Clinical trial NCT04567524
Conditions: Schizophrenia Schizoaffective
Sponsor: Lyndra Inc.
Start date: 2020-08-13; Completion date: 2020-12-22
Enrollment: 34 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Lyndra is developing an oral, extended release (ER) formulation of risperidone (LYN-005) presented in a capsule dosage form with the intent of reducing the frequency of dosing orally-administered medications to once weekly or less and thereby improving the management of schizophrenia.

Study LYN-005-C-004 will evaluate the safety, tolerability, and pharmacokinetics (PK) of multiple dose administration of the ER formulation at two dose levels of LYN-005 relative to IR risperidone.

Detailed description:
LYN-005-C-004 is a blinded, multiple-dose, randomized, parallel group, safety, tolerability and PK study of LYN-005 in subjects with a primary diagnosis of schizophrenia or schizoaffective disorder in general good health. Eligible subjects must be clinically stable and receiving a therapeutic dose of an approved oral antipsychotic drug for a minimum of 6 weeks at the time of Screening. Enrolled subjects will be evaluated under steady-state conditions on commercially-available IR risperidone tablets and then assigned in blinded fashion either to LYN-005 weekly or continued encapsulated IR risperidone daily for 3 weeks to attain (or continue) steady-state exposure.

Arms: arm 1: LYN-005: capsules containing LYN-005 stellate; the 14mg dose of LYN-005 contains 3 active arms containing risperidone, and 3 inactive arms and the 28 mg dose of LYN-005 contains 6 active arms containing risperidone.

AND

IR Risperidone Matched Placebo: Orange capsule-shaped tablets containing inactive ingredient. arm 2: LYN-005 Matched Placebo: Size 00EL capsules containing inactive ingredient with no stellate.

AND

IR Risperidone: Risperidone 2 mg (orange) capsule-shaped tablets.
Interventions: intervention 1: LYN-005
Intervention descriptions: intervention 1: LYN-005 (14 or 28 mg weekly) plus IR risperidone matched placebo.

Protocol documents:
Prot_002.pdf: 
Protocol LYN-005-C-004  
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CLINICAL RESEARCH PROTOCOL 
DRUG: 
Risperidone 
 
STUDY NUMBER: 
LYN-005-C-004 
 
PROTOCOL TITLE: 
A Multiple Dose Study to Assess the Safety, 
Tolerability and Pharmacokinetics of Risperidone 
Extended Release Capsules in Subjects with 
Schizophrenia, Schizoaffective Disorder 
 
IND NUMBER: 
143074 
 
SPONSOR: 
Lyndra® Therapeutics Inc, (US); hereafter referred to 
as Lyndra 
 
ORIGINAL PROTOCOL DATE: 
10 July 2020 
 
AMENDMENT NUMBER: 
1.0 (Protocol Version 2.0) 
 
 
AMENDMENT DATE: 
27 August 2020 
 




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TABLE OF CONTENTS 
1 
PROTOCOL SUMMARY .........................................................................................8 
1.1 
Study Synopsis ........................................................................................................8 
1.2 
Study Schematic ...................................................................................................18 
1.3 
List of Abbreviations ...........................................................................................19 
2 
INTRODUCTION AND RATIONALE .................................................................21 
2.1 
Impact of Schizophrenia and Schizoaffective Disorder ...................................21 
2.2 
Role of Adherence ................................................................................................21 
2.3 
Therapeutic Approach.........................................................................................22 
2.4 
Study Rationale ....................................................................................................23 
2.5 
Lyndra Extended Release Capsule .....................................................................23 
2.6 
Active Ingredient – Risperidone .........................................................................25 
2.7 
Benefits/Risks .......................................................................................................26 
2.7.1 
Risks Associated with Active Ingredient......................................................26 
2.7.2 
Risks Associated with Extended Release Capsule.......................................26 
2.7.3 
Risks Associated with Study Related Procedures .......................................27 
2.7.4 
Benefits/Risks Conclusions ............................................................................27 
3 
STUDY OBJECTIVES AND ENDPOINTS ..........................................................28 
4 
STUDY PLAN ...........................................................................................................29 
4.1 
Study Design .........................................................................................................29 
4.1.1 
Screening Period (Day -21 to Day -14): ........................................................31 
4.1.2 
Pre-study Preparation with IR Risperidone................................................32 
4.1.3 
IR Risperidone PK Period.............................................................................32 
4.1.4 
Randomization (Day 1) ..................................................................................32 
4.1.5 
Double-blind Dosing Period (Days 1 to 21)..................................................33 
4.1.6 
End of Study Visit (Day 35)...........................................................................34 
4.2 
Blinding Procedures.............................................................................................34 
4.3 
Justification of Dose Selection .............................................................................34 
5 
SUBJECT POPULATION .......................................................................................35 
5.1 
Inclusion Criteria .................................................................................................35 
5.2 
Exclusion Criteria ................................................................................................36 
5.3 
Screen Failure.......................................................................................................40 
5.4 
Discharge Instructions at End of Study or Early Termination Visit ..............40 
5.5 
Study Completion.................................................................................................40 
6 
STUDY DRUG MANAGEMENT ...........................................................................41 
6.1 
Description of Study Drugs .................................................................................41 
6.1.1 
LYN-005 ER ...................................................................................................41 
6.1.2 
IR Risperidone ...............................................................................................41 
6.2 
Storage ..................................................................................................................41 
6.2.1 
LYN-005 ..........................................................................................................41 
6.2.2 
IR Risperidone ...............................................................................................41 
6.3 
Dosing and Administration .................................................................................42 
6.3.1 
Run-in Preparation with IR Risperidone ....................................................42 
6.3.2 
IR Risperidone PK Period.............................................................................42 
6.3.3 
Blinded Treatment (LYN-005 or Placebo) ..................................................43 


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6.4 
Accountability and Compliance..........................................................................43 
6.5 
Prior and Concomitant Medications and Therapies ........................................43 
7 
PAUSING AND STOPPING GUIDELINES AND SUBJECT 
DISCONTINUATION/ WITHDRAWAL ..............................................................45 
7.1 
Pausing and Stopping Guidelines .......................................................................45 
7.2 
Premature Withdrawal from Study ...................................................................46 
8 
STUDY ASSESSMENTS AND PROCEDURES ...................................................47 
8.1 
Screening and Safety Assessments .....................................................................47 
8.1.1 
Informed Consent ..........................................................................................47 
8.1.2 
PILL-5 Questionnaire ....................................................................................47 
8.1.3 
Breath Test for H. Pylori ...............................................................................47 
8.1.4 
Medical and Psychiatric History ..................................................................47 
8.1.5 
Acid Reflux Severity Scale ............................................................................48 
8.1.6 
Psychiatric and Extrapyramidal Symptom Assessment ............................48 
8.1.7 
Fecal Samples for Occult Blood ....................................................................52 
8.1.8 
General Physical Examination and Directed Physical Examination ........52 
8.1.9 
Vital Signs .......................................................................................................53 
8.1.10 
Electrocardiograms........................................................................................53 
8.1.11 
CYP2D6 Genotyping .....................................................................................53 
8.1.12 
Screening Serology .........................................................................................53 
8.1.13 
Safety Laboratory Assessments ....................................................................54 
8.1.14 
Prolactin ..........................................................................................................54 
8.1.15 
Pregnancy Testing ..........................................................................................54 
8.1.16 
Compliance Laboratory Assessments ..........................................................54 
8.2 
Adverse Events and Serious Adverse Events ....................................................55 
8.2.1 
Definition of an Adverse Event .....................................................................55 
8.2.2 
Serious Adverse Events .................................................................................56 
8.2.3 
Collection of Adverse Events ........................................................................56 
8.2.4 
Evaluation and Classification of Adverse Events .......................................56 
8.2.5 
Relationship to Study Drug (Intervention) ..................................................57 
8.2.6 
Time Period and Frequency for Event Assessment and Follow-up ..........57 
8.2.7 
Procedures for Recording and Reporting Adverse Events ........................57 
8.2.8 
Reporting of Pregnancies ..............................................................................58 
8.3 
Gastrointestinal Imaging (X-ray) .......................................................................59 
8.4 
Pharmacokinetics .................................................................................................59 
8.5 
Protocol Deviations ..............................................................................................59 
9 
STATISTICS AND DATA MANAGEMENT........................................................60 
9.1 
General Procedures .............................................................................................60 
9.2 
Data Management ................................................................................................60 
9.3 
Sample Size ...........................................................................................................60 
9.4 
Statistical Methods ...............................................................................................60 
9.4.1 
Analysis Sets ...................................................................................................60 
9.4.2 
Statistical Methods .........................................................................................61 
9.4.3 
Analysis of Safety - Analysis of Adverse Events .........................................61 
9.4.4 
Analyses of Pharmacokinetics ......................................................................61 


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9.4.5 
Demographic and Baseline Characteristics .................................................62 
9.5 
Assessment of Protocol Deviations .....................................................................62 
9.6 
Safety Reviews ......................................................................................................62 
9.7 
Data Entry and Management .............................................................................62 
9.8 
Data Clarification.................................................................................................63 
9.9 
Data Protection.....................................................................................................63 
10 ETHICS AND RESPONSIBILITIES .....................................................................64 
10.1 
Good Clinical Practice .........................................................................................64 
10.2 
Sponsor Medical Monitor....................................................................................64 
10.3 
Investigator and Institutional Review Board Responsibilities.........................64 
10.4 
Subject Information and Informed Consent .....................................................65 
11 RECORDS MANAGEMENT..................................................................................66 
11.1 
Source Documentation.........................................................................................66 
11.2 
Study Files and Record Retention ......................................................................66 
12 AUDITING AND MONITORING ..........................................................................67 
13 AMENDMENTS .......................................................................................................68 
14 STUDY REPORT, PUBLICATIONS, DATA POSTING ....................................68 
15 STUDY DISCONTINUATION ...............................................................................68 
16 CONFIDENTIALITY ..............................................................................................68 
17 REFERENCES .........................................................................................................69 
18 APPENDICES ...........................................................................................................73 
18.1 
Schedules of Events ..............................................................................................73 
18.1.1 
Schedule of Events LYN-005-C-004: Screening and LYN-005 Doses 1 and 
2........................................................................................................................73 
18.1.2 
Schedule of Events LYN-005-C-004:  LYN-005 Dose 3 through Study 
Completion......................................................................................................76 
18.2 
PILL-5 Questionnaire ..........................................................................................79 
18.3 
Mini International Neuropsychiatric Interview (MINI) version 7.0.2 ............80 
18.4 
Structured Clinical Interview – Positive and Negative Syndrome Scale (SCI-
PANSS)................................................................................................................104 
18.5 
Clinical Global Impression – Severity Scale (CGI-S) .....................................119 
18.6 
Columbia Suicide Severity Rating Scale (C-SSRS) ........................................122 
18.7 
Acid Reflux Severity Scale ................................................................................127 
18.8 
Extrapyramidal Symptom Rating Scale (ESRS) ............................................128 


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LIST OF TABLES 
Table 3-1: 
Study Objectives and Endpoints.............................................................28 
Table 8-1:  
Psychiatric and EPS Assessment Timing and Durations .....................48 
 


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LIST OF FIGURES 
Figure 2-1: 
LYN-005 Extended Release Capsule and Components ........................24 
Figure 2-2: 
Overview of Mechanism of Action .........................................................25 
Figure 6-1: 
IR Risperidone Switch and Dosing Guidelines .....................................42 


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1 PROTOCOL SUMMARY 
1.1 
Study Synopsis 
Name of Sponsor 
Lyndra Therapeutics Inc. 
Investigational Product 
LYN-005: Risperidone extended release capsule 
Title: 
A Randomized, Placebo-controlled, Multiple Dose Study to Assess the Safety, 
Tolerability and Pharmacokinetics of Risperidone Extended Release Capsules in 
Subjects with Schizophrenia, Schizoaffective Disorder 
Phase: 
Phase 2 
Rationale: 
Lyndra is developing an oral, extended release (ER) formulation of risperidone 
(LYN-005) presented in a capsule dosage form with the intent of reducing the 
frequency of dosing orally-administered medications to once weekly or less and 
thereby improving the management of schizophrenia.  
Current treatment options for schizophrenia consist of acute symptom 
management for psychosis as well as efforts to prevent relapse and improve access 
to supportive treatments. Antipsychotic drug therapy is effective in most subjects 
in managing and stabilizing schizophrenia symptoms. Despite the benefits from 
treatment, approximately 75% of diagnosed subjects will experience a relapse, 
generally within two years, and the majority of subjects will experience multiple 
relapses over the course of the illness [1]. A major known risk factor leading to 
relapse is non-adherence with antipsychotic drug therapy [1]. In addition to 
improving adherence, an extended release oral risperidone may offer more 
consistent plasma levels of the pharmacologically active forms of risperidone, 
reducing both inter-subject and intra-subject variability. The target population for 
the Lyndra formulation (LYN-005) is subjects with schizophrenia who require 
maintenance treatment with risperidone and who have demonstrated tolerability of 
immediate release (IR) risperidone. An oral once weekly form of risperidone 
would offer a treatment opportunity facilitating greater clinician and subject 
contact and which could be integrated into a variety of community psychiatric 
treatment models, without need for specialized administration spaces or training. 
Once weekly dosing is anticipated to be highly convenient for both subjects and 
caregivers and provides certainty of dosing with only weekly supervision. Further, 
an oral extended release formulation, if demonstrated to be effective at achieving 
therapeutic systemic drug levels, could offer an opportunity to initiate a long-
acting treatment earlier in the disease course, potentially prior to discharge from 
hospitalization. 
Study LYN-005-C-004 will evaluate the safety, tolerability, and pharmacokinetics 
(PK) of multiple dose administration of the ER formulation at two dose levels of 
LYN-005 relative to IR risperidone.  


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Name of Sponsor 
Lyndra Therapeutics Inc. 
Investigational Product 
LYN-005: Risperidone extended release capsule 
OBJECTIVES 
Primary Objectives:  
• 
To determine the safety and tolerability of risperidone extended release 
capsules (LYN-005) administered as repeat weekly doses compared to IR 
risperidone tablets at 2 dose levels; 
• 
To characterize the PK of risperidone, active metabolite 9-hydroxyrisperidone 
and active moiety (risperidone and 9-hydroxyrisperidone combined) after 
repeat weekly doses of LYN-005 ER capsules relative to IR risperidone 
tablets at 2 dose levels. 
Secondary Objectives: 
• 
To assess the exposure to risperidone, 9-hydroxyrisperidone and active moiety 
during the switch from IR risperidone to LYN-005. 
Exploratory 
Objectives: 
• 
To model the PK of risperidone, 9-hydroxyrisperidone and active moiety 
when administered as a LYN-005 extended-release capsule. 
ENDPOINTS 
Primary Endpoints:  
• 
Incidence of treatment emergent adverse events (TEAEs). 
• 
Risperidone, 9-hydroxyrisperidone, and active moiety PK after oral 
administration of LYN-005 capsules and IR risperidone to include, as possible 
and appropriate, Cmax, Cmin, Tmax, Kel, AUC(0-24), AUC(0-t), AUC(0-168) and 
AUC(0-∞). 
Secondary Endpoints:  
• 
Exposure to risperidone, 9-hydroxyrisperidone and active moiety as assessed 
from Cmax, Tmax, AUC(0-24), AUC(0-t), and AUC(0-∞) after switching from IR 
risperidone to LYN-005. 
Exploratory 
Endpoints: 
• 
PK modelling of risperidone, 9-hydroxyrisperidone, and active moiety 
exposure. 
METHODOLOGY 
Study Duration: 
Up to 55 days 
Study Design: 
LYN-005-C-004 is a blinded, multiple-dose, randomized, parallel group, safety, 
tolerability and PK study of LYN-005 in subjects with a primary diagnosis of 
schizophrenia or schizoaffective disorder in general good health. Eligible subjects 
must be clinically stable and receiving a therapeutic dose of an approved oral 
antipsychotic drug for a minimum of 6 weeks at the time of Screening. Enrolled 
subjects will be evaluated under steady-state conditions on commercially-available 
IR risperidone tablets and then assigned in blinded fashion either to LYN-005 
weekly or continued encapsulated IR risperidone daily for 3 weeks to attain (or 
continue) steady-state exposure.  


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Name of Sponsor 
Lyndra Therapeutics Inc. 
Investigational Product 
LYN-005: Risperidone extended release capsule 
A total of 32 subjects will participate in this study. Subjects will be randomized to 
LYN-005 plus IR risperidone matched placebo OR LYN-005 matched placebo or 
IR risperidone as follows: 
• 
Arm 1:  LYN-005 (14 or 28 mg weekly) plus IR risperidone matched 
placebo (N=24). 
• 
Arm 2:  LYN-005 matched placebo plus IR risperidone (2 or 4 mg/day) 
(N=8). 
Per above, in order to maintain the blind, all subjects will either receive LYN-005 
and IR risperidone-matched placebo or LYN-005 matched placebo and IR 
risperidone, as follows: 
Arm 1: 
• 
LYN-005: Size 00EL capsules containing LYN-005 stellate; the 14mg 
dose of LYN-005 contains 3 active arms containing risperidone, and 
3 inactive arms and the 28 mg dose of LYN-005 contains 6 active arms 
containing risperidone. 
AND 
• 
IR Risperidone Matched Placebo:  Orange capsule-shaped tablets 
containing inactive ingredient. 
Arm 2: 
• 
LYN-005 Matched Placebo:  Size 00EL capsules containing inactive 
ingredient with no stellate. 
AND 
• 
IR Risperidone:  Risperidone 2 mg (orange) capsule-shaped tablets. 
Although treatment assignment is blinded; the dose level is not blinded. The dose 
of LYN-005 (14 or 28 mg)/IR risperidone (2 or 4 mg/day) administered will be 
based on the subject’s current antipsychotic medication dose. Randomization will 
be stratified by risperidone dose (LYN-005 14 mg/IR risperidone 2 mg/day [low 
dose] and LYN-005 28 mg/IR risperidone 4 mg/day [high dose], with a maximum 
of 16 subjects enrolled in each strata.  Within each strata, subjects will be 
randomized on a 3:1 basis to either LYN-005 or risperidone, respectively.   
All administrations of LYN-005/matched placebo will be supervised. Complete 
PK evaluations will be performed after each LYN-005 dose, as designated in the 
Schedules of Events (Section 18.1.1 and Section 18.1.2) and over 24 hours at 
steady-state for IR risperidone at the beginning of the study. 


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Name of Sponsor 
Lyndra Therapeutics Inc. 
Investigational Product 
LYN-005: Risperidone extended release capsule 
LYN-005 will be evaluated in subjects who meet Diagnostic and Statistical 
Manual of Mental Disorders, Fifth Edition (DSM-5) criteria for a primary 
diagnosis of schizophrenia or schizoaffective disorder of at least 2 years, who have 
already been stabilized on an oral antipsychotic medication for a minimum of 
6 weeks at the time of Screening with no psychiatric hospitalizations for relapse in 
the past 6 months. Subjects who are prescribed an antipsychotic agent other than 
risperidone or a dose of risperidone outside the range are also eligible for study 
participation if they are a) able to tolerate risperidone and b) be completed 
switched to 2 or 4 mg daily oral risperidone for a minimum of 2 weeks prior to the 
first dose of LYN-005/placebo on Day 1 (see Section 6.3.1).  
Eligible subjects must be clinically stable (i.e., mildly or moderately ill 
psychiatrically), with a low risk of relapse and otherwise healthy without history 
of significant gastrointestinal (GI) diseases. Guidelines will be in place for the use 
of recommended rescue medications for agitation, anxiety, and insomnia. In the 
event of worsening of schizophrenia symptoms while receiving risperidone during 
the study, another medication can be administered at the discretion of the Principal 
Investigator (PI), with notification of the Study Medical Monitor.  
Risperidone is primarily metabolized by cytochrome P450 (CYP) 2D6 and genetic 
testing for CYP2D6 will be conducted at Screening to determine metabolizer 
status. To reduce the inter-subject variability in exposure, subjects identified as 
poor metabolizers (PMs) will be excluded from the study.  
Study Conduct  
Subjects will be screened for study eligibility between Days -21 and -14. Subjects 
who are initially determined to be eligible, based on Screening assessments, will 
then participate in a 10-day IR risperidone run-in period, during which adherence 
with study treatment will be assessed. Subjects who remain eligible for the study 
will enter the inpatient unit on Day -2. After admittance to the inpatient unit and 
prior to the first LYN-005/matched placebo administration, samples for 
determination of IR risperidone PK will be collected from Days -2 to -1.  
Over the course of the study, subjects are to receive 3 doses of LYN-005/matched 
placebo, per their random assignment, 1 each on Days 1, 8, and 15, all on an 
inpatient basis. All subjects will also receive IR risperidone or matched placebo, 
again per their random assignment, from Days 1 to 21. 
Overall, during study participation, subjects will be housed in the inpatient unit 
twice, from Days -2 to 9 (Inpatient Stay 1) and then again from Days 14 to 16 
(Inpatient Stay 2). Subjects who are admitted to the inpatient unit on Day -2 will 
be considered enrolled. In between each inpatient stay, subjects will have study 
assessments performed on an outpatient basis daily from Days 10, 11, 12, and 13. 
After discharge from Inpatient Stay 2, subjects will again have assessments 
performed on an outpatient basis on Days 17, 18, 21, 22, and 23. An End of Study 
(EOS) visit will be conducted on Day 35.  
During study participation, guidelines will be in place for the use of recommended 
medications for agitation, anxiety, and insomnia. Rescue administration of an 
agent other than risperidone or paliperidone in the event of worsening of 
schizophrenia symptoms during the study can be administered at the discretion of 
the PI, with notification of the Study Medical Monitor. Extrapyramidal symptoms 
will be monitored throughout the study at regular intervals using the 
Extrapyramidal Symptom Rating Scale (ESRS). Severity of schizophrenia 


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Name of Sponsor 
Lyndra Therapeutics Inc. 
Investigational Product 
LYN-005: Risperidone extended release capsule 
symptoms will be monitored throughout the study at regular intervals using the 
CGI-S scale. Concomitant medications, adverse events (AEs), safety laboratory 
tests, and vital signs will be assessed throughout the study, as per the Schedule of 
Events (Section 18.1.1 and Section 18.1.2). 
Schedule of Events 
The Schedules of Events are presented in Section 18.1.1 and Section 18.1.2. 
SUBJECT POPULATION 
Number of Subjects: 
Approximately 32 subjects of whom 24 will receive LYN-005 will be enrolled in 
the study. Subjects who discontinue prematurely may be replaced at the Sponsor’s 
discretion. 
Target Population: 
Male and female subjects between the ages of 18 to 50 years of age, inclusive, 
with schizophrenia or schizoaffective disorder, as defined by DSM-5 criteria. 
Entry Criteria 
Inclusion criteria:  
Eligibility for this study is met if each one of the following inclusion criteria is 
satisfied at Screening (or at baseline when specified): 
1. Male or female aged ≥18 and ≤50 years.  
2. Current diagnosis of schizophrenia or schizoaffective disorder according to 
DSM-5 criteria as confirmed by the MINI 7.0.2. 
3. The following psychiatric criteria are to be used to determine subject 
eligibility: 
a. 
Duration of diagnosis of schizophrenia or schizoaffective disorder of 
≥2 years. 
b. Outpatient; not hospitalized for worsening of schizophrenia within the 
last 6 months (partial hospitalization for social management within this 
time period is acceptable). 
c. 
Medically stable over the last month and psychiatrically stable without 
significant symptom exacerbation over the last 3 months. 
4. Stabilized on an oral antipsychotic medication (single agent) for a minimum 
of 6 weeks at the time of Screening. 
5. On a stable dosage of all permitted non-antipsychotic medications (except for 
medication to be used on an as-needed basis) for at least 1 month prior to the 
Screening visit and for the duration of the study. 
6. CGI-S score of ≤4 (moderately ill). 
7. PANSS score of ≤80 points. 
8. Body mass index (BMI) of ≥18 kg/m2 and ≤35 kg/m2. 
9. Able to read and understand study procedures and provide written informed 
consent before the initiation of any protocol-specific procedures. 
10. Willing to comply with all protocol-specified procedures and availability for 
the duration of the study. 


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Name of Sponsor 
Lyndra Therapeutics Inc. 
Investigational Product 
LYN-005: Risperidone extended release capsule 
11. Subject has identified a caregiver or personal contact with whom the subject 
communicates with at least once a week. 
Exclusion Criteria:  
Subject will not be considered eligible to participate in this study if any one of the 
following exclusion criteria is satisfied at Screening (or at baseline when 
specified): 
1. Subjects with known clinically significant esophageal or GI disease, including 
but not limited to:   
a. 
Known strictures such as esophageal web, pyloric stenosis, or small 
intestinal stricture, or subjects with high risk of stricture, e.g., Crohn's 
disease. 
b. Diagnosis of a condition known to elevate or lower gastric pH, e.g., 
achlorhydria or hypochlorhydria. 
c. 
Prior varices or small or large bowel obstructions. 
d. Prior abdominal or upper gastrointestinal surgery (prior uncomplicated 
laparoscopic procedures including appendectomy or colectomy). 
e. 
History of dysphagia or aspiration in the last 5 years. 
f. 
History of an esophageal motility disorder or undergoing treatment for a 
gastric motility disorder. 
g. Significant history of diarrhea or constipation within 3 months of 
Screening. 
h. Multiple episodes of abdominal pain within 3 months of Screening. 
i. 
Subjects who experience moderate or severe dysmenorrhea or 
menorrhagia (with use of pain medication) within 3 months of Screening.  
j. 
History of moderate to severe Acid Reflux Disease or a score of ≥2 on the 
Acid Reflux Severity Scale (ARSS) [2], indicating moderate to severe 
symptoms. The ARSS scale is as follows: 
None = 0 no symptoms 
Mild = 1 awareness of symptom, but easily tolerated 
Moderate = 2 discomfort sufficient to cause interference with normal 
activities 
Severe = 3 incapacitating, with inability to perform normal activities.  
2. Subjects with PILL-5 questionnaire score of 5 or greater. 


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3. Medical history or current diagnoses indicating the presence of any of the 
below conditions: 
a. 
Presence of an uncontrolled, unstable, clinically significant medical 
condition could that could put the subject at risk because of participation 
in the study, interfere with the subject’s ability to participate in the study 
or influence the interpretation of safety or PK evaluations. 
b. History of a major cardiovascular event (myocardial infarction, cardiac 
surgery or revascularization, unstable angina, stroke, or transient 
ischemic attack) or a hospitalization for heart failure with 6 months of 
Screening. 
c. 
Any clinically significant illness, medical or surgical procedure or trauma 
within 4 weeks of Screening. 
d. Known immunocompromised status, including individuals who have 
undergone organ transplantation, on immunosuppression for an immune 
mediated disease, or are positive for human immunodeficiency virus 
(HIV). 
e. 
Subjects with a positive test for active hepatitis B or C at Screening. 
Subjects with successfully treated hepatitis B infection which has been 
resolved for greater than 1 year or successfully treated hepatitis C 
infection will not be excluded. 
f. 
Subjects who have donated more than 250 mL of blood within 30 days of 
Screening. 
g. Subjects who have difficulties with venipuncture/cannulation, including 
difficulty accessing veins for blood sampling and/or history of 
coagulopathy or endocarditis. 
h. Subjects with a current DSM-5 diagnosis of major depressive episode, 
panic disorder, agoraphobia, social anxiety disorder, obsessive-
compulsive disorder, post-traumatic stress disorder, generalized anxiety 
disorder on the MINI 7.0.2 or in the judgment of the Investigator. (Note 
that individuals with depression secondary to schizoaffective disorder are 
eligible). 
i. 
Suicidal ideation associated with actual intent and a method or plan in the 
past 6 months, as measured by the C-SSRS (i.e., “Yes” answers on items 
4 or 5) at Screening or having made a suicide attempt within the last 
2 years. 
j. 
Known or suspected (non-febrile) seizure disorder. 
k. History of neuroleptic malignant syndrome. 
l. 
Current or history of clinically significant tardive dyskinesia. 


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Name of Sponsor 
Lyndra Therapeutics Inc. 
Investigational Product 
LYN-005: Risperidone extended release capsule 
m. Known or suspected diagnosis of intellectual disability or organic brain 
disorder or other diagnosis that is primarily responsible for current 
symptoms and functional impairment. 
n. Medically non-adherent in the management of their 
schizophrenia/schizoaffective disorder. 
4. Use of the below medications/treatments in the 2 weeks before enrollment, 
including: 
a. 
Proton pump inhibitors or H2 blockers. 
b. Prokinetic agents. 
c. 
Medications that may interfere with the absorption, metabolism, or 
excretion of risperidone, e.g.: 
i. 
Drugs metabolized via CYP3A4 pathway, such as macrolide 
antibiotics and azole antifungals). 
ii. 
Moderate or strong CYP3A4 p-glycoprotein (P-gp) enzyme 
inducers and inhibitors (carbamazepine, phenytoin, rifampicin, 
phenobarbital, itraconazole, verapamil). 
iii. 
Moderate or strong CYP2D6 inhibitors (e.g., fluoxetine, 
fluoxetine combinations, paroxetine), or quinidine. 
d. Concomitant medications, natural remedies, supplements or vitamins 
which are associated with changes to gastric motility or pH. Use of 
antacids is permissible, except within 2 hours of dosing with LYN-005.  
e. 
Benzodiazepines; except lorazepam, diazepam and oxazepam, which are 
acceptable if for the treatment of depression, anxiety or insomnia.  
f. 
Use of more than one antidepressant; or if on just one, a change in dose 
within 6 weeks of Screening. 
g. Depot antipsychotic use within 9 months of Screening. 
h. Electroconvulsive therapy within 3 months of Screening. 
5. Subjects with clinically significant abnormal safety (e.g. physical 
examination, vital sign) or safety laboratory assessments, specifically: 
a. 
Presence of a clinically significant abnormal laboratory result on blood 
or urine safety tests at Screening. 
b. Anemia (hemoglobin below lower limit of normal reference range) at 
Screening. 


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Name of Sponsor 
Lyndra Therapeutics Inc. 
Investigational Product 
LYN-005: Risperidone extended release capsule 
c. 
Alanine aminotransferase (ALT), aspartate aminotransferase (AST) 
≥3.0 × upper limit of normal (ULN), or total bilirubin ≥1.5 × ULN.  
d. Moderate or severe renal insufficiency at Screening (glomerular 
filtration rate <60 mL/min, as determined using the Cockcroft-Gault 
formula). 
e. 
Heart rate of <50 beats per minute (bpm) at Screening. 
f. 
Systolic blood pressure <100 or ≥150 mmHg and/or diastolic blood 
pressure <60 mmg Hg or ≥100 mmHg at Screening. 
g. HbA1c ≥6.5% at Screening. 
h. Positive fecal occult blood test at Screening.  
i. 
Clinically significant prolactin elevation (≥200 ng/mL for females; 
≥100 ng/mL for males). 
6. Subjects with the below specified patterns of substance use at Screening: 
a. 
Fulfillment of the DSM-5 criteria for moderate or severe substance use 
disorder (excluding nicotine and caffeine) within 6 months of Screening. 
b. History of alcohol consumption exceeding moderate use; in males 
exceeding 21 units per week and in females exceeding 14 units per week 
(1 unit = 360 ml beer, 25 mL of 40% spirit or a 125 mL glass of wine) 
over the past month. Subjects are not permitted to consume alcohol 
during the inpatient stay nor 12 hours before any clinic visit while 
outpatient. 
c. 
Positive ethanol breathalyzer. 
d. Positive urine drug screen for substances of abuse other than cannabis.  
e. 
Heavy nicotine use (consumption of >40 cigarettes or >36 mg of nicotine 
from other sources [e.g., vaping products] daily) or daily use of 
smokeless tobacco. 
7. Subjects of reproductive potential who are (hetero) sexually active but 
unwilling to use acceptable means of contraception through the EOS. For 
clarity, subjects who are at least 1 year post-menopausal are not of 
reproductive potential. Acceptable means of contraception include: 
a. 
Subjects who have been surgically sterilized. 
b. Females of reproductive potential: diaphragm, injectable, oral/patch 
contraceptives for a minimum of 6 weeks, contraceptive sponge, implant, 
or intrauterine device in use prior to enrollment. 


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Name of Sponsor 
Lyndra Therapeutics Inc. 
Investigational Product 
LYN-005: Risperidone extended release capsule 
c. 
Males: condom in combination with any of the above means of 
contraception. 
d. All subjects: abstinence may be an acceptable means of contraception as 
long as the individual consents to initiate immediate use of double barrier 
protection for the duration of the study should (hetero) sexual intercourse 
occur. 
8. Subjects who are nursing or who have positive or indeterminate pregnancy 
tests at either Screening (serum test) or enrollment (urine test). 
9. Use of any experimental agent within 1 month or 5 half-lives of Screening, 
whichever is longer. 
10. Subjects who are employees or immediate family members of employees of 
the site, Sponsor or study-related vendors.  
11. History of a serious allergic or hypersensitivity reaction to risperidone or 
LYN-005 excipients (refer to Investigator’s Brochure). 
12. Subjects with history of X-ray, computed tomography (CT) scan or 
angiogram of the abdomen within one year of Screening. 
13. Subjects with CYP2D6 poor or underdetermined metabolizer status based on 
genetic testing. 
STATISTICAL METHODS AND ANALYSIS 
Sample Size 
The sample size of 32 (24 assigned to LYN-005 and 8 assigned to IR risperidone) 
is driven by clinical rather than statistical considerations for providing data in the 
evaluation of the endpoints.  
Pharmacokinetics and 
Pharmacodynamics 
Plasma concentration data for risperidone and 9-hydroxyrisperidone separately 
and combined as active moiety will be tabulated and plotted for each subject for 
whom concentrations are quantifiable. PK analysis of the concentration-time data 
obtained will be performed using appropriate non-compartmental analysis to 
obtain estimates of the standard PK parameters. 
The pharmacokinetics of LYN-005 relative to IR at 2 dose levels will be 
determined.  
There are no pharmacodynamic endpoints in this study. 
Safety 
Safety data will be summarized by dose group, study period and overall. 
Planned Analyses 
There is a planned safety review by the Investigator and Medical Monitor on 
interim blinded PK through Day 14 from 12 subjects. Blinded safety data will also 
be reviewed at this time and will include adverse events, laboratory data, 




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1.3 
List of Abbreviations 
Abbreviation 
Term  
AE 
Adverse event 
ALT 
Alanine aminotransferase 
APD 
Antipsychotic drug 
AST 
Aspartate aminotransferase  
AUC0-168 
Area under the concentration versus time curve, time zero to 168 hours 
AUC0-24 
Area under the concentration versus time curve, time zero to 24 hours 
AUC0-∞ 
Area under the concentration versus time curve: time zero to infinity 
AUC0-t 
Area under the concentration versus time curve:  time zero to t (time point to be specified) 
BMI 
Body mass index 
BUN 
Blood urea nitrogen 
CBC 
Complete blood count 
CGI-S 
Clinical Global Impression-Severity 
Cmax 
Maximal observed concentration 
Cmin 
Minimum observed concentration 
CRA 
Clinical Research Associate 
CRO 
Contract Research Organization 
C-SSRS 
Columbia-Suicide Severity Rating Scale  
CV 
Coefficient of variation 
CYP2D6 
Cytochrome P450 2D6 
CYP3A4 
Cytochrome P450 3A4 
DIMD 
Drug-induced movement disorders 
DIP 
Drug-induced parkinsonism 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
ECT 
Electroconvulsive therapy 
EDC 
Electronic Data Capture 
EL 
Extra Long 
EOS 
End of Study 
EPS 
Extrapyramidal symptoms 
ER 
Extended release 
ESRS 
Extrapyramidal Symptom Rating Scale  
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
h 
hour or hours 
HbA1C 
Glycated hemoglobin 
HBsAg 
Hepatitis B Surface Antigen 
HCV Ab 
Hepatitis C Virus Antibody 
HIV 
Human Immunodeficiency Virus 
ICF 
Informed consent form 


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Abbreviation 
Term  
ICH 
International Council for Harmonization 
ID 
Identifier 
IR 
Immediate release 
IRB 
Institutional Review Board 
Kel 
First order elimination rate constant 
LYN-005 
Lyndra Extended Release Capsule containing risperidone 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHP 
Mental health professional 
MINI 
Mini International Neuropsychiatric Interview version 7.0.2 
PANSS 
Positive and Negative Syndrome Scale 
PI 
Principal Investigator 
PK 
Pharmacokinetic (adj.) or pharmacokinetics (singular noun) 
QTcF 
Corrected QT interval, Fridericia’s correction 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SOE 
Schedule of Events 
SUSAR 
Serious unexpected suspected adverse reaction 
TD 
Tardive dyskinesia 
TEAE 
Treatment-emergent adverse event 
Tmax 
Time to maximum plasma concentration 
ULN 
Upper limit of normal 
US 
United States 
WHO 
World Health Organization 
 


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2 INTRODUCTION AND RATIONALE 
2.1 
Impact of Schizophrenia and Schizoaffective Disorder 
Schizophrenia and schizoaffective disorder are chronic and debilitating psychiatric illnesses 
which have a massive global burden. There are millions of adults in the United States alone 
living with schizophrenia. The estimated prevalence rate of schizophrenia is around 0.5% in the 
United States (US) [3] and globally rates can be even higher, to above 1% [4]. In 2013, the total 
societal costs of schizophrenia were estimated at $155 billion in the US, with emergency room 
care alone estimated at $2.6 billion reflecting an emphasis on acute care for patients with 
schizophrenia [5]. When non-direct healthcare costs, such as lost productivity of patients and 
their caregivers are taken into account, schizophrenia could total up to 3% of the total 
healthcare budget of western countries [6].  
Many patients suffer from lifelong persistent psychiatric symptoms and cognitive effects, which 
result in reduced quality of life and significant socio-economic impacts [7]. Approximately 75% 
of all patients diagnosed with schizophrenia will experience a relapse, generally within two 
years, and most will experience multiple relapses over the course of the illness [1]. Relapse 
associated with psychotic exacerbation can increase the risk of patients harming themselves or 
others and it can have potential negative effects on their relationships, education and work [8]. 
Furthermore, relapse can lead to long-term disability and an increased burden of health care 
needs in these patients [1, 9]. There are many factors that contribute to the risk of relapse, 
including patient-related, treatment-related, lifestyle, and disease-related factors such as an 
earlier onset of disease, severity at Baseline, lower social functioning, or substance abuse [10]. 
However, it is widely acknowledged that improving access to antipsychotic drug (APD) 
treatment for patients experiencing symptom exacerbation is critical to reduce relapses [1, 11, 
12], and that non-adherence to APD treatment is the most frequently cited risk factor for relapse 
[10].  
2.2 
Role of Adherence 
It is estimated that as many as half of all patients in developed countries are not taking their 
medications properly, and the level may be even higher in developing countries according to the 
World Health Organization (WHO) [13]. The collective impact to patients of not taking or not 
appropriately taking one’s medicines is profound, leading to disease under-treatment, treatment 
resistance, drug toxicity, and other adverse outcomes. 
“Poor adherence to long-term therapies severely compromises the effectiveness of 
treatment making this a critical issue in population health both from the perspective of 
quality of life and of health economics. Interventions aimed at improving adherence 
would provide a significant positive return on investment through primary prevention 
(of risk factors) and secondary prevention of adverse health outcomes.” [13] 
In schizophrenia, non-adherence to APD treatment is common. A study of pharmacy records 
between 1998 and 1999 demonstrated medication possession ratios under 80% in almost 40% 
of patients prescribed APDs, with adherence fluctuating over time such that more than 60% of 


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patients experienced periods of significant nonadherence over a four-year period [14]. Few 
studies have assessed APD non-adherence directly via random blood drug sampling, but one 
such study showed rates of poor adherence were even higher, at 58% [15]. The associated 
treatment costs, disease progression and risk of relapse associated with poor control of disease, 
especially in relation to non-adherence to APD treatment, have been extensively studied.  
Dosing frequency is the primary regimen factor that has been shown to influence adherence, 
where greater dosing frequency is associated with poorer outcomes [16]. A meta-analysis of all 
available randomized controlled studies of oral once daily versus oral once weekly therapy has 
demonstrated a consistent improved adherence by patients to their treatment across studies with 
a odds ratio of weekly therapy versus daily therapy of approximately 1.9 [17]. These data 
indicate that once weekly oral therapy for chronic disease could offer improved adherence as 
compared to daily oral therapy. In some analyses, the magnitude of the benefit of once weekly 
therapy versus once daily therapy expands over time, demonstrating substantial differences in 
the persistence to chronic therapy after two years [18].  
2.3 
Therapeutic Approach 
The treatment of schizophrenia begins with acute symptom management for those who are in 
crisis and is followed by relapse prevention and access to supportive treatments. APD therapy is 
effective in most patients with schizophrenia or schizoaffective disorder in managing and 
stabilizing their symptoms. However, in order to avoid symptom exacerbation, continuous 
treatment with antipsychotic medication is recommended. Longer term (e.g., >6 months) and 
abrupt discontinuation with APD therapy has been associated with an increased risk of relapse 
[19-22].  
The etiology of relapse in patients with schizophrenia or schizoaffective disorder is complex and 
multifaceted. Although some patients may never experience recurrence after their first episode, 
some patients on uninterrupted maintenance therapy may still experience changes in 
symptomology and relapse, which may require a change in treatment. It is essential that any 
intervention including treatment with an antipsychotic medication is appropriate and efficacious 
[23]. Selecting the correct medication for maintenance therapy is critical, and is largely driven by 
individual factors including symptomology (positive and negative symptoms), response to 
treatment, relapse risk profile as determined by a clinician, as well as by patient preference [24]. 
Among the second-generation atypical antipsychotics, risperidone is considered one of, if not the 
most, effective agent and is the most commonly prescribed agent in patients with schizophrenia. 
Numerous studies have shown the effectiveness of this medication, particularly with longer 
acting formulations [8, 25, 26], which is also related to the demonstrated improved medication 
adherence to these formulations of APDs [14]. For example, clinically stable patients with 
schizophrenia or schizoaffective disorder who switched to a long acting depot formulation of 
risperidone (RISPERDAL CONSTA), have demonstrated greater occurrence of sustained 
remission compared to patients on quetiapine [26]. PERSERIS is another once-monthly 
risperidone injection approved for the treatment of schizophrenia [27]. 
Lyndra Therapeutics is developing oral, extended release therapies with the intention to change 
how people take medicines to sustain therapeutic outcomes and benefits. Lyndra is targeting 








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metabolizers. Clinical studies do not suggest that poor and extensive metabolizers have different 
rates of adverse effects, and risperidone is generally well-tolerated [33].  
2.7 
Benefits/Risks 
The LYN-005 extended release (ER) capsule is a novel investigational formulation of 
risperidone designed to provide sustained oral drug delivery over 1 week, further described in the 
Investigator’s Brochure. It is being developed for patients with schizophrenia whose tolerability 
and symptom management have already been established with oral administration of immediate 
release (IR) risperidone. The oral dose range considered effective in maintaining clinical stability 
of psychiatric symptoms from schizophrenia following acute therapy is 2 to 6 mg daily or 14 to 
42 mg per week.  
This study will evaluate 3 oral doses of once-weekly risperidone using the LYN-005 ER capsule 
at doses of 14 and 28 mg, designed to release the equivalent of 2 or 4 mg risperidone daily over 
7 days. The study will be conducted in clinically stable subjects diagnosed with schizophrenia or 
schizoaffective disorder receiving a therapeutic dose of an APD for at least 6 weeks prior to 
Screening. Subjects will be in general good physical health who are mildly or moderately 
psychiatrically ill but clinically stable for at least 3 months prior to Screening and no 
hospitalization due to worsening of schizophrenia within the prior 6 months.  
LYN-005 risperidone extended release capsule development has been informed by the results of 
previous clinical studies. The Sponsor has adopted several risk mitigation measures to protect 
subjects participating in Lyndra studies, described in the following subsections. 
2.7.1 
Risks Associated with Active Ingredient 
Reference is made to the current LYN-005 Investigator’s Brochure, Section 6.3, which includes 
reference material for marketed risperidone products and potential risks associated with 
risperidone.  
2.7.2 
Risks Associated with Extended Release Capsule 
As described in the Investigator’s Brochure, LYN ER capsules have a favorable safety profile in 
previous clinical studies with different active pharmaceutical ingredients. Over time, 
modifications have been made to the dosage form to improve its safety and tolerability. Clinical 
experience now exceeds 100 subjects dosed with ER capsules. Gastrointestinal adverse events, 
particularly nausea and abdominal pain, have been the most frequent adverse events in subjects 
dosed with LYN ER capsules. To mitigate the risk of GI events, the present study has exclusion 
criteria for GI conditions that may increase any potential risks of LYN ER capsules. In addition, 
subjects will be closely monitored for safety, including GI adverse events, during the study. 
LYN-005 dosing will be supervised while the subject is housed in the inpatient unit, and exit of 
the formulation components from the body will be assessed by X-ray.  


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2.7.3 
Risks Associated with Study Related Procedures 
The following additional risks may occur associated with study-related procedures: 
• X-Rays: detection of underlying anatomic abnormality or previously unknown health 
condition, injury from radiation exposure. 
• Detection of unknown disease necessitating further evaluation and follow-up. 
• Blood sampling: excessive bleeding, bruising, presyncope/syncope, nerve damage, or 
infection at the venipuncture site. 
• Electrocardiogram (ECG) tracing: irritation or rash of the skin due to the use of adhesive 
leads. 
2.7.4 
Benefits/Risks Conclusions 
There are no direct benefits to the subjects in this study. Subjects will be housed in the inpatient 
unit for 2 inpatient periods, totaling 11 days, for the evaluation of LYN-005, allowing daily 
monitoring for AEs or changes in symptomatology that might require treatment. APD dosing 
during the inpatient portion of the study will be supervised by the study site to ensure compliance 
with therapy and control of symptoms. Following discharge from the site, in addition to follow-
up study center visits, subjects will be contacted periodically to help ensure medication 
compliance during the outpatient phase of the study.  
There is risk of AEs from risperidone; to minimize this risk, doses are limited to the low to mid-
range.  
There is a possibility that the screening and evaluation tools employed in this study may suggest 
or detect a previously unknown health condition that may warrant additional investigation by the 
individual’s general practitioner and in the case of positive human immunodeficiency virus 
(HIV) results, notification of health authorities in accordance with local and national 
requirements. 
Detailed information for potential benefits and risk for LYN-005 (risperidone) extended release 
capsules may be found in the current LYN-005 Investigator’s Brochure, Section 6.3. 


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3 STUDY OBJECTIVES AND ENDPOINTS 
The primary, secondary, and exploratory objectives along with the associated endpoints are 
summarized in Table 3-1. 
Table 3-1: 
Study Objectives and Endpoints 
Objectives 
Endpoints 
Primary: 
 
• 
To determine the safety and tolerability of 
risperidone extended release capsules (LYN-
005) administered as repeat weekly doses 
compared to IR risperidone tablets at 2 dose 
levels; 
• 
Incidence of treatment emergent adverse 
events (TEAEs). 
• 
To characterize the PK of risperidone, active 
metabolite 9-hydroxyrisperidone and active 
moiety (risperidone and 9-hydroxyrisperidone 
combined) after repeat weekly doses of LYN-
005 ER capsules relative to IR risperidone 
tablets at 2 dose levels. 
• 
Risperidone, 9-hydroxyrisperidone, and active 
moiety PK after oral administration of LYN-
005 capsules and IR risperidone to include, as 
possible and appropriate, Cmax, Cmin, Tmax, Kel, 
AUC(0-24), AUC(0-t), AUC(0-168) and AUC(0-∞). 
Secondary:  
 
• 
To assess the exposure to risperidone, 
9-hydroxyrisperidone and active moiety during the 
switch from IR risperidone to LYN-005. 
• 
Exposure to risperidone, 9-
hydroxyrisperidone and active moiety as 
assessed from Cmax, Tmax, AUC(0-24), AUC(0-t), 
and AUC(0-∞) after switching from IR 
risperidone to LYN-005. 
Exploratory: 
 
• 
To model the PK of risperidone, 9-
hydroxyrisperidone and active moiety when 
administered as a LYN-005 extended-release 
capsule. 
• 
PK modelling of risperidone, 9-
hydroxyrisperidone, and active moiety exposure. 


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4 STUDY PLAN 
4.1 
Study Design 
LYN-005-C-004 is a blinded, multiple-dose, randomized, parallel group, safety, tolerability and 
PK study of LYN-005 in subjects with a primary diagnosis of schizophrenia or schizoaffective 
disorder in general good health. Eligible subjects must be clinically stable and receiving a 
therapeutic dose of an approved oral antipsychotic drug for a minimum of 6 weeks at the time of 
Screening. Enrolled subjects will be evaluated under steady-state conditions on commercially-
available IR risperidone tablets and then assigned in blinded fashion either to LYN-005 weekly 
or continued encapsulated IR risperidone daily for 3 weeks to attain (or continue) steady-state 
exposure.  
A total of 32 subjects will participate in this study. Subjects will be randomized to LYN-005 plus 
IR risperidone matched placebo OR LYN-005 matched placebo or IR risperidone as follows: 
• Arm 1:  LYN-005 (14 or 28 mg weekly) plus IR risperidone matched placebo (N=24). 
• Arm 2:  LYN-005 matched placebo plus IR risperidone (2 or 4 mg/day) (N=8). 
Per above, in order to maintain the blind, all subjects will either receive LYN-005 and IR 
risperidone-matched placebo or LYN-005-matched placebo and IR risperidone, as follows: 
Arm 1:   
• LYN-005: Size 00EL capsules containing LYN-005 stellate; the 14 mg dose of LYN-005 
contains 3 active arms containing risperidone, and 3 inactive arms and he 28 mg dose of 
LYN-005 contains 6 active arms containing risperidone. 
AND 
• IR Risperidone Matched Placebo:  Orange capsule-shaped tablets containing inactive 
ingredient. 
Arm 2: 
• LYN-005 Matched Placebo:  Size 00EL capsules containing inactive ingredient with no 
stellate. 
AND 
• IR Risperidone:  Risperidone 2 mg (orange) capsule-shaped tablets. 
Although treatment assignment is blinded; the dose level is not blinded. The dose of LYN-005 
(14 or 28 mg)/IR risperidone (2 or 4 mg/day) administered will be based on the subject’s current 
antipsychotic medication dose. Randomization will be stratified by risperidone dose (LYN-005 
14 mg/IR risperidone 2 mg/day [low dose] and LYN-005 28 mg/IR risperidone 4 mg/day [high 
dose], with a maximum of 16 subjects enrolled in each strata. Within each strata, subjects will be 
randomized on a 3:1 basis to either LYN-005 or risperidone, respectively.   


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All administrations of LYN-005 will be supervised. Complete PK evaluations will be performed 
after each LYN-005 dose, as designated in the Schedules of Events (SOE) (Section 18.1.1 and 
Section 18.1.2) and over 24 hours at steady-state for IR risperidone at the beginning of the study. 
LYN-005 will be evaluated in subjects who meet Diagnostic and Statistical Manual of Mental 
Disorders, Fifth Edition (DSM-5) criteria for a primary diagnosis of schizophrenia or 
schizoaffective disorder of at least 2 years, who have already been stabilized on an oral 
antipsychotic medication for a minimum of 6 weeks at the time of screening with no psychiatric 
hospitalizations for relapse in the past 6 months. Subjects who are prescribed an antipsychotic 
agent other than risperidone or a dose of risperidone outside the range are also eligible for study 
participation if they are a) able to tolerate risperidone and b) be completed switched to 2 or 4 mg 
daily oral risperidone for a minimum of 2 weeks prior to the first dose of LYN-005/matched 
placebo on Day 1 (see Section 6.3.1).  
Eligible subjects must be clinically stable (i.e., mildly or moderately ill psychiatrically), with a 
low risk of relapse and otherwise healthy without history of significant GI diseases. Guidelines 
will be in place for the use of recommended rescue medications for agitation, anxiety, and 
insomnia. In the event of worsening of schizophrenia symptoms while receiving risperidone 
during the study, another medication can be administered at the discretion of the Principal 
Investigator (PI), with notification of Lyndra’s Medical Monitor.  
Subjects will be screened for study eligibility between Days -21 and -14. Subjects who are 
initially determined to be eligible, based on initial Screening assessments, will then participate in 
a 10-day IR risperidone run-in period, during which adherence with study treatment will be 
assessed. Subjects who remain eligible for the study will enter the inpatient unit on Day -2. After 
admittance to the inpatient unit and prior to the first LYN-005/matched placebo administration, 
samples for determination of IR risperidone PK will be collected from Days -2 to -1.  
Over the course of the study, subjects are to receive 3 doses of LYN-005/matched placebo, per 
their random assignment, 1 each on Days 1, 8, and 15, all on an inpatient basis. All subjects also 
will receive IR risperidone or matched placebo, again per their random assignment, from Days 1 
to 21. 
Overall, during study participation, subjects will be housed in the inpatient unit twice, from 
Days -2 to 9 (Inpatient Stay 1) and then again from Days 14 to 16 (Inpatient Stay 2). Subjects 
who are admitted to the inpatient unit on Day -2 will be considered enrolled. In between each 
inpatient stay, subjects will have study assessments performed on an outpatient basis daily from 
Days 10, 11, 12, and 13. After discharge from Inpatient Stay 2, subjects will again have 
assessments performed on an outpatient basis on Days 17, 18, 21, 22, and 23. An End of Study 
(EOS) visit will be conducted on Day 35.  
During study participation, guidelines will be in place for the use of recommended rescue 
medications for agitation, anxiety, and insomnia. Rescue administration of an agent other than 
risperidone or paliperidone in the event of worsening of schizophrenia symptoms during the 
study can be administered at the discretion of the PI, with notification of Lyndra’s Medical 
Monitor. Extrapyramidal symptoms will be monitored throughout the study at regular intervals 


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using the Extrapyramidal Symptom Rating Scale (ESRS). Severity of 
schizophrenia/schizoaffective disorder symptoms will be monitored throughout the study at 
regular intervals using the Clinical Global Impression-Severity (CGI-S) scale. Concomitant 
medications, AEs, safety laboratory tests, and vital signs will be assessed throughout the study, 
as per the SOE (Section 18.1.1 and Section 18.1.2). 
Details regarding each study period follow. 
4.1.1 
Screening Period (Day -21 to Day -14): 
All screening procedures will be performed on an outpatient basis. Prior to any screening 
procedures, the subject or designated representative must provide written informed consent. 
Male and female subjects between 18 to 50 years of age who have a diagnosis of schizophrenia 
or schizoaffective disorder, as defined by DSM-5 criteria and as confirmed by the Mini 
International Neuropsychiatric Interview (MINI) version 7.0.2. The MINI will also be used to 
exclude comorbid psychiatric diagnoses. Further eligibility requirements will include a CGI-S 
score of ≤4 (moderately ill). Subjects must have been medically stable within the last month, and 
stable in their psychiatric illness on a stable antipsychotic treatment regimen and without 
significant symptom exacerbation over the last 3 months. Additionally, subjects must be 
receiving outpatient treatment and not have been hospitalized for worsening schizophrenia in the 
last 6 months (hospitalization for social management within this time is acceptable). Subjects 
should have a Positive and Negative Syndrome Scale (PANSS) score aligned with stable and 
mild-moderate disease (i.e., ≤80 points).  
An assessment of pill swallowing will be assessed with a questionnaire, PILL-5, where a score of 
4 or below is regarded as “normal” pill swallowing. Additional screening measures to confirm 
general good health will be performed as described in the SOE (Section 18.1.1).  
To be eligible for this study, subjects must either have been stable on a therapeutic dose of an 
oral IR risperidone between 2 and 8 mg/day or been on a stable dose of another antipsychotic 
medication (single agent) for a minimum of 6 weeks. As shown in Figure 6-1, subjects already 
receiving 2 to 4 mg IR risperidone will transition to 2 mg daily administration by Day -13 to 
complete the run-in. Subjects on a daily dose of approximately 4 mg to 8 mg IR risperidone will 
be placed in a cohort based on clinical judgement of the Investigator and fully transitioned to this 
dose by Day -13 and remain at this dose during the run-in.  
Subjects who currently are on antipsychotic medications other than IR risperidone are also 
eligible for the study and are to be switched to either 2 or 4 mg/day IR risperidone based on the 
clinical judgement of the Investigator are to begin the transition to IR risperidone starting on 
Day -13; by Day -13, these subjects should only be receiving 2 or 4 mg IR daily during the run-
in. To improve toleration and management of symptoms during the transition to risperidone run-
in, short-term changes to the daily risperidone dose during the run-in may be considered in 
consultation with the PI. A home or clinic visit may also be considered at the discretion of the PI 
in order to assure subject stability.  


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4.1.2 
Pre-study Preparation with IR Risperidone 
All subjects who are eligible for study participation at the end of Screening will receive a 
medication log for use Days -13 through -3 to record the timing and dose of their IR risperidone 
during the run-in period. IR Risperidone must be taken once a day and at approximately the same 
time of day (morning or evening) on Days -13 to -3. Guidelines for switching antipsychotic 
medication to risperidone 2 or 4 mg/day prior to Day -13 are provided in Figure 6-1 in 
Section 6.3.1. 
Eligible subjects will be contacted daily on Days -13 to -3 prior to admission to the study unit on 
Day -2 to ensure medication adherence and check on safety, concomitant medications, and AEs. 
The subject must be adherent (self-report) with risperidone administration for 5 consecutive days 
prior to Day -3 to be eligible for enrollment into the study. Additional days may be added to the 
pre-study preparation to ensure 5 consecutive days of medication adherence prior to Day -3. 
Subjects who confirm medication adherence will be prepared by the site regarding the 
arrangements for subject arrival at the study unit the next day (Day -2) and the subsequent 10-
night stay. Subjects will be instructed on Day -3 to take their risperidone dose at the normal time 
and to bring risperidone tablets to the unit on Day -2. 
4.1.3 
IR Risperidone PK Period 
Subjects will be admitted to the study unit on Day -2.  
Medication adherence for IR risperidone based on the medication log should be assessed upon 
arrival to the unit on Day -2, and subjects who are non-adherent are not to be admitted to the 
inpatient unit at that time. The site should confirm the dose and time of last IR risperidone for 
subjects who remain eligible to begin the inpatient phase of the study, and a blood sample 
collected for PK analysis.  
Subjects who are switching from evening to morning dosing will be given half the regimen of 
daily oral risperidone in the evening of Day -2 (i.e., either 1 or 2 mg risperidone) to minimize 
overlapping exposure. This dose should be given after the evening (6 pm) PK sample has been 
collected. Morning administration of the full dose of IR risperidone, 2 or 4 mg respectively, must 
begin by Day -1 for all subjects. 
Patients will receive IR risperidone on Day -1, as described in Section 6.3.2, with PK samples 
collected thereafter.  
4.1.4 
Randomization (Day 1) 
Subjects who successfully complete the admission procedures will be randomized on Day 1 in a 
3:1 ratio to LYN-005 or IR risperidone, as follows: 
• 
LYN-005: Subjects randomly assigned to LYN-005 ER will receive a single LYN-005 ER 
capsule (14 or 28 mg) taken once-weekly (on Days 1, 8, and 15) plus dummy IR risperidone-
matched placebo daily though Day 21. 


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• 
IR Risperidone: Subjects randomly assigned to IR risperidone will receive a single weekly 
dummy capsule (placebo capsule representing LYN-005, but containing no stellate) taken 
once-weekly (On Days 1, 8, and 15) plus IR risperidone (2 or 4 mg/day) daily though Day 
21.  
Subjects will be split into 2 groups based on their IR risperidone run-in dose prior to 
randomization. Subjects receiving 2 mg/day IR risperidone will be randomized to receive either 
14 mg/week LYN-005 or continued 2 mg/day IR risperidone and those receiving 4 mg/day IR 
risperidone will be randomized to receive either 28 mg/week LYN-005 or continue with 
4 mg/day risperidone, respectively. Although treatment assignment is blinded; the dose level is 
not blinded. Randomization will be stratified by risperidone dose (LYN-005 14 mg/IR 
risperidone 2 mg/day [low dose] and LYN-005 28 mg/IR risperidone 4 mg/day [high dose], with 
a maximum of 16 subjects enrolled in each strata. Within each strata, subjects will be 
randomized on a 3:1 basis to either LYN-005 or risperidone, respectively.   
4.1.5 
Double-blind Dosing Period (Days 1 to 21) 
During the LYN-005 dosing period, subjects are to receive 3 doses of LYN-005 or matched 
placebo, one each on Days 1, 8, and 15. Following an overnight fast, subjects are to consume a 
light breakfast over 30 minutes or less, with the meal started 30 minutes prior to study drug 
administration. Subjects also will receive IR risperidone Study assessments are to be performed 
before and after each dose per the Schedule of Events (Section 18.1.1 and Section 18.1.2). 
Subjects will remain in the inpatient unit until Day 9 for continued safety monitoring. On Day 9, 
the Investigator will perform study assessments to confirm the subject is eligible to leave the 
inpatient unit and continue outpatient treatment with study drug.  
After discharge from the inpatient unit on Day 9, subjects will be followed on an outpatient basis 
from Days 10 to 13 until their return to the unit on Day 14. During this period, subjects will 
continue taking their daily dummy or IR risperidone as prescribed. 
In the evening of Day 14, subjects will return to the clinic for Inpatient Period 2 in advance of 
the third LYN-005/matched placebo administration on Day 15. AEs and concomitant 
medications will be assessed upon arrival.  
On the morning of Day 15, a pre-dose PK-sample will be collected, and as on Days 1 and 8, 
subjects will be administered either the third dose of LYN-005/matched placebo. PK samples 
will be collected and safety assessments performed as per the SOE (Section 18.1.1 and 
Section 18.1.2). Subjects are to remain in the unit for a minimum of 8 hours for observation prior 
to discharge on Day 16.  
On Days 16 through 21, subjects will continue taking their daily IR risperidone or matched 
placebo as outpatients, as per their random treatment assignment.  


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4.1.6 
End of Study Visit (Day 35) 
On Day 35, subjects will be asked to return to the clinic for follow-up assessments, as per the 
SOE (Section 18.1.2). Thereafter, additional follow-up telephone calls may occur as warranted if 
there are ongoing AEs at the time of the EOS Visit. 
4.2 
Blinding Procedures 
Subjects and site and Sponsor personnel associated with study conduct will be blinded to 
treatment assignment.  
During the conduct of the study, the blind should only be broken on an individual subject basis in 
the event of an emergency where it is necessary for the Investigator to know which treatment the 
subject is receiving before the subject can be treated. The code may also be broken if someone 
not in the study uses study drug (e.g., if a child in the subject’s household takes study drug, the 
blind may be broken to determine treatment for the child).  
When it is necessary to break the blind, the Investigator may unblind the treatment immediately 
(i.e., without prior notice to the Medical Monitor, sponsor, or other) via the Interactive Response 
Technology system, but must notify the IRB per local regulations and Sponsor as soon as 
possible, preferably by telephone and then in writing, regarding the necessity of code breaking.  
If the code is broken for a subject, this must be documented in the electronic case report form 
(eCRF) and source documents, together with the reasons for breaking the code. 
4.3 
Justification of Dose Selection 
The justification for dose selection is based on the target oral dose range for risperidone ranging 
from 2 to 8 mg/day in subjects with schizophrenia and schizoaffective disorder [33]. These doses 
would be expected to correspond to therapeutically equivalent weekly doses of 14 to 56 mg 
risperidone using LYN-005. Accordingly, for this study, 14 and 28 mg LYN-005 ER capsule 
formulations of risperidone will be evaluated.  
LYN-005 containing 14 and 28 mg risperidone is expected to deliver comparable exposures to 
risperidone active moiety concentrations associated with 2 mg/day and 4 mg/day, respectively, 
given orally as an immediate release formulation over 1 week. Given the metabolism of 
risperidone to the equipotent metabolite, 9-hydroxyrisperidone, and due to the exposure 
differences between poor and extensive metabolizers, it was decided to exclude poor 
metabolizers to minimize study variability.  


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5 SUBJECT POPULATION 
5.1 
Inclusion Criteria 
To be eligible to participate in the study, subjects must meet ALL of the following inclusion 
criteria at Screening (or at enrollment when specified): 
1. Male or female aged ≥18 and ≤50 years. 
2. Current diagnosis of schizophrenia or schizoaffective disorder according to DSM-5 criteria 
as confirmed by the MINI 7.0.2. 
3. The following psychiatric criteria are to be used to determine subject eligibility:  
a. Duration of diagnosis of schizophrenia or schizoaffective disorder of ≥2 years. 
b. Outpatient; not hospitalized for worsening of schizophrenia within the last 6 months 
(partial hospitalization for social management within this time period is acceptable). 
c. Medically stable over the last month and psychiatrically stable without significant 
symptom exacerbation over the last 3 months. 
4. Stabilized on an oral antipsychotic medication (single agent) for a minimum of 6 weeks at 
the time of Screening. 
5. On a stable dosage of all permitted non-antipsychotic medications (except for medication to 
be used on an as-needed basis) for at least 1 month prior to the Screening visit and for the 
duration of the study. 
6. CGI-S score of ≤4 (moderately ill). 
7. PANSS score of ≤80 points. 
8. Body mass index (BMI) of ≥18 kg/m2 and ≤35 kg/m2. 
9. Able to read and understand study procedures and provide written informed consent before 
the initiation of any protocol-specific procedures. 
10. Willing to comply with all protocol-specified procedures and availability for the duration of 
the study. 
11. Subject has identified a caregiver or personal contact with whom the subject communicates 
with at least once a week. 


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5.2 
Exclusion Criteria 
In order to be eligible to participate in the study, subjects must meet NONE of the following 
exclusion criteria at Screening (or at enrollment when specified):  
1. Subjects with known clinically significant esophageal or GI disease, including but not limited 
to:
a.
Known strictures such as esophageal web, pyloric stenosis, or small intestinal stricture, or 
subjects with high risk of stricture, e.g., Crohn's disease.
b. Diagnosis of a condition known to elevate or lower gastric pH, e.g., achlorhydria or 
hypochlorhydria.
c.
Prior varices or small or large bowel obstructions.
d. Prior abdominal or upper gastrointestinal surgery (prior uncomplicated laparoscopic 
procedures including appendectomy or colectomy).
e.
History of dysphagia or aspiration in the last 5 years.
f.
History of an esophageal motility disorder or undergoing treatment for a gastric motility 
disorder.
g. Significant history of diarrhea or constipation within 3 months of Screening.
h. Multiple episodes of abdominal pain within 3 months of Screening.
i.
Subjects who experience moderate or severe dysmenorrhea or menorrhagia (with use of 
pain medication) within 3 months of Screening.
j.
History of moderate to severe Acid Reflux Disease or a score of ≥2 on the Acid Reflux 
Severity Scale (ARSS) [2], indicating moderate to severe symptoms. The ARSS scale is as 
follows:
None = 0 no symptoms
Mild = 1 awareness of symptom, but easily tolerated
Moderate = 2 discomfort sufficient to cause interference with normal activities
Severe = 3 incapacitating, with inability to perform normal activities.
2. Subjects with PILL-5 questionnaire score of 5 or greater.


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3. Medical history or current diagnoses indicating the presence of any of the below conditions: 
a. Presence of an uncontrolled, unstable, clinically significant medical condition could that 
could put the subject at risk because of participation in the study, interfere with the 
subject’s ability to participate in the study or influence the interpretation of safety or PK 
evaluations.  
b. History of a major cardiovascular event (myocardial infarction, cardiac surgery or 
revascularization, unstable angina, stroke, or transient ischemic attack) or a 
hospitalization for heart failure with 6 months of Screening. 
c. Any clinically significant illness, medical or surgical procedure or trauma within 4 weeks 
of Screening. 
d. Known immunocompromised status, including individuals who have undergone organ 
transplantation, on immunosuppression for an immune mediated disease, or are positive 
for HIV. 
e. Subjects with a positive test for active hepatitis B or C at Screening. Subjects with 
successfully treated hepatitis B infection which has been resolved for greater than 1 year 
or successfully treated hepatitis C infection will not be excluded. 
f. Subjects who have donated more than 250 mL of blood within 30 days of Screening. 
g. Subjects who have difficulties with venipuncture/cannulation, including difficulty 
accessing veins for blood sampling and/or history of coagulopathy or endocarditis. 
h. Subjects with a current DSM-5 diagnosis of major depressive episode, panic disorder, 
agoraphobia, social anxiety disorder, obsessive-compulsive disorder, post-traumatic 
stress disorder, generalized anxiety disorder on the MINI 7.0.2 or in the judgment of the 
Investigator. (Note that individuals with depression secondary to schizoaffective disorder 
are eligible). 
i. Suicidal ideation associated with actual intent and a method or plan in the past 6 months, 
as measured by the C-SSRS (i.e., “Yes” answers on items 4 or 5) at Screening or having 
made a suicide attempt within the last 2 years. 
j. Known or suspected (non-febrile) seizure disorder. 
k. History of neuroleptic malignant syndrome. 
l. Current or history of clinically significant tardive dyskinesia. 
m. Known or suspected diagnosis of intellectual disability or organic brain disorder or other 
diagnosis that is primarily responsible for current symptoms and functional impairment. 


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n. Medically non-adherent in the management of their schizophrenia/schizoaffective 
disorder. 
4. Use of the below medications/treatments in the 2 weeks before enrollment, including: 
a. Proton pump inhibitors or H2 blockers. 
b. Prokinetic agents. 
c. Medications that may interfere with the absorption, metabolism, or excretion of 
risperidone, e.g.: 
i. 
Drugs metabolized via CYP3A4 pathway, such as macrolide antibiotics and azole 
antifungals). 
ii. 
Moderate or strong CYP3A4 p-glycoprotein (P-gp) enzyme inducers and inhibitors 
(carbamazepine, phenytoin, rifampicin, phenobarbital, itraconazole, verapamil). 
iii. 
Moderate or strong CYP2D6 inhibitors (e.g., fluoxetine, fluoxetine combinations, 
paroxetine), or quinidine. 
d. Concomitant medications, natural remedies, supplements or vitamins which are 
associated with changes to gastric motility or pH. Use of antacids is permissible, except 
within 2 hours of dosing with LYN-005.  
e. Benzodiazepines; except lorazepam, diazepam and oxazepam, which are acceptable if 
for the treatment of depression, anxiety or insomnia.  
f. Use of more than one antidepressant; or if on just one, a change in dose within 6 weeks 
of Screening. 
g. Depot antipsychotic use within 9 months of Screening. 
h. Electroconvulsive therapy within 3 months of Screening. 
5. Subjects with clinically significant abnormal safety (e.g. physical examination, vital sign) or 
safety laboratory assessments, specifically: 
a. Presence of a clinically significant abnormal laboratory result on blood or urine safety 
tests at Screening. 
b. Anemia (hemoglobin below lower limit of normal reference range) at Screening. 
c. Alanine aminotransferase (ALT), aspartate aminotransferase (AST) ≥3.0 × upper limit of 
normal (ULN), or total bilirubin ≥1.5 × ULN.  
d. Moderate or severe renal insufficiency at Screening (glomerular filtration rate 
<60 mL/min, as determined using the Cockcroft-Gault formula). 


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e. Heart rate of <50 beats per minute (bpm) at Screening. 
f. Systolic blood pressure <100 or ≥150 mmHg and/or diastolic blood pressure <60 mmHg 
or ≥100 mmHg at Screening. 
g. HbA1c ≥6.5% at Screening. 
h. Positive fecal occult blood test at Screening.  
i. Clinically significant prolactin elevation (≥200 ng/mL for females; ≥100 ng/mL for 
males). 
6. Subjects with the below specified patterns of substance use at Screening: 
a. Fulfillment of the DSM-5 criteria for moderate or severe substance use disorder 
(excluding nicotine and caffeine) within 6 months of Screening. 
b. History of alcohol consumption exceeding moderate use; in males exceeding 21 units per 
week and in females exceeding 14 units per week (1 unit = 360 ml beer, 25 mL of 40% 
spirit or a 125 mL glass of wine) over the past month. Subjects are not permitted to 
consume alcohol during the inpatient stay nor 12 hours before any clinic visit while 
outpatient. 
c. Positive ethanol breathalyzer. 
d. Positive urine drug screen for substances of abuse other than cannabis. 
e. Heavy nicotine use (consumption of >40 cigarettes or >36 mg of nicotine from other 
sources [e.g., vaping products] daily) or daily use of smokeless tobacco. 
7. Subjects of reproductive potential who are (hetero) sexually active but unwilling to use 
acceptable means of contraception through the EOS. For clarity, subjects who are at least 
1 year post-menopausal are not of reproductive potential. Acceptable means of contraception 
include: 
a. Subjects who have been surgically sterilized. 
b. Females of reproductive potential: diaphragm, injectable, oral/patch contraceptives for a 
minimum of 6 weeks, contraceptive sponge, implant, or intrauterine device in use prior to 
enrollment. 
c. Males: condom in combination with any of the above means of contraception. 
d. All subjects: abstinence may be an acceptable means of contraception as long as the 
individual consents to initiate immediate use of double barrier protection for the duration 
of the study should (hetero) sexual intercourse occur. 


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8. Subjects who are nursing or who have positive or indeterminate pregnancy tests at either 
Screening (serum test) or enrollment (urine test). 
9. Use of any experimental agent within 1 month or 5 half-lives of Screening, whichever is 
longer. 
10. Subjects who are employees or immediate family members of employees of the site, Sponsor 
or study-related vendors.  
11. History of a serious allergic or hypersensitivity reaction to risperidone or LYN-005 
excipients (refer to Investigator’s Brochure). 
12. Subjects with history of X-ray, computed tomography (CT) scan or angiogram of the 
abdomen within one year of Screening. 
13. Subjects with CYP2D6 poor or underdetermined metabolizer status based on genetic testing. 
5.3 
Screen Failure 
Screen failures are defined as subjects who consent to participate in the clinical study but who do 
not meet inclusion/exclusion criteria and hence are not subsequently enrolled in the study. (For 
the purposes of this study, subjects who are admitted to the inpatient unit on Day -2 will be 
considered enrolled.) A minimal set of screen failure information is required to be captured to 
ensure transparent reporting of screen failure subjects and to respond to queries from Regulatory 
Authorities. Information to be captured on screen failure subjects includes demography, screen 
failure details including any inclusion/exclusion criteria that were not met, the primary reason 
and the relevant data (e.g., laboratory, medical historical details) that support the determination. 
Where applicable, potential subjects may be rescreened to reassess eligibility. These subjects 
should be assigned the same subject numbers as for the initial screening.  
Subjects who consent to participate in the clinical study, meet eligibility criteria but are not 
enrolled will be referred to as Alternates (not screen failures) and may be considered for future 
enrollment.  
5.4 
Discharge Instructions at End of Study or Early Termination Visit 
The site will facilitate a review with the study subject of the planned schedule for when 
information relating to their study information (e.g., study results, treatment assignments) will be 
available. The site will also discuss how information relating to their participation in the study 
will be shared with their healthcare provider, if they choose to share this information, and with 
the relevant health authorities in the event of a positive HIV or hepatitis result. 
5.5 
Study Completion 
The site will complete the Study Termination eCRF page and this will mark the completion of 
the individual’s participation in the study. 
The date of termination is the date of the last contact (clinic visit or telephone call) in which the 
subject’s health status was assessed or, in cases where the subject does not agree to any further 


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safety follow-up, it is the date consent is withdrawn. This date should be recorded on the Study 
Termination eCRF page.  
6 STUDY DRUG MANAGEMENT 
6.1 
Description of Study Drugs 
The term ‘study drug’ refers to those drugs provided by the Sponsor, which will be evaluated as 
part of the study objectives.  
6.1.1 
LYN-005 ER 
The Lyndra ER product, LYN-005, contains risperidone 14 or 28 mg. The LYN-005 
(risperidone) ER capsule is designed with modular components to ensure the safe and controlled 
administration of risperidone in the GI tract over several days. Drug is contained only within the 
drug layers, which provide controlled drug release based on hydration. Refer to the 
Investigator’s Brochure for additional details. 
Lyndra will provide LYN-005 14 and 28 mg capsules and matched placebo.  
6.1.2 
IR Risperidone 
RISPERDAL® (risperidone) is an atypical antipsychotic agent. Lyndra will provide risperidone 
2 mg (orange) capsule-shaped tablets and matched placebo. 
6.2 
Storage 
All drugs associated with this study (study drugs) are to be stored separately from other drugs 
and medications in a secure location under appropriate storage conditions with temperature 
monitoring. All drugs associated with this study must be checked for expiration or retest date 
prior to use. Expired drugs or those beyond their retest date must not be administered to subjects. 
The Investigator or designee will be responsible for oversight of the administration of drug to 
subjects enrolled in the study according to the procedures stipulated in this study protocol. All 
drugs will be administered only by personnel who are qualified to perform that function under 
applicable local laws and regulations for the specific study site. 
6.2.1 
LYN-005 
LYN-005/matched placebo is to be stored at 15 to 25ºC (59° to 77°F). The capsules are to be 
handled in a manner to avoid squeezing or crushing. 
6.2.2 
IR Risperidone 
IR risperidone tablets/matched placebo should be stored at controlled room temperature 15° to 
25°C (59° to 77°F) and protected from light and moisture. 




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6.3.3 
Blinded Treatment (LYN-005 or Placebo) 
Subjects who successfully complete the admission procedures will be randomized on Day 1 in a 
3:1 ratio to LYN-005 or IR risperidone, as follows: 
• LYN-005: Subjects randomly assigned to LYN-005 ER will receive a single LYN-005 ER 
capsule (14 or 28 mg) taken once-weekly (on Days 1, 8, and 15) plus dummy IR risperidone-
matched placebo daily though Day 21. 
• IR Risperidone: Subjects randomly assigned to IR risperidone will receive a single weekly 
dummy capsule (placebo, representing LYN-005) taken once-weekly (On Days 1, 8, and 15) 
plus IR risperidone (2 or 4 mg/day) daily though Day 21.  
6.3.3.1 
LYN-005/Placebo Administration 
LYN-005 capsules are to be taken orally following a light breakfast with approximately 250 mL 
of water immediately after capsule administration, while the subject is in a standing position. If 
the subject requests more fluid for swallowing, they may be given additional water in increments 
of 50 mL to chase. The volume of water consumed by the subject will be recorded in the eCRF. 
The subject is to remain upright after dosing for a total of at least 15 minutes. The subject must 
not bite or chew the capsule nor hold the capsule in the mouth prior to swallowing.  
6.3.3.2 
IR Risperidone/Placebo Administration 
IR risperidone or matched placebo tablets are to be taken orally in the morning with 250 mL of 
water with the option for additional water (increments of 50 mL), as needed. 
6.4 
Accountability and Compliance 
The United States Food and Drug Administration (FDA) requires accounting of all 
investigational treatment received by each study center. Records of treatment disposition 
required by federal law include the date received by the center, date administered, quantity 
administered, and the subject to whom study treatment was administered. The investigator is 
responsible for the accountability of all used and unused study treatment containers and unused 
study treatment. 
Each study center is to use a study treatment accountability log to document study treatment 
disposition. All items on this form are to be completed in full. The area where study treatment 
accountability records are to be maintained is to be approved by the Sponsor or designee. The 
Clinical Research Associate (CRA) is to routinely review study treatment accountability records. 
6.5 
Prior and Concomitant Medications and Therapies 
All medications, drugs and blood products taken or received by the subject within 3 months and 
any over-the-counter medications, natural supplements or vitamins taken within 4 weeks 
(28 days) prior to Day -2 are to be recorded on the Concomitant Medications eCRF. Similarly, 
any medication, drug, blood product, over-the-counter medication, herbal remedy taken by the 


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subject after study enrollment through EOS will also be recorded on the Concomitant 
Medications eCRF.  
Subjects on medication who do not discontinue medications within 2 weeks of study dosing 
(unless otherwise specified in the Exclusion Criteria, Section 5.2) are not eligible for dosing with 
LYN-005 on Day 1.  
During the study, the use of contraceptives (oral or other acceptable method) to prevent 
pregnancy in subjects of childbearing potential is required. Aside from contraceptives and 
necessary psychotropic medications, the use of other concomitant medications is generally 
discouraged during the study unless deemed appropriate by the Investigator to treat new or 
worsening medical conditions, including AEs. If pain relief is required during the study, the 
Investigator is encouraged to prescribe paracetamol. Nonsteroidal anti-inflammatory medications 
are prohibited from Day -8 until the end of the study. 
Psychotherapy should not be started or stopped during a subject’s participation in the study. It is 
acceptable for a subject already receiving psychotherapy to continue such therapy during study 
participation. 
Concomitant medications include all medications (including drugs) taken by/administered to the 
subject at and after enrollment and must be documented on the Concomitant Medications eCRF. 
As a reminder: any change to medical history or onset of AEs must also be captured in the 
respective Medical History and Adverse Event eCRFs. 




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formulations, this information will be reviewed in a timely manner to understand the risks to 
these subjects. 
7.2 
Premature Withdrawal from Study 
Subjects may withdraw at any time or be removed from the study at the discretion of the 
Investigator should any untoward effects occur and/or for safety reasons. In addition, a subject 
may be withdrawn by the Investigator or the Sponsor if he/she violates the study plan or for 
administrative reasons. The Investigator or Study Coordinator must notify the Sponsor 
immediately when a subject has been withdrawn due to an AE.  
The circumstances above are referred to as premature withdrawal from the study, and the reason 
for premature withdrawal should be clearly documented and detailed in the source 
documentation. The Investigator should make every attempt to evaluate the subject’s safety, 
including resolution of ongoing AEs, at the time of premature withdrawal.  
If a subject wishes to withdraw from the study after dosing with LYN-005 and before the last 
planned study visit, efforts should be made to obtain an X-ray in lieu of the scheduled X-rays for 
all subjects without fecal recovery or prior negative X-ray demonstrating GI exit of the 
formulation.  
When a subject withdraws, or is withdrawn, from the study after dosing with any study drug, the 
procedures described for the EOS visit (Section 18.1.2) should be completed, if possible. If a 
subject withdraws or is withdrawn from the study after enrollment but before dosing with LYN-
005, that subject would complete EOS visit procedures, excluding abdominal X-ray and would 
be considered a premature withdrawal. 


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8 STUDY ASSESSMENTS AND PROCEDURES 
After signing informed consent, individual subject data will be collected from subjects 
throughout the duration of their study participation. All data collected will use deidentified 
subject identifiers such as Screening and enrollment/subject IDs.  
This study utilizes eCRFs to collect study-related data for each subject. A qualified site staff 
member(s) is required to enter subject data in the eCRFs based on the medical information 
available in each subject’s source record.  
The study day and time each assessment will be performed relative to dosing is shown in the 
SOE (Section 18.1.1 and Section 18.1.2). However, when study assessments fall on the same 
time point, the site may arrange the order of procedures according to their usual practice. 
8.1 
Screening and Safety Assessments 
8.1.1 
Informed Consent 
“Informed consent” is the voluntary agreement of an individual to participate in research. 
Consent must be given with free will of choice, and without undue inducement. The individual 
must have sufficient knowledge and understanding of the nature of the proposed research, the 
anticipated risks, and potential benefits, and the requirements of the research to be able to make 
an informed decision. 
Written informed consent following local IRB guidance must be obtained from each subject 
before conducting any study-specific procedure (i.e., all procedures described in the protocol). 
The process of obtaining informed consent should be documented in the subject source 
document in addition to maintaining a copy of the signed and dated informed consent.  
Subjects who are unable to read must not be enrolled in the study. 
8.1.2 
PILL-5 Questionnaire 
The PILL-5 Questionnaire is to be administered to subjects during Screening. Refer to 
Section 18.2 for details. 
8.1.3 
Breath Test for H. Pylori 
Breath testing will be used at Screening to test for active H. pylori infection, and all results will 
be documented. Subjects will not be excluded on the basis of the rest results. Methods for 
evaluating the H. pylori breath test are described in the Laboratory Instruction Manual. 
8.1.4 
Medical and Psychiatric History 
Medical and psychiatric history for the past 12 months will be assessed at Screening and may be 
reassessed o prior to dosing to determine if there are any clinically relevant updates. The 
assessment of medical history will include but will not be limited to any history that may be 
relevant to subject eligibility for study participation such as concomitant medications, previous 


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and ongoing illnesses or injuries, and duration of medical and psychiatric stability. Relevant 
medical history can also include any medical history that contributes to the understanding of an 
AE that occurs during study participation, if it represents an exacerbation of an underlying 
disease/pre-existing problem. Relevant psychiatric history should include any psychiatric history 
relevant to the duration and understanding of diagnosis of mental illness and time of last 
hospitalization. The Investigator or delegate should update the medical and psychiatric history as 
needed while investigating treatment-emergent AEs.  
8.1.5 
Acid Reflux Severity Scale  
History of moderate to severe Acid Reflux Disease, or a score of ≥ 2 as assessed by the Acid 
Reflux Severity Scale (ARSS) [2] at Screening is exclusionary. The ARSS is presented in 
Section 18.7. 
8.1.6 
Psychiatric and Extrapyramidal Symptom Assessment 
The following table lists the typical times to complete the psychiatric and EPS assessments in 
this study by visit date. The longest completion time occurs at Screening, lasting ~1.5 hours for 
all assessments. Thereafter, the total time to complete the assessments is <30 minutes or less.  
Table 8-1:  Psychiatric and EPS Assessment Timing and Durations 
 
8.1.6.1 
Mini International Neuropsychiatric Interview (MINI) version 7.0.2 
The Mini International Neuropsychiatric Interview version 7.0.2 is a short, structured diagnostic 
interview that was developed to assess DSM-5 and ICD-10 psychiatric disorders. The MINI was 
developed for use in clinical and epidemiological studies as a short but accurate clinical 
assessment and has been validated against the Structured Clinical Interview for DSM diagnoses 
[35]. This study will utilize the MINI at Screening in order to ascertain inclusion and exclusion 
criteria. To assess the diagnosis of schizophrenia or schizoaffective disorder for study inclusion, 
the below modules of the MINI will be assessed:  
• Module A: Major Depressive Episode;  
Assessment 
Scale 
Assessment Duration 
[Reference]  
Screening 
Day 7 
Day 9 
Day 15 
Day 21 
Day 35 
PANSS 
45 to 50 min [34] 
√ 
 
 
 
 
 
MINI 
19 min [35] 
√ 
 
 
 
 
 
CGI-S 
2 min [36] 
(after clinical interview) 
√ 
√ 
√ 
√ 
√ 
√ 
C-SSRS 
10 min [37] 
√ 
√ 
√ 
√ 
√ 
√ 
ESRS 
15 min [38] 
√ 
√ 
√ 
√ 
√ 
√ 
Total Time 
96 minutes 
27 minutes 
27 minutes 
27 minutes 
27 minutes 
27 minutes 


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• Module C: Manic and Hypomanic Episode; 
• Module K: Psychotic Disorders and Mood Disorder with Psychotic Features. 
Depression, mania, and hypomania are components of a diagnosis for schizophrenia/ 
schizoaffective disorder. However, recent major depressive episodes may be exclusionary at the 
discretion of the Investigator.  
In addition to Modules A, C and K, several further modules of the MINI will be used to assess 
for excluded psychiatric conditions, as outlined in the study exclusion criteria: 
• Module D: Panic Disorder; 
• Module E: Agoraphobia; 
• Module F: Social Anxiety Disorder; 
• Module G: Obsessive-Compulsive Disorder; 
• Module H: Posttraumatic Stress Disorder; 
• Module N: Generalized Anxiety Disorder. 
The MINI 7.0.2 will be collected at the Screening Visit and takes approximately 15 minutes to 
administer. The tool should be administered by the Investigator or a trained medical professional. 
Instructions and scales for the modules of the MINI which are to be used in this study are 
presented in Section 18.3.  
8.1.6.2 
Structured Clinical Interview-Positive and Negative Syndrome Scale (SCI-
PANSS)  
The PANSS is one of the most widely used measures of psychopathology of schizophrenia in 
clinical research, and is considered the ‘gold standard’ for measuring antipsychotic treatment 
[39]. It is a 30-item scale used to evaluate the presence, absence, and severity of Positive, 
Negative and General Psychopathology symptoms of schizophrenia. In this study, the PANSS 
will be used at Baseline in order to assess the stability and severity of subjects’ disease. Each of 
the 30 items in the PANSS has a definition and a basis for rating, and all items are rated on a 7-
point scale (1 = absent; 7 = extreme). Subjects’ PANSS scores at Screening must be aligned with 
stable, mild to moderate disease based on values of ≤4 for individual items P1, P3, P4, P6, P7, 
and G14. The strengths of the PANSS include its structured interview, robust factor dimensions, 
reliability, the availability of detailed anchor points, and validity. 
The PANSS is accompanied by a semi-structured interview, the SCI-PANSS, which will be used 
in this study at Screening to ensure that all content domains are covered during the interview 
session [40]. SCI-PANSS ratings are made after the completion of the interview, using additional 
reports of daily function from caregivers, family members and a review of available clinical 


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material as needed. Administration of the entire PANSS interview is between 45 and 50 minutes. 
In order to prevent subject fatigue during the interview, it is acceptable for subjects to take a 
short break during an assessment if needed, and then resume completion of the assessment. 
The SCI-PANSS will be administered by the Investigator or a delegate trained in PANSS 
methodology. The core principles for the use of the PANSS, which ensure maximum reliability 
and inter-rater validity, should be followed in the administration of this assessment [39]. The 
PANSS is to be conducted at the Screening Visit and should be collected as outlined in the SCI-
PANSS booklet, seen in Section 18.4.  
8.1.6.3 
Clinical Global Impression – Severity (CGI-S) 
The CGI is widely used by clinicians in clinical studies in order to assess a subject’s global 
functioning both prior to and after initiating treatment with a study medication [41]. It is 
comprised of two one-item measures; the CGI-S measures the severity of a subject’s 
psychopathology, and the CGI-Improvement captures changes from Baseline after treatment 
initiation and includes an efficacy index [41, 42]. As efficacy is not assessed in this study, solely 
the CGI-S will be used to assess subject stability at Screening, enrollment and throughout the 
study.  
The CGI-S consists of a single 7-point rating score of illness severity, to be completed by a 
clinician [41, 42]. Raters select one response based on the following question, “Considering your 
total clinical experience with this particular population, how mentally ill is your subject at this 
time?”. The CGI-S has been demonstrated as a valid and user-friendly alternative to longer 
assessments, including the PANSS, and can be used to identify subjects in remission [43]. Scores 
are as follows:  
1. Normal, not ill at all
2. Borderline mentally ill
3. Mildly ill
4. Moderately ill
5. Markedly ill
6. Severely ill
7. Among the most severely ill subjects
Subjects at Screening must have a stability score of less than or equal to 4 (moderately ill) to be 
eligible for the study. The CGI-S will also be administered to all subjects at multiple time points 
throughout the study, as specified in the SOE (Section 18.1.1 and Section 18.1.2), to monitor 
stability and may also be administered at the discretion of the Investigator. The scale and 
guidelines for its administration are found in Section 18.5.  


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8.1.6.4 
Assessment of Suicidal Ideation and Behavior – Columbia Suicide 
Severity Rating Scale (C-SSRS) 
The Columbia Suicide Severity Rating Scale (C-SSRS) is an interview-based rating scale 
intended to systematically assess suicidal ideation and suicidal behavior. This scale has is 
recognized internationally as the ‘gold standard’ for risk assessments in clinical studies due to its 
simplicity, evidence-supported validity, efficiency, and effectiveness [44]. Two versions of the C-
SSRS will be utilized in this study to ensure subject safety; Baseline/Screening and Since Last 
Visit assessments.
At the Screening Visit, the Baseline/Screening version will be used to asses study eligibility 
criteria and Baseline suicidal ideation and behavior. Subjects who have made a suicide attempt 
within the last 2 years and subjects who, in the Investigator’s judgment, pose a significant suicide 
risk are excluded from study participation. Subjects who have suicidal ideation associated with 
actual intent and a method or plan in the past 6 months (i.e., “Yes” answers on items 4 or 5 of the 
C-SSRS) are also to be excluded.
Each subsequent assessment will utilize the Since Last Visit version of the C-SSRS. Subjects felt 
to have significant suicidal ideation with actual plan and intent or suicidal behavior based on this 
assessment must be evaluated by a licensed and qualified mental health professional (MHP) 
skilled in the evaluation of suicidality in the subjects by virtue of training or experience (e.g., a 
psychiatrist or, licensed PhD level clinical psychologist) who will determine if it is safe for the 
subject to continue in the study. Specific criteria that indicate a need for such an assessment are: 
•
Scores reflecting suicidal ideation associated with actual intent and/or plan in the past
year; i.e., a “YES” answer to C-SSRS questions 4 “some intent to act without specific
plan” or 5 “specific plan and intent”;
•
Subject response of “YES” to any behavioral question of the C-SSRS during a study (as
compared to the previous assessment with the C-SSRS);
•
In the Investigator’s judgment, a risk assessment or exclusion is warranted.
Subjects who meet the above criteria must have additional assessments and have their suicidality 
managed appropriately by the Investigator together with the clinician/MHP (or the Investigator 
alone if the Investigator is a qualified mental health professional). Depending on the specifics of 
the situation as assessed by the Investigator and/or clinician/MHP, the subject may be 
discontinued from the study. 
Other possible suicidality AEs or other clinical observations may, based on the judgment of the 
Investigator and clinician/MHP, also trigger a risk assessment and a narrative using information 
from the C-SSRS and available information; including information from Baseline/ Screening, 
and the clinician/MHP assessment. With the positive response to any question on the C-SSRS, 
the Investigator should determine whether an AE has occurred.  
The C-SSRS should be collected at times specified in the SOE (Section 18.1.1 and Section 
18.1.2) by an appropriately trained site staff member, as well as at any time during the study at 
the discretion of the Investigator. Section 18.6 presents both C-SSRS scales.  


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8.1.6.5 
Extrapyramidal Symptoms – Extrapyramidal Symptom Rating Scale 
(ESRS) 
Antipsychotics are a well-recognized treatment of schizophrenia, but their use is often associated 
with drug-induced EPS or drug-induced movement disorders (DIMD). Therefore, the ESRS will 
be used at Baseline and throughout the study in order to assess the severity of and monitor 
extrapyramidal symptoms. The ESRS was developed to assess four types of drug-induced 
movement disorders [45, 46]: Parkinsonism, akathisia, dystonia, and TD. The ESRS consists of 
several components:  
•
a questionnaire of EPS or DIMD;
•
an examination of Parkinsonism and akathisia;
•
an examination of dystonia;
•
an examination of dyskinesia;
•
CGI-S scales of TD, Parkinsonism, dystonia, and akathisia.
The ESRS has been validated and is widely used in clinical research on antipsychotics and to 
differentiate drug induced EPS and symptoms of schizophrenia [46]. It has been demonstrated 
to be a sensitive and specific scale [46], and that ESRS measurement of drug-induced EPS is 
valid and discriminative from psychiatric symptoms as measured by the PANSS [47]. 
Administration of the ESRS takes approximately 10-15 minutes and should be conducted by 
medical professionals trained on the use of the scale. The ESRS should be administered at 
Baseline and throughout the study as specified in the SOE (Section 18.1.1 and Section 18.1.2). 
ESRS examination procedures and the scale are presented in Section 18.8. 
In cases of marked and clinically significant changes in EPS, the Investigator will use best 
clinical judgment on which treatment to consider in managing these symptoms. 
8.1.7 
Fecal Samples for Occult Blood 
A fecal specimen will be tested at Screening for the presence of fecal occult blood, and results 
will be documented for all participants. A positive fecal occult blood test at Screening in 
subjects will be exclusionary.  For enrolled subjects, fecal samples will be tested for the presence 
of fecal occult blood on Days 1, 7, 14, and 21, and the EOS visit.  
8.1.8 
General Physical Examination and Directed Physical Examination 
A general physical examination will be performed at Screening, Day -2 and the EOS visit. This 
examination will consist, at a minimum, of a check of general appearance; auscultation of the 
heart, lungs, and abdomen; palpation of the abdomen; abbreviated neurological examination; and 
examination of other organ systems in accordance with institutional practice. Body weight is to 
be measured as part of the general physical examination. 


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Directed physical examinations will be performed on other days as indicated in the SOE 
(Section 18.1.1 and Section 18.1.2). This examination will consist, at a minimum, of a check of 
general appearance; auscultation of the heart, lungs and abdomen; and palpation of the abdomen. 
In addition, other organ systems may be examined at the discretion of the qualified medical 
professional performing the examination and as guided by interview of the subject. 
Any new clinically significant abnormality detected during physical examinations and 
considered an AE will be captured on the AE eCRF page.  
8.1.9 
Vital Signs 
Vital signs include measurement of systolic and diastolic blood pressure, pulse, and respiratory 
rate as well as body temperature. Vital signs are to be measured at the time points indicated in 
the SOE (Section 18.1.1 and Section 18.1.2). Vital signs may be measured at additional time 
points at the Investigator’s discretion. 
8.1.10 
Electrocardiograms 
Standard 12-lead ECGs will be performed at the time points indicated in the SOE (Section 18.1.1 
and Section 18.1.2), according to the site Standard Operating Procedures, and ECG parameters 
will be collected in source documentation. ECGs are to be performed with the subject in a supine 
position for at least 5 minutes. All ECGs must be evaluated by a qualified physician for the 
presence of abnormalities, and findings should be classified as normal, abnormal not clinically 
significant or abnormal clinically significant. Additional ECGs may be performed at the 
discretion of the Investigator.  
8.1.11 
CYP2D6 Genotyping 
Risperidone is primarily metabolized by CYP2D6 and genetic testing for CYP2D6 will be 
conducted at Screening to determine metabolizer status. To reduce the inter-subject variability in 
exposure of risperidone and 9-hydroxyrisperidone, subjects identified as poor metabolizers will 
be excluded from the study. Approximately 7 mL (minimum 3 mL) of whole blood will be 
obtained at Screening for CYP2D6 genetic testing.  
8.1.12 
Screening Serology 
Blood is to be collected for serology testing including hepatitis B surface antigen (HBsAg), 
hepatitis C virus antibody (HCV Ab), and HIV, during Screening. 


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8.1.13 
Safety Laboratory Assessments 
Safety laboratory assessments will include the following parameters: 
• Clinical chemistry panel 
- blood urea nitrogen (BUN) should be calculated from urea 
- includes liver function tests  
- HbA1c will be performed at Screening only 
• Hematology panel 
- includes complete blood count (CBC) with differential  
• Coagulation tests 
• Urinalysis to be performed at Screening only, unless for pregnancy test or at Investigator 
discretion 
Safety laboratory assessments will be performed throughout the study at the time points 
indicated in the SOE (Section 18.1.1 and Section 18.1.2). Safety Laboratory Assessments are to 
be reviewed by the Investigator or delegate within 24 hours of available results and prior to 
discharge of the subject from the inpatient unit.  
For a complete list of assessments and further details relating to the collection and handling of 
laboratory specimens, please refer to the Laboratory Instruction Manual.  
8.1.14 
Prolactin 
Blood samples for prolactin will be collected at the time points indicated in the SOE (Section 
18.1.1 and Section 18.1.2). 
8.1.15 
Pregnancy Testing 
Pregnancy testing in females of childbearing potential is to be performed at the time points 
indicated in the SOE (Section 18.1.1 and Section 18.1.2). Pregnancy testing is to be repeated any 
time pregnancy is suspected. At Screening, a serum pregnancy test is to be performed. At all 
time points thereafter, a urine pregnancy test may be performed. 
Subjects with a positive pregnancy test during Screening are not eligible for study participation. 
After starting study drug, study drug is to be discontinued immediately for any subject with a 
positive pregnancy test, and pregnancies are to be reported and followed as described in Section 
8.2.8. 
8.1.16 
Compliance Laboratory Assessments 
Subjects will undergo testing to confirm the absence of alcohol or substance abuse at Screening, 
upon admission to the unit, and at any time during the study as warranted by the Investigator or 
study staff. In accordance with the exclusion criteria (Section 6.3) any individual who has a test 


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reflecting recent use of excessive alcohol or illicit substances at Screening must not be enrolled 
in the study. 
Compliance Laboratory Assessments will include breath testing for alcohol use and urine testing 
for illicit substances (drugs of abuse). Analytes for the urine drug test will be specified in the 
Laboratory Instruction Manual. 
8.2 
Adverse Events and Serious Adverse Events 
According to the International Conference on Harmonization (ICH) Guideline E2A: Clinical 
Safety Data Management: Definitions and Standards for Expedited Reporting dated 27 October 
1994, an AE is defined as follows: 
8.2.1 
Definition of an Adverse Event 
Any untoward medical occurrence in a participation or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have to have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding, for example), symptom, or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product. 
This definition includes onset of illness, injuries, and/or exacerbation of pre-existing conditions. 
The period of observation for AEs extends from the time the subject signs informed consent until 
he or she completes the specified safety follow-up period (i.e., through the End-of-Study visit) or 
terminates the study early (whichever comes first). AEs occurring after the informed consent 
form (ICF) is signed but prior to receiving study drug/product will be documented as an adverse 
event and recorded within source document. However, any AEs occurring prior to receipt of any 
study drug will be analyzed separately from “treatment-emergent” AEs (AEs occurring after 
administration of study drugs) unless there is a change in severity or frequency of AEs persisting 
after the subject is dosed. AEs present on the first day of treatment that worsen in intensity or 
frequency during the treatment or post treatment periods should be reported and recorded as 
AEs.  
Unchanged chronic conditions are not AEs and should not be recorded on the AE pages of the 
eCRF. These medical conditions should be documented on the appropriate page of the eCRF 
(medical history or physical examination). The Investigator will actively solicit this information 
from the subject and assess the event in terms of severity and relationship to the study treatment 
regimen.  
Every effort should be made by the Investigator to evaluate safety information reported by a 
subject for an underlying diagnosis and to capture this diagnosis as the event in the AE page.  


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8.2.2 
Serious Adverse Events 
An AE occurring should be classified as “Serious” if it meets one of the following criteria: 
1. It results in death (i.e., the AE caused or led to death). 
2. It is life threatening (i.e., the AE placed the subject at immediate risk of death). This 
classification does not apply to an AE that hypothetically might cause death if it is more 
severe. 
3. It requires or prolongs inpatient hospitalization (i.e., the AE requires at least a 24-hour 
inpatient hospitalization or prolongs a hospitalization beyond the expected length of stay). 
Hospitalizations for elective medical or surgical procedures, scheduled treatments, or routine 
check-ups are not SAEs by this criterion. 
4. Persistent or significant disability or incapacity (i.e., the AE results in a substantial disruption 
of the subject’s ability to carry out normal life functions). 
5. It is a congenital anomaly or birth defect (i.e., an adverse outcome in a child or fetus of a 
subject exposed to the molecule or study treatment regimen before conception or during 
pregnancy). 
6. It does not meet any of the above criteria but could jeopardize the subject and might require 
medical or surgical intervention to prevent one of the outcomes listed above. 
8.2.3 
Collection of Adverse Events 
To prompt reporting of AEs, simple unbiased questions should be used as the initial questions at 
all evaluation points during the study. Whether considered related or not, all AEs are to be 
recorded on the eCRF page and monitored until resolution or through the end of the study.  
8.2.4 
Evaluation and Classification of Adverse Events 
Both serious and non-serious AEs should be graded with respect to severity on the following 
3-point scale and reported, in detail, on the appropriate eCRF page: 
Mild:  
Discomfort noticed, but no disruption of normal daily activities; event usually 
requires no intervention. 
Moderate:  Discomfort sufficient to reduce or affect normal daily activities; even may require 
intervention. 
Severe:  
Incapacitating, with inability to perform normal daily activities; event usually 
requires treatment or other intervention. Subject may not be able to continue in the 
study. 


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8.2.5 
Relationship to Study Drug (Intervention) 
The Investigator should evaluate the relationship of each AE to the study treatment regimen, 
using the following criteria: 
Unrelated:  
Another cause of the AE is more plausible; a clinically plausible temporal 
sequence is inconsistent with the onset of the AE and administration of the 
study drug; or a causal relationship is considered biologically impossible. 
Possibly related:  There is a clinically plausible time sequence between onset of the AE and 
administration of the study drug, but the AE could also be attributed to 
concurrent or underlying disease, or the use of other drugs or procedures. 
“Possibly Related” should be used when the study drug is one of several 
biologically plausible AE causes. 
Related:  
The AE is clearly related to administration of the study drug. 
The relationship of the study drug to an AE will be determined by the Investigator or qualified 
delegate. 
All AEs, regardless of severity, will be monitored until resolution or until the Investigator 
assesses them as chronic or stable. All subjects experiencing AEs whether considered associated 
with the use of the study drug or not must be monitored until symptoms subside or until the 
Investigator determines the AE is chronic and stable and does not warrant further follow-up, or 
until death, in which case a full pathologist’s report should be supplied, if possible. 
8.2.6 
Time Period and Frequency for Event Assessment and Follow-up 
Any medical condition that is present at the time that the subject is screened will be considered 
as baseline and not reported as an AE. However, if the study subject’s condition deteriorates at 
any time during the study, it will be recorded as an AE. Changes in the severity of an AE will be 
documented accordingly to allow an assessment of the duration of the event at each level of 
severity to be performed. AEs characterized as intermittent require documentation of onset, 
offset and duration of each episode. 
Study personnel will record all reportable events with start dates occurring any time after 
informed consent is obtained until the EOS Visit. At each study visit, the Investigator will 
inquire about the occurrence of AE/SAEs since the last visit. Events will be followed for 
outcome information until resolution or stabilization. 
8.2.7 
Procedures for Recording and Reporting Adverse Events 
Adverse events suspected or confirmed as meeting the definition of SAE should be reported to 
the Lyndra Medical representative, site CRA and contract research organization (CRO) Safety 
Officer within 24 hours. Contact details for each will be provided in the Safety Reporting Plan. 
8.2.7.1 
Recording Adverse Events 
All findings regarding AEs must be reported on an Adverse Events eCRF and on the SAE 
Reporting Form, if applicable, which is part of the Investigator Site File. All findings in subjects 
experiencing AEs must also be reported in the subject’s source document. 


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To improve the quality and precision of AE data, Investigators should observe the following 
guidelines: laboratory, vital sign, ECG and physical examination abnormalities that are defined 
as clinically significant that meet the definition of an AE, are to be recorded on the AE eCRF 
page. 
8.2.7.2 
Recording and Reporting Serious Adverse Events 
Specific instructions and contact details for collecting and reporting SAEs to the Sponsor will be 
provided to the Investigator and site staff. All SAEs are also to be documented on the Adverse 
Events eCRF. Any medication or other therapeutic measures used to treat the SAE will be 
recorded on the appropriate eCRF(s) in addition to the outcome of the SAE. 
After receipt of the initial report, representatives of the Sponsor or its designee will contact the 
Investigator if it is necessary to obtain further information for assessment of the event. 
All SAEs must be reported by the Investigator in accordance with institutional policy/regulatory 
requirements or within 24 hours of their knowledge of the event. Adequate documentation of this 
notification must be provided to the Sponsor. 
The Sponsor or its designee must also comply with the applicable regulatory requirement(s) 
related to the reporting of suspected unexpected serious adverse drug reactions (also known as 
SUSARs) to the Regulatory Authority and, where applicable, the IRB. If a SUSAR or other 
safety signal relating to use of the study drugs in another research related activity is reported to 
the Sponsor or its designee, the Sponsor will communicate this information to the Investigator 
and the Investigator will be responsible for submitting this information, where applicable, to the 
IRB and other relevant authorities. 
8.2.7.3 
Post-Study Events 
Any suspected SAE that occurs outside of the protocol-specified follow-up period but considered 
to be caused by the study drug must be reported according to the procedures specified above 
(Section 8.2.7) and in the Safety Reporting Plan. These SAEs will be processed by the Sponsor 
or a designee during the study, until the last subject enrolled in the study completes the last study 
visit. After that point, the Lyndra Medical Monitor should be contacted with any suspected or 
possibly drug related SAE experienced by an individual participating in this study.  
8.2.8 
Reporting of Pregnancies 
To ensure subjects’ safety, each pregnancy in a subject which occurs during the study (from 
administration of study drug through the EOS) must be reported to the Sponsor within 24 hours 
of the site learning of its occurrence. If the subject agrees to submit this information, the 
pregnancy must be followed to determine outcome, including spontaneous or voluntary 
termination, details of the birth, and the presence or absence of any birth defects, congenital 
abnormalities, or maternal and/or newborn complications. This follow-up should occur even if 
intended duration of safety follow-up for the study has ended. 
Pregnancy data, inclusive of initial reporting and follow-up information regarding the course of 
the pregnancy and the outcome, must be recorded on a Pregnancy Reporting Form and reported 
to the Sponsor. Instructions and contact details for submitting the Pregnancy Reporting Forms 
will be provided to the Investigator in the Safety Reporting Plan. 


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Any pregnancy outcome meeting the definition of a SAE (Section 8.2.2) must also be reported 
on the SAE Reporting Form. 
8.3 
Gastrointestinal Imaging (X-ray) 
Abdominal X-rays are to be performed in all subjects where specified in the SOE (Section 18.1.1 
and Section 18.1.2). Refer to the Study Imaging Manual for details regarding the procedures for 
abdominal X-ray. 
8.4 
Pharmacokinetics 
At each time point specified in the SOE (Section 18.1.1 and Section 18.1.2), 2 mL of blood for 
PK evaluation will be drawn into a designated and labelled collection tube and processed for 
storage and shipment, as described in the Laboratory Instruction Manual. The windows around 
sample collection at each time point, as designated in the SOE, are to be observed. 
Analysis of risperidone and 9-hydroxyrisperidone will be performed using a validated assay. 
Time and date of the PK assessment will be recorded on the eCRF for each blood sample. 
Refer to the Laboratory Instruction Manual for further details. 
8.5 
Protocol Deviations 
A protocol deviation is any change, divergence, or departure from the study design or procedures 
of a study protocol. In general, subjects associated with protocol deviations may remain in the 
study unless continuation in the study jeopardizes the subject’s health, safety, or rights.  
Investigators will apply due diligence to avoid protocol deviations as no authorized deviations 
are permitted. If the Investigator feels a change to the protocol would improve the conduct of the 
study this must be considered a protocol amendment, and unless such an amendment is agreed 
upon by the Sponsor and approved by the IRB and health authorities it cannot be implemented.  
Pregnancy during the study is a protocol deviation (Section 8.2.8).  
A protocol deviation may be a reason to remove data from an analysis set at the time of analysis. 
Protocol deviations may be defined as exclusionary from the analysis according to protocol 
objectives and endpoints. Prior to the final analysis of the study data, subjects with exclusionary 
protocol deviations will be identified and specified for each analysis set and documented. In 
some cases, exclusion of data may be due to a reason other than a protocol deviation, e.g., early 
termination.  


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9 STATISTICS AND DATA MANAGEMENT 
9.1 
General Procedures 
A statistical analysis plan (SAP), providing details about the specific planned analyses and 
potential hypothesis tests, will be prepared and approved prior to study database lock. Both 
descriptive and inferential statistical methods may be used to fully explore the preliminary data. 
In addition, post hoc analyses may be performed that are not described in the SAP but will be 
described fully in the CSR where presented.  
Summary statistics will be presented by dose group, dose period, and overall. Unless otherwise 
stated, categorical data will be presented using frequency counts and percentages and continuous 
data will be presented by number of subjects reporting (n), means, standard deviations (SD), 
median, minimum, and maximum. Geometric means and coefficient of variations (%CV) will be 
presented in addition for PK data. 
9.2 
Data Management 
Data management will be performed in accordance with clinical standards. 
AEs and medications will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) (v22.0 or a more recent version) and the World Health Organization Drug Dictionary 
Enhanced (WHO DDE) Drug Reference List (2018), respectively. An independent coding 
review will also be performed within the Data Sciences department. 
Clinical chemistry and hematology data (and other safety laboratory data) will be collected by a 
central laboratory and stored electronically in their clinical pathology system. All laboratory data 
that are transferred will be reconciled, queried, and answered by the site laboratory and clinical 
staff before the database can be closed. The database will be locked when all criteria listed in the 
Data Management Plan are met. Further details are addressed in the Data Management Plan. 
SAS 9.4 or higher (SAS Institute Inc., Cary NC USA) will be used for generating individual data 
listings, summary tables and associated figures and for performing statistical analyses. 
9.3 
Sample Size 
This study is exploratory in nature and therefore not designed to test hypotheses.  
The sample size of 32 (24 assigned to LYN-005 and 8 assigned to IR risperidone) is driven by 
clinical rather than statistical considerations for providing data in the evaluation of the endpoints.  
9.4 
Statistical Methods 
9.4.1 
Analysis Sets 
The following analysis sets will be defined: 
Enrolled Set: The Enrolled Set is defined as all subjects who are enrolled in the study and 
admitted to the research unit on Day -2. The Enrolled Set will be the primary set used for 
disposition, demographic and baseline characteristic data reporting. 


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Safety Set: The Safety Set is defined as all enrolled subjects who are randomized to study drug 
(LYN-005 14mg/28mg or IR Risperidone 2mg/4mg) and receive at least one dose of randomized 
study drug. Subjects will be reported according to the treatment received. The Safety Set will be 
the primary safety analysis population. 
PK Set:  The PK Set is defined as all enrolled subjects who receive a dose of LYN 005 and have 
least 1 post-dose quantifiable (or evaluable) PK concentration data.  
Additional analysis sets, if identified, will be specified in the SAP. 
9.4.2 
Statistical Methods 
Safety endpoint data will be descriptive in nature and summarized by dose group, dose period 
and overall. Listings will also be presented. The Safety Set will be the primary population for 
analysis unless otherwise stated. Plasma concentration data for risperidone and 9-
hydroxyrisperidone separately and combined as active moiety will be tabulated and plotted for 
each subject for whom concentrations are quantifiable. PK analysis of the concentration-time 
data obtained will be performed using appropriate non-compartmental analysis to obtain 
estimates of the standard PK parameters. 
The PK of LYN-005 relative to IR at 2 dose levels will be determined.  
There are no pharmacodynamic endpoints in this study. 
9.4.3 
Analysis of Safety - Analysis of Adverse Events 
This analysis applies to all AEs occurring during the study, judged either as related, possibly 
related, or not related to study drug by the Investigator, recorded on the AE eCRF, with a start 
date on or after the date of dose of randomized study drug (i.e., TEAEs). AEs starting prior to 
administration of randomized study drug (non-treatment emergent AEs) will be listed for 
subjects in the Enrolled Set. The original verbatim terms used by Investigators to identify AE in 
the eCRFs will be mapped to preferred terms using the MedDRA dictionary. The AEs will then 
be grouped by MedDRA preferred terms into frequency tables according to system organ class.  
Analyses of TEAEs will be summarized by dose group, dose period, and overall. Events will also 
be included in subject listing by dose group and dose period. 
Further details may be found in the SAP. 
9.4.4 
Analyses of Pharmacokinetics 
PK concentrations will be summarized descriptively for both IR risperidone and LYN-005. PK 
parameters will also be presented by dose group, and plots of concentration-time data and Cmax 
and AUC will be provided. Further analyses to assess PK levels in LYN-005 relative to IR 
risperidone will be explored and detailed in the SAP. 


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9.4.5 
Demographic and Baseline Characteristics 
Descriptive statistics will be summarized for the Enrolled Set. Demographic and baseline 
characteristic data includes age, gender, ethnic group/race, height, weight, BMI at enrollment 
will be calculated. 
9.5 
Assessment of Protocol Deviations 
A protocol deviation is any change, divergence, or departure from the study design or procedures 
of a study protocol. A protocol deviation may be a reason to remove data from an analysis set at 
the time of analysis. Protocol deviations may be defined as exclusionary from the analysis 
according to protocol objectives and endpoints. Prior to the final analysis of the study data, all 
protocol deviations will be reviewed by the Sponsor Medical representatives. Subjects with 
exclusionary protocol deviations will be identified, specified, and documented. Protocol 
deviations will be listed. 
9.6 
Safety Reviews 
There is a planned safety review by the Investigator and Medical Monitor on interim blinded PK 
data after PK data through Day 14 are available from 12 subjects. Blinded safety data will also 
be reviewed at this interim look and will include adverse events, laboratory data, suicidality, and 
illness severity. Additionally, the PI or Sponsor may request an ad hoc review of safety 
information, e.g., serious adverse events, at any time during the study. 
9.7 
Data Entry and Management 
In this study, all requested data will be entered onto eCRFs in a timely manner after each 
assessment by the Investigator and/or the Investigator’s dedicated site staff. Data entered onto 
eCRFs are stored on a secure website. The data collected on this secure website are assimilated 
into an electronic data capture (EDC) system, which is compliant with Title 21 Part 11 policies 
of the Code of Federal Regulations (FDA, 1997) [48]. The data system includes password 
protection and internal quality checks. The EDC system will be designed and validated by the 
Sponsor or delegate prior to activation for data entry by sites. The Investigator or designated 
delegate must review data entered and electronically sign the eCRFs to verify their accuracy. 
Access to the EDC system for data entry or review will require training and distinct individual 
access code assignments to those site staff members who will be entering study data and those 
involved in study oversight who may review study data. Data are collected within the EDC 
system, to which the Sponsor and site monitors have exclusively “read only” access. 
Additional data collection forms (e.g., Pregnancy and SAE Reporting Forms) will be provided to 
the site by the Sponsor or delegate, should a pregnancy or SAE occur. Instructions on how to 
complete and archive these forms will be provided to the Investigator by the Sponsor or delegate 
prior to the start of the study. 


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9.8 
Data Clarification 
As part of the conduct of the study, the Sponsor may have questions about the data entered by 
the site, referred to as queries. The Clinical Research Associates and Data Management are the 
only parties that can generate a query, and they will generate queries on behalf of any other data 
reviewer with “read only” access to the EDC. All corrections and clarifications will be entered 
into the EDC system and will be identified by the person entering the information, the reason for 
the change, as well as the time of the changes made. If changes are made to a previously and 
electronically signed eCRF, the Investigator must confirm and endorse the changes. 
9.9 
Data Protection 
The Sponsor respects the subjects’ rights to privacy and will ensure the confidentiality of their 
medical information in accordance with all applicable laws and regulations. 


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10 ETHICS AND RESPONSIBILITIES 
10.1 Good Clinical Practice 
The study will be conducted in accordance with the protocol, Good Clinical Practices, the 
relevant ICH guidelines, the ethical principles that have their origins in the Declaration of 
Helsinki, and in accordance with the applicable regulatory requirements in the country where this 
study will be executed. As required by the Declaration of Helsinki; the study protocol, 
amendments, and, Informed Consent Form/Subject Information Sheet will be reviewed and 
approved by the study center’s IRB. 
10.2 Sponsor Medical Monitor 
The Sponsor’s Medical Monitor will be available to the Investigator for discussion of any safety 
events or findings. The Investigator and Lyndra Medical Monitor may review AE listings on a 
weekly basis to evaluate any trends until each subject reaches Day 35. Additionally, the Lyndra 
Medical Monitor may be engaged at an ad hoc basis at any time to review SAEs, any events that 
may trigger pausing or halting the study and will review the safety data for the final reporting of 
the study data.  
10.3 Investigator and Institutional Review Board Responsibilities 
The protocol and the proposed ICF must be reviewed and approved by a properly constituted 
IRB before study start. Properly constituted IRB is defined in ICH Guideline for Good Clinical 
Practice [49]. A signed and dated statement that the protocol and informed consent have been 
approved by the IRB must be given to the Sponsor or delegate before study initiation. Prior to 
study start and at any time the protocol is amended during study conduct, the Investigator is 
required to sign a protocol signature page confirming his/her agreement to conduct the study in 
accordance with these documents and all of the instructions and procedures found in this 
protocol and to give access to all relevant data and records to the Sponsor (or representative) 
monitors, auditors, other designated agents of the Sponsor, IRB, and regulatory authorities, as 
required. If an inspection of the clinical site is requested by a regulatory authority, the 
Investigator must inform the Sponsor immediately that this request has been made. 
At the site level, the Investigator must ensure that any person(s) assisting with the study are 
adequately trained and informed about the protocol, the investigational product(s), and their 
study-related duties and functions, including study-related medical decisions and medical care of 
subjects experiencing any AE related to the study. Additional responsibilities include 
maintaining a list of appropriately qualified persons to whom s/he has delegated significant 
study-related duties, and ensuring that s/he has the capability, time and staffing to recruit the 
required number of suitable subjects within the recruitment period and properly conduct and 
complete the study within the agreed study period. When required, and if permission is given by 
the subject, the Investigator will ensure that the subject’s primary healthcare provider is informed 
of the individual’s participation in the study.  


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The Investigator should not implement any deviation from, or changes of the protocol without 
agreement by the Sponsor and prior review and documented approval/favorable opinion from the 
IRB of an amendment, except where necessary to eliminate an immediate hazard(s) to study 
subjects, or when the change(s) involves only logistical or administrative aspects of the study 
(e.g., change in staff, change of telephone number[s]). In addition, the Investigator or delegate 
Investigator, should document and explain any deviation from the approved protocol. As soon as 
possible, the implemented deviation or change, the reasons for it, and, if appropriate, the 
proposed protocol amendment(s) should be submitted to the Sponsor for agreement, thereafter to 
the IRB for review and approval/favorable opinion, and if applicable, to the regulatory 
authority(ies). 
10.4 Subject Information and Informed Consent 
The informed consent and subject information sheets used for this study will meet requirements 
for subject information, as outlined ICH Guideline E6 and the Declaration of Helsinki.  
Prior to the start of the study, the proposed ICF must be jointly agreed upon by the site and 
Sponsor or its delegate prior to submission to the IRB and a copy of the approved version must 
be provided to the Sponsor or delegate after IRB approval. 
Eligible subjects may only be included in the study after providing written informed consent or 
assent. Before the start of the study, the Investigator will have the informed consent and any 
other materials that will be provided to the subjects reviewed and approved by the IRB. This 
review and approval will be documented and stored with other study documents. The 
Investigator or delegate must fully inform the subject of all pertinent aspects of the study. A copy 
of the written informed consent will be given to the subject. The subject be allowed ample time 
to ask about the details of the study and to decide as to whether or not to participate in the study. 
The subject must sign the consent form indicating their agreement to participate in the study 
before any study-related procedures are conducted.  
The informed consent process may be conducted up to 5 weeks prior to enrollment on Day -2.  
Men and women of childbearing potential should be reminded of the requirement to use a highly 
effective method of contraception throughout the duration of the study, which should be recorded 
in the source documentation. Women of childbearing potential should be informed that taking 
the study drug may involve unknown risks to the fetus if pregnancy were to occur during the 
study and agree that to participate in the study, they must adhere to the contraception 
requirements indicated in the protocol for the duration of the study. In case of doubts on the 
ability of a subject to adhere to these requirements, that subject should not be allowed in the 
study. 


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11 RECORDS MANAGEMENT 
11.1 Source Documentation 
Prior to the start of the study, the site staff participating in the study conduct will be instructed on 
what documents will be required for review as source documents. The documents that will serve 
as source documents will be agreed between the Sponsor or its delegate and Investigator or 
delegate and specified in the source document agreement prior to subject enrollment. 
In addition, source documentation must include all of the following: subject identification (on 
each page), eligibility and participation, proper informed consent procedures, dates of visits, 
adherence to protocol procedures, adequate reporting and follow-up of AEs, documentation of 
prior/concomitant medication/drugs, study drug receipt/dispensing/return records, study drug 
administration information, any data collected by a telephone conversation with the subject and 
date of completion and reason. 
The subject must also allow access to his or her own medical records. Each subject must be 
informed of this prior to the start of the study and consent for access to medical records may be 
required in accordance with local regulations. 
All safety data reported by subjects must be written down in source documents prior to entry of 
the data into eCRFs. If there are multiple sources of information (e.g., verbal report of the 
subject, telephone contact details, medical chart) supporting the diagnosis of an AE, these 
sources must be identified in the source documents, discrepancies between sources clarified, the 
ultimate diagnosis must be justified and written in the source documents, and this diagnosis must 
be captured in the AE eCRF. 
11.2 Study Files and Record Retention 
The Investigator must retain all study records required by the Sponsor and by the applicable 
regulations in a secure and safe facility. The Investigator must consult a Sponsor representative 
before disposal of any study records and must notify the Sponsor of any change in the location, 
disposition, or custody of the study files. Essential documents must be retained for 15 years. 
“Essential Documents” are defined as documents that individually and collectively permit 
evaluation of the conduct of a study and the quality of the data produced. These documents 
should be retained for a longer period, however, if required by the applicable national regulatory 
or institutional requirements.  
These principles of record retention will also be applied to the storage of laboratory samples, 
provided that the integrity of the stored sample permits testing. 


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12 AUDITING AND MONITORING 
Study monitoring and auditing will be standardized and performed in accordance with the 
Sponsor’s or delegated CRO standard operating procedures and applicable regulatory 
requirements (e.g., TGA and ICH guidelines). 
Prior to enrollment of the first study healthy volunteer, the Sponsor or delegate will train 
investigators and/or their study staff on the study protocol, all applicable study procedures, 
documentation practices and all electronic systems. Electronic CRFs supplied by the Sponsor or 
delegate must be completed for each enrolled subject and limited data for all screened subjects 
who have swallowing questionnaire and imaging data available. Data and documents for all 
enrolled subjects will be checked by the Sponsor and/or monitor. 
Prior to enrollment of the first study volunteer, the Sponsor or its designee (e.g., a CRO) will 
develop a Clinical Monitoring Plan to specify how remote and/or on-site monitoring, including 
clinical specimen reconciliation, will be performed for the study. Study progress will be 
monitored by the Sponsor or its designee as frequently as necessary to ensure: 
• that the rights and well-being of human subjects are protected, 
• the reported study data are accurate, complete, and verifiable from the source documents, and 
• the conduct of the study is in compliance with the current approved protocol/amendment(s), 
Good Clinical Practice (GCP) and applicable regulatory requirements. 
Contact details for the Sponsor or its designee involved in study monitoring will be provided to 
the Investigator in the Clinical Monitoring Plan. Study data recorded on eCRFs will be verified 
by checking the eCRF entries against source documents to ensure data completeness and 
accuracy as required by study protocol. 
Data verification may also be performed through remote and/or centralized review of data (e.g., 
checking for outliers or other anomalies). Additional documents such as the Investigator Site 
File, pharmacy records, and Informed Consent documentation must also be available for review 
if requested. Arrangements for monitoring visits will be made in advance in accordance with the 
Clinical Monitoring Plan, except in case of emergency. 
The Investigator and/or site staff must make source documents of subjects enrolled in this study 
available for inspection by the Sponsor or its representative at the time of each monitoring visit 
and Sponsor audits, when applicable. These documents must also be available for inspection, 
verification, and copying, as required by regulations, by officials of the regulatory health 
authorities and/or IRBs. The Investigator and study site staff must comply with applicable 
privacy, data protection and medical confidentiality laws for use and disclosure of information 
related to the study and enrolled subjects. 


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13 AMENDMENTS 
Protocol modifications, except those intended to reduce immediate risk to study subjects, may be 
made only by the Sponsor. A protocol change intended to eliminate an apparent immediate 
hazard to subjects may be implemented immediately, provided the IRB is notified within 5 days. 
Any permanent change to the protocol must be handled as a protocol amendment. The written 
amendment must be submitted to the IRB and the Investigator must await approval before 
implementing the changes. The Sponsor will submit protocol amendments to the appropriate 
regulatory authorities for approval. 
If in the judgment of the IRB, the Investigator, and/or the Sponsor, the amendment to the 
protocol substantially changes the study design and/or increases the potential risk to the subject 
and/or has an impact on the subject's involvement as a study subject, the currently approved 
written informed consent form will require similar modification. In such cases, informed consent 
will be renewed for subjects enrolled in the study before continued participation. 
14 STUDY REPORT, PUBLICATIONS, DATA POSTING 
The Sponsor is responsible for preparing and providing the appropriate regulatory authorities 
with clinical study reports according to the applicable regulatory requirements. 
The publication policy of the Sponsor is discussed in the Investigator's Clinical Research 
Agreement. 
The Sponsor assures that the key design elements of this protocol will be posted in compliance 
with current regulations. The Sponsor also assures that key results of this clinical study will be 
posted within the required time frame from the end of study as defined in Section 5.4. 
15 STUDY DISCONTINUATION 
Both the Sponsor and the Investigator reserve the right to terminate the study at the 
Investigator’s site at any time. Should this be necessary, the Sponsor or a specified designee will 
inform the appropriate regulatory authorities of the termination of the study and the reasons for 
its termination, and the Investigator will inform the IRB of the same. In terminating the study, 
the Sponsor and the Investigator will assure that adequate consideration is given to the protection 
of the subjects’ interests. 
16 CONFIDENTIALITY 
All information generated in this study is considered highly confidential and must not be 
disclosed to any person or entity not directly involved with the study unless prior written consent 
is gained from the Sponsor. However, authorized regulatory officials, IRB personnel, the 
Sponsor and its authorized representatives are allowed full access to the records. 
Identification of subjects and CRFs shall be by initials, screening and treatment numbers only. If 
required, the subject's full name may be made known to an authorized regulatory agency or other 
authorized official.  


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16. Ingersoll KS, Cohen J. The impact of medication regimen factors on adherence to chronic 
treatment: a review of literature. Journal of Behavioral Medicine. 2008;31(3):213-24 


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17. Iglay K, Cao X, Mavros P, Joshi K, Yu S, Tunceli K. Systematic Literature Review and 
Meta-analysis of Medication Adherence With Once-weekly Versus Once-daily Therapy. Clinical 
Therapeutics. 2015;37(8):1813-18210 
18. Kishimoto H, Maehara M. Compliance and persistence with daily, weekly, and monthly 
bisphosphonates for osteoporosis in Japan: analysis of data from the CISA. Arch Osteoporos. 
2015;10:231 
19. Baldessarini RJ, Viguera AC. Commentary: Neuroleptic withdrawal in schizophrenic 
patients. Arch Gen Psychiatry. 1995;52(3):189-92 
20. Gilbert PL, Harris MJ, McAdams LA, Jeste DV. Neuroleptic withdrawal in schizophrenic 
patients. A review of the literature. Arch Gen Psychiatry. 1995;52(3):173-88 
21. Leucht S, Tardy M, Komossa K, Heres S, Kissling W, Salanti G, et al. Antipsychotic drugs 
versus placebo for relapse prevention in schizophrenia: a systematic review and meta-analysis. 
The Lancet. 2012;379(9831):2063-71 
22. Moncrieff J. Does antipsychotic withdrawal provoke psychosis? Review of the literature on 
rapid onset psychosis (supersensitivity psychosis) and withdrawal-related relapse. Acta Psychiatr 
Scand. 2006;114(1):3-13 
23. Bhugra D. The global prevalence of schizophrenia. PLoS Med. 2005;2(5):e151; quiz e75 
24. Keating D, McWilliams S, Schneider I, Hynes C, Cousins G, Strawbridge J, et al. 
Pharmacological guidelines for schizophrenia: a systematic review and comparison of 
recommendations for the first episode. BMJ Open. 2017;7(1):e013881 
25. Kane JM. Review of treatments that can ameliorate nonadherence in patients with 
schizophrenia. J Clin Psychiatry. 2006;67 Suppl 5:9-14 
26. Smeraldi E, Cavallaro R, Folnegovic-Smalc V, Bidzan L, Emin Ceylan M, Schreiner A. 
Long-term remission in schizophrenia and schizoaffective disorder: results from the risperidone 
long-acting injectable versus quetiapine relapse prevention trial (ConstaTRE). Ther Adv 
Psychopharmacol. 2013;3(4):191-9 
27. Food and Drug Administration (FDA). Clinical Pharmacology and Biopharmaceutics Review 
for PERSERIS. 2019. Center for Drug Evaluation and Research (CDER): NDA-210655.[cited 10 
Jun 2019]. Available from: 
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210655Orig1s000ClinPharmR.pdf. 
28. Cutler NR. Pharmacokinetic studies of antipsychotics in healthy volunteers versus patients. J 
Clin Psychiatry. 2001;62 Suppl 5:10-3; discussion 23-4 
29. Misdrahi D, Tessier A, Daubigney A, Meissner WG, Schurhoff F, Boyer L, et al. Prevalence 
of and Risk Factors for Extrapyramidal Side Effects of Antipsychotics: Results From the 
National FACE-SZ Cohort. J Clin Psychiatry. 2019;80(1) 
30. Stroup TS, McEvoy JP, Swartz MS, Byerly MJ, Glick ID, Canive JM, et al. The National 
Institute of Mental Health Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) 
project: schizophrenia trial design and protocol development. Schizophr Bull. 2003;29(1):15-31 


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31. Moore TJ, Furberg CD. The Harms of Antipsychotic Drugs: Evidence from Key Studies. 
Drug Saf. 2017;40(1):3-14 
32. Food and Drug Administration (FDA). Clinical Pharmacology and Biopharmaceutics Review 
for Risperdal Consta Long-Acting Injection. 2003. Center for Drug Evaluation and Research 
(CDER): NDA 21-346. [NDA 21-346: Clinical Pharmacology and Biopharmaceutics 
Review(s)/:[cited 09 Mar 2019]. Available from: 
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2003/21346_RisperdalTOC.cfm. 
33. Food and Drug Administration (FDA). Labeling and Package Insert, RISPERDAL. 2019. 
NDAs 020-272, 020-588, 021-444.[cited 21 March 2019]. Available from: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/020272s082,020588s070,021444s05
6lbl.pdf. 
34. Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS) for 
schizophrenia. Schizophr Bull. 1987;13(2):261-76 
35. Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E, et al. The Mini-
International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a 
structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry. 1998;59 
Suppl 20:22-33;quiz 4-57 
36. American Psychiatric A, Task Force for the Handbook of Psychiatric M, Rush AJ. Handbook 
of psychiatric measures. Washington, DC: American Psychiatric Association; 2000. 
37. Food and Drug Administration (FDA). Suicidal Ideation and Behavior: Prospective 
Assessment of Occurrence in Clinical Trials. 2012. Division of Psychiatry Products in the Center 
for Drug Evaluation and Research (CDER): Draft Guidance for Industry. Revision 1/Silver 
Spring, MD:[cited 24 Jun 2019]. Available from: https://www.fda.gov/media/79482/download. 
38. Chouinard G, Margolese HC. Manual for the Extrapyramidal Symptom Rating Scale (ESRS). 
Schizophrenia research. 2005;76(2-3):247-65 
39. Opler MG, Yavorsky C, Daniel DG. Positive and Negative Syndrome Scale (PANSS) 
Training: Challenges, Solutions, and Future Directions. Innov Clin Neurosci. 2017;14(11-12):77-
81 
40. Opler LA, Stanley R. Kay, Lindenmayer JP, Fiszbein A. Structured Clinical Interview – 
Positive and Negative Syndrome Scale (SCI-PANSS). In: Multi-Health Systems IM, editor. 
1992. 
41. Busner J, Targum SD. The Clinical Global Impressions Scale: Applying a Research Tool in 
Clinical Practice. Psychiatry (Edgmont).4(7):28-37 
42. Guy W. ECDEU Assessment Manual for Psychopharmacology. Rockville, MD: U.S. Dept. 
of Health, Education, and Welfare, Public Health Service, Alcohol, Drug Abuse, and Mental 
Health Administration, National Institute of Mental Health, Psychopharmacology Research 
Branch, Division of Extramural Research Programs; 1976. 
43. Pinna F, Deriu L, Diana E, Perra V, Randaccio RP, Sanna L, et al. Clinical Global 
Impression-severity score as a reliable measure for routine evaluation of remission in 
schizophrenia and schizoaffective disorders. Ann Gen Psychiatry. 2015;14:6 


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44. The Columbia Lighthouse Project. Pharmaceutical-Funded Research 2019. [cited 04 May 
2019]. Available from: http://cssrs.columbia.edu/pharmaceutical-funded-research/. 
45. Chouinard G, Ross-Chouinard A, Annable L, Jones B. The extrapyramidal symptom rating 
scale. 1980;7(3) 
46. Chouinard G, Margolese HC. Erratum to “Manual for the Extrapyramidal Symptom Rating 
Scale (ESRS)”. Schizophrenia research. 2006;85(1-3).Erratum in: Chouinard G, Margolese HC. 
Manual for the Extrapyramidal Symptom Rating Scale (ESRS). Schizophr Res. 2005;76(2-
3):247-65. 
47. Marder SR, Davis JM, Chouinard G. The effects of risperidone on the five dimensions of 
schizophrenia derived by factor analysis: combined results of the North American trials. J Clin 
Psychiatry. 1997;58(12):538-46 
48. Food and Drug Administration (FDA). Code of Federal Regulations Title 21, Part 11 Online: 
Medical Devices, Database.2018. 23 Apr 2019. Source: 62 FR 13464, 20 Mar 1997. Available 
from: https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=11. 
49. International Council for Harmonisation of Technical, Requirements for Pharmaceuticals for 
Human Use (ICH). Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice 
E6(R2). 9 November 2016. ICH Harmonised Tripartite Guideline. [E6(R2): Step 4/:[cited 03 
Mar 2019]. Available from: https://www.tga.gov.au/publication/note-guidance-good-clinical-
practice. 
 






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Visit Name 
Screening 
Visit 
Run-In 
(10 days)o 
Admit to 
Unit 
IR RSP 
Prep/ PK 
LYN-005 Dose 1 
LYN-
005 
Dose 2 
DC 
From 
unit 
Out 
Patient 
Visits 
Subject Status 
Outpatient 
Inpatient Stay 1 
Study Day 
- 21 to -14 
-13 to -3 
-2 
-1 
1a 
2 
3 
4 
5 
6 
7 
8 
9 
10-13 
AEs = Adverse Events; CGI-S = Clinical Global Impression – Severity Scale; C-SSRS = Columbia-Suicide Severity Rating Scale; CYP = Cytochrome P450; ESRS = Extrapyramidal Symptom 
Rating Scale; GI = Gastrointestinal; PK = Pharmacokinetics; RSP = Risperidone; PANSS = Positive and Negative Syndrome Scale. 
General Notes: 
a. 
Prior to dosing with LYN-005 Days 1, 8, 15, and 22, vital signs, ECG, PE, safety laboratory tests, AEs, CGI-S, ESRS will be collected. After dosing, safety assessments will be performed, 
including vital signs, directed physical examination, adverse event, and concomitant medication collection. 
b. 
Subjects must receive at least 5 IR risperidone doses during the Run-in period, 3 in the outpatient setting and 2 in the inpatient setting. 
c. 
Consent form is signed prior to performing any study related procedures. 
d. 
General physical examinations will occur at Screening and Days -2; all other exams will be directed physical examinations. 
e. 
Vital signs will be collected prior to (-60 min) and 12 hours (±45 min) after IR risperidone dosing on Days -2 to Day -1 and on Day 1 at prior to dosing and 4, 8, 12, 24 and 36 hours post dose. 
The timing and addition of further assessments will occur at the Investigator’s discretion. 
f. 
Electrocardiograms should be collected 4 hours (±15 mins) after IR dosing on Day -1, prior to and 4 hours (±15 mins) after dosing with LYN-005 and additionally where indicated. 
g. 
Serological laboratory tests are for Hepatitis B, and C and HIV. 
h. 
All safety laboratory assessments include serum chemistry, hematology, and coagulation. Measurement of HbA1c concentration only occurs at Screening. 
i. 
Required in women of childbearing potential only. 
j. 
Schedule for Pharmacokinetic (PK) collection: 
k. 
S1: Date and time of last dose is to be recorded, and PK samples to be collected upon arrival at unit, 12 pm and 6 pm (±30 min) on Day -2, prior to administration of half the regimen of 
daily IR risperidone in the evening (i.e. either 1 or 2 mg). 
l. 
S2: On the morning of Day -1, a dose of IR risperidone (2 or 4 mg based on dose allocation) will be administered to each subject after fasting with PK samples collected prior to and at 15 
min (±5 min), 30 min (±5 min), 45 min (±5 min), 1 h (±5 min), 2 h (±15 min), 4 h (±15 min), 6 h (±15 min), 8 h (±15 min), 12 h (±30 min), 16 h (±30 min), and 24 h (±30 min) after 
dosing. (The 24-hour post-dose sample is equivalent to the LYN-005 pre-dose sample.) 
m. S3: PK samples to be collected just prior to and following LYN-005 administration or 00EL placebo Day 1 at 1 h (±5 min), 2 h (±15 min), 4 h (±15 min), 6 h (±15 min), 8 h (±15 min), 12 
h (±30 min) post dose and every 12 hours (±30) thereafter through Day 7, and again on Day 9 and on the morning of Day 10.  
n. 
S4: On Day 8, a PK sample will be taken prior to the administration of LYN-005 administration or 00EL placebo and at hours 4 and 8 (±15 min). 
o. Assessments during the run-in period (Days -13 to -3) may occur at any timepoint/visit during this period, at Investigator discretion. 
 






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Visit Name 
LYN-005 Dose 3 
Resume 
Prior APD 
 
EOSa 
Subject Status 
Inpatient Stay 2 
Outpatient 
Study Day 
14b 
15 
16 
17 
18 
21 
22 
23 
35 
Window 
- 
- 
- 
- 
+1 
±1 
±1 
±1 
±1 
Study Event 
Section 
 
f. 
Required in women of childbearing potential only. 
g. 
Schedule for Pharmacokinetic (PK) collection: 
h. 
S5: On Day 14, the subject will return to the clinic to prepare for an inpatient stay through Day 16. A PK sample will be collected upon arrival in the inpatient unit on Day 14. On Day 15, PK 
samples will be collected pre-dose and at 1 h (±5 min), 2 h (±15 min), 4 h (±15 min), 6 h (±15 min), 8 h (±15 min), 12 h (±30 mi), and 24 h (±30 min) (i.e., Day 16). Single samples also are to 
be collected on Days 17, 18, 21, and 22; on these study days, the sample is to be collected at the same time of day as the 24-hour post-dose sample on Day 16. 
 


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18.2 PILL-5 Questionnaire 
The italicized text below is the questionnaire, which is to be administered to the individual during 
the Screening process.  
The individual should complete this questionnaire independently and should answer all questions. 
If the subject has not experienced pill swallowing in the past week, they should answer for a 
previous week where they have taken oral medications. After the individual has provided his/her 
answers, the total score is achieved by adding together the numerical value from each question. 
Subjects with a PILL-5 questionnaire score of 5 or greater are to be excluded. 
These are statements that many people have used to describe their problems swallowing pills. 
Please circle the response that indicates how frequently you had the same experience in the past 
week. If you do not have any problem swallowing pills, please circle zero (0) in response to these 
statements. 
Please circle the response that indicates how frequently you experience these symptoms. 
 
 
Never 
Almost 
Never 
Sometimes 
Almost 
Always 
Always 
1. Pills stick in my throat  
0 
1 
2 
3 
4 
2. Pills stick in my chest  
0 
1 
2 
3 
4 
3. I have a fear of swallowing 
pills  
0 
1 
2 
3 
4 
4. My problem swallowing pills 
interferes with my ability to take 
medication  
0 
1 
2 
3 
4 
5. I can't take my pills without 
crushing, coating, or using other 
forms of assistance  
0 
1 
2 
3 
4 


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18.3 Mini International Neuropsychiatric Interview (MINI) version 7.0.2 
 


M.I.N.I.
MINI INTERNATIONAL NEUROPSYCHIATRIC INTERVIEW 
English Version 7.0.2 
For
DSM-5 
© Copyright 1992 2016 Sheehan DV 
All rights reserved.  No part of this document may be reproduced or transmitted in any form, or by any means, electronic or 
mechanical, including photocopying, or by any information storage or retrieval system, without permission in writing from Dr. 
Sheehan.  Individual researchers, clinicians and students working in nonprofit or publicly owned settings (including universities, 
nonprofit hospitals, and government institutions) may make paper copies of a M.I.N.I. instrument for their personal clinical and 
research use, but not for institutional use, or for any financial profit or gain.  Any use involving financial gain requires a license 
agreement from the copyright holder and payment of a per use license fee. 
DISCLAIMER 
Our aim is to assist in the assessment and tracking of patients with greater efficiency and accuracy.  Before action is taken on any 
data collected and processed by this program, it should be reviewed and interpreted by a licensed clinician. 
This program is not designed or intended to be used in the place of a full medical and psychiatric evaluation by a qualified licensed 
physician – psychiatrist.  It is intended only as a tool to facilitate accurate data collection and processing of symptoms elicited by 
trained personnel. It is not a diagnostic test. 
M.I.N.I. 7.0.2 (August 8, 2016) (8/8/16)
Page 1 of 23






M.I.N.I. 7.0.2 (August 8, 2016) (8/8/16)
4
GENERAL INSTRUCTIONS 
The M.I.N.I. was designed as a brief structured interview for the major psychiatric disorders in DSM-5 and ICD-10.  Validation and 
reliability studies have been done comparing the M.I.N.I. to the SCID-P for DSM-III-R and the CIDI (a structured interview developed 
by the World Health Organization).  The results of these studies show that the M.I.N.I. has similar reliability and validity properties, 
but can be administered in a much shorter period of time (mean 18.7 ± 11.6 minutes, median 15 minutes) than the above 
referenced instruments.  Clinicians can use it, after a brief training session.  Lay interviewers require more extensive training. 
INTERVIEW: 
In order to keep the interview as brief as possible, inform the patient that you will conduct a clinical interview that is more 
structured than usual, with very precise questions about psychological problems which require a yes or no answer. 
GENERAL FORMAT: 
The M.I.N.I. is divided into modules identified by letters, each corresponding to a diagnostic category. 
•At the beginning of each diagnostic module (except for psychotic disorders module), screening question(s) corresponding
to the main criteria of the disorder are presented in a gray box.
•At the end of each module, diagnostic box(es) permit the clinician to indicate whether diagnostic criteria are met.
CONVENTIONS: 
Sentences written in « normal font » should be read exactly as written to the patient in order to standardize the assessment 
of diagnostic criteria. 
Sentences written in « CAP TALS » should not be read to the patient.  They are instructions for the interviewer to assist in the 
scoring of the diagnostic algorithms. 
Sentences written in « bold » indicate the time frame being investigated.  The interviewer should read them as often as 
necessary.  Only symptoms occurring during the time frame indicated should be considered in scoring the responses. 
Answers with an arrow above them (➨) indicate that one of the criteria necessary for the diagnosis or diagnoses is not met. 
In this case, the interviewer should go to the end of the module, circle « NO » in all the diagnostic boxes and move to the 
next module. 
When terms are separated by a slash (/) the interviewer should read only those symptoms known to be present in the 
patient (for example, questions J2b or K6b). 
Phrases in (parentheses) are clinical examples of the symptom.  These may be read to the patient to clarify the question. 
RATING INSTRUCTIONS: 
All questions must be rated. The rating is done at the right of each question by circling either YES or NO.  Clinical judgment 
by the rater should be used in coding the responses.  Interviewers need to be sensitive to the diversity of cultural beliefs in 
their administration of questions and rating of responses. The rater should ask for examples when necessary, to ensure 
accurate coding.  The patient should be encouraged to ask for clarification on any question that is not absolutely clear. 
The clinician should be sure that each dimension of the question is taken into account by the patient (for example, time 
frame, frequency, severity, and/or alternatives). 
Symptoms better accounted for by an organic cause or by the use of alcohol or drugs should not be coded positive in the 
M.I.N.I.  The M.I.N.I. has questions that investigate these issues.
For any quest ons, suggest ons, need for a tra n ng sess on or nformat on about updates of the M.I.N.I., p ease contact: 
Dav d V Sheehan, M.D., M.B.A. 
Un vers ty of South F or da Co ege of Med c ne 
te  : +1 813-956-8437 
e-ma  : dsheehan@hea th.usf.edu
For cens ng, perm ss ons, or quest ons, contact: dav dvsheehan@gma .com
Page 4 of 23






M.I.N.I. 7.0.2 (August 8, 2016) (8/8/16)
10 
C. MANIC AND HYPOMANIC EPISODES
(➨MEANS:  GO TO THE DIAGNOSTIC BOXES, CIRCLE NO IN MANIC AND HYPOMANIC DIAGNOSTIC BOXES, AND MOVE TO NEXT MODULE)
Do you have any family history of manic-depressive illness or bipolar disorder,
or any family member who had mood swings treated with a medication like lithium, 
NO 
YES
sodium valproate (Depakote) or lamotrigine (Lamictal)?
TH S QUEST ON S NOT A CR TER ON FOR B POLAR D SORDER, BUT S ASKED TO NCREASE
THE CL N C AN’S V G LANCE ABOUT THE R SK FOR B POLAR D SORDER.
IF YES, PLEASE SPEC FY WHO:________________________________________
C1 
a Have you ever had a period of time when you were feeling 'up' or 'high' or ‘hyper’ 
NO 
YES 
and so active or full of energy or full of yourself that you got into trouble, - or that 
other people thought you were not your usual self?  (Do not consider 
times when you were intoxicated on drugs or alcohol.) 
F PAT ENT S PUZZLED OR UNCLEAR ABOUT WHAT YOU MEAN 
BY 'UP' OR 'H GH' OR ‘HYPER’, CLAR FY AS FOLLOWS:  By 'up' or 'high' or ‘hyper’ 
I mean: having elated mood; increased energy or increased activity; needing less sleep; 
having rapid thoughts; being full of ideas; having an increase in productivity, motivation, 
creativity, or impulsive behavior; phoning or working excessively or spending more money. 
IF NO, CODE NO TO C1b:  IF YES ASK: 
b Are you currently feeling ‘up’ or ‘high’ or ‘hyper’ or full of energy? 
NO 
YES 
C2 
a Have you ever been persistently irritable, for several days, so that you 
NO 
YES 
had arguments or verbal or physical fights, or shouted at people outside 
your family?  Have you or others noticed that you have been more irritable 
or over reacted, compared to other people, even in situations that you felt 
were justified? 
IF NO, CODE NO TO C2b:  IF YES ASK: 
b Are you currently feeling persistently irritable? 
NO 
YES
➨ 
S C1a OR C2a CODED YES? 
NO 
YES 
C3 
F C1b OR C2b = YES: EXPLORE THE CURRENT EP SODE F RST AND THEN THE MOST SYMPTOMAT C PAST EP SODE, OTHERW SE 
F C1b AND C2b = NO: EXPLORE ONLY THE MOST SYMPTOMAT C PAST EP SODE 
WHEN EXPLOR NG THE CURRENT EP SODE, PREFACE EACH QUEST ON AS FOLLOWS: 
Over the past few days including today, when you felt high and full of energy or irritable, did you: 
WHEN EXPLOR NG THE PAST EP SODE, PREFACE EACH QUEST ON AS FOLLOWS: 
Over a period of a few days in the past, when you felt most high and most full of energy or most irritable, did you: 
Current Episode 
Past Episode 
a Feel that you could do things others couldn't do, or that you were an 
NO 
YES 
NO 
YES 
especially important person? IF YES, ASK FOR EXAMPLES. 
THE EXAMPLES ARE CONS STENT W TH A DELUS ONAL DEA. 
Current Ep sode ☐ No ☐ Yes
Past Ep sode 
☐ No ☐ Yes 
b Need less sleep (for example, feel rested after only a few hours sleep)? 
NO 
YES 
NO 
YES 
Page 7 of 23




M.I.N.I. 7.0.2 (August 8, 2016) (8/8/16)
12 
HYPOMANIC EPISODE 
CURRENT ☐ NO
☐YES
PAST 
☐NO
☐YES
☐NOT EXPLORED
IS C3 SUMMARY CODED YES AND ARE C5 AND C6 CODED NO AND C7 CODED YES, 
AND S E THER C4b OR C4C CODED YES? 
AND 
S “RULE OUT ORGAN C CAUSE (O2 SUMMARY)” CODED YES? 
AND 
ARE ALL PSYCHOT C FEATURES N K1 THROUGH K8 CODED NO? 
SPEC FY F THE EP SODE S CURRENT AND / OR PAST. 
F YES TO CURRENT MAN C EP SODE, THEN CODE CURRENT HYPOMAN C EP SODE AS NO. 
F YES TO PAST MAN C EP SODE, THEN CODE PAST HYPOMAN C EP SODE AS NOT EXPLORED. 
ARE C3 SUMMARY AND C4a CODED YES AND S C5 CODED NO? 
SPEC FY F THE EP SODE S CURRENT AND / OR PAST. 
F YES TO CURRENT MAN C EP SODE OR HYPOMAN C EP SODE, 
THEN CODE CURRENT HYPOMAN C SYMPTOMS AS NO. 
F YES TO PAST MAN C EP SODE OR YES TO PAST HYPOMAN C EP SODE, 
THEN CODE PAST HYPOMAN C SYMPTOMS AS NOT EXPLORED. 
HYPOMANIC SYMPTOMS 
CURRENT ☐ NO
☐YES
PAST 
☐NO
☐YES
☐NOT EXPLORED
C8 
a) F MAN C EP SODE S POS T VE FOR E THER CURRENT OR PAST ASK:
Did you have 2 or more of these (manic) episodes lasting 7 days or more (C4c) in your
lifetime (including the current episode if present)?
NO 
YES 
b) F MAN C OR HYPOMAN C EP SODE S POS T VE FOR E THER CURRENT OR PAST ASK:
Did you have 2 or more of these (hypomanic) episodes lasting 4 days or more (C4b)
in your lifetime (including the current episode)?
NO 
YES 
c) F THE PAST “HYPOMAN C SYMPTOMS” CATEGORY S CODED POS T VE ASK:
Did you have these hypomanic symptoms lasting only 1 to 3 days (C4a) 2 or more times
in your lifetime, (including the current episode if present)?
NO 
YES 
Page 9 of 23


M.I.N.I. 7.0.2 (August 8, 2016) (8/8/16)
13 
D. PANIC DISORDER
(➨MEANS: GO TO THE DIAGNOSTIC BOX, CIRCLE NO AND MOVE TO THE NEXT MODULE)
➨ 
D1 
a Have you, on more than one occasion, had spells or attacks when you suddenly 
NO 
YES 
felt anxious, very frightened, uncomfortable or uneasy, even in situations 
where most people would not feel that way? 
➨ 
b Did the spells surge to a peak within 10 minutes of starting? 
NO 
YES
➨ 
D2 
At any time in the past, did any of those spells or attacks come on unexpectedly 
NO 
YES 
or occur in an unpredictable or unprovoked manner? 
D3 
Have you ever had one such attack followed by a month or more of persistent  
NO 
YES 
concern about having another attack, or worries about the consequences of the attack - 
or did you make any significant change in your behavior because of the attacks (e.g., avoiding 
unfamiliar situations, or avoiding leaving your house or shopping alone, or doing things 
to avoid having a panic attack or visiting your doctor or the emergency room more frequently)? 
D4 
During the worst attack that you can remember: 
a Did you have skipping, racing or pounding of your heart? 
NO 
YES 
b Did you have sweating or clammy hands? 
NO 
YES 
c Were you trembling or shaking? 
NO 
YES 
d Did you have shortness of breath or difficulty breathing or a smothering sensation? 
NO 
YES 
e Did you have a choking sensation or a lump in your throat? 
NO 
YES 
f 
Did you have chest pain, pressure or discomfort? 
NO 
YES 
g Did you have nausea, stomach problems or sudden diarrhea? 
NO 
YES 
h Did you feel dizzy, unsteady, lightheaded or feel faint? 
NO 
YES 
i 
Did you have hot flushes or chills? 
NO 
YES 
j 
Did you have tingling or numbness in parts of your body? 
NO 
YES 
k Did things around you feel strange, unreal, detached or unfamiliar, or did 
NO 
YES 
you feel outside of or detached from part or all of your body? 
l
Did you fear that you were losing control or going crazy?
NO 
YES 
m Did you fear that you were dying? 
NO 
YES 
➨
D5 
ARE BOTH D3, AND 4 OR MORE D4 ANSWERS, CODED YES? 
NO 
YES 
PANIC DISORDER 
LIFETIME
D6 
In the past month did you have persistent concern about having another attack, 
NO 
YES 
or worry about the consequences of the attacks, 
PANIC DISORDER 
or did you change your behavior in any way because of the attacks?
CURRENT
Page 10 of 23








M.I.N.I. 7.0.2 (August 8, 2016) (8/8/16)
17 
H. POSTTRAUMATIC STRESS DISORDER
(➨MEANS:  GO TO THE DIAGNOSTIC BOX, CIRCLE NO, AND MOVE TO THE NEXT MODULE)
➨ 
H1 
Have you ever experienced or witnessed or had to deal with an extremely traumatic 
NO 
YES 
event that included actual or threatened death or serious injury or sexual violence 
to you or someone else? 
EXAMPLES OF TRAUMAT C EVENTS NCLUDE: SER OUS ACC DENTS, SEXUAL OR PHYS CAL ASSAULT, 
A TERROR ST ATTACK, BE NG HELD HOSTAGE, K DNAPP NG, F RE, D SCOVER NG A BODY, WAR, 
OR NATURAL D SASTER, W TNESS NG THE V OLENT OR SUDDEN DEATH OF SOMEONE CLOSE TO YOU, 
OR A L FE-THREATEN NG LLNESS. 
➨ 
H2 
Starting after the traumatic event, did you repeatedly re-experience the event 
NO 
YES 
in an unwanted mentally distressing way, (such as in recurrent dreams related to the event, 
intense recollections or memories, or flashbacks or as if the event was recurring) or did you 
have intense physical or psychological reactions when you were reminded about the 
event or exposed to a similar event? 
H3 
In the past month: 
a Did you persistently try to avoid thinking about or remembering distressing details 
NO 
YES 
or feelings related to the event? 
b Did you persistently try to avoid people, conversations, places, situations, 
NO 
YES 
activities or things that bring back distressing recollections of the event? 
➨
ARE 1 OR MORE H3 ANSWERS CODED YES? 
NO 
YES 
H4 
In the past month: 
a Did you have trouble recalling some important part of the trauma? 
NO 
YES 
(but not because of or related to head trauma, alcohol or drugs). 
b Were you constantly and unreasonably negative about yourself or others or the world? 
NO 
YES 
c Did you constantly blame yourself or others in unreasonable ways for the trauma? 
NO 
YES 
d Were your feelings always negative (such as fear, horror, anger, guilt or shame)? 
NO 
YES 
e Have you become much less interested in participating in activities that 
NO 
YES 
were meaningful to you before? 
f 
Did you feel detached or estranged from others? 
NO 
YES 
g Were you unable to experience any good feelings (such as happiness, satisfaction 
NO 
YES 
or loving feelings)?
➨ 
ARE 2 OR MORE H4 ANSWERS CODED YES? 
NO 
YES 
Page 14 of 23














M.I.N.I. 7.0.2 (August 8, 2016) (8/8/16)
34 
d 
S MAN C EP SODE CODED YES (CURRENT OR PAST)? 
AND 
S “RULE OUT ORGAN C CAUSE (O2 SUMMARY)” CODED YES? 
SPECIFY: 
•
F THE B POLAR  D SORDER S CURRENT OR PAST OR BOTH
•
W TH S NGLE MAN C EP SODE: F MAN C EP SODE (CURRENT OR PAST) = YES
AND MAJOR DEPRESS VE EP SODE (CURRENT AND PAST) = NO
•
W TH PSYCHOT C FEATURES, CURRENT: F 1b OR 2a (CURRENT) OR 2b (CURRENT) = YES
W TH PSYCHOT C FEATURES, PAST: F 1a OR 2a (PAST) OR 2b (PAST) = YES
•
F THE MOST RECENT EP SODE S MAN C, DEPRESSED, OR HYPOMAN C (MUTUALLY EXCLUS VE)
•
F THE MOST RECENT MOOD EP SODE S W TH M XED, ANX OUS OR PSYCHOT C FEATURES
HYPO/MAN C W TH M XED FEATURES = HYPO/MAN C + AT LEAST 3 SYMPTOMS FROM A3
DEPRESSED W TH M XED FEATURES = MAJOR DEPRESS VE EP SODE + AT LEAST 3 SYMPTOMS FROM C3
W TH ANX OUS D STRESS = W TH AT LEAST 3 SYMPTOMS FROM N3
BIPOLAR I 
DISORDER 
Current Past 
Bipolar I Disorder
☐ 
☐ 
Single Manic Episode ☐ 
☐ 
With Psychotic Features 
Current
☐ 
Past
☐ 
Most Recent Episode 
Manic
☐ 
Depressed
☐ 
Hypomanic
☐ 
Most Recent Episode 
With mixed features
☐ 
With anxious distress
☐ 
Most Recent Episode 
Mild
☐ 
Moderate
☐ 
Severe
☐ 
e 
S MAJOR DEPRESS VE EP SODE CODED YES (CURRENT OR PAST)? 
AND 
S HYPOMAN C EP SODE CODED YES (CURRENT OR PAST)? 
AND 
S MAN C EP SODE CODED NO (CURRENT AND PAST)? 
AND 
S “RULE OUT ORGAN C CAUSE (O2 SUMMARY)” CODED YES? 
SPECIFY: 
•
F THE B POLAR D SORDER S CURRENT OR PAST OR BOTH
•
F THE MOST RECENT MOOD EP SODE S HYPOMAN C OR DEPRESSED (MUTUALLY EXCLUS VE)
•
F THE MOST RECENT MOOD EP SODE S W TH M XED, ANX OUS OR PSYCHOT C FEATURES
HYPOMAN C W TH M XED FEATURES = HYPOMAN C + AT LEAST 3 SYMPTOMS FROM A3
DEPRESSED W TH M XED FEATURES = MAJOR DEPRESS VE EP SODE + AT LEAST 3 SYMPTOMS FROM C3
W TH ANX OUS D STRESS = W TH AT LEAST 3 SYMPTOMS FROM N3
BIPOLAR II 
DISORDER 
Current Past 
Bipolar II Disorder
☐ 
☐ 
Most Recent Episode 
Hypomanic
☐ 
Depressed
☐ 
Most Recent Episode 
With mixed features
☐ 
With anxious distress
☐ 
Most Recent Episode 
Mild
☐ 
Moderate
☐ 
Severe
☐ 
Page 21 of 23


M.I.N.I. 7.0.2 (August 8, 2016) (8/8/16)
35 
f 
S MAJOR DEPRESS VE EP SODE CODED NO (CURRENT AND PAST)? 
AND 
S MAN C EP SODE CODED NO (CURRENT AND PAST)? 
AND 
S C4b CODED YES FOR THE APPROPR ATE T ME FRAME? 
AND 
S C8b CODED YES? 
___________________________________________________ 
OR 
___________________________________________________ 
S MAN C EP SODE CODED NO (CURRENT AND PAST)? 
AND 
S HYPOMAN C EP SODE CODED NO (CURRENT AND PAST)? 
AND 
S C4a CODED YES FOR THE APPROPR ATE T ME FRAME? 
AND 
S C8c CODED YES? 
SPEC FY F THE OTHER SPEC F ED B POLAR AND RELATED D SORDER S CURRENT OR PAST OR BOTH. 
OTHER SPECIFIED BIPOLAR 
AND RELATED DISORDER 
Current Past 
Other Specified
☐ 
☐ 
Bipolar and Related 
Disorder 
Page 22 of 23


M.I.N.I. 7.0.2 (August 8, 2016) (8/8/16)
38 
REFERENCES 
1. Sheehan DV, Lecrubier Y, Harnett-Sheehan K, Amorim P, Janavs J, Weiller E, Hergueta T, Baker R, Dunbar G: The Mini International
Neuropsychiatric Interview (M.I.N.I.): The Development and Validation of a Structured Diagnostic Psychiatric Interview. J. Clin
Psychiatry, 1998;59(suppl 20): 22-33.
2. Sheehan DV, Lecrubier Y, Harnett-Sheehan K, Janavs J, Weiller E, Bonara LI, Keskiner A, Schinka J, Knapp E, Sheehan MF, Dunbar
GC.  Reliability and Validity of the MINI International Neuropsychiatric Interview (M.I.N.I.): According to the SCID-P.  European
Psychiatry. 1997; 12:232-241.
3. Lecrubier Y, Sheehan D, Weiller E, Amorim P, Bonora I, Sheehan K, Janavs J, Dunbar G.  The MINI International Neuropsychiatric
Interview (M.I.N.I.) A Short Diagnostic Structured Interview: Reliability and Validity According to the CIDI. European Psychiatry.
1997; 12: 224-231.
4. Amorim P, Lecrubier Y, Weiller E, Hergueta T, Sheehan D: DSM-III-R Psychotic Disorders: procedural validity of the Mini
International Neuropsychiatric Interview (M.I.N.I.).  Concordance and causes for discordance with the CIDI.  European Psychiatry.
1998; 13:26-34.
ACKNOWLEDGEMENTS 
The author wishes to acknowledge the valuable contributions made to the earlier versions of the MINI for DSM III-R and DSM IV by: 
1. Yves Lecrubier, my close collaborator (now deceased) on the initial development of the MINI for DSM III-R, the DSM IV and ICD-10.
2. Juris Janavs, Emanuelle Weiller, Christer Allgulander, Kathy Harnett-Sheehan, Roxy Baker, Michael Sheehan, Chris Gray, Thierry
Hergueta, N. Kadri, David Baldwin, Christian Even, Rosario Hidalgo, Marelli Soto-Colon, Ossama Osman.
3. Patricia Amorim for her extensive work on the development of the expanded version of the Psychotic Disorders Module and
algorithms for DSM III-R.  We have evolved her model further in the MINI for Psychotic Disorders 7 and in the MINI Plus 7 for DSM-
5.
4 Executive Scientific committee for the MINI 6.0.0 for DSM-IV: 
Christer Allgulander, Stockholm, Sweden
A. Carlo Altamura, Milano, Italy
Cyril Hoschl, Praha, Czech Republic
George Papadimitriou, Athens, Greece
Hans Ågren, Göteborg, Sweden
Hans-Jürgen Möller, München, Germany
Hans-Ulrich Wittchen, Dresden, Germany
István Bitter, Budapest, Hungary
Jean-Pierre Lépine, Paris, France
Jules Angst, Zurich, Switzerland
Julio Bobes, Oviedo, Spain
Luciano Conti, Pisa, Italy
Marelli Colon-Soto MD, Puerto Rico, United States
Michael Van Ameringen MD, Toronto, Canada
Rosario Hidalgo MD, Tampa, United States
Siegfried Kasper, Vienna, Austria
Thomas Schlaepfer, Bonn, Germany
5. Mapi and the many academic translation teams internationally who collaborated in ensuring that quality translations became
available in over 70 languages or language variants. Mapi (http://www.mapigroup.com) is now the official translation and
linguistic validation service for all variants of the MINI.
6. Individual clinicians and patients who over the years made countless suggestions to help improve the accuracy and clinical value to
the MINI: JM Giddens for her advice on the MINI  7 version of the Suicidality Disorders Module, Dr. Michael Van Ameringen for
assistance with the ADHD module, and Dr Pauline Powers for her advice on the modules on Anorexia Nervosa and Bulimia.
7. Validation studies of the MINI were made possible, in part, by grants from SmithKlineBeecham and the European Commission.
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18.4 Structured Clinical Interview – Positive and Negative Syndrome Scale (SCI-
PANSS) 
 






























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18.5 Clinical Global Impression – Severity Scale (CGI-S) 
 






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18.6 Columbia Suicide Severity Rating Scale (C-SSRS) 
Note that there are two specific scales, e.g., Baseline, Since Last Visit, and differentiated by 
footers.




SUICIDAL BEHAVIOR 
(Check all that apply, so long as these are separate events; must ask about all types) 
Lifetime 
Past 
 
Years 
Actual Attempt: 
 
A potentially self-injurious act committed with at least some wish to die, as a result of act. Behavior was in part thought of as method to kill 
oneself. Intent does not have to be 100%.  If there is any intent/desire to die associated with the act, then it can be considered an actual suicide 
attempt. There does not have to be any injury or harm, just the potential for injury or harm. If person pulls trigger while gun is in 
mouth but gun is broken so no injury results, this is considered an attempt.   
Inferring Intent: Even if an individual denies intent/wish to die, it may be inferred clinically from the behavior or circumstances. For example, a 
highly lethal act that is clearly not an accident so no other intent but suicide can be inferred (e.g., gunshot to head, jumping from window of a 
high floor/story). Also, if someone denies intent to die, but they thought that what they did could be lethal, intent may be inferred.  
Have you made a suicide attempt? 
Have you done anything to harm yourself? 
Have you done anything dangerous where you could have died? 
What did you do? 
Did you______ as a way to end your life?  
Did you want to die (even a little) when you_____?  
Were you trying to end your life when you _____? 
Or Did you think it was possible you could have died from_____? 
Or did you do it purely for other reasons / without ANY intention of killing yourself (like to relieve stress, feel better, 
get sympathy, or get something else to happen)?  (Self-Injurious Behavior without suicidal intent) 
If yes, describe: 
 
Has subject engaged in Non-Suicidal Self-Injurious Behavior? 
Yes   No 
□   □ 
 
Total # of 
Attempts 
______ 
 
 
Yes   No 
□   □ 
Yes  
  
 No 
□   □ 
 
Total # of 
Attempts 
 
 
 
Yes   No 
□   □ 
Interrupted Attempt:  
When the person is interrupted (by an outside circumstance) from starting the potentially self-injurious act (if not for that, actual attempt would 
have occurred). 
Overdose: Person has pills in hand but is stopped from ingesting.  Once they ingest any pills, this becomes an attempt rather than an interrupted 
attempt. Shooting: Person has gun pointed toward self, gun is taken away by someone else, or is somehow prevented from pulling trigger. Once 
they pull the trigger, even if the gun fails to fire, it is an attempt. Jumping: Person is poised to jump, is grabbed and taken down from ledge. 
Hanging: Person has noose around neck but has not yet started to hang - is stopped from doing so. 
Has there been a time when you started to do something to end your life but someone or something stopped you before 
you actually did anything? 
If yes, describe: 
 
Yes 
  
 No 
□   □ 
 
Total # of 
interrupted 
______ 
 
Yes  
  
 No 
□   □ 
 
Total # of 
interrupted 
______ 
 
Aborted Attempt: 
  
When person begins to take steps toward making a suicide attempt, but stops themselves before they actually have engaged in any self-
destructive behavior. Examples are similar to interrupted attempts, except that the individual stops him/herself, instead of being stopped by 
something else. 
Has there been a time when you started to do something to try to end your life but you stopped yourself before you 
actually did anything? 
If yes, describe: 
 
Yes   No 
□   □ 
Total # of 
aborted 
______ 
Yes   No 
□   □ 
Total # of 
aborted 
______ 
Preparatory Acts or Behavior: 
Acts or preparation towards imminently making a suicide attempt. This can include anything beyond a verbalization or thought, such as 
assembling a specific method (e.g., buying pills, purchasing a gun) or preparing for one’s death by suicide (e.g., giving things away, writing a 
suicide note).  
Have you taken any steps towards making a suicide attempt or preparing to kill yourself (such as collecting pills, 
getting a gun, giving valuables away or writing a suicide note)? 
If yes, describe: 
 
 
Yes  
   
 No 
□   □ 
Yes   No 
□   □ 
Suicidal Behavior: 
Suicidal behavior was present during the assessment period? 
Yes   No 
□   □ 
Yes   No 
□   □ 
Answer for Actual Attempts Only
Most Recent 
Attempt 
Date: 
Most Lethal  
    
   
Attempt 
Date: 
Initial/First 
Attempt 
Date: 
Actual Lethality/Medical Damage:  
 
0.
  
No physical damage or very minor physical damage (e.g., surface scratches).
1. Minor physical damage (e.g., lethargic speech; first-degree burns; mild bleeding; sprains).
2.
  
Moderate physical damage; medical attention needed (e.g., conscious but sleepy, somewhat responsive; second-degree 
burns; bleeding of major vessel).
 
3. Moderately severe physical damage; medical hospitalization and likely intensive care required (e.g., comatose with reflexes
intact; third-degree burns less than 20% of body; extensive blood loss but can recover; major fractures).
 
4. Severe physical damage; medical hospitalization with intensive care required (e.g., comatose without reflexes; third-degree 
burns over 20% of body; extensive blood loss with unstable vital signs; major damage to a vital area).
 
5. Death
 
 
Enter Code 
 
______ 
 
 
Enter Code 
 
 
______ 
 
 
Enter Code 
 
 
______ 
 
Potential Lethality: Only Answer if Actual Lethality=0 
Likely lethality of actual attempt if no medical damage (the following examples, while having no actual medical damage, had 
potential for very serious lethality: put gun in mouth and pulled the trigger but gun fails to fire so no medical damage; laying 
on train tracks with oncoming train but pulled away before run over). 
 
0 = Behavior not likely to result in injury 
1 = Behavior likely to result in injury but not likely to cause death 
2 = Behavior likely to result in death despite available medical care 
Enter Code 
______ 
Enter Code 
 
______ 
Enter Code 
 
______ 
 
© 2008 Research Foundation for Mental Hygiene, Inc  
C-SSRS—Baseline/Screening (Version 1/14/09) 
 
                  
  Page 2 of 2  
Page 2 of 2


SUICIDAL IDEATION 
Ask questions 1 and 2.  If both are negative, proceed to “Suicidal Behavior” section. If the answer to question 2 is “yes”, 
ask questions 3, 4 and 5.  If the answer to question 1 and/or 2 is “yes”, complete “Intensity of Ideation” section below. 
 
Since Last 
Visit 
1.
  
Wish to be Dead
  
Subject endorses thoughts about a wish to be dead or not alive anymore, or wish to fall asleep and not wake up. 
Have you wished you were dead or wished you could go to sleep and not wake up?  
If yes, describe: 
 
Yes  
 
    No 
 □  □ 
2.
  
Non-Specific Active Suicidal Thoughts
General, non-specific thoughts of wanting to end one’s life/commit suicide (e.g., “I’ve thought about killing myself”) without thoughts of ways to kill 
oneself/associated methods, intent, or plan during the assessment period.  
Have you actually had any thoughts of killing yourself? 
If yes, describe: 
 Yes   No 
  □  □ 
3. Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act
Subject endorses thoughts of suicide and has thought of at least one method during the assessment period. This is different than a specific plan with time, 
place or method details worked out (e.g., thought of method to kill self but not a specific plan).  Includes person who would say, “I thought about taking an 
overdose but I never made a specific plan as to when, where or how I would actually do it…and I would never go through with it.” 
Have you been thinking about how you might do this? 
If yes, describe: 
 Yes   No 
  □  □ 
4.
  
Active Suicidal Ideation with Some Intent to Act, without Specific Plan
Active suicidal thoughts of killing oneself and subject reports having some intent to act on such thoughts, as opposed to “I have the thoughts but I 
definitely will not do anything about them.” 
Have you had these thoughts and had some intention of acting on them?  
If yes, describe: 
Yes    No 
  □  □ 
5.
  
Active Suicidal Ideation with Specific Plan and Intent
Thoughts of killing oneself with details of plan fully or partially worked out and subject has some intent to carry it out. 
Have you started to work out or worked out the details of how to kill yourself? Do you intend to carry out this plan? 
If yes, describe: 
 
 Yes    No 
  □  □ 
INTENSITY OF IDEATION 
The following features should be rated with respect to the most severe type of ideation (i.e., 1-5 from above, with 1 being the least severe 
and 5 being the most severe).  
Most Severe Ideation:  
 _____ 
 _________________________________________________ 
 Type # (1-5) 
 Description of  Ideation 
Most 
Severe 
Frequency 
How many times have you had these thoughts? 
(1) Less than once a week    (2) Once a week   (3)  2-5 times in week    (4) Daily or almost daily    (5) Many times each day
____ 
Duration 
When you have the thoughts, how long do they last? 
(1) Fleeting - few seconds or minutes
(4) 4-8 hours/most of day 
(2) Less than 1 hour/some of the time 
(5) More than 8 hours/persistent or continuous
(3) 1-4 hours/a lot of time 
____ 
Controllability 
Could/can you stop thinking about killing yourself or wanting to die if you want to? 
(1) Easily able to control thoughts
(4) Can control thoughts with a lot of difficulty
(2) Can control thoughts with little difficulty 
(5) Unable to control thoughts 
(3) Can control thoughts with some difficulty 
(0) Does not attempt to control thoughts 
____ 
Deterrents 
Are there things - anyone or anything (e.g., family, religion, pain of death) - that stopped you from wanting to die or acting on 
thoughts of committing suicide? 
(1) Deterrents definitely stopped you from attempting suicide 
(4) Deterrents most likely did not stop you
(2) Deterrents probably stopped you
(5) Deterrents definitely did not stop you
(3) Uncertain that deterrents stopped you
(0) Does not apply
____ 
Reasons for Ideation 
What sort of reasons did you have for thinking about wanting to die or killing yourself?  Was it to end the pain or stop the way 
you were feeling (in other words you couldn’t go on living with this pain or how you were feeling) or was it to get attention, 
revenge or a reaction from others? Or both? 
(1) Completely to get attention, revenge or a reaction from others
(4) Mostly to end or stop the pain (you couldn’t go on
(2) Mostly to get attention, revenge or a reaction from others
living with the pain or how you were feeling)
(3) Equally to get attention, revenge or a reaction from others
(5) Completely to end or stop the pain (you couldn’t go on 
 and to end/stop the pain
living with the pain or  how you were feeling)
(0)  Does not apply
____ 
© 2008 Research Foundation for Mental Hygiene, Inc  
C-SSRS—Since Last Visit (Version 1/14/09)
  Page 1 of 2  
Page 1 of 2


SUICIDAL BEHAVIOR 
(Check all that apply, so long as these are separate events; must ask about all types) 
Since Last 
Visit 
Actual Attempt: 
A potentially self-injurious act committed with at least some wish to die, as a result of act. Behavior was in part thought of as method to kill oneself. Intent 
does not have to be 100%.  If there is any intent/desire to die associated with the act, then it can be considered an actual suicide attempt. There does not 
have to be any injury or harm, just the potential for injury or harm. If person pulls trigger while gun is in mouth but gun is broken so no injury results, 
this is considered an attempt.   
Inferring Intent: Even if an individual denies intent/wish to die, it may be inferred clinically from the behavior or circumstances. For example, a highly 
lethal act that is clearly not an accident so no other intent but suicide can be inferred (e.g., gunshot to head, jumping from window of a high floor/story). 
Also, if someone denies intent to die, but they thought that what they did could be lethal, intent may be inferred.  
Have you made a suicide attempt? 
Have you done anything to harm yourself? 
Have you done anything dangerous where you could have died? 
What did you do? 
Did you______ as a way to end your life?  
Did you want to die (even a little) when you_____?  
Were you trying to end your life when you _____? 
Or did you think it was possible you could have died from_____? 
Or did you do it purely for other reasons / without ANY intention of killing yourself (like to relieve stress, feel better, get 
sympathy, or get something else to happen)?  (Self-Injurious Behavior without suicidal intent) 
If yes, describe: 
Has subject engaged in Non-Suicidal Self-Injurious Behavior? 
Yes   No 
□   □ 
Total # of 
Attempts 
 
Yes     No 
□   □ 
Interrupted Attempt:  
When the person is interrupted (by an outside circumstance) from starting the potentially self-injurious act (if not for that, actual attempt would have 
occurred). 
Overdose: Person has pills in hand but is stopped from ingesting.  Once they ingest any pills, this becomes an attempt rather than an interrupted attempt. 
Shooting: Person has gun pointed toward self, gun is taken away by someone else, or is somehow prevented from pulling trigger. Once they pull the trigger, 
even if the gun fails to fire, it is an attempt. Jumping: Person is poised to jump, is grabbed and taken down from ledge. Hanging: Person has noose around 
neck but has not yet started to hang - is stopped from doing so. 
Has there been a time when you started to do something to end your life but someone or something stopped you before you 
actually did anything? 
If yes, describe: 
Yes   No 
□   □ 
Total # of 
interrupted 
______ 
Aborted Attempt: 
When person begins to take steps toward making a suicide attempt, but stops themselves before they actually have engaged in any self-destructive behavior. 
Examples are similar to interrupted attempts, except that the individual stops him/herself, instead of being stopped by something else. 
Has there been a time when you started to do something to try to end your life but you stopped yourself before you 
actually did anything? 
If yes, describe: 
Yes 
 No 
□   □ 
Total # of 
aborted 
 
Preparatory Acts or Behavior: 
Acts or preparation towards imminently making a suicide attempt. This can include anything beyond a verbalization or thought, such as assembling a 
specific method (e.g., buying pills, purchasing a gun) or preparing for one’s death by suicide (e.g., giving things away, writing a suicide note).  
Have you taken any steps towards making a suicide attempt or preparing to kill yourself (such as collecting pills, getting a gun, 
giving valuables away or writing a suicide note)? 
If yes, describe: 
Yes   No 
□   □ 
Suicidal Behavior: 
Suicidal behavior was present during the assessment period? 
Yes   No 
□   □ 
Suicide: 
   Yes    No 
□   □ 
Answer for Actual Attempts Only 
Most Lethal 
Attempt 
Date: 
Actual Lethality/Medical Damage: 
0. No physical damage or very minor physical damage (e.g., surface scratches).
1. Minor physical damage (e.g., lethargic speech; first-degree burns; mild bleeding; sprains).
2. Moderate physical damage; medical attention needed (e.g., conscious but sleepy, somewhat responsive; second-degree burns; bleeding of major vessel).
3. Moderately severe physical damage; medical hospitalization and likely intensive care required (e.g., comatose with reflexes intact; third-degree burns
less than 20% of body; extensive blood loss but can recover; major fractures).
4. Severe physical damage; medical hospitalization with intensive care required (e.g., comatose without reflexes; third-degree burns over 20% of body;
extensive blood loss with unstable vital signs; major damage to a vital area).
5. Death 
Enter Code 
______ 
Potential Lethality: Only Answer if Actual Lethality=0 
Likely lethality of actual attempt if no medical damage (the following examples, while having no actual medical damage, had potential for very serious 
lethality: put gun in mouth and pulled the trigger but gun fails to fire so no medical damage; laying on train tracks with oncoming train but pulled away 
before run over). 
0 = Behavior not likely to result in injury 
1 = Behavior likely to result in injury but not likely to cause death 
2 = Behavior likely to result in death despite available medical care 
Enter Code 
______ 
© 2008 Research Foundation for Mental Hygiene, Inc  
C-SSRS—Since Last Visit (Version 1/14/09) 
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18.7 Acid Reflux Severity Scale 
The Acid Reflux Severity Scale (ARSS) [2]  is as follows. Subjects with a history of moderate to 
severe Acid Reflux Disease or a score of ≥ 2 on the ARSS are not eligible for the study: 
None = 0 no symptoms 
Mild = 1 awareness of symptom, but easily tolerated 
Moderate = 2 discomfort sufficient to cause interference with normal activities 
Severe = 3 incapacitating, with inability to perform normal activities. 


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18.8  Extrapyramidal Symptom Rating Scale (ESRS) 


Administration instructions below are excerpted 
from the article by Chouinard et al. 2005 with 
edits from the Erratum, 2006
Instruction 1: Patient is asked to remove his/her
shoes, to remove anything from his/her mouth
(except dentures) and to sit facing the examiner on
a chair with no armrests.
The removal of shoes can be omitted if an
assessment of lower extremity dyskinetic move-
ments is not required. In clinical trials it is
completed unless clinically inappropriate for the
patient (often patients do not feel comfortable
removing their shoes) or it can be delayed until
the testing of postural stability. Removing food and
gum from the mouth is necessary in order to assess
bucco–labial, lingual and jaw movements. The
armless chair is essential for detection of tremors,
decreased spontaneous movements, dyskinesia and
akathisia.
Instruction 2: Complete the questionnaire.
The questionnaire rates subjective DIMD, i.e.,
Parkinsonism, akathisia, dystonia, and dyskinesia,
as reported by the patient and which are experi-
enced at periods other than the time of examina-
tion during the last week. For demented patients
or autistic children, a nurse or key relative may
also provide information in relation to the ques-
tionnaire. The questionnaire permits the evaluator
to spend time with the patient to observe
spontaneous DIMD.
Instruction 3: Observe facial expressiveness,
speech, akathisia, dystonia and dyskinesia while
completing the questionnaire and while completing
items 4, 5, and 6.
Items in the objective examination are assessed
during the course of standard tests of neurological
examination (there is no new procedure to be
learned by the physician when the physician is the
examiner).
Instruction 4: Patient is asked to extend both arms
forward, with palms down and eyes closed.
This
test
of
posture
tremors
along
with
observing the patient’s tremors at rest and the
copying of a spiral with each hand (Instruction
6) is part of an overall assessment of tremors,
which includes rest, posture and action tremors.
Eyes are kept closed so that the patient is unable to
correct if there is a lateralized neurological lesion.
Instruction 5: The patient is asked to carry out
pronation and supination of both hands as fast as
possible and to perform rapid alternate move-
ments of both wrists simultaneously. Repeat as
necessary.
Both tests are useful in the evaluation of tardive
dyskinesia, as well as in the rating of slowness and
difficulty in initiating movement. For bradykinesia,
these two tests were selected because the initiation
of several repetitive movements can be observed
and for one test simultaneous movements of both
wrists permit the detection of impaired ability to
perform simultaneous tests. The inability to stop a
movement should also be observed. For TD, the
Table 1
Summary of the ESRS examination procedure
1. Patient is asked to remove their shoes (omitted if judged clinically inappropriate or when patient hesitates, or delayed after patient has walked
(after # 7). The patient is asked to remove anything from their mouth (except dentures). The patient is asked to sit facing the examiner on a
chair with no armrests.
2. Complete the questionnaire.
3. Observe facial expressiveness, speech and dyskinesia while completing the questionnaire and while completing items 4, 5, and 6 below.
4. Patient is asked to extend both arms forward, with palms down and eyes closed.
5. The patient is asked to carry out pronation and supination of both hands as fast as possible, and to perform rapid alternate movements of both
wrists. Repeat as necessary.
6. While the patient sits facing the examiner on a chair with no armrests about 1 foot (approx. 30 cm) from a table with his upper body turned,
the patient is asked to copy a spiral with each hand and to write the name of his town, province/state and country.
7. Patient is asked to walk a distance of 12 15 feet (4 5 m) away from, and then back towards the examiner. Repeat as necessary.
8. Patient is asked to stand erect with eyes open with feet slightly apart (1 2 cm). The examiner pushes the patient on each shoulder, the back
and pushes the chest or pulls from the back while asking the patient to keep his balance.
9. Carry out the examination of the muscular tonus of the four limbs.
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251
Page 1 of 15


oral–facial region is observed while the patient is
performing pronation–supination and alternate
movement tests; these voluntary movements help
to uncover buccal–labial–masticatory and lower
extremity dyskinesias.
Instruction 6: While the patient sits facing the
examiner on a chair with no armrests about 1 foot
(approx. 30 cm) from a table with his/her upper
body turned, the patient is asked to copy a spiral
with each hand and to write the name of his town,
province/state and country.
This test permits the assessment of action
tremors through graphic oscillation, and dyski-
netic movements may be unmasked or augmented
when the patient completes Instruction 6, for the
test is performed under some emotional tension
and uses other voluntary muscle groups. In this
regard, it is important to encourage the patient to
concentrate on the task requested.
Instruction 7: Patient is asked to walk a distance of
12–15 feet (4–5 m) away from, and then back
towards, the examiner. Repeat as necessary.
This permits the evaluator to rate gait and
posture. Absence of or a decrease in unilateral or
bilateral pendular moments is observed. Abnormal-
ities of posture are also looked for: flexed head, stiff
posture, stooped posture. TD and/or chronic dysto-
nia of upper limbs and trunk are looked for while
the patient is walking.
Instruction 8: Patient is asked to stand erect with
eyes open and feet together or slightly apart (1–2
cm). The examiner pushes the patient gently but
firmly (strongly if necessary) on each shoulder (for
lateropulsion), the back (for anteropulsion), and
pushes the chest or pulls from the back (for
retropulsion) while asking the patient to keep his
balance and resist. Preferably, the patient removes
his/her shoes before the test.
This
test
evaluates
postural
stability.
The
examiner should be ready to catch the patient from
falling especially if the patient has an obvious
impairment of balance at rest before testing. For
patients who are already unstable, the test is
completed gently.
Instruction 9: Carry out the examination of the
muscular tonus of the four limbs.
Both limbs are examined as a pair in order to
observe differences between the left and right
side. Patient is asked to relax. Both arms are
simultaneously rotated to permit examination of
shoulders and, subsequently, elbows and wrists.
Left
and
right
knees
are
then
successively
moved and a comparison between the two sides
made. Examination of hips and ankles does not
provide more sensitivity and can be disturbing
to psychotic patients. As with IPD, proximal
joints are the most affected and rigidity may be
more present in one part and/or one side of the
body.
4. Scoring instructions
4.1. Questionnaire for Parkinsonism, akathisia, dys-
tonia and dyskinesia
For the subjective examination (subscale I of the
ESRS) scoring is on a 4-point scale (0=Absent;
1=Mild, 2=Moderate, 3=Severe). The evaluator
takes into account the verbal report of the patient
on: 1) the frequency and duration of the symptom
during the day; 2) the number of days the symptom
was present during the last week; and, 3) the
subjective evaluation of the intensity of the symptom
by the patient. When rating subjective EPS, severity is
assessed over the last 7 days. One inquires about how
persistent symptoms have been on the most typical
day in the past 7 days.
4.2. Examination: Parkinsonism and akathisia
Both tremors and rigidity (items 1 and 4) are
scored on a 7-point item scale (0=none–6=severe)
for each part of the body, which are scored as separate
items. The ESRS and the Unified Parkinson’s Disease
Rating Scale (UPDRS) (Fahn and Elton, 1987) rate
each part of the body separately for tremors and
rigidity, since, in both drug-induced Parkinsonism and
IPD, the symptoms can be seen initially in one limb
and when it progresses it may involve several limbs,
thus increasing the number of items in each scale, but
permitting the rating of severity in each part of the
body involved.
Ratings for tremors are made taking into account
two axes: the amplitude of the movement and the
number of times with which it is observed during the
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interview. Assessment of tremors includes rest,
posture and action tremors. Ratings of the other items
of Parkinsonism and akathisia are recorded on a 7-
point item scale (0=absent–6=most severe) with
anchor points.
One difficulty in the rating of abnormal move-
ments was to include both the amplitude of the
abnormal movement (the higher the amplitude, the
more severe the disorder) and the frequency that an
abnormal movement is observed (the more frequent,
the greater the severity). Thus, it appeared necessary
to rate hyperkinetic disorders, tremors and dyski-
nesia, on a two-axis dimension to take into account
that a small amplitude tremor seen frequently is as
pathological as a larger amplitude tremor seen less
frequently.
4.3. Examination: dystonia
Both acute and chronic dystonic movements are
scored on a 7-point item scale (0=absent–6=most
severe). Each body part is rated separately including
right upper limb, left upper limb, right lower limb, left
lower limb, head, jaw, tongue, lips, face, trunk and
other (any other area).
4.4. Examination: dyskinesia
Dyskinetic movements at each site (tongue, jaw,
bucco–labial, trunk, upper and lower extremities,
and others {any other area including face}) are
evaluated as individual items. They are rated
similarly to tremors. Involuntary dyskinetic move-
ments are repetitive, although not rhythmic and not
oscillating along an axis, and their amplitude is
usually greater with a low
frequency cycle/s.
Consequently we applied the same logic of a two-
axis scale of amplitude and frequency as in the
rating of tremors.
5. ESRS total and subtotal scores
5.1. ESRS Parkinsonism and akathisia scores in the
era of classical antipsychotics
The score for Parkinsonism (including akathisia),
ranges from 0 to 102 (17 items), and is based on all
items of the Parkinsonism examination (subscale II):
tremor (0–48), gait and posture (0–6), postural
stability (0–6), rigidity (0–24), expressive automatic
movements (0–6), bradykinesia (0–6), akathisia (0–
6). In clinical trials, when establishing presence of
Parkinsonism to initiate an antiParkinsonian medi-
cation, a score of 3 or greater is required on at least
one of the above listed items including the 8 items
of
tremor
or
the
4
items
of
rigidity.
When
establishing the presence versus absence of Parkin-
sonism, a score of 2 on 2 items or a score of 3 or
greater on one item is required to establish the
presence.
Subscores: Two subscores were formed using
the
objective
examination
of
Parkinsonism:
a
hypokinesia
factor,
ranging
from
0
to
42,
calculated as the sum of items: gait and posture
(0–6), rigidity (0–24), expressive automatic move-
ments (0–6), and bradykinesia (0–6); and a hyper-
kinesia factor, ranging from 0 to 54, calculated as
the sum of items: tremor (0–48) and akathisia
(0–6).
5.2. ESRS Parkinsonism and akathisia scores in the
era of atypical antipsychotics
The Parkinsonism score, ranging from 0 to 96
(16 items), and the 2 factors (hypokinesia (0–42)
and hyperkinesia (0–49) used now are similar to
the previous ones (described in Section 5.1) minus
one item: akathisia (0–6). The score for akathisia is
separated from the Parkinsonism score and is based on
the combined score of subjective akathisia (item 6 of
the questionnaire) and objective akathisia (item 7 of
the Parkinsonism/Akathisia objective examination).
When establishing presence versus absence of aka-
thisia, a total score of 3 or greater on the 2 items is
required for presence.
5.3. Dystonia scores
The score for dystonia ranges from 0 to 60 (10
items), and is formed by including both acute and
chronic dystonia, based on the dystonia examination
(Subscale III). When establishing presence versus
absence of dystonia, a score of 3 or greater on at least
one item, or a score of 2 on 2 items is required to
indicate presence of dystonia.
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253
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5.4. Dyskinesia and subtotal scores
Score for TD, ranging from 0 to 42, is based on the
sum of all seven items in the TD objective examina-
tion. When scoring presence versus absence of TD, a
score of 3 or greater on at least one item or a score of
2 on 2 items is required to indicate presence of TD.
For tardive dyskinesia, scores for each item can be
analyzed separately. A buccal–lingual–masticatory
(BLM) subtotal, ranging from 0 to 18, is obtained
from the sum of items 1, 2 and 3, and an extremities
subtotal, ranging from 0 to 12, by adding the score for
items 5 and 6.
5.5. ESRS total and subtotal scores for clinical trials
and inter-rater reliability certification
For clinical trials, a total score for DIMD or EPS is
formed based on all 41 items of the ESRS. It includes
the 7 items of Subscale I (questionnaire), 17 items of
Subscale II (Parkinsonism/Akathisia), 10 items of Part
III (dystonia), and 7 items of Part IV (dyskinesia). For
inter-rater reliability certification, the ESRS 41 item
total score also includes the 4 CGI-S’s and thus
becomes ESRS 45 item total.
5.6. Clinical global impression of severity (CGI-S)
The clinical global impression of severity (CGI-S)
of Parkinsonism, akathisia, dystonia, and tardive
dyskinesia are rated according to results of the
subjective questionnaire, examination subscales, and
the evaluator’s clinical experience by applying an 8
point rating (0: absent; 1: borderline; 2: very mild; 3:
mild; 4: moderate; 5: moderately severe; 6: marked; 7:
severe; 8: extremely severe). The 4 CGI-S’s are
analyzed as separate items.
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Appendix A. ESRS Manual and scoring sheet
Extrapyramidal symptom rating scale (ESRS) (Chouinard) © 1979
In case of doubt score the lesser severity.
I. QUESTIONNAIRE : Parkinsonism, Akathisia, Dystonia and Dyskinesia.  In this questionnaire, take into account the verbal report of the
patient on the following  1) the duration of the symptom during the day; 2) the number of days where the symptom was present during
the last week; and, 3) the evaluation of the intensity of the symptom by the patient.
Enquire into the status of each symptom and rate accordingly 
1. Impression of slowness or weakness,
difficulty in carrying out routine
tasks
2. Difficulty walking or with balance
3. Stiffness, stiff posture
4. Restless, nervous, unable to
keep still
5. Tremors, shaking
6. Oculogyric crisis, abnormal
sustained posture
7. Abnormal involuntary movements
(dyskinesia) of tongue, jaw, lips,
face, extremities or trunk
Absent 
0
0 
0 
0
0 
0
0
Mild 
1 
1 
1 
1 
1 
1 
1
Moderate 
2 
2 
2 
2 
2 
2 
2
Severe 
3 
3 
3 
3 
3 
3 
3
II.
EXAMINATION: PARKINSONISM AND AKATHISIA
Constant or  
almost so  
4 
5 
6
Frequent 
3 
4 
5
None:
Borderline:
Small amplitude:
Moderate amplitude:
Large amplitude:
Right upper limb  
Left upper limb 
Right lower limb 
Left lower limb 
Head 
Tongue
Jaw/Chin 
Lips
1. Tremor
2. Bradykinesia
0:
normal 
1:
global impression of slowness 
in movements 
2:
definite slowness in movements 
3:
very mild difficulty in initiating 
movements 
4:
mild to moderate difficulty in 
initiating movements 
5:
difficulty in starting or stopping 
any movement, or freezing 
on initiating voluntary act  
6:
rare voluntary movement, almost 
completely immobile
3. Gait & posture
0:
normal 
1:
mild decrease of pendular arm  
   movement 
2:
moderate decrease of pendular
   arm movement, normal steps 
3:
no pendular arm movement, head 
flexed, steps more or less normal 
Items based on physical examinations for Parkinsonism.
Occasional
0 
1 
2 
3 
4
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259
Page 9 of 15


4:
stiff posture (neck, back) small step
   (shuffling gait) 
5: 
   more marked, festination or 
   freezing on turning 
6: 
   triple flexion, barely able to walk  
   
4. Postural stability
5. Rigidity
6 .  Expressive automatic
      movements (Facial
      mask / speech)
7 .   Akathisia
normal 
hesitation when pushed but no 
retropulsion
retropulsion but recovers unaided
exaggerated retropulsion without 
falling 
absence of postural response would
fall if not caught by examiner
unstable while standing, even  
without pushing
unable to stand without assistance 
normal muscle tone
very mild, barely perceptible
mild (some resistance to
passive movements)
moderate (definite 
difficulty to move
the limb)
moderately severe (moderate
resistance but still
easy to move limb) 
severe (marked resistance with
definite difficulty to move the limb)
extremely severe (limb nearly
frozen)
 
0: 
1:
2: 
3: 
4:
5:
6:
0: 
1: 
2:
3:
4:
5:
6:
0:
1: 
2:
3:
4:
5:
6:
0:
1:
2:
3:
Right upper limb  
Left upper limb 
Right lower limb 
Left lower limb
Items based on overall observation during examination for Parkinsonism.
normal
very mild decrease in facial
expressiveness
mild decrease in facial 
expressiveness
rare spontaneous smile, decrease
blinking, voice slightly
monotonous
no spontaneous smile, staring gaze,
low monotonous speech, mumbling 
marked facial mask, unable to
frown, slurred speech
extremely severe facial mask with
unintelligible speech
absent
looks restless, nervous, impatient, 
uncomfortable
needs to move at least one
extremity
often needs to move one extremity
or to change position
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4:
moves one extremity almost  
   constantly if sitting, or stamps
   feet while standing
5: 
   unable to sit down for more than a
   short period of time
6: 
   moves or walks constantly
Right upper limb  
Left upper limb 
Right lower limb 
Left lower limb 
Head 
Tongue 
Eyes
Jaw/Chin 
Lips 
Trunk
 
III.
EXAMINATION: DYSTONIA
Based on examination and observation
Acute torsion, and non acute or
chronic or tardive dystonia
0:
1:
2:
3:
4:
5:
6:
absent
very mild
mild
moderate
moderately severe
severe
extremely severe
IV.
EXAMINATION: DYSKINETIC MOVEMENT
0 
1 
0 
1 
0 
1 
Constant or  
almost so  
Frequent** 
1. Lingual movements (slow
lateral or torsion movement
of tongue) 
none:
borderline:
clearly present, within oral
cavity:
with occasional partial
protrusion:
with complete protusion:
2. Jaw movements (lateral
movement, chewing, biting
clenching)
none:
borderline:
clearly present, small
amplitude:
moderate amplitude: 
but without mouth opening:
large amplitude: 
with mouth opening:
3. Bucco-labial movements
(puckering, pouting,
smacking, etc.)
none:
borderline:
clearly present, small
amplitude:
moderate amplitude, forward
movement of lips:
large amplitude; 
marked, noisy smacking of lips:
Based on examination and observation
Occasional*
2 
3 
4 
2 
3 
4 
3 
4 
5 
3 
4 
5 
3 
4 
5 
4 
5 
6 
4 
5 
6 
4 
5 
6
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261
Page 11 of 15
2 
3 
4 


0 
1 
0 
1 
0 
1 
0 
1 
4. Truncal movements 
(involuntary rocking, 
twisting, pelvic gyrations)
none:
borderline:
clearly present, small 
amplitude: 
moderate amplitude:
greater amplitude:
5. Upper extremities
(choreoathetoid movements
only: arms, wrists, hands, 
fingers)
none:
borderline:
clearly present, small
amplitude, movement 
of one limb:
moderate amplitude, movement
of one limb or movement of small
amplitude involving two limbs:
greater amplitude, movement 
involving two limbs:
6. Lower extremities 
(choreoathetoid movements 
only: legs, knees, ankles, toes)
none:
borderline:
clearly present, small
amplitude, movement 
of one limb:
moderate amplitude, movement
of one limb or movement of small
amplitude involving two limbs:
greater amplitude, movement 
involving two limbs:
7. Other involuntary movements
(swallowing, irregular
respiration, frowning, blinking,
grimacing, sighing, etc.) 
none:
borderline:
clearly present, small 
amplitude: 
moderate amplitude:
greater amplitude: 
Specify……………………………..………………………………………………………………………….
2 
3 
4 
2 
3 
4 
2 
3 
4 
3 
4 
5 
3 
4 
5 
3 
4 
5 
3 
4 
5
4 
5 
6 
4 
5 
6 
4 
5 
6 
4 
5 
6
* when activated or rarely spontaneous; 
** frequently spontaneous and present when activated
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262
Page 12 of 15
2 
3 
4 


V.
CLINICAL GLOBAL IMPRESSION OF SEVERITY OF DYSKINESIA
Considering your clinical experience, how severe is the dyskinesia at this time?
0:  absent
1:  borderline
2:  very mild
3:  mild
4:  moderate
5:  moderately sever
6:  marked
7:  severe
8:  extremely severe
VI. CLINICAL GLOBAL IMPRESSION OF SEVERITY OF PARKINSONISM
Considering your clinical experience, how severe is the parkinsonism at this time?
0:  absent
1:  borderline
2:  very mild
3:  mild
4:  moderate
5:  moderately sever
6:  marked
7:  severe
8:  extremely severe
VII. CLINICAL GLOBAL IMPRESSION OF SEVERITY OF DYSTONIA
Considering your clinical experience, how severe is the dystonia at this time?
0:  absent
1:  borderline
2:  very mild
3:  mild
4:  moderate
5:  moderately sever
6:  marked
7:  severe
8:  extremely severe
VIII. CLINICAL GLOBAL IMPRESSION OF SEVERITY OF AKATHISIA
Considering your clinical experience, how severe is the akathisia at this time?
0:  absent
1:  borderline
2:  very mild
3:  mild
4:  moderate
5:  moderately sever
6:  marked
7:  severe
8:  extremely severe
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263
Page 13 of 15


Protocol LYN-005-C-004  
Pharmacokinetic Study of LYN-005 Risperidone Extended Release Capsules 
Page 1 of 140
 
 
Protocol LYN-005-C-004 | Version 1.0 | 11 June 2020 
Lyndra Confidential 
 
Clinical Research Protocol 
DRUG: 
Risperidone 
 
STUDY NUMBER(S): 
LYN-005-C-004 
 
PROTOCOL(S) TITLE: 
A Multiple Dose Study to Assess the Safety, 
Tolerability and Pharmacokinetics of Risperidone 
Extended Release Capsules in Subjects with 
Schizophrenia, Schizoaffective Disorder 
 
IND NUMBER: 
143074 
 
SPONSOR: 
Lyndra® Therapeutics Inc, (US); hereafter referred to 
as Lyndra 
 
ORIGINAL PROTOCOL DATE: 
11 June 2020 
 
VERSION NUMBER: 
1.0 
 
PROTOCOL VERSION DATE: 
11 June 2020 
 
 


Protocol LYN-005-C-004  
Pharmacokinetic Study of LYN-005 Risperidone Extended Release Capsules 
Page 2 of 140
 
 
Protocol LYN-005-C-004 | Version 1.0 | 11 June 2020 
Lyndra Confidential 
 
TABLE OF CONTENTS  
1 
PROTOCOL SUMMARY .....................................................................................................8 
1.1 
Study Synopsis ....................................................................................................................8 
1.2 
Study Schematic ...............................................................................................................18 
1.3 
List of Abbreviations .......................................................................................................19 
2 
INTRODUCTION AND RATIONALE .............................................................................21 
2.1 
Impact of Schizophrenia and Schizoaffective Disorder ...............................................21 
2.2 
Role of Adherence ............................................................................................................21 
2.3 
Therapeutic Approach.....................................................................................................22 
2.4 
Study Rationale ................................................................................................................23 
2.5 
Lyndra Extended Release Capsule .................................................................................23 
2.6 
Active Ingredient – Risperidone .....................................................................................24 
2.7 
Benefits/Risks ...................................................................................................................25 
2.7.1 
Risks Associated with Active Ingredient..................................................................25 
2.7.2 
Risks Associated with Extended Release Capsule...................................................26 
2.7.3 
Risks Associated with Study Related Procedures ...................................................26 
2.7.4 
Benefits/Risks Conclusions ........................................................................................26 
3 
STUDY OBJECTIVES AND ENDPOINTS ......................................................................28 
4 
STUDY PLAN .......................................................................................................................29 
4.1 
Study Design .....................................................................................................................29 
4.1.1 
Screening Period (Day -21 to Day -14): ....................................................................31 
4.1.2 
Pre-study Preparation with IR Risperidone............................................................32 
4.1.3 
IR Risperidone PK Period.........................................................................................32 
4.1.4 
Randomization (Day 1) ..............................................................................................32 
4.1.5 
Double-blind Dosing Period (Days 1 to 21)..............................................................33 
4.1.6 
End of Study Visit (Day 35).......................................................................................34 
4.2 
Blinding Procedures.........................................................................................................34 
4.3 
Justification of Dose Selection .........................................................................................34 
5 
SUBJECT POPULATION ...................................................................................................35 
5.1 
Inclusion Criteria .............................................................................................................35 
5.2 
Exclusion Criteria ............................................................................................................36 
5.3 
Screen Failure...................................................................................................................40 
5.4 
Discharge Instructions at End of Study or Early Termination Visit ..........................40 
5.5 
Study Completion.............................................................................................................40 
6 
STUDY DRUG MANAGEMENT .......................................................................................41 
6.1 
Description of Study Drugs .............................................................................................41 
6.1.1 
LYN-005 ER ...............................................................................................................41 
6.1.2 
IR Risperidone ...........................................................................................................41 
6.2 
Storage ..............................................................................................................................41 


Protocol LYN-005-C-004  
Pharmacokinetic Study of LYN-005 Risperidone Extended Release Capsules 
Page 3 of 140
 
 
Protocol LYN-005-C-004 | Version 1.0 | 11 June 2020 
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6.2.1 
LYN-005 ......................................................................................................................41 
6.2.2 
IR Risperidone ...........................................................................................................41 
6.3 
Dosing and Administration .............................................................................................42 
6.3.1 
Run-in Preparation with IR Risperidone ................................................................42 
6.3.2 
IR Risperidone PK Period.........................................................................................42 
6.3.3 
Blinded Treatment (LYN-005 or Placebo) ..............................................................43 
6.4 
Accountability and Compliance......................................................................................43 
6.5 
Prior and Concomitant Medications and Therapies ....................................................43 
7 
PAUSING AND STOPPING GUIDELINES AND SUBJECT 
DISCONTINUATION/ WITHDRAWAL ..........................................................................45 
7.1 
Pausing and Stopping Guidelines ...................................................................................45 
7.2 
Premature Withdrawal from Study ...............................................................................46 
8 
STUDY ASSESSMENTS AND PROCEDURES ...............................................................47 
8.1 
Screening and Safety Assessments .................................................................................47 
8.1.1 
Informed Consent ......................................................................................................47 
8.1.2 
PILL-5 Questionnaire ................................................................................................47 
8.1.3 
Breath Test for H. Pylori ...........................................................................................47 
8.1.4 
Medical and Psychiatric History ..............................................................................47 
8.1.5 
Psychiatric and Extrapyramidal Symptom Assessment ........................................48 
8.1.6 
Screening Fecal Sample for Occult Blood ...............................................................52 
8.1.7 
General Physical Examination and Directed Physical Examination ....................52 
8.1.8 
Vital Signs ...................................................................................................................53 
8.1.9 
Electrocardiograms....................................................................................................53 
8.1.10 
CYP2D6 Genotyping .................................................................................................53 
8.1.11 
Screening Serology .....................................................................................................53 
8.1.12 
Safety Laboratory Assessments ................................................................................53 
8.1.13 
Prolactin ......................................................................................................................54 
8.1.14 
Pregnancy Testing ......................................................................................................54 
8.1.15 
Compliance Laboratory Assessments ......................................................................54 
8.2 
Adverse Events and Serious Adverse Events ................................................................54 
8.2.1 
Definition of an Adverse Event .................................................................................54 
8.2.2 
Serious Adverse Events .............................................................................................55 
8.2.3 
Collection of Adverse Events ....................................................................................56 
8.2.4 
Evaluation and Classification of Adverse Events ...................................................56 
8.2.5 
Relationship to Study Drug (Intervention) ..............................................................56 
8.2.6 
Time Period and Frequency for Event Assessment and Follow-up ......................56 
8.2.7 
Procedures for Recording and Reporting Adverse Events ....................................57 
8.2.8 
Reporting of Pregnancies ..........................................................................................58 
8.3 
Gastrointestinal Imaging (X-ray) ...................................................................................58 
8.4 
Pharmacokinetics .............................................................................................................58 
8.5 
Protocol Deviations ..........................................................................................................59 
9 
STATISTICS AND DATA MANAGEMENT....................................................................60 
9.1 
General Procedures .........................................................................................................60 


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9.2 
Data Management ............................................................................................................60 
9.3 
Sample Size .......................................................................................................................60 
9.4 
Statistical Methods ...........................................................................................................60 
9.4.1 
Analysis Sets ...............................................................................................................60 
9.4.2 
Statistical Methods .....................................................................................................61 
9.4.3 
Analysis of Safety - Analysis of Adverse Events .....................................................61 
9.4.4 
Analyses of Pharmacokinetics ..................................................................................61 
9.4.5 
Demographic and Baseline Characteristics .............................................................62 
9.5 
Assessment of Protocol Deviations .................................................................................62 
9.6 
Safety Reviews ..................................................................................................................62 
9.7 
Data Entry and Management .........................................................................................62 
9.8 
Data Clarification.............................................................................................................62 
9.9 
Data Protection.................................................................................................................63 
10 ETHICS AND RESPONSIBILITIES .................................................................................64 
10.1 
Good Clinical Practice .....................................................................................................64 
10.2 
Sponsor Medical Monitor................................................................................................64 
10.3 
Investigator and Institutional Review Board Responsibilities.....................................64 
10.4 
Subject Information and Informed Consent .................................................................65 
11 RECORDS MANAGEMENT..............................................................................................66 
11.1 
Source Documentation.....................................................................................................66 
11.2 
Study Files and Record Retention ..................................................................................66 
12 AUDITING AND MONITORING ......................................................................................67 
13 AMENDMENTS ...................................................................................................................68 
14 STUDY REPORT, PUBLICATIONS, DATA POSTING ................................................69 
15 STUDY DISCONTINUATION ...........................................................................................70 
16 CONFIDENTIALITY ..........................................................................................................71 
17 REFERENCES .....................................................................................................................72 
18 APPENDICES .......................................................................................................................76 
18.1 
Schedules of Events ..........................................................................................................76 
18.1.1 
Schedule of Events LYN-005-C-004: Screening and LYN-005 Doses 1 and 
2....................................................................................................................................76 
18.1.2 
Schedule of Events LYN-005-C-004:  LYN-005 Dose 3 through Study 
Completion..................................................................................................................79 
18.2 
PILL-5 Questionnaire ......................................................................................................82 
18.3 
Mini International Neuropsychiatric Interview (MINI) version 7.0.2 ........................83 
18.4 
Structured Clinical Interview – Positive and Negative Syndrome Scale (SCI-
PANSS)............................................................................................................................107 


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18.5 
Clinical Global Impression – Severity Scale (CGI-S) .................................................122 
18.6 
Columbia Suicide Severity Rating Scale (C-SSRS) ....................................................125 
18.7 
Acid Reflux Severity Scale ............................................................................................130 
18.8 
Extrapyramidal Symptom Rating Scale (ESRS) ........................................................131 
 


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LIST OF TABLES 
Table 3-1: 
Study Objectives and Endpoints.........................................................................28 
Table 8-1:  
Psychiatric and EPS Assessment Timing and Durations .................................48 
 


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LIST OF FIGURES 
Figure 2-1: 
LYN-005 Extended Release Capsule and Components ....................................24 
Figure 2-2: 
Overview of Mechanism of Action .....................................................................24 
Figure 6-1: 
IR Risperidone Switch and Dosing Guidelines .................................................42 
 


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1 PROTOCOL SUMMARY 
1.1 
Study Synopsis 
Name of Sponsor 
Lyndra Therapeutics Inc. 
Investigational Product 
LYN-005: Risperidone extended release capsule 
Title:  
A Multiple Dose Study to Assess the Safety, Tolerability and Pharmacokinetics of 
Risperidone Extended Release Capsules in Subjects with Schizophrenia, 
Schizoaffective Disorder 
Phase: 
Phase 2 
Rationale:  
Lyndra is developing an oral, extended release (ER) formulation of risperidone 
(LYN-005) presented in a capsule dosage form with the intent of reducing the 
frequency of dosing orally-administered medications to once weekly or less and 
thereby improving the management of schizophrenia.  
Current treatment options for schizophrenia consist of acute symptom 
management for psychosis as well as efforts to prevent relapse and improve access 
to supportive treatments. Antipsychotic drug therapy is effective in most subjects 
in managing and stabilizing schizophrenia symptoms. Despite the benefits from 
treatment, approximately 75% of diagnosed subjects will experience a relapse, 
generally within two years, and the majority of subjects will experience multiple 
relapses over the course of the illness [1]. A major known risk factor leading to 
relapse is non-adherence with antipsychotic drug therapy [1]. In addition to 
improving adherence, an extended release oral risperidone may offer more 
consistent plasma levels of the pharmacologically active forms of risperidone, 
reducing both inter-subject and intra-subject variability. The target population for 
the Lyndra formulation (LYN-005) is subjects with schizophrenia who require 
maintenance treatment with risperidone and who have demonstrated tolerability of 
immediate release (IR) risperidone. An oral once weekly form of risperidone 
would offer a treatment opportunity facilitating greater clinician and subject 
contact and which could be integrated into a variety of community psychiatric 
treatment models, without need for specialized administration spaces or training. 
Once weekly dosing is anticipated to be highly convenient for both subjects and 
caregivers and provides certainty of dosing with only weekly supervision. Further, 
an oral extended release formulation, if demonstrated to be effective at achieving 
therapeutic systemic drug levels, could offer an opportunity to initiate a long-
acting treatment earlier in the disease course, potentially prior to discharge from 
hospitalization. 
Study LYN-005-C-004 will evaluate the safety, tolerability, and pharmacokinetics 
(PK) of multiple dose administration of the ER formulation at two dose levels of 
LYN-005 relative to IR risperidone.  


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Name of Sponsor 
Lyndra Therapeutics Inc. 
Investigational Product 
LYN-005: Risperidone extended release capsule 
OBJECTIVES 
Primary Objectives:  
• 
To determine the safety and tolerability of risperidone extended release 
capsules (LYN-005) administered as repeat weekly doses compared to IR 
risperidone tablets at 2 dose levels; 
• 
To characterize the PK of risperidone, active metabolite 9-hydroxyrisperidone 
and active moiety (risperidone and 9-hydroxyrisperidone combined) after 
repeat weekly doses of LYN-005 ER capsules relative to IR risperidone 
tablets at 2 dose levels. 
Secondary Objectives: 
• 
To assess the exposure to risperidone, 9-hydroxyrisperidone and active moiety 
during the switch from IR risperidone to LYN-005. 
Exploratory 
Objectives: 
• 
To model the PK of risperidone, 9-hydroxyrisperidone and active moiety 
when administered as a LYN-005 extended-release capsule. 
ENDPOINTS 
Primary Endpoints:  
• 
Incidence of treatment emergent adverse events (TEAEs). 
• 
Risperidone, 9-hydroxyrisperidone, and active moiety PK after oral 
administration of LYN-005 capsules and IR risperidone to include, as possible 
and appropriate, Cmax, Cmin, Tmax, Kel, AUC(0-24), AUC(0-t), AUC(0-168) and 
AUC(0-∞). 
Secondary Endpoints:  
• 
Exposure to risperidone, 9-hydroxyrisperidone and active moiety as assessed 
from Cmax, Tmax, AUC(0-24), AUC(0-t), and AUC(0-∞) after switching from IR 
risperidone to LYN-005. 
Exploratory 
Endpoints: 
• 
PK modelling of risperidone, 9-hydroxyrisperidone, and active moiety 
exposure. 
METHODOLOGY 
Study Duration: 
Up to 55 days 
Study Design: 
LYN-005-C-004 is a blinded, multiple-dose, randomized, parallel group, safety, 
tolerability and PK study of LYN-005 in subjects with a primary diagnosis of 
schizophrenia or schizoaffective disorder in general good health. Eligible subjects 
must be clinically stable and receiving a therapeutic dose of an approved oral 
antipsychotic drug for a minimum of 6 weeks at the time of Screening. Enrolled 
subjects will be evaluated under steady-state conditions on commercially-available 
IR risperidone tablets and then assigned in blinded fashion either to LYN-005 
weekly or continued encapsulated IR risperidone daily for 3 weeks to attain (or 
continue) steady-state exposure.  


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Name of Sponsor 
Lyndra Therapeutics Inc. 
Investigational Product 
LYN-005: Risperidone extended release capsule 
A total of 32 subjects will participate in this study. Subjects will be randomized to 
LYN-005 plus IR risperidone matched placebo OR LYN-005 matched placebo or 
IR risperidone as follows: 
• 
Arm 1:  LYN-005 (14 or 28 mg weekly) plus IR risperidone matched 
placebo (N=24). 
• 
Arm 2:  LYN-005 matched placebo plus IR risperidone (2 or 4 mg/day) 
(N=8). 
Per above, in order to maintain the blind, all subjects will either receive LYN-005 
and IR risperidone-matched placebo or LYN-005 matched placebo and IR 
risperidone, as follows: 
Arm 1: 
• 
LYN-005: Size 00EL capsules containing LYN-005 stellate; the 14mg 
dose of LYN-005 contains 3 active arms containing risperidone, and 
3 inactive arms and he 28 mg dose of LYN-005 contains 6 active arms 
containing risperidone. 
AND 
• 
IR Risperidone Matched Placebo:  Orange capsule-shaped tablets 
containing inactive ingredient. 
Arm 2: 
• 
LYN-005 Matched Placebo:  Size 00EL capsules containing inactive 
ingredient with no stellate. 
AND 
• 
IR Risperidone:  Risperidone 2 mg (orange) capsule-shaped tablets. 
Although treatment assignment is blinded; the dose level is not blinded. The dose 
of LYN-005 (14 or 28 mg)/IR risperidone (2 or 4 mg/day) administered will be 
based on the subject’s current antipsychotic medication dose. Across both arms, a 
minimum of 8 subjects are to be enrolled at each dose level (LYN-005 14 mg/IR 
risperidone 2 mg/day [low dose] and LYN-005 28 mg/IR risperidone 4 mg/day 
[high dose]); thus, if 16 subjects receiving the low dose have been enrolled, all 
remaining subjects must be enrolled at the high dose level and vice versa. 
All administrations of LYN-005/matched placebo will be supervised. Complete 
PK evaluations will be performed after each LYN-005 dose, as designated in the 
Schedules of Events (Section 18.1.1 and Section 18.1.2) and over 24 hours at 
steady-state for IR risperidone at the beginning of the study. 


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Name of Sponsor 
Lyndra Therapeutics Inc. 
Investigational Product 
LYN-005: Risperidone extended release capsule 
LYN-005 will be evaluated in subjects who meet Diagnostic and Statistical 
Manual of Mental Disorders, Fifth Edition (DSM-5) criteria for a primary 
diagnosis of schizophrenia or schizoaffective disorder of at least 2 years, who have 
already been stabilized on an oral antipsychotic medication for a minimum of 
6 weeks at the time of Screening with no psychiatric hospitalizations for relapse in 
the past 6 months. Subjects who are prescribed an antipsychotic agent other than 
risperidone or a dose of risperidone outside the range are also eligible for study 
participation if they are a) able to tolerate risperidone and b) be completed 
switched to 2 or 4 mg daily oral risperidone for a minimum of 2 weeks prior to the 
first dose of LYN-005/placebo on Day 1 (see Section 6.3.1).  
Eligible subjects must be clinically stable (i.e., mildly or moderately ill 
psychiatrically), with a low risk of relapse and otherwise healthy without history 
of significant gastrointestinal (GI) diseases. Guidelines will be in place for the use 
of recommended rescue medications for agitation, anxiety, and insomnia. In the 
event of worsening of schizophrenia symptoms while receiving risperidone during 
the study, another medication can be administered at the discretion of the Principal 
Investigator (PI), with notification of the Study Medical Monitor.  
Risperidone is primarily metabolized by cytochrome P450 (CYP) 2D6 and genetic 
testing for CYP2D6 will be conducted at Screening to determine metabolizer 
status. To reduce the inter-subject variability in exposure, subjects identified as 
poor metabolizers (PMs) will be excluded from the study.  
Study Conduct  
Subjects will be screened for study eligibility between Days -21 and -14. Subjects 
who are initially determined to be eligible, based on Screening assessments, will 
then participate in a 10-day IR risperidone run-in period, during which adherence 
with study treatment will be assessed. Subjects who remain eligible for the study 
will enter the inpatient unit on Day -2. After admittance to the inpatient unit and 
prior to the first LYN-005/matched placebo administration, samples for 
determination of IR risperidone PK will be collected from Days -2 to -1.  
Over the course of the study, subjects are to receive 3 doses of LYN-005/matched 
placebo, per their random assignment, 1 each on Days 1, 8, and 15, all on an 
inpatient basis. All subjects will also receive IR risperidone or matched placebo, 
again per their random assignment, from Days 1 to 21. 
Overall, during study participation, subjects will be housed in the inpatient unit 
twice, from Days -2 to 9 (Inpatient Stay 1) and then again from Days 14 to 16 
(Inpatient Stay 2). Subjects who are admitted to the inpatient unit on Day -2 will 
be considered enrolled. In between each inpatient stay, subjects will have study 
assessments performed on an outpatient basis daily from Days 10, 11, 12, and 13. 
After discharge from Inpatient Stay 2, subjects will again have assessments 
performed on an outpatient basis on Days 17, 18, 21, 22, and 23. An End of Study 
(EOS) visit will be conducted on Day 35.  
During study participation, guidelines will be in place for the use of recommended 
medications for agitation, anxiety, and insomnia. Rescue administration of an 
agent other than risperidone or paliperidone in the event of worsening of 
schizophrenia symptoms during the study can be administered at the discretion of 
the PI, with notification of the Study Medical Monitor. Extrapyramidal symptoms 
will be monitored throughout the study at regular intervals using the 
Extrapyramidal Symptom Rating Scale (ESRS). Severity of schizophrenia 


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Name of Sponsor 
Lyndra Therapeutics Inc. 
Investigational Product 
LYN-005: Risperidone extended release capsule 
symptoms will be monitored throughout the study at regular intervals using the 
CGI-S scale. Concomitant medications, adverse events (AEs), safety laboratory 
tests, and vital signs will be assessed throughout the study, as per the Schedule of 
Events (Section 18.1.1 and Section 18.1.2). 
Schedule of Events 
The Schedules of Events are presented in Section 18.1.1 and Section 18.1.2. 
SUBJECT POPULATION 
Number of Subjects: 
Approximately 32 subjects of whom 24 will receive LYN-005 will be enrolled in 
the study. Subjects who discontinue prematurely may be replaced at the Sponsor’s 
discretion. 
Target Population: 
Male and female subjects between the ages of 18 to 50 years of age, inclusive, 
with schizophrenia or schizoaffective disorder, as defined by DSM-5 criteria. 
Entry Criteria 
Inclusion criteria:  
Eligibility for this study is met if each one of the following inclusion criteria is 
satisfied at Screening (or at baseline when specified): 
1. Male or female aged ≥18 and ≤50 years.  
2. Current diagnosis of schizophrenia or schizoaffective disorder according to 
DSM-5 criteria as confirmed by the MINI 7.0.2. 
3. The following psychiatric criteria are to be used to determine subject 
eligibility: 
• 
Duration of diagnosis of schizophrenia or schizoaffective disorder of 
≥2 years. 
• 
Outpatient; not hospitalized for worsening of schizophrenia within the last 
6 months (partial hospitalization for social management within this time 
period is acceptable). 
• 
Medically stable over the last month and psychiatrically stable without 
significant symptom exacerbation over the last 3 months. 
4. Stabilized on an oral antipsychotic medication (single agent) for a minimum 
of 6 weeks at the time of Screening. 
5. On a stable dosage of all permitted non-antipsychotic medications (except for 
medication to be used on an as-needed basis) for at least 1 month prior to the 
Screening visit and for the duration of the study. 
6. CGI-S score of ≤4 (moderately ill). 
7. PANSS score of ≤80 points. 
8. Body mass index (BMI) of ≥18 kg/m2 and ≤35 kg/m2. 
9. Able to read and understand study procedures and provide written informed 
consent before the initiation of any protocol-specific procedures. 
10. Willing to comply with all protocol-specified procedures and availability for 
the duration of the study. 


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Name of Sponsor 
Lyndra Therapeutics Inc. 
Investigational Product 
LYN-005: Risperidone extended release capsule 
11. Subject has identified a caregiver or personal contact with whom the subject 
communicates with at least once a week. 
Exclusion Criteria:  
Subject will not be considered eligible to participate in this study if any one of the 
following exclusion criteria is satisfied at Screening (or at baseline when 
specified): 
1. Subjects with known clinically significant esophageal or GI disease, including 
but not limited to:   
a. 
Known strictures such as esophageal web, pyloric stenosis, or small 
intestinal stricture, or subjects with high risk of stricture, e.g., Crohn's 
disease. 
b. Diagnosis of a condition known to elevate or lower gastric pH, e.g., 
achlorhydria or hypochlorhydria. 
c. 
Prior small or large bowel obstructions or varices. 
d. Prior abdominal or upper gastrointestinal surgery (prior uncomplicated 
laparoscopic procedures including appendectomy or colectomy). 
e. 
History of dysphagia or aspiration in the last 5 years. 
f. 
History of an esophageal motility disorder or undergoing treatment for a 
gastric motility disorder. 
g. Multiple episodes of abdominal pain within 3 months of Screening. 
h. Subjects who experience moderate or severe dysmenorrhea or 
menorrhagia (with use of pain medication) within 3 months of Screening.  
i. 
History of moderate to severe Acid Reflux Disease or a score of ≥2 on the 
Acid Reflux Severity Scale (ARSS) [2], indicating moderate to severe 
symptoms. The ARSS scale is as follows: 
None = 0 no symptoms 
Mild = 1 awareness of symptom, but easily tolerated 
Moderate = 2 discomfort sufficient to cause interference with normal 
activities 
Severe = 3 incapacitating, with inability to perform normal activities.  
2. Subjects with PILL-5 questionnaire score of 5 or greater. 


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3. Medical history or current diagnoses indicating the presence of any of the 
below conditions: 
a. 
Presence of an uncontrolled, unstable, clinically significant medical 
condition could that could put the subject at risk because of participation 
in the study, interfere with the subject’s ability to participate in the study 
or influence the interpretation of safety or PK evaluations. 
b. History of a major cardiovascular event (myocardial infarction, cardiac 
surgery or revascularization, unstable angina, stroke, or transient 
ischemic attack) or a hospitalization for heart failure with 6 months of 
Screening. 
c. 
Any clinically significant illness, medical or surgical procedure or trauma 
within 4 weeks of Screening. 
d. Known immunocompromised status, including individuals who have 
undergone organ transplantation, on immunosuppression for an immune 
mediated disease, or are positive for human immunodeficiency virus 
(HIV). 
e. 
Subjects with a positive test for active hepatitis B or C at Screening. 
Subjects with successfully treated hepatitis B infection which has been 
resolved for greater than 1 year or successfully treated hepatitis C 
infection will not be excluded. 
f. 
Subjects who have donated more than 250 mL of blood within 30 days of 
Screening. 
g. Subjects who have difficulties with venipuncture/cannulation, including 
difficulty accessing veins for blood sampling and/or history of 
coagulopathy or endocarditis. 
h. Subjects with a current DSM-5 diagnosis of major depressive episode 
panic disorder, agoraphobia, social anxiety disorder, obsessive-
compulsive disorder, post-traumatic stress disorder, generalized anxiety 
disorder on the MINI 7.0.2 or in the judgment of the Investigator. (Note 
that individuals with depression secondary to schizoaffective disorder are 
eligible). 
i. 
Suicidal ideation associated with actual intent and a method or plan in the 
past 6 months, as measured by the C-SSRS (i.e., “Yes” answers on items 
4 or 5) at Screening or having made a suicide attempt within the last 
2 years. 
j. 
Known or suspected (non-febrile) seizure disorder. 
k. History of neuroleptic malignant syndrome. 
l. 
Current or history of clinically significant tardive dyskinesia. 


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Name of Sponsor 
Lyndra Therapeutics Inc. 
Investigational Product 
LYN-005: Risperidone extended release capsule 
m. Known or suspected diagnosis of intellectual disability or organic brain 
disorder or other diagnosis that is primarily responsible for current 
symptoms and functional impairment. 
n. Medically non-adherent in the management of their 
schizophrenia/schizoaffective disorder. 
4. Use of the below medications/treatments in the 2 weeks before enrollment, 
including: 
a. 
Proton pump inhibitors and H2 blockers. 
b. Prokinetic agents. 
c. 
Medications that may interfere with the absorption, metabolism, or 
excretion of risperidone, e.g.,: 
i. 
Drugs metabolized via CYP3A4 pathway, such as macrolide 
antibiotics and azole antifungals)Moderate or strong CYP3A4 p-
glycoprotein (P-gp) enzyme inducers and inhibitors 
(carbamazepine, phenytoin, rifampicin, phenobarbital, 
itraconazole, verapamil). 
ii. 
Moderate or strong CYP2D6 inhibitors (e.g., fluoxetine, 
fluoxetine combinations, paroxetine), or quinidine. 
d. Concomitant medications, natural remedies, supplements or vitamins 
which are associated with changes to gastric motility or pH. Use of 
antacids is permissible, except within 2 hours of dosing with LYN-005.  
e. 
Benzodiazepines; except lorazepam, diazepam and oxazepam, which are 
acceptable if for the treatment of depression, anxiety or insomnia.  
f. 
Use of more than one antidepressant; or if on just one, a change in dose 
within 6 weeks of Screening. 
g. Depot antipsychotic use within 9 months of Screening. 
h. Electroconvulsive therapy within 3 months of Screening. 
5. Subjects with clinically significant abnormal safety (e.g. physical 
examination, vital sign) or safety laboratory assessments, specifically: 
a. 
Presence of a clinically significant abnormal laboratory result on blood 
or urine safety tests at Screening. 
b. Anemia (hemoglobin below lower limit of normal reference range) at 
Screening. 


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Name of Sponsor 
Lyndra Therapeutics Inc. 
Investigational Product 
LYN-005: Risperidone extended release capsule 
c. 
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) 
≥3.0 × upper limit of normal (ULN) and total bilirubin ≥1.5 × ULN.  
d. Moderate or severe renal insufficiency at Screening (glomerular 
filtration rate <60 mL/min, as determined using the Cockcroft-Gault 
formula). 
e. 
Heart rate of <50 beats per minute (bpm) at Screening. 
f. 
Systolic blood pressure ≥150 and/or diastolic blood pressure 
≥100 mmHg at Screening. 
g. HbA1c ≥7.0% at Screening. 
h. Positive fecal occult blood test at Screening in subjects who are >45 
years unless they have had a normal colonoscopy within the past 5 years.  
i. 
Clinically significant prolactin elevation (≥200 ng/mL for females; 
≥100 ng/mL for males). 
6. Subjects with the below specified patterns of substance use at Screening: 
a. 
Fulfillment of the DSM-5 criteria for moderate or severe substance use 
disorder (excluding nicotine and caffeine) within 6 months of Screening. 
b. History of alcohol consumption exceeding moderate use; in males 
exceeding 21 units per week and in females exceeding 14 units per week 
(1 unit = 360 ml beer, 25 mL of 40% spirit or a 125 mL glass of wine) 
over the past month. Subjects are not permitted to consume alcohol 
during the inpatient stay nor 12 hours before any clinic visit while 
outpatient. 
c. 
Positive ethanol breathalyzer. 
d. Positive urine drug screen for substances of abuse other than cannabis.  
e. 
Heavy nicotine use (consumption of >40 cigarettes or >36 mg of nicotine 
from other sources [e.g., vaping products] daily) or daily use of 
smokeless tobacco. 
7. Subjects of reproductive potential who are (hetero) sexually active but 
unwilling to use acceptable means of contraception through the EOS. For 
clarity, subjects who are at least 1 year post-menopausal are not of 
reproductive potential. Acceptable means of contraception include: 
a. 
Subjects who have been surgically sterilized. 


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Name of Sponsor 
Lyndra Therapeutics Inc. 
Investigational Product 
LYN-005: Risperidone extended release capsule 
b. Females of reproductive potential: diaphragm, injectable, oral/patch 
contraceptives for a minimum of 6 weeks, contraceptive sponge, implant, 
or intrauterine device in use prior to enrollment. 
c. 
Males: condom in combination with any of the above means of 
contraception. 
d. All subjects: abstinence may be an acceptable means of contraception as 
long as the individual consents to initiate immediate use of double barrier 
protection for the duration of the study should (hetero) sexual intercourse 
occur. 
8. Subjects who are nursing or who have positive or indeterminate pregnancy 
tests at either Screening (serum test) or enrollment (urine test). 
9. Use of any experimental agent within 1 month or 5 half-lives of Screening, 
whichever is longer. 
10. Subjects who are employees or immediate family members of employees of 
the site, Sponsor or study-related vendors.  
11. History of a serious allergic or hypersensitivity reaction to risperidone or 
LYN-005 excipients (refer to Investigator’s Brochure). 
12. Subjects with history of X-ray, computed tomography (CT) scan or 
angiogram of the abdomen within one year of Screening. 
13. Subjects with CYP2D6 poor or underdetermined metabolizer status based on 
genetic testing. 
STATISTICAL METHODS AND ANALYSIS 
Sample Size 
The sample size of 32 (24 assigned to LYN-005 and 8 assigned to IR risperidone) 
is driven by clinical rather than statistical considerations for providing data in the 
evaluation of the endpoints.  
Pharmacokinetics and 
Pharmacodynamics 
Plasma concentration data for risperidone and 9-hydroxyrisperidone separately 
and combined as active moiety will be tabulated and plotted for each subject for 
whom concentrations are quantifiable. PK analysis of the concentration-time data 
obtained will be performed using appropriate non-compartmental analysis to 
obtain estimates of the standard PK parameters. 
The pharmacokinetics of LYN-005 relative to IR at 2 dose levels will be 
determined.  
There are no pharmacodynamic endpoints in this study. 
Safety 
Safety data will be summarized by dose group, study period and overall. 


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Name of Sponsor 
Lyndra Therapeutics Inc. 
Investigational Product 
LYN-005: Risperidone extended release capsule 
Planned Analyses 
There is a planned safety review by the Investigator and Medical Monitor on 
interim blinded PK through Day 14 from 12 subjects. Blinded safety data will also 
be reviewed at this time and will include adverse events, laboratory data, 
suicidality, and illness severity. Additionally, the PI or Sponsor may request an ad 
hoc review of safety information, e.g., serious adverse events, at any time during 
the study. 
 
1.2 
Study Schematic 
 
Screening 
(Day -21 to -14) 
Pre-Study Preparation 
with IR Risperidone 
(Day -13 to -3) 
IR Risperidone PK 
Period 
(Day -2 to -1) 
Double-blind Dosing 
Period 
(Day 1 to 21) 
End of Study 
(Day 35) 
Clinically stable and 
otherwise healthy patients 
with schizophrenia or 
schizoaffective disorder 
currently who are stable on 
another antipsychotic 
medication 
Open-Label IR risperidone 2 
or 4 mg/day 
(morning or evening) on 
0utpatient basis 
Switch to IR risperidone prior 
to Day -13 per protocol 
algorithm 
Admit to inpatient unit on 
Day -2 
Randomization 
Day 1: 
LYN-005 (14 or 28 mg, per 
Investigator discretion) on 
Days 1, 8, and 17 plus IR 
risperidone matched placebo 
on Days 1-21 (N=24) 
OR 
LYN-005-matched placebo 
on Days 1, 8, and 15 plus IR 
risperidone on Days 1-21 
(N=8) 
Morning IR risperidone on 
Day -1 
Serial PK samples 
Admit to inpatient unit on 
Day -2 
Initial PK sample 
Inpatient Day -2 to 9 (Stay 1) and Day 14 to 16 (Stay 2)  


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1.3 
List of Abbreviations 
Abbreviation 
Term  
AE 
Adverse event 
AECI 
Adverse events of clinical interest 
ALT 
Alanine aminotransferase 
APD 
Antipsychotic drug 
ASA 
Acetylsalicylic acid 
AST 
Aspartate aminotransferase  
AUC0-168 
Area under the concentration versus time curve, time zero to 168 hours 
AUC0-24 
Area under the concentration versus time curve, time zero to 24 hours 
AUC0-∞ 
Area under the concentration versus time curve: time zero to infinity 
AUC0-t 
Area under the concentration versus time curve:  time zero to t (time point to be specified) 
BMI 
Body mass index 
BUN 
Blood urea nitrogen 
CBC 
Complete blood count 
CGI-S 
Clinical Global Impression-Severity 
Cmax 
Maximal observed concentration 
Cmin 
Minimum observed concentration 
CRA 
Clinical Research Associate 
CRO 
Contract Research Organization 
C-SSRS 
Columbia-Suicide Severity Rating Scale  
CV 
Coefficient of variation 
CYP2D6 
Cytochrome P450 2D6 
CYP3A4 
Cytochrome P450 3A4 
DIMD 
Drug-induced movement disorders 
DIP 
Drug-induced parkinsonism 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
ECT 
Electroconvulsive therapy 
EDC 
Electronic Data Capture 
EL 
Extra Long 
EOS 
End of Study 
EPS 
Extrapyramidal symptoms 
ER 
Extended release 
ESRS 
Extrapyramidal Symptom Rating Scale  
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
h 
hour or hours 
HbA1C 
Glycated hemoglobin 
HBsAg 
Hepatitis B Surface Antigen 
HCV Ab 
Hepatitis C Virus Antibody 


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Abbreviation 
Term  
HIV 
Human Immunodeficiency Virus 
ICF 
Informed consent form 
ICH 
International Council for Harmonization 
ID 
Identifier 
ID 
Identifier 
IR 
Immediate release 
IRB 
Institutional Review Board 
Kel 
First order elimination rate constant 
LYN-005 
Lyndra Extended Release Capsule containing risperidone 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHP 
Mental health professional 
MINI 
Mini International Neuropsychiatric Interview version 7.0.2 
PANSS 
Positive and Negative Syndrome Scale 
PI 
Principal Investigator 
PK 
Pharmacokinetic (adj.) or pharmacokinetics (singular noun) 
QTcF 
Corrected QT interval, Fridericia’s correction 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SMC 
Safety Monitoring Committee 
SOE 
Schedule of Events 
SUSAR 
Serious unexpected suspected adverse reaction 
TD 
Tardive dyskinesia 
TEAE 
Treatment-emergent adverse event 
Tmax 
Time to maximum plasma concentration 
ULN 
Upper limit of normal 
US 
United States 
WHO 
World Health Organization 
WHODDE 
World Health Organization Drug Dictionary Enhanced 
 


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2 INTRODUCTION AND RATIONALE 
2.1 
Impact of Schizophrenia and Schizoaffective Disorder 
Schizophrenia and schizoaffective disorder are chronic and debilitating psychiatric illnesses 
which have a massive global burden. There are millions of adults in the United States alone 
living with schizophrenia. The estimated prevalence rate of schizophrenia is around 0.5% in the 
United States (US) [3] and globally rates can be even higher, to above 1% [4]. In 2013, the total 
societal costs of schizophrenia were estimated at $155 billion in the US, with emergency room 
care alone estimated at $2.6 billion reflecting an emphasis on acute care for patients with 
schizophrenia [5]. When non-direct healthcare costs, such as lost productivity of patients and 
their caregivers are taken into account, schizophrenia could total up to 3% of the total healthcare 
budget of western countries [6].  
Many patients suffer from lifelong persistent psychiatric symptoms and cognitive effects, which 
result in reduced quality of life and significant socio-economic impacts [7]. Approximately 75% 
of all patients diagnosed with schizophrenia will experience a relapse, generally within two 
years, and most will experience multiple relapses over the course of the illness [1]. Relapse 
associated with psychotic exacerbation can increase the risk of patients harming themselves or 
others and it can have potential negative effects on their relationships, education and work [8]. 
Furthermore, relapse can lead to long-term disability and an increased burden of health care 
needs in these patients [1, 9]. There are many factors that contribute to the risk of relapse, 
including patient-related, treatment-related, lifestyle, and disease-related factors such as an 
earlier onset of disease, severity at Baseline, lower social functioning, or substance abuse [10]. 
However, it is widely acknowledged that improving access to antipsychotic drug (APD) 
treatment for patients experiencing symptom exacerbation is critical to reduce relapses [1, 11, 
12], and that non-adherence to APD treatment is the most frequently cited risk factor for relapse 
[10].  
2.2 
Role of Adherence 
It is estimated that as many as half of all patients in developed countries are not taking their 
medications properly, and the level may be even higher in developing countries according to the 
World Health Organization (WHO) [13]. The collective impact to patients of not taking or not 
appropriately taking one’s medicines is profound, leading to disease under-treatment, treatment 
resistance, drug toxicity, and other adverse outcomes. 
“Poor adherence to long-term therapies severely compromises the effectiveness of 
treatment making this a critical issue in population health both from the perspective of 
quality of life and of health economics. Interventions aimed at improving adherence 
would provide a significant positive return on investment through primary prevention (of 
risk factors) and secondary prevention of adverse health outcomes.” [13] 
In schizophrenia, non-adherence to APD treatment is common. A study of pharmacy records 
between 1998 and 1999 demonstrated medication possession ratios under 80% in almost 40% of 
patients prescribed APDs, with adherence fluctuating over time such that more than 60% of 


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patients experienced periods of significant nonadherence over a four-year period [14]. Few 
studies have assessed APD non-adherence directly via random blood drug sampling, but one 
such study showed rates of poor adherence were even higher, at 58% [15]. The associated 
treatment costs, disease progression and risk of relapse associated with poor control of disease, 
especially in relation to non-adherence to APD treatment, have been extensively studied.  
Dosing frequency is the primary regimen factor that has been shown to influence adherence, 
where greater dosing frequency is associated with poorer outcomes [16]. A meta-analysis of all 
available randomized controlled studies of oral once daily versus oral once weekly therapy has 
demonstrated a consistent improved adherence by patients to their treatment across studies with 
a odds ratio of weekly therapy versus daily therapy of approximately 1.9 [17]. These data 
indicate that once weekly oral therapy for chronic disease could offer improved adherence as 
compared to daily oral therapy. In some analyses, the magnitude of the benefit of once weekly 
therapy versus once daily therapy expands over time, demonstrating substantial differences in the 
persistence to chronic therapy after two years [18].  
2.3 
Therapeutic Approach 
The treatment of schizophrenia begins with acute symptom management for those who are in 
crisis and is followed by relapse prevention and access to supportive treatments. APD therapy is 
effective in most patients with schizophrenia or schizoaffective disorder in managing and 
stabilizing their symptoms. However, in order to avoid symptom exacerbation, continuous 
treatment with antipsychotic medication is recommended. Longer term (e.g., >6 months) and 
abrupt discontinuation with APD therapy has been associated with an increased risk of relapse 
[19-22].  
The etiology of relapse in patients with schizophrenia or schizoaffective disorder is complex and 
multifaceted. Although some patients may never experience recurrence after their first episode, 
some patients on uninterrupted maintenance therapy may still experience changes in 
symptomology and relapse, which may require a change in treatment. It is essential that any 
intervention including treatment with an antipsychotic medication is appropriate and efficacious 
[23]. Selecting the correct medication for maintenance therapy is critical, and is largely driven by 
individual factors including symptomology (positive and negative symptoms), response to 
treatment, relapse risk profile as determined by a clinician, as well as by patient preference [24]. 
Among the second-generation atypical antipsychotics, risperidone is considered one of, if not the 
most, effective agent and is the most commonly prescribed agent in patients with schizophrenia. 
Numerous studies have shown the effectiveness of this medication, particularly with longer 
acting formulations [8, 25, 26], which is also related to the demonstrated improved medication 
adherence to these formulations of APDs [14]. For example, clinically stable patients with 
schizophrenia or schizoaffective disorder who switched to a long acting depot formulation of 
risperidone (RISPERDAL CONSTA), have demonstrated greater occurrence of sustained 
remission compared to patients on quetiapine [26]. PERSERIS is another once-monthly 
risperidone injection approved for the treatment of schizophrenia [27]. 
Lyndra Therapeutics is developing oral, extended release therapies with the intention to change 
how people take medicines to sustain therapeutic outcomes and benefits. Lyndra is targeting 


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therapeutic areas such as schizophrenia as well as Alzheimer’s disease and transplant rejection 
where the replacement of daily (or more frequently), medication doses with weekly doses would 
improve pharmacologic consistency as well as medication adherence and lead to better health 
outcomes. 
2.4 
Study Rationale 
Discussions with practicing psychiatrists and key opinion leaders around the world have 
identified a high level of interest and desire for a once-weekly oral therapeutic option. Lyndra’s 
objective is to meet this need by offering long-acting oral once-weekly formulations of approved 
antipsychotic drugs to clinicians and patients. The development of an oral, extended release 
formulation of risperidone provides an alternative to bi-weekly intramuscular depot delivery of 
risperidone or daily oral risperidone. Lyndra’s aim is to reduce the frequency of daily dosing to 
once weekly or less to help improve the management of this chronic debilitating illness. The 
target population for the Lyndra formulation (LYN-005) is subjects with schizophrenia already 
stabilized on US Food and Drug Administration-approved APDs and requiring maintenance 
therapy.  
This study will evaluate the safety, tolerability, and pharmacokinetics (PK) of multiple doses of 
LYN-005, a once-weekly, 14 and 28 mg extended release capsule of risperidone in otherwise 
healthy subjects with schizophrenia or schizoaffective disorder. Following a thorough review of 
the literature, it was determined subjects already taking risperidone may be a safer population for 
evaluating LYN-005 than healthy volunteers. Healthy volunteers who are naïve to risperidone or 
other second-generation antipsychotic agents may experience significant adverse events (AEs) 
due to D2 receptor antagonist activity when administered multiple doses at therapeutic levels 
[28]. Early clinical pharmacology studies with risperidone and other atypical antipsychotics 
involving healthy volunteers did observe dose-related AEs and laboratory changes (including 
hyperprolactinemia). The risk of side effects including extrapyramidal symptoms (EPS) such as 
drug-induced parkinsonism (DIP) and tardive dyskinesia (TD), the latter which can be permanent 
in some individuals [29], and possible AEs such as weight gain, anticholinergic effects, 
hyperprolactinemia and sexual impairment [30, 31] were considered unduly high. There is 
precedence for conducting early studies in patients rather than healthy volunteers for extended-
release injectable risperidone products in the US with RISPERDAL CONSTA [32] and 
PERSERIS [27] due to these unnecessary risks to healthy volunteers. 
2.5 
Lyndra Extended Release Capsule 
The LYN-005 (risperidone) extended release capsule is designed with modular components that 
serve specific functions for safe delivery of the formulation to the stomach. The components 
include a controlled release formulation and a capsule in which it is contained until the capsule 
disintegrates and the formulation opens in the stomach. The capsule is coated to promote transit 
through the esophagus without opening and thereafter, opening at gastric pH.
 
 


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Figure 2-2: 
Overview of Mechanism of Action 
 
Colors for illustrative purposes only 
When the coated capsule reaches the gastric environment (Figure 2-2), the exposure to acid 
causes dissolution of the acid-soluble (reverse enteric) coating, allowing the capsule to 
disintegrate and the formulation to unfold. The formulation opens into a configuration designed 
for retention within the stomach for a certain duration (i.e., gastric residence). Thereafter the 
formulation releases drug in a controlled and linear fashion, followed by safe exit and passage 
out of the stomach, transits through the intestinal tract until the formulation is excreted like other 
non-soluble materials. The design features by which the ER capsule achieves these targets are 
described in further detail in the current Lyndra Technology Background document. 
2.6 
Active Ingredient – Risperidone 
Risperidone is an established second-generation antipsychotic belonging to the class of 
antipsychotic agents, the benzisoxazole-derivatives. Risperidone is a selective monoaminergic 
antagonist with a high affinity for serotoninergic 5-HT2 and dopaminergic D2 receptors with no 
affinity for cholinergic receptors. The antipsychotic activity of risperidone is attributed to both 
risperidone and its active metabolite 9-hydroxyrisperidone, considered together as the active 
moiety of risperidone. The mechanism of action in improving positive symptoms of 


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schizophrenia is considered related to central dopamine D2 receptor antagonism. The balance of 
5-HT2 to D2 receptor binding is thought to reduce extrapyramidal side effect liability from 
dopamine antagonism and extend the therapeutic activity to reducing negative and affective 
symptoms of schizophrenia.  
Risperidone is primarily metabolized by cytochrome P450 (CYP) 2D6 to 9-hydroxyrisperidone 
which has two enantiomers with similar pharmacological activity to risperidone. Risperidone and 
9-hydroxyrisperidone together form the pharmacologically active moiety that is similar in 
extensive and poor metabolizers; approximately 24 hours. The elimination half-life of 
risperidone alone is approximately 3 hours in extensive metabolizers and 17-20 hours in poor 
metabolizers. Clinical studies do not suggest that poor and extensive metabolizers have different 
rates of adverse effects, and risperidone is generally well-tolerated [33].  
2.7 
Benefits/Risks 
The LYN-005 extended release (ER) capsule is a novel investigational formulation of 
risperidone designed to provide sustained oral drug delivery over 1 week, further described in the 
Investigator’s Brochure. It is being developed for patients with schizophrenia whose tolerability 
and symptom management have already been established with oral administration of immediate 
release (IR) risperidone. The oral dose range considered effective in maintaining clinical stability 
of psychiatric symptoms from schizophrenia following acute therapy is 2 to 6 mg daily or 14 to 
42 mg per week.  
This study will evaluate 3 oral doses of once-weekly risperidone using the LYN-005 ER capsule 
at doses of 14 and 28 mg, designed to release the equivalent of 2 or 4 mg risperidone daily over 
7 days. The study will be conducted in clinically stable subjects diagnosed with schizophrenia or 
schizoaffective disorder receiving a therapeutic dose of an APD for at least 6 weeks prior to 
Screening. Subjects will be in general good physical health who are mildly or moderately 
psychiatrically ill but clinically stable for at least 3 months prior to Screening and no 
hospitalization due to worsening of schizophrenia within the prior 6 months.  
LYN-005 risperidone extended release capsule development has been informed by the results of 
previous clinical studies. The Sponsor has adopted several risk mitigation measures to protect 
subjects participating in Lyndra studies, described in the following subsections. 
2.7.1 
Risks Associated with Active Ingredient 
Reference is made to the current LYN-005 Investigator’s Brochure, Section 6.3, which includes 
reference material for marketed risperidone products and potential risks associated with 
risperidone.  


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2.7.2 
Risks Associated with Extended Release Capsule 
Although measures have been put into place to minimize risks to participants in the study, the 
following risks may occur with dosing with LYN-005 ER:  
• Capsule dysphagia or aspiration.  
• Esophageal capsular opening with formulation release and/or lodging in the esophagus.  
• Irritation or injury to the mucosa of the gastrointestinal tract associated with passage of a 
partially or fully intact formulation.  
• Rectal bleeding or rectal retention of formulation components that may require digital 
extraction.  
• Obstipation, obstruction or perforation of the gastrointestinal tract.  
• Shortened or prolonged gastrointestinal retention of the formulation, which may warrant 
additional assessments, including imaging.  
• Abdominal events such as abdominal pain, discomfort, bloating, or nausea.  
2.7.3 
Risks Associated with Study Related Procedures 
The following additional risks may occur associated with study-related procedures: 
• X-Rays: detection of underlying anatomic abnormality or previously unknown health 
condition, injury from radiation exposure. 
• Detection of unknown disease necessitating further evaluation and follow-up. 
• Blood sampling: excessive bleeding, bruising, presyncope/syncope, nerve damage, or 
infection at the venipuncture site. 
• Electrocardiogram (ECG) tracing: irritation or rash of the skin due to the use of adhesive 
leads. 
2.7.4 
Benefits/Risks Conclusions 
There are no direct benefits to the subjects in this study. Subjects will be housed in the inpatient 
unit for 2 inpatient periods, totaling 11 days, for the evaluation of LYN-005, allowing daily 
monitoring for AEs or changes in symptomatology that might require treatment. APD dosing 
during the inpatient portion of the study will be supervised by the study site to ensure compliance 
with therapy and control of symptoms. Following discharge from the site, in addition to follow-
up study center visits, subjects will be contacted periodically to help ensure medication 
compliance during the outpatient phase of the study.  
There is risk of AEs from risperidone; to minimize this risk, doses are limited to the low to mid-
range.  


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There is a possibility that the screening and evaluation tools employed in this study may suggest 
or detect a previously unknown health condition that may warrant additional investigation by the 
individual’s general practitioner and in the case of positive human immunodeficiency virus 
(HIV) results, notification of health authorities in accordance with local and national 
requirements. 
Detailed information for potential benefits and risk for LYN-005 (risperidone) extended release 
capsules may be found in the current LYN-005 Investigator’s Brochure, Section 6.3. 


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3 STUDY OBJECTIVES AND ENDPOINTS 
The primary, secondary, and exploratory objectives along with the associated endpoints are 
summarized in Table 3-1. 
Table 3-1: 
Study Objectives and Endpoints 
Objectives 
Endpoints 
Primary: 
 
• 
To determine the safety and tolerability of 
risperidone extended release capsules (LYN-
005) administered as repeat weekly doses 
compared to IR risperidone tablets at 2 dose 
levels; 
• 
Incidence of treatment emergent adverse 
events (TEAEs). 
• 
To characterize the PK of risperidone, active 
metabolite 9-hydroxyrisperidone and active 
moiety (risperidone and 9-hydroxyrisperidone 
combined) after repeat weekly doses of LYN-
005 ER capsules relative to IR risperidone 
tablets at 2 dose levels. 
• 
Risperidone, 9-hydroxyrisperidone, and active 
moiety PK after oral administration of LYN-
005 capsules and IR risperidone to include, as 
possible and appropriate, Cmax, Cmin, Tmax, 
Kel, AUC(0-24), AUC(0-t), AUC(0-168) and 
AUC(0-∞). 
Secondary:  
 
• 
To assess the exposure to risperidone, 
9-hydroxyrisperidone and active moiety 
during the switch from IR risperidone to 
LYN-005. 
• 
Exposure to risperidone, 9-
hydroxyrisperidone and active moiety as 
assessed from Cmax, Tmax, AUC(0-24), AUC(0-t), 
and AUC(0-∞) after switching from IR 
risperidone to LYN-005. 
Exploratory: 
 
• 
To model the PK of risperidone, 9-
hydroxyrisperidone and active moiety when 
administered as a LYN-005 extended-release 
capsule. 
• 
PK modelling of risperidone, 9-
hydroxyrisperidone, and active moiety 
exposure. 
 


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4 STUDY PLAN 
4.1 
Study Design 
LYN-005-C-004 is a blinded, multiple-dose, randomized, parallel group, safety, tolerability and 
PK study of LYN-005 in subjects with a primary diagnosis of schizophrenia or schizoaffective 
disorder in general good health. Eligible subjects must be clinically stable and receiving a 
therapeutic dose of an approved oral antipsychotic drug for a minimum of 6 weeks at the time of 
Screening. Enrolled subjects will be evaluated under steady-state conditions on commercially-
available IR risperidone tablets and then assigned in blinded fashion either to LYN-005 weekly 
or continued encapsulated IR risperidone daily for 3 weeks to attain (or continue) steady-state 
exposure.  
A total of 32 subjects will participate in this study. Subjects will be randomized to LYN-005 plus 
IR risperidone matched placebo OR LYN-005 matched placebo or IR risperidone as follows: 
• Arm 1:  LYN-005 (14 or 28 mg weekly) plus IR risperidone matched placebo (N=24). 
• Arm 2:  LYN-005 matched placebo plus IR risperidone (2 or 4 mg/day) (N=8). 
Per above, in order to maintain the blind, all subjects will either receive LYN-005 and IR 
risperidone-matched placebo or LYN-005-matched placebo and IR risperidone, as follows: 
Arm 1:   
• LYN-005: Size 00EL capsules containing LYN-005 stellate; the 14mg dose of LYN-005 
contains 3 active arms containing risperidone, and 3 inactive arms and he 28 mg dose of 
LYN-005 contains 6 active arms containing risperidone. 
AND 
• IR Risperidone Matched Placebo:  Orange capsule-shaped tablets containing inactive 
ingredient. 
Arm 2: 
• LYN-005 Matched Placebo:  Size 00EL capsules containing inactive ingredient with no 
stellate. 
AND 
• IR Risperidone:  Risperidone 2 mg (orange) capsule-shaped tablets. 
Although treatment assignment is blinded; the dose level is not blinded. The dose of LYN-005 
(14 or 28 mg)/IR risperidone (2 or 4 mg/day) administered will be based on the subject’s current 
antipsychotic medication dose. Across both arms, a minimum of 8 subjects are to be enrolled at 
each dose level (LYN-005 14 mg/IR risperidone 2 mg/day [low dose] and LYN-005 28 mg/IR 
risperidone 4 mg/day [high dose]); thus, if 16 subjects receiving the low dose have been enrolled, 
all remaining subjects must be enrolled at the high dose level and vice versa. 


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All administrations of LYN-005 will be supervised. Complete PK evaluations will be performed 
after each LYN-005 dose, as designated in the Schedules of Events (SOE) (Section 18.1.1 and 
Section 18.1.2) and over 24 hours at steady-state for IR risperidone at the beginning of the study. 
LYN-005 will be evaluated in subjects who meet Diagnostic and Statistical Manual of Mental 
Disorders, Fifth Edition (DSM-5) criteria for a primary diagnosis of schizophrenia or 
schizoaffective disorder of at least 2 years, who have already been stabilized on an oral 
antipsychotic medication for a minimum of 6 weeks at the time of screening with no psychiatric 
hospitalizations for relapse in the past 6 months. Subjects who are prescribed an antipsychotic 
agent other than risperidone or a dose of risperidone outside the range are also eligible for study 
participation if they are a) able to tolerate risperidone and b) be completed switched to 2 or 4 mg 
daily oral risperidone for a minimum of 2 weeks prior to the first dose of LYN-005/placebo on 
Day 1 (see Section 6.3.1).  
Eligible subjects must be clinically stable (i.e., mildly or moderately ill psychiatrically), with a 
low risk of relapse and otherwise healthy without history of significant GI diseases. Guidelines 
will be in place for the use of recommended rescue medications for agitation, anxiety, and 
insomnia. In the event of worsening of schizophrenia symptoms while receiving risperidone 
during the study, another medication can be administered at the discretion of the Principal 
Investigator (PI), with notification of Lyndra’s Medical Monitor.  
Subjects will be screened for study eligibility between Days -21 and -14. Subjects who are 
initially determined to be eligible, based on initial Screening assessments, will then participate in 
a 10-day IR risperidone run-in period, during which adherence with study treatment will be 
assessed. Subjects who remain eligible for the study will enter the inpatient unit on Day -2. After 
admittance to the inpatient unit and prior to the first LYN-005/matched placebo administration, 
samples for determination of IR risperidone PK will be collected from Days -2 to -1.  
Over the course of the study, subjects are to receive 3 doses of LYN-005/matched placebo, per 
their random assignment, 1 each on Days 1, 8, and 15, all on an inpatient basis. All subjects also 
will receive IR risperidone or matched placebo, again per their random assignment, from Days 1 
to 21. 
Overall, during study participation, subjects will be housed in the inpatient unit twice, from 
Days -2 to 9 (Inpatient Stay 1) and then again from Days 14 to 16 (Inpatient Stay 2). Subjects 
who are admitted to the inpatient unit on Day -2 will be considered enrolled. In between each 
inpatient stay, subjects will have study assessments performed on an outpatient basis daily from 
Days 10, 11, 12, and 13. After discharge from Inpatient Stay 2, subjects will again have 
assessments performed on an outpatient basis on Days 17, 18, 21, 22, and 23. An End of Study 
(EOS) visit will be conducted on Day 35.  
During study participation, guidelines will be in place for the use of recommended rescue 
medications for agitation, anxiety, and insomnia. Rescue administration of an agent other than 
risperidone or paliperidone in the event of worsening of schizophrenia symptoms during the 
study can be administered at the discretion of the PI, with notification of Lyndra’s Medical 
Monitor. Extrapyramidal symptoms will be monitored throughout the study at regular intervals 


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using the Extrapyramidal Symptom Rating Scale (ESRS). Severity of 
schizophrenia/schizoaffective disorder symptoms will be monitored throughout the study at 
regular intervals using the Clinical Global Impression-Severity (CGI-S) scale. Concomitant 
medications, AEs, safety laboratory tests, and vital signs will be assessed throughout the study, 
as per the SOE (Section 18.1.1 and Section 18.1.2). 
Details regarding each study period follow. 
4.1.1 
Screening Period (Day -21 to Day -14): 
All screening procedures will be performed on an outpatient basis. Prior to any screening 
procedures, the subject or designated representative must provide written informed consent. 
Male and female subjects between 18 to 50 years of age who have a diagnosis of schizophrenia 
or schizoaffective disorder, as defined by DSM-5 criteria and as confirmed by the Mini 
International Neuropsychiatric Interview (MINI) version 7.0.2. The MINI will also be used to 
exclude comorbid psychiatric diagnoses. Further eligibility requirements will include a CGI-S 
score of ≤4 (moderately ill). Subjects must have been medically stable within the last month, and 
stable in their psychiatric illness on a stable antipsychotic treatment regimen and without 
significant symptom exacerbation over the last 3 months. Additionally, subjects must be 
receiving outpatient treatment and not have been hospitalized for worsening schizophrenia in the 
last 6 months (hospitalization for social management within this time is acceptable). Subjects 
should have a Positive and Negative Syndrome Scale (PANSS) score aligned with stable and 
mild-moderate disease (i.e., ≤80 points).  
An assessment of pill swallowing will be assessed with a questionnaire, PILL-5, where a score of 
4 or below is regarded as “normal” pill swallowing. Additional screening measures to confirm 
general good health will be performed as described in the SOE (Section 18.1.1).  
To be eligible for this study, subjects must either have been stable on a therapeutic dose of an 
oral IR risperidone between 2 and 8 mg/day or been on a stable dose of another antipsychotic 
medication (single agent) for a minimum of 6 weeks. As shown in Figure 6-1, subjects already 
receiving 2 to 4 mg IR risperidone will transition to 2 mg daily administration by Day -13 to 
complete the run-in. Subjects on a daily dose of approximately 4 mg to 8 mg IR risperidone will 
be placed in a cohort based on clinical judgement of the Investigator and fully transitioned to this 
dose by Day -13 and remain at this dose during the run-in.  
Subjects who currently are on antipsychotic medications other than IR risperidone are also 
eligible for the study and are to be switched to either 2 or 4 mg/day IR risperidone based on the 
clinical judgement of the Investigator are to begin the transition to IR risperidone starting on 
Day -13; by Day -13, these subjects should only be receiving 2 or 4 mg IR daily during the run-
in. To improve toleration and management of symptoms during the transition to risperidone run-
in, short-term changes to the daily risperidone dose during the run-in may be considered in 
consultation with the PI. A home or clinic visit may also be considered at the discretion of the PI 
in order to assure subject stability.  


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4.1.2 
Pre-study Preparation with IR Risperidone 
All subjects who are eligible for study participation at the end of Screening will receive a 
medication log for use Days -13 through -3 to record the timing and dose of their IR risperidone 
during the run-in period. IR Risperidone must be taken once a day and at approximately the same 
time of day (morning or evening) on Days -13 to -3. Guidelines for switching antipsychotic 
medication to risperidone 2 or 4 mg/day prior to Day -13 are provided in Figure 6-1 in 
Section 6.3.1. 
Eligible subjects will be contacted daily on Days -13 to -3 prior to admission to the study unit on 
Day -2 to ensure medication adherence and check on safety, concomitant medications, and AEs. 
The subject must be adherent (self-report) with risperidone administration for 5 consecutive days 
prior to Day -3 to be eligible for enrollment into the study. Additional days may be added to the 
pre-study preparation to ensure 5 consecutive days of medication adherence prior to Day -3. 
Subjects who confirm medication adherence will be prepared by the site regarding the 
arrangements for subject arrival at the study unit the next day (Day -2) and the subsequent 10-
night stay. Subjects will be instructed on Day -3 to take their risperidone dose at the normal time 
and to not bring risperidone tablets to the unit on Day -2. 
4.1.3 
IR Risperidone PK Period 
Subjects will be admitted to the study unit on Day -2.  
Medication adherence for IR risperidone based on the medication log should be assessed upon 
arrival to the unit on Day -2, and subjects who are non-adherent are not to be admitted to the 
inpatient unit at that time. The site should confirm the dose and time of last IR risperidone for 
subjects who remain eligible to begin the inpatient phase of the study, and a blood sample 
collected for PK analysis.  
Subjects who are switching from evening to morning dosing will be given half the regimen of 
daily oral risperidone in the evening of Day -2 (i.e., either 1 or 2 mg risperidone) to minimize 
overlapping exposure. This dose should be given after the evening (6 pm) PK sample has been 
collected. Morning administration of the full dose of IR risperidone, 2 or 4 mg respectively, must 
begin by Day -1 for all subjects. 
Patients will receive IR risperidone on Day -1, as described in Section 6.3.2, with PK samples 
collected thereafter.  
4.1.4 
Randomization (Day 1) 
Subjects who successfully complete the admission procedures will be randomized on Day 1 in a 
3:1 ratio to LYN-005 or IR risperidone, as follows: 
• 
LYN-005: Subjects randomly assigned to LYN-005 ER will receive a single LYN-005 ER 
capsule (14 or 28 mg) taken once-weekly (on Days 1, 8, and 15) plus dummy IR risperidone-
matched placebo daily though Day 21. 


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• 
IR Risperidone: Subjects randomly assigned to IR risperidone will receive a single weekly 
dummy capsule (placebo capsule representing LYN-005, but containing no stellate) taken 
once-weekly (On Days 1, 8, and 15) plus IR risperidone (2 or 4 mg/day) daily though Day 
21.  
Subjects will be split into 2 groups based on their IR risperidone run-in dose prior to 
randomization. Subjects receiving 2 mg/day IR risperidone will be randomized to receive either 
14 mg/week LYN-005 or continued 2 mg/day IR risperidone and those receiving 4 mg/day IR 
risperidone will be randomized to receive either 28 mg/week LYN-005 or continue with 
4 mg/day risperidone, respectively. Although treatment assignment is blinded; the dose level is 
not blinded. Within each treatment arm, a minimum of 8 subjects are to be enrolled at each dose 
level; thus, if 16 subjects have been enrolled at a given dose level, all remaining subjects must be 
enrolled at the other dose level.  
4.1.5 
Double-blind Dosing Period (Days 1 to 21) 
During the LYN-005 dosing period, subjects are to receive 3 doses of LYN-005 or matched 
placebo, one each on Days 1, 8, and 15. Following an overnight fast, subjects are to consume a 
light breakfast over 30 minutes or less, with the meal started 30 minutes prior to study drug 
administration. Subjects also will receive IR risperidone Study assessments are to be performed 
before and after each dose per the Schedule of Events (Section 18.1.1 and Section 18.1.2). 
Subjects will remain in the inpatient unit until Day 9 for continued safety monitoring. On Day 9, 
the Investigator will perform study assessments to confirm the subject is eligible to leave the 
inpatient unit and continue outpatient treatment with study drug.  
After discharge from the inpatient unit on Day 9, subjects will be followed on an outpatient basis 
from Days 10 to 13 via safety calls until their return to the unit on Day 14. During this period, 
subjects will continue taking their daily dummy or IR risperidone as prescribed. 
In the evening of Day 14, subjects will return to the clinic for Inpatient Period 2 in advance of 
the third LYN-005/matched placebo administration on Day 15. AEs and concomitant 
medications will be assessed upon arrival.  
On the morning of Day 15, a pre-dose PK-sample will be collected, and as on Days 1 and 8, 
subjects will be administered either the third dose of LYN-005/matched placebo. PK samples 
will be collected and safety assessments performed as per the SOE (Section 18.1.1 and 
Section 18.1.2). Subjects are to remain in the unit for a minimum of 8 hours for observation prior 
to discharge on Day 16.  
On Days 16 through 21, subjects will continue taking their daily IR risperidone or matched 
placebo as outpatients, as per their random treatment assignment.  


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4.1.6 
End of Study Visit (Day 35) 
On Day 35, subjects will be asked to return to the clinic for follow-up assessments, as per the 
SOE (Section 18.1.2). Thereafter, additional follow-up telephone calls may occur as warranted if 
there are ongoing AEs at the time of the EOS Visit. 
4.2 
Blinding Procedures 
Subjects and site and Sponsor personnel associated with study conduct will be blinded to 
treatment assignment.  
During the conduct of the study, the blind should only be broken on an individual subject basis in 
the event of an emergency where it is necessary for the Investigator to know which treatment the 
subject is receiving before the subject can be treated. The code may also be broken if someone 
not in the study uses study drug (e.g., if a child in the subject’s household takes study drug, the 
blind may be broken to determine treatment for the child).  
When it is necessary to break the blind, the Investigator may unblind the treatment immediately 
(i.e., without prior notice to the Medical Monitor, sponsor, or other) via the Interactive Response 
Technology system, but must notify the IRB per local regulations and Sponsor as soon as 
possible, preferably by telephone and then in writing, regarding the necessity of code breaking.  
If the code is broken for a subject, this must be documented in the electronic case report form 
(eCRF) and source documents, together with the reasons for breaking the code. 
4.3 
Justification of Dose Selection 
The justification for dose selection is based on the target oral dose range for risperidone ranging 
from 2 to 8 mg/day in subjects with schizophrenia and schizoaffective disorder [33]. These doses 
would be expected to correspond to therapeutically equivalent weekly doses of 14 to 56 mg 
risperidone using LYN-005. Accordingly, for this study, 14 and 28 mg LYN-005 ER capsule 
formulations of risperidone will be evaluated.  
LYN-005 containing 14 and 28 mg risperidone is expected to deliver comparable exposures to 
risperidone active moiety concentrations associated with 2 mg/day and 4 mg/day, respectively, 
given orally as an immediate release formulation over 1 week. Given the metabolism of 
risperidone to the equipotent metabolite, 9-hydroxyrisperidone, and due to the exposure 
differences between poor and extensive metabolizers, it was decided to exclude poor 
metabolizers to minimize study variability.  


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5 SUBJECT POPULATION 
5.1 
Inclusion Criteria 
To be eligible to participate in the study, subjects must meet ALL of the following inclusion 
criteria at Screening (or at enrollment when specified): 
1. Male or female aged ≥18 and ≤50 years. 
2. Current diagnosis of schizophrenia or schizoaffective disorder according to DSM-5 criteria 
as confirmed by the MINI 7.0.2. 
3. The following psychiatric criteria are to be used to determine subject eligibility:  
• Duration of diagnosis of schizophrenia or schizoaffective disorder of ≥2 years. 
• Outpatient; not hospitalized for worsening of schizophrenia within the last 6 months 
(partial hospitalization for social management within this time period is acceptable). 
• Medically stable over the last month and psychiatrically stable without significant 
symptom exacerbation over the last 3 months. 
4. Stabilized on an oral antipsychotic medication (single agent) for a minimum of 6 weeks at 
the time of Screening. 
5. On a stable dosage of all permitted non-antipsychotic medications (except for medication to 
be used on an as-needed basis) for at least 1 month prior to the Screening visit and for the 
duration of the study. 
6. CGI-S score of ≤4 (moderately ill). 
7. PANSS score of ≤80 points. 
8. Body mass index (BMI) of ≥18 kg/m2 and ≤35 kg/m2. 
9. Able to read and understand study procedures and provide written informed consent before 
the initiation of any protocol-specific procedures. 
10. Willing to comply with all protocol-specified procedures and availability for the duration of 
the study. 
11. Subject has identified a caregiver or personal contact with whom the subject communicates 
with at least once a week. 


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5.2 
Exclusion Criteria 
In order to be eligible to participate in the study, subjects must meet NONE of the following 
exclusion criteria at Screening (or at enrollment when specified):  
1. Subjects with known clinically significant esophageal or GI disease, including but not limited 
to:   
a. Known strictures such as esophageal web, pyloric stenosis, or small intestinal stricture, or 
subjects with high risk of stricture, e.g., Crohn's disease. 
b. Diagnosis of a condition known to elevate or lower gastric pH, e.g., achlorhydria or 
hypochlorhydria. 
c. Prior small or large bowel obstructions or varices. 
d. Prior abdominal or upper gastrointestinal surgery (prior uncomplicated laparoscopic 
procedures including appendectomy or colectomy). 
e. History of dysphagia or aspiration in the last 5 years. 
f. History of an esophageal motility disorder or undergoing treatment for a gastric motility 
disorder. 
g. Multiple episodes of abdominal pain within 3 months of Screening. 
h. Subjects who experience moderate or severe dysmenorrhea or menorrhagia (with use of 
pain medication) within 3 months of Screening.  
i. History of moderate to severe Acid Reflux Disease or a score of ≥2 on the Acid Reflux 
Severity Scale (ARSS) [2], indicating moderate to severe symptoms. The ARSS scale is 
as follows: 
None = 0 no symptoms 
Mild = 1 awareness of symptom, but easily tolerated 
Moderate = 2 discomfort sufficient to cause interference with normal activities 
Severe = 3 incapacitating, with inability to perform normal activities.  
2. Subjects with PILL-5 questionnaire score of 5 or greater. 
3. Medical history or current diagnoses indicating the presence of any of the below conditions: 
a. Presence of an uncontrolled, unstable, clinically significant medical condition could that 
could put the subject at risk because of participation in the study, interfere with the 
subject’s ability to participate in the study or influence the interpretation of safety or PK 
evaluations.  


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b. History of a major cardiovascular event (myocardial infarction, cardiac surgery or 
revascularization, unstable angina, stroke, or transient ischemic attack) or a 
hospitalization for heart failure with 6 months of Screening. 
c. Any clinically significant illness, medical or surgical procedure or trauma within 4 weeks 
of Screening. 
d. Known immunocompromised status, including individuals who have undergone organ 
transplantation, on immunosuppression for an immune mediated disease, or are positive 
for HIV. 
e. Subjects with a positive test for active hepatitis B or C at Screening. Subjects with 
successfully treated hepatitis B infection which has been resolved for greater than 1 year 
or successfully treated hepatitis C infection will not be excluded. 
f. Subjects who have donated more than 250 mL of blood within 30 days of Screening. 
g. Subjects who have difficulties with venipuncture/cannulation, including difficulty 
accessing veins for blood sampling and/or history of coagulopathy or endocarditis. 
h. Subjects with a current DSM-5 diagnosis of major depressive episode panic disorder, 
agoraphobia, social anxiety disorder, obsessive-compulsive disorder, post-traumatic 
stress disorder, generalized anxiety disorder on the MINI 7.0.2 or in the judgment of the 
Investigator. (Note that individuals with depression secondary to schizoaffective disorder 
are eligible). 
i. Suicidal ideation associated with actual intent and a method or plan in the past 6 months, 
as measured by the C-SSRS (i.e., “Yes” answers on items 4 or 5) at Screening or having 
made a suicide attempt within the last 2 years. 
j. Known or suspected (non-febrile) seizure disorder. 
k. History of neuroleptic malignant syndrome. 
l. Current or history of clinically significant tardive dyskinesia. 
m. Known or suspected diagnosis of intellectual disability or organic brain disorder or other 
diagnosis that is primarily responsible for current symptoms and functional impairment. 
n. Medically non-adherent in the management of their schizophrenia/schizoaffective 
disorder. 
4. Use of the below medications/treatments in the 2 weeks before enrollment, including: 
a. Proton pump inhibitors and H2 blockers. 
b. Prokinetic agents. 


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c. Medications that may interfere with the absorption, metabolism, or excretion of 
risperidone, e.g.,: 
i. 
Drugs metabolized via CYP3A4 pathway, such as macrolide antibiotics and azole 
antifungals)Moderate or strong CYP3A4 p-glycoprotein (P-gp) enzyme inducers 
and inhibitors (carbamazepine, phenytoin, rifampicin, phenobarbital, itraconazole, 
verapamil). 
ii. 
Moderate or strong CYP2D6 inhibitors (e.g., fluoxetine, fluoxetine combinations, 
paroxetine), or quinidine. 
d. Concomitant medications, natural remedies, supplements or vitamins which are 
associated with changes to gastric motility or pH. Use of antacids is permissible, except 
within 2 hours of dosing with LYN-005.  
e. Benzodiazepines; except lorazepam, diazepam and oxazepam, which are acceptable if 
for the treatment of depression, anxiety or insomnia.  
f. Use of more than one antidepressant; or if on just one, a change in dose within 6 weeks 
of Screening. 
g. Depot antipsychotic use within 9 months of Screening. 
h. Electroconvulsive therapy within 3 months of Screening. 
5. Subjects with clinically significant abnormal safety (e.g. physical examination, vital sign) or 
safety laboratory assessments, specifically: 
a. Presence of a clinically significant abnormal laboratory result on blood or urine safety 
tests at Screening. 
b. Anemia (hemoglobin below lower limit of normal reference range) at Screening. 
c. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥3.0 × upper limit 
of normal (ULN) and total bilirubin ≥1.5 × ULN.  
d. Moderate or severe renal insufficiency at Screening (glomerular filtration rate 
<60 mL/min, as determined using the Cockcroft-Gault formula). 
e. Heart rate of <50 beats per minute (bpm) at Screening. 
f. Systolic blood pressure ≥150 and/or diastolic blood pressure ≥100 mmHg at Screening. 
g. HbA1c ≥7.0% at Screening. 
h. Positive fecal occult blood test at Screening in subjects who are >45 years unless they 
have had a normal colonoscopy within the past 5 years.  


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i. Clinically significant prolactin elevation (≥200 ng/mL for females; ≥100 ng/mL for 
males). 
6. Subjects with the below specified patterns of substance use at Screening: 
a. Fulfillment of the DSM-5 criteria for moderate or severe substance use disorder 
(excluding nicotine and caffeine) within 6 months of Screening. 
b. History of alcohol consumption exceeding moderate use; in males exceeding 21 units per 
week and in females exceeding 14 units per week (1 unit = 360 ml beer, 25 mL of 40% 
spirit or a 125 mL glass of wine) over the past month. Subjects are not permitted to 
consume alcohol during the inpatient stay nor 12 hours before any clinic visit while 
outpatient. 
c. Positive ethanol breathalyzer. 
d. Positive urine drug screen for substances of abuse other than cannabis. 
e. Heavy nicotine use (consumption of >40 cigarettes or >36 mg of nicotine from other 
sources [e.g., vaping products] daily) or daily use of smokeless tobacco. 
7. Subjects of reproductive potential who are (hetero) sexually active but unwilling to use 
acceptable means of contraception through the EOS. For clarity, subjects who are at least 
1 year post-menopausal are not of reproductive potential. Acceptable means of contraception 
include: 
a. Subjects who have been surgically sterilized. 
b. Females of reproductive potential: diaphragm, injectable, oral/patch contraceptives for a 
minimum of 6 weeks, contraceptive sponge, implant, or intrauterine device in use prior to 
enrollment. 
c. Males: condom in combination with any of the above means of contraception. 
d. All subjects: abstinence may be an acceptable means of contraception as long as the 
individual consents to initiate immediate use of double barrier protection for the duration 
of the study should (hetero) sexual intercourse occur. 
8. Subjects who are nursing or who have positive or indeterminate pregnancy tests at either 
Screening (serum test) or enrollment (urine test). 
9. Use of any experimental agent within 1 month or 5 half-lives of Screening, whichever is 
longer. 
10. Subjects who are employees or immediate family members of employees of the site, Sponsor 
or study-related vendors.  


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11. History of a serious allergic or hypersensitivity reaction to risperidone or LYN-005 
excipients (refer to Investigator’s Brochure). 
12. Subjects with history of X-ray, computed tomography (CT) scan or angiogram of the 
abdomen within one year of Screening. 
13. Subjects with CYP2D6 poor or underdetermined metabolizer status based on genetic testing. 
5.3 
Screen Failure 
Screen failures are defined as subjects who consent to participate in the clinical study but who do 
not meet inclusion/exclusion criteria and hence are not subsequently enrolled in the study. (For 
the purposes of this study, subjects who are admitted to the inpatient unit on Day -2 will be 
considered enrolled.) A minimal set of screen failure information is required to be captured to 
ensure transparent reporting of screen failure subjects and to respond to queries from Regulatory 
Authorities. Information to be captured on screen failure subjects includes demography, screen 
failure details including any inclusion/exclusion criteria that were not met, the primary reason 
and the relevant data (e.g., laboratory, medical historical details) that support the determination. 
Where applicable, potential subjects may be rescreened to reassess eligibility. These subjects 
should be assigned the same subject numbers as for the initial screening.  
Subjects who consent to participate in the clinical study, meet eligibility criteria but are not 
enrolled will be referred to as Alternates (not screen failures) and may be considered for future 
enrollment.  
5.4 
Discharge Instructions at End of Study or Early Termination Visit 
The site will facilitate a review with the study subject of the planned schedule for when 
information relating to their study information (e.g., study results, treatment assignments) will be 
available. The site will also discuss how information relating to their participation in the study 
will be shared with their healthcare provider, if they choose to share this information, and with 
the relevant health authorities in the event of a positive HIV or hepatitis result. 
5.5 
Study Completion 
The site will complete the Study Termination eCRF page and this will mark the completion of 
the individual’s participation in the study. 
The date of termination is the date of the last contact (clinic visit or telephone call) in which the 
subject’s health status was assessed or, in cases where the subject does not agree to any further 
safety follow-up, it is the date consent is withdrawn. This date should be recorded on the Study 
Termination eCRF page.  


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6 STUDY DRUG MANAGEMENT 
6.1 
Description of Study Drugs 
The term ‘study drug’ refers to those drugs provided by the Sponsor, which will be evaluated as 
part of the study objectives.  
6.1.1 
LYN-005 ER 
The Lyndra ER product, LYN-005, contains risperidone 14 or 28 mg. The LYN-005 
(risperidone) ER capsule is designed with modular components to ensure the safe and controlled 
administration of risperidone in the GI tract over several days. Drug is contained only within the 
drug layers, which provide controlled drug release based on hydration. Refer to the 
Investigator’s Brochure for additional details. 
Lyndra will provide LYN-005 14 and 28 mg capsules and matched placebo.  
6.1.2 
IR Risperidone 
RISPERDAL® (risperidone) is an atypical antipsychotic agent. Lyndra will provide risperidone 
2 mg (orange) capsule-shaped tablets and matched placebo. 
6.2 
Storage 
All drugs associated with this study (study drugs) are to be stored separately from other drugs 
and medications in a secure location under appropriate storage conditions with temperature 
monitoring. All drugs associated with this study must be checked for expiration or retest date 
prior to use. Expired drugs or those beyond their retest date must not be administered to subjects. 
The Investigator or designee will be responsible for oversight of the administration of drug to 
subjects enrolled in the study according to the procedures stipulated in this study protocol. All 
drugs will be administered only by personnel who are qualified to perform that function under 
applicable local laws and regulations for the specific study site. 
6.2.1 
LYN-005 
LYN-005 is to be stored at 15 to 25ºC (59° to 77°F). The capsules are to be handled in a manner 
to avoid squeezing or crushing. 
6.2.2 
IR Risperidone 
IR risperidone tablets should be stored at controlled room temperature 15° to 25°C (59° to 77°F) 
and protected from light and moisture. 


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6.3 
Dosing and Administration 
6.3.1 
Run-in Preparation with IR Risperidone 
All subjects must take IR risperidone once a day and at approximately the same time of day 
(morning or evening) on Days -13 to -3.  
Subjects who are receiving antipsychotic medications must switch to either 2 or 4 mg/day IR 
risperidone based on the clinical judgement of the Investigator are to begin the transition to IR 
risperidone starting on Day -13; by Day -13, these subjects should only be receiving 2 or 4 mg 
IR daily. Guidelines for switching antipsychotic medication to risperidone 2 or 4 mg/day prior to 
Day -13 are provided in Figure 6-1. 
Figure 6-1: 
IR Risperidone Switch and Dosing Guidelines 
 
 
6.3.2 
IR Risperidone PK Period 
Morning administration of the full dose of IR risperidone, 2 or 4 mg respectively, must begin by 
Day -1 for all subjects. 
Subjects who must switch from evening to morning dosing will be given half the regimen of 
daily oral risperidone in the evening of Day -2 (i.e., either 1 or 2 mg risperidone) to minimize 
overlapping exposure. This dose should be given after the evening (6 pm) PK sample has been 
collected.  
On Day -1, following an overnight fast, subjects will consume a light breakfast over 30 minutes 
or less, with the mean started 30 minutes prior to study drug administration. IR risperidone will 
be administered thereafter with 250 mL of water with the option for additional water (increments 
of 50 mL), as needed. Following risperidone administration, blood samples for PK will be 
obtained per the SOE (Section 18.1.1 and Section 18.1.2).  
2 mg daily oral
28 mg LYN-005
4 mg daily oral
14 mg LYN-005
2 – 4 mg daily oral risperidone
4 – 8 mg daily oral risperidone
Other antipsychotic
(mid to high dose)
Other antipsychotic
(low to mid dose) 
Baseline Therapy
Study Phase LYN-005
2 Weeks Prior to 
LYN-005/Placebo
*all subjects transition to risperidone monotherapy prior to dosing LYN-005


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6.3.3 
Blinded Treatment (LYN-005 or Placebo) 
Subjects who successfully complete the admission procedures will be randomized on Day 1 in a 
3:1 ratio to LYN-005 or IR risperidone, as follows: 
• LYN-005: Subjects randomly assigned to LYN-005 ER will receive a single LYN-005 ER 
capsule (14 or 28 mg) taken once-weekly (on Days 1, 8, and 15) plus dummy IR 
risperidone-matched placebo daily though Day 21. 
• IR Risperidone: Subjects randomly assigned to IR risperidone will receive a single weekly 
dummy capsule (placebo, representing LYN-005) taken once-weekly (On Days 1, 8, and 
15) plus IR risperidone (2 or 4 mg/day) daily though Day 21.  
6.3.3.1 
LYN-005/Placebo Administration 
LYN-005 capsules are to be taken orally following a light breakfast with approximately 250 mL 
of water immediately after capsule administration, while the subject is in a standing position. If 
the subject requests more fluid for swallowing, they may be given additional water in increments 
of 50 mL to chase. The volume of water consumed by the subject will be recorded in the eCRF. 
The subject is to remain upright after dosing for a total of at least 15 minutes. The subject must 
not bite or chew the capsule nor hold the capsule in the mouth prior to swallowing.  
6.3.3.2 
IR Risperidone/Placebo Administration 
IR risperidone or matched placebo tablets are to be taken orally in the morning with 250 mL of 
water with the option for additional water (increments of 50 mL), as needed. 
6.4 
Accountability and Compliance 
The United States Food and Drug Administration (FDA) requires accounting of all 
investigational treatment received by each study center. Records of treatment disposition 
required by federal law include the date received by the center, date administered, quantity 
administered, and the subject to whom study treatment was administered. The investigator is 
responsible for the accountability of all used and unused study treatment containers and unused 
study treatment. 
Each study center is to use a study treatment accountability log to document study treatment 
disposition. All items on this form are to be completed in full. The area where study treatment 
accountability records are to be maintained is to be approved by the Sponsor or designee. The 
Clinical Research Associate (CRA) is to routinely review study treatment accountability records. 
6.5 
Prior and Concomitant Medications and Therapies 
All medications, drugs and blood products taken or received by the subject within 3 months and 
any over-the-counter medications, natural supplements or vitamins taken within 4 weeks 
(28 days) prior to Day -2 are to be recorded on the Concomitant Medications eCRF. Similarly, 
any medication, drug, blood product, over-the-counter medication, herbal remedy taken by the 


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subject after study enrollment through EOS will also be recorded on the Concomitant 
Medications eCRF.  
Subjects on medication who do not discontinue medications within 2 weeks of study dosing 
(unless otherwise specified in the Exclusion Criteria, Section 5.2) are not eligible for dosing with 
LYN-005 on Day 1.  
During the study, the use of contraceptives (oral or other acceptable method) to prevent 
pregnancy in subjects of childbearing potential is required. Aside from contraceptives and 
necessary psychotropic medications, the use of other concomitant medications is generally 
discouraged during the study unless deemed appropriate by the Investigator to treat new or 
worsening medical conditions, including AEs. If pain relief is required during the study, the 
Investigator is encouraged to prescribe paracetamol.  
Psychotherapy should not be started or stopped during a subject’s participation in the study. It is 
acceptable for a subject already receiving psychotherapy to continue such therapy during study 
participation. 
Concomitant medications include all medications (including drugs) taken by/administered to the 
subject at and after enrollment and must be documented on the Concomitant Medications eCRF. 
As a reminder: any change to medical history or onset of AEs must also be captured in the 
respective Medical History and Adverse Event eCRFs. 


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7 PAUSING AND STOPPING GUIDELINES AND SUBJECT 
DISCONTINUATION/ WITHDRAWAL 
7.1 
Pausing and Stopping Guidelines 
Dosing of study subjects is to be paused if any of the following occurs:   
• 
 
 
 
 
 
 
• 
 
  
Under these circumstances, clinical study dosing would be paused to allow for the evaluation of 
potential underlying causes and treatment assignments. If a clinically significant injury (or risk 
thereof) is directly attributed to the 
, further study dosing will be stopped. Should 
study dosing resume, the study would remain observer blinded for subsequent subject dosing.  
The study will be stopped if any subject experiences clinically significant injuries including:  
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
• Any confirmed trend identified by ongoing review of safety data suggesting unacceptable 
risk of clinically significant injury to subjects. 
In addition, if a trend in the review of the safety data suggests the risk of a clinically significant 
injury for subjects participating in other clinical studies evaluating the modified release 
formulations, this information will be reviewed in a timely manner to understand the risks to 
these subjects. 


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7.2 
Premature Withdrawal from Study 
Subjects may withdraw at any time or be removed from the study at the discretion of the 
Investigator should any untoward effects occur and/or for safety reasons. In addition, a subject 
may be withdrawn by the Investigator or the Sponsor if he/she violates the study plan or for 
administrative reasons. The Investigator or Study Coordinator must notify the Sponsor 
immediately when a subject has been withdrawn due to an AE.  
The circumstances above are referred to as premature withdrawal from the study, and the reason 
for premature withdrawal should be clearly documented and detailed in the source 
documentation. The Investigator should make every attempt to evaluate the subject’s safety, 
including resolution of ongoing AEs, at the time of premature withdrawal.  
If a subject wishes to withdraw from the study after dosing with LYN-005 and before the last 
planned study visit, efforts should be made to obtain an X-ray in lieu of the scheduled X-rays for 
all subjects without fecal recovery or prior negative X-ray demonstrating GI exit of the 
formulation.  
When a subject withdraws, or is withdrawn, from the study after dosing with any study drug, the 
procedures described for the EOS visit (Section 18.1.2) should be completed, if possible. If a 
subject withdraws or is withdrawn from the study after enrollment but before dosing with LYN-
005, that subject would complete EOS visit procedures, excluding abdominal X-ray and would 
be considered a premature withdrawal. 


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8 STUDY ASSESSMENTS AND PROCEDURES 
After signing informed consent, individual subject data will be collected from subjects 
throughout the duration of their study participation. All data collected will use deidentified 
subject identifiers such as Screening and enrollment/subject IDs.  
This study utilizes eCRFs to collect study-related data for each subject. A qualified site staff 
member(s) is required to enter subject data in the eCRFs based on the medical information 
available in each subject’s source record.  
The study day and time each assessment will be performed relative to dosing is shown in the 
SOE (Section 18.1.1 and Section 18.1.2). However, when study assessments fall on the same 
time point, the site may arrange the order of procedures according to their usual practice. 
8.1 
Screening and Safety Assessments 
8.1.1 
Informed Consent 
“Informed consent” is the voluntary agreement of an individual to participate in research. 
Consent must be given with free will of choice, and without undue inducement. The individual 
must have sufficient knowledge and understanding of the nature of the proposed research, the 
anticipated risks, and potential benefits, and the requirements of the research to be able to make 
an informed decision. 
Written informed consent following local IRB guidance must be obtained from each subject 
before conducting any study-specific procedure (i.e., all procedures described in the protocol). 
The process of obtaining informed consent should be documented in the subject source 
document in addition to maintaining a copy of the signed and dated informed consent.  
Subjects who are unable to read must not be enrolled in the study. 
8.1.2 
PILL-5 Questionnaire 
The PILL-5 Questionnaire is to be administered to subjects during Screening. Refer to 
Section 18.2 for details. 
8.1.3 
Breath Test for H. Pylori 
Breath testing will be used at Screening to test for active H. pylori infection, and all results will 
be documented. Subjects will not be excluded on the basis of the rest results. Methods for 
evaluating the H. pylori breath test are described in the Laboratory Instruction Manual. 
8.1.4 
Medical and Psychiatric History 
Medical and psychiatric history for the past 12 months will be assessed at Screening and may be 
reassessed o prior to dosing to determine if there are any clinically relevant updates. The 
assessment of medical history will include but will not be limited to any history that may be 
relevant to subject eligibility for study participation such as concomitant medications, previous 


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and ongoing illnesses or injuries, and duration of medical and psychiatric stability. Relevant 
medical history can also include any medical history that contributes to the understanding of an 
AE that occurs during study participation, if it represents an exacerbation of an underlying 
disease/pre-existing problem. Relevant psychiatric history should include any psychiatric history 
relevant to the duration and understanding of diagnosis of mental illness and time of last 
hospitalization. The Investigator or delegate should update the medical and psychiatric history as 
needed while investigating treatment-emergent AEs.  
8.1.5 
Psychiatric and Extrapyramidal Symptom Assessment 
The following table lists the typical times to complete the psychiatric and EPS assessments in 
this study by visit date. The longest completion time occurs at Screening, lasting ~1.5 hours for 
all assessments. Thereafter, the total time to complete the assessments is <30 minutes or less.  
Table 8-1:  
Psychiatric and EPS Assessment Timing and Durations 
 
8.1.5.1 
Mini International Neuropsychiatric Interview (MINI) version 7.0.2 
The Mini International Neuropsychiatric Interview version 7.0.2 is a short, structured diagnostic 
interview that was developed to assess DSM-5 and ICD-10 psychiatric disorders. The MINI was 
developed for use in clinical and epidemiological studies as a short but accurate clinical 
assessment and has been validated against the Structured Clinical Interview for DSM diagnoses 
[35]. This study will utilize the MINI at Screening in order to ascertain inclusion and exclusion 
criteria. To assess the diagnosis of schizophrenia or schizoaffective disorder for study inclusion, 
the below modules of the MINI will be assessed:  
• Module A: Major Depressive Episode;  
• Module C: Manic and Hypomanic Episode; 
• Module K: Psychotic Disorders and Mood Disorder with Psychotic Features. 
Assessment 
Scale 
Assessment Duration 
[Reference]  
Screening 
Day 7 
Day 9 
Day 15 
Day 21 
Day 35 
PANSS 
45 to 50 min [34] 
√ 
 
 
 
 
 
MINI 
19 min [35] 
√ 
 
 
 
 
 
CGI-S 
2 min [36] 
(after clinical interview) 
√ 
√ 
√ 
√ 
√ 
√ 
C-SSRS 
10 min [37] 
√ 
√ 
√ 
√ 
√ 
√ 
ESRS 
15 min [38] 
√ 
√ 
√ 
√ 
√ 
√ 
Total Time 
96 minutes 
27 minutes 
27 minutes 
27 minutes 
27 minutes 
27 minutes 


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Depression, mania, and hypomania are components of a diagnosis for schizophrenia/ 
schizoaffective disorder. However, recent major depressive episodes may be exclusionary at the 
discretion of the Investigator.  
In addition to Modules A, C and K, several further modules of the MINI will be used to assess 
for excluded psychiatric conditions, as outlined in the study exclusion criteria: 
• Module D: Panic Disorder; 
• Module E: Agoraphobia; 
• Module F: Social Anxiety Disorder; 
• Module G: Obsessive-Compulsive Disorder; 
• Module H: Posttraumatic Stress Disorder; 
• Module N: Generalized Anxiety Disorder. 
The MINI 7.0.2 will be collected at the Screening Visit and takes approximately 15 minutes to 
administer. The tool should be administered by the Investigator or a trained medical professional. 
Instructions and scales for the modules of the MINI which are to be used in this study are 
presented in Section 0.  
8.1.5.2 
Structured Clinical Interview-Positive and Negative Syndrome Scale (SCI-
PANSS)  
The PANSS is one of the most widely used measures of psychopathology of schizophrenia in 
clinical research, and is considered the ‘gold standard’ for measuring antipsychotic treatment 
[39]. It is a 30-item scale used to evaluate the presence, absence, and severity of Positive, 
Negative and General Psychopathology symptoms of schizophrenia. In this study, the PANSS 
will be used at Baseline in order to assess the stability and severity of subjects’ disease. Each of 
the 30 items in the PANSS has a definition and a basis for rating, and all items are rated on a 7-
point scale (1 = absent; 7 = extreme). Subjects’ PANSS scores at Screening must be aligned with 
stable, mild to moderate disease based on values of ≤4 for individual items P1, P3, P4, P6, P7, 
and G14. The strengths of the PANSS include its structured interview, robust factor dimensions, 
reliability, the availability of detailed anchor points, and validity. 
The PANSS is accompanied by a semi-structured interview, the SCI-PANSS, which will be used 
in this study at Screening to ensure that all content domains are covered during the interview 
session [40]. SCI-PANSS ratings are made after the completion of the interview, using additional 
reports of daily function from caregivers, family members and a review of available clinical 
material as needed. Administration of the entire PANSS interview is between 45 and 50 minutes. 
In order to prevent subject fatigue during the interview, it is acceptable for subjects to take a 
short break during an assessment if needed, and then resume completion of the assessment. 


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The SCI-PANSS will be administered by the Investigator or a delegate trained in PANSS 
methodology. The core principles for the use of the PANSS, which ensure maximum reliability 
and inter-rater validity, should be followed in the administration of this assessment [39]. The 
PANSS is to be conducted at the Screening Visit and should be collected as outlined in the SCI-
PANSS booklet, seen in Section 18.4.  
8.1.5.3 
Clinical Global Impression – Severity (CGI-S) 
The CGI is widely used by clinicians in clinical studies in order to assess a subject’s global 
functioning both prior to and after initiating treatment with a study medication [41]. It is 
comprised of two one-item measures; the CGI-S measures the severity of a subject’s 
psychopathology, and the CGI-Improvement captures changes from Baseline after treatment 
initiation and includes an efficacy index [41, 42]. As efficacy is not assessed in this study, solely 
the CGI-S will be used to assess subject stability at Screening, enrollment and throughout the 
study.  
The CGI-S consists of a single 7-point rating score of illness severity, to be completed by a 
clinician [41, 42]. Raters select one response based on the following question, “Considering your 
total clinical experience with this particular population, how mentally ill is your subject at this 
time?”. The CGI-S has been demonstrated as a valid and user-friendly alternative to longer 
assessments, including the PANSS, and can be used to identify subjects in remission [43]. Scores 
are as follows:  
1. Normal, not ill at all 
2. Borderline mentally ill 
3. Mildly ill 
4. Moderately ill 
5. Markedly ill 
6. Severely ill 
7. Among the most severely ill subjects  
Subjects at Screening must have a stability score of less than or equal to 4 (moderately ill) to be 
eligible for the study. The CGI-S will also be administered to all subjects at multiple time points 
throughout the study, as specified in the SOE (Section 18.1.1 and Section 18.1.2), to monitor 
stability and may also be administered at the discretion of the Investigator. The scale and 
guidelines for its administration are found in Section 18.5.  
8.1.5.4 
Assessment of Suicidal Ideation and Behavior – Columbia Suicide Severity Rating 
Scale (C-SSRS) 
The Columbia Suicide Severity Rating Scale (C-SSRS) is an interview-based rating scale 
intended to systematically assess suicidal ideation and suicidal behavior. This scale has is 
recognized internationally as the ‘gold standard’ for risk assessments in clinical studies due to its 
simplicity, evidence-supported validity, efficiency, and effectiveness [44]. Two versions of the 


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C-SSRS will be utilized in this study to ensure subject safety; Baseline/Screening and Since Last 
Visit assessments.  
At the Screening Visit, the Baseline/Screening version will be used to asses study eligibility 
criteria and Baseline suicidal ideation and behavior. Subjects who have made a suicide attempt 
within the last 2 years and subjects who, in the Investigator’s judgment, pose a significant suicide 
risk are excluded from study participation. Subjects who have suicidal ideation associated with 
actual intent and a method or plan in the past 6 months (i.e., “Yes” answers on items 4 or 5 of the 
C-SSRS) are also to be excluded. 
Each subsequent assessment will utilize the Since Last Visit version of the C-SSRS. Subjects felt 
to have significant suicidal ideation with actual plan and intent or suicidal behavior based on this 
assessment must be evaluated by a licensed and qualified mental health professional (MHP) 
skilled in the evaluation of suicidality in the subjects by virtue of training or experience (e.g., a 
psychiatrist or, licensed PhD level clinical psychologist) who will determine if it is safe for the 
subject to continue in the study. Specific criteria that indicate a need for such an assessment are: 
• Scores reflecting suicidal ideation associated with actual intent and/or plan in the past 
year; i.e., a “YES” answer to C-SSRS questions 4 “some intent to act without specific 
plan” or 5 “specific plan and intent”; 
• Subject response of “YES” to any behavioral question of the C-SSRS on more than one 
occasion during a study (as compared to the previous assessment with the C-SSRS); 
• In the Investigator’s judgment, a risk assessment or exclusion is warranted. 
Subjects who meet the above criteria must have their suicidality managed appropriately by the 
Investigator together with the clinician/MHP (or the Investigator alone if the Investigator is a 
qualified mental health professional). Depending on the specifics of the situation as assessed by 
the Investigator and/or clinician/MHP, the subject may be discontinued from the study. 
Other possible suicidality AEs or other clinical observations may, based on the judgment of the 
Investigator and clinician/MHP, also trigger a risk assessment and a narrative using information 
from the C-SSRS and available information; including information from Baseline/ Screening, 
and the clinician/MHP assessment. With the positive response to any question on the C-SSRS, 
the Investigator should determine whether an AE has occurred.  
The C-SSRS should be collected at times specified in the SOE (Section 18.1.1 and Section 
18.1.2) by an appropriately trained site staff member, as well as at any time during the study at 
the discretion of the Investigator. Section 18.6 presents both C-SSRS scales.  
8.1.5.5 
Extrapyramidal Symptoms – Extrapyramidal Symptom Rating Scale (ESRS) 
Antipsychotics are a well-recognized treatment of schizophrenia, but their use is often associated 
with drug-induced EPS or drug-induced movement disorders (DIMD). Therefore, the ESRS will 
be used at Baseline and throughout the study in order to assess the severity of and monitor 
extrapyramidal symptoms. The ESRS was developed to assess four types of drug-induced 


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movement disorders [45, 46]: Parkinsonism, akathisia, dystonia, and TD. The ESRS consists of 
several components:  
• a questionnaire of EPS or DIMD; 
• an examination of Parkinsonism and akathisia; 
• an examination of dystonia; 
• an examination of dyskinesia; 
• CGI-S scales of TD, Parkinsonism, dystonia, and akathisia. 
The ESRS has been validated and is widely used in clinical research on antipsychotics and to 
differentiate drug induced EPS and symptoms of schizophrenia [46]. It has been demonstrated to 
be a sensitive and specific scale [46], and that ESRS measurement of drug-induced EPS is valid 
and discriminative from psychiatric symptoms as measured by the PANSS [47]. 
Administration of the ESRS takes approximately 10-15 minutes and should be conducted by 
medical professionals trained on the use of the scale. The ESRS should be administered at 
Baseline and throughout the study as specified in the SOE (Section 18.1.1 and Section 18.1.2). 
ESRS examination procedures and the scale are presented in Section 18.8. 
In cases of marked and clinically significant changes in EPS, the Investigator will use best 
clinical judgment on which treatment to consider in managing these symptoms. 
8.1.6 
Screening Fecal Sample for Occult Blood 
A fecal specimen will be tested at Screening for the presence of fecal occult blood, and results 
will be documented for all participants. Positive fecal occult blood test at Screening in subjects 
who are >45 years will be exclusionary unless the subjects have had a normal colonoscopy 
within the past 5 years. 
8.1.7 
General Physical Examination and Directed Physical Examination 
A general physical examination will be performed at Screening, Day -2 and the EOS visit. This 
examination will consist, at a minimum, of a check of general appearance; auscultation of the 
heart, lungs, and abdomen; palpation of the abdomen; abbreviated neurological examination; and 
examination of other organ systems in accordance with institutional practice. Body weight is to 
be measured as part of the general physical examination. 
Directed physical examinations will be performed on other days as indicated in the SOE 
(Section 18.1.1 and Section 18.1.2). This examination will consist, at a minimum, of a check of 
general appearance; auscultation of the heart, lungs and abdomen; and palpation of the abdomen. 
In addition, other organ systems may be examined at the discretion of the qualified medical 
professional performing the examination and as guided by interview of the subject. 
Any new clinically significant abnormality detected during physical examinations and 
considered an AE will be captured on the AE eCRF page.  


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8.1.8 
Vital Signs 
Vital signs include measurement of systolic and diastolic blood pressure, pulse, and respiratory 
rate as well as body temperature. Vital signs are to be measured at the time points indicated in 
the SOE (Section 18.1.1 and Section 18.1.2). Vital signs may be measured at additional time 
points at the Investigator’s discretion. 
8.1.9 
Electrocardiograms 
Standard 12-lead ECGs will be performed at the time points indicated in the SOE (Section 18.1.1 
and Section 18.1.2), according to the site Standard Operating Procedures, and ECG parameters 
will be collected in source documentation. ECGs are to be performed with the subject in a supine 
position for at least 5 minutes. All ECGs must be evaluated by a qualified physician for the 
presence of abnormalities, and findings should be classified as normal, abnormal not clinically 
significant or abnormal clinically significant. Additional ECGs may be performed at the 
discretion of the Investigator.  
8.1.10 
CYP2D6 Genotyping 
Risperidone is primarily metabolized by CYP2D6 and genetic testing for CYP2D6 will be 
conducted at Screening to determine metabolizer status. To reduce the inter-subject variability in 
exposure of risperidone and 9-hydroxyrisperidone, subjects identified as poor metabolizers will 
be excluded from the study. Approximately 7 mL (minimum 3 mL) of whole blood will be 
obtained at Screening for CYP2D6 genetic testing.  
8.1.11 
Screening Serology 
Blood is to be collected for serology testing including hepatitis B surface antigen (HBsAg), 
hepatitis C virus antibody (HCV Ab), and HIV, during Screening. 
8.1.12 
Safety Laboratory Assessments 
Safety laboratory assessments will include the following parameters: 
• Clinical chemistry panel 
- blood urea nitrogen (BUN) should be calculated from urea 
- includes liver function tests  
- HbA1c will be performed at Screening only 
• Hematology panel 
- includes complete blood count (CBC) with differential  
• Coagulation tests 
• Urinalysis to be performed at Screening only, unless for pregnancy test or at Investigator 
discretion 


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Safety laboratory assessments will be performed throughout the study at the time points 
indicated in the SOE (Section 18.1.1 and Section 18.1.2). Safety Laboratory Assessments are to 
be reviewed by the Investigator or delegate within 24 hours of available results and prior to 
discharge of the subject from the inpatient unit.  
For a complete list of assessments and further details relating to the collection and handling of 
laboratory specimens, please refer to the Laboratory Instruction Manual.  
8.1.13 
Prolactin 
Blood samples for prolactin will be collected at the time points indicated in the SOE (Section 
18.1.1 and Section 18.1.2). 
8.1.14 
Pregnancy Testing 
Pregnancy testing in females of childbearing potential is to be performed at the time points 
indicated in the SOE (Section 18.1.1 and Section 18.1.2). Pregnancy testing is to be repeated any 
time pregnancy is suspected. At Screening, a serum pregnancy test is to be performed. At all 
time points thereafter, a urine pregnancy test may be performed. 
Subjects with a positive pregnancy test during Screening are not eligible for study participation. 
After starting study drug, study drug is to be discontinued immediately for any subject with a 
positive pregnancy test, and pregnancies are to be reported and followed as described in Section 
8.2.8. 
8.1.15 
Compliance Laboratory Assessments 
Subjects will undergo testing to confirm the absence of alcohol or substance abuse at Screening, 
upon admission to the unit, and at any time during the study as warranted by the Investigator or 
study staff. In accordance with the exclusion criteria (Section 6.3) any individual who has a test 
reflecting recent use of excessive alcohol or illicit substances at Screening must not be enrolled 
in the study. 
Compliance Laboratory Assessments will include breath testing for alcohol use and urine testing 
for illicit substances (drugs of abuse). Analytes for the urine drug test will be specified in the 
Laboratory Instruction Manual. 
8.2 
Adverse Events and Serious Adverse Events 
According to the International Conference on Harmonization (ICH) Guideline E2A: Clinical 
Safety Data Management: Definitions and Standards for Expedited Reporting dated 27 October 
1994, an AE is defined as follows: 
8.2.1 
Definition of an Adverse Event 
Any untoward medical occurrence in a participation or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have to have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended sign 


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(including an abnormal laboratory finding, for example), symptom, or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product. 
This definition includes onset of illness, injuries, and/or exacerbation of pre-existing conditions. 
The period of observation for AEs extends from the time the subject signs informed consent until 
he or she completes the specified safety follow-up period (i.e., through the End-of-Study visit) or 
terminates the study early (whichever comes first). AEs occurring after the informed consent 
form (ICF) is signed but prior to receiving study drug/product will be documented as an adverse 
event and recorded within source document. However, any AEs occurring prior to receipt of any 
study drug will be analyzed separately from “treatment-emergent” AEs (AEs occurring after 
administration of study drugs) unless there is a change in severity or frequency of AEs persisting 
after the subject is dosed. AEs present on the first day of treatment that worsen in intensity or 
frequency during the treatment or post treatment periods should be reported and recorded as 
AEs.  
Unchanged chronic conditions are not AEs and should not be recorded on the AE pages of the 
eCRF. These medical conditions should be documented on the appropriate page of the eCRF 
(medical history or physical examination). The Investigator will actively solicit this information 
from the subject and assess the event in terms of severity and relationship to the study treatment 
regimen.  
Every effort should be made by the Investigator to evaluate safety information reported by a 
subject for an underlying diagnosis and to capture this diagnosis as the event in the AE page.  
8.2.2 
Serious Adverse Events 
An AE occurring should be classified as “Serious” if it meets one of the following criteria: 
1. It results in death (i.e., the AE caused or led to death). 
2. It is life threatening (i.e., the AE placed the subject at immediate risk of death). This 
classification does not apply to an AE that hypothetically might cause death if it is more 
severe. 
3. It requires or prolongs inpatient hospitalization (i.e., the AE requires at least a 24-hour 
inpatient hospitalization or prolongs a hospitalization beyond the expected length of stay). 
Hospitalizations for elective medical or surgical procedures, scheduled treatments, or routine 
check-ups are not SAEs by this criterion. 
4. Persistent or significant disability or incapacity (i.e., the AE results in a substantial disruption 
of the subject’s ability to carry out normal life functions). 
5. It is a congenital anomaly or birth defect (i.e., an adverse outcome in a child or fetus of a 
subject exposed to the molecule or study treatment regimen before conception or during 
pregnancy). 
6. It does not meet any of the above criteria but could jeopardize the subject and might require 
medical or surgical intervention to prevent one of the outcomes listed above. 


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8.2.3 
Collection of Adverse Events 
To prompt reporting of AEs, simple unbiased questions should be used as the initial questions at 
all evaluation points during the study. Whether considered related or not, all AEs are to be 
recorded on the eCRF page and monitored until resolution or through the end of the study.  
8.2.4 
Evaluation and Classification of Adverse Events 
Both serious and non-serious AEs should be graded with respect to severity on the following 
3-point scale and reported, in detail, on the appropriate eCRF page: 
Mild:  
Discomfort noticed, but no disruption of normal daily activities; event usually 
requires no intervention. 
Moderate:  Discomfort sufficient to reduce or affect normal daily activities; even may require 
intervention. 
Severe:  
Incapacitating, with inability to perform normal daily activities; event usually 
requires treatment or other intervention. Subject may not be able to continue in the 
study. 
8.2.5 
Relationship to Study Drug (Intervention) 
The Investigator should evaluate the relationship of each AE to the study treatment regimen, 
using the following criteria: 
Unrelated:  
Another cause of the AE is more plausible; a clinically plausible temporal 
sequence is inconsistent with the onset of the AE and administration of the 
study drug; or a causal relationship is considered biologically impossible. 
Possibly related:  There is a clinically plausible time sequence between onset of the AE and 
administration of the study drug, but the AE could also be attributed to 
concurrent or underlying disease, or the use of other drugs or procedures. 
“Possibly Related” should be used when the study drug is one of several 
biologically plausible AE causes. 
Related:  
The AE is clearly related to administration of the study drug. 
The relationship of the study drug to an AE will be determined by the Investigator or qualified 
delegate. 
All AEs, regardless of severity, will be monitored until resolution or until the Investigator 
assesses them as chronic or stable. All subjects experiencing AEs whether considered associated 
with the use of the study drug or not must be monitored until symptoms subside or until the 
Investigator determines the AE is chronic and stable and does not warrant further follow-up, or 
until death, in which case a full pathologist’s report should be supplied, if possible. 
8.2.6 
Time Period and Frequency for Event Assessment and Follow-up 
Any medical condition that is present at the time that the subject is screened will be considered 
as baseline and not reported as an AE. However, if the study subject’s condition deteriorates at 
any time during the study, it will be recorded as an AE. Changes in the severity of an AE will be 


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documented accordingly to allow an assessment of the duration of the event at each level of 
severity to be performed. AEs characterized as intermittent require documentation of onset, 
offset and duration of each episode. 
Study personnel will record all reportable events with start dates occurring any time after 
informed consent is obtained until the EOS Visit. At each study visit, the Investigator will 
inquire about the occurrence of AE/SAEs since the last visit. Events will be followed for 
outcome information until resolution or stabilization. 
8.2.7 
Procedures for Recording and Reporting Adverse Events 
Adverse events suspected or confirmed as meeting the definition of SAE should be reported to 
the Lyndra Medical representative, site CRA and contract research organization (CRO) Safety 
Officer within 24 hours. Contact details for each will be provided in the Safety Reporting Plan. 
8.2.7.1 
Recording Adverse Events 
All findings regarding AEs must be reported on an Adverse Events eCRF and on the SAE 
Reporting Form, if applicable, which is part of the Investigator Site File. All findings in subjects 
experiencing AEs must also be reported in the subject’s source document. 
To improve the quality and precision of AE data, Investigators should observe the following 
guidelines: laboratory, vital sign, ECG and physical examination abnormalities that are defined 
as clinically significant that meet the definition of an AE, are to be recorded on the AE eCRF 
page. 
8.2.7.2 
Recording and Reporting Serious Adverse Events 
Specific instructions and contact details for collecting and reporting SAEs to the Sponsor will be 
provided to the Investigator and site staff. All SAEs are also to be documented on the Adverse 
Events eCRF. Any medication or other therapeutic measures used to treat the SAE will be 
recorded on the appropriate eCRF(s) in addition to the outcome of the SAE. 
After receipt of the initial report, representatives of the Sponsor or its designee will contact the 
Investigator if it is necessary to obtain further information for assessment of the event. 
All SAEs must be reported by the Investigator in accordance with institutional policy/regulatory 
requirements or within 24 hours of their knowledge of the event. Adequate documentation of this 
notification must be provided to the Sponsor. 
The Sponsor or its designee must also comply with the applicable regulatory requirement(s) 
related to the reporting of suspected unexpected serious adverse drug reactions (also known as 
SUSARs) to the Regulatory Authority and, where applicable, the IRB. If a SUSAR or other 
safety signal relating to use of the study drugs in another research related activity is reported to 
the Sponsor or its designee, the Sponsor will communicate this information to the Investigator 
and the Investigator will be responsible for submitting this information, where applicable, to the 
IRB and other relevant authorities. 


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8.2.7.3 
Post-Study Events 
Any suspected SAE that occurs outside of the protocol-specified follow-up period but considered 
to be caused by the study drug must be reported according to the procedures specified above 
(Section 8.2.7) and in the Safety Reporting Plan. These SAEs will be processed by the Sponsor 
or a designee during the study, until the last subject enrolled in the study completes the last study 
visit. After that point, the Lyndra Medical Monitor should be contacted with any suspected or 
possibly drug related SAE experienced by an individual participating in this study.  
8.2.8 
Reporting of Pregnancies 
To ensure subjects’ safety, each pregnancy in a subject which occurs during the study (from 
administration of study drug through the EOS) must be reported to the Sponsor within 24 hours 
of the site learning of its occurrence. If the subject agrees to submit this information, the 
pregnancy must be followed to determine outcome, including spontaneous or voluntary 
termination, details of the birth, and the presence or absence of any birth defects, congenital 
abnormalities, or maternal and/or newborn complications. This follow-up should occur even if 
intended duration of safety follow-up for the study has ended. 
Pregnancy data, inclusive of initial reporting and follow-up information regarding the course of 
the pregnancy and the outcome, must be recorded on a Pregnancy Reporting Form and reported 
to the Sponsor. Instructions and contact details for submitting the Pregnancy Reporting Forms 
will be provided to the Investigator in the Safety Reporting Plan. 
Any pregnancy outcome meeting the definition of a SAE (Section 8.2.2) must also be reported 
on the SAE Reporting Form. 
8.3 
Gastrointestinal Imaging (X-ray) 
Abdominal X-rays are to be performed in all subjects where specified in the SOE (Section 18.1.1 
and Section 18.1.2). Refer to the Study Imaging Manual for details regarding the procedures for 
abdominal X-ray. 
8.4 
Pharmacokinetics 
At each time point specified in the SOE (Section 18.1.1 and Section 18.1.2), 2 mL of blood for 
PK evaluation will be drawn into a designated and labelled collection tube and processed for 
storage and shipment, as described in the Laboratory Instruction Manual. The windows around 
sample collection at each time point, as designated in the SOE, are to be observed. 
Analysis of risperidone and 9-hydroxyrisperidone will be performed using a validated assay. 
Time and date of the PK assessment will be recorded on the eCRF for each blood sample. 
Refer to the Laboratory Instruction Manual for further details. 


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8.5 
Protocol Deviations 
A protocol deviation is any change, divergence, or departure from the study design or procedures 
of a study protocol. In general, subjects associated with protocol deviations may remain in the 
study unless continuation in the study jeopardizes the subject’s health, safety, or rights.  
Investigators will apply due diligence to avoid protocol deviations as no authorized deviations 
are permitted. If the Investigator feels a change to the protocol would improve the conduct of the 
study this must be considered a protocol amendment, and unless such an amendment is agreed 
upon by the Sponsor and approved by the IRB and health authorities it cannot be implemented.  
Pregnancy during the study is a protocol deviation (Section 8.2.8).  
A protocol deviation may be a reason to remove data from an analysis set at the time of analysis. 
Protocol deviations may be defined as exclusionary from the analysis according to protocol 
objectives and endpoints. Prior to the final analysis of the study data, subjects with exclusionary 
protocol deviations will be identified and specified for each analysis set and documented. In 
some cases, exclusion of data may be due to a reason other than a protocol deviation, e.g., early 
termination.  


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9 STATISTICS AND DATA MANAGEMENT 
9.1 
General Procedures 
A statistical analysis plan (SAP), providing details about the specific planned analyses and 
potential hypothesis tests, will be prepared and approved prior to study database lock. Both 
descriptive and inferential statistical methods may be used to fully explore the preliminary data. 
In addition, post hoc analyses may be performed that are not described in the SAP but will be 
described fully in the CSR where presented.  
Summary statistics will be presented by dose group, dose period, and overall. Unless otherwise 
stated, categorical data will be presented using frequency counts and percentages and continuous 
data will be presented by number of subjects reporting (n), means, standard deviations (SD), 
median, minimum, and maximum. Geometric means and coefficient of variations (%CV) will be 
presented in addition for PK data. 
9.2 
Data Management 
Data management will be performed in accordance with clinical standards. 
AEs and medications will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) (v22.0 or a more recent version) and the World Health Organization Drug Dictionary 
Enhanced (WHO DDE) Drug Reference List (2018), respectively. An independent coding 
review will also be performed within the Data Sciences department. 
Clinical chemistry and hematology data (and other safety laboratory data) will be collected by a 
central laboratory and stored electronically in their clinical pathology system. All laboratory data 
that are transferred will be reconciled, queried, and answered by the site laboratory and clinical 
staff before the database can be closed. The database will be locked when all criteria listed in the 
Data Management Plan are met. Further details are addressed in the Data Management Plan. 
SAS 9.4 or higher (SAS Institute Inc., Cary NC USA) will be used for generating individual data 
listings, summary tables and associated figures and for performing statistical analyses. 
9.3 
Sample Size 
This study is exploratory in nature and therefore not designed to test hypotheses.  
The sample size of 32 (24 assigned to LYN-005 and 8 assigned to IR risperidone) is driven by 
clinical rather than statistical considerations for providing data in the evaluation of the endpoints.  
9.4 
Statistical Methods 
9.4.1 
Analysis Sets 
The following analysis sets will be defined: 
Enrolled Set: The Enrolled Set is defined as all subjects who are enrolled in the study and 
admitted to the research unit on Day -2. The Enrolled Set will be the primary set used for 
disposition, demographic and baseline characteristic data reporting. 


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Safety Set: The Safety Set is defined as all enrolled subjects who are randomized to study drug 
(LYN-005 14mg/28mg or IR Risperidone 2mg/4mg) and receive at least one dose of randomized 
study drug. Subjects will be reported according to the treatment received. The Safety Set will be 
the primary safety analysis population. 
PK Set:  The PK Set is defined as all enrolled subjects who receive a dose of LYN 005 and have 
least 1 post-dose quantifiable (or evaluable) PK concentration data. Additional analysis sets 
within the PK population, if identified, will be specified in the PK Analysis Plan. 
Additional analysis sets, if identified, will be specified in the SAP. 
9.4.2 
Statistical Methods 
Safety endpoint data will be descriptive in nature and summarized by dose group, dose period 
and overall. Listings will also be presented. The Safety Set will be the primary population for 
analysis unless otherwise stated. Plasma concentration data for risperidone and 9-
hydroxyrisperidone separately and combined as active moiety will be tabulated and plotted for 
each subject for whom concentrations are quantifiable. PK analysis of the concentration-time 
data obtained will be performed using appropriate non-compartmental analysis to obtain 
estimates of the standard PK parameters. 
The PK of LYN-005 relative to IR at 2 dose levels will be determined.  
There are no pharmacodynamic endpoints in this study. 
9.4.3 
Analysis of Safety - Analysis of Adverse Events 
This analysis applies to all AEs occurring during the study, judged either as related, possibly 
related, or not related to study drug by the Investigator, recorded on the AE eCRF, with a start 
date on or after the date of dose of randomized study drug (i.e., TEAEs). AEs starting prior to 
administration of randomized study drug (non-treatment emergent AEs) will be listed for 
subjects in the Enrolled Set. The original verbatim terms used by Investigators to identify AE in 
the eCRFs will be mapped to preferred terms using the MedDRA dictionary. The AEs will then 
be grouped by MedDRA preferred terms into frequency tables according to system organ class.  
Analyses of TEAEs will be summarized by dose group, dose period, and overall. Events will also 
be included in subject listing by dose group and dose period. 
Further details may be found in the SAP. 
9.4.4 
Analyses of Pharmacokinetics 
PK concentrations will be summarized descriptively for both IR risperidone and LYN-005. PK 
parameters will also be presented by dose group, that plots of concentration-time data and Cmax 
and AUC will be provided. Further analyses to assess PK levels in LYN-005 relative to IR 
risperidone will be explored and detailed in the SAP. 


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9.4.5 
Demographic and Baseline Characteristics 
Descriptive statistics will be summarized for the Enrolled Set. Demographic and baseline 
characteristic data includes age, gender, ethnic group/race, height, weight, BMI at enrollment 
will be calculated. 
9.5 
Assessment of Protocol Deviations 
A protocol deviation is any change, divergence, or departure from the study design or procedures 
of a study protocol. A protocol deviation may be a reason to remove data from an analysis set at 
the time of analysis. Protocol deviations may be defined as exclusionary from the analysis 
according to protocol objectives and endpoints. Prior to the final analysis of the study data, all 
protocol deviations will be reviewed by the Sponsor Medical representatives. Subjects with 
exclusionary protocol deviations will be identified, specified, and documented. Protocol 
deviations will be listed. 
9.6 
Safety Reviews 
There is a planned safety review by the Investigator and Medical Monitor on interim blinded PK 
data after PK data through Day 14 are available from 12 subjects. Blinded safety data will also 
be reviewed at this interim look and will include adverse events, laboratory data, suicidality, and 
illness severity. Additionally, the PI or Sponsor may request an ad hoc review of safety 
information, e.g., serious adverse events, at any time during the study. 
9.7 
Data Entry and Management 
In this study, all requested data will be entered onto eCRFs in a timely manner after each 
assessment by the Investigator and/or the Investigator’s dedicated site staff. Data entered onto 
eCRFs are stored on a secure website. The data collected on this secure website are assimilated 
into an electronic data capture (EDC) system, which is compliant with Title 21 Part 11 policies 
of the Code of Federal Regulations (FDA, 1997) [48]. The data system includes password 
protection and internal quality checks. The EDC system will be designed and validated by the 
Sponsor or delegate prior to activation for data entry by sites. The Investigator or designated 
delegate must review data entered and electronically sign the eCRFs to verify their accuracy. 
Access to the EDC system for data entry or review will require training and distinct individual 
access code assignments to those site staff members who will be entering study data and those 
involved in study oversight who may review study data. Data are collected within the EDC 
system, to which the Sponsor and site monitors have exclusively “read only” access. 
Additional data collection forms (e.g., Pregnancy and SAE Reporting Forms) will be provided to 
the site by the Sponsor or delegate, should a pregnancy or SAE occur. Instructions on how to 
complete and archive these forms will be provided to the Investigator by the Sponsor or delegate 
prior to the start of the study. 
9.8 
Data Clarification 
As part of the conduct of the study, the Sponsor may have questions about the data entered by 
the site, referred to as queries. The Clinical Research Associates and Data Management are the 


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only parties that can generate a query, and they will generate queries on behalf of any other data 
reviewer with “read only” access to the EDC. All corrections and clarifications will be entered 
into the EDC system and will be identified by the person entering the information, the reason for 
the change, as well as the time of the changes made. If changes are made to a previously and 
electronically signed eCRF, the Investigator must confirm and endorse the changes. 
9.9 
Data Protection 
The Sponsor respects the subjects’ rights to privacy and will ensure the confidentiality of their 
medical information in accordance with all applicable laws and regulations. 


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10 ETHICS AND RESPONSIBILITIES 
10.1 
Good Clinical Practice 
The study will be conducted in accordance with the protocol, Good Clinical Practices, the 
relevant ICH guidelines, the ethical principles that have their origins in the Declaration of 
Helsinki, and in accordance with the applicable regulatory requirements in the country where this 
study will be executed. As required by the Declaration of Helsinki; the study protocol, 
amendments, and, Informed Consent Form/Subject Information Sheet will be reviewed and 
approved by the study center’s IRB. 
10.2 
Sponsor Medical Monitor 
The Sponsor’s Medical Monitor will be available to the Investigator for discussion of any safety 
events or findings. The Investigator and Lyndra Medical Monitor may review AE listings on a 
weekly basis to evaluate any trends until each subject reaches Day 35. Additionally, the Lyndra 
Medical Monitor may be engaged at an ad hoc basis at any time to review SAEs, any events that 
may trigger pausing or halting the study and will review the safety data for the final reporting of 
the study data.  
10.3 
Investigator and Institutional Review Board Responsibilities 
The protocol and the proposed ICF must be reviewed and approved by a properly constituted 
IRB before study start. Properly constituted IRB is defined in ICH Guideline for Good Clinical 
Practice [49]. A signed and dated statement that the protocol and informed consent have been 
approved by the IRB must be given to the Sponsor or delegate before study initiation. Prior to 
study start and at any time the protocol is amended during study conduct, the Investigator is 
required to sign a protocol signature page confirming his/her agreement to conduct the study in 
accordance with these documents and all of the instructions and procedures found in this 
protocol and to give access to all relevant data and records to the Sponsor (or representative) 
monitors, auditors, other designated agents of the Sponsor, IRB, and regulatory authorities, as 
required. If an inspection of the clinical site is requested by a regulatory authority, the 
Investigator must inform the Sponsor immediately that this request has been made. 
At the site level, the Investigator must ensure that any person(s) assisting with the study are 
adequately trained and informed about the protocol, the investigational product(s), and their 
study-related duties and functions, including study-related medical decisions and medical care of 
subjects experiencing any AE related to the study. Additional responsibilities include 
maintaining a list of appropriately qualified persons to whom s/he has delegated significant 
study-related duties, and ensuring that s/he has the capability, time and staffing to recruit the 
required number of suitable subjects within the recruitment period and properly conduct and 
complete the study within the agreed study period. When required, and if permission is given by 
the subject, the Investigator will ensure that the subject’s primary healthcare provider is informed 
of the individual’s participation in the study.  


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The Investigator should not implement any deviation from, or changes of the protocol without 
agreement by the Sponsor and prior review and documented approval/favorable opinion from the 
IRB of an amendment, except where necessary to eliminate an immediate hazard(s) to study 
subjects, or when the change(s) involves only logistical or administrative aspects of the study 
(e.g., change in staff, change of telephone number[s]). In addition, the Investigator or delegate 
Investigator, should document and explain any deviation from the approved protocol. As soon as 
possible, the implemented deviation or change, the reasons for it, and, if appropriate, the 
proposed protocol amendment(s) should be submitted to the Sponsor for agreement, thereafter to 
the IRB for review and approval/favorable opinion, and if applicable, to the regulatory 
authority(ies). 
10.4 
Subject Information and Informed Consent 
The informed consent and subject information sheets used for this study will meet requirements 
for subject information, as outlined ICH Guideline E6 and the Declaration of Helsinki.  
Prior to the start of the study, the proposed ICF must be jointly agreed upon by the site and 
Sponsor or its delegate prior to submission to the IRB and a copy of the approved version must 
be provided to the Sponsor or delegate after IRB approval. 
Eligible subjects may only be included in the study after providing written informed consent or 
assent. Before the start of the study, the Investigator will have the informed consent and any 
other materials that will be provided to the subjects reviewed and approved by the IRB. This 
review and approval will be documented and stored with other study documents. The 
Investigator or delegate must fully inform the subject of all pertinent aspects of the study. A copy 
of the written informed consent will be given to the subject. The subject be allowed ample time 
to ask about the details of the study and to decide as to whether or not to participate in the study. 
The subject must sign the consent form indicating their agreement to participate in the study 
before any study-related procedures are conducted.  
The informed consent process may be conducted up to 5 weeks prior to enrollment on Day -2.  
Men and women of childbearing potential should be reminded of the requirement to use a highly 
effective method of contraception throughout the duration of the study, which should be recorded 
in the source documentation. Women of childbearing potential should be informed that taking 
the study drug may involve unknown risks to the fetus if pregnancy were to occur during the 
study and agree that to participate in the study, they must adhere to the contraception 
requirements indicated in the protocol for the duration of the study. In case of doubts on the 
ability of a subject to adhere to these requirements, that subject should not be allowed in the 
study. 


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11 RECORDS MANAGEMENT 
11.1 
Source Documentation 
Prior to the start of the study, the site staff participating in the study conduct will be instructed on 
what documents will be required for review as source documents. The documents that will serve 
as source documents will be agreed between the Sponsor or its delegate and Investigator or 
delegate and specified in the source document agreement prior to subject enrollment. 
In addition, source documentation must include all of the following: subject identification (on 
each page), eligibility and participation, proper informed consent procedures, dates of visits, 
adherence to protocol procedures, adequate reporting and follow-up of AEs, documentation of 
prior/concomitant medication/drugs, study drug receipt/dispensing/return records, study drug 
administration information, any data collected by a telephone conversation with the subject and 
date of completion and reason. 
The subject must also allow access to his or her own medical records. Each subject must be 
informed of this prior to the start of the study and consent for access to medical records may be 
required in accordance with local regulations. 
All safety data reported by subjects must be written down in source documents prior to entry of 
the data into eCRFs. If there are multiple sources of information (e.g., verbal report of the 
subject, telephone contact details, medical chart) supporting the diagnosis of an AE, these 
sources must be identified in the source documents, discrepancies between sources clarified, the 
ultimate diagnosis must be justified and written in the source documents, and this diagnosis must 
be captured in the AE eCRF. 
11.2 
Study Files and Record Retention 
The Investigator must retain all study records required by the Sponsor and by the applicable 
regulations in a secure and safe facility. The Investigator must consult a Sponsor representative 
before disposal of any study records and must notify the Sponsor of any change in the location, 
disposition, or custody of the study files. Essential documents must be retained for 15 years. 
“Essential Documents” are defined as documents that individually and collectively permit 
evaluation of the conduct of a study and the quality of the data produced. These documents 
should be retained for a longer period, however, if required by the applicable national regulatory 
or institutional requirements.  
These principles of record retention will also be applied to the storage of laboratory samples, 
provided that the integrity of the stored sample permits testing. 


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12 AUDITING AND MONITORING 
Study monitoring and auditing will be standardized and performed in accordance with the 
Sponsor’s or delegated CRO standard operating procedures and applicable regulatory 
requirements (e.g., TGA and ICH guidelines). 
Prior to enrollment of the first study healthy volunteer, the Sponsor or delegate will train 
investigators and/or their study staff on the study protocol, all applicable study procedures, 
documentation practices and all electronic systems. Electronic CRFs supplied by the Sponsor or 
delegate must be completed for each enrolled subject and limited data for all screened subjects 
who have swallowing questionnaire and imaging data available. Data and documents for all 
enrolled subjects will be checked by the Sponsor and/or monitor. 
Prior to enrollment of the first study volunteer, the Sponsor or its designee (e.g., a CRO) will 
develop a Clinical Monitoring Plan to specify how remote and/or on-site monitoring, including 
clinical specimen reconciliation, will be performed for the study. Study progress will be 
monitored by the Sponsor or its designee as frequently as necessary to ensure: 
• that the rights and well-being of human subjects are protected, 
• the reported study data are accurate, complete, and verifiable from the source documents, 
and 
• the conduct of the study is in compliance with the current approved 
protocol/amendment(s), Good Clinical Practice (GCP) and applicable regulatory 
requirements. 
Contact details for the Sponsor or its designee involved in study monitoring will be provided to 
the Investigator in the Clinical Monitoring Plan. Study data recorded on eCRFs will be verified 
by checking the eCRF entries against source documents to ensure data completeness and 
accuracy as required by study protocol. 
Data verification may also be performed through remote and/or centralized review of data (e.g., 
checking for outliers or other anomalies). Additional documents such as the Investigator Site 
File, pharmacy records, and Informed Consent documentation must also be available for review 
if requested. Arrangements for monitoring visits will be made in advance in accordance with the 
Clinical Monitoring Plan, except in case of emergency. 
The Investigator and/or site staff must make source documents of subjects enrolled in this study 
available for inspection by the Sponsor or its representative at the time of each monitoring visit 
and Sponsor audits, when applicable. These documents must also be available for inspection, 
verification, and copying, as required by regulations, by officials of the regulatory health 
authorities and/or IRBs. The Investigator and study site staff must comply with applicable 
privacy, data protection and medical confidentiality laws for use and disclosure of information 
related to the study and enrolled subjects. 


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13 AMENDMENTS 
Protocol modifications, except those intended to reduce immediate risk to study subjects, may be 
made only by the Sponsor. A protocol change intended to eliminate an apparent immediate 
hazard to subjects may be implemented immediately, provided the IRB is notified within 5 days. 
Any permanent change to the protocol must be handled as a protocol amendment. The written 
amendment must be submitted to the IRB and the Investigator must await approval before 
implementing the changes. The Sponsor will submit protocol amendments to the appropriate 
regulatory authorities for approval. 
If in the judgment of the IRB, the Investigator, and/or the Sponsor, the amendment to the 
protocol substantially changes the study design and/or increases the potential risk to the subject 
and/or has an impact on the subject's involvement as a study subject, the currently approved 
written informed consent form will require similar modification. In such cases, informed consent 
will be renewed for subjects enrolled in the study before continued participation. 


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14 STUDY REPORT, PUBLICATIONS, DATA POSTING 
The Sponsor is responsible for preparing and providing the appropriate regulatory authorities 
with clinical study reports according to the applicable regulatory requirements. 
The publication policy of the Sponsor is discussed in the Investigator's Clinical Research 
Agreement. 
The Sponsor assures that the key design elements of this protocol will be posted in compliance 
with current regulations. The Sponsor also assures that key results of this clinical study will be 
posted within the required time frame from the end of study as defined in Section 5.4. 


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15 STUDY DISCONTINUATION 
Both the Sponsor and the Investigator reserve the right to terminate the study at the 
Investigator’s site at any time. Should this be necessary, the Sponsor or a specified designee will 
inform the appropriate regulatory authorities of the termination of the study and the reasons for 
its termination, and the Investigator will inform the IRB of the same. In terminating the study, 
the Sponsor and the Investigator will assure that adequate consideration is given to the protection 
of the subjects’ interests. 


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16 CONFIDENTIALITY 
All information generated in this study is considered highly confidential and must not be 
disclosed to any person or entity not directly involved with the study unless prior written consent 
is gained from the Sponsor. However, authorized regulatory officials, IRB personnel, the 
Sponsor and its authorized representatives are allowed full access to the records. 
Identification of subjects and CRFs shall be by initials, screening and treatment numbers only. If 
required, the subject's full name may be made known to an authorized regulatory agency or other 
authorized official.  


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17 REFERENCES 
1. Emsley R, Chiliza B, Asmal L, Harvey BH. The nature of relapse in schizophrenia. BMC 
Psychiatry. 2013;13:50 
2. Junghard O, Wiklund I. Validation of a four-graded scale for severity of heartburn in patients 
with symptoms of gastroesophageal reflux disease. Value Health. 2008;11(4):765-70 
3. Wu Y, Kang R, Yan Y, Gao K, Li Z, Jiang J, et al. Epidemiology of schizophrenia and risk 
factors of schizophrenia-associated aggression from 2011 to 2015. The Journal of 
international medical research. 2018;46(10):4039-49 
4. Saha S, Chant D, Welham J, McGrath J. A Systematic Review of the Prevalence of 
Schizophrenia. PLoS Med. 2005;2(5) 
5. Center TA. Serious Mental Illness and Treatment Prevalence; Background Paper. 2017 
6. Tajima-Pozo K, de Castro Oller MJ, Lewczuk A, Montanes-Rada F. Understanding the direct 
and indirect costs of patients with schizophrenia. F1000 Research. 2015;4:182 
7. Volavka J, Vevera J. Very long-term outcome of schizophrenia. Int J Clin Pract. 
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8. Kane JM. Treatment adherence and long-term outcomes. CNS Spectr. 2007;12(10 Suppl 
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9. Higashi K, Medic G, Littlewood KJ, Diez T, Granström O, De Hert M. Medication 
adherence in schizophrenia: factors influencing adherence and consequences of 
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10. Olivares JM, Sermon J, Hemels M, Schreiner A. Definitions and drivers of relapse in patients 
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Disorder. Archives of General Psychiatry. 1999;56(3):241-7 
12. Ascher-Svanum H, Zhu B, Faries DE, Salkever D, Slade EP, Peng X, et al. The cost of 
relapse and the predictors of relapse in the treatment of schizophrenia. BMC Psychiatry. 
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13. World Health Organization (WHO). Adherence to Long-Term Therapies: Evidence for 
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14. Kane JM, Kishimoto T, Correll CU. Non-adherence to medication in patients with psychotic 
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15. Jonsdottir H, Opjordsmoen S, Birkenaes AB, Engh JA, Ringen PA, Vaskinn A, et al. 
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16. Ingersoll KS, Cohen J. The impact of medication regimen factors on adherence to chronic 
treatment: a review of literature. Journal of Behavioral Medicine. 2008;31(3):213-24 


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17. Iglay K, Cao X, Mavros P, Joshi K, Yu S, Tunceli K. Systematic Literature Review and 
Meta-analysis of Medication Adherence With Once-weekly Versus Once-daily Therapy. 
Clinical Therapeutics. 2015;37(8):1813-18210 
18. Kishimoto H, Maehara M. Compliance and persistence with daily, weekly, and monthly 
bisphosphonates for osteoporosis in Japan: analysis of data from the CISA. Arch Osteoporos. 
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19. Baldessarini RJ, Viguera AC. Commentary: Neuroleptic withdrawal in schizophrenic 
patients. Arch Gen Psychiatry. 1995;52(3):189-92 
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patients. A review of the literature. Arch Gen Psychiatry. 1995;52(3):173-88 
21. Leucht S, Tardy M, Komossa K, Heres S, Kissling W, Salanti G, et al. Antipsychotic drugs 
versus placebo for relapse prevention in schizophrenia: a systematic review and meta-
analysis. The Lancet. 2012;379(9831):2063-71 
22. Moncrieff J. Does antipsychotic withdrawal provoke psychosis? Review of the literature on 
rapid onset psychosis (supersensitivity psychosis) and withdrawal-related relapse. Acta 
Psychiatr Scand. 2006;114(1):3-13 
23. Bhugra D. The global prevalence of schizophrenia. PLoS Med. 2005;2(5):e151; quiz e75 
24. Keating D, McWilliams S, Schneider I, Hynes C, Cousins G, Strawbridge J, et al. 
Pharmacological guidelines for schizophrenia: a systematic review and comparison of 
recommendations for the first episode. BMJ Open. 2017;7(1):e013881 
25. Kane JM. Review of treatments that can ameliorate nonadherence in patients with 
schizophrenia. J Clin Psychiatry. 2006;67 Suppl 5:9-14 
26. Smeraldi E, Cavallaro R, Folnegovic-Smalc V, Bidzan L, Emin Ceylan M, Schreiner A. 
Long-term remission in schizophrenia and schizoaffective disorder: results from the 
risperidone long-acting injectable versus quetiapine relapse prevention trial (ConstaTRE). 
Ther Adv Psychopharmacol. 2013;3(4):191-9 
27. Food and Drug Administration (FDA). Clinical Pharmacology and Biopharmaceutics Review 
for PERSERIS. 2019. Center for Drug Evaluation and Research (CDER): NDA-
210655.[cited 10 Jun 2019]. Available 
from: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210655Orig1s000ClinPhar
mR.pdf. 
28. Cutler NR. Pharmacokinetic studies of antipsychotics in healthy volunteers versus patients. J 
Clin Psychiatry. 2001;62 Suppl 5:10-3; discussion 23-4 
29. Misdrahi D, Tessier A, Daubigney A, Meissner WG, Schurhoff F, Boyer L, et al. Prevalence 
of and Risk Factors for Extrapyramidal Side Effects of Antipsychotics: Results From the 
National FACE-SZ Cohort. J Clin Psychiatry. 2019;80(1) 
30. Stroup TS, McEvoy JP, Swartz MS, Byerly MJ, Glick ID, Canive JM, et al. The National 
Institute of Mental Health Clinical Antipsychotic Trials of Intervention Effectiveness 
(CATIE) project: schizophrenia trial design and protocol development. Schizophr Bull. 
2003;29(1):15-31 


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31. Moore TJ, Furberg CD. The Harms of Antipsychotic Drugs: Evidence from Key Studies. 
Drug Saf. 2017;40(1):3-14 
32. Food and Drug Administration (FDA). Clinical Pharmacology and Biopharmaceutics Review 
for Risperdal Consta Long-Acting Injection. 2003. Center for Drug Evaluation and Research 
(CDER): NDA 21-346. [NDA 21-346: Clinical Pharmacology and Biopharmaceutics 
Review(s)/:[cited 09 Mar 2019]. Available 
from: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2003/21346_RisperdalTOC.cfm. 
33. Food and Drug Administration (FDA). Labeling and Package Insert, RISPERDAL. 2019. 
NDAs 020-272, 020-588, 021-444.[cited 21 March 2019]. Available 
from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/020272s082,020588s070,
021444s056lbl.pdf. 
34. Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS) for 
schizophrenia. Schizophr Bull. 1987;13(2):261-76 
35. Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E, et al. The Mini-
International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a 
structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry. 
1998;59 Suppl 20:22-33;quiz 4-57 
36. American Psychiatric A, Task Force for the Handbook of Psychiatric M, Rush AJ. Handbook 
of psychiatric measures. Washington, DC: American Psychiatric Association; 2000. 
37. Food and Drug Administration (FDA). Suicidal Ideation and Behavior: Prospective 
Assessment of Occurrence in Clinical Trials. 2012. Division of Psychiatry Products in the 
Center for Drug Evaluation and Research (CDER): Draft Guidance for Industry. Revision 
1/Silver Spring, MD:[cited 24 Jun 2019]. Available 
from: https://www.fda.gov/media/79482/download. 
38. Chouinard G, Margolese HC. Manual for the Extrapyramidal Symptom Rating Scale (ESRS). 
Schizophrenia research. 2005;76(2-3):247-65 
39. Opler MG, Yavorsky C, Daniel DG. Positive and Negative Syndrome Scale (PANSS) 
Training: Challenges, Solutions, and Future Directions. Innov Clin Neurosci. 2017;14(11-
12):77-81 
40. Opler LA, Stanley R. Kay, Lindenmayer JP, Fiszbein A. Structured Clinical Interview – 
Positive and Negative Syndrome Scale (SCI-PANSS). In: Multi-Health Systems IM, editor. 
1992. 
41. Busner J, Targum SD. The Clinical Global Impressions Scale: Applying a Research Tool in 
Clinical Practice. Psychiatry (Edgmont).4(7):28-37 
42. Guy W. ECDEU Assessment Manual for Psychopharmacology. Rockville, MD: U.S. Dept. 
of Health, Education, and Welfare, Public Health Service, Alcohol, Drug Abuse, and Mental 
Health Administration, National Institute of Mental Health, Psychopharmacology Research 
Branch, Division of Extramural Research Programs; 1976. 


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43. Pinna F, Deriu L, Diana E, Perra V, Randaccio RP, Sanna L, et al. Clinical Global 
Impression-severity score as a reliable measure for routine evaluation of remission in 
schizophrenia and schizoaffective disorders. Ann Gen Psychiatry. 2015;14:6 
44. The Columbia Lighthouse Project. Pharmaceutical-Funded Research 2019. [cited 04 May 
2019]. Available from: http://cssrs.columbia.edu/pharmaceutical-funded-research/. 
45. Chouinard GR-C, A., Annable LJ, B. The extrapyramidal symptom rating scale. 1980;7(3) 
46. Chouinard G, Margolese HC. Erratum to “Manual for the Extrapyramidal Symptom Rating 
Scale (ESRS)”. Schizophrenia research. 2006;85(1-3). Erratum in: Chouinard G, Margolese 
HC. Manual for the Extrapyramidal Symptom Rating Scale (ESRS). Schizophr Res. 
2005;76(2-3):247-65. 
47. Marder SR, Davis JM, Chouinard G. The effects of risperidone on the five dimensions of 
schizophrenia derived by factor analysis: combined results of the North American trials. J 
Clin Psychiatry. 1997;58(12):538-46 
48. Food and Drug Administration (FDA). Code of Federal Regulations Title 21, Part 11 Online: 
Medical Devices, Database.2018. 23 Apr 2019. Source: 62 FR 13464, 20 Mar 1997. 
Available 
from: https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=11
. 
49. International Council for Harmonisation of Technical, Requirements for Pharmaceuticals for 
Human Use (ICH). Integrated Addendum to ICH E6(R1): Guideline for Good Clinical 
Practice E6(R2). 9 November 2016. ICH Harmonised Tripartite Guideline. [E6(R2): Step 
4/:[cited 03 Mar 2019]. Available from: https://www.tga.gov.au/publication/note-guidance-
good-clinical-practice. 
 


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18 APPENDICES 
18.1 
Schedules of Events 
18.1.1 
Schedule of Events LYN-005-C-004: Screening and LYN-005 Doses 1 and 2 
Visit Name 
Screening 
Visit 
Run-In 
(10 days) 
Admit to 
Unit 
IR RSP 
Prep/ PK 
LYN-005 Dose 1 
LYN-
005 
Dose 2 
DC 
From 
unit 
Out 
Patient 
Subject Status 
Outpatient 
Inpatient Stay 1 
Study Day 
- 21 to -14 
-13 to -3 
-2 
-1 
1a 
2 
3 
4 
5 
6 
7 
8 
9 
10-13 
Study Event 
Section 
 
Study Treatment LYN-005 (N=24) 
Oral antipsychotic 
4.1.1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
IR risperidone run-inb 
4.1.2 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
Randomization 
4.1.4 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
00EL placebo 
6.3.3 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
LYN-005 
6.3.3 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
Study Treatment IR (00EL) risperidone (N=8) 
Oral antipsychotic 
4.1.1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
IR risperidone run-in 
4.1.2 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
Randomization 
4.1.4 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
00EL placebo 
6.3.3 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
00EL risperidone  
6.3.3 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Screening and Safety Assessments 
Informed Consentc 
8.1.1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
PILL-5 Questionnaire 
8.1.2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
H. Pylori breath test 
8.1.3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
8.1.4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
MINI 
8.1.5.1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
PANSS 
8.1.5.2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Visit Name 
Screening 
Visit 
Run-In 
(10 days) 
Admit to 
Unit 
IR RSP 
Prep/ PK 
LYN-005 Dose 1 
LYN-
005 
Dose 2 
DC 
From 
unit 
Out 
Patient 
Subject Status 
Outpatient 
Inpatient Stay 1 
Study Day 
- 21 to -14 
-13 to -3 
-2 
-1 
1a 
2 
3 
4 
5 
6 
7 
8 
9 
10-13 
CGI-S 
8.1.5.3 
X 
 
 
 
X 
 
 
 
 
 
X 
 
X 
 
C-SSRS 
8.1.5.4 
X 
 
 
 
X 
 
 
 
 
 
X 
 
X 
 
ESRS 
8.1.5.5 
X 
 
 
 
X 
 
 
 
 
 
X 
 
X 
 
Fecal Occult Blood  
8.1.6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examinationd 
8.1.7 
X 
 
X 
X 
X 
 
 
 
 
 
 
X 
 
X 
Vital Signs e 
8.1.8 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Electrocardiogram f 
8.1.9 
X 
X 
X 
X 
X 
 
 
X 
 
 
 
X 
 
 
CYP2D6 Genotype 
8.1.10 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serology Assessments g  
8.1.11 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety Laboratory Assessments h 
8.1.12 
X 
X 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
Prolactin 
8.1.13 
X 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
Pregnancy Test i 
8.1.14 
X 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
Compliance Lab Assessments  
8.1.15 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/ Exclusion Criteria  
5.1, 5.2 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Acid Reflux Symptom Severity 
Scale 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Solicitation of AEs 
8.2.3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
6.5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
GI Imaging (On Study) 
Abdominal X-ray  
8.3 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 


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Visit Name 
Screening 
Visit 
Run-In 
(10 days) 
Admit to 
Unit 
IR RSP 
Prep/ PK 
LYN-005 Dose 1 
LYN-
005 
Dose 2 
DC 
From 
unit 
Out 
Patient 
Subject Status 
Outpatient 
Inpatient Stay 1 
Study Day 
- 21 to -14 
-13 to -3 
-2 
-1 
1a 
2 
3 
4 
5 
6 
7 
8 
9 
10-13 
Pharmacokinetic Assessments (see Note)j 
Blood Sample/PK 
8.4 
 
 
S1k 
S2 l 
S3 m 
S3 m 
S3 m 
S3 m 
S3 m 
S3 m 
S3 m 
S4 n 
S3 m 
S3 m 
AEs = Adverse Events; CGI-S = Clinical Global Impression – Severity Scale; C-SSRS = Columbia-Suicide Severity Rating Scale; CYP = Cytochrome P450; ESRS = Extrapyramidal Symptom 
Rating Scale; GI = Gastrointestinal; PK = Pharmacokinetics; RSP = Risperidone; PANSS = Positive and Negative Syndrome Scale. 
General Notes: 
a. 
Prior to dosing with LYN-005 Days 1, 8, 15, and 22, vital signs, ECG, PE, safety laboratory tests, AEs, CGI-S, ESRS will be collected. After dosing, safety assessments will be performed, 
including vital signs, directed physical examination, adverse event, and concomitant medication collection. 
b. 
Subjects must receive at least 5 IR risperidone doses during the Run-in period, 3 in the outpatient setting and 2 in the inpatient setting. 
c. 
Consent form is signed prior to performing any study related procedures. 
d. 
General physical examinations will occur at Screening and Days -2; all other exams will be directed physical examinations. 
e. 
Vital signs will be collected prior to (-60 min) and 12 hours (±45 min) after IR risperidone dosing on Days -2 to Day -1 and on Day 1 at prior to dosing and 4, 8, 12, 24 and 36 hours post dose. 
The timing and addition of further assessments will occur at the Investigator’s discretion. 
f. 
Electrocardiograms should be collected 4 hours (±15 mins) after IR dosing on Day -1, prior to and 4 hours (±15 mins) after dosing with LYN-005 and additionally where indicated. 
g. 
Serological laboratory tests are for Hepatitis B, and C and HIV. 
h. 
All safety laboratory assessments include serum chemistry, hematology, and coagulation. Measurement of HbA1C concentration only occurs at Screening. 
i. 
Required in women of childbearing potential only. 
j. 
Schedule for Pharmacokinetic (PK) collection: 
k. 
S1: Date and time of last dose is to be recorded, and PK samples to be collected upon arrival at unit, 12 pm and 6 pm (±30 min) on Day -2, prior to administration of half the regimen of 
daily IR risperidone in the evening (i.e. either 1 or 2 mg). 
l. 
S2: On the morning of Day -1, a dose of IR risperidone (2 or 4 mg based on dose allocation) will be administered to each subject after fasting with PK samples collected prior to and at 15 
min (±5 min), 30 min (±5 min), 45 min (±5 min), 1 h (±5 min), 2 h (±15 min), 4 h (±15 min), 6 h (±15 min), 8 h (±15 min), 12 h (±30 min), 16 h (±30 min), and 24 h (±30 min) after 
dosing. (The 24-hour post-dose sample is equivalent to the LYN-005 pre-dose sample.) 
m. S3: PK samples to be collected just prior to and following LYN-005 administration or 00EL placebo Day 1 at 1 h (±5 min), 2 h (±15 min), 4 h (±15 min), 6 h (±15 min), 8 h (±15 min), 12 
h (±30 min) post dose and every 12 hours (±30) thereafter through Day 7, and again on Day 9 through the morning of Day 10.  
n. 
S4: On Day 8, a PK sample will be taken prior to the administration of LYN-005 administration or 00EL placebo and at hours 4 and 8 (±15 min). 
 


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18.1.2 
Schedule of Events LYN-005-C-004:  LYN-005 Dose 3 through Study Completion 
Visit Name 
LYN-005 Dose 3 
Resume 
Prior APD 
 
EOSa 
Subject Status 
Inpatient Stay 2 
Outpatient 
Study Day 
14b 
15 
16 
17 
18 
21 
22 
23 
35 
Window 
- 
- 
- 
- 
+1 
±1 
±1 
±1 
±1 
Study Event 
Section 
 
Study Treatment: LYN-005 (N=24) 
Oral antipsychotic 
4.1.1 
 
 
 
 
 
 
X 
X 
X 
IR risperidone run-in 
4.1.2 
 
 
 
 
 
 
 
 
 
Randomization 
4.1.4 
 
 
 
 
 
 
 
 
 
00EL placebo 
6.3.3 
X 
X 
X 
X 
X 
X 
 
 
 
LYN-005 
6.3.3 
 
X 
 
 
 
 
 
 
 
Study Treatment: IR (00EL) risperidone (N=8) 
Oral antipsychotic 
4.1.1 
 
 
 
 
 
 
X 
X 
X 
IR risperidone run-in 
4.1.2 
 
 
 
 
 
 
 
 
 
Randomization 
4.1.4 
 
 
 
 
 
 
 
 
 
00EL placebo 
6.3.3 
 
X 
 
 
 
 
 
 
 
00EL risperidone  
6.3.3 
X 
X 
X 
X 
X 
X 
 
 
 
Safety Assessment 
Informed Consent 
8.1.1 
 
 
 
 
 
 
 
 
 
Medical History  
8.1.2 
 
 
 
 
 
 
 
 
 
PILL-5 Questionnaire 
8.1.3 
 
 
 
 
 
 
 
 
 
H. Pylori breath test 
8.1.4 
 
 
 
 
 
 
 
 
 
MINI 
8.1.5.1 
 
 
 
 
 
 
 
 
 
PANSS 
8.1.5.2 
 
 
 
 
 
 
 
 
 
CGI-S  
8.1.5.3 
 
X 
 
 
 
X 
 
 
X 
C-SSRS 
8.1.5.4 
 
X 
 
 
 
X 
 
 
X 
ESRS 
8.1.5.5 
 
X 
 
 
 
X 
 
 
X 


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Visit Name 
LYN-005 Dose 3 
Resume 
Prior APD 
 
EOSa 
Subject Status 
Inpatient Stay 2 
Outpatient 
Study Day 
14b 
15 
16 
17 
18 
21 
22 
23 
35 
Window 
- 
- 
- 
- 
+1 
±1 
±1 
±1 
±1 
Fecal Occult Blood  
8.1.6 
 
 
 
 
 
 
 
 
 
Physical Examinationc 
8.1.7 
 
X 
 
X 
 
 
 
X 
X 
Vital Signs 
8.1.8 
 
X 
X 
X 
X 
X 
X 
X 
X 
Electrocardiogramd 
8.1.9 
 
X 
 
X 
 
 
X 
 
 
CYP2D6 Genotype  
8.1.10 
 
 
 
 
 
 
 
 
 
Serology Assessments  
8.1.11 
 
 
 
 
 
 
 
 
 
Safety Laboratory Assessments e 
8.1.12 
 
X 
X 
 
 
 
 
 
X 
Prolactin 
8.1.13 
 
X 
 
 
 
X 
 
 
X 
Pregnancy Test f 
8.1.14 
 
X 
 
 
 
 
 
 
 
Compliance Laboratory Assessments  
8.1.15 
 
 
 
X 
 
 
 
 
 
Inclusion/ Exclusion Criteria  
5.1, 5.2 
 
 
 
 
 
 
 
 
 
Solicitation of AEs 
8.2.3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
6.5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
GI Imaging (on study) 
Abdominal X-ray 
8.3 
X 
 
 
 
 
X 
 
 
X 
Pharmacokinetics Assessments (see Note)g 
Blood Sample/PK 
8.4 
S5h 
S5h 
S5h 
S5h 
S5h 
S5h 
S5h 
 
 
AEs = Adverse Events; CGI-S = Clinical Global Impression – Severity Scale; C-SSRS = Columbia-Suicide Severity Rating Scale; CYP = Cytochrome P450; ESRS = Extrapyramidal Symptom Rating 
Scale; GI = Gastrointestinal; PK = Pharmacokinetics; RSP = Risperidone; PANSS = Positive and Negative Syndrome Scale. 
General Notes: 
a. 
Final outpatient clinic visit will occur on Day 35 (EOS Visit). 
b. 
Subjects will return to clinic on the evening of Day 14 to prepare for dosing on the morning of Day 15. 
c. 
General physical examinations will occur on Day 35; all other examinations will be directed physical examinations. 
d. 
4 hours (±15 mins) after IR dosing on Day -1, prior to and 4 hours (±15 mins) after dosing with LYN-005 and additionally where indicated. 
e. 
All safety laboratory assessments include serum chemistry, hematology, and coagulation. 


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f. 
Required in women of childbearing potential only. 
g. 
Schedule for Pharmacokinetic (PK) collection: 
h. 
S5: On Day 14, the subject will return to the clinic to prepare for an inpatient stay through Day 16. A PK sample will be collected upon arrival in the inpatient unit on Day 14. On Day 15, PK 
samples will be collected pre-dose and at 1 h (±5 min), 2 h (±15 min), 4 h (±15 min), 6 h (±15 min), 8 h (±15 min), 12 h (±30 mi), and 24 h (±30 min) (i.e., Day 16). Single samples also are to be 
collected on Days 17, 18, 21, and 22; on these study days, the sample is to be collected at the same time of day as the 24-hour post-dose sample on Day 16. 
 


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18.2 
PILL-5 Questionnaire 
The italicized text below is the questionnaire, which is to be administered to the individual during 
the Screening process.  
The individual should complete this questionnaire independently and should answer all questions. 
If the subject has not experienced pill swallowing in the past week, they should answer for a 
previous week where they have taken oral medications. After the individual has provided his/her 
answers, the total score is achieved by adding together the numerical value from each question. 
Subjects with a PILL-5 questionnaire score of 5 or greater are to be excluded. 
These are statements that many people have used to describe their problems swallowing pills. 
Please circle the response that indicates how frequently you had the same experience in the past 
week. If you do not have any problem swallowing pills, please circle zero (0) in response to these 
statements. 
Please circle the response that indicates how frequently you experience these symptoms. 
Never 
Almost 
Never 
Sometimes 
Almost 
Always 
Always 
1. Pills stick in my throat
0 
1 
2 
3 
4 
2. Pills stick in my chest
0 
1 
2 
3 
4 
3. I have a fear of swallowing
pills 
0 
1 
2 
3 
4 
4. My problem swallowing pills
interferes with my ability to take 
medication  
0 
1 
2 
3 
4 
5. I can't take my pills without
crushing, coating, or using other 
forms of assistance  
0 
1 
2 
3 
4 


Protocol LYN-005-C-004  
Pharmacokinetic Study of LYN-005 Risperidone Extended Release Capsules 
Page 83 of 140
Protocol LYN-005-C-004 | Version 1.0 | 11 June 2020 
Lyndra Confidential 
18.3 
Mini International Neuropsychiatric Interview (MINI) version 7.0.2 


M.I.N.I.
MINI INTERNATIONAL NEUROPSYCHIATRIC INTERVIEW 
English Version 7.0.2 
For
DSM-5 
© Copyright 1992-2016 Sheehan DV 
All rights reserved.  No part of this document may be reproduced or transmitted in any form, or by any means, electronic or 
mechanical, including photocopying, or by any information storage or retrieval system, without permission in writing from Dr. 
Sheehan.  Individual researchers, clinicians and students working in nonprofit or publicly owned settings (including universities, 
nonprofit hospitals, and government institutions) may make paper copies of a M.I.N.I. instrument for their personal clinical and 
research use, but not for institutional use, or for any financial profit or gain.  Any use involving financial gain requires a license 
agreement from the copyright holder and payment of a per use license fee. 
DISCLAIMER 
Our aim is to assist in the assessment and tracking of patients with greater efficiency and accuracy.  Before action is taken on any 
data collected and processed by this program, it should be reviewed and interpreted by a licensed clinician. 
This program is not designed or intended to be used in the place of a full medical and psychiatric evaluation by a qualified licensed 
physician – psychiatrist.  It is intended only as a tool to facilitate accurate data collection and processing of symptoms elicited by 
trained personnel. It is not a diagnostic test. 
M.I.N.I. 7.0.2 (August 8, 2016) (8/8/16)
Page 1 of 23


M.I.N.I. 7.0.2 (August 8, 2016) (8/8/16)
2
Patient Name: 
 Patient Number: 
Date of Birth: 
Time Interview Began: 
Interviewer’s Name: 
 Time Interview Ended: 
Date of Interview: 
Total Time: 
MEETS 
  PRIMARY
MODULES 
TIME FRAME 
CRITERIA 
ICD-10-CM 
  DIAGNOSIS 
A 
MAJOR DEPRESSIVE EPISODE 
Current (2 weeks) 
☐ 
Past
☐ 
Recurrent 
☐ 
MAJOR DEPRESSIVE DISORDER 
Current (2 weeks) 
☐ 
F32.x
☐ 
Past
☐ 
F32.x
☐ 
Recurrent 
☐ 
F33.x
☐ 
B 
SUICIDALITY 
Current (Past Month) 
☐  
☐ 
Lifetime attempt 
☐  
☐   Low   ☐   Moderate  ☐   High 
☐ 
SUICIDE BEHAVIOR DISORDER 
Current 
☐  
(In Past Year)
☐ 
In early remission 
☐  
(1 - 2 Years Ago)
☐ 
C 
MANIC EPISODE 
Current 
☐ 
Past 
☐ 
HYPOMANIC EPISODE 
Current 
☐ 
Past 
☐ 
☐    Not Explored
BIPOLAR I DISORDER 
Current 
☐ 
F31.0 - F31.76
☐ 
Past 
☐ 
F31.0 - F31.76
☐ 
BIPOLAR I DISORDER WITH PSYCHOTIC FEATURES 
Current 
☐ 
F31.2/31.5/F31.64
☐ 
Past 
☐ 
F31.2/31.5/F31.64
☐ 
BIPOLAR II DISORDER 
Current 
☐ 
F31.81
☐ 
Past 
☐ 
F31.81
☐ 
OTHER SPECIFIED BIPOLAR AND RELATED DISORDER 
Current 
☐ 
F31.89
☐ 
Past 
☐ 
F31.89
☐ 
D 
PANIC DISORDER 
Current (Past Month) 
☐ 
F41.0
☐ 
Lifetime 
☐ 
F40.0
☐ 
E 
AGORAPHOBIA 
Current 
☐ 
F40.00
☐ 
F 
SOCIAL ANXIETY DISORDER (Social Phobia) 
Current (Past Month) 
☐ 
F40.10
☐ 
G 
OBSESSIVE-COMPULSIVE DISORDER 
Current (Past Month) 
☐ 
F42.2
☐ 
H 
POSTTRAUMATIC STRESS DISORDER 
Current (Past Month) 
☐ 
F43.10
☐ 
I 
ALCOHOL USE DISORDER 
Past 12 Months 
☐
F10.10 - F10.21
☐ 
J 
SUBSTANCE USE DISORDER (Non-alcohol) 
Past 12 Months 
☐
F11.10 - F19.21
☐ 
Page 2 of 23


M.I.N.I. 7.0.2 (August 8, 2016) (8/8/16)
3 
K 
ANY PSYCHOTIC DISORDER 
Current 
☐ 
F20.81-F29
☐ 
Lifetime 
☐ 
F20.81-F29
☐ 
MAJOR DEPRESSIVE DISORDER WITH PSYCHOTIC FEATURES
Current 
☐ 
F32.3/F33.3
☐ 
Past 
☐ 
F32.3/F33.3
☐ 
BIPOLAR I DISORDER WITH PSYCHOTIC FEATURES
Current 
☐ 
F31.2/F31.5/F31.64
☐ 
Past 
☐ 
F31.2/F31.5/F31.64
☐ 
L 
ANOREXIA NERVOSA 
Current (Past 3 Months) 
☐ 
F50.01/F50.02
☐ 
M 
BULIMIA NERVOSA 
Current (Past 3 Months) 
☐ 
F50.2
☐ 
MB BINGE-EATING DISORDER
Current (Past 3 Months) 
☐ 
F50.81
☐ 
N 
GENERALIZED ANXIETY DISORDER 
Current (Past 6 Months) 
☐ 
F41.1
☐ 
O
MEDICAL, ORGANIC, DRUG CAUSE RULED OUT 
☐  No   ☐   Yes 
☐   Uncertain
P 
ANTISOCIAL PERSONALITY DISORDER 
Lifetime 
☐ 
F60.2
☐ 
IDENTIFY THE PRIMARY DIAGNOSIS BY CHECKING THE APPROPRIATE CHECK BOX. 
(Which problem troubles you the most or dominates the others or came first in the natural history?) 
Page 3 of 23


M.I.N.I. 7.0.2 (August 8, 2016) (8/8/16)
4
GENERAL INSTRUCTIONS 
The M.I.N.I. was designed as a brief structured interview for the major psychiatric disorders in DSM-5 and ICD-10.  Validation and 
reliability studies have been done comparing the M.I.N.I. to the SCID-P for DSM-III-R and the CIDI (a structured interview developed 
by the World Health Organization).  The results of these studies show that the M.I.N.I. has similar reliability and validity properties, 
but can be administered in a much shorter period of time (mean 18.7 ± 11.6 minutes, median 15 minutes) than the above 
referenced instruments.  Clinicians can use it, after a brief training session.  Lay interviewers require more extensive training. 
INTERVIEW: 
In order to keep the interview as brief as possible, inform the patient that you will conduct a clinical interview that is more 
structured than usual, with very precise questions about psychological problems which require a yes or no answer. 
GENERAL FORMAT: 
The M.I.N.I. is divided into modules identified by letters, each corresponding to a diagnostic category. 
•At the beginning of each diagnostic module (except for psychotic disorders module), screening question(s) corresponding
to the main criteria of the disorder are presented in a gray box.
•At the end of each module, diagnostic box(es) permit the clinician to indicate whether diagnostic criteria are met.
CONVENTIONS: 
Sentences written in « normal font » should be read exactly as written to the patient in order to standardize the assessment 
of diagnostic criteria. 
Sentences written in « CAPITALS » should not be read to the patient.  They are instructions for the interviewer to assist in the 
scoring of the diagnostic algorithms. 
Sentences written in « bold » indicate the time frame being investigated.  The interviewer should read them as often as 
necessary.  Only symptoms occurring during the time frame indicated should be considered in scoring the responses. 
Answers with an arrow above them (➨) indicate that one of the criteria necessary for the diagnosis or diagnoses is not met. 
In this case, the interviewer should go to the end of the module, circle « NO » in all the diagnostic boxes and move to the 
next module. 
When terms are separated by a slash (/) the interviewer should read only those symptoms known to be present in the 
patient (for example, questions J2b or K6b). 
Phrases in (parentheses) are clinical examples of the symptom.  These may be read to the patient to clarify the question. 
RATING INSTRUCTIONS: 
All questions must be rated. The rating is done at the right of each question by circling either YES or NO.  Clinical judgment 
by the rater should be used in coding the responses.  Interviewers need to be sensitive to the diversity of cultural beliefs in 
their administration of questions and rating of responses. The rater should ask for examples when necessary, to ensure 
accurate coding.  The patient should be encouraged to ask for clarification on any question that is not absolutely clear. 
The clinician should be sure that each dimension of the question is taken into account by the patient (for example, time 
frame, frequency, severity, and/or alternatives). 
Symptoms better accounted for by an organic cause or by the use of alcohol or drugs should not be coded positive in the 
M.I.N.I.  The M.I.N.I. has questions that investigate these issues.
For any questions, suggestions, need for a training session or information about updates of the M.I.N.I., please contact: 
David V Sheehan, M.D., M.B.A. 
University of South Florida College of Medicine 
tel : +1 813-956-8437 
e-mail : dsheehan@health.usf.edu
For licensing, permissions, or questions, contact: davidvsheehan@gmail.com
Page 4 of 23


M.I.N.I. 7.0.2 (August 8, 2016) (8/8/16)
5 
A. MAJOR DEPRESSIVE EPISODE
(➨MEANS:  GO TO THE DIAGNOSTIC BOX, CIRCLE NO IN THE DIAGNOSTIC BOX, AND MOVE TO THE NEXT MODULE)
NO 
YES 
most of the day, nearly every day, for two weeks? 
IF NO, CODE NO TO A1b:  IF YES ASK: 
NO 
YES 
empty or hopeless, most of the day, nearly every day? 
A2 
a Were you ever much less interested in most things or much less able to 
NO 
YES 
enjoy the things you used to enjoy most of the time, for two weeks? 
IF NO, CODE NO TO A2b:    IF YES ASK: 
b In the past two weeks, were you much less interested in most things or 
NO 
YES 
much less able to enjoy the things you used to enjoy, most of the time? 
➨ 
IS A1a OR A2a CODED YES? 
NO 
YES 
A3 
IF A1b OR A2b = YES: EXPLORE THE CURRENT AND THE MOST SYMPTOMATIC PAST EPISODE, OTHERWISE 
IF A1b AND A2b = NO: EXPLORE ONLY THE MOST SYMPTOMATIC PAST EPISODE. 
Past 2 Weeks 
Past Episode 
Over that two-week period, when you felt depressed or uninterested: a 
Was your appetite decreased or increased nearly every day?  Did your 
NO 
YES 
NO 
YES 
weight decrease or increase without trying intentionally (i.e., by ±5% of 
body weight or ±8 lb or ± 3.5 kg, for a 160 lb/70 kg person in a month)? 
IF YES TO EITHER, CODE YES. 
b Did you have trouble sleeping nearly every night 
NO 
YES 
NO 
YES 
(difficulty falling asleep, waking up in the middle of the night, 
early morning wakening or sleeping excessively)? 
c Did you talk or move more slowly than normal or were you fidgety, restless 
NO 
YES 
NO 
YES 
or having trouble sitting still almost every day? Did anyone notice this? 
d Did you feel tired or without energy almost every day? 
NO 
YES 
NO 
YES 
e Did you feel worthless or guilty almost every day? 
NO 
YES 
NO 
YES 
IF YES, ASK FOR EXAMPLES.  LOOK FOR DELUSIONS OF FAILURE, OF INADEQUACY, OF RUIN OR OF GUILT, OR 
OF NEEDING PUNISHMENT OR DELUSIONS OF DISEASE OR DEATH OR NIHILISTIC OR SOMATIC DELUSIONS. 
THE EXAMPLES ARE CONSISTENT WITH A DELUSIONAL IDEA.     Current Episode ☐ No  ☐ Yes
Past Episode 
☐ No  ☐ Yes 
f 
Did you have difficulty concentrating, thinking or making decisions 
NO 
YES 
NO 
YES 
almost every day? 
g Did you repeatedly think about death (FEAR OF DYING DOES NOT COUNT HERE), 
NO 
YES 
NO 
YES 
or have any thoughts of killing yourself, or have any intent 
or plan to kill yourself? Did you attempt suicide? IF YES TO EITHER, CODE YES. 
A4 
Did these symptoms cause significant distress or problems at home, 
NO 
YES 
NO 
YES 
at work, at school, socially, in your relationships, or in some other 
important way, and are they a change from your previous functioning? 
A1 
a Were you ever depressed or down, or did you feel sad, empty or hopeless, 
b For the past two weeks, were you depressed or down, or did you feel sad, 
a 
Page 5 of 23


M.I.N.I. 7.0.2 (August 8, 2016) (8/8/16)
6 
A5 
In between 2 episodes of depression, did you ever have an interval of at least 2 
months, without any significant depression or any significant loss of interest? 
N/A 
NO 
YES 
ARE 5 OR MORE ANSWERS (A1-A3) CODED YES AND IS A4 CODED YES 
FOR THAT TIME FRAME? 
AND 
IS “RULE OUT ORGANIC CAUSE (O2 SUMMARY)” CODED YES? 
SPECIFY IF THE EPISODE IS CURRENT AND / OR PAST. 
IF A5 IS CODED YES, CODE YES FOR RECURRENT. 
NO
YES 
MAJOR DEPRESSIVE 
EPISODE 
CURRENT 
☐ 
PAST 
☐ 
RECURRENT 
☐ 
A6 
a How many episodes of depression did you have in your lifetime?    _____ 
Between each episode there must be at least 2 months without any significant depression. 
Page 6 of 23


M.I.N.I. 7.0.2 (August 8, 2016) (8/8/16)
10 
C. MANIC AND HYPOMANIC EPISODES
(➨MEANS:  GO TO THE DIAGNOSTIC BOXES, CIRCLE NO IN MANIC AND HYPOMANIC DIAGNOSTIC BOXES, AND MOVE TO NEXT MODULE)
Do you have any family history of manic-depressive illness or bipolar disorder,
or any family member who had mood swings treated with a medication like lithium, 
NO 
YES
sodium valproate (Depakote) or lamotrigine (Lamictal)?
THIS QUESTION IS NOT A CRITERION FOR BIPOLAR DISORDER, BUT IS ASKED TO INCREASE
THE CLINICIAN’S VIGILANCE ABOUT THE RISK FOR BIPOLAR DISORDER.
IF YES, PLEASE SPECIFY WHO:________________________________________
C1 
a Have you ever had a period of time when you were feeling 'up' or 'high' or ‘hyper’ 
NO 
YES 
and so active or full of energy or full of yourself that you got into trouble, - or that 
other people thought you were not your usual self?  (Do not consider 
times when you were intoxicated on drugs or alcohol.) 
IF PATIENT IS PUZZLED OR UNCLEAR ABOUT WHAT YOU MEAN 
BY 'UP' OR 'HIGH' OR ‘HYPER’, CLARIFY AS FOLLOWS:  By 'up' or 'high' or ‘hyper’ 
I mean: having elated mood; increased energy or increased activity; needing less sleep; 
having rapid thoughts; being full of ideas; having an increase in productivity, motivation, 
creativity, or impulsive behavior; phoning or working excessively or spending more money. 
IF NO, CODE NO TO C1b:  IF YES ASK: 
b Are you currently feeling ‘up’ or ‘high’ or ‘hyper’ or full of energy? 
NO 
YES 
C2 
a Have you ever been persistently irritable, for several days, so that you 
NO 
YES 
had arguments or verbal or physical fights, or shouted at people outside 
your family?  Have you or others noticed that you have been more irritable 
or over reacted, compared to other people, even in situations that you felt 
were justified? 
IF NO, CODE NO TO C2b:  IF YES ASK: 
b Are you currently feeling persistently irritable? 
NO 
YES
➨ 
IS C1a OR C2a CODED YES? 
NO 
YES 
C3 
IF C1b OR C2b = YES: EXPLORE THE CURRENT EPISODE FIRST AND THEN THE MOST SYMPTOMATIC PAST EPISODE, OTHERWISE 
IF C1b AND C2b = NO: EXPLORE ONLY THE MOST SYMPTOMATIC PAST EPISODE 
WHEN EXPLORING THE CURRENT EPISODE, PREFACE EACH QUESTION AS FOLLOWS: 
Over the past few days including today, when you felt high and full of energy or irritable, did you: 
WHEN EXPLORING THE PAST EPISODE, PREFACE EACH QUESTION AS FOLLOWS: 
Over a period of a few days in the past, when you felt most high and most full of energy or most irritable, did you: 
Current Episode 
Past Episode 
a Feel that you could do things others couldn't do, or that you were an 
NO 
YES 
NO 
YES 
especially important person? IF YES, ASK FOR EXAMPLES. 
THE EXAMPLES ARE CONSISTENT WITH A DELUSIONAL IDEA. 
Current Episode ☐ No ☐ Yes
Past Episode 
☐ No ☐ Yes 
b Need less sleep (for example, feel rested after only a few hours sleep)? 
NO 
YES 
NO 
YES 
Page 7 of 23


M.I.N.I. 7.0.2 (August 8, 2016) (8/8/16)
11 
Current Episode 
Past Episode 
c Talk too much without stopping, or felt a pressure to keep talking? 
NO 
YES 
NO 
YES 
d Notice your thoughts going very fast or running together or racing 
NO 
YES 
NO 
YES 
or moving very quickly from one subject to another? 
e Become easily distracted so that any little interruption could distract you? 
NO 
YES 
NO 
YES 
f 
Have a significant increase in your activity or drive, at work, at school, 
NO 
YES 
NO 
YES 
socially or sexually or did you become physically or mentally restless? 
This increase in activity may be with or without a purpose. 
g Want so much to engage in pleasurable activities that you ignored the risks or NO 
YES 
NO 
YES 
consequences (for example, spending sprees, reckless driving, or sexual 
indiscretions)? 
C3 SUMMARY:  WHEN RATING CURRENT EPISODE: 
NO 
YES 
NO 
YES 
IF C1b IS NO, ARE 4 OR MORE C3 ANSWERS INCLUDING C3f CODED YES? 
IF C1b IS YES, ARE 3 OR MORE C3 ANSWERS INCLUDING C3f CODED YES? 
WHEN RATING PAST EPISODE: 
IF C1a IS NO, ARE 4 OR MORE C3 ANSWERS INCLUDING C3f CODED YES? 
IF C1a IS YES, ARE 3 OR MORE C3 ANSWERS INCLUDING C3f CODED YES? 
CODE YES ONLY IF THE ABOVE 3 OR 4 SYMPTOMS OCCURRED DURING THE SAME TIME PERIOD. 
RULE:  ELATION/EXPANSIVENESS REQUIRES ONLY 3 OF THE C3 SYMPTOMS, WHILE 
IRRITABLE MOOD ALONE REQUIRES 4 OF THE C3 SYMPTOMS. 
C4 
What is the longest time these symptoms lasted (most of the day nearly every day)? 
ASSESS THIS DURATION FROM THE VERY START TO THE VERY END OF SYMPTOMS, NOT JUST THE PEAK. 
a)
3 consecutive days or less
☐   
☐ 
b)
4, 5 or 6 consecutive days or more
☐   
☐ 
c)
7 consecutive days or more
☐   
☐ 
C5 
Were you hospitalized for these problems? 
NO 
YES 
NO 
YES 
IF YES, CIRCLE YES IN MANIC EPISODE FOR THAT TIME FRAME AND GO TO C7. 
C6 
Did these symptoms cause significant problems at home, at work, socially, 
NO 
YES 
NO 
YES 
in your relationships, at school or in some other important way? 
C7 
Were these symptoms associated with a clear change in the way that you 
NO 
YES 
NO 
YES 
previously functioned and that was different from the way that you usually are? 
ARE C3 SUMMARY AND C7 AND (C4C OR C5 OR C6 OR ANY PSYCHOTIC FEATURE IN K1 THROUGH K8) 
CODED YES? 
AND 
IS “RULE OUT ORGANIC CAUSE (O2 SUMMARY)” CODED YES? 
SPECIFY IF THE EPISODE IS CURRENT AND / OR PAST. 
NO
YES 
MANIC EPISODE 
CURRENT 
☐ 
PAST 
☐
Page 8 of 23


M.I.N.I. 7.0.2 (August 8, 2016) (8/8/16)
12 
IS C3 SUMMARY CODED YES AND ARE C5 AND C6 CODED NO AND C7 CODED YES, 
AND IS EITHER C4b OR C4C CODED YES? 
AND 
IS “RULE OUT ORGANIC CAUSE (O2 SUMMARY)” CODED YES? 
AND 
ARE ALL PSYCHOTIC FEATURES IN K1 THROUGH K8 CODED NO? 
SPECIFY IF THE EPISODE IS CURRENT AND / OR PAST. 
IF YES TO CURRENT MANIC EPISODE, THEN CODE CURRENT HYPOMANIC EPISODE AS NO. 
IF YES TO PAST MANIC EPISODE, THEN CODE PAST HYPOMANIC EPISODE AS NOT EXPLORED. 
HYPOMANIC EPISODE 
CURRENT ☐ NO
☐YES
PAST 
☐NO
☐YES
☐NOT EXPLORED
ARE C3 SUMMARY AND C4a CODED YES AND IS C5 CODED NO? 
SPECIFY IF THE EPISODE IS CURRENT AND / OR PAST. 
IF YES TO CURRENT MANIC EPISODE OR HYPOMANIC EPISODE, 
THEN CODE CURRENT HYPOMANIC SYMPTOMS AS NO.  
IF YES TO PAST MANIC EPISODE OR YES TO PAST HYPOMANIC EPISODE, 
THEN CODE PAST HYPOMANIC SYMPTOMS AS NOT EXPLORED. 
HYPOMANIC SYMPTOMS 
CURRENT ☐ NO
☐YES
PAST 
☐NO
☐YES
☐NOT EXPLORED
C8 
a) IF MANIC EPISODE IS POSITIVE FOR EITHER CURRENT OR PAST ASK:
Did you have 2 or more of these (manic) episodes lasting 7 days or more (C4c) in your
lifetime (including the current episode if present)?
NO 
YES 
b) IF MANIC OR HYPOMANIC EPISODE IS POSITIVE FOR EITHER CURRENT OR PAST ASK:
Did you have 2 or more of these (hypomanic) episodes lasting 4 days or more (C4b)
in your lifetime (including the current episode)?
NO 
YES 
c) IF THE PAST “HYPOMANIC SYMPTOMS” CATEGORY IS CODED POSITIVE ASK:
Did you have these hypomanic symptoms lasting only 1 to 3 days (C4a) 2 or more times
in your lifetime, (including the current episode if present)?
NO 
YES 
Page 9 of 23


M.I.N.I. 7.0.2 (August 8, 2016) (8/8/16)
13 
D. PANIC DISORDER
(➨MEANS: GO TO THE DIAGNOSTIC BOX, CIRCLE NO AND MOVE TO THE NEXT MODULE)
➨ 
D1 
a Have you, on more than one occasion, had spells or attacks when you suddenly 
NO 
YES 
felt anxious, very frightened, uncomfortable or uneasy, even in situations 
where most people would not feel that way? 
➨ 
b Did the spells surge to a peak within 10 minutes of starting? 
NO 
YES
➨ 
D2 
At any time in the past, did any of those spells or attacks come on unexpectedly 
NO 
YES 
or occur in an unpredictable or unprovoked manner? 
D3 
Have you ever had one such attack followed by a month or more of persistent  
NO 
YES 
concern about having another attack, or worries about the consequences of the attack - 
or did you make any significant change in your behavior because of the attacks (e.g., avoiding 
unfamiliar situations, or avoiding leaving your house or shopping alone, or doing things 
to avoid having a panic attack or visiting your doctor or the emergency room more frequently)? 
D4 
During the worst attack that you can remember: 
a Did you have skipping, racing or pounding of your heart? 
NO 
YES 
b Did you have sweating or clammy hands? 
NO 
YES 
c Were you trembling or shaking? 
NO 
YES 
d Did you have shortness of breath or difficulty breathing or a smothering sensation? 
NO 
YES 
e Did you have a choking sensation or a lump in your throat? 
NO 
YES 
f 
Did you have chest pain, pressure or discomfort? 
NO 
YES 
g Did you have nausea, stomach problems or sudden diarrhea? 
NO 
YES 
h Did you feel dizzy, unsteady, lightheaded or feel faint? 
NO 
YES 
i 
Did you have hot flushes or chills? 
NO 
YES 
j 
Did you have tingling or numbness in parts of your body? 
NO 
YES 
k Did things around you feel strange, unreal, detached or unfamiliar, or did 
NO 
YES 
you feel outside of or detached from part or all of your body? 
l
Did you fear that you were losing control or going crazy?
NO 
YES 
m Did you fear that you were dying? 
NO 
YES 
➨
D5 
ARE BOTH D3, AND 4 OR MORE D4 ANSWERS, CODED YES? 
NO 
YES 
PANIC DISORDER 
LIFETIME
D6 
In the past month did you have persistent concern about having another attack, 
NO 
YES 
or worry about the consequences of the attacks, 
PANIC DISORDER 
or did you change your behavior in any way because of the attacks?
CURRENT
Page 10 of 23


M.I.N.I. 7.0.2 (August 8, 2016) (8/8/16)
14 
IS EITHER D5 OR D6 CODED YES? 
AND 
IS “RULE OUT ORGANIC CAUSE (O2 SUMMARY)” CODED YES? 
SPECIFY IF THE EPISODE IS CURRENT AND / OR LIFETIME. 
NO 
YES 
PANIC DISORDER 
LIFETIME 
☐ 
CURRENT 
☐ 
E. AGORAPHOBIA
(➨MEANS: GO TO THE DIAGNOSTIC BOX, CIRCLE NO AND MOVE TO THE NEXT MODULE)
E1 
Do you feel anxious or uneasy in places or situations where help might not be available 
or escape might be difficult if you had a panic attack or panic-like or embarrassing symptoms, like: 
being in a crowd, or standing in a line (queue), 
being in an open space or when crossing a bridge, 
being in an enclosed space, 
when you are alone away from home, or alone at home,
➨
or traveling in a bus, train or car or using public transportation? 
NO 
YES 
➨
ARE 2 OR MORE OF THE ABOVE SITUATIONS IN E1 CODED YES? 
NO 
YES 
➨
E2 
Do these situations almost always bring on fear or anxiety? 
NO 
YES 
➨
E3 
Do you fear these situations so much that you avoid them, or suffer 
NO 
YES 
through them, or need a companion to face them? 
➨
E4 
Is this fear or anxiety excessive or out of proportion to the real danger in the situation? 
NO 
YES 
➨ 
E5 
Did this avoidance, fear or anxiety persist for at least 6 months? 
NO 
YES 
➨
E6 
Did these symptoms cause significant distress or problems at home, 
NO 
YES 
at work, socially, at school or in some other important way? 
IS E6 CODED YES? 
NO 
YES 
AGORAPHOBIA
CURRENT 
Page 11 of 23


M.I.N.I. 7.0.2 (August 8, 2016) (8/8/16)
15 
F. SOCIAL ANXIETY DISORDER (Social Phobia)
(➨MEANS:  GO TO THE DIAGNOSTIC BOX, CIRCLE NO AND MOVE TO THE NEXT MODULE)
➨ 
F1 
In the past month, did you have persistent fear and significant anxiety at being watched, 
NO 
YES 
being the focus of attention, or of being humiliated or embarrassed or rejected? 
This includes things like speaking in public, eating in public or with others, writing 
while someone watches, performing in front of others or being in social situations. 
EXAMPLES OF SUCH SOCIAL SITUATIONS TYPICALLY INCLUDE 
•
INITIATING OR MAINTAINING A CONVERSATION,
•
PARTICIPATING IN SMALL GROUPS,
•
DATING,
•
SPEAKING TO AUTHORITY FIGURES,
•
ATTENDING PARTIES,
•
PUBLIC SPEAKING,
•
EATING IN FRONT OF OTHERS,
•
PERFORMING IN FRONT OF OTHERS,
•
URINATING IN A PUBLIC WASHROOM, ETC.
➨
F2 
Do these social situations almost always bring on fear or anxiety? 
NO 
YES 
➨
F3 
Do you fear these social situations so much that you avoid them, or suffer 
NO 
YES 
through them, or need a companion to face them? 
➨
F4 
Is this social fear or anxiety excessive or unreasonable in these social situations? 
NO 
YES 
➨ 
F5 
Did this social avoidance, fear or anxiety persist for at least 6 months? 
NO 
YES 
➨
F6 
Did these social fears cause significant distress or interfere with your ability 
NO 
YES 
to function at work, at school or socially or in your relationships or 
in some other important way? 
IS F6 CODED YES? 
AND 
IS “RULE OUT ORGANIC CAUSE (O2 SUMMARY)” CODED YES? 
NOTE TO CLINICIAN: PLEASE SPECIFY IF THE SUBJECT’S FEARS ARE RESTRICTED TO SPEAKING OR 
PERFORMING IN PUBLIC.
NO 
YES 
SOCIAL ANXIETY 
DISORDER 
(Social Phobia) 
CURRENT
RESTRICTED TO PERFORMANCE 
SAD ONLY 
☐ 
Page 12 of 23


M.I.N.I. 7.0.2 (August 8, 2016) (8/8/16)
16 
G. OBSESSIVE-COMPULSIVE DISORDER
(➨MEANS:  GO TO THE DIAGNOSTIC BOX, CIRCLE NO AND MOVE TO THE NEXT MODULE)
G1a 
In the past month, have you been bothered by recurrent thoughts, impulses, or 
NO 
YES 
images that were unwanted, distasteful, inappropriate, intrusive, or distressing? -
¯
(For example, the idea that you were dirty, contaminated or had germs, or fear of 
SKIP TO G3a 
contaminating others, or fear of harming someone even though it disturbs or distresses 
you, or fear you would act on some impulse, or fear or superstitions that you would 
be responsible for things going wrong, or obsessions with sexual thoughts, images 
or impulses, or religious obsessions.) 
G1b 
In the past month, did you try to suppress these thoughts, impulses, or 
NO 
YES 
images or to neutralize or to reduce them with some other thought or action?
¯
SKIP TO G3a 
(DO NOT INCLUDE SIMPLY EXCESSIVE WORRIES ABOUT REAL LIFE PROBLEMS.  DO NOT 
INCLUDE OBSESSIONS DIRECTLY RELATED TO HOARDING, HAIR PULLING, SKIN PICKING, 
BODY DYSMORPHIC DISORDER, EATING DISORDERS, SEXUAL DEVIATIONS, 
PATHOLOGICAL GAMBLING, OR ALCOHOL OR DRUG ABUSE BECAUSE THE PATIENT MAY 
DERIVE PLEASURE FROM THE ACTIVITY AND MAY WANT TO RESIST IT ONLY BECAUSE OF 
ITS NEGATIVE CONSEQUENCES.) 
G2 
Did they keep coming back into your mind even when you tried to ignore or 
NO 
YES 
get rid of them?
obsessions
G3a 
In the past month, did you feel driven to do something repeatedly in response to an 
NO 
YES 
obsession or in response to a rigid rule, like washing or cleaning excessively, counting or 
checking things over and over, or repeating or arranging things, 
or other superstitious rituals? 
G3b 
Are these rituals done to prevent or reduce anxiety or distress or to prevent something 
NO 
YES 
bad from happening and are they excessive or unreasonable? 
compulsions
➨ 
ARE (G1a AND G1b AND G2) OR (G3a AND G3b) CODED YES?
NO 
YES 
G4 
In the past month, did these obsessive thoughts and/or compulsive behaviors 
cause significant distress, or interfere with your ability to function at home, at work, at 
school or socially or in your relationships or in some other important way or did they 
take more than one hour a day? 
AND 
IS “RULE OUT ORGANIC CAUSE (O2 SUMMARY)” CODED YES? 
(CHECK FOR ANY OBSESSIVE-COMPULSIVE SYMPTOMS STARTING WITHIN 3 WEEKS OF AN INFECTION) 
SPECIFY THE LEVEL OF INSIGHT AND IF THE EPISODE IS TIC-RELATED. 
NO 
YES 
O.C.D.
CURRENT 
INSIGHT: 
GOOD OR FAIR 
☐
POOR 
☐ 
ABSENT 
☐ 
DELUSIONAL 
☐ 
TIC-RELATED 
☐
Page 13 of 23


M.I.N.I. 7.0.2 (August 8, 2016) (8/8/16)
17 
H. POSTTRAUMATIC STRESS DISORDER
(➨MEANS:  GO TO THE DIAGNOSTIC BOX, CIRCLE NO, AND MOVE TO THE NEXT MODULE)
➨ 
H1 
Have you ever experienced or witnessed or had to deal with an extremely traumatic 
NO 
YES 
event that included actual or threatened death or serious injury or sexual violence 
to you or someone else? 
EXAMPLES OF TRAUMATIC EVENTS INCLUDE: SERIOUS ACCIDENTS, SEXUAL OR PHYSICAL ASSAULT, 
A TERRORIST ATTACK, BEING HELD HOSTAGE, KIDNAPPING, FIRE, DISCOVERING A BODY, WAR, 
OR NATURAL DISASTER, WITNESSING THE VIOLENT OR SUDDEN DEATH OF SOMEONE CLOSE TO YOU, 
OR A LIFE-THREATENING ILLNESS. 
➨ 
H2 
Starting after the traumatic event, did you repeatedly re-experience the event 
NO 
YES 
in an unwanted mentally distressing way, (such as in recurrent dreams related to the event, 
intense recollections or memories, or flashbacks or as if the event was recurring) or did you 
have intense physical or psychological reactions when you were reminded about the 
event or exposed to a similar event? 
H3 
In the past month: 
a Did you persistently try to avoid thinking about or remembering distressing details 
NO 
YES 
or feelings related to the event? 
b Did you persistently try to avoid people, conversations, places, situations, 
NO 
YES 
activities or things that bring back distressing recollections of the event? 
➨
ARE 1 OR MORE H3 ANSWERS CODED YES? 
NO 
YES 
H4 
In the past month: 
a Did you have trouble recalling some important part of the trauma? 
NO 
YES 
(but not because of or related to head trauma, alcohol or drugs). 
b Were you constantly and unreasonably negative about yourself or others or the world? 
NO 
YES 
c Did you constantly blame yourself or others in unreasonable ways for the trauma? 
NO 
YES 
d Were your feelings always negative (such as fear, horror, anger, guilt or shame)? 
NO 
YES 
e Have you become much less interested in participating in activities that 
NO 
YES 
were meaningful to you before? 
f 
Did you feel detached or estranged from others? 
NO 
YES 
g Were you unable to experience any good feelings (such as happiness, satisfaction 
NO 
YES 
or loving feelings)?
➨ 
ARE 2 OR MORE H4 ANSWERS CODED YES? 
NO 
YES 
Page 14 of 23


M.I.N.I. 7.0.2 (August 8, 2016) (8/8/16)
18 
H5 
 
In the past month: 
 
a Were you especially irritable or did you have outbursts of anger with little or no provocation? 
NO 
YES 
b Were you more reckless or more self-destructive? 
NO 
YES 
c Were you more nervous or constantly on your guard? 
NO 
YES 
d Were you more easily startled? 
NO 
YES 
e Did you have more difficulty concentrating? 
NO 
YES 
f 
Did you have more difficulty sleeping? 
NO 
YES 
➨ 
ARE 2 OR MORE H5 ANSWERS CODED YES? 
NO 
YES 
➨
H6 
Did all these problems start after the traumatic event and last for more than one month? 
NO 
YES 
H7 
During the past month, did these problems cause significant distress, 
or interfere with your ability to function at home, at work, at 
school or socially or in your relationships or in some other important way? 
AND 
IS “RULE OUT ORGANIC CAUSE (O2 SUMMARY)” CODED YES? 
SPECIFY IF THE CONDITION IS ASSOCIATED WITH DEPERSONALIZATION, DEREALIZATION OR 
WITH DELAYED EXPRESSION. 
NO 
YES 
POSTTRAUMATIC 
STRESS DISORDER
CURRENT 
WITH 
DEPERSONALIZATION 
☐ 
DEREALIZATION 
☐ 
DELAYED EXPRESSION 
☐ 
Page 15 of 23


M.I.N.I. 7.0.2 (August 8, 2016) (8/8/16)
24 
ASK FOR AN EXAMPLE OF EACH QUESTION ANSWERED POSITIVELY.  CODE YES ONLY IF THE EXAMPLES CLEARLY SHOW A DISTORTION OF THOUGHT OR OF 
PERCEPTION OR IF THEY ARE NOT CULTURALLY APPROPRIATE.  THE PURPOSE OF THIS MODULE IS TO EXCLUDE PATIENTS WITH PSYCHOTIC DISORDERS. THIS MODULE 
NEEDS EXPERIENCE. 
Now I am going to ask you about unusual experiences that some people have. 
K1 
a Have you ever believed that people were spying on you, or that someone 
NO 
YES 
was plotting against you, or trying to hurt you? 
NOTE:  ASK FOR EXAMPLES TO RULE OUT ACTUAL STALKING. 
b 
IF YES: do you currently believe these things? 
NO 
YES
K2 
a Have you ever believed that someone was reading your mind or could hear 
NO 
YES 
your thoughts, or that you could actually read someone’s mind or hear what 
another person was thinking? 
b 
IF YES: do you currently believe these things? 
NO 
YES 
K3 
a Have you ever believed that someone or some force outside of yourself 
NO 
YES 
put thoughts in your mind that were not your own, or made you act in a 
way that was not your usual self?  Have you ever felt that you were 
possessed? 
CLINICIAN: ASK FOR EXAMPLES AND DISCOUNT ANY THAT ARE NOT PSYCHOTIC. 
b 
IF YES: do you currently believe these things? 
NO 
YES 
K4 
a Have you ever believed that you were being sent special messages through 
NO 
YES 
the TV, radio, internet, newspapers, books, or magazines or that a person 
you did not personally know was particularly interested in you? 
b 
IF YES: do you currently believe these things? 
NO 
YES
K5 
a Have your relatives or friends ever considered any of your beliefs odd 
NO 
YES 
or unusual? 
CLINICIAN: ASK FOR EXAMPLES. ONLY CODE YES IF THE EXAMPLES ARE CLEARLY 
DELUSIONAL IDEAS NOT EXPLORED IN QUESTIONS K1 TO K4. FOR EXAMPLE, RELIGIOUS, DEATH, 
DISEASE OR SOMATIC DELUSIONS, DELUSIONS OF GRANDIOSITY, JEALOUSY OR GUILT, OR OF 
FAILURE, INADEQUACY, RUIN, OR DESTITUTION, OR NIHILISTIC DELUSIONS. 
b 
IF YES: do they currently consider your beliefs strange or unusual? 
NO 
YES 
K6 
a Have you ever heard things other people couldn't hear, such as voices? 
NO 
YES 
IF YES TO VOICE HALLUCINATION: Was the voice commenting on your thoughts 
NO 
YES 
or behavior or did you hear two or more voices talking to each other? 
b 
IF YES TO K6a: have you heard sounds / voices in the past month? 
NO 
YES 
IF YES TO VOICE HALLUCINATION: Was the voice commenting on your thoughts 
NO 
YES 
or behavior or did you hear two or more voices talking to each other? 
K. PSYCHOTIC DISORDERS AND MOOD DISORDER WITH PSYCHOTIC FEATURES
Page 16 of 23


M.I.N.I. 7.0.2 (August 8, 2016) (8/8/16)
25 
K7 
a Have you ever had visions when you were awake or have you ever seen things 
NO 
YES 
other people couldn't see? 
CLINICIAN: CHECK TO SEE IF THESE ARE CULTURALLY INAPPROPRIATE. 
b 
IF YES:  have you seen these things in the past month? 
NO 
YES 
CLINICIAN'S JUDGMENT 
K8 
a 
DID THE PATIENT EVER IN THE PAST EXHIBIT DISORGANIZED, INCOHERENT OR DERAILED 
NO 
YES 
SPEECH, OR MARKED LOOSENING OF ASSOCIATIONS? 
K8 
b 
IS THE PATIENT CURRENTLY EXHIBITING INCOHERENCE, DISORGANIZED OR DERAILED 
NO 
YES 
SPEECH, OR MARKED LOOSENING OF ASSOCIATIONS? 
K9 
a 
DID THE PATIENT EVER IN THE PAST EXHIBIT DISORGANIZED OR CATATONIC  
NO 
YES 
BEHAVIOR? 
K9 
b 
IS THE PATIENT CURRENTLY EXHIBITING DISORGANIZED OR CATATONIC  
NO 
YES 
BEHAVIOR? 
K10 a 
DID THE PATIENT EVER IN THE PAST HAVE NEGATIVE SYMPTOMS, E.G. SIGNIFICANT REDUCTION OF 
NO 
YES 
EMOTIONAL EXPRESSION OR AFFECTIVE FLATTENING, POVERTY OF SPEECH (ALOGIA) OR 
AN INABILITY TO INITIATE OR PERSIST IN GOAL-DIRECTED ACTIVITIES (AVOLITION)? 
K10 b 
ARE NEGATIVE SYMPTOMS OF SCHIZOPHRENIA, E.G. SIGNIFICANT REDUCTION OF EMOTIONAL 
NO 
YES 
EXPRESSION OR AFFECTIVE FLATTENING, POVERTY OF SPEECH (ALOGIA) OR AN INABILITY 
TO INITIATE OR PERSIST IN GOAL-DIRECTED ACTIVITIES (AVOLITION), PROMINENT DURING  
THE INTERVIEW? 
K11 a 
ARE 1 OR MORE « a » QUESTIONS FROM K1a TO K7a, CODED YES? 
AND IS EITHER: 
MAJOR DEPRESSIVE EPISODE, (CURRENT, RECURRENT OR PAST) 
OR 
 MANIC OR HYPOMANIC EPISODE, (CURRENT OR PAST) CODED YES? 
AND 
HOW LONG HAS THE MOOD EPISODE LASTED? _________ 
HOW LONG HAS THE PSYCHOTIC EPISODE LASTED? _________
IF SUCH A MOOD EPISODE IS PRESENT, CODE YES TO K11a ONLY IF THE MOOD DISTURBANCE IS PRESENT 
FOR THE MAJORITY OF THE TOTAL DURATION OF THE ACTIVE AND RESIDUAL PERIODS OF THE 
PSYCHOTIC SYMPTOMS. OTHERWISE CODE NO. 
NO 
YES 
9 K13
IF NO TO K11a AND THE TOTAL DURATION OF THE MOOD EPISODE IS LESS THAN THE TOTAL DURATION 
OF THE PSYCHOTIC EPISODE, THEN CIRCLE NO IN BOTH ‘MOOD DISORDER WITH PSYCHOTIC FEATURES’ 
DIAGNOSTIC BOXES AND MOVE TO K13. 
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M.I.N.I. 7.0.2 (August 8, 2016) (8/8/16)
26 
b You told me earlier that you had period(s) when you felt (depressed/high/persistently 
irritable). 
 
Were the beliefs and experiences you just described (SYMPTOMS CODED YES FROM K1a TO
K7a) restricted exclusively to times when you were feeling depressed/high/irritable? 
 
IF THE PATIENT EVER HAD A PERIOD OF AT LEAST 2 WEEKS OF HAVING THESE BELIEFS OR EXPERIENCE 
(PSYCHOTIC SYMPTOMS) WHEN THEY WERE NOT DEPRESSED/HIGH/IRRITABLE, CODE NO TO THIS 
DISORDER. 
 
IF THE ANSWER IS NO TO THIS DISORDER GROUPING, ALSO CIRCLE NO TO K12 AND MOVE TO K13 
NO 
YES 
MOOD DISORDER WITH 
PSYCHOTIC FEATURES 
 
LIFETIME 
K12 
a ARE 1 OR MORE « b » QUESTIONS FROM K1b TO K7b CODED YES? 
 
AND IS EITHER: 
MAJOR DEPRESSIVE EPISODE (CURRENT) 
OR 
MANIC OR HYPOMANIC EPISODE (CURRENT) CODED YES? 
 
IF THE ANSWER IS YES TO THIS DISORDER (LIFETIME OR CURRENT), CIRCLE NO TO K13 AND K14 AND 
MOVE TO THE NEXT MODULE. 
NO 
YES 
MOOD DISORDER WITH 
PSYCHOTIC FEATURES 
 
CURRENT 
K13 
ARE 1 OR MORE « b » QUESTIONS FROM K1b TO K8b, CODED YES? 
 
AND 
 
ARE 2 OR MORE « b » QUESTIONS FROM K1b TO K10b, CODED YES? 
 
AND DID AT LEAST TWO OF THE PSYCHOTIC SYMPTOMS OCCUR DURING THE SAME 1-MONTH PERIOD? 
 
AND 
 
IS “RULE OUT ORGANIC CAUSE (O2 SUMMARY)” CODED YES? 
NO 
YES 
PSYCHOTIC DISORDER 
CURRENT 
K14 
IS K13 CODED YES? 
 
OR 
 
(ARE 1 OR MORE « a » QUESTIONS FROM K1a TO K8a, CODED YES? 
 
AND 
 
ARE 2 OR MORE « a » QUESTIONS FROM K1a TO K10a, CODED YES 
 
AND 
 
DID AT LEAST 2 OF THE PSYCHOTIC SYMPTOMS OCCUR DURING THE SAME 1-MONTH PERIOD?) 
 
AND 
 
IS “RULE OUT ORGANIC CAUSE (O2 SUMMARY)” CODED YES? 
NO 
YES 
PSYCHOTIC DISORDER 
LIFETIME 
 
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M.I.N.I. 7.0.2 (August 8, 2016) (8/8/16)
31 
N. GENERALIZED ANXIETY DISORDER
(➨MEANS:  GO TO THE DIAGNOSTIC BOX, CIRCLE NO, AND MOVE TO THE NEXT MODULE)
➨ 
N1 
a 
Were you excessively anxious or worried about several routine things, 
NO 
YES 
over the past 6 months? 
IN ENGLISH, IF THE PATIENT IS UNCLEAR ABOUT WHAT YOU MEAN, PROBE BY ASKING 
(Do others think that you are a worrier or a “worry wart”?) AND GET EXAMPLES.
➨ 
b 
Are these anxieties and worries present most days? 
NO 
YES 
➨ 
ARE THE PATIENT’S ANXIETY AND WORRIES RESTRICTED EXCLUSIVELY 
NO 
YES 
TO, OR BETTER EXPLAINED BY, ANY DISORDER PRIOR TO THIS POINT? 
➨ 
N2 
Do you find it difficult to control the worries? 
NO 
YES 
N3 
FOR THE FOLLOWING, CODE NO IF THE SYMPTOMS ARE CONFINED TO 
FEATURES OF ANY DISORDER EXPLORED PRIOR TO THIS POINT. 
When you were anxious over the past 6 months, did you, most of the time: 
a Feel restless, keyed up or on edge? 
NO 
YES 
b Have muscle tension? 
NO 
YES 
c Feel tired, weak or exhausted easily? 
NO 
YES 
d Have difficulty concentrating or find your mind going blank? 
NO 
YES 
e Feel irritable? 
NO 
YES 
f Have difficulty sleeping (difficulty falling asleep, waking up in the middle 
NO 
YES 
of the night, early morning wakening or sleeping excessively)? 
➨ 
ARE 3 OR MORE N3 ANSWERS CODED YES? 
NO 
YES 
N4 
Do these anxieties and worries significantly disrupt your ability to work, 
to function socially or in your relationships or in other important areas of
your life or cause you significant distress? 
AND IS “RULE OUT ORGANIC CAUSE (O2 SUMMARY)” CODED YES? 
NO 
YES 
GENERALIZED ANXIETY 
DISORDER 
CURRENT
O. RULE OUT MEDICAL, ORGANIC OR DRUG CAUSES FOR ALL DISORDERS
IF THE PATIENT CODES POSITIVE FOR ANY CURRENT DISORDER OR A MAJOR DEPRESSIVE EPISODE OR A MANIC OR A HYPOMANIC EPISODE ASK: 
Just before these symptoms began: 
O1a 
Were you taking any drugs or medicines or in withdrawal from any of these?
☐ No 
☐ Yes ☐ Uncertain
O1b 
Did you have any medical illness?
☐ No 
☐ Yes ☐ Uncertain
O2 
IF O1a OR O1b IS CODED YES, IN THE CLINICIAN’S JUDGMENT, IS EITHER LIKELY TO BE A DIRECT 
CAUSE OF THE PATIENT'S DISORDER?  IF NECESSARY, ASK ADDITIONAL OPEN-ENDED QUESTIONS. 
☐ No 
☐ Yes ☐ Uncertain
O2 SUMMARY: HAS AN “ORGANIC” / MEDICAL / DRUG RELATED CAUSE BEEN RULED OUT?
☐ No 
☐ Yes ☐ Uncertain
IF O2 IS YES, THEN O2 SUMMARY IS NO. IF O2 IS NO, THEN O2 SUMMARY IS YES. OTHERWISE IT IS UNCERTAIN.
Page 19 of 23


M.I.N.I. 7.0.2 (August 8, 2016) (8/8/16)
33 
MOOD DISORDERS: DIAGNOSTIC ALGORITHM 
Consult Modules: 
A 
Major Depressive Episode 
C 
(Hypo)manic Episode 
K 
Psychotic Disorders 
MODULE K: 
1a  IS K11b CODED YES? 
NO 
YES 
1b 
IS K12a CODED YES? 
NO 
YES 
MODULES A and C: 
Current 
  Past 
2 
a 
CIRCLE YES IF A DELUSIONAL IDEA IS IDENTIFIED IN A3e
YES
YES
OR IN ANY PSYCHOTIC FEATURE IN K1 THROUGH K7 
b 
CIRCLE YES IF A DELUSIONAL IDEA IS IDENTIFIED IN C3a
YES
YES
OR IN ANY PSYCHOTIC FEATURE IN K1 THROUGH K7
c 
IS MAJOR DEPRESSIVE EPISODE CODED YES (CURRENT OR PAST)? 
AND 
IS MANIC EPISODE CODED NO (CURRENT AND PAST)? 
AND 
IS HYPOMANIC EPISODE CODED NO (CURRENT AND PAST)? 
AND 
IS “RULE OUT ORGANIC CAUSE (O2 SUMMARY)” CODED YES? 
SPECIFY: 
•
IF THE DEPRESSIVE EPISODE IS CURRENT OR PAST OR BOTH
•
WITH PSYCHOTIC FEATURES, CURRENT: IF 1b OR 2a (CURRENT) = YES
WITH PSYCHOTIC FEATURES, PAST: IF 1a OR 2a (PAST) = YES
MAJOR DEPRESSIVE 
DISORDER 
Current Past 
MDD
☐ 
☐ 
With Psychotic Features 
Current
☐ 
Past
☐ 
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M.I.N.I. 7.0.2 (August 8, 2016) (8/8/16)
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d IS MANIC EPISODE CODED YES (CURRENT OR PAST)? 
AND 
IS “RULE OUT ORGANIC CAUSE (O2 SUMMARY)” CODED YES? 
SPECIFY: 
•
IF THE BIPOLAR I DISORDER IS CURRENT OR PAST OR BOTH
•
WITH SINGLE MANIC EPISODE: IF MANIC EPISODE (CURRENT OR PAST) = YES
AND MAJOR DEPRESSIVE EPISODE (CURRENT AND PAST) = NO
•
WITH PSYCHOTIC FEATURES, CURRENT: IF 1b OR 2a (CURRENT) OR 2b (CURRENT) = YES
WITH PSYCHOTIC FEATURES, PAST: IF 1a OR 2a (PAST) OR 2b (PAST) = YES
•
IF THE MOST RECENT EPISODE IS MANIC, DEPRESSED, OR HYPOMANIC (MUTUALLY EXCLUSIVE)
•
IF THE MOST RECENT MOOD EPISODE IS WITH MIXED, ANXIOUS OR PSYCHOTIC FEATURES
HYPO/MANIC WITH MIXED FEATURES = HYPO/MANIC + AT LEAST 3 SYMPTOMS FROM A3
DEPRESSED WITH MIXED FEATURES = MAJOR DEPRESSIVE EPISODE + AT LEAST 3 SYMPTOMS FROM C3
WITH ANXIOUS DISTRESS = WITH AT LEAST 3 SYMPTOMS FROM N3
BIPOLAR I 
DISORDER 
Current Past 
Bipolar I Disorder
☐ 
☐ 
Single Manic Episode ☐ 
☐ 
With Psychotic Features 
Current
☐ 
Past
☐ 
Most Recent Episode 
Manic
☐ 
Depressed
☐ 
Hypomanic
☐ 
Most Recent Episode 
With mixed features
☐ 
With anxious distress
☐ 
Most Recent Episode 
Mild
☐ 
Moderate
☐ 
Severe
☐ 
e IS MAJOR DEPRESSIVE EPISODE CODED YES (CURRENT OR PAST)? 
AND 
IS HYPOMANIC EPISODE CODED YES (CURRENT OR PAST)? 
AND 
IS MANIC EPISODE CODED NO (CURRENT AND PAST)? 
AND 
IS “RULE OUT ORGANIC CAUSE (O2 SUMMARY)” CODED YES? 
SPECIFY: 
• IF THE BIPOLAR DISORDER IS CURRENT OR PAST OR BOTH
• IF THE MOST RECENT MOOD EPISODE IS HYPOMANIC OR DEPRESSED (MUTUALLY EXCLUSIVE)
• IF THE MOST RECENT MOOD EPISODE IS WITH MIXED, ANXIOUS OR PSYCHOTIC FEATURES
HYPOMANIC WITH MIXED FEATURES = HYPOMANIC + AT LEAST 3 SYMPTOMS FROM A3
DEPRESSED WITH MIXED FEATURES = MAJOR DEPRESSIVE EPISODE + AT LEAST 3 SYMPTOMS FROM C3
WITH ANXIOUS DISTRESS = WITH AT LEAST 3 SYMPTOMS FROM N3
BIPOLAR II 
DISORDER 
Current Past 
Bipolar II Disorder
☐ 
☐ 
Most Recent Episode 
Hypomanic
☐ 
Depressed
☐ 
Most Recent Episode 
With mixed features
☐ 
With anxious distress
☐ 
Most Recent Episode 
Mild
☐ 
Moderate
☐ 
Severe
☐ 
Page 21 of 23


M.I.N.I. 7.0.2 (August 8, 2016) (8/8/16)
35 
f 
IS MAJOR DEPRESSIVE EPISODE CODED NO (CURRENT AND PAST)? 
AND 
IS MANIC EPISODE CODED NO (CURRENT AND PAST)? 
AND 
IS C4b CODED YES FOR THE APPROPRIATE TIME FRAME? 
AND 
IS C8b CODED YES? 
___________________________________________________ 
OR 
___________________________________________________ 
IS MANIC EPISODE CODED NO (CURRENT AND PAST)? 
AND 
IS HYPOMANIC EPISODE CODED NO (CURRENT AND PAST)? 
AND 
IS C4a CODED YES FOR THE APPROPRIATE TIME FRAME? 
AND 
IS C8c CODED YES? 
SPECIFY IF THE OTHER SPECIFIED BIPOLAR AND RELATED DISORDER IS CURRENT OR PAST OR BOTH. 
OTHER SPECIFIED BIPOLAR 
AND RELATED DISORDER 
Current Past 
Other Specified
☐ 
☐ 
Bipolar and Related 
Disorder 
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M.I.N.I. 7.0.2 (August 8, 2016) (8/8/16)
38 
REFERENCES 
1. Sheehan DV, Lecrubier Y, Harnett-Sheehan K, Amorim P, Janavs J, Weiller E, Hergueta T, Baker R, Dunbar G: The Mini International
Neuropsychiatric Interview (M.I.N.I.): The Development and Validation of a Structured Diagnostic Psychiatric Interview. J. Clin
Psychiatry, 1998;59(suppl 20): 22-33.
2. Sheehan DV, Lecrubier Y, Harnett-Sheehan K, Janavs J, Weiller E, Bonara LI, Keskiner A, Schinka J, Knapp E, Sheehan MF, Dunbar
GC.  Reliability and Validity of the MINI International Neuropsychiatric Interview (M.I.N.I.): According to the SCID-P.  European
Psychiatry. 1997; 12:232-241.
3. Lecrubier Y, Sheehan D, Weiller E, Amorim P, Bonora I, Sheehan K, Janavs J, Dunbar G.  The MINI International Neuropsychiatric
Interview (M.I.N.I.) A Short Diagnostic Structured Interview: Reliability and Validity According to the CIDI. European Psychiatry.
1997; 12: 224-231.
4. Amorim P, Lecrubier Y, Weiller E, Hergueta T, Sheehan D: DSM-III-R Psychotic Disorders: procedural validity of the Mini
International Neuropsychiatric Interview (M.I.N.I.).  Concordance and causes for discordance with the CIDI.  European Psychiatry.
1998; 13:26-34.
ACKNOWLEDGEMENTS 
The author wishes to acknowledge the valuable contributions made to the earlier versions of the MINI for DSM III-R and DSM IV by: 
1. Yves Lecrubier, my close collaborator (now deceased) on the initial development of the MINI for DSM III-R, the DSM IV and ICD-10.
2. Juris Janavs, Emanuelle Weiller, Christer Allgulander, Kathy Harnett-Sheehan, Roxy Baker, Michael Sheehan, Chris Gray, Thierry
Hergueta, N. Kadri, David Baldwin, Christian Even, Rosario Hidalgo, Marelli Soto-Colon, Ossama Osman.
3. Patricia Amorim for her extensive work on the development of the expanded version of the Psychotic Disorders Module and
algorithms for DSM III-R.  We have evolved her model further in the MINI for Psychotic Disorders 7 and in the MINI Plus 7 for DSM-
5.
4 Executive Scientific committee for the MINI 6.0.0 for DSM-IV: 
Christer Allgulander, Stockholm, Sweden
A. Carlo Altamura, Milano, Italy
Cyril Hoschl, Praha, Czech Republic
George Papadimitriou, Athens, Greece
Hans Ågren, Göteborg, Sweden
Hans-Jürgen Möller, München, Germany
Hans-Ulrich Wittchen, Dresden, Germany
István Bitter, Budapest, Hungary
Jean-Pierre Lépine, Paris, France
Jules Angst, Zurich, Switzerland
Julio Bobes, Oviedo, Spain
Luciano Conti, Pisa, Italy
Marelli Colon-Soto MD, Puerto Rico, United States
Michael Van Ameringen MD, Toronto, Canada
Rosario Hidalgo MD, Tampa, United States
Siegfried Kasper, Vienna, Austria
Thomas Schlaepfer, Bonn, Germany
5. Mapi and the many academic translation teams internationally who collaborated in ensuring that quality translations became
available in over 70 languages or language variants. Mapi (http://www.mapigroup.com) is now the official translation and
linguistic validation service for all variants of the MINI.
6. Individual clinicians and patients who over the years made countless suggestions to help improve the accuracy and clinical value to
the MINI: JM Giddens for her advice on the MINI  7 version of the Suicidality Disorders Module, Dr. Michael Van Ameringen for
assistance with the ADHD module, and Dr Pauline Powers for her advice on the modules on Anorexia Nervosa and Bulimia.
7. Validation studies of the MINI were made possible, in part, by grants from SmithKlineBeecham and the European Commission.
Page 23 of 23


Protocol LYN-005-C-004  
Pharmacokinetic Study of LYN-005 Risperidone Extended Release Capsules 
Page 107 of 140
Protocol LYN-005-C-004 | Version 1.0 | 11 June 2020 
Lyndra Confidential 
18.4 
Structured Clinical Interview – Positive and Negative Syndrome Scale (SCI-PANSS) 


Lewis A
Lewis A
Lewis A
Lewis A
Lewis A. Opler
. Opler
. Opler
. Opler
. Opler, M.D., Ph.D.
, M.D., Ph.D.
, M.D., Ph.D.
, M.D., Ph.D.
, M.D., Ph.D.
Stanley R
Stanley R
Stanley R
Stanley R
Stanley R. Kay
. Kay
. Kay
. Kay
. Kay, Ph.D.
, Ph.D.
, Ph.D.
, Ph.D.
, Ph.D.
J.P
J.P
J.P
J.P
J.P. Lindenmayer
. Lindenmayer
. Lindenmayer
. Lindenmayer
. Lindenmayer, M.D., &
, M.D., &
, M.D., &
, M.D., &
, M.D., &
Abraham Fiszbein, M.D.
Abraham Fiszbein, M.D.
Abraham Fiszbein, M.D.
Abraham Fiszbein, M.D.
Abraham Fiszbein, M.D.
Structured Clinical Interview –
Positive and Negative
Syndrome Scale
S C I
S C I
S C I
S C I
S C I - P A N S
P A N S
P A N S
P A N S
P A N S S
S C I - P A N S S
Page 1 of 14


Page 3
SCI–PANSS BOOKLET
PAGE 3
Copyright © 1992, 1999, Multi-Health Systems Inc. All rights reserved. In the U.S.A., P.O. Box 950, North Tonawanda, NY 14120-0950, 1-800-456-3003.
In Canada, 3770 Victoria Park Ave., Toronto, ON  M2H 3M6, 1-800-268-6011. Internationally, +1-416-492-2627. Fax, +1-416-492-3343 or 1-888-540-4484.
Structured Clinical Interview for the Positive and Negative Syndrome Scale
SCI-P
SCI-P
SCI-P
SCI-P
SCI-PANS
ANS
ANS
ANS
ANSS
L. A. Opler, M.D., Ph.D.        S. R. Kay, Ph.D.        J. P. Lindenmayer, M.D.      A. Fiszbein, M.D.
Patient Name or ID: ______________________________________________________________________
Interviewer: ____________________________________________________   Date: _____ / _____ / _____
Data on “Lack of Spontaneity and Flow of Conversation” (N6),
“Poor Rapport” (N3), and “Conceptual Disorganization” (P2)
Hi, I’m ... We’re going to be spending the next 30 to 40 minutes talking about you and your reasons for being here. Maybe you
can start out by telling me something about yourself and your background?
(Instruction to interviewer: Allow at least 5 minutes for a non-directive phase serving to establish rapport in the context of an
overview before proceeding to the specific questions listed below.)
Data on “Anxiety” (G2)
1.
Have you been feeling worried or nervous in the past week? _________________________________
IF YES, skip to question 3. IF NO, continue.
2.
Would you say that you’re usually calm and relaxed? ______________________________________
IF YES, skip to question 8. IF NO, continue.
3.
What’s been making you feel nervous (worried, not calm, not relaxed)? ________________________
4.
Just how nervous (worried, etc.) have you been feeling? ____________________________________
5.
Have you been shaking at times, or has your heart been racing? ______________________________
6.
Do you get into a state of panic? _______________________________________________________
7.
Has your sleep, eating, or participation in activities been affected? ____________________________
Data on “Delusions (General)” (PI) and “Unusual Thought Content” (G9)
8.
Have things been going well for you? ___________________________________________________
9.
Has anything been bothering you lately? _________________________________________________
10.
Can you tell me something about your thoughts on life and its purpose? ________________________
Page 2 of 14


Page 4
SCI–PANSS BOOKLET
PAGE 4
Copyright © 1992, 1999, Multi-Health Systems Inc. All rights reserved. In the U.S.A., P.O. Box 950, North Tonawanda, NY 14120-0950, 1-800-456-3003.
In Canada, 3770 Victoria Park Ave., Toronto, ON  M2H 3M6, 1-800-268-6011. Internationally, +1-416-492-2627. Fax, +1-416-492-3343 or 1-888-540-4484.
11.
Do you follow a particular philosophy (any special rules, teachings, or religious doctrine)? ____________
12.
Some people tell me they believe in the Devil; what do you think? ____________________________
IF NO (i.e., he/she doesn’t believe in the Devil), skip to question 14.
IF YES (i.e., he/she does believe), continue.
13.
Can you tell me more about this?_______________________________________________________
14.
Can you read other people’s minds? ____________________________________________________
IF NO, skip to question 16. IF YES, continue.
15.
How does that work? ________________________________________________________________
16.
Can others read your mind? ___________________________________________________________
IF NO, skip to question 19. IF YES, continue.
17.
How can they do that? _______________________________________________________________
18.
Is there any reason that someone would want to read your mind? _____________________________
19.
Who controls your thoughts? __________________________________________________________
Data on “Suspiciousness/Persecution” (P6) and “Poor Impulse Control” (GI4)
20.
How do you spend your time these days? ________________________________________________
21.
Do you prefer to be alone? ____________________________________________________________
22.
Do you join in activities with others? ___________________________________________________
IF YES, skip to question 25. IF NO, continue.
23.
Why not? ... Are you afraid of people, or do you dislike them? _______________________________
IF NO, skip to question 26. IF YES, continue.
24.
Can you explain?
__________________________________________________________________
Skip to question 26.
25.
Tell me about it.
__________________________________________________________________
26.
Do you have many friends? ___________________________________________________________
IF YES, skip to question 30. IF NO, continue.
27.
Just a few?
__________________________________________________________________
IF YES, skip to question 29. IF NO, continue.
Page 3 of 14


Page 5
SCI–PANSS BOOKLET
PAGE 5
Copyright © 1992, 1999, Multi-Health Systems Inc. All rights reserved. In the U.S.A., P.O. Box 950, North Tonawanda, NY 14120-0950, 1-800-456-3003.
In Canada, 3770 Victoria Park Ave., Toronto, ON  M2H 3M6, 1-800-268-6011. Internationally, +1-416-492-2627. Fax, +1-416-492-3343 or 1-888-540-4484.
28.
Any? .... Why?
__________________________________________________________________
Skip to question 32.
29.
Why just a few friends? ______________________________________________________________
30.
Close friends?
__________________________________________________________________
IF YES, skip to question 32. IF NO, continue.
31.
Why not?
__________________________________________________________________
32.
Do you feel that you can trust most people? ______________________________________________
IF YES, skip to question 34. IF NO, continue.
33.
Why not?
__________________________________________________________________
34.
Are there some people in particular who you don’t trust? ____________________________________
IF NO to question 34 and YES to question 32, skip to question 41.
IF NO to question 34 and NO to question 32, skip to question 36.
IF YES to question 34, continue.
35.
Can you tell me who they are? _________________________________________________________
36.
Why don’t you trust people (or name specific person)? _____________________________________
IF “DON’T KNOW” OR “DON’T WANT TO SAY,” continue. Otherwise, skip to question 41.
37.
Do you have a good reason not to trust ...?
               ______________________________________________________________________________
38.
Is there something that .... did to you? ___________________________________________________
39.
Perhaps something that ... might do to you now? __________________________________________
IF NO, skip to question 41. IF YES, continue.
40.
Can you explain to me? ______________________________________________________________
41.
Do you get along well with others? _____________________________________________________
IF YES, skip to question 43. IF NO, continue.
42.
What’s the problem? ________________________________________________________________
43.
Do you have a quick temper? __________________________________________________________
Page 4 of 14


Page 6
SCI–PANSS BOOKLET
PAGE 6
Copyright © 1992, 1999, Multi-Health Systems Inc. All rights reserved. In the U.S.A., P.O. Box 950, North Tonawanda, NY 14120-0950, 1-800-456-3003.
In Canada, 3770 Victoria Park Ave., Toronto, ON  M2H 3M6, 1-800-268-6011. Internationally, +1-416-492-2627. Fax, +1-416-492-3343 or 1-888-540-4484.
44.
Do you get into fights? _______________________________________________________________
IF NO, skip to question 48. IF YES, continue.
45.
How do these fights start? ____________________________________________________________
46.
Tell me about these fights. ____________________________________________________________
47.
How often does this happen? __________________________________________________________
48.
Do you sometimes lose control of yourself? ______________________________________________
IF NO, skip to question 50. IF YES, continue.
49.
What happens when you lose control of yourself? _________________________________________
50.
Do you like most people? _____________________________________________________________
IF YES, skip to question 52. IF NO, continue.
51.
Why not?
__________________________________________________________________
52.
Are there perhaps some people who don’t like you? ________________________________________
IF NO, skip to question 54. IF YES, continue.
53.
For what reason?
__________________________________________________________________
54.
Do others talk about you behind your back? ______________________________________________
IF NO, skip to question 57. IF YES, continue.
55.
What do they say about you? __________________________________________________________
56.
Why?_____________________________________________________________________________
57.
Does anyone ever spy on you or plot against you? _________________________________________
58.
Do you sometimes feel in danger? ______________________________________________________
IF NO, skip to question 64. IF YES, continue.
59.
Would you say that your life is in danger? _______________________________________________
60.
Is someone thinking of harming you or even perhaps thinking of killing you? ___________________
61.
Have you gone to the police for help? ___________________________________________________
62.
Do you sometimes take matters into your own hands or take action against those who might harm you?
__________________________________________________________________________________
IF NO, skip to question 64. IF YES, continue.
Page 5 of 14


Page 7
SCI–PANSS BOOKLET
PAGE 7
Copyright © 1992, 1999, Multi-Health Systems Inc. All rights reserved. In the U.S.A., P.O. Box 950, North Tonawanda, NY 14120-0950, 1-800-456-3003.
In Canada, 3770 Victoria Park Ave., Toronto, ON  M2H 3M6, 1-800-268-6011. Internationally, +1-416-492-2627. Fax, +1-416-492-3343 or 1-888-540-4484.
63.
What have you done? ________________________________________________________________
Data on “Hallucinatory Behavior” (P3) and associated delusions
64.
Do you once in a while have strange or unusual experiences? ________________________________
65.
Sometimes people tell me that they can hear noises or voices inside their head that others can’t hear.
What about you?
__________________________________________________________________
IF YES, skip to question 68. IF NO, continue.
66.
Do you sometimes receive personal communications from the radio or TV? _____________________
IF YES, skip to question 68. IF NO, continue.
67.
From God or the Devil?: _____________________________________________________________
IF NO, skip to question 83. IF YES, continue.
68.
What do you hear? __________________________________________________________________
69.
Are these as clear and loud as my voice?_________________________________________________
70.
How often do you hear these voices, noises, messages, etc.? _________________________________
71.
Does this happen at a particular time of day or all the time? __________________________________
IF HEARING NOISES ONLY, skip to question 80. IF HEARING VOICES, continue.
72.
Can you recognize whose voices these are? ______________________________________________
73.
What do the voices say? ______________________________________________________________
74.
Are the voices good or bad? ___________________________________________________________
75.
Pleasant or unpleasant? ______________________________________________________________
76.
Do the voices interrupt your thinking or your activities? ____________________________________
77.
Do they sometimes give you orders or instructions? ________________________________________
IF NO, skip to question 80. IF YES, continue.
78.
For example?
__________________________________________________________________
79.
Do you usually obey these orders (instructions)? __________________________________________
80.
What do you make of these voices (or noises); where do they really come from? _________________
81.
Why do you have these experiences?____________________________________________________
Page 6 of 14


Page 8
SCI–PANSS BOOKLET
PAGE 8
Copyright © 1992, 1999, Multi-Health Systems Inc. All rights reserved. In the U.S.A., P.O. Box 950, North Tonawanda, NY 14120-0950, 1-800-456-3003.
In Canada, 3770 Victoria Park Ave., Toronto, ON  M2H 3M6, 1-800-268-6011. Internationally, +1-416-492-2627. Fax, +1-416-492-3343 or 1-888-540-4484.
82.
Are these normal experiences?_________________________________________________________
83.
Do ordinary things sometimes look strange or distorted to you?_______________________________
84.
Do you sometimes have “visions” or see things that others can’t see? __________________________
IF NO, skip to question 88. IF YES, continue.
85.
For example?
__________________________________________________________________
86.
Do these visions seem very real or life-like? ______________________________________________
87.
How often do you have these experiences? _______________________________________________
88.
Do you sometimes smell things that are unusual or that others don’t smell? _____________________
IF NO, skip to question 90. IF YES, continue.
89.
Please explain.
__________________________________________________________________
90.
Do you get any strange or unusual sensations from your body? _______________________________
IF NO, skip to question 92. IF YES, continue.
91.
Tell me about this. __________________________________________________________________
Data on “Somatic Concern” (GI)
92.
How have you been feeling in terms of your health?________________________________________
IF OTHER THAN “GOOD,” skip to question 94. IF “GOOD,” continue.
93.
Do you consider yourself to be in top health? _____________________________________________
IF YES, skip to question 95. IF NO, continue.
94.
What has been troubling you? _________________________________________________________
95.
Do you have any medical illness or disease? ______________________________________________
96.
Has any part of your body been troubling you? ____________________________________________
IF YES, skip to question 98. IF NO, continue.
97.
How is your head?  Your heart?  Stomach?  The rest of your body? ___________________________
98.
Could you explain?__________________________________________________________________
Page 7 of 14


Page 9
SCI–PANSS BOOKLET
PAGE 9
Copyright © 1992, 1999, Multi-Health Systems Inc. All rights reserved. In the U.S.A., P.O. Box 950, North Tonawanda, NY 14120-0950, 1-800-456-3003.
In Canada, 3770 Victoria Park Ave., Toronto, ON  M2H 3M6, 1-800-268-6011. Internationally, +1-416-492-2627. Fax, +1-416-492-3343 or 1-888-540-4484.
99.
Has your head or body changed in shape or size? __________________________________________
IF NO, skip to question 102. IF YES, continue.
100. Please explain.
__________________________________________________________________
101. What is causing these changes? ________________________________________________________
Data on “Depression” (G6)
102. How has your mood been in the past week: mostly good, mostly bad? _________________________
IF “MOSTLY BAD,” skip to question 104. IF “MOSTLY GOOD,” continue.
103. Have there been times in the past week when you were feeling sad or unhappy? _________________
IF NO, skip to question 114. IF YES, continue.
104. Is there something in particular that is making you sad? ____________________________________
105. How often do you feel sad? ___________________________________________________________
106. Just how sad have you been feeling? ____________________________________________________
107. Have you been crying lately? __________________________________________________________
108. Has your mood in any way affected your sleep? ___________________________________________
109. Has it affected your appetite?__________________________________________________________
110. Do you participate less in activities on account of your mood? _______________________________
111. Have you had any thoughts of harming yourself? __________________________________________
IF NO, skip to question 114. IF YES, continue.
112. Any thoughts about ending your life? ___________________________________________________
IF NO, skip to question 114. IF YES, continue.
113. Have you attempted suicide? __________________________________________________________
Page 8 of 14


Page 10
SCI–PANSS BOOKLET
PAGE 10
Copyright © 1992, 1999, Multi-Health Systems Inc. All rights reserved. In the U.S.A., P.O. Box 950, North Tonawanda, NY 14120-0950, 1-800-456-3003.
In Canada, 3770 Victoria Park Ave., Toronto, ON  M2H 3M6, 1-800-268-6011. Internationally, +1-416-492-2627. Fax, +1-416-492-3343 or 1-888-540-4484.
Data on “Guilt Feelings” (G3) and “Grandiosity” (P5)
114. If you were to compare yourself to the average person, how would you come out: a little better, maybe
a little worse, or about the same? _______________________________________________________
IF “BETTER,” skip to question 117.
IF “ABOUT THE SAME,” skip to question 118.
IF “WORSE,” continue.
115. Worse in what ways? ________________________________________________________________
116. Just how do you feel about yourself? ____________________________________________________
Skip to question 120.
117. Better in what ways? ________________________________________________________________
Skip to question 120.
118. Are you special in some ways? ________________________________________________________
IF NO, skip to question 120. IF YES, continue.
119. In what ways?
__________________________________________________________________
120. Would you consider yourself gifted? ____________________________________________________
121. Do you have talents or abilities that most people don’t have?_________________________________
IF NO, skip to question 123. IF YES, continue.
122. Please explain.
__________________________________________________________________
123. Do you have any special powers? ______________________________________________________
IF NO, skip to question 126. IF YES, continue.
124. What are these?
__________________________________________________________________
125. Where do these powers come from? ____________________________________________________
126. Do you have extrasensory perception (ESP), or can you read other people’s minds?_______________
127. Are you very wealthy? _______________________________________________________________
IF NO, skip to question 129. IF YES, continue.
128. Explain please.
__________________________________________________________________
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Page 11
SCI–PANSS BOOKLET
PAGE 11
Copyright © 1992, 1999, Multi-Health Systems Inc. All rights reserved. In the U.S.A., P.O. Box 950, North Tonawanda, NY 14120-0950, 1-800-456-3003.
In Canada, 3770 Victoria Park Ave., Toronto, ON  M2H 3M6, 1-800-268-6011. Internationally, +1-416-492-2627. Fax, +1-416-492-3343 or 1-888-540-4484.
129. Can you be considered to be very bright? ________________________________________________
IF NO, skip to question 131. IF YES, continue.
130. Why would you say so? ______________________________________________________________
131. Would you describe yourself as famous?_________________________________________________
132. Would some people recognize you from TV, radio, or the newspaper? _________________________
IF NO, skip to question 134. IF YES, continue.
133. Can you tell me about it? _____________________________________________________________
134. Are you a religious person? ___________________________________________________________
IF NO, skip to question 140. IF YES, continue.
135. Are you close to God? _______________________________________________________________
IF NO, skip to question 140. IF YES, continue.
136. Did God assign you some special role or purpose? _________________________________________
137. Can you be one of God’s messengers or angels? ___________________________________________
IF NO, skip to question 139. IF YES, continue.
138. What special powers do you have as God’s messenger (angel)?_______________________________
139. Do you perhaps consider yourself to be God? _____________________________________________
140. Do you have some special mission in life? _______________________________________________
IF NO, skip to question 143. IF YES, continue.
141. What is your mission? _______________________________________________________________
142. Who assigned you to that mission? _____________________________________________________
143. Did you ever do something wrong — something you feel bad or guilty about? ___________________
IF NO, skip to question 149. IF YES, continue.
144. Just how much does that bother you now?________________________________________________
145. Do you feel that you deserve punishment for that? _________________________________________
IF NO, skip to question 149. IF YES, continue.
Page 10 of 14


Page 12
SCI–PANSS BOOKLET
PAGE 12
Copyright © 1992, 1999, Multi-Health Systems Inc. All rights reserved. In the U.S.A., P.O. Box 950, North Tonawanda, NY 14120-0950, 1-800-456-3003.
In Canada, 3770 Victoria Park Ave., Toronto, ON  M2H 3M6, 1-800-268-6011. Internationally, +1-416-492-2627. Fax, +1-416-492-3343 or 1-888-540-4484.
146. What kind of punishment would you deserve? ____________________________________________
147. Have you at times thought of punishing yourself?__________________________________________
IF NO, skip to question 149. IF YES, continue.
148. Have you ever acted on those thoughts of punishing yourself? ________________________________
 Data on “Disorientation” (GlO)
149. Can you tell me today’s date (i.e., the day, month, and year)? ________________________________
IF YES, skip to question 151. IF NO, continue.
150. Can you tell me what day of the week it is? ______________________________________________
151. What is the name of the place that you are in now?_________________________________________
IF NOT HOSPITALIZED, skip to question 154. IF HOSPITALIZED, continue.
152. What ward are you on?_______________________________________________________________
153. What is the address of where you’re now staying? _________________________________________
IF ABLE TO TELL, skip to question 155. IF NOT ABLE TO TELL, continue.
154. Can you tell me your home address? ____________________________________________________
IF NOT HOSPITALIZED, skip to question 156. IF HOSPITALIZED, continue.
155. If someone had to reach you by phone, what number would that person call? ____________________
156. If someone had to reach you at home, what number would that person call? _____________________
157. What is the name of the doctor who is treating you? ________________________________________
IF NOT HOSPITALIZED, skip to question 159. IF HOSPITALIZED, continue.
158. Can you tell me who else is on the staff and what they do? __________________________________
159. Do you know who is currently the president (prime minister, etc.)? ____________________________
160. Who is our governor (premier, etc.)? ____________________________________________________
161. Who is the mayor (town supervisor, etc.) of this city (town, etc.)? _____________________________
Page 11 of 14


Page 13
SCI–PANSS BOOKLET
PAGE 13
Copyright © 1992, 1999, Multi-Health Systems Inc. All rights reserved. In the U.S.A., P.O. Box 950, North Tonawanda, NY 14120-0950, 1-800-456-3003.
In Canada, 3770 Victoria Park Ave., Toronto, ON  M2H 3M6, 1-800-268-6011. Internationally, +1-416-492-2627. Fax, +1-416-492-3343 or 1-888-540-4484.
Data on “Difficulty in Abstract Thinking” (N5)
I’m going to now say a pair of words, and I’d like you to tell me in what important way they’re alike.  Let’s start, for example, with the words
“apple” and “banana.” How are they alike — what do they have in common? IF THE RESPONSE IS THAT “THEY’RE BOTH FRUIT”,
THEN SAY:  Good.  Now what about ...?  (Select three other items from the Similarities list at varying levels of difficulty from Appendix A.)
IF AN ANSWER IS GIVEN THAT IS CONCRETE, TANGENTIAL, OR IDIOSYNCRATIC (E.G., “THEY BOTH HAVE SKINS,”
“YOU CAN EAT THEM,” “THEY’RE SMALL,” OR “MONKEYS LIKE THEM”), THEN SAY:  OK, but they’re both fruit.  Now
how about ... and ... : how are these alike?  (Select three other items from the Similarities list at varying levels of difficulty from Appendix A.)
APPENDIX A
Items for Similarities in the evaluation of “Difficulty in Abstract Thinking”
1. How are a ball and an orange alike?
2. Apple and banana ?
3. Pencil and pen?
4. Nickel and dime?
______________
5. Table and chair?
6. Tiger and elephant?
7. Hat and shirt?
8. Bus and train?
______________
9. Arm and leg?
10. Rose and tulip?
11. Uncle and cousin?
12. The sun and the moon?
_______________
13. Painting and poem?
14. Hilltop and valley?
15. Air and water?
16. Peace and prosperity?
You’ve probably heard the expression, “Carrying a chip on the shoulder.” What does that really mean? There’s a very old saying,
“Don’t judge a book by its cover.” What is the deeper meaning of this proverb? (Select two other proverbs from the list in Appendix
B at varying levels of difficulty.)
APPENDIX B
Items for assessing PROVERB INTERPRETATION in the evaluation of “Difficulty in Abstract Thinking”
What does the saying mean:
1. “Plain as the nose on your face”
2. “Carrying a chip on your shoulder”
3. “Two heads are better than one”
4. “Too many cooks spoil the broth”
___________________
5. “Don’t judge a book by its cover”
6. One man’s food is another man’s poison”
7. “All that glitters is not gold”
8. “Don’t cross the bridge until you come to it”
____________________
9. “What’s good for the goose is good for the gander”
10. “The grass always looks greener on the other side”
11. “Don’t keep all your eggs in one basket”
12. “One swallow does not make a summer”
____________________
13. “A stitch in time saves nine”
14. “A rolling stone gathers no moss”
15. “The acorn never falls far from the tree”
16. “People who live in glass houses should not throw stones at others”
Note on Appendix A: Similarities are generally assessed by sampling
four items at different levels of difficulty (i.e., one item selected from
each quarter of the full set). When using the PANSS longitudinally,
items should be systematically altered with successive interviews so
as to provide different selections from the various levels of difficulty
and thus minimize repetition.
Notes on Similarities responses:
________________________________________________
________________________________________________
________________________________________________
________________________________________________
Circle the Similarities Used
Note on Appendix B: Proverb interpretation is generally assessed by
sampling four items at different levels of difficulty (i.e., one item
selected from each quarter of the full set). When using the PANSS
longitudinally, items should be systematically altered with succes-
sive interviews so as to provide different selections from the various
levels of difficulty and thus minimize repetition.
Notes on Proverb responses:
________________________________________________
________________________________________________
________________________________________________
________________________________________________
Circle the Proverbs Used
Page 12 of 14


Page 14
PAGE 14
Copyright © 1992, 1999, Multi-Health Systems Inc. All rights reserved. In the U.S.A., P.O. Box 950, North Tonawanda, NY 14120-0950, 1-800-456-3003.
In Canada, 3770 Victoria Park Ave., Toronto, ON  M2H 3M6, 1-800-268-6011. Internationally, +1-416-492-2627. Fax, +1-416-492-3343 or 1-888-540-4484.
Data on “Lack of Judgment and Insight” (G12)
162. How long have you been in the hospital (clinic, etc.)? ______________________________________
163. Why did you come to the hospital (clinic, etc.)? ___________________________________________
164. Did you need to be in a hospital (clinic, etc.)? _____________________________________________
IF YES, skip to question 167. IF NO, continue.
165. Did you have a problem that needed treatment? ___________________________________________
IF NO, skip to question 169. IF YES, continue.
166. Would you say that you had a psychiatric or mental problem? ________________________________
IF NO, skip to question 169. IF YES, continue.
167. Why?....would you say that you had a psychiatric or mental problem? _________________________
IF NO, skip to question 169. IF YES, continue.
168. Can you tell me about it and what it consisted of? _________________________________________
169. In your own opinion, do you need to be taking medicine? ___________________________________
IF YES, skip to question 171.
IF NO and unmedicated, skip to question 172.
IF NO and medicated, continue.
170. Why then are you taking medicines? ____________________________________________________
Skip to question 172.
171. Why?... Does the medicine help you in any way? __________________________________________
172. Do you at this time have any psychiatric or mental problems? ________________________________
IF YES, skip to question 174. IF NO, continue.
173. For what reason are you at the hospital (clinic, etc.)? _______________________________________
Skip to question 175.
174. Please explain
__________________________________________________________________
Page 13 of 14


Page 15
PAGE 15
Copyright © 1992, 1999, Multi-Health Systems Inc. All rights reserved. In the U.S.A., P.O. Box 950, North Tonawanda, NY 14120-0950, 1-800-456-3003.
In Canada, 3770 Victoria Park Ave., Toronto, ON  M2H 3M6, 1-800-268-6011. Internationally, +1-416-492-2627. Fax, +1-416-492-3343 or 1-888-540-4484.
175. Just how serious are these problems? _____________________________________________________
IF UNHOSPITALIZED, skip to question 178.
IF HOSPITALIZED, continue.
176. Are you ready yet for discharge from the hospital? _________________________________________
177. Do you think you’ll be taking medicine for your problems after discharge? _____________________
178. What are your future plans? ___________________________________________________________
179. What about your longer-range goals? ___________________________________________________
Well, that’s about all I have to ask of you now.  Are there any questions that you might like to ask of me?
Thank you for your cooperation.
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Protocol LYN-005-C-004 | Version 1.0 | 11 June 2020 
Lyndra Confidential 
18.5 
Clinical Global Impression – Severity Scale (CGI-S) 


Rating Clinician-rated
Administration time Varies with familiarity with
patient
Main purpose To provide a global rating of illness
severity, improvement and response to treatment
Population Adults
Commentary
Amongst the most widely used of extant brief assessment
tools in psychiatry, the CGI is a 3-item observer-rated
scale that measures illness severity (CGIS), global
improvement or change (CGIC) and therapeutic response.
The illness severity and improvement sections of the
instrument are used more frequently than the therapeutic
response section in both clinical and research settings. The
Early Clinical Drug Evaluation Program (ECDEU) ver-
sion of the CGI (reproduced here) is the most widely used
format, and asks that the clinician rate the patient relative
to their past experience with other patients with the same
diagnosis, with or without collateral information. Several
alternative versions of the CGI have been developed, how-
ever, such as the FDA Clinicians’ Interview-Based
Impression of Change (CIBIC), which uses only informa-
tion collected during the interview, not collateral. The
CGI has proved to be a robust measure of efficacy in
many clinical drug trials, and is easy and quick to admin-
ister, provided that the clinician knows the patient well. 
Scoring
The CGI is rated on a 7-point scale, with the severity of
illness scale using a range of responses from 1 (normal)
through to 7 (amongst the most severely ill patients).
CGI-C scores range from 1 (very much improved)
through to 7 (very much worse). Treatment response
ratings should take account of both therapeutic efficacy
and treatment-related adverse events and range from 0
(marked improvement and no side-effects) and 4
(unchanged or worse and side-effects outweigh the thera-
peutic effects). Each component of the CGI is rated sepa-
rately; the instrument does not yield a global score.
Versions
CGI for bipolar disorder (CGI-BD), FDA Clinicians’
Interview-Based Impression of Change (CIBIC),
Clinicians’ Interview-Based Impression of Change-Plus
(CIBIC+), NYU CIBIC+, Parke-Davis Pharmaceuticals
Clinical Interview-Based Impression (CIBI); the CGI has
been translated into most languages.
Additional references 
Leon AC, Shear MK, Klerman GL, Portera L,
Rosenbaum JF, Goldenberg I. A comparison of
symptom determinants of patient and clinician global
ratings in patients with panic disorder and depression. J
Clin Psychopharmacol 1993; 13(5):327–31. 
Spearing MK, Post RM, Leverich GS, Brandt D, Nolen
W. Modification of the Clinical Global Impressions
(CGI) Scale for use in bipolar illness (BP): the CGI-BP.
Psychiatry Res 1997; 73(3):159–71.
Zaider TI, Heimberg RG, Fresco DM, Schneier FR,
Liebowitz MR. Evaluation of the clinical global
impression scale among individuals with social anxiety
disorder. Psychol Med 2003; 33(4):611–22. 
Address for correspondence
Not applicable – the CGI is in the public domain.
125
Clinical Global Impression (CGI)
Reference: Guy W, editor. ECDEU Assessment Manual for Psychopharmacology. 1976.
Rockville, MD, U.S. Department of Health, Education, and Welfare
Page 1 of 2


126
1. Severity of illness
Considering your total clinical experience with this particular population, how mentally ill is the
patient at this time?
4 = Moderately ill
0 = Not assessed
5 = Markedly ill
2 = Borderline mentally ill
3 = Mildly ill
7 = Among the most extremely ill patients
Reproduced from Guy W, editor. ECDEU Assessment Manual for Psychopharmacology. 1976. Rockville, MD, U.S. Department of Health,
Education, and Welfare
Clinical Global Impression - Severity (CGI-S)
CGI-S is to be collected at Screening and throughout the study where indicated in Schedule of Events
1 = Normal, not at all ill
6 = Severely ill
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Protocol LYN-005-C-004  
Pharmacokinetic Study of LYN-005 Risperidone Extended Release Capsules 
Page 125 of 140
Protocol LYN-005-C-004 | Version 1.0 | 11 June 2020 
Lyndra Confidential 
18.6 
Columbia Suicide Severity Rating Scale (C-SSRS) 
Note that there are two specific scales, e.g., Baseline, Since Last Visit, and differentiated by 
footers.


SUICIDAL IDEATION 
Ask questions 1 and 2.  If both are negative, proceed to “Suicidal Behavior” section. If the answer to 
question 2 is “yes”, ask questions 3, 4 and 5.  If the answer to question 1 and/or 2 is “yes”, complete 
“Intensity of Ideation” section below. 
Lifetime: Time 
He/She Felt 
Most Suicidal 
Past __ 
Months 
1.
  
Wish to be Dead
  
Subject endorses thoughts about a wish to be dead or not alive anymore, or wish to fall asleep and not wake up. 
Have you wished you were dead or wished you could go to sleep and not wake up?  
If yes, describe: 
 
Yes    No 
□  
 
□ 
Yes   No 
□   □ 
2.
  
Non-Specific Active Suicidal Thoughts
General non-specific thoughts of wanting to end one’s life/commit suicide (e.g., “I’ve thought about killing myself”) without thoughts 
of ways to kill oneself/associated methods, intent, or plan during the assessment period.  
Have you actually had any thoughts of killing yourself? 
If yes, describe: 
    Yes 
 No 
    □  
 
□ 
Yes   No 
□   □ 
3. Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act
Subject endorses thoughts of suicide and has thought of at least one method during the assessment period. This is different than a 
specific plan with time, place or method details worked out (e.g.  thought of method to kill self but not a specific plan).  Includes person 
who would say, “I thought about taking an overdose but I never made a specific plan as to when, where or how I would actually do 
it…and I would never go through with it.” 
Have you been thinking about how you might do this? 
If yes, describe: 
 
 Yes    No 
 □  
 
□ 
Yes   No 
□   □ 
4. Active Suicidal Ideation with Some Intent to Act, without Specific Plan
Active suicidal thoughts of killing oneself and subject reports having some intent to act on such thoughts, as opposed to “I have the 
thoughts but I definitely will not do anything about them.” 
Have you had these thoughts and had some intention of acting on them?  
If yes, describe: 
 
   Yes   No 
□  
 
□ 
Yes   No 
□   □ 
5. Active Suicidal Ideation with Specific Plan and Intent
Thoughts of killing oneself with details of plan fully or partially worked out and subject has some intent to carry it out. 
Have you started to work out or worked out the details of how to kill yourself? Do you intend to carry out this plan? 
If yes, describe: 
 
 Yes    No 
 □  
 
□ 
Yes   No 
□   □ 
INTENSITY OF IDEATION 
The following features should be rated with respect to the most severe type of ideation (i.e., 1-5 from above, with 1 being 
the least severe and 5 being the most severe).  Ask about time he/she was feeling the most suicidal.  
                                   
Lifetime - 
  Most Severe Ideation:  _______ 
________________________________________
               
                                              
  Type # (1-5)  
                          
  Description of  Ideation 
Past X Months - Most Severe Ideation:  _______ 
 ________________________________________ 
                                                                    
  Type # (1-5)  
                         
 Description of  Ideation
 
Most 
Severe 
Most 
Severe 
Frequency 
How many times have you had these thoughts? 
(1) Less than once a week    (2) Once a week   (3)  2-5 times in week    (4) Daily or almost daily    (5) Many times each day
____ 
____ 
Duration 
When you have the thoughts how long do they last? 
(1) Fleeting - few seconds or minutes
                                
(4) 4-8 hours/most of day 
(2) Less than 1 hour/some of the time 
  
(5) More than 8 hours/persistent or continuous
(3) 1-4 hours/a lot of time 
____ 
____ 
Controllability 
Could/can you stop thinking about killing yourself or wanting to die if you want to? 
(1) Easily able to control thoughts
                                                      
(4) Can control thoughts  with a lot of difficulty
(2) Can control thoughts with little difficulty 
  
(5) Unable to control thoughts
 
(3) Can control thoughts with some difficulty 
  
(0) Does not attempt to control thoughts
____ 
____ 
Deterrents 
Are there things - anyone or anything (e.g., family, religion, pain of death) - that stopped you from wanting to 
die or acting on thoughts of committing suicide? 
(1) Deterrents definitely stopped you from attempting suicide 
(4) Deterrents most likely did not stop you
(2) Deterrents probably stopped you
                                      
  
(5) Deterrents definitely did not stop you
 
(3) Uncertain that deterrents stopped you
   
(0) Does not apply
 
____ 
____ 
Reasons for Ideation 
What sort of reasons did you have for thinking about wanting to die or killing yourself?  Was it to end the pain 
or stop the way you were feeling (in other words you couldn’t go on living with this pain or how you were 
feeling) or was it to get attention, revenge or a reaction from others? Or both? 
(1) Completely to get attention, revenge or a reaction from others
       
(4) Mostly to end or stop the pain (you couldn’t go on
(2) Mostly to get attention, revenge or a reaction from others
     
        
living with the pain or how you were feeling)
 
(3) Equally to get attention, revenge or a reaction from others
(5) Completely to end or stop the pain (you couldn’t go on 
     
 and to end/stop the pain
                                                   
      
living with the pain or  how you were feeling)
 
                                      
(0)  Does not apply
 
____ 
 
____ 
 
© 2008 Research Foundation for Mental Hygiene, Inc. 
C-SSRS—Baseline/Screening (Version 1/14/09) 
  Page 1 of 2  
Page 1 of 2


SUICIDAL BEHAVIOR 
(Check all that apply, so long as these are separate events; must ask about all types) 
Lifetime 
Past __ 
Years 
Actual Attempt: 
 
A potentially self-injurious act committed with at least some wish to die, as a result of act. Behavior was in part thought of as method to kill 
oneself. Intent does not have to be 100%.  If there is any intent/desire to die associated with the act, then it can be considered an actual suicide 
attempt. There does not have to be any injury or harm, just the potential for injury or harm. If person pulls trigger while gun is in 
mouth but gun is broken so no injury results, this is considered an attempt.   
Inferring Intent: Even if an individual denies intent/wish to die, it may be inferred clinically from the behavior or circumstances. For example, a 
highly lethal act that is clearly not an accident so no other intent but suicide can be inferred (e.g., gunshot to head, jumping from window of a 
high floor/story). Also, if someone denies intent to die, but they thought that what they did could be lethal, intent may be inferred.  
Have you made a suicide attempt? 
Have you done anything to harm yourself? 
Have you done anything dangerous where you could have died? 
What did you do? 
Did you______ as a way to end your life?  
Did you want to die (even a little) when you_____?  
Were you trying to end your life when you _____? 
Or Did you think it was possible you could have died from_____? 
Or did you do it purely for other reasons / without ANY intention of killing yourself (like to relieve stress, feel better, 
get sympathy, or get something else to happen)?  (Self-Injurious Behavior without suicidal intent) 
If yes, describe: 
 
Has subject engaged in Non-Suicidal Self-Injurious Behavior? 
Yes   No 
□   □ 
 
Total # of 
Attempts 
______ 
 
 
Yes   No 
□   □ 
Yes  
  
 No 
□   □ 
 
Total # of 
Attempts 
______ 
 
 
Yes   No 
□   □ 
Interrupted Attempt:  
When the person is interrupted (by an outside circumstance) from starting the potentially self-injurious act (if not for that, actual attempt would 
have occurred). 
Overdose: Person has pills in hand but is stopped from ingesting.  Once they ingest any pills, this becomes an attempt rather than an interrupted 
attempt. Shooting: Person has gun pointed toward self, gun is taken away by someone else, or is somehow prevented from pulling trigger. Once 
they pull the trigger, even if the gun fails to fire, it is an attempt. Jumping: Person is poised to jump, is grabbed and taken down from ledge. 
Hanging: Person has noose around neck but has not yet started to hang - is stopped from doing so. 
Has there been a time when you started to do something to end your life but someone or something stopped you before 
you actually did anything? 
If yes, describe: 
 
Yes 
  
 No 
□   □ 
 
Total # of 
interrupted 
______ 
 
Yes  
  
 No 
□   □ 
 
Total # of 
interrupted 
______ 
 
Aborted Attempt: 
  
When person begins to take steps toward making a suicide attempt, but stops themselves before they actually have engaged in any self-
destructive behavior. Examples are similar to interrupted attempts, except that the individual stops him/herself, instead of being stopped by 
something else. 
Has there been a time when you started to do something to try to end your life but you stopped yourself before you 
actually did anything? 
If yes, describe: 
 
Yes   No 
□   □ 
Total # of 
aborted 
______ 
Yes   No 
□   □ 
Total # of 
aborted 
______ 
Preparatory Acts or Behavior: 
Acts or preparation towards imminently making a suicide attempt. This can include anything beyond a verbalization or thought, such as 
assembling a specific method (e.g., buying pills, purchasing a gun) or preparing for one’s death by suicide (e.g., giving things away, writing a 
suicide note).  
Have you taken any steps towards making a suicide attempt or preparing to kill yourself (such as collecting pills, 
getting a gun, giving valuables away or writing a suicide note)? 
If yes, describe: 
 
 
Yes  
   
 No 
□   □ 
Yes   No 
□   □ 
Suicidal Behavior: 
Suicidal behavior was present during the assessment period? 
Yes   No 
□   □ 
Yes   No 
□   □ 
Answer for Actual Attempts Only
Most Recent 
Attempt 
Date: 
Most Lethal  
    
   
Attempt 
Date: 
Initial/First 
Attempt 
Date: 
Actual Lethality/Medical Damage:  
 
0.
  
No physical damage or very minor physical damage (e.g., surface scratches).
1. Minor physical damage (e.g., lethargic speech; first-degree burns; mild bleeding; sprains).
2.
  
Moderate physical damage; medical attention needed (e.g., conscious but sleepy, somewhat responsive; second-degree 
burns; bleeding of major vessel).
 
3. Moderately severe physical damage; medical hospitalization and likely intensive care required (e.g., comatose with reflexes
intact; third-degree burns less than 20% of body; extensive blood loss but can recover; major fractures).
 
4. Severe physical damage; medical hospitalization with intensive care required (e.g., comatose without reflexes; third-degree 
burns over 20% of body; extensive blood loss with unstable vital signs; major damage to a vital area).
 
5. Death
 
 
Enter Code 
 
______ 
 
 
Enter Code 
 
 
______ 
 
 
Enter Code 
 
 
______ 
 
Potential Lethality: Only Answer if Actual Lethality=0 
Likely lethality of actual attempt if no medical damage (the following examples, while having no actual medical damage, had 
potential for very serious lethality: put gun in mouth and pulled the trigger but gun fails to fire so no medical damage; laying 
on train tracks with oncoming train but pulled away before run over). 
 
0 = Behavior not likely to result in injury 
1 = Behavior likely to result in injury but not likely to cause death 
2 = Behavior likely to result in death despite available medical care 
Enter Code 
______ 
Enter Code 
 
______ 
Enter Code 
 
______ 
 
© 2008 Research Foundation for Mental Hygiene, Inc. 
C-SSRS—Baseline/Screening (Version 1/14/09) 
 
                  
  Page 2 of 2  
Page 2 of 2


SUICIDAL IDEATION 
Ask questions 1 and 2.  If both are negative, proceed to “Suicidal Behavior” section. If the answer to question 2 is “yes”, 
ask questions 3, 4 and 5.  If the answer to question 1 and/or 2 is “yes”, complete “Intensity of Ideation” section below. 
 
Since Last 
Visit 
1.
  
Wish to be Dead
  
Subject endorses thoughts about a wish to be dead or not alive anymore, or wish to fall asleep and not wake up. 
Have you wished you were dead or wished you could go to sleep and not wake up?  
If yes, describe: 
 
Yes  
 
    No 
 □  □ 
2.
  
Non-Specific Active Suicidal Thoughts
General, non-specific thoughts of wanting to end one’s life/commit suicide (e.g., “I’ve thought about killing myself”) without thoughts of ways to kill 
oneself/associated methods, intent, or plan during the assessment period.  
Have you actually had any thoughts of killing yourself? 
If yes, describe: 
 Yes   No 
  □  □ 
3. Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act
Subject endorses thoughts of suicide and has thought of at least one method during the assessment period. This is different than a specific plan with time, 
place or method details worked out (e.g., thought of method to kill self but not a specific plan).  Includes person who would say, “I thought about taking an 
overdose but I never made a specific plan as to when, where or how I would actually do it…and I would never go through with it.” 
Have you been thinking about how you might do this? 
If yes, describe: 
 Yes   No 
  □  □ 
4.
  
Active Suicidal Ideation with Some Intent to Act, without Specific Plan
Active suicidal thoughts of killing oneself and subject reports having some intent to act on such thoughts, as opposed to “I have the thoughts but I 
definitely will not do anything about them.” 
Have you had these thoughts and had some intention of acting on them?  
If yes, describe: 
Yes    No 
  □  □ 
5.
  
Active Suicidal Ideation with Specific Plan and Intent
Thoughts of killing oneself with details of plan fully or partially worked out and subject has some intent to carry it out. 
Have you started to work out or worked out the details of how to kill yourself? Do you intend to carry out this plan? 
If yes, describe: 
 
 Yes    No 
  □  □ 
INTENSITY OF IDEATION 
The following features should be rated with respect to the most severe type of ideation (i.e., 1-5 from above, with 1 being the least severe 
and 5 being the most severe).  
Most Severe Ideation:  
 _____ 
 _________________________________________________ 
 Type # (1-5) 
 Description of  Ideation 
Most 
Severe 
Frequency 
How many times have you had these thoughts? 
(1) Less than once a week    (2) Once a week   (3)  2-5 times in week    (4) Daily or almost daily    (5) Many times each day 
____ 
Duration 
When you have the thoughts, how long do they last? 
(1) Fleeting - few seconds or minutes  
 (4) 4-8 hours/most of day 
(2) Less than 1 hour/some of the time  
  (5) More than 8 hours/persistent or continuous 
(3) 1-4 hours/a lot of time     
____ 
Controllability 
Could/can you stop thinking about killing yourself or wanting to die if you want to? 
(1) Easily able to control thoughts      
 (4) Can control thoughts with a lot of difficulty 
(2) Can control thoughts with little difficulty   
 (5) Unable to control thoughts 
(3) Can control thoughts with some difficulty  
 (0) Does not attempt to control thoughts 
____ 
Deterrents 
Are there things - anyone or anything (e.g., family, religion, pain of death) - that stopped you from wanting to die or acting on 
thoughts of committing suicide? 
(1) Deterrents definitely stopped you from attempting suicide  
  (4) Deterrents most likely did not stop you 
(2) Deterrents probably stopped you     
  (5) Deterrents definitely did not stop you  
(3) Uncertain that deterrents stopped you     
  (0) Does not apply 
____ 
Reasons for Ideation 
What sort of reasons did you have for thinking about wanting to die or killing yourself?  Was it to end the pain or stop the way 
you were feeling (in other words you couldn’t go on living with this pain or how you were feeling) or was it to get attention, 
revenge or a reaction from others? Or both? 
(1) Completely to get attention, revenge or a reaction from others 
  (4) Mostly to end or stop the pain (you couldn’t go on 
(2) Mostly to get attention, revenge or a reaction from others     
     living with the pain or how you were feeling) 
(3) Equally to get attention, revenge or a reaction from others     
 (5) Completely to end or stop the pain (you couldn’t go on 
  and to end/stop the pain 
     living with the pain or  how you were feeling) 
 (0)  Does not apply 
____ 
© 2008 Research Foundation for Mental Hygiene, Inc. 
  C-SSRS—Since Last Visit (Version 1/14/09)   
  Page 1 of 2  
Page 1 of 2


SUICIDAL BEHAVIOR 
(Check all that apply, so long as these are separate events; must ask about all types) 
Since Last 
Visit 
Actual Attempt: 
A potentially self-injurious act committed with at least some wish to die, as a result of act. Behavior was in part thought of as method to kill oneself. Intent 
does not have to be 100%.  If there is any intent/desire to die associated with the act, then it can be considered an actual suicide attempt. There does not 
have to be any injury or harm, just the potential for injury or harm. If person pulls trigger while gun is in mouth but gun is broken so no injury results, 
this is considered an attempt.   
Inferring Intent: Even if an individual denies intent/wish to die, it may be inferred clinically from the behavior or circumstances. For example, a highly 
lethal act that is clearly not an accident so no other intent but suicide can be inferred (e.g., gunshot to head, jumping from window of a high floor/story). 
Also, if someone denies intent to die, but they thought that what they did could be lethal, intent may be inferred.  
Have you made a suicide attempt? 
Have you done anything to harm yourself? 
Have you done anything dangerous where you could have died? 
What did you do? 
Did you______ as a way to end your life?  
Did you want to die (even a little) when you_____?  
Were you trying to end your life when you _____? 
Or did you think it was possible you could have died from_____? 
Or did you do it purely for other reasons / without ANY intention of killing yourself (like to relieve stress, feel better, get 
sympathy, or get something else to happen)?  (Self-Injurious Behavior without suicidal intent) 
If yes, describe: 
Has subject engaged in Non-Suicidal Self-Injurious Behavior? 
Yes   No 
□   □ 
Total # of 
Attempts 
______ 
Yes     No 
□   □ 
Interrupted Attempt:  
When the person is interrupted (by an outside circumstance) from starting the potentially self-injurious act (if not for that, actual attempt would have 
occurred). 
Overdose: Person has pills in hand but is stopped from ingesting.  Once they ingest any pills, this becomes an attempt rather than an interrupted attempt. 
Shooting: Person has gun pointed toward self, gun is taken away by someone else, or is somehow prevented from pulling trigger. Once they pull the trigger, 
even if the gun fails to fire, it is an attempt. Jumping: Person is poised to jump, is grabbed and taken down from ledge. Hanging: Person has noose around 
neck but has not yet started to hang - is stopped from doing so. 
Has there been a time when you started to do something to end your life but someone or something stopped you before you 
actually did anything? 
If yes, describe: 
Yes   No 
□   □ 
Total # of 
interrupted 
______ 
Aborted Attempt: 
When person begins to take steps toward making a suicide attempt, but stops themselves before they actually have engaged in any self-destructive behavior. 
Examples are similar to interrupted attempts, except that the individual stops him/herself, instead of being stopped by something else. 
Has there been a time when you started to do something to try to end your life but you stopped yourself before you 
actually did anything? 
If yes, describe: 
Yes 
 No 
□   □ 
Total # of 
aborted 
 
Preparatory Acts or Behavior: 
Acts or preparation towards imminently making a suicide attempt. This can include anything beyond a verbalization or thought, such as assembling a 
specific method (e.g., buying pills, purchasing a gun) or preparing for one’s death by suicide (e.g., giving things away, writing a suicide note).  
Have you taken any steps towards making a suicide attempt or preparing to kill yourself (such as collecting pills, getting a gun, 
giving valuables away or writing a suicide note)? 
If yes, describe: 
Yes   No 
□   □ 
Suicidal Behavior: 
Suicidal behavior was present during the assessment period? 
Yes   No 
□   □ 
Suicide: 
   Yes    No 
□   □ 
Answer for Actual Attempts Only 
Most Lethal 
Attempt 
Date: 
Actual Lethality/Medical Damage: 
0. No physical damage or very minor physical damage (e.g., surface scratches).
1. Minor physical damage (e.g., lethargic speech; first-degree burns; mild bleeding; sprains).
2. Moderate physical damage; medical attention needed (e.g., conscious but sleepy, somewhat responsive; second-degree burns; bleeding of major vessel).
3. Moderately severe physical damage; medical hospitalization and likely intensive care required (e.g., comatose with reflexes intact; third-degree burns
less than 20% of body; extensive blood loss but can recover; major fractures).
4. Severe physical damage; medical hospitalization with intensive care required (e.g., comatose without reflexes; third-degree burns over 20% of body;
extensive blood loss with unstable vital signs; major damage to a vital area).
5. Death 
Enter Code 
______ 
Potential Lethality: Only Answer if Actual Lethality=0 
Likely lethality of actual attempt if no medical damage (the following examples, while having no actual medical damage, had potential for very serious 
lethality: put gun in mouth and pulled the trigger but gun fails to fire so no medical damage; laying on train tracks with oncoming train but pulled away 
before run over). 
0 = Behavior not likely to result in injury 
1 = Behavior likely to result in injury but not likely to cause death 
2 = Behavior likely to result in death despite available medical care 
Enter Code 
______ 
© 2008 Research Foundation for Mental Hygiene, Inc. 
C-SSRS—Since Last Visit (Version 1/14/09) 
  Page 2 of 2  
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Protocol LYN-005-C-004  
Pharmacokinetic Study of LYN-005 Risperidone Extended Release Capsules 
Page 130 of 140
Protocol LYN-005-C-004 | Version 1.0 | 11 June 2020 
Lyndra Confidential 
18.7 
Acid Reflux Severity Scale 
The ARSS scale is as follows: 
None = 0 no symptoms 
Mild = 1 awareness of symptom, but easily tolerated 
Moderate = 2 discomfort sufficient to cause interference with normal activities 
Severe = 3 incapacitating, with inability to perform normal activities. 


Protocol LYN-005-C-004  
Pharmacokinetic Study of LYN-005 Risperidone Extended Release Capsules 
Page 131 of 140
Protocol LYN-005-C-004 | Version 1.0 | 11 June 2020 
Lyndra Confidential 
18.8 
 Extrapyramidal Symptom Rating Scale (ESRS) 


Administration instructions below are excerpted 
from the article by Chouinard et al. 2005 with 
edits from the Erratum, 2006
Instruction 1: Patient is asked to remove his/her
shoes, to remove anything from his/her mouth
(except dentures) and to sit facing the examiner on
a chair with no armrests.
The removal of shoes can be omitted if an
assessment of lower extremity dyskinetic move-
ments is not required. In clinical trials it is
completed unless clinically inappropriate for the
patient (often patients do not feel comfortable
removing their shoes) or it can be delayed until
the testing of postural stability. Removing food and
gum from the mouth is necessary in order to assess
bucco–labial, lingual and jaw movements. The
armless chair is essential for detection of tremors,
decreased spontaneous movements, dyskinesia and
akathisia.
Instruction 2: Complete the questionnaire.
The questionnaire rates subjective DIMD, i.e.,
Parkinsonism, akathisia, dystonia, and dyskinesia,
as reported by the patient and which are experi-
enced at periods other than the time of examina-
tion during the last week. For demented patients
or autistic children, a nurse or key relative may
also provide information in relation to the ques-
tionnaire. The questionnaire permits the evaluator
to spend time with the patient to observe
spontaneous DIMD.
Instruction 3: Observe facial expressiveness,
speech, akathisia, dystonia and dyskinesia while
completing the questionnaire and while completing
items 4, 5, and 6.
Items in the objective examination are assessed
during the course of standard tests of neurological
examination (there is no new procedure to be
learned by the physician when the physician is the
examiner).
Instruction 4: Patient is asked to extend both arms
forward, with palms down and eyes closed.
This
test
of
posture
tremors
along
with
observing the patient’s tremors at rest and the
copying of a spiral with each hand (Instruction
6) is part of an overall assessment of tremors,
which includes rest, posture and action tremors.
Eyes are kept closed so that the patient is unable to
correct if there is a lateralized neurological lesion.
Instruction 5: The patient is asked to carry out
pronation and supination of both hands as fast as
possible and to perform rapid alternate move-
ments of both wrists simultaneously. Repeat as
necessary.
Both tests are useful in the evaluation of tardive
dyskinesia, as well as in the rating of slowness and
difficulty in initiating movement. For bradykinesia,
these two tests were selected because the initiation
of several repetitive movements can be observed
and for one test simultaneous movements of both
wrists permit the detection of impaired ability to
perform simultaneous tests. The inability to stop a
movement should also be observed. For TD, the
Table 1
Summary of the ESRS examination procedure
1. Patient is asked to remove their shoes (omitted if judged clinically inappropriate or when patient hesitates, or delayed after patient has walked
(after # 7). The patient is asked to remove anything from their mouth (except dentures). The patient is asked to sit facing the examiner on a
chair with no armrests.
2. Complete the questionnaire.
3. Observe facial expressiveness, speech and dyskinesia while completing the questionnaire and while completing items 4, 5, and 6 below.
4. Patient is asked to extend both arms forward, with palms down and eyes closed.
5. The patient is asked to carry out pronation and supination of both hands as fast as possible, and to perform rapid alternate movements of both
wrists. Repeat as necessary.
6. While the patient sits facing the examiner on a chair with no armrests about 1 foot (approx. 30 cm) from a table with his upper body turned,
the patient is asked to copy a spiral with each hand and to write the name of his town, province/state and country.
7. Patient is asked to walk a distance of 12–15 feet (4–5 m) away from, and then back towards the examiner. Repeat as necessary.
8. Patient is asked to stand erect with eyes open with feet slightly apart (1–2 cm). The examiner pushes the patient on each shoulder, the back
and pushes the chest or pulls from the back while asking the patient to keep his balance.
9. Carry out the examination of the muscular tonus of the four limbs.
G. Chouinard, H.C. Margolese / Schizophrenia Research 76 (2005) 247–265
251


oral–facial region is observed while the patient is
performing pronation–supination and alternate
movement tests; these voluntary movements help
to uncover buccal–labial–masticatory and lower
extremity dyskinesias.
Instruction 6: While the patient sits facing the
examiner on a chair with no armrests about 1 foot
(approx. 30 cm) from a table with his/her upper
body turned, the patient is asked to copy a spiral
with each hand and to write the name of his town,
province/state and country.
This test permits the assessment of action
tremors through graphic oscillation, and dyski-
netic movements may be unmasked or augmented
when the patient completes Instruction 6, for the
test is performed under some emotional tension
and uses other voluntary muscle groups. In this
regard, it is important to encourage the patient to
concentrate on the task requested.
Instruction 7: Patient is asked to walk a distance of
12–15 feet (4–5 m) away from, and then back
towards, the examiner. Repeat as necessary.
This permits the evaluator to rate gait and
posture. Absence of or a decrease in unilateral or
bilateral pendular moments is observed. Abnormal-
ities of posture are also looked for: flexed head, stiff
posture, stooped posture. TD and/or chronic dysto-
nia of upper limbs and trunk are looked for while
the patient is walking.
Instruction 8: Patient is asked to stand erect with
eyes open and feet together or slightly apart (1–2
cm). The examiner pushes the patient gently but
firmly (strongly if necessary) on each shoulder (for
lateropulsion), the back (for anteropulsion), and
pushes the chest or pulls from the back (for
retropulsion) while asking the patient to keep his
balance and resist. Preferably, the patient removes
his/her shoes before the test.
This
test
evaluates
postural
stability.
The
examiner should be ready to catch the patient from
falling especially if the patient has an obvious
impairment of balance at rest before testing. For
patients who are already unstable, the test is
completed gently.
Instruction 9: Carry out the examination of the
muscular tonus of the four limbs.
Both limbs are examined as a pair in order to
observe differences between the left and right
side. Patient is asked to relax. Both arms are
simultaneously rotated to permit examination of
shoulders and, subsequently, elbows and wrists.
Left
and
right
knees
are
then
successively
moved and a comparison between the two sides
made. Examination of hips and ankles does not
provide more sensitivity and can be disturbing
to psychotic patients. As with IPD, proximal
joints are the most affected and rigidity may be
more present in one part and/or one side of the
body.
4. Scoring instructions
4.1. Questionnaire for Parkinsonism, akathisia, dys-
tonia and dyskinesia
For the subjective examination (subscale I of the
ESRS) scoring is on a 4-point scale (0=Absent;
1=Mild, 2=Moderate, 3=Severe). The evaluator
takes into account the verbal report of the patient
on: 1) the frequency and duration of the symptom
during the day; 2) the number of days the symptom
was present during the last week; and, 3) the
subjective evaluation of the intensity of the symptom
by the patient. When rating subjective EPS, severity is
assessed over the last 7 days. One inquires about how
persistent symptoms have been on the most typical
day in the past 7 days.
4.2. Examination: Parkinsonism and akathisia
Both tremors and rigidity (items 1 and 4) are
scored on a 7-point item scale (0=none–6=severe)
for each part of the body, which are scored as separate
items. The ESRS and the Unified Parkinson’s Disease
Rating Scale (UPDRS) (Fahn and Elton, 1987) rate
each part of the body separately for tremors and
rigidity, since, in both drug-induced Parkinsonism and
IPD, the symptoms can be seen initially in one limb
and when it progresses it may involve several limbs,
thus increasing the number of items in each scale, but
permitting the rating of severity in each part of the
body involved.
Ratings for tremors are made taking into account
two axes: the amplitude of the movement and the
number of times with which it is observed during the
G. Chouinard, H.C. Margolese / Schizophrenia Research 76 (2005) 247–265
252


interview. Assessment of tremors includes rest,
posture and action tremors. Ratings of the other items
of Parkinsonism and akathisia are recorded on a 7-
point item scale (0=absent–6=most severe) with
anchor points.
One difficulty in the rating of abnormal move-
ments was to include both the amplitude of the
abnormal movement (the higher the amplitude, the
more severe the disorder) and the frequency that an
abnormal movement is observed (the more frequent,
the greater the severity). Thus, it appeared necessary
to rate hyperkinetic disorders, tremors and dyski-
nesia, on a two-axis dimension to take into account
that a small amplitude tremor seen frequently is as
pathological as a larger amplitude tremor seen less
frequently.
4.3. Examination: dystonia
Both acute and chronic dystonic movements are
scored on a 7-point item scale (0=absent–6=most
severe). Each body part is rated separately including
right upper limb, left upper limb, right lower limb, left
lower limb, head, jaw, tongue, lips, face, trunk and
other (any other area).
4.4. Examination: dyskinesia
Dyskinetic movements at each site (tongue, jaw,
bucco–labial, trunk, upper and lower extremities,
and others {any other area including face}) are
evaluated as individual items. They are rated
similarly to tremors. Involuntary dyskinetic move-
ments are repetitive, although not rhythmic and not
oscillating along an axis, and their amplitude is
usually greater with a low frequency cycle/s.
Consequently we applied the same logic of a two-
axis scale of amplitude and frequency as in the
rating of tremors.
5. ESRS total and subtotal scores
5.1. ESRS Parkinsonism and akathisia scores in the
era of classical antipsychotics
The score for Parkinsonism (including akathisia),
ranges from 0 to 102 (17 items), and is based on all
items of the Parkinsonism examination (subscale II):
tremor (0–48), gait and posture (0–6), postural
stability (0–6), rigidity (0–24), expressive automatic
movements (0–6), bradykinesia (0–6), akathisia (0–
6). In clinical trials, when establishing presence of
Parkinsonism to initiate an antiParkinsonian medi-
cation, a score of 3 or greater is required on at least
one of the above listed items including the 8 items
of
tremor
or
the
4
items
of
rigidity.
When
establishing the presence versus absence of Parkin-
sonism, a score of 2 on 2 items or a score of 3 or
greater on one item is required to establish the
presence.
Subscores: Two subscores were formed using
the
objective
examination
of
Parkinsonism:
a
hypokinesia
factor,
ranging
from
0
to
42,
calculated as the sum of items: gait and posture
(0–6), rigidity (0–24), expressive automatic move-
ments (0–6), and bradykinesia (0–6); and a hyper-
kinesia factor, ranging from 0 to 54, calculated as
the sum of items: tremor (0–48) and akathisia
(0–6).
5.2. ESRS Parkinsonism and akathisia scores in the
era of atypical antipsychotics
The Parkinsonism score, ranging from 0 to 96
(16 items), and the 2 factors (hypokinesia (0–42)
and hyperkinesia (0–49) used now are similar to
the previous ones (described in Section 5.1) minus
one item: akathisia (0–6). The score for akathisia is
separated from the Parkinsonism score and is based on
the combined score of subjective akathisia (item 6 of
the questionnaire) and objective akathisia (item 7 of
the Parkinsonism/Akathisia objective examination).
When establishing presence versus absence of aka-
thisia, a total score of 3 or greater on the 2 items is
required for presence.
5.3. Dystonia scores
The score for dystonia ranges from 0 to 60 (10
items), and is formed by including both acute and
chronic dystonia, based on the dystonia examination
(Subscale III). When establishing presence versus
absence of dystonia, a score of 3 or greater on at least
one item, or a score of 2 on 2 items is required to
indicate presence of dystonia.
G. Chouinard, H.C. Margolese / Schizophrenia Research 76 (2005) 247–265
253


5.4. Dyskinesia and subtotal scores
Score for TD, ranging from 0 to 42, is based on the
sum of all seven items in the TD objective examina-
tion. When scoring presence versus absence of TD, a
score of 3 or greater on at least one item or a score of
2 on 2 items is required to indicate presence of TD.
For tardive dyskinesia, scores for each item can be
analyzed separately. A buccal–lingual–masticatory
(BLM) subtotal, ranging from 0 to 18, is obtained
from the sum of items 1, 2 and 3, and an extremities
subtotal, ranging from 0 to 12, by adding the score for
items 5 and 6.
5.5. ESRS total and subtotal scores for clinical trials
and inter-rater reliability certification
For clinical trials, a total score for DIMD or EPS is
formed based on all 41 items of the ESRS. It includes
the 7 items of Subscale I (questionnaire), 17 items of
Subscale II (Parkinsonism/Akathisia), 10 items of Part
III (dystonia), and 7 items of Part IV (dyskinesia). For
inter-rater reliability certification, the ESRS 41 item
total score also includes the 4 CGI-S’s and thus
becomes ESRS 45 item total.
5.6. Clinical global impression of severity (CGI-S)
The clinical global impression of severity (CGI-S)
of Parkinsonism, akathisia, dystonia, and tardive
dyskinesia are rated according to results of the
subjective questionnaire, examination subscales, and
the evaluator’s clinical experience by applying an 8
point rating (0: absent; 1: borderline; 2: very mild; 3:
mild; 4: moderate; 5: moderately severe; 6: marked; 7:
severe; 8: extremely severe). The 4 CGI-S’s are
analyzed as separate items.
G. Chouinard, H.C. Margolese / Schizophrenia Research 76 (2005) 247–265
254


Appendix A. ESRS Manual and scoring sheet
Extrapyramidal symptom rating scale (ESRS) (Chouinard) © 1979
In case of doubt score the lesser severity.
I.   QUESTIONNAIRE : Parkinsonism, Akathisia, Dystonia and Dyskinesia.  In this questionnaire, take into account the verbal report of the  
     patient on the following: 1) the duration of the symptom during the day; 2) the number of days where the symptom was present during  
     the last week; and, 3) the evaluation of the intensity of the symptom by the patient. 
Enquire into the status of each symptom and rate accordingly 
1. Impression of slowness or weakness,
difficulty in carrying out routine
tasks
2. Difficulty walking or with balance
3. Stiffness, stiff posture
4. Restless, nervous, unable to
keep still
5. Tremors, shaking
6. Oculogyric crisis, abnormal
sustained posture
7. Abnormal involuntary movements
(dyskinesia) of tongue, jaw, lips,
face, extremities or trunk
Absent 
0
0 
0 
0
0 
0
0
Mild 
1 
1 
1 
1 
1 
1 
1
Moderate 
2 
2 
2 
2 
2 
2 
2
Severe 
3 
3 
3 
3 
3 
3 
3
II.
EXAMINATION: PARKINSONISM AND AKATHISIA
Constant or  
almost so  
4 
5 
6
Frequent 
3 
4 
5
None:
Borderline:
Small amplitude:
Moderate amplitude:
Large amplitude:
Right upper limb  
Left upper limb 
Right lower limb 
Left lower limb 
Head 
Tongue
Jaw/Chin 
Lips
1. Tremor
2. Bradykinesia
0:
normal 
1:
global impression of slowness 
in movements 
2:
definite slowness in movements 
3:
very mild difficulty in initiating 
movements 
4:
mild to moderate difficulty in 
initiating movements 
5:
difficulty in starting or stopping 
any movement, or freezing 
on initiating voluntary act  
6:
rare voluntary movement, almost 
completely immobile
3. Gait & posture
0:
normal 
1:
mild decrease of pendular arm  
   movement 
2:
moderate decrease of pendular
   arm movement, normal steps 
3:
no pendular arm movement, head 
flexed, steps more or less normal 
Items based on physical examinations for Parkinsonism.
Occasional
0 
1 
2 
3 
4
G. Chouinard, H.C. Margolese / Schizophrenia Research 76 (2005) 247–265
259


4:
stiff posture (neck, back) small step
   (shuffling gait) 
5: 
   more marked, festination or 
   freezing on turning 
6: 
   triple flexion, barely able to walk  
   
4. Postural stability
5. Rigidity
6 .  Expressive automatic
      movements (Facial
      mask / speech)
7 .   Akathisia
normal 
hesitation when pushed but no 
retropulsion
retropulsion but recovers unaided
exaggerated retropulsion without 
falling 
absence of postural response would
fall if not caught by examiner
unstable while standing, even  
without pushing
unable to stand without assistance 
normal muscle tone
very mild, barely perceptible
mild (some resistance to
passive movements)
moderate (definite 
difficulty to move
the limb)
moderately severe (moderate
resistance but still
easy to move limb) 
severe (marked resistance with
definite difficulty to move the limb)
extremely severe (limb nearly
frozen)
 
0: 
1:
2: 
3: 
4:
5:
6:
0: 
1: 
2:
3:
4:
5:
6:
0:
1: 
2:
3:
4:
5:
6:
0:
1:
2:
3:
Right upper limb  
Left upper limb 
Right lower limb 
Left lower limb
Items based on overall observation during examination for Parkinsonism.
normal
very mild decrease in facial
expressiveness
mild decrease in facial 
expressiveness
rare spontaneous smile, decrease
blinking, voice slightly
monotonous
no spontaneous smile, staring gaze,
low monotonous speech, mumbling 
marked facial mask, unable to
frown, slurred speech
extremely severe facial mask with
unintelligible speech
absent
looks restless, nervous, impatient, 
uncomfortable
needs to move at least one
extremity
often needs to move one extremity
or to change position
G. Chouinard, H.C. Margolese / Schizophrenia Research 76 (2005) 247–265
260


4:
moves one extremity almost  
   constantly if sitting, or stamps
   feet while standing
5: 
   unable to sit down for more than a
   short period of time
6: 
   moves or walks constantly
Right upper limb  
Left upper limb 
Right lower limb 
Left lower limb 
Head 
Tongue 
Eyes
Jaw/Chin 
Lips 
Trunk
 
III.
EXAMINATION: DYSTONIA
Based on examination and observation
Acute torsion, and non acute or
chronic or tardive dystonia
0:
1:
2:
3:
4:
5:
6:
absent
very mild
mild
moderate
moderately severe
severe
extremely severe
IV.
EXAMINATION: DYSKINETIC MOVEMENT
0 
1 
0 
1 
0 
1 
Constant or  
almost so  
Frequent** 
1. Lingual movements (slow
lateral or torsion movement
of tongue) 
none:
borderline:
clearly present, within oral
cavity:
with occasional partial
protrusion:
with complete protusion:
2. Jaw movements (lateral
movement, chewing, biting
clenching)
none:
borderline:
clearly present, small
amplitude:
moderate amplitude: 
but without mouth opening:
large amplitude: 
with mouth opening:
3. Bucco-labial movements
(puckering, pouting,
smacking, etc.)
none:
borderline:
clearly present, small
amplitude:
moderate amplitude, forward
movement of lips:
large amplitude; 
marked, noisy smacking of lips:
Based on examination and observation
Occasional*
2 
3 
4 
2 
3 
4 
3 
4 
5 
3 
4 
5 
3 
4 
5 
4 
5 
6 
4 
5 
6 
4 
5 
6
G. Chouinard, H.C. Margolese / Schizophrenia Research 76 (2005) 247–265
261
2 
3 
4 


0 
1 
0 
1 
0 
1 
0 
1 
4. Truncal movements 
(involuntary rocking, 
twisting, pelvic gyrations)
none:
borderline:
clearly present, small 
amplitude: 
moderate amplitude:
greater amplitude:
5. Upper extremities
(choreoathetoid movements
only: arms, wrists, hands, 
fingers)
none:
borderline:
clearly present, small
amplitude, movement 
of one limb:
moderate amplitude, movement
of one limb or movement of small
amplitude involving two limbs:
greater amplitude, movement 
involving two limbs:
6. Lower extremities 
(choreoathetoid movements 
only: legs, knees, ankles, toes)
none:
borderline:
clearly present, small
amplitude, movement 
of one limb:
moderate amplitude, movement
of one limb or movement of small
amplitude involving two limbs:
greater amplitude, movement 
involving two limbs:
7. Other involuntary movements
(swallowing, irregular
respiration, frowning, blinking,
grimacing, sighing, etc.) 
none:
borderline:
clearly present, small 
amplitude: 
moderate amplitude:
greater amplitude: 
Specify……………………………..………………………………………………………………………….
2 
3 
4 
2 
3 
4 
2 
3 
4 
3 
4 
5 
3 
4 
5 
3 
4 
5 
3 
4 
5
4 
5 
6 
4 
5 
6 
4 
5 
6 
4 
5 
6
* when activated or rarely spontaneous; 
** frequently spontaneous and present when activated
G. Chouinard, H.C. Margolese / Schizophrenia Research 76 (2005) 247–265
262
2 
3 
4 


V.
CLINICAL GLOBAL IMPRESSION OF SEVERITY OF DYSKINESIA
Considering your clinical experience, how severe is the dyskinesia at this time?
0:  absent
1:  borderline
2:  very mild
3:  mild
4:  moderate
5:  moderately sever
6:  marked
7:  severe
8:  extremely severe
VI. CLINICAL GLOBAL IMPRESSION OF SEVERITY OF PARKINSONISM
Considering your clinical experience, how severe is the parkinsonism at this time?
0:  absent
1:  borderline
2:  very mild
3:  mild
4:  moderate
5:  moderately sever
6:  marked
7:  severe
8:  extremely severe
VII. CLINICAL GLOBAL IMPRESSION OF SEVERITY OF DYSTONIA
Considering your clinical experience, how severe is the dystonia at this time?
0:  absent
1:  borderline
2:  very mild
3:  mild
4:  moderate
5:  moderately sever
6:  marked
7:  severe
8:  extremely severe
VIII. CLINICAL GLOBAL IMPRESSION OF SEVERITY OF AKATHISIA
Considering your clinical experience, how severe is the akathisia at this time?
0:  absent
1:  borderline
2:  very mild
3:  mild
4:  moderate
5:  moderately sever
6:  marked
7:  severe
8:  extremely severe
G. Chouinard, H.C. Margolese / Schizophrenia Research 76 (2005) 247–265
263

SAP_003.pdf: 
 
 
A Multiple Dose Study to Assess the Safety, Tolerability and 
Pharmacokinetics of Risperidone Extended Release 
Capsules in Subjects with Schizophrenia, Schizoaffective 
Disorder 
 
 
Statistical Analysis Plan 
 
 
 
VERSION: FINAL 1.0 
DATE OF PLAN: 
21-Oct-2020 
 
 
STUDY DRUG / PROTOCOL ID:  
Risperidone extended release capsule / LYN-005-C-004 
 
 
PREPARED FOR: 
Lyndra Therapeutics, Inc. (US) 




Sponsor: Lyndra Therapeutics, Inc. (US) 
Protocol Number: LYN-005-C-004 
SAP Version and Date: Final 1.0, 21OCT2020 
 
Approval Signatures: Lyndra Therapeutics, Inc. (US) 
 
 
 
 
 
 
 
 
Date 
 
 
 
 
 
 
 
Date 
 
 
 
 
 
 


Sponsor: Lyndra Therapeutics, Inc. (US) 
Protocol Number: LYN-005-C-004 
SAP Version and Date: Final 1.0, 21OCT2020 
 
Contents 
1 
Introduction .........................................................................................................................7 
2 
Study Objectives and Endpoints ..........................................................................................7 
 
Study Objectives ...........................................................................................................7 
2.1.1 
Primary Objectives.................................................................................................7 
2.1.2 
Secondary Objectives .............................................................................................7 
2.1.3 
Exploratory Objectives...........................................................................................7 
 
Study Endpoints ............................................................................................................7 
2.2.1 
Primary Endpoints .................................................................................................7 
2.2.2 
Secondary Endpoint ...............................................................................................8 
2.2.3 
Exploratory Endpoint .............................................................................................8 
3 
Study Design .......................................................................................................................8 
 
Study Design and Population ........................................................................................8 
 
Randomization and Blinding .........................................................................................8 
 
Sample Size Considerations ..........................................................................................8 
 
Safety Monitoring Committee .......................................................................................9 
 
Interim Analysis ............................................................................................................9 
 
Timing of Analyses .......................................................................................................9 
4 
Data Analysis Considerations ..............................................................................................9 
 
Stratification and Covariates ....................................................................................... 10 
 
Evaluation of Subgroups ............................................................................................. 10 
 
Multiple Comparisons and Multiplicity ....................................................................... 10 
5 
General Data Handling Conventions .................................................................................. 10 
 
Assigned and Actual Treatment ................................................................................... 10 
 
Reference Dates .......................................................................................................... 10 
 
Study Day and Duration Variables .............................................................................. 11 
 
Study Time Periods ..................................................................................................... 11 
 
Baseline and Post-Baseline Changes ........................................................................... 12 
 
Imputation of Partial Dates .......................................................................................... 12 
 
Multiple Assessments and Visit Windows ................................................................... 12 
 
Missing Data ............................................................................................................... 12 
6 
Study Subject Data ............................................................................................................ 13 
 
Analysis Populations ................................................................................................... 13 


Sponsor: Lyndra Therapeutics, Inc. (US) 
Protocol Number: LYN-005-C-004 
SAP Version and Date: Final 1.0, 21OCT2020 
 
 
Subject Disposition ..................................................................................................... 13 
 
Protocol Deviations ..................................................................................................... 13 
 
Demographic and Baseline Characteristics .................................................................. 13 
 
Medical History .......................................................................................................... 14 
 
Psychiatric History ...................................................................................................... 14 
 
Prior and Concomitant Medication .............................................................................. 14 
 
Study Drug Exposure .................................................................................................. 14 
6.8.1 
................................................ 15 
7 
Pharmacokinetics .............................................................................................................. 15 
 
Pharmacokinetic Parameters ....................................................................................... 15 
8 
Safety ................................................................................................................................ 15 
 
Adverse Events ........................................................................................................... 15 
 
Psychiatric Assessments .............................................................................................. 16 
8.2.1 
Structured Clinical Interview-Positive and Negative Syndrome Scale (SCI-PANSS)
 
16 
8.2.2 
Clinical Global Impression – Severity (CGI-S) .................................................... 17 
8.2.3 
Assessment of Suicidal Ideation and Behavior – Columbia Suicide Severity Rating 
Scale (C-SSRS) ................................................................................................................. 17 
 
Clinical Laboratory Evaluations .................................................................................. 18 
 
Other Safety Evaluations ............................................................................................. 18 
8.4.1 
Extrapyramidal Symptoms – Extrapyramidal Symptom Rating Scale (ESRS) ...... 18 
8.4.2 
Vital Signs ........................................................................................................... 18 
8.4.3 
Electrocardiogram (ECG) .................................................................................... 19 
8.4.4 
Physical Examinations ......................................................................................... 19 
8.4.5 
Prolactin .............................................................................................................. 19 
8.4.6 
Acid Reflux Severity Scale .................................................................................. 19 
8.4.7 
Fecal Occult Blood Test ....................................................................................... 19 
9 
Changes to the planned analysis ........................................................................................ 20 
10 References ......................................................................................................................... 21 
11 APPENDICES .................................................................................................................. 22 
 
APPENDIX 1. Partial Date Conventions ................................................................. 22 
 
APPENDIX 2: Tables, Listings, and Figures ........................................................... 24 
 


Sponsor: Lyndra Therapeutics, Inc. (US) 
Protocol Number: LYN-005-C-004 
SAP Version and Date: Final 1.0, 21OCT2020 
 
ABBREVIATIONS 
AE 
Adverse Event 
ATC 
Anatomic Therapeutic Chemical 
AUC 
Area Under the Concentration vs Time Curve 
Cmax 
Maximal Observed Concentration 
CGI-S 
Clinical Global Impression of Severity 
CRF 
Case Report Form 
CRU 
Clinical Research Unit 
CSR 
Clinical Study Report 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DIMD 
Drug-Induced Movement Disorders 
ECG  
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EPS 
Extrapyramidal Symptoms 
ER 
Extended Release 
ESRS 
Extrapyramidal Symptom Rating Scale 
GI 
Gastrointestinal 
IRT 
Interactive Response Technology 
Kel 
First Order Elimination Rate Constant 
LLN 
Lower limit of normal 
MedDRA 
Medical Dictionary for Medical Activities 
PANSS 
Positive and Negative Syndrome Scale 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
PT 
Preferred Term 
Q1 
First Quartile 
Q3 
Third Quartile 
SAE 
Serious adverse events 
SAF 
Safety Analysis Set 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SOC 
System Organ Class 
Tmax 
Time to Maximum Plasma Concentration 
TEAE 
Treatment Emergent Adverse Event 
ULN 
Upper limit of normal 
 
 
 


Sponsor: Lyndra Therapeutics, Inc. (US) 
Protocol Number: LYN-005-C-004 
SAP Version and Date: Final 1.0, 21OCT2020 
 
1 INTRODUCTION 
The statistical analysis plan (SAP) details the planned analysis required to satisfy the Clinical 
Study Report (CSR) of study number LYN-005-C-004:  A Multiple Dose Study to Assess the 
Safety, Tolerability and Pharmacokinetics of Risperidone Extended Release Capsules in Subjects 
with Schizophrenia, Schizoaffective Disorder.  The content of this SAP is based on the protocol 
dated 29AUG2020 V2.0. 
Revision Chronology: 
 
 
1.0 
16OCT2020 
Original 
Mock shells for tables, listings, and figures will be included in a separate document.  
2 STUDY OBJECTIVES AND ENDPOINTS 
 
Study Objectives 
2.1.1 Primary Objectives 
• To determine the safety and tolerability of risperidone extended release capsules (LYN-
005) administered as repeat weekly doses compared to IR risperidone tablets at 2 dose 
levels; 
• To characterize the PK of risperidone, active metabolite 9-hydroxyrisperidone and active 
moiety risperidone and 9-hydroxyrisperidone combined) after repeat weekly doses of 
LYN-005 ER capsules relative to IR risperidone tablets at 2 dose levels.  
2.1.2 Secondary Objectives 
• To assess the exposure to risperidone, 9-hydroxyrisperidone and active moiety during the 
switch from IR risperidone to LYN-005. 
2.1.3 Exploratory Objectives 
• To model the PK of risperidone, 9-hydroxyrisperidone and active moiety when 
administered as a LYN-005 extended-release capsule. 
 
Study Endpoints 
2.2.1 Primary Endpoints 
• Incidence of treatment emergent adverse events (TEAEs). 
• Risperidone, 9-hydroxyrisperidone, and active moiety PK after oral administration of 
LYN-005 capsules and IR risperidone to include, as possible and appropriate, Cmax, Cmin, 
Tmax, Kel, AUC0-24, AUC0-t, AUC0-168, AUC0-∞. 
 
 


Sponsor: Lyndra Therapeutics, Inc. (US) 
Protocol Number: LYN-005-C-004 
SAP Version and Date: Final 1.0, 21OCT2020 
 
2.2.2 Secondary Endpoint 
• Exposure to risperidone, 9-hydroxyrisperidone and active moiety as assessed from Cmax, 
Tmax, AUC0-24, AUC0-t, AUC0-∞ after switching from IR risperidone to LYN-005. 
2.2.3 Exploratory Endpoint 
• PK modelling of risperidone, 9-hydroxyrisperidone and active moiety exposure. 
3 STUDY DESIGN 
 
Study Design and Population 
LYN-005-C-004 is a blinded, multiple-dose, randomized, parallel group, safety, tolerability and 
PK study of LYN-005 in subjects with a primary diagnosis of schizophrenia or schizoaffective 
disorder in general good health. 
Eligible subjects must be clinically stable and receiving a therapeutic dose of an approved oral 
antipsychotic drug for a minimum of 6 weeks at the time of Screening. Enrolled subjects will be 
evaluated under steady-state conditions on commercially-available IR risperidone tablets and 
then assigned in blinded fashion either to LYN-005 weekly or continued encapsulated IR 
risperidone daily for 3 weeks to attain (or continue) steady-state exposure.  
 
Randomization and Blinding 
A total of 32 subjects will be randomized to receive either LYN-005 (14 or 28 mg weekly) or 
continue receiving IR risperidone (2 or 4 mg/day). Randomization will be performed in a 3:1 
ratio in a blinded fashion. Twenty-four subjects are randomized to receive LYN-005 (N=12 
receiving 14 mg weekly and N=12 receiving 28 mg weekly) and 8 subjects to continue receiving 
IR risperidone (N=4 receiving 2 mg/day and N=4 receiving 4 mg/day). The dose of LYN-005 or 
IR risperidone administered will be based on the patient’s current antipsychotic medication dose. 
Although treatment assignment is blinded; the dose level is not blinded.  To maintain the blind, 
all subjects will either receive LYN-005 and IR risperidone-placebo or LYN-005-placebo and IR 
risperidone. 
Subjects who successfully complete the admission procedures on Day -2 will be randomized on 
Day 1, using an Interactive Response Technology (IRT) system, to one of the 2 treatment groups. 
 
Sample Size Considerations 
This study is exploratory in nature and therefore not designed to test hypotheses.  Approximately 
32 subjects of whom 24 will receive LYN-005 will be enrolled in the study. Subjects who 
discontinue prematurely may be replaced at the Sponsor’s discretion. 
 
 


Sponsor: Lyndra Therapeutics, Inc. (US) 
Protocol Number: LYN-005-C-004 
SAP Version and Date: Final 1.0, 21OCT2020 
 
 
Safety Monitoring Committee 
There is a planned safety review of interim, blinded safety data including PK by the Investigator 
and Medical Monitor once data through Day 14 are available from 12 subjects. The safety data 
reviewed will include adverse events, vital signs, laboratory data, suicidality, and illness severity. 
Additionally, the PI or Sponsor may request an ad hoc review of blinded safety information, e.g., 
serious adverse events, at any time during the study. 
 
Interim Analysis 
No interim analysis is planned for this study. 
 
Timing of Analyses 
The final analysis will occur when the last subject completes the end-of-study visit (Day 35) and 
the database has been locked and unblinded.  
4 DATA ANALYSIS CONSIDERATIONS 
All analyses will be conducted based on SAS 9.4 or higher.  PK analyses will be performed in 
Watson LIMS (version 7.5). 
All data in the database will be presented in by subject data listings. 
Unless otherwise stated, all listings will be sorted by randomized treatment group, dose level, 
subject ID, treatment period, and time point (and time, if available).   
In general, continuous data will be summarized based on n, mean, median, standard deviation 
(SD), minimum value, and maximum value. Categorical data will be summarized by counts and 
percentages. Percentages will be derived from the number of subjects in the population of 
interest. Counts of zero will be presented without percentages. 
The following levels of precision for reporting data will be applied: 
• Mean, Median: one additional decimal place to that reported for Minimum and 
Maximum 
• SD: two additional decimal places than the Minimum and Maximum  
• Percentages <100% will be reported to one decimal place. Percentages of 100% 
will be reported with no decimal place. 
All data up to the time of study completion/withdrawal from the study will be included in the 
analysis. Unscheduled visits will be included in listings only. 
Numbering for data displays will be based on ICH E3(1). 
 
 


Sponsor: Lyndra Therapeutics, Inc. (US) 
Protocol Number: LYN-005-C-004 
SAP Version and Date: Final 1.0, 21OCT2020 
 
 
Stratification and Covariates 
Subjects will be split into 2 groups based on their IR risperidone run-in dose prior to 
randomization. A maximum of 16 subjects in each group will be enrolled and randomized. 
Subjects receiving 2 mg/day IR risperidone will be randomized (3:1 ratio) to receive either 14 
mg/week LYN-005 (N=12) or continued 2 mg/day IR risperidone (N=4) and those receiving 4 
mg/day IR risperidone will be randomized (3:1 ratio) to receive either 28 mg/week LYN-005 
(N=12) or continue with 4 mg/day risperidone (N=4), respectively. 
 
Evaluation of Subgroups 
There are no formal plans for examining subgroups. Subgroups may be identified during PK 
modelling. 
 
Multiple Comparisons and Multiplicity 
No formal hypothesis testing will be performed, Type 1 error will not be addressed.     
5 GENERAL DATA HANDLING CONVENTIONS 
 
Assigned and Actual Treatment 
As described in Section 3.2, subjects will be randomized to LYN-005 or IR risperidone.  The 
randomized treatment assignments will be used for listings as well as selected analyses indicated 
for the Safety Population. 
Actual treatment groups are based on exposure data to treatment received and will be the basis 
for all safety and PK analyses. 
The following 2 treatment groups (actual or as-randomized) are planned in this study: 
• LYN-005 
• IR risperidone 
 
Within the treatment groups, there will be 2 dose levels: 
• LYN-005 → 14 mg 
• LYN-005 → 28 mg 
• IR risperidone → 2 mg 
• IR risperidone → 4 mg 
 
Reference Dates 
The following reference definitions will be applied for this study: 
• Screening date is defined as the eCRF provided date on which a subject was screened for 
trial entry. 
• Informed consent date will be the reference date for prior history data reporting. 


Sponsor: Lyndra Therapeutics, Inc. (US) 
Protocol Number: LYN-005-C-004 
SAP Version and Date: Final 1.0, 21OCT2020 
 
• Enrollment date is defined as Study Day -2, date subject is admitted into the Clinical 
Research Unit (CRU) 
• Run-in Period date is defined as the date of first dose of IR risperidone during the run-in 
period starting on Day -13. This data will be collected in the Case Report Form (CRF). 
• Double-blind Period date is defined as the date of first dose of randomized treatment on 
Day 1. 
• AEs allocated to the IR Run-in Period will be based on the date of first dose in the Run-in 
Period as the reference date. 
• TEAEs will be based on the first dose of randomized treatment in the double-blind period 
as the reference date. 
• Study day will be based on the first dose of randomized treatment in the double-blind 
period as the reference date.  
• On-therapy Period 1 (OTP1) start date is defined as the date subject received first dose of 
randomized treatment on Day 1. 
• On-therapy Period 2 (OTP2) start date is defined as the date subject received second dose 
of randomized treatment on Day 8. 
• On-therapy Period 3 (OTP3) start date is defined as the date subject received third dose 
of randomized treatment on Day 15.  
• Follow up Period (FUP) start date is defined as the date subject resumes prior 
antipsychotic drug on Day 22. 
 
Study Day and Duration Variables 
Reference date calculations will generally be defined as the following, assuming non- missing 
dates:  
• Datetime of interest – reference datetime;  
• If time is not available, date will be used. 
o Date of interest – reference date + 1 when the date of interest ≥ reference date; 
o otherwise, date of interest – reference date. 
 
Date imputation will be performed as identified in Section 5.6. Otherwise, if either date is 
missing, reference date calculations will not be performed.   
 
For instance, study day will be based on the first randomized dose date as the reference date. 
Study day will either have a negative value if collected before dosing or a positive value if 
collected on or after the day of first randomized dosing; there will be no study day zero.  
Duration of time is dependent on reference dates and will be calculated in a manner similar to 
that of the reference date calculation, assuming that dates of interest will strictly follow reference 
dates (e.g. no negative values).  For example, duration on study will use date (not datetime) and 
is defined as the end of study date – screening date + 1. 
 
Study Time Periods 
Safety reporting will be classified by the following study periods for analysis: 


Sponsor: Lyndra Therapeutics, Inc. (US) 
Protocol Number: LYN-005-C-004 
SAP Version and Date: Final 1.0, 21OCT2020 
 
• Screening Period is defined as the period between Day -21 and Day -14: pre-dose 
(Screening visit date up to the day before Run-in IR dosing). 
• Run-in Period is defined as the period between Day -13 and Day -1: pre-dose (First Day 
of IR dosing to Day -1). 
• Double-blind Period is defined as the period between Day 1 to Day 35 (Day of first dose 
of randomized treatment to end of study). 
• OTP1 is defined as the period between Day 1 and Day 7 (prior to dosing on Day 8) 
• OTP2 is defined as the period between Day 8 and Day 14 (prior to dosing on Day 15) 
• OTP3 is defined as the period between Day 15 and Day 21. 
• FUP is defined as the period between Day 22 and Day 35. 
 
Baseline and Post-Baseline Changes 
Unless stated otherwise, baseline and post-baseline change values will be based on the following: 
Baseline values will be based on the last assessment performed prior to the first randomized 
treatment dose. Unscheduled/repeat assessments performed prior to ER dosing in the CRU on 
Day 1 can be used as baseline values should the planned assessment result in a missing value. 
Post-baseline values will be those collected after the first dose of randomized treatment.   
Change from baseline is defined as: post-baseline value – baseline value.  
 
Imputation of Partial Dates 
Appendix 1 details partial date conventions that will be used for the determination of treatment-
emergent adverse events, and prior and concomitant medications. 
 
End of Study Date 
Missing study end dates will not necessarily be imputed at the end of the study.  However, in the 
event of an ongoing reporting need, end of study dates may be imputed as the earliest of the data 
cutoff date, date of death, or last date recorded on the CRF. 
 
Multiple Assessments and Visit Windows 
Nominal visits (e.g. those identified by the study CRF) will be the basis of summarization; no 
visit date windowing will be conducted. Unscheduled data will be included in subject data 
listings.  
 
Missing Data 
AE and concomitant medication partial date imputations are described in Appendix 1.  Imputing 
partial dates will only be used to identify if the AE is a TEAE or not, or if a collected medication 
is prior or concomitant.  Otherwise, missing data will not be imputed.  In the listings, the true 
CRF collected date will be reported.  With respect to PK data, parameters will be derived as 
defined in Section 7.1 and although these methods may employ some inherent estimation of 
missing values (i.e., calculation of AUC), no formal imputation methods will be performed for 
the study. 


Sponsor: Lyndra Therapeutics, Inc. (US) 
Protocol Number: LYN-005-C-004 
SAP Version and Date: Final 1.0, 21OCT2020 
 
6 STUDY SUBJECT DATA  
 
Analysis Populations 
Enrollment Set (ENR): Defined as all subjects who are enrolled in the study and admitted to the 
research unit on Day -2. The Enrollment Population will be the primary set used for disposition, 
demographic and baseline characteristic data reporting. 
 
Safety Population (SAF): Defined as all enrolled subjects who are randomized to study drug 
(LYN-005 14mg/28mg or IR Risperidone 2mg/4mg) and receive at least one dose of randomized 
study drug. Subjects will be reported according to the treatment received. The Safety Population 
will be the primary safety analysis population. 
 
PK Population: Defined all enrolled subjects who receive at least one dose of randomized study 
drug and have at least 1 post-dose quantifiable (or evaluable) PK concentration data. Additional 
analysis sets within the PK population, if identified, will be specified in the PK Analysis Plan.    
 
Subject Disposition 
Summaries of number of subjects screened, analysis population membership, number of subjects 
who received IR risperidone run-in and weekly treatment dose, and final subject status 
(completed, discontinued), including reasons for withdrawal, will be produced based on the ENR 
Set.     
Analysis populations, weekly treatment dosing, and final subject disposition status will be listed. 
 
Protocol Deviations 
A protocol deviation is any change, divergence, or departure from the study design or procedures 
of a study protocol. In general, subjects associated with protocol deviations may remain in the 
study unless continuation in the study jeopardizes the subject’s health, safety, or rights. A 
protocol deviation may be a reason to remove data from an analysis set at the time of analysis. 
Protocol deviations may be defined as exclusionary from the analysis according to protocol 
objectives and endpoints. Prior to the final analysis of the study data, subjects with exclusionary 
protocol deviations will be identified and specified for each analysis set and documented. In 
some cases, exclusion of data may be due to a reason other than a protocol deviation, e.g., early 
termination.  Any protocol deviations related to COVID-19 will be documented.  
A listing of major protocol deviations will be provided for all enrolled subjects. A listing of 
COVID-19 protocol deviations will be provided for the ENR Set. 
 
Demographic and Baseline Characteristics 
Subject demographics will be summarized and listed for the ENR Set.  These will include age in 
years, sex, ethnicity, race, baseline height (cm), baseline weight (kg), and baseline BMI (kg/m2) 
calculated from baseline height and baseline weight.  Age will not be calculated and will come 
directly from the Case Report Form (CRF).   


Sponsor: Lyndra Therapeutics, Inc. (US) 
Protocol Number: LYN-005-C-004 
SAP Version and Date: Final 1.0, 21OCT2020 
 
 
Total scores collected from PILL-5, Extrapyramidal Symptom Rating Scale (ESRS), Clinical 
Global Impression – Severity (CGI-S), Columbia Suicide Severity Rating Scale (C-SSRS) 
ideation past 6 months, C-SSRS behavior lifetime, C-SSRS aborted attempts lifetime, C-SSRS 
interrupted attempts lifetime, and C-SSRS actual attempts lifetime at Screening will be 
summarized.  Total scores collected from ESRS, CGI-S, C-SSRS ideation past 6 months, C-
SSRS behavior lifetime, C-SSRS aborted attempts lifetime, C-SSRS interrupted attempts 
lifetime, and C-SSRS actual attempts lifetime will be included as baseline characteristics, and 
will be summarized. 
 
Medical History 
Medical History will be coded based on the Medical Dictionary for Regulatory Activities 
(MedDRA) for reporting by system organ class (SOC) and preferred term (PT).   
A listing of medical history will be provided for all subjects in the ENR Set. 
 
Psychiatric History 
Primary diagnosis of schizophrenia or schizoaffective disorder, years since primary diagnosis, 
years since last hospitalization for worsening of schizophrenia, previously hospitalized, and prior 
documented tolerability to IR risperidone will be summarized.  Total scores collected from the 
Structured Clinical Interview-Positive and Negative Syndrome Scale (SCI-PANSS) 
questionnaire at Screening will be summarized. 
 
All psychiatric history data will be listed for subjects in the ENR Set. 
 
Prior and Concomitant Medication  
Prior medications are those which have been identified to have been discontinued prior to 
admittance into the CRU on Day -2. Concomitant medications are those which have been 
identified to have been taken at any point after admittance into the CRU.  For study day 
calculations, the reference date will be the Day -2 date.   
All prior and concomitant medication data will be listed for subjects in the ENR population and 
will include the verbatim and preferred drug name and WHO Drug Dictionary anatomic 
therapeutic class (ATC) Level 2 classification (i.e. therapeutic main group). A flag for 
concomitant medications to identify in which study period the medication was taken will be 
provided. 
 
Study Drug Exposure 
The number and percent of subjects receiving IR dosing and randomized treatment will be 
displayed.  Number of days in the study and IR dosing compliance will be summarized. This 
study drug exposure will be presented for SAF subjects.  
Listings of study drug administration will be produced for the SAF population.   




Sponsor: Lyndra Therapeutics, Inc. (US) 
Protocol Number: LYN-005-C-004 
SAP Version and Date: Final 1.0, 21OCT2020 
 
A similar overview of TEAEs will be produced by On-Therapy weekly dose, as well as, for 
specific time intervals post-LYN-005. Time intervals for AEs reported between these periods 
will be presented for each of the on-therapy periods. 
• Within 24 hours post-LYN-005 (0 hours ≤ and ≤ 24 hours),  
• Between 24 and 48 hours post-LYN-005 (24 hours < and ≤ 48 hours), 
• From 48 hours to EOS (>48 hours to EOS). 
The number and percent of subjects experiencing the following AEs will be summarized for each 
on therapy period, follow-up period, and overall by system organ class (SOC) and preferred term 
(PT) in descending order of overall incidence.  For these summaries, subjects will be counted 
once within each SOC and PT. 
- 
TEAEs 
- 
TEAEs related to study treatment 
- 
TEAEs leading to study withdrawal  
- 
SAEs.   
A conservative approach for missing AE severity and relationship will be taken. AE with 
missing severity will be assumed to be severe and AEs with missing relationship will be assumed 
to be related to active drug.  As relationship to LYN-005 and relationship to IR risperidone are 
both collected in the eCRF, the following reporting structure will be followed. If an AE is 
marked as related to both IR risperidone and LYN-005, as the study is blinded, the relationship 
will be assumed to be related to active drug (ie: if marked as related to LYN-005 (active) and 
related to IR risperidone (placebo) the AE will be reported under LYN-005).  If an AE is marked 
as not related to either IR risperidone or LYN-005, the TEAE will be assigned to active drug. If 
the event is related to the placebo and not to active, the event will be reported under the placebo 
and vice versa for active treatment relationship.  
A comprehensive listing of all reported AEs will be provided in a by-subject data listing for the 
ENR Population. In addition, the following listings will be provided:  
• SAEs  
• TEAEs leading to study withdrawal 
• Fatal AEs 
 
 
Psychiatric Assessments 
8.2.1 Structured Clinical Interview-Positive and Negative Syndrome Scale (SCI-
PANSS)  
The SCI-PANSS is a 30-item scale used to evaluate the presence, absence and severity of 
Positive, Negative and General Psychopathology symptoms of schizophrenia accompanied by a 
semi-structured interview. In this study, the PANSS will be used at baseline in order to assess the 
stability and severity of subjects’ disease. Each of the 30 items in the PANSS has a definition 


Sponsor: Lyndra Therapeutics, Inc. (US) 
Protocol Number: LYN-005-C-004 
SAP Version and Date: Final 1.0, 21OCT2020 
 
and a basis for rating, and all items are rated on a 7-point scale (1 = absent; 7 = extreme). 
Subjects’ PANSS scores at Screening must be aligned with stable, mild to moderate disease 
based on values of <4 for individual items P1, P3, P4, P6, P7 and G14. The strengths of the 
PANSS include its structured interview, robust factor dimensions, reliability, the availability of 
detailed anchor points, and validity. 
PANSS will be administered to all subjects at screening. 
PANSS total score data will be provided in data listings and presented for all subjects in the 
SAF. 
8.2.2 Clinical Global Impression – Severity (CGI-S) 
The CGI-S measures the severity of a subject’s psychopathology.  As efficacy is not assessed in 
this study, the CGI-S will be used to assess subject stability at screening, enrollment and 
throughout the study.  Scores are as follows: 
1. Normal, not ill at all 
2. Borderline mentally ill 
3. Mildly ill 
4. Moderately ill 
5. Markedly ill 
6. Severely ill 
7. Among the most severely ill subjects 
 
Observed values and changes from baseline for CGI-S total score will be summarized for each 
time point collected for subjects in the SAF.  
All CGI-S data will be presented in data listings for all subjects in the SAF. 
8.2.3 Assessment of Suicidal Ideation and Behavior – Columbia Suicide Severity 
Rating Scale (C-SSRS) 
The C-SSRS is an interview-based rating scale intended to systematically assess suicidal ideation 
and suicidal behavior. Two versions of the C-SSRS will be utilized in this study to ensure subject 
safety; Baseline/Screening and Since Last Visit assessments. 
At the Screening Visit, the Baseline/Screening version will be used to assess study eligibility 
criteria and baseline suicidal ideation and behavior. Each subsequent assessment will utilize the 
Since Last Visit version of the C-SSRS. 
The C-SSRS will be administered to all subjects to monitor stability at multiple predefined visits 
and at the discretion of the PI.  
Observed values and changes from baseline for C-SSRS ideation past 6 months score will be 
summarized for maximum ideation score during the DBP collected for subjects in the SAF. 
Observed values and changes from C-SSRS preparatory acts or behavior lifetime, C-SSRS 
aborted attempts lifetime, C-SSRS interrupted attempts lifetime, and C-SSRS actual attempts 


Sponsor: Lyndra Therapeutics, Inc. (US) 
Protocol Number: LYN-005-C-004 
SAP Version and Date: Final 1.0, 21OCT2020 
 
lifetime at baseline will be summarized for behavior score during all OTP collected for subjects 
in the SAF. 
All C-SSRS data will be presented in data listings for all subjects in the SAF. 
 
Clinical Laboratory Evaluations 
Clinical chemistry and hematology parameters will be reported based on the International 
System of Units (SI). The following laboratory evaluations will be reported in data summaries: 
Hematology, Coagulation, Clinical Chemistry, Urinalysis. 
Observed values and changes from baseline for continuous laboratory evaluations, including 
hematology, clinical chemistry, and coagulation will be summarized for each time point for 
subjects with clinically significant results collected for SAF.  See Section 5.5 for the baseline 
definition. 
All laboratory parameters will be provided in subject data listings for the SAF population.   
Results from urine drug screening (benzodiazepines, cocaine, opiates, cannabis, and other), 
Serology lab assessments (Hepatitis B, Hepatitis C, HIV), H. pylori breath test, Compliance lab 
assessments (Alcohol breath test), Nicotine History, Pregnancy results (serum and urine), and 
CYP2D6 genotype will be provided in subject data listings for the SAF population.   
 
Other Safety Evaluations 
8.4.1  Extrapyramidal Symptoms – Extrapyramidal Symptom Rating Scale 
(ESRS) 
The Extrapyramidal Symptom Rating Scale (ESRS) will be used at baseline and throughout the 
study in order to assess the severity of and monitor extrapyramidal symptoms. The ESRS 
consists of several components:  
• a questionnaire of EPS or DIMD; 
• an examination of Parkinsonism and akathisia; 
• an examination of dystonia; 
• an examination of dyskinesia; 
• clinical global impression severity (CGI-S) scales of tardive dyskinesia, Parkinsonism, 
dystonia and akathisia. 
Observed values and changes from baseline for ESRS total score will be summarized for each 
time point collected for subjects in the SAF.  See Section 5.5 for the baseline definition.   
All ESRS data will be presented in data listings for all subjects in the SAF. 
8.4.2 Vital Signs 
Vital signs include: respiratory rate (bpm); temperature (ºF); systolic and diastolic blood pressure 
(mmHg); heart rate (beats/min). Observed values and changes from baseline for vital signs will 


Sponsor: Lyndra Therapeutics, Inc. (US) 
Protocol Number: LYN-005-C-004 
SAP Version and Date: Final 1.0, 21OCT2020 
 
be summarized for each time point collected for subjects in the SAF.  See Section 5.5 for the 
baseline definition. 
All vital signs data will be presented in data listings for all subjects in the SAF. 
8.4.3  Electrocardiogram (ECG) 
Electrocardiogram (ECG) parameters include:  HR (beats/min), PR (msec), QRS (msec), QT 
(msec), QTcF (msec). Observed values and changes from baseline for ECG parameters will be 
summarized at each time point for subjects in the SAF.   
The number and percent of subjects with specified evaluation of QTcF values will be 
summarized overall for the DBP (using all evaluations, including unscheduled assessments) and 
by visit.  The QTcF evaluations consist of: 
• Absolute QTc interval prolongation: 
o QTc interval > 450 
o QTc interval > 480 
o QTc interval > 500 
• Change from baseline in QTc interval: 
o QTc interval increases from baseline > 30 
o QTc interval increases from baseline > 60 
All ECG data will be presented in data listings for all subjects in the SAF. 
8.4.4  Physical Examinations 
A general physical examination will be performed at Screening, Day -2 and the EOS visit.  
Physical examinations will be presented in subject data listings for all subjects in the SAF. 
8.4.5 Prolactin 
Samples to assess Prolactin will be performed at Screening, Day 1, Day 8, Day 15, Day 21, and 
the EOS visit.  Observed values and changes from baseline and from screening for Prolactin will 
be summarized at each time point for subjects in the SAF.   
Prolactin results will be presented in subject data listings for all subjects in the SAF. 
8.4.6 Acid Reflux Severity Scale 
The acid reflux severity scale is performed during screening to ensure compliance with exclusion 
criteria. Data will be listed for all subjects in the SAF. 
8.4.7 Fecal Occult Blood Test 
Observed values and changes from baseline for fecal occult blood tests will be summarized for 
each time point for subjects in the SAF population.  See Section 5.5 for the baseline definition. 
Fecal occult blood test details will be presented in subject data listing for all subjects in the SAF. 


Sponsor: Lyndra Therapeutics, Inc. (US) 
Protocol Number: LYN-005-C-004 
SAP Version and Date: Final 1.0, 21OCT2020 
 
9 CHANGES TO THE PLANNED ANALYSIS 
No changes from the analyses in the protocol are planned. 
 
 


Sponsor: Lyndra Therapeutics, Inc. (US) 
Protocol Number: LYN-005-C-004 
SAP Version and Date: Final 1.0, 21OCT2020 
 
10 REFERENCES 
 
(1) International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use.  ICH Harmonised Tripartite Guideline: Structure and content of 
clinical study reports E3. Step 4. 1995. 
https://database.ich.org/sites/default/files/E3_Guideline.pdf 
 






Sponsor: Lyndra Therapeutics, Inc. (US) 
Protocol Number: LYN-005-C-004 
SAP Version and Date: Final 1.0, 21OCT2020 
 
 APPENDIX 2: Tables, Listings, and Figures 
All tables, listings, and figures will be numbers according to the ICH-E3 Guideline.  A table of 
contents containing the tables and listings to be produced based on the SAP text are included in a 
separate mock shell document appended to the SAP.