Conditions: Schizophrenia Schizo-affective Disorder
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 66
Healthy volunteers: no

Brief summary:
The study will be a 6-month, open-label, multiple center study in approximately 50 stable subjects diagnosed with schizophrenia or schizoaffective disorder to evaluate the safety, tolerability, and pharmacokinetics of Risperidone and 9-OH-Risperidone following implantation of two or three, 300 mg Risperidone Implants.

Detailed description:
The study will be a 6-month, open-label, study in approximately 50 stable subjects diagnosed with schizophrenia or schizoaffective disorder to evaluate the safety, tolerability, and pharmacokinetics of Risperidone and 9-OH-Risperidone following implantation of two or three, 300 mg Risperidone Implants.

Subjects who are diagnosed with schizophrenia or schizoaffective disorder according to DSM-V and are stable on a daily 4 mg oral dose of Risperidone for at least 8 weeks will be recruited into the study.

Subjects stable on a 4 mg oral dose of Risperidone will be implanted with two or three, 300 mg, Risperidone Implants. All implants will be placed in the inner aspect of the upper arm. Plasma concentrations of Risperidone and the active moiety will be measured prior to placement of the Risperidone Implants, throughout the implantation period, and after re-converting to oral Risperidone following the removal of the Risperidone Implants.

Arms:
arm 1: Two, 300 mg Risperidone Implants arm 2: Three, 300 mg Risperidone Implants

Interventions: intervention 1: Risperidone Implant
Intervention descriptions: intervention 1: None

Protocol document:
Prot_SAP_000.pdf: 
BB-PK-103 
Braeburn Pharmaceuticals
Confidential 
- 
12-Feb-2017                                
        
                                  1 
 
 
 
 
 
 
 
BB-PK-103 
 
A PHASE II, OPEN-LABEL PHARMACOKINETIC 
STUDY IN SCHIZOPHRENIC PATIENTS ON A STABLE 
DOSE OF 4 MG ORAL RISPERIDONE TO EVALUATE 
THE SAFETY, TOLERABILITY, AND 
PHARMACOKINETICS OF RISPERIDONE AND 9-
HYDROXY (OH)- RISPERIDONE WHEN RISPERIDONE 
IS ADMINISTERED WITH A SIX MONTH IMPLANT 
Date: 
Version 7: February 12, 2017 
Replaces Version 6: October 20, 2016, Version 5: May 10, 2016, Version 4:  March 9, 2016, 
Version 3:  November  25, 2015, Version 2: October 30, 2015 and Version 1: September 29, 
2015 
 
 
Sponsor: 
Braeburn Pharmaceuticals Inc. 
47 Hulfish Street, Princeton NJ 08452 
Telephone: 609-751-5375 
 
 
 
 
 
 
CONFIDENTIALITY STATEMENT 
This protocol is the property of Braeburn Pharmaceuticals and is intended solely for the 
guidance of the clinical investigation. This protocol may not — in full or part — be passed on, 
reproduced, published, or distributed to any person or entity who is not bound by written 
confidentiality agreement, for any purpose, without the prior consent of Braeburn 
Pharmaceuticals.


BB-PK-103 
Braeburn Pharmaceuticals
Confidential 
- 
12-Feb-2017                                
        
                                  2 
 
 
SPONSOR AND KEY PERSONNEL CONTACT INFORMATION  
 
Role in Study  
Name 
 Contact Information 
Study Sponsor 
Braeburn 
Pharmaceuticals, Inc. 
47 Hulfish Street, Suite 441 
Princeton, NJ  08542 
Medical Monitor(s) 
Lawrence Blob, MD 
Cognitive Research 
Corporation - Medical 
Oversight 
lblob@cogres.com 
727-897-9000 (office) 
410-262-1908 (mobile) 
Sponsor Project Manager 
Jamie Jarecki-Smith, 
Project Manager 
jjarecki@braeburnpharma.com
719.494.6500 (mobile) 
Principal Investigator 
Rishi Kakar, MD 
Board Certified 
Psychiatrist 
Segal Institute for Clinical 
Research 
Rkakar@segalinstitute.com 
954-990-7194 (office) 
786-512-4106 (mobile) 
 
 
 


BB-PK-103 
Braeburn Pharmaceuticals
Confidential 
- 
12-Feb-2017                                
        
                                  3 
 
SYNOPSIS 
 
Name of Sponsor/Company: Braeburn Pharmaceuticals 
Name of Investigational Product: Risperidone Implant 
Name of Active Ingredient: Risperidone 
Title of Study: A PHASE II, OPEN-LABEL PHARMACOKINETIC STUDY IN 
SCHIZOPHRENIC PATIENTS ON A STABLE DOSE OF 4 MG ORAL RISPERIDONE TO 
EVALUATE THE SAFETY, TOLERABILITY, AND PHARMACOKINETICS OF RISPERIDONE 
AND 9-HYDROXY (OH)- RISPERIDONE WHEN RISPERIDONE IS ADMINISTERED WITH A 
SIX MONTH IMPLANT  
Study center(s): Study will be conducted at approximately 2 centers within the United States. 
Study Period (Planned): 
Estimated date first subject enrolled: October 2015 
Estimated date last subject completed: February 2017 
Estimated date last subject completed in safety extension: 
August 2017 
 
Phase of Development: 2 
Objectives: 
Primary: The primary objective of this study is to characterize the pharmacokinetics of 6-month 
Risperidone Implants containing 300 mg risperidone each compared to an oral 4-mg risperidone 
tablet. 
Secondary:  
• 
To explore the efficacy of  Risperidone Implant as assessed by the Positive and Negative 
Syndrome Scale (PANSS) 
• 
To explore the safety of Risperidone Implant as assessed by vital signs, clinical laboratory 
evaluations, electrocardiograms (ECGs), physical examinations, implant site assessments, 
extrapyramidal symptom (EPS) assessments, Columbia Suicide Severity Scale (C-SSRS) 
assessments, Abnormal Involuntary Movement Scale (AIMS), Simpson Rating Scale 
(SAS), Barnes Akathisia Scale (BARS), and adverse event (AE) monitoring. 
 


BB-PK-103 
Braeburn Pharmaceuticals
Confidential 
- 
12-Feb-2017                                
        
                                  4 
 
Name of Sponsor/Company: Braeburn Pharmaceuticals 
Name of Investigational Product: Risperidone Implant 
Name of Active Ingredient: Risperidone 
Methodology: The study will be a 6 month, open-label, multiple center study in approximately 60 
stable subjects diagnosed with schizophrenia or schizoaffective disorder to evaluate the safety, 
tolerability, and pharmacokinetics of risperidone and 9-OH-risperidone following implantation of two 
or three, 300 mg  Risperidone Implants.  It will be followed by a 6 month safety extension for subjects 
who agree to receive a second implant. Subjects who are diagnosed with schizophrenia or 
schizoaffective disorder according to DSM-V and are stable on a daily 4 mg oral dose of risperidone 
for at least 8 weeks will be recruited into the study. Subjects will be implanted with two or three 300 
mg Risperidone Implants.  Approximately the first 10 subjects will receive two 300 mg implants; 
approximately 50 additional subjects will receive three 300 mg implants. All implants will be placed in 
the inner aspect of the upper arm. Samples for determination of plasma concentrations of risperidone, 
9-OH-risperidone and the active moiety (risperidone plus 9-OH-risperidone) will be obtained prior to 
and after insertion of the Risperidone Implants.  
The additional 50 subjects who receive the three 300 mg implants will stay in the treatment center for 
7 days prior to and 7 days post implantation of the initial Risperidone Implants. Subjects can check in 
up to 16 days prior to allow flexibility for subject check in. Safety monitoring and pharmacokinetic 
sampling will be conducted during the in-house period of the study. Scheduled outpatient visits, that 
will include safety monitoring and pharmacokinetic sampling, will be conducted for the remainder of 
the implantation period. After 6 months, the first implants will be explanted and subjects may be 
implanted (at their same dose level) with two or three additional implants for an additional six 
months in the same site in a safety extension.  Again, scheduled outpatient visits that will include 
safety monitoring will be conducted for the remainder of the implant period.  A subset of study 
participants (approximately 15 subjects) will also have pharmacokinetic sampling during the 7 days 
following reimplantation, as well as throughout the remainder of the study. A subset of 
approximately 10 subjects who are re-implanted during the safety extension will be followed with 
serial monthly ultrasounds for 6 months to characterize ability of high resolution ultrasound to 
localize implanted rods. Following explantation of the second set of Risperidone Implants, each 
subject will be converted back to his/her pre-implant oral risperidone dosing regimen.  
Number of Subjects (Planned):  Approximately 10 subjects will receive the two 300 Risperidone 
Implants (600 mg risperidone) and approximately 50 subjects will receive three Risperidone 
Implants (900 mg risperidone). A subset of approximately 15 subjects in the 900 mg risperidone 
group will have additional pharmacokinetic sampling during the 7 days following re-implantation, 
as well as throughout the remainder of the safety extension.   
 
 


BB-PK-103 
Braeburn Pharmaceuticals
Confidential 
- 
12-Feb-2017                                
        
                                  5 
 
Name of Sponsor/Company: Braeburn Pharmaceuticals 
Name of Investigational Product: Risperidone Implant 
Name of Active Ingredient: Risperidone 
Diagnosis and Main Criteria for Inclusion: 
Inclusion Criteria: 
1. Subject (and/or a subject’s authorized legal representative) has provided written informed consent
2. Subject has been on a stable dose of 4 mg of oral risperidone for at least 8 weeks  
3. Meets the following criteria that is related to subject’s stability on current 4 mg 
risperidone: 
a. Outpatient status 
b. PANSS Total Score ≤ 80 at screening and if PANSS score at baseline is ≥ 20% change 
from screening, the patients cannot participate in the study.  
c. A score of ≤ 3 on the following PANSS items: 
• Conceptual disorganization 
• Suspiciousness 
• Hallucinatory behavior 
• Unusual thought content 
4. Subject has identified a caregiver or personal contact with whom the subject has 
significant contact with at least once per week 
5. Subject is male or female between 18 to 60 years of age.   
6. Female participants (if of childbearing potential and sexually active) and male participants (if 
sexually active with a partner of childbearing potential) who agree to use a medically acceptable 
and effective birth control method throughout the study. Medically acceptable methods of 
contraception that may be used by the participant and/or his/her partner include abstinence, birth 
control pills or patches, diaphragm with spermicide, intrauterine device (IUD), surgical 
sterilization, condoms with spermicide, or progestin injection. All Females of childbearing 
potential must have a negative serum pregnancy test at the Screening visit.  All females of non-
child-bearing potential must have the following documentation: 
a) Medical documentation of surgical sterility OR. 
b) Are post-menopausal defined as 12 consecutive months of amenorrhea and confirmed by a 
Follicle Stimulating Hormone (FSH) test  
7. 
Subject has a diagnosis of schizophrenia or schizoaffective disorder according to 
Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-V) criteria 
8. 
Subject has a body mass index (BMI) ≥18.5 and ≤35.0 kg/m2 
9. 
Subject is assessed by the Investigator to be symptomatically stable with regard to his or 
her psychiatric condition at screening and baseline 
10. Subject is assessed by the Investigator to be symptomatically stable with regard to pre-existing 
medical conditions as evidenced by medical history, clinically significant findings on physical 
examination, vital signs, clinical laboratory evaluations (hematology, serum chemistries, and 
urinalysis) or 12-lead electrocardiogram (ECG). Subjects may continue on their current 
prescribed medication regimens to control pre-existing medical and psychiatric conditions 
(other than schizophrenia) including the use of prescribed PRN medications. 


BB-PK-103 
Braeburn Pharmaceuticals
Confidential 
- 
12-Feb-2017                                
        
                                  6 
 
Name of Sponsor/Company: Braeburn Pharmaceuticals 
Name of Investigational Product: Risperidone Implant 
Name of Active Ingredient: Risperidone 
Exclusion Criteria: 
1. 
Known hypersensitivity or allergy to lidocaine or any local anesthetic agent of the amide 
type (local anesthetic used during implant and explant procedures) 
2. 
Known sensitivity to polyurethane 
3. 
Hospitalized or required acute crisis intervention for exacerbation of symptoms of 
Schizophrenia or Schizoid Disorder in the 60 days prior to admission as determined by the 
Investigator 
4. 
Subject has a history of suicide attempt in the last year, or in the opinion of the investigator 
is currently at imminent risk of suicide 
5. 
Reports or reveals a presence of clinically significant skin disorders (such as, but not limited 
to, skin cancer, psoriasis, eczema, or atopic dermatitis), evidence of recent sunburn, scar 
tissue, tattoo, open sore, body piercing or branding at the intended implantation site that 
would interfere with the implantation procedure or interfere with implant site assessments as 
determined by the Investigator 
6. 
History of abnormal scar formation at insertion site or elsewhere on the body or family history 
of keloid formation 
7. 
Has a current or recent (within 12 months) DSM-V diagnosis of moderate or severe 
substance use disorder (except for tobacco use disorder) or has a positive urine drug 
screen for prohibited substances at screening.    
8. 
Have impaired hepatic (ALT/AST >1.5 times higher than the upper limit of normal) or 
renal function (eGFR<50 mL/min) 
9. 
Previously defined hypersensitivity to risperidone 
10. History of neuromalignant syndrome (NMS) 
11. Electroconvulsive therapy within 6 months of admission 
12. Requires current use of agents that are strong inhibitors and inducers of cytochrome P450 
2D6  
13. Current diagnosis of Acquired Immune Deficiency Syndrome (AIDS) and active hepatitis.  
Subjects with no detectable viral load, no detectable acute inflammation and no clinical 
necessity for HIV therapy will be allowed, at the discretion of the Investigator.   
14. Participation in the treatment phase of a clinical study or receipt of an investigational drug 
within 30 days prior to study drug administration on Day 1; for investigational drugs with an 
elimination half-life greater than 15 days, this time period will be extended to 60 days 
15. Prior participation in a risperidone study within the last 6 months 
16. Involvement in the planning and/or conduct of the study (applies to both Braeburn staff or staff 
at the investigational site) 


BB-PK-103 
Braeburn Pharmaceuticals
Confidential 
- 
12-Feb-2017                                
        
                                  7 
 
Name of Sponsor/Company: Braeburn Pharmaceuticals 
Name of Investigational Product: Risperidone Implant 
Name of Active Ingredient: Risperidone 
17. History of difficulty with phlebotomy procedures 
Investigational Product, Dosage, and Mode of Administration: 
2x or 3x Risperidone Implant 300 mg  
risperidone, 4 mg, oral tablet 
Reference Therapy, Dosage, and Mode of Administration: None 
Duration of Treatment:  Approximately 56 weeks, up to 50 weeks of Risperidone Implant. 
Criteria for Evaluation: 
Pharmacokinetics: Blood samples for pharmacokinetic assessment of risperidone and 9-OH-risperidone 
plasma concentrations will be obtained for the oral risperidone dose and for the Risperidone Implants.  
 
The following pharmacokinetic parameters will be determined for risperidone, 9-OH-risperidone, and 
active moiety (risperidone + 9-OH-risperidone) after the 4 mg oral dose of risperidone on Day -1: 
AUC0-24h, Cavg, Cmax, Ctrough, and Tmax.  
 
The following parameters will be determined for risperidone, 9-OH-risperidone and active moiety 
following the Risperidone Implants: AUC3-180 days, AUC3-t (where t represents the duration of 
pharmacokinetic sampling in subjects not completing the 180 day sampling schedule), AUC monthly 
for each month of the 6 month periods, Cavg monthly for the each month of the 6 month period, Cavg 3-180 
days and Cavg 3-t. The Cavg values for risperidone, 9-OH-risperidone and active moiety over time will be 
calculated as their respective AUC value divided by the number of days over which the data was 
collected. In the event a subject discontinues during the implantation period AUC3-t and Cavg will be 
assessed, if determined evaluable by the pharmacokineticist. 
 
 
Efficacy Assessment:  Positive and Negative Syndrome Scale (PANSS) will be summarized using 
appropriate descriptive statistics for pharmacokinetic population. 
 
Safety: Safety parameters will be monitored throughout the study by collection of vital signs, clinical 
laboratory evaluations, ECGs, physical examinations, implant site assessments, extrapyramidal 
symptom assessments, (EPS), Columbia Suicide Severity Scale assessments (C-SSRS), Abnormal 
Involuntary Movement Scale (AIMS), Simpson Rating Scale (SAS), and Barnes Akathisia Scale 
(BARS) and adverse event (AE) monitoring.


BB-PK-103 
Braeburn Pharmaceuticals
Confidential 
- 
12-Feb-2017                                
        
                                  8 
 
Name of Sponsor/Company: Braeburn Pharmaceuticals 
Name of Investigational Product: Risperidone Implant 
Name of Active Ingredient: Risperidone 
Statistical Methods: 
Approximately 40 will provide over 90% power to establish that implant is non-inferior to the oral 4 mg 
dose of risperidone.   In the sample size calculation it was assumed that the true ratio was 1.1 and the 
coefficient of variance (CV) was less than 0.45.  These assumptions were based on internal data.  
Therefore, approximately 50 subjects will be enrolled to ensure approximately 40 subjects completing 
the study assuming that the drop rate is less than 20%.   
 
Analysis Populations: Safety population will consist of all subjects who have received any study 
medication. 
 
The pharmacokinetic (PK) population will consist of subjects who receive 4 mg oral risperidone daily 
and the Risperidone Implant.  
Pharmacokinetic Analyses: All pharmacokinetic results (concentration and pharmacokinetic variables) 
will be summarized using appropriate descriptive statistics where applicable. The total active moiety 
will be considered the primary interest.  The ratios of Risperidone Implant Cavg  over oral Cmax, over 
the oral Cavg  and over the oral Ctrough will analyzed based on log-transformed scales using an 
ANOVA model with treatment effects.  The two sided 95% confidence intervals will be presented.   
Safety/Tolerability Analyses: The frequency of AEs will be tabulated using the Medical Dictionary 
for Regulatory Activities (MedDRA) by system organ class (SOC) and preferred terms and treatment 
for each cohort. The maximum intensity and frequency of AEs will also be summarized by treatment 
and cohort. 
Vital sign measurements, clinical laboratory evaluations, assessment of implant site, EPS assessment 
and ECGs will be summarized by treatment and study day (visit) using descriptive statistics or 
frequency distribution, as appropriate.
 
 


12-Feb-2017 
BB-PK-103 
Braeburn Pharmaceuticals
Confidential 
Page 9
 
 
 
 
TABLE OF CONTENTS 
1 
INTRODUCTION .......................................................................................................................... 14 
1.1 
Background ....................................................................................................................................... 14 
1.1.1 
Summary of Nonclinical Findings and Safety ............................................................................... 15 
1.1.2 
Pharmacokinetics and Drug Metabolism in Humans ................................................................... 17 
1.2 
Previous Human Experience ............................................................................................................. 18 
1.3 
PK Model Summary .......................................................................................................................... 19 
2 
STUDY OBJECTIVES AND PURPOSE ............................................................................................. 20 
2.1 
Primary Objective ............................................................................................................................. 20 
2.2 
Secondary Objectives ........................................................................................................................ 20 
3 
INVESTIGATIONAL PLAN .............................................................................................................. 21 
3.1 
Overall Study Design and Plan: Description ..................................................................................... 21 
3.1.1 
Overview of Treatment ................................................................................................................ 22 
4 
SELECTION AND WITHDRAWAL OF SUBJECTS ............................................................................ 31 
4.1 
Subject Inclusion Criteria .................................................................................................................. 31 
4.2 
Subject Exclusion Criteria ................................................................................................................. 32 
4.3 
PK Subset Inclusion .......................................................................................................................... 33 
4.4 
Subject Withdrawal Criteria .............................................................................................................. 33 
4.4.1 
Criteria and Procedures for Discontinuation ................................................................................ 33 
5 
TREATMENT OF SUBJECTS .......................................................................................................... 35 
5.1 
Identity of Study Drug and Duration of Treatment ........................................................................... 35 
5.1.1 
Investigational Product, Dosage, and Mode of Administration ................................................... 35 
5.1.2 
Duration of Treatment ................................................................................................................. 35 
5.2 
Concomitant Medications .................................................................................................................. 35 
5.3 
Treatment Compliance ...................................................................................................................... 35 
5.4 
Restrictions on Study Subjects .......................................................................................................... 36 
5.5 
Randomization and Blinding ............................................................................................................. 36 
5.5.1 
Randomization ............................................................................................................................. 36 
5.5.2 
Blinding ........................................................................................................................................ 36 
6 
STUDY DRUG MATERIALS AND MANAGEMENT ........................................................................... 37 
6.1 
Study Drug ........................................................................................................................................ 37 
6.2 
Study Drug Description, Packaging, and Labeling ............................................................................ 37 
6.3 
Study Drug Storage ........................................................................................................................... 37 
6.4 
Study Drug Preparation ..................................................................................................................... 37 
6.5 
Administration ................................................................................................................................... 37 
6.6 
Study Drug Accountability ................................................................................................................ 38 
6.7 
Study Drug Handling and Disposal ................................................................................................... 38 
7 
ASSESSMENT OF PHARMACOKINETICS ....................................................................................... 39 
7.1 
Pharmacokinetic Assessments ........................................................................................................... 39 
7.1.1 
Blood Sample Collections ............................................................................................................. 39 
7.1.2 
Sample Storage and Shipment ..................................................................................................... 39 
7.1.3 
Analytical Methodology ............................................................................................................... 39 


12-Feb-2017 
BB-PK-103 
Braeburn Pharmaceuticals
Confidential 
Page 10
 
 
8 
ASSESSMENT OF EFFICACY .......................................................................................................... 40 
8.1 
Psychiatric Rating Scales ................................................................................................................... 40 
8.1.1 
Positive and Negative Syndrome Scale (PANSS) ........................................................................... 40 
9 
CLINICAL CRITERION FOR LACK OF EFFICACY .............................................................................. 41 
10 
ASSESSMENT OF SAFETY ............................................................................................................. 42 
10.1 
Timing of Safety Assessments .......................................................................................................... 42 
10.2 
Safety Parameters .............................................................................................................................. 42 
10.2.1 
Medical/Medication History and Demographic Information ................................................... 42 
10.2.2 
Physical Examinations ............................................................................................................. 42 
10.2.3 
Laboratory Evaluations ............................................................................................................ 43 
10.2.4 
Vital Signs ................................................................................................................................ 44 
10.2.5 
12-Lead Electrocardiograms .................................................................................................... 44 
10.2.6 
Implant Site Assessments ........................................................................................................ 45 
10.2.7 
Extrapyramidal Symptom Assessments ................................................................................... 45 
10.2.8 
Columbia Suicide Severity Scale ............................................................................................... 45 
10.3 
Early Explantation and Subject Withdrawal Criteria ......................................................................... 45 
10.3.1 
Suspicion of Implant Breakage ................................................................................................ 45 
10.3.2 
Subject Manipulation or Attempted Removal of RISPERIDONE IMPLANT ............................... 46 
10.3.3 
Documentation of Implant Events ........................................................................................... 46 
10.4 
Recording and Reporting Adverse Events ......................................................................................... 46 
10.4.1 
Adverse Event Definitions ........................................................................................................ 47 
10.5 
Procedures in Case of Pregnancy ...................................................................................................... 49 
10.6 
Precautions ........................................................................................................................................ 49 
10.7 
Observation ....................................................................................................................................... 50 
11 
STATISTICS .................................................................................................................................. 51 
11.1 
Sample Size Consideration ................................................................................................................ 51 
11.2 
Analysis Population ........................................................................................................................... 51 
11.3 
Subject Disposition ............................................................................................................................ 51 
11.4 
Demographics and Baseline Characteristics ...................................................................................... 51 
11.5 
Concomitant Medications .................................................................................................................. 51 
11.6 
Pharmacokinetic Analysis ................................................................................................................. 52 
11.6.1 
Calculation of Pharmacokinetic Variables ............................................................................... 52 
11.6.2 
Analysis of Pharmacokinetic Data ........................................................................................... 53 
11.7 
Handling of Missing Values .............................................................................................................. 53 
11.8 
Safety Analysis .................................................................................................................................. 54 
11.9 
Protocol Deviations ........................................................................................................................... 54 
12 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS ........................................................................ 55 
12.1 
Study Monitoring .............................................................................................................................. 55 
12.2 
Audits and Inspections ...................................................................................................................... 55 
13 
QUALITY CONTROL AND QUALITY ASSURANCE ........................................................................... 56 
14 
ETHICS ......................................................................................................................................... 57 
14.1 
Ethics Review .................................................................................................................................... 57 
14.2 
Ethical Conduct of the Study ............................................................................................................. 57 
14.3 
Written Informed Consent ................................................................................................................. 57 
15 
DATA HANDLING AND RECORDKEEPING ..................................................................................... 58 


12-Feb-2017 
BB-PK-103 
Braeburn Pharmaceuticals
Confidential 
Page 11
 
 
15.1 
Source Data Capture .......................................................................................................................... 58 
15.2 
Case Report Forms ............................................................................................................................ 58 
15.3 
Data Recording and Handling ........................................................................................................... 58 
15.4 
Inspection of Records ........................................................................................................................ 58 
15.5 
Retention of Records ......................................................................................................................... 59 
16 
PROTOCOL MODIFICATIONS ....................................................................................................... 60 
17 
REFERENCES ................................................................................................................................ 61 
17.1 
INVESTIGATOR AGREEMENT .................................................................................................... 62 
 
 
 
LIST OF TABLES 
 
 
Table 1:  600 mg and 900 mg Treatment Design ............................................................................ 23 
Table 2:  900 mg Non PK Run-in Treatment Design (Enrollment for this group is complete) ...... 23 
Table 3:  600 mg and 900 mg Schedule of Study Evaluations: Screening through Day 7 ............. 24 
Table 4:  900 mg Non-PK run-in group - Schedule of Study Evaluations: Screening through Day 7 
(Enrollment complete for this group) ..................................................................................... 26 
Table 5:  Post-Implantation Outpatient Treatment Period: Weeks 2-26 (All Subjects) ................. 28 
Table 6:  900 mg PK Subset Subjects Only: Week 26 to Week 27 ................................................ 29 
Table 7:  Post-Implantation Outpatient Treatment Period: Weeks 28-50 (All Subjects) ............... 30 
Table 8:  Safety Laboratory Tests to be monitored during the Study ............................................. 43 
Table 9:  Pharmacokinetic Variables .............................................................................................. 53 
  
 
 
 
 


12-Feb-2017 
BB-PK-103 
Braeburn Pharmaceuticals
Confidential 
Page 12
 
 
 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
Abbreviations and Specialist Terms 
 
Abbreviation or Specialist Term Explanation 
5-HT2 
5-hydroxytryptamine receptor type 2 
AE 
Adverse event 
AIMS 
Abnormal Involuntary Movement Scale 
API 
Active Pharmaceutical Ingredient 
AUC0-24h 
area under the plasma concentration-time curve from time zero to 24 
hours post-dose of the oral tablet (Day -1 dose) 
AUC3-180days 
area under the plasma concentration-time curve from Day 3 to 180 
post-implantation 
AUC3-t 
area under the plasma concentration-time curve from Day 3 to the 
last collected sample (post-implantation) for subjects who do not 
complete the 180 pharmacokinetic sampling period 
BARS 
Barnes Akathisia Rating Scale 
BLQ 
Below the limit of quantification 
BMI 
Body mass index 
Cavg 
average steady-state concentration 
Cmax 
observed maximum concentration 
Css 
plasma concentrations at steady-state 
Ctrough 
trough concentration  
CNS 
Central nervous system 
CRF 
Case report form 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CYP 
cytochrome P-450 system 
CYP3A4 - 2D6 
Cytochrome P450, family 2, subfamily D, polypeptide 6 
D2 
Dopamine receptor type 2 
DSM-V 
Diagnostic and Statistical Manual of Mental Disorders, 5th edition 
ECG 
Electrocardiogram 
eCRFs 
electronic case report forms 
EDC 
electronic data capturing 
EM 
Extensive metabolizers 
EPS 
Extrapyramidal symptoms 
FDA 
Food and Drug Administration 
FSH 
Follicle-Stimulating Hormone 
GCP 
Good Clinical Practice 
anti HCV 
Hepatitis C Antibody 
HIV 
human immunodeficiency virus 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 


12-Feb-2017 
BB-PK-103 
Braeburn Pharmaceuticals
Confidential 
Page 13
 
 
IM 
Intramuscular 
IRB 
Institutional Review Board 
LC-MS/MS 
liquid chromatography-tandem mass spectrophotometry 
LOE 
Lack of efficacy 
MedDRA 
Medical Dictionary for Regulatory Activities 
NDA 
New Drug Application 
NF 
National Formulation 
NMS 
neuromalignant syndrome 
OTC 
Over-the-counter 
PANSS 
Positive and Negative Syndrome Scale 
PK 
Pharmacokinetics 
PM 
Poor metabolizers 
PT 
Preferred term 
SAE 
Serious adverse event 
SAS 
Simpson-Angus Scale 
SC 
Subcutaneous 
SOC 
System organ class 
Tmax 
Time to maximum concentration 
ULN 
Upper limit of normal reference range 
 


12-Feb-2017 
BB-PK-103 
Braeburn Pharmaceuticals
Confidential 
Page 14
 
 
1 
INTRODUCTION 
1.1 
Background 
Schizophrenia is a chronic debilitating mental illness, which is estimated to affect 0.4% to 0.71% 
of the population (Goldner et al., 2002). Men and women are equally affected by the disease 
although men usually present with the illness in their late teens or early 20s; whereas, women 
usually present 10 years later in their late 20s or early 30s (Castle et al, 1991). The course of 
schizophrenia is typically characterized by episodes of psychotic behaviors occurring at varying 
intervals between periods of relative symptomatic stability. The symptoms may involve multiple 
psychological realms, such as perception (hallucinations), ideation, reality testing (delusions), 
thought processes (loose associations), feeling (flatness, inappropriate affect), behavior (catatonia, 
disorganization), attention, concentration, motivation (avolition, impaired intention and planning), 
and judgment. These psychological and behavioral characteristics are associated with a variety of 
impairments in occupational or social functioning. Although there can be marked deterioration 
with impairments in multiple domains of functioning (e.g., learning, self-care, working, 
interpersonal relationships, and living skills), the disorder is noted for great heterogeneity across 
persons and variability within persons over time.  
Patients with schizophrenia usually do not return to baseline functioning, and there is often further 
deterioration after each relapse. Prevention of future exacerbations is a critical goal of therapy, 
and patients who stay on continual treatment are more likely to achieve better outcomes. Patients 
with schizophrenia generally have impaired insight and do not recognize that they have the 
illness. This lack of insight leads to poor or partial compliance with their prescribed medication 
which in turn results in reduced treatment efficacy, earlier relapses, higher psychiatric admissions, 
reduced quality of life, increased suicide rates, and a shortened life expectancy. An estimated 50% 
of patients do not adhere to prescribed medication regimens for a variety of reasons.  The lack of 
compliance leads to increased morbidity, decreased quality of life, and consequently, an 
associated increase in healthcare costs. One of the patient-driven reasons for noncompliance is the 
patient’s inability to adhere to daily dosing on a long-term basis. Current depot formulations of 
antipsychotic only provide medication coverage up to one month.  A formulation such as 
Risperidone Implant, provides therapeutic dose levels of Risperidone over 6 months and should 
further enhance patient compliance and therefore improve patient outcomes   
Risperidone, the active pharmacological ingredient (API) in the Risperidone Implant, was first 
marketed by Janssen Research Foundation under the brand name Risperdal® (NDA 20-272) and 
was approved in the United States in 1993 and in Europe in 2008 to treat schizophrenia (Van Peer 
et al., 1996). The mechanism of action of risperidone is believed to be through blockade of both 
the serotonin 5-hydroxytryptamine receptor type 2 (5-HT2) and dopamine type 2 receptor (D2) 
(Page et al., 2010).  Risperidone is also marketed by the Janssen Research Foundation as a depot 
intramuscular injection under the brand name Risperdal CONSTA® (NDA21-346).  Three dosage 
strengths are marketed (25 mg, 37.5 mg and 50 mg) given every 2 weeks; following this regimen, 
plasma concentrations during the dosing interval are maintained within the range achieved by oral 
therapeutic doses of risperidone. The steady state average exposure of the 25 mg and 50 mg 
intramuscular depot injections (Risperdal CONSTA) and the corresponding daily administration 
of 2 mg and 4 mg oral tablets, respectively, were comparable.  


12-Feb-2017 
BB-PK-103 
Braeburn Pharmaceuticals
Confidential 
Page 15
 
 
Risperidone Implant utilizes a novel drug delivery implant technology (polyurethane polymer 
technology), that had been developed by Endo Pharmaceuticals Solutions Inc. in order to deliver a 
wide range of drugs and small molecules for an extended period of time. The Risperidone Implant 
is a subcutaneous implant composed of 300 mg USP grade risperidone, National Formulation 
(NF) grade croscarmellose sodium, NF grade stearic acid, and biomedical grade polyurethane 
(Tecoflex® EG-80A). Tecoflex EG-80A is an, aliphatic, polyether-based polyurethane membrane 
that controls the rate of risperidone release. The dimensions of the implant are approximately 
50 mm long with an outside diameter of approximately 4 mm. Risperidone is delivered 
systemically via passive diffusion at an anticipated release rate of 1.2 to 1.5 mg/day (based on 6-
month dog data) for a period of up to 6 months (RISI-TR-10-007, Endo Pharmaceuticals,  2010). 
This release rate is expected to result in achieving similar steady-state trough levels from a 4 
mg/day oral dose of risperidone. 
The Risperidone Implant is a reservoir-type drug delivery system in which risperidone pellets are 
enclosed within a sealed, cylindrical polymer membrane, made of Tecoflex EG-80A. The polymer 
membrane controls the rate of diffusion of the drug substance to provide the release appears 
superficially to be a pseudo-zero-order however a more detailed analysis of models development 
is presented in a separate report. The polymer membrane is not intended to exert therapeutic 
effects although it acts to improve product delivery via controlled release of the drug substance. 
The proposed initial indication for the Risperidone Implant is “maintenance treatment of 
schizophrenia in adults”. The Risperidone Implant may offer significant advantages over 
risperidone oral tablets and long-acting depot formulations of antipsychotics (i.e., Risperdal® 
Consta®) including: 1) reduced pain, anxiety, and risk of infection associated with frequent IM 
injections; 2) ability to remove the implant if treatment needs to be discontinued urgently, which 
is not possible with the depot injectable formulation; 3) improved patient compliance, which is 
expected to lead to improved functional outcomes and reduced relapse rates and EPS; 4) 
improved convenience for patients and healthcare providers due to less frequent clinic visits; and 
5) reduced healthcare costs because of improved functional outcomes, reduced relapse rates, 
reduced clinic visits for drug dosing, and reduced hospitalizations. 
For adults with schizophrenia, the effective dose range of oral risperidone tablets is 4 to 
16 mg/day with a target dose of 4 to 6 mg/day.  
Additional information about the Risperidone Implant can be found in the Investigator’s 
Brochure/Prescribing Information. 
1.1.1 Summary of Nonclinical Findings and Safety 
The endocrine, central nervous system (CNS), and cardiovascular effects of risperidone have 
been characterized as part of the original Risperdal® New Drug Application (NDA 20-272) 
(Risperdal NDA 20-272, 1993). The safety and efficacy of risperidone have also been 
demonstrated in acute, sub chronic and chronic toxicity, reproductive and developmental 
toxicity, genotoxicity, and carcinogenicity studies in support of the original Risperdal NDA 20-
272 (Risperdal NDA 20-272, 1993). Findings in these studies were consistent with the 
proposed mechanism of action, i.e., antagonism of 5-HT2 and dopamine receptor type 2 (D2) of 
risperidone. 
Comprehensive biocompatibility testing of Tecoflex EG-80A implant was performed in 


12-Feb-2017 
BB-PK-103 
Braeburn Pharmaceuticals
Confidential 
Page 16
 
 
accordance with ISO 10993 requirements for a permanent, tissue contact implantable 
biomaterial. Testing included acute toxicity, genotoxicity, local tolerance, cytotoxicity, 
implantation, and pyrogenicity. Extracts of blank Tecoflex EG-80A were not systemically toxic, 
mutagenic, cytotoxic, or pyrogenic, and did not elicit a dermal sensitization response. Extracts of 
blank Tecoflex EG-80A were not irritating when injected intradermally in rabbits and 
subcutaneous (SC) implantation of empty Tecoflex EG-80A implants for up to 6 months in dogs, 
4 weeks and 6 months in rats , or 36 weeks in rabbits were very well tolerated systemically, and 
did not elicit an adverse local reaction. 
The safety of risperidone and empty (blank) Tecoflex EG-80A implant was demonstrated in the 
3- and 6-month toxicity studies in Beagle dogs. There was no systemic toxicity observed with 
empty (blank) Tecoflex EG-80A implants in both studies.  In both studies, findings related to the 
perturbations of the pituitary-reproductive axis, consistent with the previously reported effects 
of risperidone, have been observed with Risperidone Implants. In the 3-month dog toxicity 
study, chronic inflammation (mild to severe) was noted microscopically at the implantation site 
in 1 of 8 blank Tecoflex EG-80A animals and two (2) of 8 Risperidone Implant animals. The 
inflammatory changes were consistent with infection, and not indicative of a local reaction to 
Tecoflex. 
In the 6-month dog toxicity study, blank Tecoflex implant-related findings included local dark 
red area noted at primary necropsy in one animal, mild to severe fibrosis, minimal to mild 
chronic-active inflammation, and minimal to moderate hemorrhage at the implant sites. At the 
end of recovery, only mild fibrosis and minimal brown pigment were observed microscopically 
in 1 out of 4 blank implant animals, indicating local implant site recovery. At the primary 
necropsy, dark red and yellow areas at the implant site were observed in 1 male in the 
risperidone group. These observations were considered potentially related to the implant. 
Microscopic findings of mild to severe fibrosis, minimal hemorrhage, minimal to mild chronic-
active inflammation, and minimal to mild brown pigmentation at the implant sites were noted 
in the risperidone group. At the end of recovery, only minimal fibrosis and mild brown pigment 
were observed in 1 out of 4 risperidone group animals, indicating local implant site recovery. 
These findings indicate implant biocompatibility with no toxic leachables and no 
biodegradation of either blank Tecoflex or risperidone-containing Tecoflex implants. No 
particles or foreign body reaction to particulate were identified in any of the implant sites 
indicating that biodegradation, by any mechanism, with loss of integrity of the devices was not 
present. Histological evaluation of the recovery necropsy implantation sites and recovery 
necropsy-incision sites showed no inflammation, granulation tissue, foreign body reaction, or 
fibrous capsule formation. These findings indicate reversibility of the inflammatory and wound 
healing responses following removal of the implant, and no persistence or delayed occurrence 
of test article-related effects. 
The effects of age, moderate and severe renal impairment, and liver disease on the 
pharmacokinetics of risperidone and 9-OH-risperidone have been evaluated (Snoeck et al., 
1995). The elimination rate and clearance of 9-OH-risperidone was reduced in the elderly and 
patients with renal disease because of a diminished creatinine clearance, while the PK of 
risperidone in the elderly and cirrhotic patients were comparable to those in young patients. The 
total clearance of oral risperidone was reduced in patients with renal disease. Based on the 
pharmacokinetics of the active moiety, a dose reduction and a cautious dose titration in the 


12-Feb-2017 
BB-PK-103 
Braeburn Pharmaceuticals
Confidential 
Page 17
 
 
elderly and in patients with renal disease is recommended (Snoeck et al., 1995). In patients with 
cirrhosis of the liver, the single-dose pharmacokinetics were comparable to those in healthy 
young subjects, thus no dose adjustment is required. 
1.1.2 Pharmacokinetics and Drug Metabolism in Humans 
The PK and metabolism of the active ingredient risperidone, has been extensively studied in 
human subjects, patients with schizophrenia, and patients with bipolar disorders. In addition, 
the PK of risperidone has been evaluated in subjects with impaired hepatic and renal function 
(Snoeck et al., 1995).  
Risperidone metabolism in humans, as well as in rats and dogs, results in the formation of an 
active metabolite, 9-OH-risperidone. In humans, this metabolite has a different PK profile 
(longer half-life: 20 hours versus 3 hours compared with risperidone), but has in vitro 
pharmacological and potency profiles comparable to that of risperidone (Mannens et al., 1993). 
For this reason, the sum concentrations of risperidone and 9-OH-risperidone are generally 
considered the “active drug moiety.” 
The hydroxylation of risperidone to the 9-OH metabolite is catalyzed mainly by cytochrome P-
450 system (CYP) 2D6, a polymorphically expressed CYP in humans. The ratios of risperidone 
to 9-OH-risperidone in plasma and urine differ in humans phenotyped as extensive metabolizers 
(EMs) or poor metabolizers (PMs) of debrisoquine or dextromethorphan (Mannens et al., 1993; 
Huang et al., 1993). 
Following an oral dose of 14C-risperidone to healthy subjects, Mannens et al., 1993 found that in 
the urine of EM subjects, only 3.5% of the dose was the parent compound, while 30% of the 
dose was recovered in the urine of PM subjects (Mannens et al., 1993). Although the primary 
elimination pathway of risperidone is through metabolism, the active metabolite 9-OH-
risperidone is primarily eliminated by renal excretion. In urine, 9-OH-risperidone represented 
32% of the dose in the EM, but only 8% in the PM. Other metabolites, of far less importance, 
were detected in urine. Only 3% to 5% of the dose could be identified as glucuronide conjugates 
in urine, indicating that glucuronidation is a minor metabolic pathway (Mannens et al., 1993).  
After intravenous dosing, risperidone plasma concentrations fell in a biphasic manner with a 
distribution half-life of 6 minutes followed by a terminal half-life of 3 hours in EM and 17 to 
22 hours in PM. The apparent volume of distribution of risperidone (1.1 L/kg) was independent 
of the metabolic phenotype. Renal clearance of risperidone represented 3% of the total 
clearance in the EMs (394 mL/min), and about 20% of the total clearance in the PMs (54 
mL/min) (Huang et al., 1993). Although the clearance of risperidone differed by 7-fold 
between EMs and PMs, the plasma AUC and also the clearance of the active moiety differed 
only by 20% between PMs and EMs because the EMs extensively form the active metabolite 
(Van Peer et al., 1996). The terminal half-life of the active moiety averaged 20 hours (Huang 
et al., 1993). 
The effects of age, moderate and severe renal impairment, and liver disease on the 
pharmacokinetics of risperidone and 9-OH-risperidone have been evaluated (Snoeck et al., 
1995). The elimination rate and clearance of 9-OH-risperidone was reduced in the elderly and 
patients with renal disease because of a diminished creatinine clearance, while the PK of 
risperidone in the elderly and cirrhotic patients were comparable to those in young patients. The 


12-Feb-2017 
BB-PK-103 
Braeburn Pharmaceuticals
Confidential 
Page 18
 
 
total oral clearance of risperidone was reduced in patients with renal disease. Based on the 
pharmacokinetics of the active moiety, a dose reduction and a cautious dose titration in the 
elderly and in patients with renal disease is recommended (Snoeck et al., 1995). In cirrhotic 
patients, the single-dose pharmacokinetics was comparable to those in healthy young subjects, 
thus not requiring dose adjustment. 
1.2 Previous Human Experience 
Endo has completed two clinical studies, first a 3-month first in human Phase 1 study (EN3342-
101) in 6 subjects diagnosed with schizophrenia whose disease was maintained with a daily 4 mg 
oral dose of risperidone.  In this study there were no serious adverse events (SAEs), or 
discontinuations due to an AE occurred. Adverse events were reported in five (5) of the 6 enrolled 
subjects. There was 1 treatment-emergent adverse event (TEAE) of erectile dysfunction. The AE 
reported included incisional site pain, paresthesia, and hypoesthesia in the arm of the 
implantation, constipation, arthralgia, join swelling, worsening of extrapyramidal disorder, 
worsening of schizophrenia, and suicidal ideation.  The PK data indicated that the active moiety 
Cave from the risperidone Implant over a 3-month period averaged approximately 77% of the 
subjects’ oral risperidone Ctrough level.  The implants used in Risperidone Implant-101 contained 
375 mg risperidone. 
The second study was another Phase 1 study with a 6-month in duration in 35 subjects (EN3342-
102) study, including 5 subjects who only received oral risperidone and discontinued prior to 
receiving EN3342 implants, and there were 10 subjects each in the 480 mg, 720 mg, and 960 mg 
Risperidone Implant doses/treatment groups. The most common TEAE overall was injection site 
pain (40.0%), which occurred in 1 subject (10.0%) in the EN3342 480 mg group, 7 subjects 
(70.0%) in the 720 mg group and 4 subjects (40.0%) in the 960 mg group. Injection site 
hemorrhage, incision site edema, anxiety and psychotic disorder were also relatively common 
(occurring in 13.3%) of subjects overall. Implant site pain, difficult device use and weight 
increased were reported in 10.0% of subjects overall, while other TEAEs were each reported in 
only 1 or 2 subjects, overall. There was no discernible difference in patterns of TEAEs between 
the 3 treatment groups, other than possibly a higher incidence of implantation-type events in the 
720 mg group, and a higher incidence of psychotic disorder in the 960 mg group (30.0% of 
subjects vs. 10% in the 720 mg group and 0% in the 480 mg group). Comparison of oral 
risperidone and the Risperidone Implants demonstrate that while Cmax and Cavg were higher in oral 
risperidone, Ctrough for oral risperidone was more comparable to Css for EN3342 implants at 
respective dose levels. 
Summary of Selected Pharmacokinetic Parameters of the Active Moiety (risperidone + 9-
OH-risperidone) (Pharmacokinetic Population) 
Treatment Group 
Oral risperidone 
 
EN3342 
Cmax 
(ng/mL) 
AUC0-24h 
hr*(ng/mL) 
Cavg 
(ng/mL) 
Ctrough 
(ng/mL) 
 
Css 
(ng/ml) 
480 mg EN3342 (4 mg oral) 
53.3 
724.6 
34.4 
19.6 
 
19.1 
720 mg EN3342 (6 mg oral) 
82.8 
1203 
56.2 
29.7 
 
31.0 
960 mg EN3342 (8 mg oral) 
80.6 
1177 
54.9 
32.8 
 
32.7 


12-Feb-2017 
BB-PK-103 
Braeburn Pharmaceuticals
Confidential 
Page 19
 
 
AUC0-24h=area under the concentration versus time curve from time 0 to 24 hours after oral dose; Cavg=average 
steady-state concentration; Cmax=observed maximum plasma concentration; Css=plasma concentration at steady-state; 
Ctrough=plasma concentration at 24 hours following an oral dose risperidone. 
 
1.3 PK Model Summary  
 
All PK data (risperidone, 9-OH-risperidone, and total active drug) from study EN3342-102 could 
be modeled.  Total active drug concentration (risperidone + 9OH-risperidone) is the best 
representation of compound activity. EN3342 PK data show an immediate release of risperidone 
once implanted consistent with a single day’s dose, then constant (the release appears superficially 
to be a pseudo-zero-order however a more detailed analysis of models development is presented in a 
separate report) delivery of risperidone over a 180-day period. PK modeling comparisons of 
EN3342 three 300 mg Risperidone Implants  (900 mg risperidone)  to daily oral risperidone 4 mg 
dosing suggests EN3342 maintains concentrations above Ctrough and below Cmax, and comparable 
to Cavg over 180 days and which is being tested in this clinical study. 


12-Feb-2017 
BB-PK-103 
Braeburn Pharmaceuticals
Confidential 
Page 20
 
 
2 
STUDY OBJECTIVES AND PURPOSE 
2.1 
Primary Objective 
 
The primary objective of this study is to characterize the pharmacokinetics of 6-month Risperidone 
Implants containing 300 mg risperidone each compared to an oral 4-mg risperidone tablet 
2.2 
Secondary Objectives 
 
The secondary objectives are: 
• To explore the efficacy of a Risperidone Implant as assessed by the Positive and 
Negative Syndrome Scale (PANSS) 
• To explore the safety of Risperidone implant as assessed by vital signs, clinical 
laboratory evaluations, electrocardiograms (ECGs), physical examinations, implant site 
assessments, extrapyramidal symptom (EPS) assessments, Columbia Suicide Severity 
Scale (C-SSRS) assessments, Abnormal Involuntary Movement Scale (AIMS), 
Simpson Rating Scale (SAS), Barnes Akathisia Scale (BARS), and adverse event 
(AE) monitoring. 


12-Feb-2017 
BB-PK-103 
Braeburn Pharmaceuticals
Confidential 
Page 21
 
 
3 
INVESTIGATIONAL PLAN 
3.1 
Overall Study Design and Plan: Description 
The study will be a 26 week, open-label, multiple sites, Phase 2 study in stabilized subjects with 
schizophrenia or schizoaffective disorder to evaluate the PK of risperidone its active metabolite, 
9-OH-risperidone and the active moiety (risperidone plus 9-OH risperidone) following 
implantation of the Risperidone Implants. A 24 week safety extension will follow.  Subjects 
diagnosed with schizophrenia or schizoaffective disorder who are stable on a daily dose of 4 mg 
oral risperidone will be recruited into the study.  
Subjects will be implanted with two or three 300 mg Risperidone Implants.  All implants will be 
placed in the inner aspect of the upper arm.  Plasma concentrations of risperidone and the active 
moiety will be measured prior to placement of the Risperidone Implants, throughout the first 6-
month implantation period 
The subjects will check into the clinic 16 to 7 days prior to implantation for the two or three 300 
mg Risperidone Implants and check-out 7 days’ post implantation of the Risperidone Implants. 
Safety monitoring and PK sampling will be conducted during the in-house period of the study.  
Scheduled outpatient visits, that will include safety monitoring and PK sampling, will be 
conducted for the remainder of the implantation period. After 6 months, the first implants will be 
explanted and subjects may be implanted (at their same dose level) in the same location in the 
arm with two or three 300 mg Risperidone Implants for an additional 6 months in the safety 
extension.  Again, scheduled outpatient visits that will include safety monitoring, will be 
conducted for the remainder of the implant period. A subset of subjects in the PK group 
(approximately 15 subjects) will have pharmacokinetic sampling during the 7 days following 
reimplantation, as well as throughout the remainder of the study in the extension.  Following 
explantation of the second Risperidone Implants each subject will be converted back to his/her 
pre-implant oral risperidone dosing regimen. The four non-PK run in subjects who received the 
three 300 mg implant checked in up to 4 days and a minimum of two days prior to implantation.  
The treatment design for those subjects receiving 600 mg or 900 mg is illustrated in Table 1 and 
the schedule of study evaluations is provided in Table 3. The treatment design for the non-PK run 
in subjects who received 900 mg is illustrated in Table 2 and the schedule of study evaluations is 
provided in Table 3. 
 
 


12-Feb-2017 
BB-PK-103 
Braeburn Pharmaceuticals
Confidential 
Page 22
 
 
 
3.1.1 
Overview of Treatment 
Informed consent must be obtained prior to the initiation of all screening and study specific 
procedures. During screening and prior to admission to the research center, subjects will be 
evaluated against the inclusion and exclusion criteria to determine eligibility. Subjects stable on 
4 mg oral risperidone will be admitted to the research center at any time from Day -16 to  
Day -7 (for the two 300 mg and the three 300 mg implants).  Subjects receiving the three 300 
mg implants will be admitted to the research center at any time from Day -4 to Day -2 
(enrollment is complete for this non-PK run in group). 
• 
Day – 16 to Day -7 (or Day -4 to Day – 2): subjects admitted to the research center for in-
house confinement period, eligibility confirmed, and admission procedures conducted 
• 
Day – 16 to Day -7 to -1 (or Day -4 to Day -2): subjects will receive their once daily oral 
dose of risperidone in the AM 
• 
Day -7 to -2: daily PK sampling, before daily 4 mg oral risperidone dose for all of the PK 
run in dose groups.   
• 
Day -1: serial PK sampling begins prior to oral risperidone administration for all of the PK 
run in dose groups.   
 
• 
Days 1 to 7: Daily PK sampling will continue 2 hours post implantation 
• 
Day 7: subjects released from research center following completion of all Day 7 study 
evaluations  
• 
Outpatient visits: Weeks 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24  
• 
Weekly phone calls from sites to patients on non-inpatient visit weeks 
• 
Week 26: Risperidone Implant explantation and implantation of the second 6-month 
Risperidone Implant in the same location for the safety extension 
• 
Week 26 Days 1 (PK subset of subjects only): PK sampling 2 and 6 hours post 
implantation 
• 
Week 26 Days 2 to 7 (PK subset of subjects only): Daily PK sampling 
• 
Week 26 Day 7 (PK subset of subjects only): subjects released from research center 
following completion of all Day 7 study evaluations  
• 
Outpatient visits:  Weeks 28, 32, 36, 40, 44, and 48 
• 
Week 48:  Risperidone Implant explantation 
• 
Follow-up visit/EOS: week 50 
 
 


BB-PK-103 
 
 
 
Table 1:  600 mg and 900 mg Treatment Design 
Days 
-7 to – 1 
Day  
-1 
Day 
1
Days 
1-7
Weeks 
2 – 26
Week  
26 
Week 26 
Days 1-7
Weeks 
28 – 48
Week 
48
Week 50
Check-in to 
CPU/Oral 
Dosing 
(Variable 
Check-in: 
Day -16 to Day 
-7, to permit 
flexibility in 
subject check-in 
schedule). 
Oral PK 
Profile/ 
Safety 
Assessments 
Risperidone 
Implant  
Administered 
 
 
PK/Safety 
/Efficacy 
Assessments 
 
Check-Out 
of CPU 
(Day 7 only) 
PK/Safety/ 
Efficacy/ 
Assessments 
(Weekly, Bi-
Weekly with 
weekly phone 
calls on non-on 
site visit weeks) 
Initial 
Risperidone 
Implant 
Removed and 
Second 
Risperidone 
Implant  
Administered 
in the same 
implant site  
PK subset 
subjects only:  
PK/Safety 
Assessments 
 
Check-Out of 
CPU (Day 7 
only) 
PK/Safety / 
Efficacy/ 
Assessments 
 
Second 
Risperidone 
Implant 
Removed 
Follow-Up 
Visit 
Subject Confined 
Total 14 days (With variable check-in up to 23 days)
Outpatient
Outpatient 
Inpatient
Outpatient
Outpatient
Outpatient 
 
Table 2:  900 mg Non PK Run-in Treatment Design (Enrollment for this group is complete) 
Days 
-2 to – 1 
Day 
1 
Days
1-7
Weeks 
2 – 26
Week 
26
Weeks  
28 – 48 
Week 
48
Week 50 
Check-in to 
CPU/Oral Dosing 
(Variable Check-
in: Day -4 to Day 
-2, to permit 
flexibility in 
subject check-in 
schedule). 
Risperidone 
Implant  
Administered 
PK/Safety/
Efficacy 
Assessments 
Check-Out of 
CPU 
PK/Safety 
/Efficacy/ 
Assessments 
(Weekly, Bi-
Weekly with 
weekly phone 
calls on non-on 
site visit weeks) 
Initial
Risperidone 
Implant 
Removed and 
Second 
Risperidone 
Implant  
Administered 
in the same 
implant site 
PK/Safety / 
Efficacy/ 
Assessments 
 
Second
Risperidone 
Implant 
Removed 
Follow-Up 
Visit 
Subject Confined 
Total 9 days (With variable check-in up to 11 days)
Outpatient
Outpatient
Outpatient 
Outpatient
Outpatient
 
 


12-Feb-2017 
BB-PK-103 
Braeburn Pharmaceuticals
Confidential 
Page 24
 
 
Table 3:  600 mg and 900 mg Schedule of Study Evaluations: Screening through Day 7 
Phase 
Screening 
Risperidone Oral 
Dosing 
Risperidone Implant TREATMENT 
DAY 
-28 to -8 
-16 
to -7
From 
day 
after 
Check-
in to -2
-1 
1 
2 
3 
4 
5 
6 
7 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
Psychiatric/Medical 
History 
X 
X 
 
 
 
 
 
 
 
 
 
Prior/Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Complete Physical 
Examination 
Xa 
 
 
 
 
 
 
 
 
 
 
HIV/Hepatitis Screenb 
X 
 
 
 
 
 
 
 
 
 
 
Substances of Abuse 
Urine Screenc 
X 
X 
 
 
 
 
 
 
 
 
 
Clinical Laboratory Testsd 
X 
 
 
 
 
 
 
 
 
 
X 
Serum Pregnancy 
Test/FSH 
X 
X 
 
 
 
 
 
 
 
 
 
12-lead 
Electrocardiogram 
X 
X 
 
 
 
 
 
 
 
 
X 
Vital Sign Measurementse 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PANSS 
X 
Xf 
 
 
X 
 
 
 
 
 
X 
AIMS 
 
X 
 
 
 
 
 
 
 
 
X 
SAS 
 
X 
 
 
 
 
 
 
 
 
X 
BARS 
 
X 
 
 
 
 
 
 
 
 
X 
C-SSRS (Baseline) 
X 
 
 
 
 
 
 
 
 
 
 
C-SSRS (Since Last 
Visit) 
 
 
 
 
 
 
 
 
 
 
X 
4 mg Oral risperidone 
Administration 
 
X 
X 
X 
X 
 
 
 
 
 
 
                                                 
a PE exam to include, general appearance, skin, head and neck (including eyes, ears, nose, and throat), lymph nodes, 
thyroid, musculoskeletal/extremities (including spine), cardiovascular, lungs, abdomen and neurological systems, 
height, weight 
b It is the Investigator’s responsibility to understand and comply with all laws and regulations that apply to HIV, 
Hepatitis B, and Hepatitis C and testing of blood.  Hepatitis B/C and HIV testing is required unless a site’s IRB 
prohibits such testing. 
c Urine dipstick test only 
d Subjects should be fasting for at least 8 hours prior to all laboratory evaluations. 
e Consists of blood pressure, heart rate after 5 minutes of rest in the supine position, temperature and respiration rate 
at Screening; blood pressure, heart rate at all other time points. 
f If PANSS score at baseline is ≥ 20% change from screening, the patients cannot participate in the study. 
 


12-Feb-2017 
BB-PK-103 
Braeburn Pharmaceuticals
Confidential 
Page 25
 
 
Phase 
Screening 
Risperidone Oral 
Dosing 
Risperidone Implant TREATMENT 
DAY 
-28 to -8 
-16 
to -7
From 
day 
after 
Check-
in to -2
-1 
1 
2 
3 
4 
5 
6 
7 
PK Sample Collectiong, h 
 
Xh 
Xh 
Xh 
X 
X 
X 
X 
X 
X 
X 
Risperidone Implant 
Insertion 
 
 
 
 
X 
 
 
 
 
 
 
Implant user survey 
 
 
 
 
X 
 
 
 
 
 
 
Assessment of Implant 
Sitei 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Confinement to Research 
Center 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Discharge from Research 
Center 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
                                                 
g PK samples will be drawn at pre-dose during days -7 to -1 then at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 18, 24 after dosing on 
Day -1 
h On implant day, PK samples will be drawn pre-implantation, 2 and 6 hours post implant, then daily from day 2 to 
day 7 at approximately the same time each day. 
i Implant site assessments will include monitoring for signs and symptoms of infection, (e.g., pain, tenderness, 
swelling, erythema, exudate), expulsion, and tolerability. The presence of the implants will be assessed by palpation 
in addition to the visual examination at the times. 
   
 


12-Feb-2017 
BB-PK-103 
Braeburn Pharmaceuticals
Confidential 
Page 26
 
 
Table 4:  900 mg Non-PK run-in group - Schedule of Study Evaluations: Screening through 
Day 7 (Enrollment complete for this group) 
Phase 
Screening Risperidone 
Oral 
Dosing 
Risperidone Implant TREATMENT 
DAY 
-28 to -3 
-4 to -1 
1 
2 
3 
4 
5 
6 
7 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
X 
 
 
 
 
 
 
 
Psychiatric/Medical 
History 
X 
X 
 
 
 
 
 
 
 
Prior/Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Complete Physical 
Examination 
Xj 
 
 
 
 
 
 
 
 
HIV/Hepatitis Screenk 
X 
 
 
 
 
 
 
 
 
Substances of Abuse 
Urine Screenl 
X 
X 
 
 
 
 
 
 
 
Clinical Laboratory 
Testsm 
X 
 
 
 
 
 
 
 
X 
Serum Pregnancy 
Test/FSH 
X 
X 
 
 
 
 
 
 
 
12-lead 
Electrocardiogram 
X 
X 
 
 
 
 
 
 
X 
Vital Sign 
Measurementsn 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PANSS 
X 
Xo 
X 
 
 
 
 
 
X 
AIMS 
 
X 
 
 
 
 
 
 
X 
SAS 
 
X 
 
 
 
 
 
 
X 
BARS 
 
X 
 
 
 
 
 
 
X 
C-SSRS (Baseline) 
X 
 
 
 
 
 
 
 
 
C-SSRS (Since Last 
Visit) 
 
 
 
 
 
 
 
 
X 
4 mg Oral risperidone 
Administration 
 
X 
X 
 
 
 
 
 
 
PK Sample Collectionp 
 
X 
Xp 
X 
X 
X 
X 
X 
X 
Risperidone Implant 
 
 
X 
 
 
 
 
 
 
                                                 
j PE exam to include, general appearance, skin, head and neck (including eyes, ears, nose, and throat), lymph nodes, 
thyroid, musculoskeletal/extremities (including spine), cardiovascular, lungs, abdomen and neurological systems, 
height, weight 
k It is the Investigator’s responsibility to understand and comply with all laws and regulations that apply to HIV, 
Hepatitis B, and Hepatitis C and testing of blood.  Hepatitis B/C and HIV testing is required unless a site’s IRB 
prohibits such testing. 
l Urine dipstick test only 
m Subjects should be fasting for at least 8 hours prior to all laboratory evaluations. 
n Consists of blood pressure, heart rate after 5 minutes of rest in the supine position, temperature and respiration rate 
at Screening; blood pressure, heart rate at all other time points. 
o If PANSS score at baseline is ≥ 20% change from screening, the patients cannot participate in the study. 
p On implant day, PK samples will be drawn pre-implantation, 2 and 6 hours post implant, then daily from day 2 to 
day 7 at approximately the same time each day. 
 


12-Feb-2017 
BB-PK-103 
Braeburn Pharmaceuticals
Confidential 
Page 27
 
 
Phase 
Screening Risperidone 
Oral 
Dosing 
Risperidone Implant TREATMENT 
DAY 
-28 to -3 
-4 to -1 
1 
2 
3 
4 
5 
6 
7 
Insertion 
Implant user survey 
 
 
X 
 
 
 
 
 
 
Assessment of Implant 
Siteq 
 
 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Confinement to Research 
Center 
 
X 
X 
X 
X 
X 
X 
X 
X 
Discharge from Research 
Center 
 
 
 
 
 
 
 
 
X 
 
 
                                                 
q Implant site assessments will include monitoring for signs and symptoms of infection, (e.g., pain, tenderness, 
swelling, erythema, exudate), expulsion, and tolerability. The presence of the implants will be assessed by palpation 
in addition to the visual examination at the times 
   
 


12-Feb-2017 
BB-PK-103 
Braeburn Pharmaceuticals
Confidential 
Page 28
 
 
Table 5:  Post-Implantation Outpatient Treatment Period: Weeks 2-26 (All Subjects) 
Phase 
Risperidone Implant Treatment 
Week 
2 
3 
4 
6 
8
10
12
14
16
18
20 
22 
24 
26
Brief PE 
(including 
weight) 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
Clinical 
Laboratory Testsr 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
Urine Pregnancy 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
 
 
Serum Pregnancy 
Test  
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
12-lead 
Electrocardiogram 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Vital Sign 
Measurements 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
PANSS 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
AIMS 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
SAS 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
BARS 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
C-SSRS (Since 
Last Visit) 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
Risperidone 
Implant removal 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Risperidone 
Implant Insertion 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
PK Sample 
Collection 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xs 
Assessment of 
Implant Site 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Phone call to 
patients 
Phone calls to patients will occur on weeks that patients are not attending the site 
 
Outpatient Visitt 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
                                                 
r Subjects should be fasting for at least 8 hours prior to all laboratory evaluations.  Lipid profile will be measured in 
addition to all other clinical laboratory tests. 
s PK sample should be collected approximately 60 minutes prior to explant. 
t Outpatient visit windows are +/- 2 days.   
 


12-Feb-2017 
BB-PK-103 
Braeburn Pharmaceuticals
Confidential 
Page 29
 
 
Table 6:  900 mg PK Subset Subjects Only: Week 26 to Week 27 
Phase 
PK Sampling Period 
Week 26, DAY 
1 
2 
3 
4 
5 
6 
7 
Prior/Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
Vital Sign Measurementsu 
X 
X 
X 
X 
X 
X 
X 
PK Sample Collectionv 
X 
X 
X 
X 
X 
X 
X 
Risperidone Implant Insertion 
X 
 
 
 
 
 
 
Implant user survey 
X 
 
 
 
 
 
 
Assessment of Implant Sitew 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
Confinement to Research Center 
X 
X 
X 
X 
X 
X 
X 
Discharge from Research Center 
 
 
 
 
 
 
X 
 
                                                 
u Blood pressure and heart rate only 
v On implant day, PK samples will be drawn 2 and 6 hours post implant, then daily from day 2 to day 7 at 
approximately the same time each day. 
w Implant site assessments will include monitoring for signs and symptoms of infection, (e.g., pain, tenderness, 
swelling, erythema, exudate), expulsion, and tolerability. The presence of the implant will be assessed by palpation 
in addition to the visual examination at the times 
   
 
 


12-Feb-2017 
BB-PK-103 
Braeburn Pharmaceuticals
Confidential 
Page 30
 
 
Table 7:  Post-Implantation Outpatient Safety Extension Treatment Period: Weeks 28-50 
(All Subjects) 
Phase 
Risperidone Implant Treatment 
Week 
28 
32
36
40
44
48
50 - FU 
Brief PE (including weight) 
 
 
 
X 
 
X 
 
Clinical Laboratory Testsx 
 
 
 
X 
 
X 
 
Urine Pregnancy 
X 
X 
X 
X 
X 
X 
 
12-lead Electrocardiogram 
 
 
 
 
 
X 
 
Vital Sign Measurements 
X 
X 
X 
X 
X 
Xy 
X 
PANSS 
 
 
 
X 
 
X 
 
AIMS 
 
 
X 
 
 
X 
 
SAS 
 
 
X 
 
 
X 
 
BARS 
 
 
X 
 
 
X 
 
C-SSRS (Since Last Visit) 
X 
X 
X 
X 
X 
X 
 
Risperidone Implant removal 
 
 
 
 
 
X 
 
Transfer to 4 mg oral risperidone 
 
 
 
 
 
X 
 
PK Sample Collectionz 
X 
X 
X 
X 
X 
X 
 
Ultrasoundaa 
 
X 
X 
X 
X 
X 
 
Assessment of Implant Site 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
Phone call to patients 
Phone calls to patients will occur approximately 2 weeks 
following each visit
 
Outpatient Visitbb 
X 
X 
X 
X 
X 
X 
X 
 
                                                 
x Subjects should be fasting for at least 8 hours prior to all laboratory evaluations. 
y Consists of blood pressure, heart rate after 5 minutes of rest in the supine position, temperature and respiration rate. 
z Subjects in the second implant PK subset only. 
aa Subjects in the second implant ultrasound subset only. 
bb Outpatient visit windows are +/- 2 days. 
 


12-Feb-2017 
BB-PK-103 
Braeburn Pharmaceuticals
Confidential 
Page 31
 
 
4 
SELECTION AND WITHDRAWAL OF SUBJECTS 
4.1 
Subject Inclusion Criteria 
Inclusion Criteria: 
1. Subject (and/or a subject’s authorized legal representative) has provided written informed 
consent 
2. Subject has been on a stable dose of 4 mg of oral risperidone for at least 8 weeks  
3. Meets the following criteria that is related to subject’s stability on current 4 mg risperidone: 
a. Outpatient status 
b. PANSS Total Score ≤ 80 at screening and if PANSS score at baseline is ≥ 20% change 
from screening, the patients cannot participate in the study.  
c. A score of ≤ 3 on the following PANSS items: 
• Conceptual disorganization 
• Suspiciousness 
• Hallucinatory behavior 
• Unusual thought content 
4. Subject has identified a caregiver or personal contact with whom the subject has significant 
contact with at least once per week 
5. Subject is male or female between 18 to 60 years of age. 
6.  Female participants (if of childbearing potential and sexually active) and male participants (if 
sexually active with a partner of childbearing potential) who agree to use a medically 
acceptable and effective birth control method throughout the study. Medically acceptable 
methods of contraception that may be used by the participant and/or his/her partner include 
abstinence, birth control pills or patches, diaphragm with spermicide, intrauterine device 
(IUD), surgical sterilization, condoms with spermicide, or progestin injection. All females of 
childbearing potential must have a negative serum pregnancy test at the Screening visit.  All 
females of non-childbearing potential must have the following documentation: 
a. Medical documentation of surgical sterility OR 
b. Are post-menopausal as defined as 12 consecutive months of amenorrhea and confirmed 
by a Follicle Stimulating Hormone (FSH) test 
7. Subject has a diagnosis of schizophrenia or schizoaffective disorder according to Diagnostic 
and Statistical Manual of Mental Disorders, 5th edition (DSM-V) criteria 
8. Subject has a body mass index (BMI) ≥18.5 and ≤35.0 kg/m2 
9. Subject is assessed by the Investigator to be symptomatically stable with regard to his or her 
psychiatric condition at screening and baseline 
10. Subject is assessed by the Investigator to be symptomatically stable with regard to pre-existing 
medical conditions as evidenced by medical history, clinically significant findings on physical 
examination, vital signs, clinical laboratory evaluations (hematology, serum chemistries, and 


12-Feb-2017 
BB-PK-103 
Braeburn Pharmaceuticals
Confidential 
Page 32
 
 
urinalysis) or 12-lead electrocardiogram (ECG). Subjects may continue on their current 
prescribed medication regimens to control pre-existing medical and psychiatric conditions 
(other than schizophrenia) including the use of prescribed PRN medications. 
 
4.2 
Subject Exclusion Criteria 
1. Known hypersensitivity or allergy to lidocaine or any local anesthetic agent of the amide 
type (local anesthetic used during implant and explant procedures) 
2. Known sensitivity to polyurethane 
3. Hospitalized or required acute crisis intervention for  exacerbation of symptoms of 
Schizophrenia or Schizoid Disorder in the 60 days prior to admission as determined by the 
Investigator 
4. Subject has a history of suicide attempt in the last year, or in the opinion of the 
investigator is currently at imminent risk of suicide 
5. Reports or reveals a presence of clinically significant skin disorders (such as, but not limited 
to, skin cancer, psoriasis, eczema, or atopic dermatitis), evidence of recent sunburn, scar 
tissue, tattoo, open sore, body piercing or branding at the intended implantation site that 
would interfere with the implantation procedure or interfere with implant site assessments as 
determined by the Investigator 
6. History of abnormal scar formation at insertion site or elsewhere on body or family history of 
keloid formation 
7. Has a current or recent (within 12 months) DSM-V diagnosis of moderate or severe 
substance use disorder (except for tobacco use disorder) or has a positive urine drug 
screen for prohibited substances at screening.    
8. Have impaired hepatic (ALT/AST >1.5 times higher than the upper limit of normal) or 
renal function (eGFR<50 mL/min) 
9. Previously defined hypersensitivity to risperidone 
10. History of neuromalignant syndrome (NMS) 
11. Electroconvulsive therapy within 6 months of admission 
12. Requires current use of agents that are strong inhibitors and inducers of cytochrome P450 
2D6  
13. Current diagnosis of Acquired Immune Deficiency Syndrome (AIDS) and active hepatitis.  
Subjects with no detectable viral load, no detectable acute inflammation and no clinical 
necessity for therapy will be allowed, at the discretion of the Investigator.   
14. Participation in the treatment phase of a clinical study or receipt of an investigational drug 
within 30 days prior to study drug administration on Day 1; for investigational drugs with an 


12-Feb-2017 
BB-PK-103 
Braeburn Pharmaceuticals
Confidential 
Page 33
 
 
elimination half-life greater than 15 days, this time period will be extended to 60 days 
15. Prior participation in a risperidone study within the last 6 months 
16. Involvement in the planning and/or conduct of the study (applies to both Braeburn staff or 
staff at the investigational site) 
17. History of difficulty with phlebotomy procedures 
4.3 
PK Subset Inclusion 
Approximately 15 subjects who complete through Week 26 will be included in the PK subset of 
subjects in the safety extension.  These PK subset subjects will remain in the clinic for 7 days 
after the explants and implant procedure on Week 26.  After Week 27, the PK subset subjects 
will have the same procedures performed as the remaining subjects from Weeks 27 through 48.  
These subjects will be selected based on order of completion of the Week 26 visit, Investigator 
judgment, and subject informed consent. 
4.4 
Subject Withdrawal Criteria 
4.4.1 
Criteria and Procedures for Discontinuation 
Subjects may be discontinued from the study for the following reasons, if deemed appropriate by 
the Sponsor or Investigator: 
• 
Entered the study in violation of this protocol 
• 
Safety and/or Efficacy reasons as judged by the Investigator and/or Sponsor (see 
section 10.3 and/or section 9) 
• 
Non-compliance to the protocol as judged by the Investigator and/or Sponsor 
• 
Required the use of a prohibited concomitant medication (see section 5.2) 
• 
Withdrawal of informed consent; any subject who withdraws consent as a result of an 
AE, regardless of severity or Investigator’s opinion, must be reported as a discontinuation 
due to an AE 
• 
In the Investigator’s opinion, it is not in the subject’s best interest to continue 
• 
Sponsor decision 
The date a subject discontinues, the treatment, and the reason for discontinuation will be 
recorded in the case report form (CRF). If a subject discontinues from the study, all end-of-study 
procedures should be conducted. If, however, a subject withdraws consent, no end-of-study 
procedures are required except the collection of AE information and removal of the implant. This 
information should be recorded in the CRF. The decision whether to enroll replacement subjects 
will be made by joint agreement of the Investigator and Sponsor. 
When a subject is “lost to follow-up” (i.e., fails to return for study visits), a reasonable effort will 
be made to contact him/her to determine a reason for the failure to return and encourage the 
subject to return for removal of the implant. The detailed plan that the research center will follow 
in attempts to contact a subject that fails to return for a visit is listed below. 


12-Feb-2017 
BB-PK-103 
Braeburn Pharmaceuticals
Confidential 
Page 34
 
 
In the event a subject misses a scheduled outpatient visit during the study, the following 
procedures will be conducted to locate the patient:   
• 
The study coordinator will attempt to contact the subject (e.g., phone, email, or text) 4 
consecutive weeks in an effort to locate the subject and coordinate his/her return to the 
research site. 
• 
If unsuccessful in contacting the subject the coordinator will contact the subject’s 
caregiver/emergency contact. 
• 
The study coordinator will contact the treating psychiatrist, therapist, case manager, and all 
other listed contacts and alert them of the urgency to call the research site 24/7 if they have 
contact with the subject or can provide a location where the subject can be found. 
• 
Once contact is established, the Investigator will assess the subject’s ability to continue in 
the study. 
• 
If the patient does not contact his/her caregiver, treating psychiatrist, therapist, case 
manager, or site, the Sponsor will request for a third party to locate the patient to have the 
implant removed. 
All attempts to contact the subject must be documented in the source data. 
The subject will be considered lost to follow up if the subject is not successfully located using 
the plan outlined above and should be identified as “lost to follow-up” in the CRF. However, the 
research site will request that all listed contacts continue to monitor for the subject and request 
that they call the emergency numbers if contact is made with the subject. The research site will 
also continue to monitor their psychiatric network in efforts to locate the subject. 
 


12-Feb-2017 
BB-PK-103 
Braeburn Pharmaceuticals
Confidential 
Page 35
 
 
5 
TREATMENT OF SUBJECTS 
5.1 
Identity of Study Drug and Duration of Treatment 
5.1.1 
Investigational Product, Dosage, and Mode of Administration 
Two 300 or three 300 mg Risperidone Implants. 
Risperidone, 4 mg, oral tablet 
5.1.2 
Duration of Treatment 
Two or three 300 mg Risperidone Implants will be inserted for a period of up to 26 weeks.  An 
additional set of Risperidone Implants will be inserted for a period of up to 24 weeks as part of 
the safety extension.   
 
5.2 
Concomitant Medications 
Subjects will be permitted to continue on their current prescribed medication regimens, including 
prescribed PRN medications, to treat stable coexisting medical and psychiatric conditions that are 
not associated with schizophrenia or schizoaffective disorder while enrolled in the study. At 
entry to the study, if a subject’s current medication regimen includes the use of a CYP450 2D6 
inducer or inhibitor the Investigator will inform the Sponsor. The Investigator must use caution 
when prescribing new medications to ensure that they are not inducers or inhibitors of CYP2D6. 
The following medications, defined as strong CYP inducers, are excluded from Screening 
through week 50:  carbamazepine, phenytoin, rifampin, and St. John’s wort. 
Any medication taken by a subject during the course of the study (from Day -7 through week 
50) and the reason for use of the medication will be recorded onto the appropriate CRF page. 
Upon entering the study, each subject will be instructed to report the use of all and any new 
medication to the Investigator. Subjects will also be instructed about the importance of not 
taking any new medication (including OTC [over-the-counter] medication) without 
consulting the Investigator. 
5.3 
Treatment Compliance 
All oral Risperidone will be dispensed by the Investigator or designee and will be administered 
under supervision. All doses will be recorded in the subject’s CRF (dose, route of administration, 
frequency, date and time of each administration). During the patients in the clinical research 
facility stay, all efforts will be made to dispense the 4 mg oral risperidone to the patient for 
administration as close to the same time each day.  A mouth and hand check will be performed 
after each oral risperidone dose administration to ensure treatment compliance.  
A Sponsor-trained, licensed physician will insert the Risperidone Implants subcutaneously into 
the upper, inner aspect of the subject’s non-dominant arm between the bicep and triceps. At the 
completion of the implantation period, the Risperidone Implants will be removed by a Sponsor 
trained, licensed physician. The date and time of implantation and explantation and the arm that 
the implant was inserted in will be recorded in the subject’s CRF. If the subject is reimplanted, 
the same site and dose will be used, and the dose, date and time will be recorded.  Detailed 


12-Feb-2017 
BB-PK-103 
Braeburn Pharmaceuticals
Confidential 
Page 36
 
 
instructions for the insertion and removal procedures for the Risperidone Implants will be 
provided to the Investigator separately. 
 
5.4 
Restrictions on Study Subjects 
Subjects will be served standardized meals during the confinement periods in the clinical 
research facility; no other foods will be permitted. A record of the menu served will be 
maintained. Water is permitted ad libitum throughout the study. 
No alcohol containing foods or beverages may be consumed within 24 hours prior to check-in 
and extending until the subjects are discharged from the study site. 
All sexually active females of childbearing potential and all male subjects who are sexually active 
with a partner of childbearing potential must agree to use a medically acceptable method of 
contraception throughout the entire study. Medically acceptable methods of contraception for the 
subject and/or partner include abstinence, birth control pills or patches, diaphragm with 
spermicide, IUD, surgical sterilization, condom with spermicide, or progestin injection. 
Additionally, all males treated with Risperidone Implants must avoid donating sperm during 
treatment and for 3 months following the final explants procedure. 
 
5.5 
Randomization and Blinding 
5.5.1 
Randomization 
This is an open-label study that requires no randomization. 
5.5.2 
Blinding 
This is an open-label study that requires no blinding. 
 


12-Feb-2017 
BB-PK-103 
Braeburn Pharmaceuticals
Confidential 
Page 37
 
 
6 
STUDY DRUG MATERIALS AND MANAGEMENT 
6.1 
Study Drug 
The risperidone Implant drug product is supplied as a sterile implant. The 300 mg Risperidone 
Implant is composed of 5 pellets of 60 mg risperidone and a membrane composed of aliphatic, 
polyether-based polyurethane that controls the rate of risperidone release.  The implants are 
manufactured by a Contract Management Organization, Xcelience, Tampa FL.    
Commercially available 4 mg risperidone oral tablets will be provided at no cost to subjects and 
sites from check-in to Day -1.   
6.2 
Study Drug Description, Packaging, and Labeling 
Risperidone Implant is packaged in a sealed clear polyester/foil pouch containing one sterilized 
implant per package. Each pouch is labeled with a single-panel label containing product 
description, dose of risperidone contained in implant, lot number and Sponsor name. Each pouch 
is packaged into a carton with a single-panel label containing protocol number, product 
description, lot number, storage conditions, caution statement and name and address of Sponsor. 
Kits containing all supplies needed for implantation and explantation will be provided. 
6.3 
Study Drug Storage 
Risperidone Implant should be stored at controlled room temperature, i.e., 25°C (77°F); 
excursions allowed 15°C to 30°C (59°F to 86°F). 
Risperidone tablets should be stored at controlled room temperature 15°C to 25°C (59° to 77°F) 
and protected from light and moisture. 
6.4 
Study Drug Preparation 
Record the lot number on the CRF prior to opening the pouch. Once the implants pouches are 
opened, the implants should be used within 1 hour. 
6.5 
Administration 
A Sponsor trained, licensed physician will insert the Risperidone Implants subcutaneously into 
the upper, inner aspect of the subject’s non-dominant arm (between the bicep and triceps). 
Reinsertions will be made in the same incision location following explantation. Detailed 
instructions for implantation and explantation procedures will be provided to the Investigator 
separately. The implantation/explantation kit will contain all the ancillary supplies necessary for 
implantation and/or explantation of the Risperidone Implants. The implantation and explantation 
procedure must be performed using aseptic technique and the use of a local anesthetic. 
 
Subjects will be administered their oral risperidone at approximately the same time each morning 
under direct supervision of the study site personnel. If a subject is on an evening dosing regimen 
of 4 mg risperidone prior to study entry, the subject will be converted to a morning dosing 
regimen one week prior to admission to the clinical research center. The dosing regimen a subject 
will follow once admitted to the research center will be the same regimen they will be converted 


12-Feb-2017 
BB-PK-103 
Braeburn Pharmaceuticals
Confidential 
Page 38
 
 
back to the day after explantation of the second set of Risperidone Implants.  
 
6.6 
Study Drug Accountability 
The Principal Investigator is responsible for ensuring that all study medication received at the 
site is inventoried and accounted for and that dispensed study medication is recorded both in the 
CRF and in the Study Medication Log. Drug accountability will be verified by the monitor 
during site visits. 
Upon completion of the study and verification of the final study medication inventory by the 
monitor, a list of all the remaining study medication will be provided to the Sponsor.  
The Principal Investigator will not supply the study drug to any person except those named as 
sub-investigators on Form FDA 1572, designated staff reflected on the Delegation of Authority 
Log, and consented subjects in this study. Study drug may not be relabeled or reassigned for use 
by other subjects. 
 
6.7 
Study Drug Handling and Disposal 
All study medication and kits must be kept in a locked area with access restricted to designated 
study personnel. After completion of the study, all unused study drug will be returned to the 
Sponsor. The monitor will provide instructions to the site for the return drug shipment. 


12-Feb-2017 
BB-PK-103 
Braeburn Pharmaceuticals
Confidential 
Page 39
 
 
7 
ASSESSMENT OF PHARMACOKINETICS 
7.1 
Pharmacokinetic Assessments 
7.1.1 
Blood Sample Collections 
Pharmacokinetic assessments for risperidone, 9-OH-risperidone and active moiety (risperidone 
plus 9-OH-risperidone) will be performed for all subjects in the study. Samples of venous blood 
will be obtained according to the clinical research facility standard procedure and collected at the 
times indicated in the Schedule of Study Evaluations (Table 3-7). PK samples should be drawn 
from the arm contralateral to the implant. Samples collected within 10% of the specified times 
will not be considered protocol deviations; however, every attempt will be made by the clinical 
research facility to collect samples at the specified times. The exact sample collection times will 
be recorded in the CRF to the nearest minute. 
All plasma samples will be placed into a freezer at -20°C or below within 1 hour after collection 
and further plasma sample handling instructions will be provided and detailed by the central 
laboratory.   
 
7.1.2 
Sample Storage and Shipment 
All plasma samples will be stored frozen (at -20°C or below) until they are shipped to the 
analytical facility. Prior to shipping, the samples will be packed into thermal insulated containers 
and packed in sufficient dry ice to assure they remain frozen, and are protected from breakage 
during shipment to the analytical facility. Samples will be shipped by ground courier with 
appropriate documentation to identify the samples. The samples will be divided into 2 shipments, 
each containing 1 aliquot of plasma for each time point. The second aliquot will remain at the 
site until Sponsor notification of the receipt of the 1st sample is received. 
The shipment schedule, shipping address, and contact information will be provided to the site in 
a separate document. The analytical facility will be notified by telephone, fax, and/or email prior 
to shipment of any samples 
 
7.1.3 
Analytical Methodology 
A validated liquid chromatography-tandem mass spectrophotometry (LC-MS/MS) method will 
be used for the determination of concentrations of risperidone and 9-OH-risperidone from the 
plasma samples. Details of the method validation and sample analysis will be included in the 
final report. 
 


12-Feb-2017 
BB-PK-103 
Braeburn Pharmaceuticals
Confidential 
Page 40
 
 
8 
ASSESSMENT OF EFFICACY 
8.1 
Psychiatric Rating Scales 
All assessments will be completed as indicated in the Schedule of Study Evaluations (Table 3-
7) by clinicians trained in the use of the rating scales. The number of clinicians who make these 
assessments should be kept to a minimum. It is most desirable to have only one person making 
all the assessments for a given day. 
 
8.1.1 
Positive and Negative Syndrome Scale (PANSS) 
The PANSS is a rating scale used to assess the positive symptoms, negative symptoms, and 
general psychopathology specifically associated with schizophrenia. The scale consists of 
30 items. Each item is rated on a scale from 1 (symptom not present) to 7 (symptom extremely 
severe). The sum of the 30 items is defined as the PANSS total score and ranges from 30 to 210. 
The PANSS positive sub-scale and the PANSS negative sub-scale contain seven items of the 
30 items, and the scores range from 7 to 49. The PANSS general psychopathology sub-scale 
includes 16 of the 30 PANSS items, and the score ranges from 16 to 112. To optimize the scales 
objectivity and standardization a tightly structured interview is important.  
 


12-Feb-2017 
BB-PK-103 
Braeburn Pharmaceuticals
Confidential 
Page 41
 
 
9 
CLINICAL CRITERION FOR LACK OF EFFICACY 
Any subject presenting with signs and symptoms of lack-of-efficacy (LOE) will be evaluated by 
the Investigator, or designee. LOE will be evaluated using PANSS.  The subject will be 
withdrawn from the study and will be scheduled for implant removal as soon as possible if LOE 
is determined. Once the implant has been removed, the subject will be restarted on his/her pre-
implant oral Risperidone dosing regimen. The Investigator will notify the Medical Monitor and 
Sponsor of each case of LOE.  
 


12-Feb-2017 
BB-PK-103 
Braeburn Pharmaceuticals
Confidential 
Page 42
 
 
10 
ASSESSMENT OF SAFETY 
10.1 
Timing of Safety Assessments 
Safety assessments will be obtained throughout the study. The timing of these measurements is 
detailed in the Schedule of Study Evaluations (Table 3-7). PK samples will be drawn before the 4 
mg oral risperidone dose during days -7 to -1 then at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 18, 24 hours on 
Day -1 prior to implantation of Risperidone Implant for the patients that will be implanted with 
600 mg (2, 300 mg) and 900 mg (3, 300 mg).  The initial four “Non-PK run in” subjects in the 
three 300 mg implant group will not have PK draws done until the pre-implant draw on Day 1 
(this group is no longer enrolling). 
On implant day, PK samples will be drawn pre-implantation, 2 and 6 hours post implant, then 
daily from day 2 to day 7.  The following “priority order” will be in effect when more than 1 
assessment is required at a particular time point: 
• 
PK blood sampling will take priority over all study procedures unless there is a LOE. 
The exact time of collection to nearest minute will be documented in the CRF. 
• 
Safety parameters will be monitored throughout the study by collection of vital signs, 
clinical laboratory evaluations, ECGs, physical examinations, implant site assessments, 
extrapyramidal symptom assessments, (EPS), Columbia Suicide Severity Scale 
assessments (C-SSRS), Abnormal Involuntary Movement Scale (AIMS), Simpson 
Rating Scale (SAS), and Barnes Akathisia Scale (BARS) and adverse event (AE) 
monitoring will be performed at a similar time per day.  The exact time of assessments 
to nearest minute will be documented in the CRF. 
10.2 
Safety Parameters 
10.2.1 
Medical/Medication History and Demographic Information 
A detailed relevant medical history and medication history will be recorded for each subject at 
screening and reviewed/updated upon admission to the clinical research facility to confirm 
eligibility for the study. Significant medical conditions or conditions that are ongoing (e.g., 
headache, indigestion, diabetes, hypertension) will be recorded in the CRF. The medication 
history must identify any known drug allergies, present or history of drug abuse and use of acute 
or chronic medications. 
Demographic information (i.e., age, sex, and race) will be collected for all subjects and recorded 
on the appropriate CRF. 
10.2.2 
Physical Examinations 
The complete physical examination assessment will be completed at the time points indicated in 
the Schedule of Study Evaluations (Table 3-7) and will include an assessment of the following: 
general appearance, skin, head and neck (including eyes, ears, nose, and throat), lymph nodes, 
thyroid, musculoskeletal/extremities (including spine), cardiovascular, lungs, abdomen and 
neurological systems. The screening physical examination will also include a measurement of 
body height and weight (without shoes) for determination of the subject’s BMI. 


12-Feb-2017 
BB-PK-103 
Braeburn Pharmaceuticals
Confidential 
Page 43
 
 
Except for the screening examination, if there has been a change from the previous examination, 
only that information need be recorded. 
10.2.3 
Laboratory Evaluations 
Subjects should be fasting for at least 8 hours prior to all laboratory evaluations. A complete 
series of laboratory evaluations (i.e., clinical chemistry, hematology, and urinalysis), substances 
of abuse screen, virology screen, and serum pregnancy test (female subjects only) will be 
performed at the screening visit. A complete series of laboratory evaluations (i.e., clinical 
chemistry, hematology, lipid profile, and urinalysis), substances of abuse screen, and urine and 
serum pregnancy tests (female subjects only) will be performed in accordance with the 
Schedule of Study Evaluations on (Table 3-7). 
Lipid profile evaluations will be conducted at week 12 and 26, and also 40 and 48 in the safety 
extension. The required laboratory evaluations are detailed in Table 8. 
Test results for the substances of abuse screen, virology screen, and serum pregnancy (females 
only) will be confirmed negative prior to implant of the Risperidone Implants as indicated in 
(Table 3-7) documentation will be maintained with the source worksheets; the test results will not 
be entered into the database. 
Table 8:  Safety Laboratory Tests to be monitored during the Study 
 
Clinical Chemistry 
Hematology
Urinalysis 
Sodium 
Hemoglobin
pH
Potassium 
Hematocrit
Specific Gravity 
Chloride 
Red Blood Cell Count
Protein
Carbon Dioxide 
White Blood Cell Count
Glucose
Blood Urea Nitrogen (BUN) 
White Blood Cell Differential
Ketones
Creatinine 
Platelet Count
Urobilinogen  
Calcium 
 
Blood
Phosphorus 
Substance of Abuse Screena
Albumin 
Amphetamines
Virology
Total Bilirubin 
Barbiturates
Hepatitis C Antibody (anti-HCV)
Aspartate aminotransferase (AST) 
Benzodiazepinesb
Human Immunodeficiency Virus (HIV)
Alanine aminotransferase (ALT) 
Cocaine
Hepatitis B surface Antigen
Gamma-glutamyl transferase (GGT) 
Phencyclidine (PCP)
Alkaline phosphatase 
Opiates
Serum/Urine Pregnancy (females of 
childbearing potential only)
Lactate dehydrogenase (LDH) 
Ethanol (breath test acceptable)
Beta-human chorionic gonadotropin 
(β-HCG)
Glucose 
 
Lipid Profile 
 
FSH (post-menopausal females only) 
Total cholesterol 
 
HDL (high-density lipoprotein) 
 
LDL (low-density lipoprotein) 
 
Triglycerides 
 
HDL/Total Cholesterol 
 
a  Substance of abuse screen will be conducted using urine samples. 
b Positive results for benzodiazepines are permitted if the subject is on a currently prescribed medication regimen 
A blood sample for a serology panel testing for hepatitis B surface antigen, anti-hepatitis C 


12-Feb-2017 
BB-PK-103 
Braeburn Pharmaceuticals
Confidential 
Page 44
 
 
Antibodies, and HIV will be performed for all subjects, unless a site’s IRB prohibits such 
testing. 
It is the Investigator’s responsibility to understand and comply with all laws and regulations that 
apply to the testing of blood for HIV and hepatitis B and C. These laws and regulations may 
include state laws related to written consent, separate from the ICF for this study, and pre- and 
post-test counseling.  
Any clinically significant abnormalities should be fully investigated and reported as AEs. 
Whenever possible, the etiology of the abnormal findings will be documented in the CRF. 
Laboratory results with clinically significantly abnormal values should be repeated for 
confirmation. Additional tests and other evaluations required to establish the clinical 
significance or etiology of an abnormal laboratory result or to monitor the course of an AE 
should be obtained when clinically indicated. In particular, if a clinically significant abnormal 
result is observed that is not resolved by the final study visit, repeat tests should be performed to 
document resolution or stability of the abnormality. 
The diagnosis associated with any clinically significant laboratory abnormality will be recorded 
as an AE on the CRF. Recorded AEs should indicate the underlying abnormality or diagnosis 
(e.g., renal insufficiency) as opposed to the observed deviation in laboratory results (e.g., 
elevated creatinine). 
Any significant laboratory abnormalities that are either serious or unexpected should be 
promptly reported to the Medical Monitor. Any additional relevant laboratory results obtained 
by the Investigator during the course of this study will be supplied to the Sponsor. 
 
10.2.4 
Vital Signs 
Routine vital signs, including blood pressure, heart rate, respiration rate, and oral body 
temperature will be obtained at the times indicated in the Schedule of Study Evaluations 
(Table 3-7).  Blood pressure assessments should be conducted in the arm contralateral to the 
implant. 
Blood pressure, heart rate and respiration rate will be obtained after the subject is in the supine 
position for at least 5 minutes. Additional vital signs will be obtained when clinically indicated. 
Any additional relevant data obtained by the Investigator during the course of this study will be 
supplied to the Sponsor. 
 
10.2.5 
12-Lead Electrocardiograms 
A standard 12-lead ECG will be obtained at the times indicated in the Schedule of Study 
Evaluations (Table 3-7). The ECG will be obtained after the subject has been resting in the 
supine position for at least 5 minutes. The ECG intervals (PR, QRS, QT, and QTc), heart 
rate, and ECG findings will be recorded in the CRF. Additional ECGs may be obtained if 
clinically indicated. A follow-up ECG will be obtained at the Investigator’s discretion if any 
symptom-oriented abnormalities are detected after dose administration. Any additional 
relevant data obtained by the Investigator during the course of this study will be supplied to 
the Sponsor. Clinically significant ECG findings will be reported to the Medical Monitor. 
 


12-Feb-2017 
BB-PK-103 
Braeburn Pharmaceuticals
Confidential 
Page 45
 
 
10.2.6 
Implant Site Assessments 
 
Implant site assessments will include monitoring for signs and symptoms of infection, (e.g., 
pain, tenderness, swelling, erythema, exudate) and tolerability. The presence of the implant will 
be assessed by palpation in addition to the visual examination at the times indicated in the 
Schedule of Study Evaluations (Table 3-7). Clinically significant findings, as judged by the 
Investigator, resulting from the implant site assessment will be recorded as AEs. If an infection 
develops at the implant site, the subject will be withdrawn from the study and the implant will 
be removed. The infection will be treated in accordance with standard medical practice. Once 
the implant has been removed the subject will be restarted on his/her pre-implant oral 
risperidone dosing regimen.  Additionally, ultrasounds may be performed at the discretion of the 
Investigator to confirm implant location.  
The Investigator will inform the Sponsor’s Medical Monitor of any clinically significant findings 
related to implant assessments. 
 
10.2.7 
Extrapyramidal Symptom Assessments 
Safety testing to monitor for signs of EPS will assessed at the times indicated in the Schedule of 
Study Evaluations (Table 3-7).  The assessments will be conducted with the use of the following 
objective rating scales: Abnormal Involuntary Movement Scale (AIMS), Simpson Rating Scale 
(SAS), and Barnes Akathisia Scale (BARS). 
Assessments will be completed by clinicians trained in the use of the rating scales. The number 
of clinicians who make these assessments should be kept to a minimum. It is most desirable to 
have only one person making all the assessments for a given day. 
 
10.2.8 
Columbia Suicide Severity Scale 
Suicidality will be assessed at the times indicated in the Schedule of Study Evaluations (Table 3-
7). 
 
10.3 
Early Explantation and Subject Withdrawal Criteria 
10.3.1 
Suspicion of Implant Breakage 
If it is suspected that an implant has been broken or damaged during the insertion procedure the 
implant will be removed and the subject will be withdrawn from the study. If there is no 
immediate suspicion of implant breakage or damage during the insertion procedure, subjects will 
be followed closely during the inpatient stay with assessments of symptoms, vital signs, ECGs, 
and plasma drug concentrations. Previous experience with implant technology has shown that 
plasma levels rise more quickly than predicted and to higher levels than expected when an 
implant is damaged during insertion. The occurrence of EPS and tachycardia have been observed 
in cases of excessive ingestion of oral risperidone (Page et al., 2010) and these signs and 
symptoms should be monitored after implantation of the Risperidone Implants. 
 
After discharge from the inpatient phase the following criteria should be followed to identify if an 


12-Feb-2017 
BB-PK-103 
Braeburn Pharmaceuticals
Confidential 
Page 46
 
 
implant may have been damaged: 
• 
During the outpatient phase of the study all subjects will be instructed to call the site if 
they have a sudden change in feelings of wellness that may be related to possible 
exaggerated pharmacologic effects. If a severe or serious adverse event (SAE) is 
reported within 24 hours following implantation of the Risperidone Implant and is 
considered at least possibly related to the Risperidone Implant the subject will be 
withdrawn from the study and have the implant removed. 
At the time of explantation, it is expected that the implant will be removed as a single piece. If 
any breakage occurs, attempts will be made to remove the remaining piece(s). If the remaining 
piece(s) is not found, the patient will be observed closely for clinical symptoms and plasma drug 
levels will be monitored for higher than expected levels, and treatment will be provided per 
standard medical practice. 
10.3.2 
Subject Manipulation or Attempted Removal of RISPERIDONE IMPLANT 
If a subject attempts to remove the Risperidone Implants once implanted, or in any way 
attempts to manipulate the Risperidone Implants while implanted, the subject will be 
withdrawn from the study and the implant will be removed. 
10.3.3 
Documentation of Implant Events 
In the event implant breakage is observed, excessive increase or decrease in plasma 
concentrations is reported, or a subject manipulates or attempts to remove the implant, the 
Investigator will evaluate the finding, inform the Sponsor, and report any clinically significant 
abnormality as an AE. 
10.4 
Recording and Reporting Adverse Events 
Throughout the study, AEs will be documented on the appropriate page of the CRF whether or 
not considered treatment-related. This includes any new signs, symptoms, injury or illness, 
including increased severity of previously existing signs, symptoms, injury, or illness. 
Conditions existing prior to dosing will be recorded as part of the subject’s medical history. The 
Investigator is responsible for assessing the relationship of AEs to the study medication; 
relationship will be classified as not related, unlikely related, possibly related, or probably related 
(see section 10.4.1.2 for definitions). 
All AEs will be collected by the Investigator from the time informed consent is signed through 
the follow up visit. This includes any AEs that are ongoing at the completion/termination of the 
study, and any AEs that start after the last dose of study medication. A follow-up safety visit will 
be conducted approximately 14 days after discharge from the research center.  
All SAEs will be collected from the time the informed consent is signed at screening through the 
follow up visit. Any SAEs considered related to study medication should be reported to the 
Sponsor without regards to these timelines. 
Any SAE, including death resulting from any cause, which occurs to any subject participating in 
this study or within 14 days following cessation of the study treatment or premature 
discontinuation from the study whether or not related to the investigational product, must be 
reported via email, facsimile or telephone within 24 hours of first being advised of the SAE. 


12-Feb-2017 
BB-PK-103 
Braeburn Pharmaceuticals
Confidential 
Page 47
 
 
Follow-up information collected for any initial report of an SAE must be reported to the Sponsor 
or designee within 24 hours of receipt by the Investigator. In the event discussion is necessary 
call the Medical Monitor. 
The Sponsor or designee will determine whether the SAE must be reported within 7 or 15 days 
to the FDA. If so, the Sponsor (or the Sponsor’s representative) will report the event to the 
FDA. The Investigator will transmit a written report of the circumstances and outcome to the 
Sponsor as soon as he or she is made aware of the circumstances. The Investigator will report 
SAEs to the Institutional Review Board (IRB) per IRB policy. 
10.4.1 
Adverse Event Definitions 
An AE is any unfavorable or unintended change in body structure (signs), body function 
(symptoms), laboratory result (e.g., chemistry, ECG, etc.), or worsening of a pre-existing 
condition associated temporally with the use of the study medication whether or not considered 
related to the study medication. 
A treatment-emergent AE is any condition that was not present prior to treatment with study 
medication but appeared following treatment, was present at treatment initiation but worsened 
during treatment, or was present at treatment initiation but resolved and then reappeared while 
the individual was on treatment (regardless of the intensity of the AE when the treatment was 
initiated). 
 
All AEs, including either observed or volunteered problems, complaints, signs, or symptoms 
must be recorded on the AE page of the CRF, regardless of whether associated with the use of 
study medication. This would include AEs resulting from concurrent illness, reactions to 
concurrent medication use, or progression of disease states (excluding the disease under study).  
AEs should be recorded in standard medical terminology. 
The Investigator will evaluate each AE for duration, intensity, and relationship to study 
medication, record the action taken, and any treatment given. Recurrent symptoms of a chronic 
pre-existing condition are not considered AEs unless they occur in a worse or unexpected pattern 
during study drug administration. 
 
10.4.1.1 Intensity of AEs 
The intensity (or severity) of AEs is characterized as mild, moderate, or severe: 
Mild AEs are usually transient, requiring no special treatment, and do not interfere with the 
subject’s daily activities. 
Moderate AEs introduce a low level of inconvenience or concern to the subject and may 
interfere with daily activities, but are usually ameliorated by simple therapeutic measures. 
Severe AEs interrupt a subject’s usual daily activity and typically require systemic drug therapy 
or other treatment. 
When the intensity category of the AE changes more frequently than once daily, the maximum 
intensity for the event is recorded. If the intensity category changes after a number of days, then 
these sub-events or changes are recorded separately (i.e., having distinct onset and stop dates). 


12-Feb-2017 
BB-PK-103 
Braeburn Pharmaceuticals
Confidential 
Page 48
 
 
10.4.1.2 Relationship to Study Medication 
The degree of “relatedness” of the AE to the study drug may be described using the following 
scale: 
Not related indicates that the AE is definitely not related to the study drug. 
Unlikely related indicates that there are other, more likely causes and study drug is not 
suspected as a cause. 
Possibly related indicates that a direct cause and effect relationship between study drug and the 
AE has not been demonstrated but there is a reasonable possibility that the event was caused by 
the study drug. 
Probably related indicates that there probably is a direct cause and effect relationship between 
the AE and the study drug. 
It is the Sponsor’s policy to consider “Probable” and “Possible” causality assessments as positive 
causality. It is the Sponsor’s policy to consider “Not” and “Unlikely” causality assessments as 
negative causality. 
Assessments are to be recorded on the CRF and must indicate clearly the relationship being 
assessed.  
10.4.1.3 
Serious Adverse Events (SAEs) 
An SAE is defined as an AE that: 
• 
Results in death 
• 
Is immediately life-threatening (there is an immediate risk of death from the AE as it 
occurred; this does not include an AE that had it occurred in a more serious form 
may have caused death) 
• 
Results in or prolongs an inpatient hospitalization (Note: a hospitalization for elective or 
pre-planned surgery, procedure, or drug therapy does not constitute an SAE unless there 
is complication resulting in hospitalization prolongation). An AE that results in a visit to 
an Emergency Room that does not require an inpatient stay is not always classified as an 
SAE. 
• 
Results in permanent or substantial disability (permanent or substantial disruption 
of one’s ability to conduct normal life functions) 
• 
Is a congenital anomaly/birth defect (in offspring of a patient using the study 
medication regardless of time to diagnosis) 
• 
Is considered an important medical event 
Life-threatening events are defined as events that place the subject, in the view of the 
Investigator, at immediate risk of death from the reaction as it occurred, i.e., it does not include 
a reaction that, had it occurred in a more severe form, might have caused death. 
Disability is defined as a substantial disruption of a person’s ability to conduct normal life 
functions. 


12-Feb-2017 
BB-PK-103 
Braeburn Pharmaceuticals
Confidential 
Page 49
 
 
Important medical events are defined as events that, based upon appropriate medical judgment, 
may jeopardize the subject and may require medical or surgical intervention to prevent one of the 
outcomes. Examples of important medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do 
not result in inpatient hospitalization, or the development of drug dependency or drug abuse. 
10.5 
Procedures in Case of Pregnancy 
All pregnancies of a subject or their partner will be reported to the Sponsor using the same 
reporting timelines as indicated for SAEs in section 10.4.1.3. Pregnancy itself is not regarded as 
an AE unless there is a suspicion that the investigational product under study may have 
interfered with the effectiveness of a contraceptive medication. However, the outcome of all 
pregnancies (i.e., spontaneous miscarriage, elective abortion, normal birth or congenital 
abnormality) must be followed up and documented even if the subject was discontinued from 
the study. 
All reports of congenital abnormalities/birth defects are SAEs. Spontaneous miscarriages should 
also be reported and handled as SAEs. Elective abortions without complications should not be 
handled as AEs unless the decision to abort was based on a diagnostic test that indicated there 
was a problem. All outcomes of pregnancy must be reported to the Sponsor on the pregnancy 
outcomes report form. 
10.6 
Precautions 
It is expected that the Risperidone Implants will have a safety and efficacy profiles similar to 
risperidone oral tablets and the long-acting IM depot injectable formulation of risperidone. 
Risperidone is considered to be generally safe and well tolerated. The most common adverse 
reactions (≥10%) in clinical studies with risperidone oral tablets include somnolence, increased 
appetite, fatigue, rhinitis, upper respiratory tract infection, vomiting, coughing, urinary 
incontinence, saliva increased, constipation, fever, Parkinsonism, dystonia, abdominal pain, 
anxiety, nausea, dizziness, dry mouth, tremor, rash, akathisia, and dyspepsia. Subjects will be 
monitored closely throughout the study for potential adverse events. 
There are no additional risks expected with implantation of the Risperidone Implants beyond 
those normally encountered during similar minor surgical procedures. A Sponsor-trained, 
licensed physician, must insert and remove the Risperidone Implants Aseptic technique should 
be followed at all times during the implant procedure to minimize the chance of infection. 
Sterile gloves are required at all times throughout the implantation and explantation procedure. 
The implantation/explantation procedure may result in bruising, pain/soreness/tenderness, skin 
redness, and swelling at the site of implantation. Subjects will be monitored closely throughout 
the study for signs and symptoms of implantation site reactions.   
The Investigator should treat all adverse experiences in accordance with standard medical 
practice. Due to the investigational nature of the method of delivery of Risperidone, the AE 
profile cannot be defined with certainty; all subjects will be carefully evaluated. 
Additional information regarding AEs is provided in the Investigator Brochure and the MOP. 


12-Feb-2017 
BB-PK-103 
Braeburn Pharmaceuticals
Confidential 
Page 50
 
 
10.7 
Observation 
All subjects will remain in the clinical research facility from approximately Day -7 until 
discharged by the Investigator at the end of the in-house confinement period. The subjects will 
be kept under observation during their time in the clinical research facility in a manner 
consistent with the standard operating procedures of the clinical research facility and as 
medically indicated. 
AEs should be treated in accordance with the standard medical practice. During the course of the 
study, the overall safety and tolerability of the study medications will be reviewed by the 
Investigator and Sponsor. 
 


12-Feb-2017 
BB-PK-103 
Braeburn Pharmaceuticals
Confidential 
Page 51
 
 
11 
STATISTICS 
This section describes the statistical methods to be used. These methods may be revised and 
updated due to reasons such as regulatory requirements or need for further clarifications. The final 
analysis plan will be documented in a formal statistical analysis plan (SAP) that must be finalized 
before database lock. The SAP will include details on how variables will be derived, how missing 
data will be handled, and how data will be presented as well as the details on statistical methods to 
be used for safety and efficacy analyses. The final clinical study report will discuss deviations 
from the SAP, if any. 
 
For bridging the efficacy of the Risperidone Implant to oral risperidone, the mean concentrations 
after the insertion of the Implants is expected to approximate the mean Cavg of oral 4 mg 
risperidone and not to exceed oral Cmax. In addition, the average concentrations after the implant 
is expected to be higher than the oral Ctrough.  The target concentration is to provide consistent 
levels between the relevant oral Ctrough and Cmax, where efficacy and safety could be preserved.  
 
 
11.1 
Sample Size Consideration 
Approximately 40 will provide over 90% power to establish that implant is non-inferior to the 
oral dose of risperidone. .   In the sample size calculation it was assumed that the true ratio was 
at least 1.1 and the coefficient of variance (CV) was less than 0.45.  These assumptions were 
based on internal data.  Therefore, approximately 50 subjects will be enrolled to ensure 
approximately 40 subjects completing the study assuming that the drop rate is less than 20%. 
11.2 
Analysis Population 
The safety population will consist of all subjects who have received at least one dose of 
study treatment. 
The PK population will consist of subjects who receive 4-mg oral risperidone daily and the 
Risperidone Implants.  
The primary PK analyses will be based on the subjects who provide Month 6 PK results.   
11.3 
Subject Disposition 
Subject disposition will be summarized. The overall summary will be comprised of the number 
and percentage of subjects for each analysis population, as well as the number and percentage of 
subjects who completed and discontinued early with reasons for discontinuation. 
11.4 
Demographics and Baseline Characteristics 
Demographic and baseline characteristics will be summarized using appropriate descriptive 
statistics. 
11.5 
Concomitant Medications 
Medications administered prior to and concomitantly with study treatment will be tabulated and 
listed. 


12-Feb-2017 
BB-PK-103 
Braeburn Pharmaceuticals
Confidential 
Page 52
 
 
 
11.6 
Pharmacokinetic Analysis 
11.6.1 
Calculation of Pharmacokinetic Variables 
Pharmacokinetic variables of AUC0-24 (oral dose only), AUC3-180 days, (Risperidone Implant 
only), AUC3-t, (Risperidone Implant only), Cmax, Ctrough and Tmax (oral dose only), for 
risperidone, 9-OH-risperidone will be derived. The active moiety will be calculated as the sum 
of the risperidone and 9-OH-risperidone concentrations at each sampling time point.  In 
order to minimize the contribution that the Day 1 oral dose of risperidone will have on the 
AUC during implantation, the AUC calculation for the implantation period will initiate 3 days 
after implantation (Day 3).  The concentrations of risperidone, 9-OH risperidone and active 
moiety on Days 1 to 3 will be summarized to characterize the pharmacokinetics of risperidone 
and 9-OH-risperidone when changing the oral tablet to implant.  The Cavg values for 
risperidone, 9-OH-risperidone and active moiety from the Risperidone Implants will be 
calculated as the plasma AUC3-t divided by t-3 (in days). The Cavg for the oral tablet will be 
calculated as the plasma AUC0-24 on Day -1 divided by 24 hours.  Actual sample times (relative 
to the corresponding implantation time) rounded to two decimal digits and negative pre-dose 
times set to zero, will be used in the computation of the pharmacokinetic variables, rather than 
scheduled times. Refer to section 11.7 for the handling of missing values. 
The definition and method of determination for each pharmacokinetic variable are summarized 
in Table 9. 
 
 


12-Feb-2017 
BB-PK-103 
Braeburn Pharmaceuticals
Confidential 
Page 53
 
 
 
Table 9:  Pharmacokinetic Variables 
 
Variable 
Definition 
AUC0-24hr 
Area under the concentration versus time curve from time 0 to 24 hours after oral 
dose; calculated using the linear trapezoid rule. 
AUC3-180day 
Area under the concentration versus time curve from time Day 3 to 180 days after 
Risperidone Implant for the subsequent subjects; calculated using the linear trapezoid 
rule 
AUC3-t 
Area under the concentration versus time curve from time Day 3 to t days after 
t h e  Risperidone Implant for subjects who do not complete the implantation 
period; calculated using the linear trapezoid rule. 
Cavg 
Average steady-state concentration 
Oral tablet: measured as AUC0-24 hr on Day -1 divided by 24 
Risperidone Implant: measured as AUC3-t divided by t-3; t=days Risperidone Implant
remained in situ. 
Cmax 
Observed maximum plasma concentration; the highest concentration observed after 
the oral dose and after implantation with Risperidone Implant. 
Ctrough 
The concentration at 24 hours following an oral dose of risperidone. 
Tmax 
The time that Cmax was observed. 
 
11.6.2 
Analysis of Pharmacokinetic Data 
All PK data (concentration and pharmacokinetic variables) will be summarized using appropriate 
descriptive statistics. The ratios of Risperidone Implant Cavg  over oral Cmax, over oral Cavg  and over oral 
Ctrough will be analyzed based on log-transformed scales using an ANOVA model with treatment effects.  
The two sided 95% confidence intervals will be presented.  Inferiority is defined as the lower bound of 
95% confidence interval of the ratio is <0.8. 
 
The active moiety will be considered the primary interest.  To control for Type I error rate, active moiety 
will be analyzed first, followed by the analysis for risperidone. 
The concentrations of risperidone, 9-OH risperidone and active moiety on Days 1 to 3 will be 
summarized to characterize the pharmacokinetics of risperidone when changing the oral tablet 
to implant. 
The study is designed to evaluate the PK profiles of the 900 mg implant arm.  PK profile for 600 
mg arm is exploratory. 
11.7 
Handling of Missing Values 
Plasma concentrations below the limit of quantification (BLQ) will be set to half of BLQ value 
in the computation of mean concentration values; however, BLQ concentrations between 2 
non-BLQ concentrations will be set to missing. For the computation of PK variables, the BLQ 


12-Feb-2017 
BB-PK-103 
Braeburn Pharmaceuticals
Confidential 
Page 54
 
 
concentrations prior to the first measurable concentration will be set to half of the BLQ value; 
other BLQ concentrations will be set to missing. 
No imputation will be performed for demographic and safety data. 
11.8 
Safety Analysis 
The safety analysis will be based on all subjects who received any study medication. The 
frequency of AEs will be tabulated using the Medical Dictionary for Regulatory Activities 
(MedDRA) by system organ class (SOC) and preferred term (PT), and treatment for each cohort. 
The maximum intensity and frequency of AEs will be summarized by treatment and cohort. 
Vital sign, clinical laboratory, EPS assessments and ECG measurements will be summarized by 
treatment and study day (visit) using descriptive statistics or frequency distribution, as 
appropriate. 
11.9 
Protocol Deviations 
A list of subjects with protocol deviations will be compiled. Prior to database lock, an evaluation 
of subjects with significant protocol deviations will be performed to assess the appropriateness of 
their inclusion into the PK analysis. 
 


12-Feb-2017 
BB-PK-103 
Braeburn Pharmaceuticals
Confidential 
Page 55
 
 
12 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
12.1 
Study Monitoring 
The monitoring of the study will be performed in accordance with the principles of Good 
Clinical Practice (GCP) as described in the International Conference on Harmonization (ICH) E6 
titled “Good Clinical Practice.” Monitoring including source data verification should be routinely 
performed prior to the transfer of data to Data Management. 
It is a prerequisite of this study that the study monitor has direct access to source data for data 
verification. This will be done by comparing data from the CRFs with those in the subject’s 
medical notes (permission from the subject will be sought as part of the consent process). Such 
verification is an essential element of quality control, as it allows the rectification of transcription 
errors and omissions. 
The Sponsor expects that, during monitoring visits, the study coordinator and Investigator will be 
available, the source documentation will be available, and a suitable environment will be 
provided for review of study related documents. 
12.2 
Audits and Inspections 
Authorized representatives from the Sponsor, a regulatory authority or an IRB/independent 
ethics committee (IEC) may request access to all study records, including direct access to source 
data/documents, for inspection, audit and/or copying, in keeping with applicable regulations. The 
Investigator will permit study related monitoring, audits, IRB/IEC review, and regulatory 
inspections, providing direct access to source data/ documents. The Investigator should 
immediately notify the Sponsor of an upcoming regulatory authority inspection. 
 


12-Feb-2017 
BB-PK-103 
Braeburn Pharmaceuticals
Confidential 
Page 56
 
 
13 
QUALITY CONTROL AND QUALITY ASSURANCE 
Steps to assure the accuracy and reliability of data include the selection of qualified investigators 
and appropriate clinical research facilities, review of protocol procedures with the Principal 
Investigator and associated personnel prior to start of the study, and periodic monitoring visits by 
the Sponsor or Sponsor representative. 
Additional steps will include the design of suitable source documents by the Investigator with 
appropriate instructions for use; the monitoring of source data according to GCP and internal 
procedures to ensure their accuracy, completeness, and verifiability. Written instructions will be 
provided for collection, preparation, and shipment of blood and plasma samples. The Sponsor or 
Sponsor representative will review source documents for accuracy and completeness; any 
discrepancies will be resolved with the Investigator or designee, as appropriate. The data will be 
entered into the clinical study database and verified for accuracy, using the study specific data 
management plan. 
 


12-Feb-2017 
BB-PK-103 
Braeburn Pharmaceuticals
Confidential 
Page 57
 
 
14 
ETHICS 
14.1 
Ethics Review 
The Principal Investigator must have written and dated approval/favorable opinion from the 
IRB/IEC for the protocol, informed consent form, subject recruitment materials/process 
(e.g., advertisements), and any other written information to be provided to subjects. The Principal 
Investigator should also provide the IRB/IEC with a copy of the Investigator’s Brochure or 
product labeling, information to be provided to subjects and any updates. 
The Principal Investigator will provide the IRB/IEC with reports, updates, and other information 
(e.g., Safety Updates, Amendments) according to local regulations and guidelines. 
Copies of all IRB/IEC approvals must be provided to the Sponsor prior to the start of the study 
and throughout the study as applicable. 
14.2 
Ethical Conduct of the Study 
The study will be performed in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with Good Clinical Practice and ICH guidelines and 
other applicable regulatory requirements. 
14.3 
Written Informed Consent 
The Principal Investigator will ensure that each subject is given full and adequate oral and 
written information about the nature, purpose, possible risk and benefit of the study. Subjects 
must also be notified that they are free to discontinue from the study at any time. The subject 
should be given the opportunity to ask questions and allowed time to consider the information 
provided. 
Each subject, or subject’s authorized legal representative, must voluntarily sign and date the 
informed consent form (and other locally required documents) prior to the performance of any 
study-related activity. The consent form must be approved by both the reviewing IRB/IEC and 
by the Sponsor prior to use. 
The consent form will incorporate (or, in some cases, be accompanied by a separate document 
incorporating) wording that complies with relevant data protection and privacy legislation. 
Pursuant to this wording, subjects will authorize the collection, use and disclosure of their study 
data by the Investigator and by those persons who need that information for the purposes of the 
study. 
The consent form will explain that study data will be stored in a computer database, maintaining 
confidentiality in accordance with national data legislation. For data verification purposes, 
authorized representatives of the Sponsor, a regulatory authority or an IRB/IEC may require 
direct access to source data relevant to the study, including the subjects’ medical history. 
 


12-Feb-2017 
BB-PK-103 
Braeburn Pharmaceuticals
Confidential 
Page 58
 
 
15 
DATA HANDLING AND RECORDKEEPING 
15.1 
Source Data Capture 
Source worksheets will be used to record data at the clinical research facility. Data on the source 
worksheets will be transferred to the eCRF. All information requested on the source worksheet 
should be completed legibly. If the data are not available, the source worksheet and CRF should 
be documented as such. 
15.2 
Case Report Forms 
Data collected will be entered at the clinical research facility into electronic case report forms 
(eCRFs). The eCRFs will be available through the electronic data capturing (EDC) system 
provided by the Sponsor. As the data are entered, they will be subjected to range checks and 
other edits to ensure accuracy. Electronic CRFs are to be completed on an ongoing basis during 
the study. The medical chart and the source documents are the source of verification of data. 
Electronic CRFs should be completed according to the instructions provided by the Sponsor. The 
Principal Investigator is responsible for maintaining accurate, complete and up-to-date records 
for each subject and for authenticating the data recorded in the eCRF. 
15.3 
Data Recording and Handling 
Data collection and handling will involve the use of the Sponsor’s EDC system to which only 
authorized personnel will have access. In addition to periodic monitoring occurring within the 
system by the Sponsor monitor, programmatic edit checks will be used to review the data for 
completeness, logic, and adherence to the study protocol. As a result of this monitoring and these 
edit checks, queries may be issued electronically to the clinical study site and closed 
electronically by the monitor, Sponsor’s data management staff or authorized study site staff. 
The identifying information (assigned username, date, and time) for both the originator of the 
data change (if applicable), as well as the Investigator’s approval of all changes performed on the 
subjects’ data, will be recorded in various features of the EDC system. 
All data collected in the context of this study will be stored and evaluated per regulatory 
requirements and applicable guidance for electronic records. Also, data will be stored and 
evaluated in such a way as to guarantee subject confidentiality in accordance with the legal 
stipulations applying to confidentiality of subject data. Study records (i.e., copies of eCRF, 
regulatory documents) will be retained at the study site, along with adequate source 
documentation in accordance with GCP and ICH guidelines. All study records will be available 
for inspection by the Sponsor, their authorized representatives, or regulatory agencies. At the 
completion of the study, the Sponsor or its representatives will supply the site with a copy of all 
data captured in the EDC system. 
 
15.4 
Inspection of Records 
Periodically the Sponsor or Sponsor representative will review study documents to verify 
compliance with the protocol and accuracy of the data. All corrections or changes made to study 
data (e.g., source worksheet, CRF) must be appropriately documented (e.g., initialed and dated, 
audit trail) as per GCP/ICH guidelines. 


12-Feb-2017 
BB-PK-103 
Braeburn Pharmaceuticals
Confidential 
Page 59
 
 
15.5 
Retention of Records 
All regulatory documents (i.e., investigator study file), CRFs and all source documents 
(i.e., informed consent forms, laboratory reports, progress notes, medical histories, physical and 
diagnostic findings, diagnoses and dates of therapy prior to and during this study, drug 
dispensing and disposition records) that support CRFs must be retained by the responsible 
Principal Investigator for a minimum of 2 years following notification by the Sponsor that all 
investigations have been discontinued or 2 years after the last approval of a marketing 
application in an ICH region. 
If the responsible Investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping the study records, custody must be transferred to a person who will 
accept the responsibility and the Sponsor must be notified. 
 


12-Feb-2017 
BB-PK-103 
Braeburn Pharmaceuticals
Confidential 
Page 60
 
 
16 
PROTOCOL MODIFICATIONS 
Neither the Investigator nor the Sponsor will modify this protocol without obtaining the 
concurrence of the other. All protocol amendments must be signed and dated by the Investigator, 
and submitted and approved by the IRB/IEC prior to implementation of the amendment, unless it 
is administrative in nature or to protect the immediate well-being of study subjects. The Sponsor 
will submit protocol modifications to the appropriate regulatory authority as called for under 
applicable regulations. 
If a protocol amendment requires a change to the informed consent form, then the Sponsor and 
the IRB/IEC must be notified. Approval of the revised informed consent form by the Sponsor 
and IRB/IEC is required before the revised form may be used. All ongoing subjects should be 
advised of any changes and they should be documented appropriately. 
In situations requiring a departure from the protocol, the Investigator or other physician in 
attendance will contact the medical monitor by fax or telephone. If possible, this contact will be 
made before implementing any departure from protocol. In all cases, contact with the medical 
monitor must be made as soon as possible in order to discuss the situation and agree on an 
appropriate course of action. The CRF and source document will reflect any departure from the 
protocol procedures and the circumstances requiring it. All departures will be a deviation; no 
waivers will be granted. 
 
 


12-Feb-2017 
BB-PK-103 
Braeburn Pharmaceuticals
Confidential 
Page 61
 
 
17 
REFERENCES 
1. Goldner EM, Hsu L, Waraich P, Somers JM. Prevalence and incidence studies 
of schizophrenic disorders: a systematic review of the literature. Can J 
Psychiatry. 2002; 47(9):833-43. 
2. Castle D, Wessely S, Der G, Murray RM. The incidence of operationally 
defined schizophrenia in Camberwell, 1965-84. Brit J Psychiatry. 
1991;159:790-94. 
3. Kampman O, Illi A, Poutanen P, Leinonen E. Four-year outcome in non-compliant 
schizophrenia patients treated with or without home-based ambulatory outpatient 
care. Eur Psychiatry. 2003;18(1):1-5. 
4. RIS1-TR-10-007, Evaluation of Risperidone and Blank Tecoflex® EG-80A Implants 
From “A Three Month Toxicity and Toxicokinetic Study with Risperidone in Beagle 
Dogs Utilizing Tecoflex and Carbothane Subcutaneous Implants.” Endo 
Pharmaceuticals; Braeburn Pharmaceuticals; 2010. 
5. Leysen JE, Gommeren W, Eens A, De Chaffoy De Courcelles D, Stoof JC, Janssen 
PA. Biochemical profile of risperidone, a new antipsychotic. J Pharmacol Exp Ther. 
1988;247(2):661-72. 
6. Risperdal NDA 20-272. December 29, 1993. 
7. Snoeck E, Van Peer A, Sack M, et al. Influence of age, renal and liver impairment on 
the pharmacokinetics of risperidone in man. Psychopharmacology (Berl). 
1995;123(3):223-29. 
8. Mannens G, Huang ML, Meuldermans W, Hendrickx J, Woestenborghs R, Heykants 
J. Absorption, metabolism, and excretion of risperidone in humans. Drug Metab 
Dispos. 1993;21(6):1134-41. 
9. Huang ML, Van Peer A, Woestenborghs R, et al. Pharmacokinetics of the novel 
antipsychotic agent risperidone and the prolaction response in healthy subjects. 
Clin Pharmacol Ther. 1993;54(3):257-68. 
10. Van Peer A, Meuldermans W, Woestenborghs R, Heykants J. Clinical 
pharmacokinetics of risperidone. In: Kane JM, Moller JH, Awouters F, eds. Serotonin 
in Antipsychotic Treatment: Mechanisms and Clinical Practice. New York, NY: 
Marcel Dekker; 1996:277-91 
11. Page CB, Calver LA, Isbister GK. Risperidone overdose causes extrapyramidal 
effects but not cardiac toxicity. J Clin Psychopharmacol. 2010;(30)4:387-90. 


12-Feb-2017 
BB-PK-103 
Braeburn Pharmaceuticals
Confidential 
Page 62
 
 
 
 
 
17.1 
INVESTIGATOR AGREEMENT 
RISPERIDONE IMPLANT Protocol Version 7: A PHASE II, OPEN-LABEL 
PHARMACOKINETIC STUDY IN SCHIZOPHRENIC PATIENTS ON A STABLE DOSE OF 4 MG 
ORAL RISPERIDONE TO EVALUATE THE SAFETY, TOLERABILITY, AND 
PHARMACOKINETICS OF RISPERIDONE AND 9-HYDROXY (OH)- RISPERIDONE WHEN 
RISPERIDONE IS ADMINISTERED WITH A SIX MONTH IMPLANT  
I have read the protocol and agree that it along with the related Clinical Trial Agreement contain 
all the details necessary to carry out the study. I will conduct this study according to the protocol 
and will complete the study in the time agreed. Potential additions or modifications to the study 
will be by mutual written agreement between the Sponsor and me and will be documented and 
filed, if required, with the Institutional Review Board and the Food and Drug Administration. 
I will provide copies of the protocol and other pertinent information to all individuals responsible 
to me who will assist in the study. 
The Sponsor will have access to source documentation from which case reports have been 
generated. 
 
 
 
 
 
 
Signature of Investigator 
Date 
 
 
 
 
Typed or Printed Name of Investigator 
Site Number