explore the efficacy, safety, tolerability and PK of 2 different doses of CPL500036 (PDE10A 
inhibitor) in patients with an acute exacerbation of schizophrenia when administered for 28 days. 
The study will be conducted at multiple clinical units.  Approximately 165 patients will be 
randomized at a 1:1:1 ratio to receive 20 mg CPL500036, 40 mg CPL500036 or placebo. 
The study will comprise of a Screening Period (that will include a prior Medication Washout 
Period), a Treatment Period and a Follow-up Period. 
For the Screening Period, patients will undergo screening assessments from Day -10 to Day -8 in 
multiple settings (i.e., emergency departments, outpatient clinics, etc.).  Rolling admission will be 
employed in this study.  Patients that fulfil all the inclusion criteria and none of the exclusion 
criteria will immediately be admitted to the Clinical Unit and enter a Medication Washout Period 
of up to 7 days (Day -7 to Day -1) before the randomization on Day 0.  The duration of the 
Medication Washout Period may be shorter or omitted for non-medicated patients. 
During the Treatment Period, patients will be dosed with 20 mg CPL500036, 40 mg CPL500036 
or placebo once daily for 28 consecutive days (Day 1 to Day 28).  Patients will remain in-house 
for the duration of the Treatment Period. 
Approximately 30% of the patients (17 patients in each of the 3 treatment groups) will undergo 
extensive PK sampling during the Treatment Period, and the remaining 70% of the patients will 
only undergo sparse PK sampling. 
On Day 29, the patients may resume anti-psychotics treatment.  The Investigator will continue to 
monitor the patient for safety and clinical stability.  Patients will be discharged from the Clinical 
Unit based on local standards of care if the patient is in a stable condition under the regular 
medication(s). 
After discharge from the Clinical Unit, patients will return to the Clinical Unit for 2 once weekly 
Follow-
 
 1) days after the last dose of the investigational medicinal 
product (IMP) (Day 35 and Day 42). 
Patients that withdraw or are withdrawn from the study will attend an early termination visit at the 
Clinical Unit and 2 safety Follow-up V
 
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4.2. 
Scientific Rationale for the Study Design 
This study evaluates the efficacy, safety, tolerability and PK of 2 different doses of CPL500036 
(PDE10A inhibitor) in patients with an acute exacerbation of schizophrenia.  The design is 
standard and is considered appropriate to meet the objectives of the study. 
The study design meets 
investigation of medicinal products, including depot preparations in the treatment of 
 30).  This is a proof-of-concept study 
assessing CPL500036 compound with new mechanism of action in treating positive symptoms 
of schizophrenia so comparison to placebo is considered appropriate to assess treatment 
benefit.  To better characterize the effect size two doses of CPL500036 as monotherapy will 
be used.  Risks in the study, especially those of using placebo were acknowledge and the study 
was design to minimize it (see section 2.5).  For efficacy assessment validated scales 
recommended in the guideline are to be used as an assessment tools.  PANSS will be used for 
primary endpoint measurements, including the recommended definition of responders used in 
short term trials with acute/exacerbated symptoms is to be used for clinical response evaluation.  
For secondary efficacy measures both CGI-S and CGI-I assessments are planned in the study.  
Extrapyramidal symptoms (EPS) are potential adverse events that according to guideline are 
to be monitored during the studies in schizophrenia patients, which was addressed by using 
ESRS scale for EPS monitoring. 
The safety assessments for the study are accepted measures for ensuring safety of subjects during 
a clinical trial.  The PK sampling schedule is considered appropriate given the information 
available.  The rationale for dose selection is discussed in Section 4.3. 
4.3. 
Justification for Dose 
4.4. 
Order of Assessments 
The following priority order will be in effect when more than one assessment is required at a 
pre-dose and post-dose time point, with PK blood sampling being performed in the specified time: 
1.  Vital signs, 

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2.  12-lead ECG, 
3.  Blood sampling for safety and PK assessments, 
4. PANSS, CGI-S, CGI-I and BACS, 
5. ESRS monitoring, 
6. Columbia Suicide Severity Rating Scale (C-SSRS). 
4.5. 
Study Duration 
The duration of participation for each subject will be approximately 8 weeks.  The estimated study 
duration includes: 
7. Screening Period: Up to 10 days. 
8. Treatment Period: Days 1 to 28. 
9. Follow-up Period: 7 to 14 days after the post-last dose of IMP (Day 28)  Days 35 to 42. 
4.6. 
End of the Study 
For the entire study, end of the study is defined as the last visit of the last subject for any protocol 
related activity (last subject, last visit).  - 
4.7. 
Study Completion 
A subject is to be considered to have completed the double-blind treatment phase if he/she has 
completed all the assessments and procedures on Day 28. Subject who, for any reason, 
discontinues the study before Day 28 is not to be considered to have completed the study. 
4.8. 
Early Termination 
If a subject withdraws prematurely after dosing, all data normally collected at discharge from the 
clinical site should be collected at the time of premature discontinuation or at the scheduled 
discharge.  If deemed necessary by the Investigator, the subject will be asked to return for an 
unscheduled visit for safety follow-up. 

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5. 
STUDY POPULATION 
The study population will consist of male and female patients with an acute exacerbation of 
schizophrenia.  Subjects must be able to provide written informed consent and meet all the 
inclusion criteria and none of the exclusion criteria. 
NOTE: Investigators should ensure that all study enrollment criteria have been met at screening 
and on Day -1.  If a patient status after screening changes at baseline (Day -1) such that the study 
patient no longer meets all eligibility criteria, then the patient should be excluded from 
participation in the study (such patient is to be considered as screen failure). It should be 
remembered that all baseline procedures must be performed on Day -1, but final patient 
qualification should be made when all results are available, before randomization on Day 0. 
5.1. 
Number of Subjects 
A total of 165 subjects will be enrolled in the clinical study. 
5.2. 
Inclusion Criteria 
Patients eligible for inclusion in this study have to fulfil all of the following criteria: 
1. The patient has a primary diagnosis of schizophrenia (Diagnostic and Statistical Manual of 
Mental Disorders, 5th Edition [DSM-5], 295.90) confirmed by clinical interview (Structured 
Clinical Interview for DSM-5 Clinical Trial Version [SCID-5-CT]).  The participant's initial 
2 year before Screening. 
2. Male or female patient aged 18 to 65, inclusive, at Screening. 
3. The patient's psychotic symptoms were exacerbated within 2 months (60 days) prior to 
Screening (e.g., aggravated delusion). 
4. The patient has a score of 5 (moderate severe) or higher in 3 or more items of the following 
PANSS items at Screening and Day -1: delusions (P1), conceptual disorganization (P2), 
hallucinations (P3), suspiciousness (P6), and unusual thought content (G9). 
5. The patient has a PANSS Total Score of 80 or higher during Screening and on Day -1.  
6. A female is eligible to participate if she is not pregnant (negative pregnancy test at Screening 
and Day -1), not breastfeeding, and at least 1 of the following conditions applies: 
a) Not a woman of childbearing potential (a woman is considered to be of non-childbearing 
potential if she is post-menopausal for at least 12 months or is surgically sterile 
[hysterectomy, bilateral oophorectomy, tubal ligation]). 

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b) Woman of childbearing potential, who agree to use contraceptive methods during the 
Treatment Period and for at least 28 days after the last dose of the study drug. 
 
The following are acceptable contraceptive methods: bilateral tubal occlusion, male 
sterilization, established proper use of hormonal contraceptives that inhibit ovulation, 
hormone-releasing intrauterine devices and copper intrauterine devices, male or female 
condom with spermicide; and cap, diaphragm, or sponge with spermicide. 
7.  Male patients must agree to use a barrier method of contraceptive (condom + spermicide gel) 
for at least 90 days after the last dose of the study drug. 
8. The patient has a Clinical Global Impression Scale- Severity of Illness Scale (CGI-S) of 4 or 
greater at Screening and Day -1. 
9. The patient is able to and agrees to remain off prior antipsychotic medication and all excluded 
medications as outlined in the protocol for the duration of the Treatment Period. 
10. The patient is able to sign informed consent after receiving information about the trial. 
11. The patient has the ability and willingness to comply with the requirements and restrictions of 
the study protocol. 
5.3. 
Exclusion Criteria 
Patients eligible for inclusion in this study must not fulfil any of the following criteria: 
1.  The patient has a decrease in the PANSS Total Score by 20 percent (%) or more at Baseline 
(Day -1) compared with the Total Score at Screening ([PANSS Total Score at 
Screening - PANSS Total Score at Baseline]/[PANSS Total Score at Screening- 30)]*100 
 20%).  
2. Patient participated in another interventional clinical study with an IMP during the last 30 days 
or 5 half-lives, whichever is longer, prior to the first dose of study drug. 
3. The patient has uncontrolled, hypertension, hypotension, clinically significant neurologic, 
cardiovascular, pulmonary, hepatic, renal, metabolic, gastrointestinal, or endocrine disease or 
other abnormality (other than the disease being studied), which may impact the ability of the 
patient to participate or potentially confound the study results. 
4. The patient has a history of severe head injury, traumatic brain injury, myocardial infarction 
or stroke. 
5. The patient has a positive urine drug result (illicit, illegal or without valid prescription or 
medical need) at Screening. 

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6. The patient has a moderate or severe substance use disorder (meeting more than 4 diagnostic 
criteria of DSM-5 either currently or within the last 6 months) for alcohol or other substances 
of abuse except nicotine or caffeine. 
7. If female, the patient is pregnant (a positive pregnancy test at Screening or Day -1) or lactating 
or intending to become pregnant or intending to donate ova, before or during the course of the 
study or within 12 weeks after the last dose. 
8. The patient has a history of or known personality disorder or other psychiatric disorder that, in 
the opinion of the Investigator, would interfere with participation in the study. 
9. The patient has a history of neuroleptic malignant syndrome, water intoxication, or paralytic 
ileus or other conditions that may interfere with absorption of study drug. 
10. The patient is considered by the Investigator to be at imminent risk of suicide or injury to self, 
others, or property or participants who within the past year prior to Screening have attempted 
suicide or have positive answers on item 4 or 5 on the C-SSRS at Screening or on Day -1. 
11. 
that may interfere with the interpretation of study results. 
12. The patient has any existing or previous history of cancer that has been in remission for less 
than 5 years prior to Screening. 
Note: this criterion does not include those participants with basal cell, stage I squamous cell 
skin cancer or in situ cervical cancer. 
13. The patient has newly diagnosed diabetes or requires insulin for their treatment; diabetic 
patients that have had changes to their diabetic treatment regimen within 30 days prior to 
Screening or diabetic patients that have been hospitalized for their diabetes and/or diabetes 
related conditions in the past year prior to Screening. 
14. The patient has long QT syndrome or is under treatment with Class 1A (e.g., quinidine, 
procainamide) or Class 3 (e.g., amiodarone, sotalol) anti-arrhythmic drugs. 
15. The patient with acute or chronic hepatitis B or C infection (positive test for hepatitis B surface 
antigen; positive hepatitis C antibody), known human immunodeficiency virus (HIV) 
infection, or other acute or ongoing clinically significant viral or bacterial infections.. 
16. The patient has received any depot preparation (sustained-release formulation) of antipsychotic 
drugs within 1 month (30 days) prior to Screening. 

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17. The patient is considered to be treatment resistant.  Treatment resistance is defined as prior 
non-response to 2 courses of treatment with anti-psychotics of different chemical classes for 
at least 4 weeks each at doses considered to be effective. 
18. The patient has received monoamine oxidase (MAO) inhibitors or fluoxetine within 1 month 
(30 days) before Screening. 
19. The patient has received electroconvulsive therapy within 6 months (180 days) before 
Screening. 
20. The patient has 1 or more laboratory values outside the normal range that are considered by 
the Investigator to be clinically significant at Screening; or has any of the following at 
Screening: 
 A serum creatinine value > 1.5 times the upper limit of normal (ULN). 
 A total serum total bilirubin value > 1.5*ULN. 
 A serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) 
value > 2*ULN. 
5.4. 
Restrictions 
5.4.1. 
Dietary and Fluid Restrictions 
Caffeine 
Xanthine containing products (e.g., caffeine in coffee, tea, chocolate) will not be allowed from 
24 hours prior to Day 1 to Day 28, inclusive. Subjects should not consume caffeine containing 
beverages exceeding 500 mg caffeine per day (5 cups of coffee) during the off-site days during the 
study.  
Alcohol 
Consumption of alcohol and alcohol-containing foods, medications or beverages must be avoided 
from 48 hours prior to Day -1 and while subjects are confined to the study center.  Subjects should 
not consume more than 3 units (males) or 2 units (females) per day during the  study Follow-up 
period 
 mL] of 
wine, or one measure [25 mL] of spirits). 
Meals 
No outside food or drink is permitted at the study center.  During in-house stay at the study center 
only meals and fluid intake according to the study 
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Fasting 
Dosing Day: Dosing during treatment period will take place after an overnight fast of at least 
10 hours.  Water intake will be allowed up to 1 hour before dosing and from 1 hour after dosing 
(excluding amount of water allowed for IMP administration). 
After IMP administration patients should remain fasting: 
 On Day 1, Days 2-6, Day 7 and Day 28: up to 2 hours, 
 On every other day: up to 2h but starting from 0.5h after IMP administration consumption of 
low calorie snack i.e. plain rice cakes is allowed till breakfast. 
5.4.2. 
Lifestyle Considerations 
Drugs of abuse 
Subjects must refrain from use of recreational drugs for the duration of the study. 
Nicotine 
Cigarette smokers will be allowed to smoke in designated areas provided by the clinic and the 
number of cigarettes per day should be recorded.  The number of cigarettes will be limited to a 
maximum of 20 per day.  No smoking will be allowed 90 minutes before efficacy testing. 
Strenuous activity 
Subjects should refrain from carrying out heavy physical training (e.g., long distance running, 
weight-lifting, or any physical activity to which the subject is not accustomed) from 48 hours prior 
to Day -7  Day -1 (depending if/ how long washout period is included) until the final Follow-up 
Visit.  Subjects should neither start any new physical training nor increase the intensity of their 
usual training during study participation.  Subjects may participate in light recreational activities 
during studies (e.g., watch television, play computer games, read). 
5.4.3. 
Prior and Concomitant Treatments 
Medication restrictions applicable before dosing are described in Section 5.3 (exclusion criteria).  
Prior medication will be recorded. 
Any medicinal product, prescribed or over-the-counter (OTC), taken by a subject other than the 
IMP, is considered concomitant medication.  Permitted medication (for prolonged use) includes 
only paracetamol in recommended doses (  2 g per day) after approval by the Investigator or 
designee.  Higher doses of paracetamol, up to 4 g per day may be given at the discretion of the 

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Investigator or designee to treat AEs such as fever and headache (only for short terms issues).  Any 
concomitant treatment will be given only if deemed strictly necessary by the Investigator or 
designee.  Use of concomitant medication will be recorded and reported. 
Allowed concomitant medications taken by the patient in fasting conditions can be taken 
consistently with the current recommendations, but at least 1 hour interval between concomitant 
medication and IMP administration must be maintained with IMP taken as first. 
Starting on the first day of Screening Period and as applicable, all antipsychotic or other 
psychotropic medications will be stopped with clinically appropriate titration down as per 
Investigator clinical judgment.  Thereafter, patients will be instructed not to take any medications 
during the conduct of the study unless approved by the Investigator.  Any patient who is unable to 
be safely discontinued from current antipsychotic therapy or other psychotropic medications will 
not be eligible for the study (see Section 7). 
Medication history (psychotropic medication history during the previous 5 years and all other 
medications during the past 12 months) will be recorded at Screening (Visit 1) in the eCRF.  
Thereafter, any changes in concomitant medications or new medications added will be recorded 
in the eCRF. 
Patients will not be eligible for the study if they have used any depot antipsychotic within   1 month 
(30 days) prior to Screening. The using of mianserin, mirtazapine, nefazadone, cyproheptadine, or 
fluvoxamine within 1 month (30 days) before Screening is not recommended. 
During the study lorazepam may be administered for anxiety/agitation or to aid sleep; from other 
medications to manage insomnia, known as z-drugs, zolpidem is preferred and allowed.  
Lorazepam and zolpidem are not to be used in close temporal proximity (administration within 4h 
of each other). In addition, benzatropine/biperiden may be administered for treatment of 
extrapyramidal side effects and propranolol may be administered for treatment of akathisia.  
Lorazepam, zolpidem, benzatropine/biperiden and propranolol are allowed according to the 
instructions outlined in Table 5 below.  Within the daily and weekly limits shown in Table 5, 
lorazepam, zolpidem, benzatropine/biperiden, and propranolol are permitted upon the Investigator 
or designee decision and are allowed on a PRN (as needed) basis. 
lorazepam, zolpidem, 
benzatropine/biperiden, or propranolol (exceeding the limits given in Table 5), it must be recorded 
as Serious Adverse Event (SAE). 

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The adverse event (AE) associated with the need for lorazepam, zolpidem, benzatropine/biperiden, 
or propranolol should be recorded on the AE eCRF.  The amount and timing of each lorazepam, 
zolpidem, benzatropine/biperiden, or propranolol administration should be recorded for each 
patient in the eCRF. 
Table 5 
Restrictions on the Use of Lorazepam, Zolpidem, Benzatropine/Biperiden, and 
Propranolol during the Study 
Medication 
Study Period 
Dosage Allowed 
Timing 
Restrictions 
Lorazepam 
Screening Period and 
Treatment Period to Day 28, 
inclusive 
Maximum of 6 mg/day 
AND 
Not within 8 hours 
prior to PANSS, 
CGI-S, CGI-I or 
C-SSRS, BACS 
Not within 4 h of 
zolpidem 
administration 
Maximum 6 times/week 
(at least 1 day break between 
weeks) 
Follow up period  Since 
Day 29 and onwards 
According to SmPC 
Zolpidem 
Screening Period and 
Treatment Period to Day 28, 
inclusive 
Maximum of 10 mg/day 
Not within 8 hours 
prior to PANSS, 
CGI-S, CGI-I or 
C-SSRS, BACS 
Not within 4 h of 
lorazepam 
administration 
Maximum 4 times/week 
Follow up period  Since 
Day 29 and onwards 
According to SmPC 
Benzatropine 
Screening Period to Day 28, 
inclusive 
Maximum of 4 mg/day 
Not within 8 hours 
of BACS, ESRS 
Biperiden 
According to SmPC 
Propranolol 
Screening Period to Day 28, 
inclusive 
Maximum of 40 mg/day 
BACS: Brief Assessment of Cognition in Schizophrenia; C-SSRS: Columbia Suicide Severity Rating Scale; 
CGI-I: Clinical Global Impression Scale - Improvement; CGI-S: Clinical Global Impression Scale - Severity; 
PANSS: Positive and Negative Syndrome Scale 
A list of example medications that are allowed and not allowed as concomitant medications for 
either episodic or chronic use is provided in Table 9 in the Appendices (Section 13). 

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Strong inducers and inhibitors of CYP3A4 should be avoided due to possible effects on the 
pharmacokinetics of CPL500036 (PDE10A inhibitor), however, moderate to weak inducers or 
inhibitors may be allowed.  
Precaution should be exercised in patients using concomitant treatment with agents being BCRP 
(Breast Cancer Resistance Protein) substrates (e.g. ezetimibe, pravastatin, rosuvastatin), as the 
Investigational Product may inhibit the BCRP. As per Table 9, the dose of these drugs should be 
related to the cha
Medical Monitor. 
5.4.4. 
Contraception Rules 
Refer to Section 5.2 (inclusion criteria). 

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6. 
INVESTIGATIONAL MEDICINAL PRODUCT 
6.1. 
Study Agent 
6.1.1. 
Physico-chemical characteristics 
Active substance: 
 
CPL500036 
Chemical name: 
7-5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl}-2- 
phenylimidazo[1,2-a]pyrimidine 
Chemical structure:   
 
 
 
 
 
 
Molecular formula: 
 
C19H15N7 
Molecular weight: 
 
341,37 g/mol 
6.1.2. 
Formulation 
 

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Table 6 
The composition of powder filled into gelatin capsule. 
6.2. 
Identity of the Investigational Medicinal Products 
6.3. 
Supply, Packaging, Labelling and Storage 

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6.4. 
Subject Identification and Randomization 
6.4.1. 
Screening Numbers 
At Screening, subjects will be assigned a unique subject identification number (or subject 
identifier).  Enrolled subjects who drop out of the clinical study before randomization will retain 
their subject identification number. 
6.4.2. 
Randomization Numbers 
Prior to dosing, on Day 0, subjects will be assigned a randomization number in accordance with 
the randomization code generated by eCRF platform. Randomization procedure is to be performed 
to minimize bias in the assignment of subjects to treatment groups. Subjects are to be randomized 
in 1:1:1 ratio (a stratified block is to be implemented: geographical location, PK group, PANSS 
baseline score). 
Once a randomization number has been allocated to one subject, it may not be assigned to another 
subject. 
6.5. 
Administration of Investigational Medicinal Products 
Starting from Day 1, the IMP will be administered after a minimum 10-hours overnight fast with 
approximately 240 mL water.  Subjects must remain in an upright position for at least 2 hours after 
dosing.  The IMP is to be administered approximately at the same time each day. 
 Fasting requirement after IMP intake are described in Section 5.4.1. 
For dosing details, see Section 6.6 below. 
6.6. 
Dosing 
To maintain double-blind manner, every patient will take the same number of capsules. Depending 
on the dose (20 mg or 40 mg) and the type of product (PG20 or placebo) intended for patient, 
he/she will take: 
- 4 capsules of PG20: 40 mg, 
- 2 capsules of PG20 and 2 capsules of placebo: 20 mg, 
- 4 capsules of placebo. 
In this way, both the patient and the Investigator will not know which product is administered to 
the patient. 

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6.7. 
Compliance, IMP accountability 
Dosing will be performed by trained, qualified personnel designated by the Investigator.  A hand 
and mouth check will be performed after dosing to ensure the subjects have swallowed the dose 
administered.  The date and time of dosing will be documented on each dosing day.  Comments 
will be recorded if there are any deviations from the planned dosing procedures. A single dose is 
to be considered as a compliant when all 4 capsules are administered and administration is without 
any emesis occurring within 2h after IMP administration.  A patient is to be considered as  
compliant with dosing regimen when at least 80 % of the doses are compliant (at least 22 doses). 
The Sponsor shall supply an adequate quantity of the investigational medicinal product (IMP) and 
the placebo, both for administration and as a backup, along with the respective certificates of 
analysis (CoA).  Appropriate sealing of packages with the IMP/placebo and adequacy of the 
information included on the package labels is to be examined by the designated unblinded study 
person (pharmacist) in the clinical centre.  The amount of each product is to be sufficient to account 
for 
  The unblinded persons 
are obliged to store the products in a safe place, with limited access to third parties.  The products 
are to be securely stored under pre-specified conditions, in accordance with applicable regulatory 
requirements.  The products are to remain under the supervision of the designated study person 
and are to be released solely for the administration purposes, according to the study protocol.  The 
study designated person is to be responsible for the investigational product during the whole study 
period. At the end of the study, a number of unused IMP is to be determined, and the product is to 
be returned to the Sponsor along with used containers.  Adequate records documenting receipt, use 
or other disposition of the investigational product is to be kept by the designated person.  The 
unblinded study monitor is to verify these documents throughout the course of the study. 
6.8. 
Blinding and Breaking the Blind 
The clinical study will be performed in a double-blind manner, so the identity of investigational 
drug and placebo will not be known to investigators, research staff and subjects.  At the Clinical 
Units are to be at minimum two staff members, who are to be unblinded: pharmacist preparing the 
products to be administered based on randomization list and one person from the team who is to 
be responsible for verifying the proper preparation of the product doses (quality control). They are 
not to be involved in any evaluation and examination of the study patients.  The unblinded staff 
members are obligated  not to share the randomization list with other staff members during the 
whole study. The adequate pharmaceutical manual is to be prepared by the clinical units and is to 
be followed. 

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The study blind  may be broken only in medical emergency (where knowledge of the study drug 
administered would affect the treatment of the emergency).  The decision to break the blind will 
be made on a case-by-case basis, at the discretion of the Investigator, and if possible,  in 
collaboration with the Sponsor and/or Medical Monitor.  If the blind is broken the CRO and 
Sponsor must be informed as soon as possible.  The date, time and reason for unblinding is to be 
documented in the CRF and in the source data.  The applicable standard operating procedure (SOP) 
will be followed for blind breaking procedures. 
After database lock, the overall randomization code will be broken only for reporting purposes. 
Suspected unexpected serious adverse reactions (SUSARs), that are subject to expedited reporting, 
should be unblinded by the Sponsor before submission to the regulatory authority and the 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC).  Information about 
SUSAR should be sent to all Investigators too (after unblinding the patient). 
6.9. 
Treatment of Overdose 
Standard symptomatic support measures should be used in the case of excessive pharmacological 
effects or overdose. 
 by Investigator.  Each 
case of overdose will be reported immediately to the Sponsor. The Investigator should follow-up 
and document the course and the outcome of each overdose even if the subject was withdrawn 
from the clinical study or if the clinical study has finished and if the patient agrees. Any SAE that 
occurs due to overdose must be recorded on the Serious Adverse Event Report Form and must be 
reported by Investigator to the Sponsor within 24 hours of becoming aware of the event. 

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7. 
DISCONTINUATION 
7.1. 
Study Stopping Rules 
The stopping rules described in this section of the clinical study protocol (CSP) are applicable to 
stopping the study.  IMP dosing may be halted temporarily to investigate before the entire study is 
terminated. 
Measures to ensure data integrity and safety of research subjects will be detailed in the Safety 
Monitoring Plan (SMP) and Data Management Plan (DMP). 
If the Investigator, the Medical Monitor or the Sponsor becomes aware of conditions or events that 
suggest a possible hazard to subjects if the clinical study continues, then the clinical study may be 
terminated after appropriate consultation among the involved parties. If the investigator considers, 
-benefit 
considerations have changed, the Investigator may decide the termination of the study for this 
subject without the consent/consulting Sponsor.  The clinical study may be terminated at the 
  
Should the study be terminated, and/or the study centre closed for whatever reason, all 
documentation pertaining to the study and study drug must be returned to the Sponsor.  Any actions 
of the contract research organization (CRO) required for assessing or maintaining subject safety 
will continue as required, despite termination of the study by the Sponsor. 
7.1.1. 
Stopping Rules 
7.1.1.1. 
Safety Criteria 
After the first dose of IMP, a subject may discontinue from the study for a variety of reasons.  
Treatment discontinuations may be initiated by a subject or may become medically necessary due 
to AEs, required treatment with a disallowed medication or therapy, or other reasons, as 
determined by the Investigator.  If a subject discontinues treatment, their participation in the trial 
will be discontinued. Discontinued subjects should be encouraged to complete all early termination 
and Follow-up assessments with early termination assessments conducted as soon as possible after 
the subject is withdrawn. 
An individual subject is to be withdrawn from the study if: 
 the subject withdraws his/her consent, what he/she is allowed to do at any time and without 
the need to justify his/her decision, 

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study medication in the opinion of the Investigator or designee 
event), 
 in spite of the earlier evaluation upon recruitment  is suspected or found not to 
comply with eligibility criteria,  
directives (compliance with the treatment schedule, non-adherence to dietary rules or other 
study restrictions that may have influence on study results, non-attendance at study 
assessments), 
permits a safe participation of the subject. 
Each subject has the right to withdraw from the study at any time without prejudice. The 
 
necessary, for any reason including adverse events or Clinical Study Protocol violation. The 
subject is to be always informed about the reason for his discontinuation. Reasons for the 
withdrawal of an individual subject from the study are to be recorded by the Investigator in the 
Case Report Form and in the Clinical Study Report. In the case of withdrawal caused by 
adverse drug reaction, the subject is to be under observation until symptoms of the reaction 
have subsided. 
In case of emesis an individual subject is to be withdrawn from the study if: 
 the subject suffers from severe emesis within 4 hours after two consecutive days of drug 
administration. If emesis occurs within 4 hours post-dose and is to be mild or moderate or 
emesis occurs after 4 hours post-
judgement and decision. 
7.2. 
Subject Withdrawal and Replacement 
In addition to the stopping rules described in Section 7.1.1, a subject will be withdrawn by the 
Investigator or designee from the study and not be allowed to continue with the study if any of the 
following criteria are fulfilled: 
 If discovered that the subject has entered the study in violation of the inclusion/exclusion 
criteria stated in the protocol, 

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 Investigator or the Sponsor stops the study, for any reason (e.g., suspension or discontinuation 
of study drug development). 
While subjects are encouraged to complete all study evaluations, they may withdraw from the 
study at any time and for any reason.  Every effort will be made to determine why any subject 
withdraws from the study prematurely.  All subjects who withdraw from the study with an ongoing 
AE must be followed until the event is resolved or deemed stable.  If a subject withdraws 
prematurely after dosing, all data to be collected prior to discharge from the clinical site should be 
collected at the time of premature discontinuation or at the scheduled discharge. 
Subject participation may be terminated prior to completing the study and the reason recorded as 
follows: 
1.  Adverse event, 
2.  Protocol violation, 
3.  Loss to follow-up, 
4.  Subject withdrew consent at own request, 
5.  Other. 
A genuine effort must be made to determine the reason(s) why a subject fails to return for the 
necessary visits or is discontinued from the study.  At least 3 documented attempts of telephone 
contacts must be documented by the site. If the subject is unreachable by telephone, a registered 
letter, at the minimum, should be sent to the subject requesting him/her to contact the clinic.  In 
case of failure, patient is considered lost to follow up. 
The subject who cannot participate in the study due to not meeting the inclusion or exclusion 
criteria or is going to withdraw the informed consent before the first IMP administration is to be 
replaced by the next qualifying alternate. 
The subject who withdraws from the study for any reason after any IMP administration or before 
completion the study, may be replaced by another qualifying alternate only in case if total number 
of subjects in a given study arm who would complete the study would be insufficient and there are 
no safety concerns. The subject replacement is defined as recruiting additional patient, but it should 
be remembered that results from all randomized patients will be analyzed according to the 
population set definitions described in section 10.1.3. 

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The replacing subject is to follow the same treatment and protocol procedures as the withdrawn 
one.  The replacing alternate subject is to receive the study products under the same conditions as 
the withdrawn subjects, and they are to undergo the entire protocol procedure. 

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8. 
STUDY ASSESSMENTS AND PROCEDURES 
For timing of assessments, refer to the Schedule of Assessments (Table 1). 
8.1. 
Eligibility Screening 
For patient eligibility screening assessments and procedures, please refer to Schedule of 
Assessments (Table 1). 
8.2. 
Medical History, Demographic and Other Baseline Information 
The medical history comprises: 
 General medical history, 
 Medication history, 
 Reproductive history. 
The following demographic information will be recorded: 
 Age, 
 Race/ethnicity, 
 Height, without shoes (cm), 
 Body weight, without shoes (kg), 
 Body mass index (BMI) (kg/m2). 
Other baseline characteristics will be recorded as follows: 
 History of drug abuse, 
 History of alcohol abuse, 
 Smoking history, 
 Special diet (e. g. vegetarian), 
 History of blood or plasma donation. 
8.3. 
Safety Variables 
8.3.1. 
Adverse Events 
Adverse event reporting will begin for each subject from the date the informed consent form (ICF) 
is signed and will continue until the final Follow-up Visit. 

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8.3.1.1. 
Definitions 
8.3.1.1.1. 
Definition of Adverse Event 
Any untoward medical occurrence in a subject administered an IMP and which does not 
necessarily have a causal relationship with this treatment.  An adverse event (AE) can therefore be 
any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a medicinal (investigational) product, whether or not 
related to the medicinal (investigational) product. 
Other untoward events occurring in the framework of a clinical study will be recorded as AEs, 
e.g. those occurring during treatment-free periods (including Screening or post-treatment follow-
up periods), in association with study-related procedures and assessments, or under placebo.  For 
study drugs, lack of efficacy may be an expected potential outcome and should not be reported as 
an AE unless the event is unusual in some way, e.g., greater in severity. 
Concomitant illnesses, which existed prior to entry into the clinical study, will not be considered 
AEs unless they worsen during the Treatment Period.  Pre-existing conditions will be recorded as 
 
8.3.1.1.2. 
Definition of Serious Adverse Event 
A SAE is defined as any untoward medical occurrence that at any dose: 
 Results in death, 
 Is life-threatening; this means that the subject was at risk of death at the time of the event; it 
does not mean that the event hypothetically might have caused death if it were more severe, 
 Requires in-patient hospitalization or prolongation in existing hospitalization, 
 Results in persistent or significant disability/incapacity or substantial disruption of the ability 
to conduct normal life functions, 
 Is a congenital anomaly/birth defect, or 
 Is another important medical event (see below). 
Important medical events that do not result in death, are not life-threatening or do not require 
hospitalization may be considered SAEs when, based on appropriate medical judgment, they may 
jeopardize the subject and may require medical or surgical intervention to prevent one of the 
outcomes listed above.  Examples of such medical events include allergic bronchospasm requiring 

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that do not result in in-patient hospitalization, and the development of drug dependency or drug 
abuse. 
A distinction should be drawn between serious and severe AEs.  Severity is a measure of intensity 
whereas seriousness is defined by the criteria above.  For example, a mild degree of gastrointestinal 
bleeding requiring an overnight hospitalization for monitoring purposes would be considered 
a SAE but is not necessarily severe.  Similarly, an AE that is severe in intensity is not necessarily 
a SAE.  For example, alopecia may be assessed as severe in intensity but would not be considered 
a SAE. 
Medical and scientific judgment should be exercised in deciding if an AE is serious and if 
expedited reporting is appropriate. 
8.3.1.2. 
Recording of Adverse Events 
Adverse events should be collected and recorded for each subject from the date the ICF is signed 
until the end of their participation in the study, i.e. the subject has discontinued or completed the 
study. 
Adverse events may be volunteered spontaneously by the subject, or discovered by the study staff 
during physical examinations or by asking an open, non-
 remedial action will be 
recorded. The nature of AE, date (and time, if known) of AE onset, date (and time, if known) of 
AE outcome to date, severity and action taken of the AE will be documented together with the 
Investigator
ss of the AE and causal relationship to study drug and/or 
study procedure. 
opinion of the Investigator, the AEs constitute components of a recognized condition, disease or 
syndrome.  In the latter case, the condition, disease or syndrome should be named rather than each 
individual symptom.  The AEs will subsequently be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA). 
8.3.1.3. 
Assessment of Adverse Events 
Each AE will be assessed by the Investigator about the categories discussed in the following 
sections. 

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8.3.1.3.1. 
Intensity 
The Investigator will assess all AEs for severity in accordance with the following standard ratings. 
 
activities.  Treatment is not ordinarily indicated. 
 Moderate: Marked symptoms, sufficient to make the subject uncomfortable.  Moderate 
 
 
activities.  May be unable to continue in the study and treatment may be necessary. 
When changes in the intensity of an AE occur more frequently than once a day, the maximum 
intensity for the event should be noted for that day.  Any change in severity of signs and symptoms 
over a number of days will be captured by recording a new AE, with the amended severity grade, 
and the date (and time, if known) of the change. 
8.3.1.3.2. 
Causality 
The Investigator will assess the causality/relationship between the study drug and the AE.  One of 
the categories described in Table 7 should be selected based on medical judgment, considering the 
definitions below and all contributing factors. 
Table 7 
Assessment of Relationship of Adverse Events to Investigational Product 
Related 
A clinical event, including laboratory test abnormality, occurs in a plausible time 
relationship to treatment administration, and which concurrent disease or other drugs or 
chemicals cannot explain.  The response to withdrawal of the treatment (dechallenge*) 
should be clinically plausible.  The event must be definitive pharmacologically or 
 
Probably related 
A clinical event, including laboratory test abnormality, with a reasonable time sequence to 
administration of the treatment, unlikely to be attributed to concurrent disease or other 
drugs or chemicals, and which follows a clinically reasonable response on withdrawal 
(dechallenge).  Rechallenge information is not required to fulfil this definition. 
Possibly related 
A clinical event, including laboratory test abnormality, with a reasonable time sequence to 
administration of the treatment, but which could also be explained by concurrent disease or 
other drugs or chemicals.  Information on treatment withdrawal may be lacking or unclear. 
Unlikely to be 
related 
A clinical event, including laboratory test abnormality, with a temporal relationship to 
treatment administration which makes a causal relationship improbable, and in which other 
drugs, chemicals or underlying disease provide plausible explanations. 
Unrelated 
A clinical event, including laboratory test abnormality, with little or no temporal 
relationship with treatment administration.  May have negative dechallenge and rechallenge 
information.  Typically explained by extraneous factors (e.g., concomitant disease, 
environmental factors or other drugs or chemicals). 
*Dechallenge is when a drug suspected of causing an AE is discontinued. If the symptoms of the AE disappear partially 
or completely, within a reasonable time from drug discontinuation, this is termed a positive dechallenge.  If the 
symptoms continue despite withdrawal of the drug, this is termed a negative dechallenge.  Note that there are 

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exceptions when an AE does not disappear upon discontinuation of the drug, yet drug-relatedness clearly exists (for 
example, as in bone marrow suppression, fixed drug eruptions, or tardive dyskinesia). 
subject.  If the AE recurs upon exposure, this is termed a positive rechallenge.  If the AE does not recur, this is 
termed a negative rechallenge. 
8.3.1.4. 
Reporting of Serious Adverse Events 
The Investigator will review each SAE and evaluate the intensity and the causal relationship of the 
event to study drug.  All SAEs will be recorded from signing of the ICF until the final Follow-up 
Visit.  Serious AEs occurring after the final Follow-up Visit and coming to the attention of the 
Investigator must be reported only if there is (in the opinion of the Investigator) reasonable causal 
relationship with the study drug. 
The Investigator is responsible for providing notification to the Sponsor of any SAE, whether 
deemed IMP-related or not, that a subject experiences during their participation in study within 24 
hours of becoming aware of the event. 
SERIOUS ADVERSE EVENT REPORTING INSTRUCTIONS 
Notify and send the SAE Report Form and any supporting documentation  
via email within 24 hours of becoming aware of the event. 
As a minimum requirement, the initial notification should provide the following information: 
 Study number, 
 Patient number, 
 Sex, 
 Date of birth, 
 Name of Investigator and full clinical site address, 
 Details of SAE, 
 Criterion for 
, 
 Study drug name, or code if unblinded, and treatment start date, 
 Date of SAE onset, 
 Causality assessment (if sufficient information is available to make this classification). 

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The Sponsor will request clarification of omitted or discrepant information from the initial 
notification.  The Investigator or an authorized delegate is responsible for sending via email the 
requested information to the Sponsor within 24 
 
Initial reports of SAEs must be followed later with detailed descriptions, including clear 
photocopies of other documents as necessary (e.g. hospital reports, consultant reports, autopsy 
ant information obtained by the 
Investigator through review of these documents will be recorded and emailed to the Sponsor within 
24 hours of receipt of the information.  If a new SAE report form is emailed, then the Investigator 
must sign and date the form.  The Sponsor may also request additional information on the SAE, 
which the Investigator or an authorized delegate must send via email to the Sponsor within 
24 hours of the request. 
8.3.1.5. 
Reporting of Suspected Unexpected Serious Adverse Reaction 
Information on SUSARs will be collected and reported to the regulatory authority and the IEC in 
accordance with European Commission Guidance 2011/C 172/01 or as per national regulatory 
requirements in the participating country.  Details of reporting on country level will be described 
in the Safety Management Plan. 
8.3.1.6. 
Follow-up of Adverse Events 
All AEs experienced by a subject, irrespective of the suspected causality, will be monitored until 
the event has resolved, until any abnormal laboratory values have returned to baseline or stabilized 
at a level acceptable to the Investigator and Medical Monitor, until there is a satisfactory 
explanation for the changes observed or until the subject is lost to follow-up. 
8.3.1.7. 
Pregnancy 
The Sponsor has a responsibility to monitor the outcome of all pregnancies reported during the 
clinical study. 
Pregnancy alone is not regarded as an AE unless there is a suspicion that the study drug may have 
interfered with the effectiveness of a contraceptive medication.  Elective abortions without 
complications should not be regarded as AEs, unless they were therapeutic abortions (see below).  
Hospitalization for normal delivery of a healthy new-born should not be considered a SAE. 
Each pregnancy must be reported by the Investigator to the Sponsor within 2 days after becoming 
aware of the pregnancy.  The Investigator must follow-up and document the course and the 

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outcome of all pregnancies even if the subject was withdrawn from the clinical study or if the 
clinical study has finished and if the patient agrees. 
All outcomes of pregnancy must be reported by the Investigator to the Sponsor on the pregnancy 
outcome report form within 2 days after he/she has gained knowledge of the normal delivery or 
elective abortion. 
Any SAE that occurs during pregnancy must be recorded on the Pregnancy Report Form(e.g., 
maternal serious complications, therapeutic abortion, ectopic pregnancy, stillbirth, neonatal death, 
congenital anomaly, birth defect) and reported within 24 hours in accordance with the procedure 
for reporting SAEs. 
8.3.2. 
Clinical Laboratory Assessments 
Samples for clinical laboratory assessments will be collected at the time points detailed in the 
Schedule of Assessments (Table 1). During administration days samples will be collected pre-dose 
(
 before IMP administration).  Samples will be collected in appropriate tubes and handled 
according to standard procedures of the applicable laboratory. 
Clinical laboratory variables will be determined as outlined in Table 8. 

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Table 8 
Clinical Laboratory Assessments 
Hematology 
White blood cell (WBC) count 
Neutrophils (percentage and absolute count) 
Red blood cell (RBC) count 
Lymphocytes (percentage and absolute count)  
Hemoglobin (Hb) 
Monocytes (percentage and absolute count)  
Hematocrit (HCT) 
Eosinophils (percentage and absolute count)  
Mean corpuscular volume (MCV) 
Basophils (percentage and absolute count)  
Mean corpuscular hemoglobin (MCH) 
Platelet count 
Mean corpuscular hemoglobin concentration (MCHC) 
RBC distribution width 
Coagulation 
Prothrombin time (PT) 
International Normalized Ratio (INR) 
Activated partial thromboplastin time (aPTT) 
 
Clinical Chemistry 
Alanine aminotransferase (ALT) 
Gamma glutamyl transferase (GGT) 
Albumin 
Glucose 
Alkaline phosphatase (ALP) 
Lactate dehydrogenase (LDH) 
Aspartate aminotransferase (AST) 
Phosphorus 
Blood urea nitrogen (BUN) 
Potassium 
Calcium 
Sodium 
Chloride 
Total bilirubin 
Cholesterol 
Total protein 
Creatinine 
Triglycerides 
Creatine kinase (CK) 
Uric acid 
Follicle stimulating hormone (FSH) (Screening Visit only; all female subjects) 
Urinalysis 
Bilirubin 
Blood 
Glucose 
pH and specific gravity 
Ketones 
Protein 
Leukocytes 
Urobilinogen 
Nitrite 
 
Microscopic (only for abnormal urine stick test findings) 
Viral Serology 
Hepatitis B surface antigen (HBsAg) 
Human immunodeficiency virus (HIV)  
(Types 1 and 2) antibodies 
Hepatitis C virus antibody (anti-HCV) 
Urine Drug Screening 
Amphetamines 
Cocaine 
Barbiturates 
Opiates 
Benzodiazepines 
Phencyclidine (PCP) 
Cannabinoids 
 
Pregnancy Testing 
Serum/urine human beta chorionic gonadotrophin (women of childbearing potential only) 

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Any value outside the normal range will be flagged for the attention of the Investigator or designee 
at the site.  The Investigator or designee will indicate whether the value is of clinical significance.  
If the result of any test (or repeat test, if done) from the samples taken during the Screening Period 
is indicated as clinically significant, the subject will not be allowed to be enrolled into the study 
without permission of the Medical Monitor and Sponsor.  Additional testing during the study may 
be done if medically indicated.  If a clinically significant abnormality in laboratory tests is found 
during the course of treatment period study, and/or at the final Follow-up Visit, it should be 
recorded as an AE and the subject will be followed until the test(s) has (have) normalized or 
stabilized, at the discretion of the Investigator. 
8.3.3. 
Alcohol test 
An estimation of blood alcohol content from a breath sample or from an urine sample is to be 
performed to determine if subject is not under influence of alcohol. 
8.3.4. 
Vital Signs 
Vital signs will be assessed at the time points detailed in the Schedule of Assessments (Table 1) 
and as detailed below: 
Respiratory rate (breaths per minute), body temperature 
, 3-positional blood pressure (systolic 
and diastolic [mmHg]) and pulse (beats per minute [bpm]) (after 3 minutes lying down; after 
3 minute sitting, immediately upon standing; and after 3 minutes standing) will be taken taken 
once at Screening (Day -10 to -2); once at Baseline (Day -1); thrice on Day 1, Days 2-6 (each day), 
Day 7, 14, 21 and 28: pre-
after 1h 45 minutes and 9h post-dose; once during the follow-up visits . 
8.3.5. 
Standard 12-lead Electrocardiograms 
Standard safety 12-lead ECGs will be performed at the time points detailed in the Schedule of 
Assessments (Table 1) and as detailed below. The ECGs will be performed once, pre-dose 
before IMP administration) at all scheduled visits when IMP is administered. 
 Once at Screening (Days -10 to -2) and at Baseline (Day -1), 
 On Days 7, 14, 21 and 28: pre-dose, 
 On Follow-up Visits (Days 35 to 42). 
 

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The12-lead ECGs will be performed after the subject has been resting supine for  5 minutes.  The 
ECG will include all 12 standard leads and a Lead II rhythm strip on the bottom of the tracing.  
The ECG will be recorded at a paper speed of 25 mm/sec.  The following ECG parameters will be 
collected: PR interval, QRS interval, RR interval, QT interval and QTc interval (QT interval 
corrected for heart rate using QTcF). 
All ECGs must be evaluated by a qualified designee for the presence of abnormalities. 
8.3.6. 
Physical Examinations 
Physical examinations will be performed at the time points detailed in the Schedule of Assessments 
(Table 1)  and as detailed below: 
 at Screening (Days -10 to -2) and at Baseline (Day -1), 
 On Day 28; not earlier than 5h post-dose, 
 On Follow-up Visits (Days 35 to 42). 
An assessment of general appearance and a review of systems (dermatologic, head, eyes, ears, 
nose, mouth/throat/neck, thyroid, lymph nodes, respiratory, cardiovascular, gastrointestinal, 
extremities, musculoskeletal, neurologic and psychiatric systems) will be performed. 
8.3.7. 
Extrapyramidal Side Effects 
Extrapyramidal side effects monitoring will be performed at the time points detailed in the 
Schedule of Assessments (Table 1) and as detailed below: 
Extrapyramidal side effects will be monitored starting from Screening, Baseline, and on Day 1 , 
Day 7, Day 14, Day 21, Day 28 and follow-up visits, using the Extrapyramidal Symptom Rating 
Scale (ESRS).  ESRS was developed to assess four types of drug-induced movement disorders 
(DIMD): Parkinsonism, akathisia, dystonia, and tardive dyskinesia
ESRS to be conducted during IMP administration days, when start of ratings is to be within 5 
minutes before or after 2h post-dose (it will be performed after PANSS, CGI-S, CGI-I and BACS). 
8.3.8. 
Columbia Suicide Severity Rating Scale 
Columbia Suicide Severity Rating Scale is a suicidal ideation rating scale created by researchers 
at Columbia University to evaluate suicide risk. Questions are phrased for use in an interview 
format, but the C-SSRS may be completed as a self-report measure if necessary. The scale contains 

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An individual exhibiting even a single behaviour identified by the scale 
was 8 to 10 times more likely to commit suicide. 
CSSRS will be performed at the time points detailed in the Schedule of Assessments (Table 1) and 
as detailed below: 
Columbia Suicide Severity Rating Scale will be conducted starting from Screening, baseline, on 
Day 14 and Day 28, and during the follow-up visits,.  The C-SSRS should be done AFTER all 
efficacy and safety assessments/scales. 
8.3.9. 
Additional Safety Variables 
Basic neurological, ophthalmological and dermatological assessment will be performed by 
Investigator.  In case of a need, consultation with specialist may be considered and it remains at 
the Investigator  discretion. 
Neurological, ophthalmological, and dermatological examinations will be performed at the time 
points detailed in the Schedule of Assessments (Table 1) and as detailed below: 
Neurological examinations: 
 At Screening (Days -10 to -2) and at Baseline (Day -1), 
 On Days 7, 14, 21 and 28; not earlier than 5h post-dose, 
 On Follow-up Visits (Days 35 to 42). 
Ophthalmological examinations: 
 At Screening (Days -10 to -2) and at Baseline (Day -1), 
 On Day 28 not earlier than 5h post-dose. 
Dermatological examinations: 
 At Screening (Days -10 to -2) and at Baseline (Day -1), 
 On Day 28; not earlier than 5h post-dose. 
8.4. 
Pharmacokinetics Variables 
8.4.1. 
Blood Sample Collection 
Blood for the analysis of CPL500036 will be collected at the time points detailed in the Schedule 
of Assessments (Table 1) and as detailed below. 

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Blood samples for PK analysis will be collected at the following time-points for extensive PK 
sampling (approximately 30% of patients): 
 Day 1 and Day 7 (steady-state): pre-dose and 0.5, 1, 1.5, 2, 4, 8, 12, and 24* hours post-dose, 
 Days 2 to 6: pre-dose* and around 2 hours post-dose, 
 Day 28: pre-dose and around 2 hours post-dose. 
*please note  the sample 24 hours post-dose on Day 1 it is the same sample as pre-dose on Day 2. 
Blood samples for PK analysis will be collected at the following time-points for sparse PK 
sampling (approximately 70% of the patients): 
 Day 1 and Day 7 (steady state): pre-dose and 1, 2, 4 and 8 hours post-dose, 
 Day 28: pre-dose and around 2 hours post-dose. 
Blood samples are to be collected according to the presented schedule, with the allowable deviation 
2 h
 2 minutes for 4-
-dose. 
Blood samples are to be collected, centrifuged, processed and stored for analysis in accordance 
with bioanalytical laboratory specified procedure, which is to be provided before the start of the 
study. 
8.5. 
Efficacy Variables 
The efficacy will be assessed by using various psychometric scales. Every scale will be performed 
by experienced and trained raters (certified in PANSS scale) according to planned schedule of 
assessments. 
8.5.1. 
Positive and Negative Syndrome Scale 
The PANSS is a 30-item scale used to measure symptoms of schizophrenia.  The scale has 7 
positive symptom items, 7 negative symptom items, and 16 general psychopathology symptom 
items.  Each item is scored on a 7-point scale by the clinical rater based on a clinical interview 
with the patient. 
Positive and Negative Syndrome Scale will be performed at the time points detailed in the 
Schedule of Assessments (Table 1) and as detailed below: 
The efficacy assessment (PANSS) will be performed once at Screening (Day -10 to -2); once at 
Baseline (Day -1); on Days 1, 7, 14, 21 and 28 when start of ratings is to be within 5 minutes 
before or after 2h post-dose (it will be performed before any other scale). 

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8.5.2. 
Clinical Global Impression Scale - Severity 
The Clinical Global Impression (CGI) Scale is a standardized assessment tool that the Investigator 
can use to rate the severity of illness, change over time, and efficacy of medication, taking into 
 The CGI Scale consists of 
3 global subscales formatted for use with the Global Scoring Sheet.  The first subscale, Severity 
of Illness, assesses the Investigator
used both before and after treatment.  Scores on the Severity of Illness subscale range from 1 = not 
ill at all to 7 = among the most extremely ill. 
Clinical Global Impression Scale - Severity will be performed at the time points detailed in the 
Schedule of Assessments (Table 1) and as detailed below: 
The efficacy assessment (CGI-S) will be performed once at Screening (Days -10 to 2), once at 
baseline (Day -1); on Days 7, 14, 21 and 28 when start of ratings is to be within 5 minutes before 
or after 2h post-dose (after PANSS).   
8.5.3. 
Clinical Global Impression Scale - Improvement 
Clinical Global Impression Scale - Improvement is a 7 points scale that requires the clinician to 
assess how much the patient's illness has improved or worsened relative to a baseline state at the 
beginning of the intervention. CGI-I will be performed at the time points detailed in the Schedule 
of Assessments (Table 1) and as detailed below: 
The efficacy assessment (CGI-I) will be performed on Days 7, 14, 21 and 28 when start of ratings 
is to be within 5 minutes before or after 2h post-dose (after PANSS and CGI-S)  
8.5.4. 
Brief Assessment of Cognition in Schizophrenia 
The Brief Assessment of Cognition in Schizophrenia (BACS) is specifically designed to measure 
treatment-related improvements in cognition and includes alternate forms. BACS is a reliable and 
sensitive measure of cognitive function in schizophrenia. The BACS is a cognition assessment 
battery that assesses 6 domains of cognitive function found to be consistently impaired in 
schizophrenia: verbal memory, working memory, motor speed, attention, executive functions, and 
verbal fluency. Brief Assessment of Cognition in Schizophrenia will be performed at the time 
points detailed in the Schedule of Assessments (Table 1) and as detailed below: 
The BACS assessment will be performed at Baseline (Day -1) and on Days 14 and 28 when start 
of ratings is to be within 5 minutes before or after 2h post-dose (after PANSS, CGI-S and CGI-I).. 

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8.6. 
Total Amount of Blood 
The maximum volume of blood planned for collection from each subject over the course of the 
entire study (from the Screening Visit to the final Follow-up Visit, but not including repeat or 
additional tests ordered by the Investigator) will not exceed 500 ml and presents no undue risk to 
the subjects. 
8.7. 
Hospitalization 
Patients are to be hospitalized after the screening qualification for washout period of up to 7 days 
(if necessary) before the start of the 28-day Treatment Period.  Patients are to be hospitalized 
during the treatment period (Day 1 to Day 28).  On Day 29 patients may be discharged from the 
clinical centre based on local standards of care if the patient is in stable condition under the regular 
medication(s). 

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9. 
STUDY SCHEDULE 
9.1. 
Screening 
Before providing the potential study patient with the information leaflet and informed consent 
form, the physician responsible for the enrollment provides them detailed information on: 
 The purpose of the study, 
 Any potential risk and inconveniences associated with the study, among others the number of 
visits and all study procedures that are to be performed, 
 Patient
 
 Right to refuse to participate or withdraw from the study at any time, 
 Confidentiality of patient
 
 Person to contact for further information regarding the study and whom to contact in case of 
any side effects occur, 
 Expected duration of the patient
 
 Entities granted direct access to the patient
clinical study procedures. 
The potential patient is to be given enough time to make a fully conscious and informed decision 
to participate in the study. 
After obtaining the written Informed Consent Form signed and dated by the patient Screening 
procedures as detailed in the Schedule of Assessments (Table 1) are to be performed.  For 
description of these procedures see Sections 8.3.2 - 8.3.9 and for all of the inclusion/exclusion 
criteria patients must meet see Sections 5.2 and 5.3. 
Patients will undergo screening assessments from Day -10 to Day  8 in multiple settings (i.e. 
emergency departments, outpatient clinics etc.).  Patients that fulfil all the inclusion and none of 
the exclusion criteria will immediately be admitted to the Clinical Unit and enter Medication 
Washout Period of up to 7 days (Day -7 to Day -1) before treatment phase, if needed.  The duration 
of Medication Washout Period may be shorter or omitted for non-medicated patients. 
Approximately 165 patients who meet all of the inclusion and none of the exclusion criteria are to 
be enrolled into the study.  Patients identification numbers (or subject identifier) are to be given to 
each patient during the Screening. 

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9.2. 
Baseline (Day -1) 
Visit on Day -1 is to performed to confirm inclusion/exclusion criteria and collect baseline values 
for further assessments. 
Patients identification is to be followed by alcohol test, urine drugs screen test and urine pregnancy 
test (for women).  Vital signs measurements (respiratory rate, body temperature, 3-positional blood 
pressure and pulse) are to be performed, followed by 12-lead ECG.  Afterwards blood and urine 
samples for clinical laboratory assessments are to be collected.  Baseline assessment of scales is 
to be performed and the scales are to be performed in order as follows: PANSS, CGI-S, BACS, 
ESRS, C-SSRS.  Afterwards physical, neurological, ophthalmological and dermatological 
examination are to be performed. 
After all the procedures Investigator is to confirm that the inclusion/ exclusion are met.  If a patient 
status after screening changes at Baseline (Day -1) such that the study patient no longer meets all 
eligibility criteria, then the patient should be excluded from participation in the study (such patient 
is to be considered as screen failure). It should be remembered that all baseline procedures must 
be performed on Day -1, but final patient qualification should be made when all results are 
available, before randomization on Day 0. 
Requests for AEs and information about the concomitant medications if any, are to be performed 
by the Investigator to each patient during the study as well as patient is to be asked to report 
spontaneously all symptoms and complaint. 
9.3. 
Day 0 
On Day 0, the Investigator is to performed the final patient qualification to the study based on all 
baseline results  this is the case, when not all baseline results (especially laboratory values) are to 
be available on Day -1. 
For a patient meeting all of the inclusion and none of the exclusion criteria the randomization 
procedure is to be performed. 
9.4. 
Day 1 
On Day 1, patient is to receive the first dose of IMP.  Before administration 
administration) vital signs measurements are to performed (respiratory rate, body temperature, 3-
positional blood pressure and pulse).  Afterwards blood and urine samples for clinical laboratory 
assessments, and blood sample for pre-dose PK time point (extensive and sparse group) are to be 
collected (
administration).  With the first PK sampling cannula might be inserted 

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into a vein shortly prior to the event.  If there is cannula occlusion, samples may be obtained via 
direct venepuncture.  IMP is to be administered with hand and mouth check afterwards to ensure 
the patient have swallowed all capsules.  Serial time-points after IMP administration for PK 
analysis (extensive and sparse group) are to be collected in scheduled time-points (see Section 
8.4.1).  Within 5 minutes before or after 1h 45 minutes after IMP administration vital signs 
measurements are to be performed (respiratory rate, body temperature, 3-positional blood pressure 
and pulse).  Start of ratings is to be within 5 minutes before or after 2h post-dose but after PK 
blood collection 2h timepoint and the scales are to be performed in order as follows: PANSS, 
ESRS.  Within 5 minutes before or after 9h post-dose vital signs measurements are to be performed 
(respiratory rate, body temperature, 3-positional blood pressure and pulse). 
Requests for AEs and information about the concomitant medications if any, are to be performed 
by the Investigator to each patient during the study as well as subject is to be asked to report 
spontaneously all symptoms and complaints. 
Patient is to fast from supper on Day -1 (fasting at least 10 hours prior to dosing) with continued 
fasting for 2 hours post-dose.  Water and other fluids are to be restricted one hour before and one 
hour after dosing (excluding amount of water allowed for IMP administration). 
9.5. 
Days 2 to 6 
On Days 2-6, patient is to receive the consecutive doses of IMP.  
before IMP administration) vital signs measurements are to performed (respiratory rate, body 
temperature, 3-positional blood pressure and pulse).  Afterwards blood sample for pre-dose PK 
time point (only extensive group) are to be collected (
be administered  with hand and mouth check afterwards to ensure the patient have swallowed all 
capsules. Within 5 minutes before or after 1h 45 minutes after IMP administration vital signs 
measurements are to be performed (respiratory rate, body temperature, 3-positional blood pressure 
and pulse).  PK blood sample are to be collected 2h post-dose for extensive group only.  Within 5 
minutes before or after 9h post-dose vital signs measurements are to be performed (respiratory 
rate, body temperature, 3-positional blood pressure and pulse). 
Requests for AEs and information about the concomitant medications if any, are to be performed 
by the Investigator to each patient during the study as well as subject is to be asked to report 
spontaneously all symptoms and complaints. 

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Patient is to fast from supper on day before (fasting at least 10 hours prior to dosing) with continued 
fasting for 2 hours post-dose.  Water and other fluids are to be restricted one hour before and one 
hour after dosing (excluding amount of water allowed for IMP administration). 
9.6. 
Day 7 
On Day7
IMP administration).  Vital signs measurements (respiratory rate, body temperature, 3-positional 
blood pressure and pulse) are to be performed, followed by 12-lead ECG.  Afterwards blood and 
urine samples for clinical laboratory assessments, and blood sample for pre-dose PK time point 
(extensive and sparse group) are to be collected (
 With the first 
PK sampling cannula might to be inserted into a vein shortly prior to the event.  If there is cannula 
occlusion, samples may be obtained via direct venepuncture.  IMP is to be administered with hand 
and mouth check afterwards to ensure the patient have swallowed all capsules.  Serial time-points 
after IMP administration for PK analysis (extensive group) are to be collected in scheduled time-
points (see Section 8.4.1).  Within 5 minutes before or after 1h 45 minutes after IMP administration 
vital signs measurements are to be performed (respiratory rate, body temperature, 3-positional 
blood pressure and pulse).  Start of ratings is to be within 5 minutes before or after 2h post-dose 
but after PK blood collection 2h timepoint (extensive and sparse group) and the scales are to be 
performed in order as follows: PANSS, CGI-S, CGI-I, ESRS.  Not earlier than 5h postdose 
neurological examination is to be performed.  Within 5 minutes before or after 9h post-dose vital 
signs measurements are to be performed (respiratory rate, body temperature, 3-positional blood 
pressure and pulse). 
Requests for AEs and information about the concomitant medications if any, are to be performed 
by the Investigator to each patient during the study as well as subject is to be asked to report 
spontaneously all symptoms and complaints. 
Patient is to fast from supper on day before (fasting at least 10 hours prior to dosing) with continued 
fasting for 2 hours post-dose.  Water and other fluids are to be restricted one hour before and one 
hour after dosing (excluding amount of water allowed for IMP administration). 
9.7. 
Days 8 to 13 
On Days 8-13, patient is to receive the consecutive doses of IMP.  
Requests for AEs and information about the concomitant medications if any, are to be performed 
by the Investigator to each patient during the study as well as subject is to be asked to report 
spontaneously all symptoms and complaints. 

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Patient is to fast from supper on day before (fasting at least 10 hours prior to dosing) with continued 
fasting for 2 hours post-dose but starting from 0.5h after IMP administration consumption of low 
calorie snack i.e. plain rice cakes is allowed till breakfast.  Water and other fluids are to be 
restricted one hour before and one hour after dosing (excluding amount of water allowed for IMP 
administration). 
9.8. 
Day 14 
On Day 14, patient is to receive the consecutive dose of IMP.  
IMP administration) vital signs measurements (respiratory rate, body temperature, 3-positional 
blood pressure and pulse) are to be performed, followed by 12-lead ECG.  Afterwards blood and 
urine samples for clinical laboratory assessments are to be collected (
administration). IMP is to be administered with hand and mouth check afterwards to ensure the 
patient have swallowed all capsules.  Within 5 minutes before or after 1h 45 minutes after IMP 
administration vital signs measurements are to be performed (respiratory rate, body temperature, 
3-positional blood pressure and pulse).  Start of ratings is to be within 5 minutes before or after 2h 
post-dose and the scales are to be performed in order as follows: PANSS, CG-S, CGI-I, BACS, 
ESRS, C-SSRS.  Not earlier than 5h post-dose neurological examination is to be performed.  
Within 5 minutes before or after 9h post-dose vital signs measurements are to be performed 
(respiratory rate, body temperature, 3-positional blood pressure and pulse). 
Requests for AEs and information about the concomitant medications if any, are to be performed 
by the Investigator to each patient during the study as well as subject is to be asked to report 
spontaneously all symptoms and complaints. 
Patient is to fast from supper on day before (fasting at least 10 hours prior to dosing) with continued 
fasting for 2 hours post-dose but starting from 0.5h after IMP administration consumption of low 
calorie snack i.e. plain rice cakes is allowed till breakfast.  Water and other fluids are to be 
restricted one hour before and one hour after dosing (excluding amount of water allowed for IMP 
administration). 
9.9. 
Days 15 to 20 
On Days 15-20, patient is to receive the consecutive doses of IMP. 
Requests for AEs and information about the concomitant medications if any, are to be performed 
by the Investigator to each patient during the study as well as subject is to be asked to report 
spontaneously all symptoms and complaints. 

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Patient is to fast from supper on day before (fasting at least 10 hours prior to dosing) with continued 
fasting for 2 hours post-dose but starting from 0.5h after IMP administration consumption of low 
calorie snack i.e. plain rice cakes is allowed till breakfast.  Water and other fluids are to be 
restricted one hour before and one hour after dosing (excluding amount of water allowed for IMP 
administration). 
9.10. Day 21 
On Day 21, patient is to receive the consecutive dose of IMP.  
IMP administration) vital signs measurements (respiratory rate, body temperature, 3-positional 
blood pressure and pulse) are to be performed, followed by 12-lead ECG.  Afterwards blood and 
urine samples for clinical laboratory assessments are to be collected (
administration).  IMP is to be administered with hand and mouth check afterwards to ensure the 
patient have swallowed all capsules.  Within 5 minutes before or after 1h 45 minutes after IMP 
administration vital signs measurements are to be performed (respiratory rate, body temperature, 
3-positional blood pressure and pulse).  Start of ratings is to be within 5 minutes before or after 2h 
post-dose and the scales are to be performed in order as follows: PANSS, CGI-S, CGI-I, ESRS.  
Not earlier than 5h post-dose neurological examination is to be performed.  Within 5 minutes 
before or after 9h post-dose vital signs measurements are to be performed (respiratory rate, body 
temperature, 3-positional blood pressure pulse). 
Requests for AEs and information about the concomitant medications if any, are to be performed 
by the Investigator to each patient during the study as well as subject is to be asked to report 
spontaneously all symptoms and complaints. 
Patient is to fast from supper on day before (fasting at least 10 hours prior to dosing) with continued 
fasting for 2 hours post-dose but starting from 0.5h after IMP administration consumption of low 
calorie snack i.e. plain rice cakes is allowed till breakfast.  Water and other fluids are to be 
restricted one hour before and one hour after dosing (excluding amount of water allowed for IMP 
administration). 
9.11. Days 22 to 27 
On Days 22-27, patient is to receive the consecutive doses of IMP. 
Requests for AEs and information about the concomitant medications if any, are to be performed 
by the Investigator to each patient during the study as well as subject is to be asked to report 
spontaneously all symptoms and complaints. 

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Patient is to fast from supper on day before (fasting at least 10 hours prior to dosing) with continued 
fasting for 2 hours post-dose but starting from 0.5h after IMP administration consumption of low 
calorie snack i.e. plain rice cakes is allowed till breakfast.  Water and other fluids are to be 
restricted one hour before and one hour after dosing (excluding amount of water allowed for IMP 
administration. 
9.12. Day 28 
administration) vital signs measurements (respiratory rate, body temperature, 3-positional blood 
pressure and pulse) are to be performed, followed by 12-lead ECG.  Afterwards blood and urine 
samples for clinical laboratory assessments, and blood sample for pre-dose PK time point 
(extensive and sparse group) are to be collected (
blood sampling cannula might to be inserted into a vein shortly prior to the event. If there is cannula 
occlusion, samples may be obtained via direct venepuncture.  IMP is to be administered with hand 
and mouth check afterwards to ensure the patient have swallowed all capsules.  Within 5 minutes 
before or after 1h 45 minutes after IMP administration vital signs measurements are to be 
performed (respiratory rate, body temperature, 3-positional blood pressure and pulse).  Start of 
ratings is to be within 5 minutes before or after 2h post-dose but after PK blood collection 2h 
timepoint (extensive and sparse group) and the scales are to be performed in order as follows: 
PANSS, CGI-S, CGI-I, BACS, ESRS, C-SSRS.  Not earlier than 5h post-dose physical, 
neurological, ophthalmological and dermatological examination are to be performed.  Within 5 
minutes before or after 9h post-dose vital signs measurements are to be performed (respiratory 
rate, body temperature, 3-positional blood pressure and pulse). 
Requests for AE and information about the concomitant medications if any, are to be performed 
by the Investigator to each patient during the study as well as subject is to be asked to report 
spontaneously all symptoms and complaints. 
Patient is to fast from supper on day before (fasting at least 10 hours prior to dosing) with continued 
fasting for 2 hours post-dose.  Water and other fluids are to be restricted one hour before and one 
hour after dosing (excluding amount of water allowed for IMP administration. 
9.13. Day 29 
Starting from Day 29 there are no IMP administration. On Day 29, the patient may resume 
antipsychotic treatment.  Urine pregnancy test is to performed for women patients.  Requests for 
AE and information about the concomitant medications, if any, are to be performed by the 

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Investigator to each patient during the study as well as subject is to be asked to report 
spontaneously all symptoms and complaints. 
At the Investigator discretion patients will be discharged from the clinical unit based on local 
standards of care, if the patient is in a stable condition under the regular medication(s). 
9.14. Follow-up visits 
To follow-
-last dose are to be 
performed. 
After arrival at the clinic patient identification is to be followed by alcohol test, urine drug screen 
and urine pregnancy test (for women).  Vital signs measurements (respiratory rate, body 
temperature, 3-positional blood pressure and pulse) are to be performed, followed by 12-lead ECG.  
Afterwards blood and urine samples for clinical laboratory assessments are to be collected.  Rating 
using ESRS and C-SSRS scales and also physical and neurological examinations are to be 
performed. 
Requests for AE and information about the concomitant medications, if any, are to be performed 
by the Investigator to each patient during the study as well as subject is to be asked to report 
spontaneously all symptoms and complaints. 

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10. 
STATISTICAL CONSIDERATIONS 
Before database lock, a statistical analysis plan (SAP) will be issued as a separate document, 
providing detailed methods for the analyses outlined below.  Any deviations from the planned 
analyses will be described and justified in the clinical study report (CSR). 
10.1. Study Population 
10.1.1. 
Disposition of Subjects 
The number and percentage of subjects entering and completing the clinical study will be presented 
by treatment. 
10.1.2. 
Protocol Deviations 
Protocol deviations will be listed by subject. 
10.1.3. 
Analysis population 
 Full Analysis Set (FAS): All patients randomized to either CPL500036 or placebo  based on 
planned treatment regimen irrespective of their compliance to the planned course of treatment 
(intent-to-treat principle). 
 Per Protocol (PP) Set: Patients from the FAS who completed the Treatment Period (Day 28) 
on study treatment without a major protocol deviation.  Protocol deviations will be determined 
prior to unblinding. 
 Safety Set (SS): All patients who received at least 1 dose of study treatment (either CPL500036 
or placebo). 
 Pharmacokinetic Set (PS):  All subjects in the safety set with at least 1 evaluable PK parameter.  
 Pharmacokinetic Set for parameter calculation (PSPC): All subjects in the safety set with 
extensive PK sampling that have at least 1 PK parameter evaluable and without any major 
protocol deviation thought to interfere with the absorption, distribution, metabolism, and 
excretion of CPL500036. 
The FAS will be the primary analysis set used for all efficacy analyses and the PP analysis set will 
be used for supportive analyses of the primary and secondary efficacy endpoints.  Patients will be 
included in the treatment group they were randomized to.  The SS will be used for all safety 
analyses and patients will be included in the treatment group based on the treatment they actually 
received. 

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10.2. Evaluation of Efficacy 
Descriptive statistics will be displayed to provide an overview of the study results.  For categorical 
variables, the number and percentage of subjects in each category will be presented.  The 
denominator for percentages will be based on the number of subjects appropriate for the purpose 
of analysis for the respective treatment group.  For continuous variables, descriptive statistics will 
include number of subjects (n), mean, standard deviation (SD), median, minimum, and maximum.  
For all analyses data from all centres will be pooled. 
10.3. Primary Efficacy Analysis 
The null hypothesis is that there is no difference in the primary endpoint between either dose group 
compared to placebo, versus the alternative hypothesis, that at least 1 dose group is significantly 
different, using a 2-sided 10% significance level.  The primary endpoint will be analysed using a 
mixed effect repeated measures model (MRMM), with treatment, timepoint, clinical site and 
interaction between treatment and timepoint as fixed effects and baseline score as a covariate.  If 
there will be many clinical sites with few subjects, they can be pooled into bigger groups. Subject 
will be treated as a random effect, with an unstructured covariance structure to account for the 
correlation among repeated measurements.  If the model does not converge, another covariance 
structure, (e.g., AR(1), CS, etc.) will be explored.  Missing data will be assumed to be missing at 
random.  A sensitivity analysis will be conducted whereby missing data is imputed using multiple 
imputation.  The primary analysis will compare each dose group with placebo based on estimated 
marginal means (aka least square means, LS-means) from the model.  
10.4. Secondary Efficacy Analyses 
All secondary endpoints will be analysed without adjustment for multiplicity.  The secondary 
endpoints, which are continuous, will be analysed using the same approach as described for the 
primary endpoint.  Missing data will be assumed to be missing at random.  At each timepoint, the 
LS-means will be reported (by treatment group and for the treatment difference for each dose 
group, compared to placebo).  The secondary endpoints which are binary (i.e., 
responder/non-responder) will be analysed at each timepoint using a Logistic regression model 
with treatment and clinical site (or country if there will be many clinical sites) as a fixed effect and 
baseline score as a covariate.  In sensitivity analysis, if a patient is missing data in order to derive 
their response at a given time point, the missing data will be imputed using multiple imputation 
for continuous endpoints and non-responder imputation for binary endpoints prior to the analysis. 

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10.5. General Considerations 
Continuous data will be summarized by treatment group using descriptive statistics (number, 
mean, SD, minimum, median and maximum).  Categorical data will be summarized by treatment 
group using frequency tables (number and percentage). 
10.6. Protocol Deviations 
All protocol deviations will be listed by subject. 
Protocol deviations will be handled in accordance with the CRO SOPs. 
10.7. Subject Disposition 
Subjects excluded from the safety, PK and PD analysis sets and data excluded from the PK and 
PD analysis sets will be listed including the reason for exclusion.  Subject disposition will be 
summarized and will include the following information: number of subjects randomized and 
dosed, number and percentage of subjects completing the study and the number and percentage of 
subjects who were withdrawn (including reasons for withdrawal).  Disposition data will be 
presented based on all subjects randomized. 
Subject discontinuations will be listed including the date of study exit, duration of treatment and 
reason for discontinuation.  A listing of informed consent response will also be presented. 
subject/patient has been randomized and the location of the Clinical Unit. 
10.8. Demographic and Anthropometric Information and Baseline Characteristics 
Demographic and anthropometric variables (age, sex, ethnicity, race, height, weight and BMI) will 
be listed by subject.  Demographic characteristics (age, sex, ethnicity and race) and anthropometric 
characteristics (height, weight and BMI) will be summarized by treatment and for all subjects in 
the  FAS, SS, PP and PSPC populations.  The denominator for percentages will be the number of 
subjects in the given analysis set for each treatment or for all subjects as applicable. 
Medical history data will be listed by subject including visit, description of the disease/procedure, 
MedDRA SOC, MedDRA preferred term, start date, and stop date (or ongoing if applicable), as 
well as summarized by treatment group and overall for full analysis set. 

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10.9. Prior and Concomitant Medication and Drug Administration 
Prior medications are those that started and stopped prior to the first dose of IMP.  Concomitant 
medications are those taken after first dosing (including medications that started prior to dosing 
and continued after). 
Prior and concomitant medication will be classified using the ATC codes contained in Register of 
Medicinal Products Approved for Marketing on the territory of the Republic of Poland and listed 
by subject and will include the following information: reported name, preferred term, ATC level 
2 (therapeutic subgroup) and 4 (chemical subgroup), the route of administration, dose, frequency, 
start date/time, duration and indication. Summary of prior and concomitant medications will be 
provided as a count and frequency for ATC level 2 and 4. 
 . 
Drug administration dates and times will be listed for each subject. 
10.10. Exposure 
A listing of drug administration will be created and will include the date and time of administration.  
When appropriate, a summary table of compliance will also be created. 
10.11. Safety Analyses 
10.11.1. 
Adverse Events 
All AEs will be listed.  The number and percent of subjects experiencing an event will be tabulated 
for each SOC and preferred term.  The AEs will also be tabulated according to intensity and 
causality. An overview table presenting the incidence of AE will be presented. All tables will be 
prepared separately by number of patients and number of events. 
Serious AEs will be listed separately. 
10.11.2. 
Clinical Laboratory Tests 
Individual data listings of laboratory results will be presented for each subject.  Flags will be 
Investigator
assessment.  Clinically significant laboratory test abnormalities that were considered AEs by the 
Investigator will be presented in the AE listings. 

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Clinical laboratory tests (observed values) as well as change from baseline and categorization of 
results will be summarized descriptively in tabular format.  Shift tables will be presented for 
selected laboratory parameters. 
10.11.3. 
Vital Signs 
Individual data listings of vital signs (observed and change from baseline) will be presented for 
each subject.  Individual clinically significant vital signs findings that were considered AEs by the 
Investigator will be presented in the AE listings. 
Observed values as well as change from baseline will be summarized descriptively in tabular 
format. 
10.11.4. 
Standard 12-lead Electrocardiogram 
Standard 12-lead ECG data (observed and change from baseline) will be listed for each subject 
and time point.  Observed values will be summarized descriptively in tabular format.  Change from 
baseline will be summarized descriptively for all parameters.  A categorical analysis will also be 
performed as well as shift tables. 
10.11.5. 
Physical Examination 
Abnormal physical examination findings will be listed. 
10.11.6. 
Other Safety Variables 
Abnormal neurological, ophthalmological and dermatological examinations findings will be listed. 
Descriptive statistics of the score and change from baseline will be summarized at each scheduled 
time point for extrapyramidal side effects - ESRS scale. 
10.12. Pharmacokinetics Analyses 
The concentration of CPL500036 in plasma will be summarized by dose at each scheduled 
sampling time using descriptive statistics.  Individual plasma concentration data versus time will 
be presented in a data listing.  Plasma PK parameters for CPL500036 will be summarized by dose 
for subjects with extensive and sparse PK separate using descriptive statistics.  Additional analysis, 
if deemed appropriate, will be described in the SAP.   
A population pharmacokinetic model may be developed.  If so, the analysis plan and the results 
would not be included in the CSR but in separate documents. 

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The concentration-time data will be summarized descriptively in tabular and graphical formats 
(linear and log scales).  The PK parameter data will be listed and summarized descriptively in 
tabular format. 
10.13. Pharmacokinetics/Pharmacodynamics Analyses 
An exploratory PK/PD analysis between the AUC0-24 and Cmax of CPL500036 and the PD 
assessments may be performed if deemed appropriate following review of the summary PK and 
PD data.  The decision to perform this analysis will be made by the Sponsor upon review of the 
tables, figures and listings produced at the end of the study. 
10.14. Interim Analyses 
No formal interim analysis is planned. 
10.15. Timing of analysis 
Baseline characteristics and efficacy analyses will be performed after the last subject completes a 
28-day treatment period. All data until the Day 28 visit  will be verified and locked before the 
unblinding. A safety analysis will be performed after all the data, including follow-up visits will 
be completed, verified and whole database will be locked. 
10.16. Determination of Sample Size 
This proof of concept study is powered to rule out an effect size of 0.5 or greater for the primary 
endpoint.  With 50 patients per group, the study has 80% power to detect an effect size of 0.5 or 
greater for 1 of the 2 dose groups, compared to placebo, given a 2-sample t-test, and a 2-sided 10% 
significance level.  Each dose will be compared to placebo, without adjustment for multiplicity so 
the type-I error will be slightly inflated, however, as this is a proof of concept study, the slight 
inflation is acceptable.  Assuming an approximately 10% of patients may drop out, approximately 
165 patients will be randomized (55 patients per group). 

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11. 
ETHICAL, LEGAL AND ADMINISTRATIVE ASPECTS 
11.1. Data Quality Assurance 
To ensure accurate, complete, and reliable data, Celon Pharma S.A. or its representative will ensure 
the following: 
 development and provision of instructional material to the study sites, as appropriate; 
 start-up training session to instruct the investigators and study coordinators.  This session 
will give instruction on the protocol, the completion of the CRFs, and study procedures as 
well as IMP handling and management; 
 periodic monitoring visits to the study site by blinded and unblinded Clinical Research 
Associates; 
 availability for consultation and regular contact with the study site personnel by mail, 
telephone; 
 revision and evaluation of CRF data and use standard computer edits to detect errors in 
data collection; 
 quality review of the database. 
Celon Pharma S.A.  or its representative will periodically check a sample of the patient data 
recorded against source documents at the study site during monitoring visits. 
The study may be also audited by Celon Pharma S.A. or designee, and/or regulatory agencies at 
any time.  Investigators will be given notice before an audit occurs. 
The Investigator must prepare and maintain adequate and accurate records of all observations and 
other data pertinent to the clinical study for each study participant.  Frequent communication 
between the clinical site and the Sponsor is essential to ensure that the safety of the study is 
monitored adequately.  The Investigator will make all appropriate safety assessments on an 
ongoing basis.  The Medical Monitor may review safety information as it becomes available 
throughout the study. 
All aspects of the study will be carefully monitored with respect to Good Clinical Practice (GCP) 
and SOPs for compliance with applicable government regulations.  The Study Monitor will be an 
authorized individual designated by the Sponsor.  The Study Monitor will have access to all records 
necessary to ensure integrity of the data and will periodically review the progress of the study with 
the Investigator. 
Protocol deviations will be handled in accordance with the CRO SOPs. 

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11.2. Data collection and Access to Source Data/Documents 
Celon Pharma S.A. will use an electronic data capture (EDC) system to completely collect all 
medical data during this study.  Electronic data capture system is a software tool designed similarly 
to an electronic medical record for the documentation of e.g., medical history, demographics, vital 
signs, and AEs. 
The Investigator will ensure the accuracy, completeness and timeliness of the data reported to the 
Sponsor.  System supported data collection processes and procedures are validated to ensure 
completeness, accuracy, reliability and consistency.  A complete audit trail is maintained of all 
the periodic review of study documents to ensure the accuracy and completeness of the data 
capture system at each scheduled monitoring visit. 
Electronic consistency checks (plausibility and completeness) will be used along with the 
Investigator review to identify any errors or inconsistencies in the data.  Data clarification requests 
will be provided to the study team by means of electronic or manual queries. 
During the study setup, adequate and accurate clinical procedure forms are used to generate 
medical records, digital ECGs, AE and concomitant medication reporting, raw data collection 
forms, etc., which are designed as protocol to record all observations and other pertinent data for 
each subject receiving study medication.  The only regularly used paper-based study document is 
the ICF, because it requires wet-ink signatures.  The ICFs will be archived in paper form at the 
end of the study. 
The Investigator will allow Sponsor representatives, contract designees, authorized regulatory 
authority inspectors and the IEC to have direct access to all electronic records pertaining to the 
study. 
All data should be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation and verification. 
11.3. Archiving Study Documents 
All source documents generated in connection with the study will be retained in the limited access 
file storage area, respecting the privacy and confidentiality of all records that could identify the 
subjects.  Direct access is allowed only for authorized people for monitoring and auditing purposes.  
Source documents will be handled, stored and archived according to in-house procedures. 

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The Investigator's Site File will be archived by the Clinical Centre for 15 years after completion 
of the study. The Trial Master File will be archived by the Sponsor for 15 years after completion 
of the study. 
11.4. Good Clinical Practice 
The procedures set out in this CSP are designed to ensure that the Sponsor and the Investigator 
abide by the principles of the ICH guidelines on GCP.  The clinical study also will be carried out 
in keeping with national and local legal requirements  
11.5. Informed Consent 
Eligible subjects may only be included in the study after providing IRB/IEC approved informed 
consent. 
Informed consent must be obtained from the subject before conducting any study-specific 
procedure. 
As part of the informed consent procedure, the Investigator must explain orally and in writing the 
nature, duration and purpose of the study and the action of the drug in such a manner that the 
subject is aware of the potential risks, inconveniences or AEs that may occur.  The subject should 
be informed that he/she is free to withdraw from the study at any time.  Subjects will receive all 
information that is required by local regulations and ICH guidelines.  The ICF must be signed and 
dated; 1 copy will be handed to the subject, and the Investigator will retain a copy as part of the 
clinical study records.  The Investigator will not undertake any investigation specifically required 
for the clinical study until written consent has been obtained.  The terms of the consent and when 
it was obtained must be documented in the subject source documents. 
If a protocol amendment is required, then the ICF may need to be revised to reflect the changes to 
the protocol.  If the ICF is revised, it must be reviewed and approved by the responsible IRB/IEC 
and signed by all subjects subsequently enrolled in the clinical study, as well as those currently 
enrolled in the clinical study as applicable. 
11.6. Insurance and Compensation for Injury 
The Sponsor has covered this clinical study by means of an insurance of the clinical study 
according to national requirements.  The name and address of the relevant insurance company, the 
certificate of insurance, the policy number and the sum insured are 
Site File. 

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11.7. Protocol Approval and Amendment(s) 
Before the start of the clinical study, the CSP and other relevant documents will be approved by 
the IRB/IEC, in accordance with local legal requirements.  The Sponsor must ensure that all ethical 
and legal requirements have been met before the first subject is enrolled in the clinical study. 
This protocol is to be followed exactly.  To alter the protocol, amendments must be written, which 
must be released by the responsible staff and receive IRB/IEC approval prior to implementation 
(as appropriate).  
Administrative changes may be made without the need for a formal amendment but will also be 
mentioned in the integrated CSR.  All amendments will be distributed to all study protocol 
recipients, with appropriate instructions. 
11.8. Confidentiality Data Protection 
The CRO and the Sponsor will take appropriate measures to ensure the processing of personal data 
and the free movement of such data are handled according to the European Union General Data 
Protection Regulation 2016/679. 
All clinical study findings and documents will be regarded as confidential.  Study documents 
(protocols, IBs and other material) will be stored appropriately to ensure their confidentiality.  The 
Investigator and members of his/her research team (including the IRB/IEC) must not disclose such 
information without prior written approval from the Sponsor, except to the extent necessary to 
obtain informed consent from subjects who wish to participate in the trial or to comply with 
regulatory requirements. 
The anonymity of participating subjects must be maintained.  Subjects will be specified on study 
documents by their subject number, initial or birth date, not by name, or by subject number and 
birth year only, if required and to comply with local data protection regulations.  Documents that 
identify the subject (e.g., the signed ICF) must be maintained in confidence by the Investigator. 
11.9. Publication Policy 
By signing the CSP, the Investigator agrees with the use of results of the clinical study for the 
purposes of national and international registration, publication and information for medical and 
pharmaceutical professionals.  If necessary, the regulatory authorities will be notified of the 
Investigator
 

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An Investigator shall not publish any data (poster, abstract, paper, etc.) without having consulted 
with the Sponsor in advance. 

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12. 
REFERENCE LIST 
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clinical use. Pharmacological Reviews, 58(3), 488 520. 
2. Charych, E. I., Jiang, L.-X., Lo, F., Sullivan, K., & Brandon, N. J. (2010). Interplay of Palmitoylation 
and Phosphorylation in the Trafficking and Localization of Phosphodiesterase 10A: Implications for 
the Treatment of Schizophrenia. Journal of Neuroscience, 30(27), 9027 9037. 
3. Fujishige, K., Kotera, J., Omori, K., 1999a. Striatum- and testis-specific phos- phodiesterase PDE10A 
isolation and characterization of a rat PDE10A. Eur. J. Biochem. 266, 1118e1127. 
4. DeLong MR, Wichmann T. Circuits and circuit disorders of the basal ganglia. Arch Neurol. 
2007;64:20  4. 
5. Beaulieu, J.-M., & Gainetdinov, R. R. (2011).  The Physiology, Signaling, and Pharmacology of 
Dopamine Receptors. Pharmacological Reviews, 63(1), 182 217. 
6. Heckman, P. R. A., van Duinen, M. A., Bollen, E. P. P., Nishi, A., Wennogle, L. P., Blokland, A., & 
Prickaerts, J. (2016). Phosphodiesterase Inhibition and Regulation of Dopaminergic Frontal and Striatal 
Functioning: Clinical Implications. International Journal of Neuropsychopharmacology, 19(10). 
7. Graybiel AM. The basal ganglia. Curr Biol. 2000;10:R509 11. 
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9. Suzuki, K., Harada, A., Suzuki, H., Miyamoto, M., & Kimura, H. (2016). TAK-063, a PDE10A 
Inhibitor with Balanced Activation of Direct and Indirect Pathways, Provides Potent Antipsychotic-
Like Effects in Multiple Paradigms. Neuropsychopharmacology, (November 2015), 1 43. 
10. Shiraishi, E., Suzuki, K., Harada, A., Suzuki, N., & Kimura, H. (2015). The phosphodiesterase 10A 
selective inhibitor TAK-063 improves cognitive functions associated with schizophrenia in rodent 
models. Journal of Pharmacology and Experimental Therapeutics, 4. 
11. 
Phosphodiesterase 10A inhibitor activity in preclinical models of the positive, cognitive, and negative 
symptoms of schizophrenia. The Journal of Pharmacology and Experimental Therapeutics, 331(2), 
574 90. 
12. Shunsuke Maehara, Keita Arakawa, Natsuko Yuge, Yuki Matsui, Y. N., Makoto Ishikawa, Hiroyasu 
Naba, Takaaki Negishi, Yutaka Kato, Kazunari Nakao, S. F., Tong, H. M., Iturrino, L., Macdonald, G. 
-Ceide, S. (2014). Discovery of a potent, selective, and orally active 

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phosphodiesterase 10A inhibitor for the potential treatment of schizophrenia. Journal of Medicinal 
Chemistry, 57(10), 4196 4212. 
13. Patel, K. R., Cherian, J., Gohil, K., & Atkinson, D. (2014). Schizophrenia: overview and treatment 
options. P & T : A Peer-Reviewed Journal for Formulary Management, 39(9), 638 45. 
14. Matuszczyk M. (2005). Schizofrenia-wyzwania w leczeniu. http:// www.psychiatria.pl. 
15. 
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16. Laruelle, M., Kegeles, L. S., & Abi-Dargham, A. (2003). Glutamate, dopamine, and schizophrenia: 
from pathophysiology to treatment. Annals of the New York Academy of Sciences, 1003, 138 58. 
17. Wadenberg, M. L. G., & Hicks, P. B. (1999). The conditioned avoidance response test re-evaluated: Is 
it a sensitive test for the detection of potentially atypical antipsychotics? Neuroscience and 
Biobehavioral Reviews, 23(6), 851 862. 
18. Gleason, S. D., & Shannon, H. E. (1997). Blockade of phencyclidine-induced hyperlocomotion by 
olanzapine, 
clozapine 
and 
serotonin 
receptor 
subtype 
selective 
antagonists 
in 
mice. 
Psychopharmacology, 129(1), 79-84. 
19. Wan, F. J., Taaid, N., & Swerdlow, N. R. (1996). Do D 1/D 2 interactions regulate prepulse inhibition 
in rats?. Neuropsychopharmacology, 14(4), 265. 
20. Birrell, J. M., & Brown, V. J. (2000). Medial frontal cortex mediates perceptual attentional set shifting 
in the rat. Journal of Neuroscience, 20(11), 4320-4324. 
21. Remmelink, E., Chau, U., Smit, A. B., Verhage, M., & Loos, M. (2017). A one-week 5-choice serial 
reaction time task to measure impulsivity and attention in adult and adolescent mice. Scientific reports, 
7, 42519. 
22. Wilson, C. A., & Koenig, J. I. (2014). Social interaction and social withdrawal in rodents as readouts 
for investigating the negative symptoms of schizophrenia. European Neuropsychopharmacology, 
24(5), 759-773. 
23. 
. 
24. Suzuki, K., Harada, A., Shiraishi, E., & Kimura, H. (2015). In vivo pharmacological characterization 
of TAK-063, a potent and selective phosphodiesterase 10A inhibitor with antipsychotic-like activity in 
rodents. Journal of Pharmacology and Experimental Therapeutics, 352(3), 471-479. 

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25. Macek TA, McCue M, Dong X, Hanson E, Goldsmith P, Affinito J, Mahableshwarkar AR. A phase 2, 
randomized, placebo-controlled study of the efficacy and safety of TAK-063 in subjects with an acute 
exacerbation of schizophrenia. Schizophrenia Research. 2019; 204, 289-294. 
26. Goldsmith P, Affinito J, McCue M, Tsai M, Roepcke S, Xie J, et al. A randomized multiple dose 
pharmacokinetic study of a novel PDE10A inhibitor TAK-063 in subjects with stable schizophrenia 
and Japanese subjects and modeling of exposure relationships to adverse events. Drugs in R & D. 2017; 
17 (4), 631 643. 
27. Tsai M, Chrones L, Xie J, Gevorkyan H, Macek TA. A phase 1 study of the safety, tolerability, 
pharmacokinetics, and pharmacodynamics of TAK-063, a selective PDE10A inhibitor. 
Psychopharmacology. 2016. 233, 3787 3795. 
28. Kinon, B. J., Potts, A. J., & Watson, S. B. (2011). Placebo response in clinical trials with 
schizophrenia patients. Current opinion in psychiatry, 24(2), 107-113. 
29. Oliveira, I. R. D., Nunes, P. M., Coutinho, D. M., & Sena, E. P. D. (2009). Review of the 
efficacy of placebo in comparative clinical trials between typical and atypical antipsychotics. 
Brazilian Journal of Psychiatry, 31(1), 52-56. 
30. Guideline on clinical investigation of medicinal products, including depot preparations in the 
treatment of schizophrenia
EMA/CHMP/40072/2010 Rev. 1) 
 

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13. 
APPENDICES 
Appendix No.1 Table 9. Drugs Allowed (Y) and Not Allowed (N) as Concomitant Medications. 
Appendix No. 2 Investigator Signature Page Template. 
 

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Table 9. Drugs Allowed (Y) and Not Allowed (N) as Concomitant Medications 
Drugs name or Class 
Episodic Use (PRN) 
Chronic Use 
Restrictions 
Akathisia management 
Y 
N 
Only episodic propranolol 
administration is allowed, detailes on 
dosage  and restrictions outlined in 
Section 5.4.3, Table 5, 
Analgesics 
Y 
Y 
Nonnarcotic analgesics are allowed. 
Tramadol and indomethacin are not 
allowed.   
Pregabalin, gabapentin and other 
gabapentinoids are not allowed. 
Medically appropriate episodic use of 
narcotic analgesics for acute medical 
indications limited to 3 days for an 
episode is allowed, except on days of 
efficacy evaluations. 
Anesthetics, general 
Y 
N/A 
If procedures requiring general 
anesthesia are to occur/have occurred, 
please contact the Forest Medical 
Monitor to report the medical 
condition(s). 
Anesthetics, local 
Y 
N 
- 
Antacids 
Y 
Y 
Not within 8h before and 4h after IMP 
administration. 
Anti-acne  
 
Y 
Y 
Topical agents only, including topical 
antibiotics.  
Antianginal agents 
N 
N 
- 
Antiarrhythmics 
N 
Y 
Dosages should be stable for 1 month 
before Visit 1 (Screening).  For 
patients on digoxin, there should be a 
digoxin level obtained within 2 months 
before Screening. 
Anti-asthma agents 
Y 
Y 
Systemic corticosteroids are not 
allowed. 

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Drugs name or Class 
Episodic Use (PRN) 
Chronic Use 
Restrictions 
Inhaled steroids at approved dosages 
are allowed. 
Antibiotics 
Y 
N 
Chronic use of topical antibiotics for 
acne is allowed.  Linezolid (Zyvox) 
and isoniazid are not allowed.  
Erythromycin, clarithromycin, 
telithromycin, chloramphenicol, 
rifampicin and rifabutin are not 
allowed. Azithromycin is 
recommended if a macrolide antibiotic 
is needed. 
Anticholinergics in 
extrapyramidal 
symptoms management 
Y 
N 
Only episodic benzatropine/biperiden 
administration is allowed, detailes on 
dosage  and restrictions outlined in 
Section 5.4.3, Table 5, 
Anticoagulants 
N 
N 
Warfarin (Coumadin) use is not 
allowed. 
Some antiplatelet agents are allowed 
(see below). 
Anticonvulsants 
N 
N 
- 
Antidepressants 
N 
N 
- 
Antidiarrheal 
preparations 
Y 
N 
Only loperamide HCl (Imodium), 
bismuth subsalicylate (Pepto-Bismol), 
and kaolin preparations are allowed. 
Antiemetics 
Y 
N 
Antidopaminergic agents (such as 
metoclopramide, domperidone and 
phenothiazines), scopolamine, 5-HT3 
receptor antagonists (e.g., ondansetron) 
and sedating (H1) antihistamines are 
not allowed.  Phosphoric acid 
preparations (Emetrol, Emecheck), 
bismuth subsalicylate (Pepto-Bismol), 
and cola syrup are allowed. 

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Drugs name or Class 
Episodic Use (PRN) 
Chronic Use 
Restrictions 
Antifungals, systemic 
N 
N 
- 
Antifungals, topical 
Y 
Y 
- 
Anti-gout medications 
Y 
Y 
Probenicid is not allowed. 
Antihistamines 
Y 
Y 
Sedating antihistamines are not 
allowed. 
Only fexofenadine (Allegra), 
loratadine (Claritin), desloratadine 
(Clarinex), cetirizine (Zyrtec) and 
levcetirizine (Xyzal) are allowed for 
episodic or chronic use.  Terfenadine is 
not allowed.  See Cough and Cold 
Preparations for combination products. 
Antihypertensives 
N 
Y 
Reserpine (Diupres), clonidine 
(Catapres), guanabenz (Wytensin), 
guanfacine (Tenex and Intuniv), 
guanethidine (Ismelin), methyldopa 
(Aldomet), direct vasodilators 
(hydralazine, minoxidil), nitroglycerin, 
sodium nitroprusside, and diazoxide 
are not allowed.  Propranolol (Inderal) 
is not allowed.  For all others 
-blockers, -blockers, calcium 
channel blockers, ACE inhibitors, etc), 
the medication and dosage should be 
stable for 1 month before Screening 
(for diuretics, the patient should have 
been treated with the diuretic for at 
least 3 months, with at least 1 month 
on the current dose). 
Anti-inflammatory 
drugs 
Y 
Y 
Chronic use is allowed if dosage is 
stable 
for 1 month prior to Screening. 
Indomethacin (Indocin) and systemic 

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Drugs name or Class 
Episodic Use (PRN) 
Chronic Use 
Restrictions 
corticosteroids are not allowed. 
Antimigraine 
Y 
N 
Ergotamine or ergot derivatives are not 
allowed. Narcotics, antidepressants, 
and anticonvulsants are not allowed. 
Antinauseants 
Y 
N 
Only phosphoric acid preparations 
(Emetrol, Emecheck), bismuth 
subsalicylate (Pepto-Bismol), and cola 
syrup are allowed. 5-HT3 receptor 
antagonists (e.g. ondansetron), sedating 
(H1) antihistamines, and prokinetic 
agents (metoclopramide) are not 
allowed. 
Antineoplastics 
N 
N 
- 
Antiobesity/Appetite 
suppressants 
N 
N 
- 
Antiplatelet agents 
N 
Y 
Only Aspirin (maximum 325 mg/d) 
and clopidogrel (Plavix) are allowed. 
Ticlopidine is not allowed. 
Medication dosage must be stable for 
1 month prior to Screening. 
Antipsoriatic treatments 
Y 
Y 
Acitretin (Soriatane) is not allowed. 
Antipsychotics 
N 
N 
- 
Antismoking 
medications 
Y 
Y 
Only nicotine replacement therapy 
patches are allowed. 
Antiviral agents 
Y 
Y 
Only oral or topical agents are allowed. 
Only acyclovir, famciclovir, 
valacyclovir, penciclovir, docosanal, 
trifluridine, and vidarabine are 
allowed.  Amantadine and rimantadine 
are permitted for influenza prophylaxis 
but use is limited to a 7- to 14-day 
course.  Interferons are not allowed. 
Anti-HIV drugs are not allowed. 

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Drugs name or Class 
Episodic Use (PRN) 
Chronic Use 
Restrictions 
Anxiolytics 
Y 
N 
Only episodic lorazepam 
administration is allowed, detailes on 
dosage  and restrictions outlined in 
Section 5.4.3, Table 5,  
Cough and /Cold 
preparations 
Y 
N 
Cough/cold preparations containing 
dextromethorphan or narcotics are not 
allowed.  Decongestant preparations 
containing pseudoephedrine or 
phenylpropanolamine are not allowed. 
Phenylephrine nasal sprays are allowed 
for brief medically appropriate use, for 
up to 5 days. Combination products 
containing 
some synonym routinely include a 
sedating antihistamine and are not 
allowed.  Combination products 
stimulant such as pseudoephedrine or 
phenylpropanolamine and are not 
allowed (also see Antihistamines). 
Diuretics 
Y 
Y 
For chronic use, medication 
and dosage should be stable for 
1 month before Screening (note, as a 
antihypertensive, diuretics should have 
been prescribed for at least 3 months, 
with at least 1 month on the current 
dose). 
Gastrointestinal: 
H2-blockers/ 
proton pump inhibitors/ 
prokinetic agents 
Y 
Y 
Cimetidine (Tagamet) is not allowed. 
Metoclopramide is not allowed. 
Hormonal 
(noncontraceptive) 
N 
Y 
- 

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Drugs name or Class 
Episodic Use (PRN) 
Chronic Use 
Restrictions 
therapies 
Hormone suppressants 
N 
Y 
Only finasteride (Proscar) and 
dutasteride (Avodart) are allowed. 
Dosage must be stable for 3 months 
prior to Screening 
Hormones: reproductive 
N 
Y 
Hormonal contraception such as oral 
contraceptives (estrogen-progestin 
combination or progestin alone), 
transdermally delivered contraceptives 
(e.g., Ortho Evra), depot injections 
(e.g., Depo-Provera), vaginal 
contraceptive ring (e.g., NuvaRing) 
and contraceptive implant (e.g., 
Implanon, Norplant) are allowed. 
Hormones: thyroid 
N 
Y 
Thyroid hormone replacement is 
allowed (dosage of thyroid medication 
should be stable for 2 months before 
Screening).  Therapeutic use for 
psychiatric disorders (e.g., T3 
antidepressant augmentation) is not 
allowed 
Hypoglycemic agents 
N 
Y 
Oral hypoglycemic agents are allowed, 
except pioglitazone and troglitaxone 
are not allowed. 
Insulin is not allowed. 
Hypolipidemics: 
bile acid sequestrants; 
fibrates; 
niacin; statins 
N 
Y 
*Niacin and niacinamide are allowed if 
the dose has been stable for 3 months 
prior to Screening, and AST and ALT 
are 
1.5 times the upper limit of 
normal. 
Ezetimibe (Zetia) is allowed. 
Gemfibrozil and fenofibrate are 
allowed.  Statins (e.g., Lovastatin, 

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Drugs name or Class 
Episodic Use (PRN) 
Chronic Use 
Restrictions 
simvastatin, pravastatin, atorvastatin, 
fluvastatin, and rosuvastatin) are 
allowed.  Dosage must be 
stable for 1 month prior to Screening. 
Bile sequestrants are not allowed.  Call 
the Medical Monitor to discuss 
combinations. 
Insulin 
N 
N 
- 
Laxatives 
Y 
Y 
Episodic and chronic use of bulk 
laxatives and emollient laxatives are 
allowed.  Episodic use of stimulant 
laxatives containing senna, bisacodyl, 
and anthraquinone derivatives is 
allowed.  Episodic use of osmotic 
laxatives such as oral magnesium 
hydroxide (milk of magnesia), oral 
sodium citrate and sodium biphosphate 
is allowed.  Hyperosmotic laxatives 
such as sorbitol, lactulose, and 
polyethylene glycol are not allowed. 
Lithium 
N 
N 
- 
Muscle relaxants 
N 
N 
Soma, Flexeril, Skelaxin, etc. are not 
allowed. 
Psychotropic drugs not 
otherwise specified 
(including herbal 
products) 
N 
N 
No drugs with psychomotor effects or 
with anxiolytic, antidepressant, 
stimulant, antipsychotic, mood 
stabilizers or sedative properties are 
allowed except as stipulated by the 
protocol.  Herbal/dietary products and 
supplements with potential 
psychoactive actions, including St. 
 biloba, kava kava, 
SAMe, valerian root, DHEA, tyrosine, 

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Drugs name or Class 
Episodic Use (PRN) 
Chronic Use 
Restrictions 
tryptophan  5-HTP and melatonin are 
not allowed.  Omega-3 supplements 
are not allowed.. 
Sedatives/Hypnotics 
Y 
N 
Only episodic lorazepam and zolpidem 
administration is allowed, details on 
dosage and restrictions outlined in 
Section 5.4.3, Table 5,  Other 
benzodiazepines and z-drugs are not 
allowed. 
Steroids, systemic 
N 
N 
- 
Steroids, local 
Y 
Y 
- 
Stimulants/ADHD 
medications 
N 
N 
Oral or transdermal methylphenidate, 
amphetamine products or prodrugs, 
pemoline (Cylert), pseudoephedrine, 
modafinil (Provigil), and armodafinil 
(Nuvigil) are not allowed.  Clonidine 
(Catapres), guanfacine (Tenex) and 
guanfacine extended-release (Intuniv) 
are not allowed. 
Vaccines 
Y 
N/A 
- 
PRN = as needed 

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SIGNATURE PAGE 
Declaration of the Investigator 
I have read and understood the protocol version 4.0, dated 16th May 2024, specified below, 
and agree on the contents. 
Protocol Title: Phase II, Double-blind, Randomized, Placebo-controlled, Parallel-group, Trial to 
Explore Efficacy, Safety and Pharmacokinetics of CPL500036 (PDE10A inhibitor) in Patients 
With an Acute Exacerbation of Schizophrenia. 
This clinical study protocol was subjected to critical review and has been released by the Sponsor.  
The information it contains is consistent with current risk and benefit evaluation of the 
investigational medicinal product, as well as with the moral, ethical and scientific principles 
governing clinical research as set out in the guidelines on Good Clinical Practice applicable to this 
clinical study. 
I have read all pages of this clinical study protocol, version 4.0, dated 16th May 2024 and confirm 
that it contains all the information required to conduct this study.  I agree to conduct the study as 
detailed in the protocol and comply with all the terms and conditions set out therein.  I confirm 
that I is to conduct the study in accordance with the provisions of the Declaration of Helsinki.  I 
will also ensure that Investigator(s) and other relevant members of my staff have access to copies 
of this protocol and the Declaration of Helsinki to enable them to work in accordance with the 
provisions of the documents and standard operating procedures of designated CRO company.  
Furthermore, current ICH-GCP, and local regulations is to be followed. 
I acknowledge that all data included in the clinical study protocol are confidential.  Copying, 
disclosing and publishing without assent of Sponsor is prohibited. 
Investigator Signatory 
 
Signature 
Name 
 
Title 
 
Institution 
 
 
 
Date