Clinical trial NCT02773576
Conditions: Schizophrenia
Sponsor: Braeburn Pharmaceuticals
Start date: 2016-04-01; Completion date: 2017-09-01
Enrollment: 140 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A one year, open-label, study to evaluate the safety and tolerability of risperidone implants as a maintenance treatment in patients with schizophrenia

Detailed description:
The trial is to evaluate the 48-week safety and tolerability of risperidone implants as maintenance therapy in subjects with schizophrenia. This will be measured by the incidence of psychotic symptoms exacerbation/impending relapse, PANSS, CGI-I, CGI-S, adverse events, vital signs, clinical laboratory, physical exam and ECG findings, Abnormal Involuntary Movement Scale (AIMS), Barnes Akathisia Rating Scale (BARS), and Simpson-Angus Scale (SAS) and Investigator assessments.

Arms: arm 1: 2, 360 mg risperidone implants arm 2: 3, 300 mg risperidone implants
Interventions: intervention 1: Risperidone implant
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_SAP_000.pdf: 
B B -R S P -3 0 1
B B -R S P -3 0 1
B B -R S P -3 0 1
B B -R S P -3 0 1
1 5 -J U L-2 0 1 6                                           Brae b ur n P har mace uticals
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Cli nic al Tri al Pr ot oc ol
B B -R S P -3 0 1
A O ne Ye ar, O pe n -l a bel, St u d y t o E v al u ate t he S afet y a n d
T oler a bilit y of Ris peri d o ne I m pl a nt s as a M ai nte n a nce
Tre at me nt i n P atie nts wit h Sc hiz o p hre ni a
RI S P E RI D O N E I M P L A N T
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Versi o n 2: A me n d me nt # 1: Fe br uar y 2 2, 2 0 1 6
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C O N FI D E N TI A LI T Y S T A T E M E N T
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Clinical Trial Protocol
Braeburn Pharmaceuticals
BB-RSP-301
CONFIDENTIAL
Version: Final 4.0, 15JUL2016
Page 2 of 67
1.
SPONSOR AND KEY PERSONNEL CONTACT INFORMATION
ROLE IN STUDY
NAME
CONTACT INFORMATION
Sponsor
Braeburn
Pharmaceuticals, Inc.
(609) 436-9627
47 Hulfish Street, Suite 441
Princeton, NJ  08542
Medical Monitor
Lawrence F. Blob, MD
Cognitive Research
Corporation Medical
Director
lblob@cogres.com
727-897-9000 (office)
410-262-1908 (mobile)
Sponsor Project Manager
John Carlos Diaz, MS
Associate Director
Clinical Operations
john@braeburnpharma.com
609.436.9538 (office)
484.568.3952 (mobile)
Safety/Serious Adverse
Event Reporting
Lawrence F. Blob, MD
Cognitive Research
Corporation Medical
Director
lblob@cogres.com
727-897-9000 (office)
410-262-1908 (mobile)
Primary Investigator
David Walling, Ph.D.
Chief Executive Officer
and Principal
Investigator, CNS
Network
davidwalling@cnstrial.com
714-799-7799 (office)
714-225-8831 (mobile)


Clinical Trial Protocol
Braeburn Pharmaceuticals
BB-RSP-301
CONFIDENTIAL
Version: Final 4.0, 15JUL2016
Page 3 of 67
2.
PROTOCOL SYNOPSIS
Name of Sponsor/Company: Braeburn Pharmaceuticals
Name of Investigational Product: Risperidone Implant
Name of Active Ingredient: risperidone
Study Title: A One Year, Open-label, Study to Evaluate the Safety and Tolerability of Risperidone
Implants as a Maintenance Treatment in Patients with Schizophrenia
Principal Investigator:
David Walling, Ph.D.
Study Centers: Up to 15 centers
Countries: United States
Study Period:
Phase of Development:
Estimated date first subject enrolled: 15-Mar-2016
Estimated date last subject completed:  Oct-2017
Phase 3
Objectives:
The primary objective of the trial is to evaluate the 48-week safety and tolerability of Risperidone
Implants as maintenance therapy in subjects with schizophrenia. Safety and tolerability will be
measured by the incidence of psychotic symptoms exacerbation/impending relapse, PANSS, CGI-I,
CGI-S, adverse events, vital signs, clinical laboratory, physical exam and ECG findings, Abnormal
Involuntary Movement Scale (AIMS), Barnes Akathisia Rating Scale (BARS), and Simpson-Angus
Scale (SAS) and Investigator assessments.
Study Design: Open-label maintenance study of two consecutively administered 6 month Risperidone
Implants in the treatment of subjects with schizophrenia.
Methodology
The study consists of a Screening Period, a Conversion Phase, a 48-week Maintenance Treatment
Phase and a Follow-up Visit.
Screening Period (Up to Six Weeks):
Eligibility for the study will be determined during the Screening period. The Screening period will
include psychiatric and medical evaluations, screening tests, physical examination/medical history and
other assessments to establish whether the patient meets the inclusion/exclusion criteria for the study.
During the Screening period, subjects will be washed out of all prohibited concomitant medications.
Subjects receiving an antipsychotic other than oral risperidone (4 mg/day), long acting risperidone
injection (37.5 mg/dose), Invega® (6 mg/day)or Invega® Sustenna® (156 mg dose) will be required to
enter the Conversion Phase.
To enter the 48-week Maintenance Treatment Phase, subjects are required to be taking only one
antipsychotic medication: risperidone.  Subjects who are receiving oral risperidone (4 mg/day), long-
acting risperidone injection (37.5 mg/dose), Invega® (6 mg/day) or Invega® Sustenna® (156 mg dose)
at the time of Screening will be eligible to directly enter the 48-week Maintenance Treatment Phase.
All other eligible subjects will enter the Conversion Phase.


Clinical Trial Protocol
Braeburn Pharmaceuticals
BB-RSP-301
CONFIDENTIAL
Version: Final 4.0, 15JUL2016
Page 4 of 67
Name of Sponsor/Company: Braeburn Pharmaceuticals
Name of Investigational Product: Risperidone Implant
Name of Active Ingredient: risperidone
Conversion Phase (Two to Six Weeks):
During the weekly visits in the Conversion Phase, subjects will cross-titrate from other antipsychotic(s)
to oral risperidone therapy over a minimum of 2 - 6 weeks. The objective of the oral conversion Phase
is for all subjects to achieve an oral risperidone dose of 4 mg by the end of Week 6 of the Conversion
Phase.
Maintenance Phase (48 Weeks):
At the beginning of the 48-week Maintenance Treatment Phase, all subjects will receive Risperidone
Implants (two, 360 mg or three, 300 mg 6-month implants, each containing risperidone). Oral dosing
with risperidone will continue for one day after the subject has received the Risperidone Implants.
During the Maintenance Phase, subjects will be evaluated in the clinic and at any unscheduled visits
for signs of exacerbation of psychotic symptoms/impending relapse as defined in Section 9.3.1.
Subjects (or their caregiver) will be contacted by phone periodically throughout the trial to check-in on
the subjects in between on-site visits. The appearance of any clinically significant signs of exacerbation
of psychotic symptoms/impending relapse criteria will result in withdrawal from the trial. Additionally,
any subject withdrawn for lack of efficacy in the Maintenance Phase per the Principal Investigator has
to meet at least one of the criteria for exacerbation of psychotic symptoms/impending relapse.
Number of Subjects (Planned):
Screening Phase – approximately 250 subjects.
Conversion Phase – It is anticipated that approximately 120 subjects will enter the Conversion Phase.
Maintenance Phase – approximately 140 subjects will be implanted.
Study Population: Patients with a diagnosis of schizophrenia as defined by DSM-5 criteria.
Inclusion/Exclusion Criteria:
Inclusion Criteria during Screening Period:
1.
Subject has provided written informed consent.
2.
Male and female subjects 18 to 70 years of age, inclusive, at time of informed consent.
3.
Subjects with a current diagnosis of schizophrenia as defined by DSM-5 criteria and a history
of the illness for at least 2 years prior to screening (as per subject, family, healthcare provider,
and/or by previous medical records).
4.
Subject is assessed by the Investigator to be symptomatically stable with regard to his or her
psychiatric condition at screening and baseline.
5.
Subject must be stable on their current antipsychotic medication for at least 30 days prior to
screening.
6.
Subject has identified a caregiver or personal contact with whom the subject has significant
contact with at least once per week.
7.
Subjects who have shown a previous response to antipsychotic treatment (other than
clozapine) in the past year, according to the Investigator’s opinion.


Clinical Trial Protocol
Braeburn Pharmaceuticals
BB-RSP-301
CONFIDENTIAL
Version: Final 4.0, 15JUL2016
Page 5 of 67
Name of Sponsor/Company: Braeburn Pharmaceuticals
Name of Investigational Product: Risperidone Implant
Name of Active Ingredient: risperidone
8.
Subjects who are currently being treated with one or two antipsychotics other than clozapine,
and who, in the Investigator’s judgment, require chronic treatment with an antipsychotic
medication and would benefit from treatment with Risperidone Implants.
Note: Subjects taking oral risperidone (4 mg/day), long-acting risperidone injection
(37.5 mg/dose), Invega® (6 mg/day) or Invega® Sustenna® (156 mg dose) at the time
of Screening can be directly enrolled into the Maintenance Phase of the study.
9.
Subjects who meet the following criteria:
a.
Outpatient status
b.
PANSS Total Score ≤ 80, and if PANSS score at baseline increases by ≥ 20% change
from screening, the subject cannot participate in the study.
c.
PANSS scores of ≤ 4 on all of the following items:
• Conceptual disorganization
• Suspiciousness
• Hallucinatory behavior
• Unusual thought content
• Hostility
d.
CGI-S ≤ 4 (moderately ill)
e.
Lack of clinically significant suicidal ideation or behavior in Investigator’s judgment
10. Subjects who are able to understand the nature of the trial and follow protocol requirements,
have the ability to read and understand the written word, and who can be reliably rated on
assessment scales.
11. Subjects who have completed adequate washout (5 half-lives unless otherwise specified) of
prohibited concomitant medications, including mood stabilizers and strong inducers or
inhibitors of CYP2D6 activity, prior to receiving oral risperidone or implant Risperidone.
12. Subject has completed washout of 42 days for any fluoxetine containing compound.
13. 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, condom with
spermicide, intrauterine device (IUD), surgical sterilization, or progestin injection. All females
of childbearing potential must have a negative serum pregnancy at the screening visit.
Females of non-childbearing potential must meet the following:
a.
Have medical documentation of surgical sterility OR
b.
Be post-menopausal, defined as 12 consecutive months of amenorrhea and confirmed
by a Follicle-Stimulating Hormone (FSH) test.
14. Subject has a body mass index (BMI) ≥18.5 and ≤38.0 kg/m2.
15. Subject is assessed by the Investigator to be symptomatically stable with regard to pre-
existing medical conditions as evidenced by medical history, non-clinically significant


Clinical Trial Protocol
Braeburn Pharmaceuticals
BB-RSP-301
CONFIDENTIAL
Version: Final 4.0, 15JUL2016
Page 6 of 67
Name of Sponsor/Company: Braeburn Pharmaceuticals
Name of Investigational Product: Risperidone Implant
Name of Active Ingredient: risperidone
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.
Inclusion Criteria at entry into the Risperidone Implant 48-week Maintenance Treatment Phase
The subject is tolerating oral risperidone 4 mg/day in the Conversion Phase or the subject directly
enters the 48-week Maintenance Treatment Phase because they are receiving at Screening either
oral risperidone (4 mg/day), long-acting risperidone injection (37.5 mg/dose), Invega® (6 mg/day)
or Invega® Sustenna® (156 mg dose) and meets the following criteria:
a.
Outpatient status
b.
PANSS Total Score ≤ 80 (if PANSS score at baseline increases by ≥ 20% change from
screening, the subject cannot participate in the study)
c.
PANSS scores of ≤ 4 on all of the following items:
• Conceptual disorganization
• Suspiciousness
• Hallucinatory behavior
• Unusual thought content
• Hostility
d.
CGI-S ≤ 4 (moderately ill)
e.
Lack of clinically significant suicidal ideation or behavior in Investigator’s judgment
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.
Reports or reveals a presence of clinically significant skin disorders (such as, but not limited
to, skin cancer, psoriasis, eczema, or atopic dermatitis), and/or 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.
4.
History of abnormal scar formation or family history of keloid formation.
5.
Subjects with a current DSM-5 diagnosis other than schizophrenia, including schizoaffective
disorder, major depressive disorder, bipolar disorder, delirium, dementia, amnestic or other
cognitive disorders. Also, subjects with borderline, paranoid, histrionic, schizotypal, schizoid,
or antisocial personality disorder are excluded.
6.
Subjects experiencing acute depressive symptoms within the past 30 days, according to the
Investigator’s opinion, that required treatment with an antidepressant.


Clinical Trial Protocol
Braeburn Pharmaceuticals
BB-RSP-301
CONFIDENTIAL
Version: Final 4.0, 15JUL2016
Page 7 of 67
Name of Sponsor/Company: Braeburn Pharmaceuticals
Name of Investigational Product: Risperidone Implant
Name of Active Ingredient: risperidone
7.
Subjects considered by the Investigator to be at imminent risk of suicide or injury to self, or
subjects who within the past 6 months prior to Screening have attempted suicide, or who
within the past 3 months prior to Screening have had active suicide ideation (positive answers
to item 4 or 5 on the C-SSRS).
8.
Subjects with schizophrenia that are considered resistant/refractory to antipsychotic treatment
by history.
9.
Subjects with a history of failure to clozapine treatment or response to clozapine treatment
only.
10. Subjects with a documented history of failure to respond to an adequate dose of risperidone or
paliperidone treatment including long acting injectable formulations.
11. Subjects with a significant risk of violent behavior or a significant risk of committing suicide
based on history or Investigator’s judgment.
12. Subjects who currently meet DSM-5 criteria for substance use disorder (moderate or severe);
including alcohol and benzodiazepines, but excluding caffeine, nicotine, and marijuana.
13. Females who are breast-feeding or will be breast feeding during the course of the study, and/or
who have a positive serum pregnancy test result prior to receiving trial medication.
14. Subjects with uncontrolled hypothyroidism or hyperthyroidism (unless condition has been
stabilized with medications for at least the past 90 days).
15. Subjects who have a clinically significant history or evidence of a medical condition that
would expose them to an undue risk of a significant AE or interfere with assessments of safety
or efficacy during the course of the trial, including but not limited to hepatic, renal, respiratory,
cardiovascular, endocrine, neurologic, hematologic, or immunologic disease as determined by
the clinical judgment of the Investigator.
16. Subjects with epilepsy or a history of seizures, except for a single childhood febrile seizure,
post traumatic, alcohol withdrawal, etc. A subject with a history of any seizure activity will
have their case discussed with the medical monitor prior to subject’s study enrollment.
17. Subjects with a positive drug screen at screening for drugs of abuse without a prescription,
excluding marijuana, will be discussed with the medical monitor. If the subject has a second
positive drug screen during the Screening Phase, the Conversion Phase, or at Maintenance
Baseline, the subject will be excluded from the trial.
18. The following laboratory test, vital sign, and ECG results are exclusionary:
a.
Platelets ≤75,000/mm3
b.
Hemoglobin ≤ 9 g/dL
c.
Neutrophils, absolute ≤1000/mm3
d.
Aspartate aminotransferase > 3x upper limit of normal
e.
Alanine aminotransferase > 3x upper limit of normal
f.
Creatinine ≥ 2 mg/dL
g.
Diastolic blood pressure > 105 mmHg


Clinical Trial Protocol
Braeburn Pharmaceuticals
BB-RSP-301
CONFIDENTIAL
Version: Final 4.0, 15JUL2016
Page 8 of 67
Name of Sponsor/Company: Braeburn Pharmaceuticals
Name of Investigational Product: Risperidone Implant
Name of Active Ingredient: risperidone
h.
QTc > 470 msec for females and QTc > 450 msec for males using the QTcF
(Fridericia) correction
NOTE: Consultation with the medical monitor may allow for retesting. In addition, subjects
are excluded if they have any other clinically significant abnormal laboratory tests, vital sign
results, or ECG findings that, in the Investigator’s judgment, are medically significant or
would impact the safety of the subject or the interpretation of the trial results. Criteria are
provided in the protocol to assist Investigators in their assessments of results that are
potentially medically significant, depending on the subject’s medical history and clinical
presentation. Abnormal results for laboratory parameters or vital signs will be repeated to
ensure reproducibility of the abnormality before excluding a subject based on the criteria noted
above. If a repeated ECG has a triplicate corrected QTcF < 470 msec for females on the
correction that was initially > 470 msec, or if a repeated ECG has a triplicate corrected QTcF <
450 msec for males on the correction that was initially > 450msec, the subject could be
included in the trial.
19. Subject is HIV positive.
20. Active hepatitis. Subjects with no viral load, no acute inflammation and no clinical necessity
for therapy will be allowed, at the discretion of the Investigator.
21. Subjects with a history of an allergic hypersensitivity to antipsychotic agents.
22. Subjects with a history of significant intolerance or who are refractory to antipsychotic agents.
23. Subjects with a history of neuroleptic malignant syndrome.
24. Subjects with clinically significant tardive dyskinesia at screening [any one AIMS item (1-7)
with a score >2].
25. Subjects likely to require prohibited concomitant therapy during the trial (see Section 8.6.1).
26. Subjects who require current use of agents that are strong inhibitors (e.g. quinidine) and
inducers (e.g. carbamazepine, phenytoin, rifampin, and phenobarbital) of cytochrome P450
2D6.
27. Subjects who have received any investigational agent in a clinical trial within 30 days prior to
screening; for investigational drugs with an elimination half-life greater than 15 days, this time
period will be extended to 60 days.
28. Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for treatment
of either a psychiatric or physical (e.g., infectious disease) illness, or who have ongoing legal
issues that could affect their ability to continue to participate in this trial.
29. Subjects who have been hospitalized, including hospitalization for psychosocial reasons, for
more than 30 days total in the last 60 days prior to entry into the Screening Phase.
30. Electroconvulsive therapy within 180 days prior to entry into the Screening Phase.
31. Any other finding that, in the Investigator’s opinion, would present undue risk to the subject or
may confound the interpretation of study results.
Reference Therapy, Dosage and Mode of Administration:
Risperidone Implants inserted every 24 weeks (see Instructions for User)


Cli nical Trial Pr ot oc ol
Brae b ur n P har mace uticals
B B -R S P -3 0 1
C O N FI D E N TI A L
Versi o n: Fi nal 4 . 0, 1 5J U L 2 0 1 6
Pa ge 9 of 6 7
N a me of S p o ns or/ C o m p a n y: Brae b ur n P har mace uticals
N a me of I n vesti g ati o n al Pr o d uct: Ris peri d o ne I m pla nt
N a me of Acti ve I n gre die nt: ris peri d o ne
Oral ris peri d o ne 4 m g ( C o n versi o n P hase)
D ur ati o n of St u d y: 1 4. 5 M o nt hs
Scree ni n g: 4 5 da ys
C o n versi o n P hase: 2 - 6 wee ks
Mai nte na nce P hase:
4 8 wee ks
Criteri a f or E v al u ati o n:
Pri m ary E n d p oi nts :
1)
Safet y para meters will be m o nit ore d t hr o u g h o ut t he st u d y b y c ollecti o n of vital si g ns, cli nical
la b orat or y e val uati o ns, E C Gs, p h ysical e xa mi nati o ns, i m pla nt site assess me nts, e xtra p yra mi dal
s y m pt o m assess me nts ( E P S), C ol u m bia Se verit y Scale assess me nts ( C -S S R S), A b n or mal
I n v ol u ntar y M o ve me nt Scale ( AI M S), Si m ps o n-A n g us Scale ( S A S), a n d Bar nes A kat hisia
Scale ( B A R S), a n d a d verse e ve nt ( A E) m o nit ori n g.
2)
Ti me t o disc o nti n uati o n d ue t o all ca uses
3)
Mea n c ha n ge fr o m baseli ne t o e n d p oi nt i n P A N S S Total Sc ore
4)
Mea n c h a n ge fr o m baseli ne t o e n d p oi nt i n Cli nical Gl o bal I m pressi o n of Se verit y ( C GI -S)
5)
Mea n c ha n ge fr o m baseli ne t o e n d p oi nt i n P A N S S p ositi ve a n d ne gati ve s u bscales
6)
Mea n C GI -I sc ore at e n d p oi nt
Sec o n d ary E n d p oi nt:
T he sec o n dary e n d p oi nt of t he trial will be t he i nci de nce of ps yc h otic s y m pt o m
e xacer bati o n/i m pe n di n g rela pse i n t he 4 8 -wee k Mai nte na nce Treat me nt P hase, defi ne d as meeti n g a n y
of t he f oll o wi n g 4 criteria:
1)
Cli nical Gl o bal I m pressi o n of I m pr o ve me nt ( C GI -I) of ≥ 5 ( mi ni mall y w orse)
A N D

a n i ncrease o n a n y of t he f oll o wi n g i n di vi d ual P ositi ve a n d Ne gati ve S y n dr o me Scale ( P A N S S)
ite ms (c o nce pt ual dis or ga nizati o n, hall uci nat or y be ha vi or, s us pici o us ness, u n us ual t h o u g ht
c o nte nt, h ostilit y) t o a sc ore > 4 wit h a n a bs ol ute i ncrease of ≥ 2 o n t h at s pecific ite m si nce
baseli ne O R

a n i ncrease o n a n y of t he f oll o wi n g i n di vi d ual P A N S S ite ms (c o nce pt ual dis or ga nizati o n,
hall uci nat or y be ha vi or, s us pici o us ness, u n us ual t h o u g ht c o nte nt, h ostilit y) t o a sc ore > 4 a n d a n
a bs ol ute i ncrease of ≥ 4 o n t he c o m bi ne d fi ve P A N S S ite ms (c o nce pt ual dis or ga nizati o n,
hall uci nat or y be ha vi or, s us pici o us ness, u n us ual t h o u g ht c o nte nt, h ostilit y) si nce baseli ne O R
2)
H os pitalizati o n d ue t o w orse ni n g of ps yc h otic s y m pt o ms (i ncl u di n g partial h os pitalizati o n
pr o gra ms), b ut e xcl u di n g h os pitalizati o n f or ps yc h os ocial reas o ns O R
3)
Cli nicall y si g nifica nt s uici dal i deati o n or be ha vi or i n I n vesti gat or ’s j u d g me nt O R
4)
Vi ole nt be ha vi or res ulti n g i n cli nicall y rele va nt self -i nj ur y, i nj ur y t o a n ot her pers o n, or
pr o pert y da ma ge


Clinical Trial Protocol
Braeburn Pharmaceuticals
BB-RSP-301
CONFIDENTIAL
Version: Final 4.0, 15JUL2016
Page 10 of 67
Name of Sponsor/Company: Braeburn Pharmaceuticals
Name of Investigational Product: Risperidone Implant
Name of Active Ingredient: risperidone
Exploratory Endpoint
1) Pittsburgh Sleep Quality Index (PSQI)
Statistical Methods (Data Analysis):
The safety results will be based on the safety population that will include all subjects who receive
study medication.  The efficacy results will be based on intent-to-treat population that will include all
enrolled subjects.  The efficacy measures will be summarized at baseline and over time.  The safety
assessments and AEs will be summarized appropriately.


Clinical Trial Protocol
Braeburn Pharmaceuticals
BB-RSP-301
CONFIDENTIAL
Version: Final 4.0, 15JUL2016
Page 11 of 67
3.
TABLE OF CONTENTS
1.
Sponsor and Key Personnel Contact Information.......................................................2
2.
Protocol Synopsis............................................................................................................3
3.
Table of Contents ..........................................................................................................11
4.
List of Abbreviations and Definition of Terms...........................................................14
5.
Introduction...................................................................................................................16
5.1.
Background ..............................................................................................................16
5.2.
Study Rationale ........................................................................................................19
6.
Study Objectives ...........................................................................................................21
6.1.
Primary Objective ....................................................................................................21
6.2.
Overall Study Design and Plan ................................................................................21
6.3.
Discussion of Study Design .....................................................................................23
7.
Selection of Study Population......................................................................................24
7.1.
Inclusion Criteria......................................................................................................24
7.2.
Exclusion Criteria.....................................................................................................26
7.3.
Qualification Criteria ...............................................................................................28
7.4.
Removal of Subjects from Therapy or Assessment .................................................28
7.5.
Study Restrictions ....................................................................................................30
8.
Treatments.....................................................................................................................31
8.1.
Treatment Administration.........................................................................................31
8.1.1.
Implant Insertion and Removal Procedures ...........................................................31
8.2.
Identity of Investigational Product(s).......................................................................32
8.2.1.
Handling, Storage, and Accountability ..................................................................32
8.2.2.
Dispensing and Administration ..............................................................................32
8.3.
Selection of Doses....................................................................................................33
8.4.
Selection and Timing of Dose..................................................................................33
8.5.
Blinding....................................................................................................................33
8.6.
Prior and Concomitant Therapy ...............................................................................33
8.6.1.
Permitted, Prohibited, and Restricted concomitant medications............................34
8.7.
Treatment Compliance .............................................................................................35
9.
Study Procedures and Assessments.............................................................................36
9.1.
Demographics and Other Baseline Characteristics ..................................................45
9.1.1.
Informed Consent...................................................................................................45
9.1.2.
Demographics.........................................................................................................45
9.1.3.
Medical History......................................................................................................45


Clinical Trial Protocol
Braeburn Pharmaceuticals
BB-RSP-301
CONFIDENTIAL
Version: Final 4.0, 15JUL2016
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9.1.4.
Medication History and Alcohol/Drug Use............................................................45
9.2.
Eligibility Review and Randomization ....................................................................45
9.3.
Study Assessments ...................................................................................................46
9.3.1.
Primary Endpoints..................................................................................................46
9.3.2.
Secondary Endpoint ...............................................................................................47
9.3.3.
Exploratory Endpoint .............................................................................................48
9.4.
Safety Assessments ..................................................................................................48
9.4.1.
Adverse Events (AEs) and Serious Adverse Events (SAEs)..................................48
9.4.2.
Pregnancy...............................................................................................................50
9.4.3.
Clinical Laboratory Assessments ...........................................................................51
9.4.4.
Urine Drug Screen and Breath Alcohol Testing.....................................................53
9.4.5.
Vital Signs ..............................................................................................................53
9.4.6.
12-Lead Electrocardiograms ..................................................................................54
9.4.7.
Physical Examination.............................................................................................54
9.4.8.
Physical Measurements..........................................................................................54
9.4.9.
Implant Site Examination and Wound Care ...........................................................55
9.4.10. Other Assessments..................................................................................................55
10. Data Quality Assurance................................................................................................57
10.1. Data Collection.........................................................................................................57
10.2. Study Auditing and Monitoring ...............................................................................57
11. Statistical Methods and Determination of Sample Size ............................................59
11.1. Statistical and Analytical Plans ................................................................................59
11.2. Analysis Populations................................................................................................59
11.3. Planned Analyses .....................................................................................................59
11.3.1. Subject disposition .................................................................................................59
11.3.2. Demographics and Other Baseline Characteristics ................................................59
11.3.3. Prior and concomitant medication..........................................................................59
11.3.4. Analysis of Safety Assessments (Primary Endpoints) ...........................................59
11.3.5. Efficacy assessment................................................................................................60
11.4. Determination of Sample Size .................................................................................61
12. Study Administration and Investigator Responsibilities...........................................62
12.1. Regulatory and Ethical Considerations....................................................................62
12.1.1. Ethical Conduct of the Study .................................................................................62
12.1.2. Regulatory Authority and Ethics Approval ............................................................62
12.1.3. Subject Informed Consent......................................................................................62
12.2. Privacy and Confidentiality......................................................................................63
12.3. Study and Site Closure.............................................................................................63
12.4. Regulatory Documents and Records Retention .......................................................64


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12.5. Delegation of Responsibilities and Adequate Resources .........................................65
12.6. Protocol Amendments ..............................................................................................65
12.7. Financial Disclosure.................................................................................................65
13. Investigator Protocol Agreement Page........................................................................66
14. References......................................................................................................................67
Table of Tables
Table 1: Schedule of Assessments – Screening and Conversion Phase................................37
Table 2: Schedule of Assessments – Maintenance Phase: Baseline – Week 24 ...................40
Table 3: Schedule of Assessments – Maintenance Phase: Week 26 – Follow-Up................42


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4.
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
5-HT2
5-hydroxytryptamine receptor type 2
AE
Adverse event
AIDS
Acquired Immune Deficiency Syndrome
AIMS
Abnormal Involuntary Movement Scale
AUC
Area Under the Curve
BARS
Barnes Akathisia Rating Scale
BMI
Body mass index
Cmax
Concentration (maximum)
Cave
Concentration (average)
Cmin
Concentration (minimum)
Css
Concentration (steady state)
Ctrough
Concentration (trough)
CGI-I
Clinical Global Impression of Improvement
CGI-S
Clinical Global Impression of Severity
CRF
Case Report Form (may include electronic data capture systems or paper forms)
C-SSRS
Columbia-Suicide Severity Rating Scale
D2
Dopamine receptor type 2
dL
Deciliter
DSM-5
Diagnostic and Statistical Manual of Mental Disorders, 5th edition
ECG
Electrocardiogram
eCRF
Electronic case report form
EDC
Electronic data capture
EKG
Electrocardiogram
EPS
Extrapyramidal symptoms
FDA
Food and Drug Administration
FSH
Follicle-Stimulating Hormone


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GCP
Good Clinical Practice
HIV
Human immunodeficiency virus
ICF
Informed consent form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IFU
Instructions for User
IND
Investigational New Drug
IRB
Institutional Review Board
Mg
Milligram
Msec
millisecond
NF
National Formulation
NSAID
Non-steroidal anti-inflammatory
PANSS
Positive and Negative Syndrome Scale
PRN
As needed
PR
Pulse Rate
PSQI
Pittsburgh Sleep Quality Index
QTc
Q wave, T wave, corrected value
QTcB
Q wave, T wave, corrected Bazett
QTcF
Q wave, T wave, corrected Fridericia
SAE
Serious adverse events
SAS
Simpson-Angus Scale
SOC
System organ class


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5.
INTRODUCTION
5.1.
Background
Schizophrenia is a debilitating mental illness estimated to affect 1% of the United States (US)
population (Diagnostic, 2000). 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 (Schultz et al., 2007). The neurotransmitter dopamine is
thought to play an important role in the disease as drugs that increase dopamine
neurotransmission induce psychosis similar to the positive symptoms of schizophrenia; almost
all of the treatments for schizophrenia act to decrease dopamine neurotransmission (Freedman,
2003). Schizophrenia is characterized by positive and negative symptoms as well as disorganized
thought which is manifested in patient’s speech and behaviors (Diagnostic, 2000). Positive
symptoms include hallucinations, voices that converse with, or about the patient, and delusions.
Negative symptoms include lack of emotion, loss of will or drive, and social withdrawal.
Disorganized behaviors may lead to difficulty for patients to live normal lives, which includes
preparing meals, maintaining employment, or interacting with friends, family, and colleagues
(Diagnostic, 2000). The life-long nature of schizophrenia requires long-term treatment and
usually involves pharmacological, psychological, and psychosocial treatment strategies. The aim
of long-term treatment is to maintain symptom stability, adequately treat any increases in
symptoms, maintain or improve daily function and quality of life, and to prevent relapse
(Harrison, Goa, 2004). 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
prescribed medication, which in turn results in reduced treatment efficacy (Urquhart, 1994),
earlier relapses, higher psychiatric admissions (Valenstein et al., 2002), reduced quality of life,
increased suicide rates (Herings, Erkends, 2003), and a shortened life expectancy (Schultz et al.,
2007).
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 antipsychotics 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 improving patient outcomes.
Risperidone, the active pharmacological agent in the Risperidone Implant, was first marketed by
Janssen Research Foundation under the brand name Risperdal® (IND 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).
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 8 mg/day. Extensive experience with risperidone supports
favorable efficacy and tolerability with relatively little weight gain, less extrapyramidal side


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effects, and the absence of anticholinergic effects compared to older antipsychotic agents (Keks,
Culhane, 1999).
Risperidone Implant utilizes a novel drug delivery implant technology (polyurethane polymer
technology), that was 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 or 360 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 38 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, Braeburn 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.
Study EN3342-101 was the first in human study of Risperidone Implants and investigated the
pharmacokinetics of a single dose strength implant (375 mg total risperidone; estimated to
deliver 1.2-1.5 mg risperidone daily). Patients with schizophrenia participating in the study (n=6)
were required to receive a stable 4 mg daily dose of oral risperidone prior to implant placement.
The first patient’s implant was removed 1 month post-implantation and subsequent patient (n=5)
implants were left in place for 3 months.
Plasma concentration of risperidone and its active metabolite 9-OH-risperidone were measured
at various time points to determine the pharmacokinetic parameters of the active moiety
(risperidone +9-OH risperidone) responsible for risperidone’s clinical effects.
Safety was assessed as were pharmacodynamics measures including the Clinical Global
Impressions scale and the Positive and Negative Syndrome Scale (PANSS) for schizophrenia.


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F oll o wi n g t he 4 m g oral d ose, t he a vera ge ris peri d o ne Ctr o u g h c o nce ntrati o n was 1. 9 7 n g/ m L a n d
9 -O H ris peri d o n e was 1 6. 4 0 n g/ m L a n d t h e t otal acti ve m oiet y (ris peri d o ne + 9-O H ris p eri d o ne)
C ma x a n d C tr o u g h c o nce ntrati o ns were 5 4. 3 6 n g/ m L a n d 1 8. 3 7 n g/ m L, res pecti vel y. T ma x of t otal
acti ve m oiet y oc c urre d at 2. 5 h o urs f oll o wi n g t he oral ris peri d o ne d os e a n d t he A U C0 -2 4 h of t otal
acti ve m oiet y was 6 8 1. 5 2 n g/ m L ·hr. After i m pla nt ati o n, t he ris peri d o ne Ca ve at 1 m o nt h a n d 3
m o nt h were 6. 3 0 n g/ m L a n d 4. 4 2 n g/ m L, res pecti vel y ( wit h 9 -O H ris peri d o ne ha vi n g 1 2. 3 3
n g/ m L a n d 9. 4 n g/ m L, res pecti vel y). T he P K v al ues f or t he acti ve m oiet y d e m o nstrate d C a ve
val ues of 1 8. 6 2 n g/ m L a n d 1 4. 1 9 n g/ m L f or t he 1 m o nt h a n d 3 m o nt h i m pla nt peri o d,
res pecti vel y. T he a vera ge A U C3 -3 0 d of t otal acti ve m oiet y was 5 4 0. 1 2 n g/ m L ·hr a n d 1 2 6 2. 5 0
n g/ m L ·hr f or A U C 3 -9 0 d. F or all 6 s u bjects, t he E N 3 3 4 2 ( Ris peri d o ne Im pla nt) C a ve was 8 1. 3 % of
t he oral ( Ctr o u g h) le vel a n d 2 7. 5 % of t he Cma x val ues f oll o wi n g a dail y 4 m g oral d ose of
ris peri d o ne.
I n t his st u d y t here were n o seri o us a d vers e e v e nts ( S A Es), n or a n y disc o nti n uati o ns d ue t o a n
a d verse e ve nt ( A E ). Treat me nt-e mer ge nt a d vers e e ve nts ( T E A Es) were eit her mil d or m o derate
i n se verit y.
C GI -I, C GI-S, P A N S S sc ores were all little c ha n ge d fr o m ba seli ne a n d re mai ne d sta ble
t hr o u g h o ut t he 3-m o nt h i m pla ntati o n peri o d.
St u d y E N 3 3 4 2 -1 0 2 i n vesti gate d th e p har m ac o ki neti cs of 3 i m pla nt d ose stre ng t hs (4 8 0 m g. n = 1 0
patie n ts, 7 2 0 m g n = 1 0 patie n ts, a n d 9 6 0 m g n = 1 0 patie n ts) ov er a 6 m o nt h i m pla ntati o n peri o d .
3 0 t ot al patie nts wit h sc hizo p hre nia recei ve d i m pla nts.
Patie nts recei vi n g t h e 48 0 m g im pla nts were p rev i o usl y sta bilize d o n a 4 m g dail y or al d ose of
ris peri d o ne.
Patie nts recei vi n g t h e 72 0 m g im pla nts were p rev i o usl y sta bilize d o n a 6 m g dail y or al d ose of
ris peri d o ne.
Patie nts recei vi n g t h e 96 0 m g im pla nts were p rev i o usl y sta bilize d o n a n 8 m g dail y or al d ose of
ris peri d o ne.
Plas ma c o nce ntrati o ns of ris peri d o ne a n d its acti ve meta b olite 9-O H -Res piri d o ne were meas ure d
at vari o us ti me p oi nts t o deter mi ne t he p har mac o ki netic para met ers of t he acti ve m oiet y
(ris peri d o ne + 9-O H ris peri d o ne) res p o nsi ble f or ris peri d o ne’s cli nical effects.
Safet y was ass esse d as w ere p har mac o d y n a mics meas ures i ncl u di n g t he Cli nical Gl o bal
I m pressi o ns scale a n d t he P ositi ve a n d Ne gati ve S y n dr o me Scale ( P A N S S) f or sc hiz o p hre nia.
C o m paris o n of oral ris peri d o ne a n d t he Ris peri d o ne Im pl a nts de m o nstrate t hat w hile Cma x a n d
C a v g were hi g her, C tr o u g h f or oral ris peri d o n e was m ore c o m para ble t o Css f or E N 3 3 4 2 i m pla nts at
res pecti ve d os e le vels.
T he plas ma c o n ce ntrati o ns after 4 m g oral ris peri d o ne s h o we d Cma x of a p pr o xi matel y 1 8 n g/ m L
f or ris peri d o n e a n d a p pr o xi matel y 3 5 n g/ m L f or 9-O H ris peri d o ne a n d Ctr o u g h of a p pr o xi matel y 2
n g/ m L f or ris peri d o ne a n d 1 8 n g/ m L f or 9-O H ris peri d o ne. A d diti o nall y, t h e Ca ve f or t he 4 8 0 m g
ris peri d o ne I m pla nt w as a p pr o xi matel y 5 n g/ m L f or ris peri d o ne a n d a p pr oxi matel y 1 4 n g/ m L f or
9 -O H ris peri d o n e.


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Four subjects (13.3%) in the safety population experienced SAEs during the study; 1 subject
each (10.0%) in the 480 mg and 720 mg groups and 2 subjects (20.0%) in the 960 mg group. The
SAEs were chest pain and pulmonary embolism in the 480 mg group, Psychotic disorder in the
720 mg group, and Psychotic disorder and Schizophrenia in the 960 mg group.
Four subjects experienced adverse events leading to discontinuation. They were Sluggishness
and Psychotic disorder in the 960 mg group.
Injury, poisoning and procedural complications were the most common types of TEAEs overall,
followed by general disorders and administration site conditions, psychiatric disorders,
gastrointestinal disorders, and musculoskeletal and connective tissue disorders. The most
common TEAE overall was injection site pain. Injection site haemorrhage, incision site oedema,
anxiety and psychotic disorder were also relatively common. Implant site pain, device difficult to
use and weight increased were less common, while other TEAEs were each reported in only 1 or
2 subjects, overall.
There were no marked differences in patterns of TEAEs between the 3 treatment groups. Overall,
36.7% of subjects had TEAEs considered to be related to the study drug; and treatment-related
TEAEs were somewhat more common in the 2 higher dose groups. Anxiety was the most
common TEAE overall, followed by weight increased, sluggishness and device difficult to use.
Most subjects had TEAEs that were considered mild or moderate in severity; the incidence of
moderate TEAEs did not appear to be dose-related, although the incidence was slightly higher in
the EN3342 960 mg group.
Implantation-related TEAEs (implant site pain, device difficult to use, device breakage and
implant site pruritus) were relatively uncommon (<10% of subjects). Incision-related TEAEs
(incision site pain, incision site oedema and incision site complications) were somewhat more
common, within incidences ranging from 6.7% to 40.0% of subjects overall.
Generally, this safety profile was consistent with what has been observed either with oral
risperidone or the implantation procedure itself.
CGI-I and CGI-S scores showed little variation from baseline and remained stable over the 6
month implantation period. PANSS scores were slightly decreased from baseline and remained
stable throughout the 6 month implantation period.
5.2.
Study Rationale
The current trial is a pivotal Phase 3 trial designed to evaluate the safety and tolerability of the
Risperidone Implants (two, 360 mg or three, 300 mg 6-month implants each containing
risperidone) administered to adult subjects with a diagnosis of schizophrenia as defined by the
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5).  To enter the 48-


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week Maintenance Treatment Phase, subjects are required to be taking only one antipsychotic
medication: risperidone.  Subjects who are receiving oral risperidone (4 mg/day), long-acting
risperidone injection (37.5 mg/dose), Invega® (6 mg/day) or Invega® Sustenna® (156 mg dose)
at the time of Screening will be eligible to directly enter the 48-week Maintenance Treatment
Phase.  All other eligible subjects will enter the Conversion Phase with the goal of the stabilizing
subjects on 4 mg of oral risperidone.
Subjects who achieve stability during the 2 - 6 week Conversion Phase are eligible to enter the
Maintenance Phase and will receive Risperidone Implants (two or three 6-month implants each
containing risperidone).
The Risperidone Implant has the ability to improve patient compliance and can therefore
decrease the time to relapse and frequency of relapse by delivering a therapeutic dose of
risperidone. Two 360 mg Risperidone Implants (720 mg total dose) will deliver, over 24 weeks,
comparable Cmin plasma levels of oral risperidone 4 mg/day. Three 300 mg Risperidone
Implants (900 mg total dose) will deliver, over 24 weeks, comparable Cavg plasma levels of oral
risperidone 4 mg/day. Risperidone 4 mg/day is considered a therapeutic dose in the long term
treatment of schizophrenia.


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6.
STUDY OBJECTIVES
6.1.
Primary Objective
The primary objective of the study is to evaluate the 48-week safety and tolerability of
Risperidone Implants as maintenance therapy in subjects with schizophrenia. Safety and
tolerability will be measured by the incidence of psychotic symptoms exacerbation/impending
relapse, PANSS, CGI-I, CGI-S, adverse events, vital signs, clinical laboratory, physical exam and
ECG findings, AIMS, BARS and SAS rating scales and Investigator assessments.
6.2.
Overall Study Design and Plan
This is an open-label maintenance study of two consecutively administered 6 month Risperidone
Implants in the treatment of subjects with schizophrenia.
The study consists of a Screening period, a Conversion Phase, a 48-week Maintenance Treatment
Phase and a Follow-up Visit.
Screening Period (Up to Six Weeks):
Eligibility for the study will be determined during the Screening period (a maximum of 45 days).
The Screening period will include psychiatric and medical evaluations, screening tests, physical
examination/medical history and other assessments to establish whether the patient meets the
inclusion/exclusion criteria for the study. During the Screening period, subjects will be washed
out of all prohibited concomitant medications.
Subjects receiving an antipsychotic other than oral risperidone (4 mg/day), long acting
risperidone injection (37.5 mg/dose), Invega® (6 mg/day) or Invega® Sustenna® (156 mg dose)
will be required to enter the Conversion Phase.
To enter the 48-week Maintenance Treatment Phase, subjects are required to be taking only one
antipsychotic medication: risperidone. Subjects who are receiving oral risperidone (4 mg/day),
long-acting risperidone injection (37.5 mg/dose), Invega® (6 mg/day) or Invega® Sustenna®
(156 mg dose) at the time of Screening will be eligible to directly enter the 48-week Maintenance
Treatment Phase. All other eligible subjects will enter the Conversion Phase.
Conversion Phase (Two to Six Weeks):
During the weekly visits in the Conversion Phase, subjects will cross-titrate from other
antipsychotic(s) to 4 mg/day of oral risperidone therapy over 2 - 6 weeks. The objective of the
oral Conversion Phase is for all subjects to achieve an oral risperidone dose of 4 mg/day by no
later than the end of Week 6 of the Conversion Phase.
Maintenance Phase (48 Weeks):
At the beginning of the 48-week Maintenance Treatment Phase, all subjects will receive
Risperidone Implants (two, 360mg or three, 300mg 6-month implants each containing
risperidone). Oral dosing with 4 mg Risperidone will continue for one day after the subject has


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received the Risperidone Implants. During the Maintenance Phase, subjects will be evaluated per
schedule of events in the clinic and at any unscheduled visits for signs of exacerbation of
psychotic symptoms/impending relapse as defined in Section 9.3.1. Subjects (or their caregiver)
will be periodically contacted by phone between visits per the Investigator’s discretion to
determine whether or not the scheduled visit should be moved to an earlier time, based upon the
subject’s clinical need. The appearance of any of the signs of exacerbation of psychotic
symptoms/impending relapse criteria will result in withdrawal from the trial. Any subject
withdrawn for lack of efficacy in the Maintenance Phase per the Principal Investigator has to
meet at least one of the criteria for exacerbation of psychotic symptoms/impending relapse.


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6.3.
Discussion of Study Design
The study design is intended to evaluate the safety and tolerability for Risperidone Implants in
patients with chronic schizophrenia who would benefit from long-term treatment. Two or three
Risperidone Implants are inserted every 24 weeks and deliver comparable plasma exposure level
of oral risperidone 4 mg/day.
This is a multi-center, open-label study. Screening procedures will be completed during a period
of up to 45 days, after which, eligible subjects, aged 18-70 years, will enter into a Conversion
Phase or the Maintenance Treatment Phase. Subjects will receive Risperidone Implants twice for
24 weeks each. The second implant will occur in the opposite arm of the originally implanted
arm.  If the risperidone implants are expelled from the subjects’ arm, the subjects will have the
risperidone implants removed from the arm and new risperidone implants will be placed into the
opposite arm.  When the subjects return for their second implant, the subjects will have the
risperidone implants implanted into the originally implanted arm. Subjects will be seen per the
schedule of events for the duration of the study.


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7.
SELECTION OF STUDY POPULATION
Approximately 250 subjects will be screened and approximately 140 subjects will be implanted
during the Maintenance Phase. Enough subjects will be enrolled to complete 100 subjects and
subjects who enter the Maintenance Phase will receive two or three Risperidone Implants twice
during the 48 week trial period. The study is planned to recruit at approximately 15 sites in the
United States. See Section 11 for a discussion of sample size.
7.1.
Inclusion Criteria
Subjects must meet each one of the following inclusion criteria at Screening in order to be
eligible for participation in the study:
Inclusion Criteria during Screening Period:
1. Subject has provided written informed consent.
2. Male and female subjects 18 to 70 years of age, inclusive, at time of informed consent.
3. Subjects with a current diagnosis of schizophrenia as defined by DSM-5 criteria and a
history of the illness for at least 2 years prior to screening (as per subject, family,
healthcare provider, and/or by previous medical records).
4. Subject is assessed by the Investigator to be symptomatically stable with regard to his or
her psychiatric condition at screening and baseline.
5. Subject must be stable on their current antipsychotic medication for at least 30 days prior
to screening.
6. Subject has identified a caregiver or personal contact with whom the subject has
significant contact with at least once per week.
7. Subjects who have shown a previous response to antipsychotic treatment (other than
clozapine) in the past year, according to the Investigator’s opinion.
8. Subjects who are currently being treated with one or two antipsychotics other than
clozapine, and who, in the Investigator’s judgment, require chronic treatment with an
antipsychotic medication and would benefit from treatment with Risperidone Implants.
Note: Subjects taking oral risperidone (4 mg/day), long-acting risperidone
injection (37.5 mg/dose), Invega® (6 mg/day) or Invega® Sustenna® (156 mg
dose) at the time of Screening can be directly enrolled into the Maintenance Phase
of the study.
9. Subjects who meet the following criteria:
a.
Outpatient status
b. PANSS Total Score ≤ 80, and if PANSS score at baseline increases by ≥ 20%
change from screening, the subject cannot participate in the study.
c.
PANSS scores of ≤ 4 on all of the following items:
• Conceptual disorganization
• Suspiciousness
• Hallucinatory behavior
• Unusual thought content


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• H ostilit y
d.
C GI -S ≤ 4 ( m o deratel y ill)
e.
Lac k of cli nicall y si g nifi ca nt s uici dal i deati o n or be ha vi or i n I n vesti gat or ’s
j u d g me nt
1 0. S u bjects w h o are a ble t o u n dersta n d t he nat ure of t he trial a n d f oll o w pr ot oc ol
re q uire me nts, ha v e t he a bilit y t o rea d a n d u n d erst a n d t he writte n w or d, a n d w h o ca n be
relia bl y rate d o n assess m e nt scales.
1 1. S u bjects w h o ha ve c o m plete d a de q u ate was h o ut ( 5 half-li ves u nless ot her wise s pecifie d)
of pr o hi bite d c o nc o mita nt me dicati o ns, i ncl u di n g m o o d sta bilizers a n d str o n g i n d ucers or
i n hi bit ors of C Y P 2 D 6 acti vit y, pri or t o recei vi n g oral ris peri d o ne or i m pla nt Ris peri d o ne.
1 2. S u bject has c o m plete d w as h o ut of 4 2 da ys f or a n y fl u o x eti n e c o ntai ni n g c o m p o u n d.
1 3. Fe male p artici pa nts (if of c hil d beari n g p ote ntial a n d se x uall y acti ve) a n d male
partici pa nts (if se x uall y acti ve wit h a part ner of c hil d beari n g p ot e ntial) w h o a gree t o us e a
me dicall y acce pta ble a n d effecti ve birt h c o ntr ol m et h o d t hr o u g h o ut t he st u d y. Me dicall y
acce pta ble met h o ds of c o ntrace pti o n t hat ma y be use d b y t h e partici pa nt a n d/ or his/ her
part ner i ncl u d e a bsti ne nce, birt h c o ntr ol pills or patc hes, dia p hra g m wit h s p er mici de,
c o n d o m wit h s per mici de, i ntra uteri ne de vice (I U D), s ur gical sterilizati o n, or pr o gesti n
i njecti o n. All fe males of c hil d beari n g p ote ntial m ust ha ve a ne gati ve ser u m pre g n a nc y at
t he scree ni n g visit. Fe males of n o n -c hil d beari n g p ote ntial m ust meet t he f oll o wi n g:
a.
Ha ve m e dical d oc u me ntati o n of s ur gical sterilit y O R
b.
Be p ost -me n o p a usal defi ne d as 1 2 c o nsec uti ve m o nt hs of a me n orr h ea a n d
c o nfir me d b y a F ollicle -Sti m ulati n g H or m o ne ( F S H) test.
1 4. S u bject has a b o d y mass i n de x ( B MI) ≥1 8. 5 a n d ≤3 8. 0 k g/ m 2.
1 5. S u bject is assesse d b y t he I n vesti gat or t o be s y m pt o maticall y sta b le wit h re gar d t o pre-
e xisti n g me dical c o n diti o ns as e vi de nce d b y me dical hist or y, n o n -cli nicall y si g nifica nt
fi n di n gs o n p h ysical e x a mi nati o n, vital si g ns, cli nical la b orat or y e val uati o ns ( he mat ol o g y,
ser u m c he mistries, a n d uri nal ysis) or 1 2-lea d electr ocar di o gra m ( E C G). S u bjects ma y
c o nti n ue o n t heir c urre nt prescri be d m e dicati o n re gi me ns t o c o ntr ol pre -e xisti n g me dical
a n d ps yc hiatric c o n diti o ns ( ot her t ha n sc hiz o p hre nia) i ncl u di n g t he us e of prescri be d
P R N me dicati o ns.
I ncl usi o n Criteri a at e ntr y i nt o t he Ris peri d o ne I m pl a nt 4 8 -w ee k M ai nte n a nce Tre at me nt
P h ase
T he s u bject is t olerati n g oral ris peri d o ne 4 m g/ da y i n t he C o n versi o n P has e or the s u bject
directl y e nters t he 4 8 -wee k Mai nte na nce Treat me nt P hase beca us e t he y are recei vi n g at
Scree ni n g eit her oral ris p eri d o ne ( 4 m g/ da y), l o n g-acti n g ris peri d o n e i njecti o n ( 3 7. 5 m g/ d ose),
I n v e ga ® (6 m g/ da y) or I n ve ga ® S uste n na ® ( 1 5 6 m g d ose) a n d meets t he f oll o wi n g criteria:
a.
O ut patie nt stat us
b.
P A N S S Total Sc ore ≤ 8 0 (if P A N S S sc ore at baseli ne i ncreases b y ≥ 2 0 % c ha n ge
fr o m scree ni n g, t he s u bj ect ca n n ot partici pate i n t he st u d y)
c.
P A N S S sc ores of ≤ 4 o n all of t he f oll o wi n g ite ms:

C o nce pt ual dis or ga nizati o n

S us pici o us ness


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
Hall uci nat or y be h a vi or

U n us ual t h o u g h t c o nte nt

H ostilit y
d.
C GI -S ≤ 4 ( m o deratel y ill)
e.
Lac k of c li nicall y si g nifi ca nt s uici dal i deati o n or be ha vi or i n I n vesti gat or’s
j u d g me nt
7. 2.
E xcl usi o n Criteri a
1.
K n o w n h y p erse nsiti vit y or aller g y t o li d ocai ne or a n y l o cal a n est hetic a ge nt of t he a mi de
t y pe (l o cal a n est hetic use d d uri n g i m pla nt a n d e x pla nt pr oce d ures).
2.
K n o w n se nsiti vit y t o p ol y uret ha ne.
3.
Re p orts or re v eals a pres e nce of cli nicall y si g nifi ca nt s ki n dis or ders (s uc h as, b ut n ot
li mite d t o, s ki n ca ncer, ps oriasis, ecze ma, or at o pi c der matitis), a n d/ or e vi de nce of rece nt
s u n b ur n, scar tiss ue, tatt o o, o pe n s ore, b o d y pierci n g or bra n di n g at t he i nte n de d
i m pla ntati o n site t hat w o ul d i nterfere wit h t he i m pla ntati o n pr oce d ure or i nt erfere wit h
i m pla nt site assess me nts as deter mi ne d b y t he I n v esti gat or.
4.
Hist or y of a b n or mal scar f or mati o n or fa mil y hist or y of kel oi d f or mati o n.
5.
S u bjects wit h a c urre nt D S M -5 dia g n osis ot her t ha n sc hiz o p hre nia, i ncl u di n g
sc hiz oaffecti ve dis or d er, maj or de pressi ve dis or d er, bi p olar dis or der, d eliri u m, de me ntia,
a m nestic or ot her c o g n iti ve dis or ders. Als o, s u bjects wit h b or derli ne, para n oi d, histri o nic,
sc hiz ot y p al, sc hiz oi d, or a ntis ocial pers o nalit y dis or der are e x cl u de d .
6.
S u bjects e x perie nci n g ac ute de pressi ve s y m pt o ms wit hi n t he past 3 0 da ys, acc or di n g t o
t he In v esti gat or ’s o pi ni o n, t hat re q uire d treat me nt wit h a n a nti de pressa nt.
7.
S u bjects c o nsi dere d b y t he I n vesti gat or t o be at i m mi ne nt ris k of s uici de or i nj ur y t o self,
or s u bjects w h o wit hi n t he past 6 m o nt hs pri or t o Scree ni n g ha v e atte m pte d s uici de, or
w h o wit hi n t he past 3 m o nt h s pri or t o Scree ni n g h a ve ha d acti ve s uici de i d eati o n
( p ositi ve a ns wers t o ite m 4 or 5 o n t he C-S S R S).
8.
S u bjects wit h sc hiz o p hre nia t hat are c o nsi dere d resista nt/refract or y t o a nti ps yc h otic
treat me nt b y hist or y.
9.
S u bjects wit h a hist or y of fail ure t o cl oza pi ne treat me nt or res p o nse t o cl oza pi ne
treat me nt o nl y.
1 0. S u bjects wit h a d oc u me nte d hist or y of fail ure t o res p o n d t o a n a de q u ate d ose of
ris peri d o ne or p ali peri d o ne treat me nt i ncl u di n g l o n g acti n g i njecta ble f or m ulati o ns.
1 1. S u bjects wit h a si g nifica nt ris k of v i ole nt be ha vi or or a si g nifica nt ris k of c o m mitti n g
s uici de base d o n hist or y or In vesti gat or ’s j u d g me nt.
1 2. S u bjects w h o c urre ntl y meet D S M -5 criteri a f or s u bsta nce use dis or d er ( m o derate or
se vere); i ncl u di n g alc o h ol a n d be nz o diaze pi nes, b ut e x cl u di n g caffei ne, nic oti ne, a n d
marij ua na.
1 3. Fe males w h o are breast -fee di n g or will be breast fee di n g d uri n g t he c o urse of t he st u d y,
a n d/ or w h o ha v e a p ositi ve ser u m pre g na nc y test res ult pri or t o recei vi n g trial me dicati o n.
1 4. S u bjects wit h u nc o ntr olle d h y p ot h yr oi dis m or h y p ert h yr oi dis m ( u nless c o n diti o n has
bee n sta bilize d wit h me dicati o ns f or at least t he p ast 9 0 da ys).


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15. Subjects who have a clinically significant history or evidence of a medical condition that
would expose them to an undue risk of a significant AE or interfere with assessments of
safety or efficacy during the course of the trial, including but not limited to hepatic, renal,
respiratory, cardiovascular, endocrine, neurologic, hematologic, or immunologic disease
as determined by the clinical judgment of the Investigator.
16. Subjects with epilepsy or a history of seizures, except for a single childhood febrile
seizure, post traumatic, alcohol withdrawal, etc. A subject with a history of any seizure
activity will have their case discussed with the medical monitor prior to subject’s study
enrollment.
17. Subjects with a positive drug screen at screening for drugs of abuse without a
prescription, excluding marijuana, will be discussed with the medical monitor. If the
subject has a second positive drug screen during the Screening Phase, the Conversion
Phase or at Maintenance Baseline, the subject will be excluded from the trial.
18. The following laboratory test, vital sign, and ECG results are exclusionary:
a.
Platelets ≤75,000/mm3
b. Hemoglobin ≤ 9 g/dL
c.
Neutrophils, absolute ≤1000/mm3
d. Aspartate aminotransferase > 3x upper limit of normal
e.
Alanine aminotransferase > 3x upper limit of normal
f.
Creatinine ≥ 2 mg/dL
g. Diastolic blood pressure > 105 mmHg
h. QTc > 470 msec for females and QTc > 450 msec for males using the QTcF
(Fridericia) correction
NOTE: Consultation with the medical monitor may allow for retesting. In addition,
subjects are excluded if they have any other clinically significant abnormal laboratory
tests, vital sign results, or ECG findings that, in the Investigator’s judgment, are
medically significant or would impact the safety of the subject or the interpretation of the
trial results. Criteria are provided in the protocol to assist Investigators in their
assessments of results that are potentially medically significant, depending on the
subject’s medical history and clinical presentation. Abnormal results for laboratory
parameters or vital signs will be repeated to ensure reproducibility of the abnormality
before excluding a subject based on the criteria noted above. If a repeated ECG has a
triplicate corrected QTc < 470 msec for females on the correction that was initially > 470
msec, or if a repeated ECG has a triplicate corrected QTcF < 450 msec for males on the
correction that was initially > 450msec, the subject could be included in the trial.
19. Subject is HIV positive.
20. Active hepatitis.  Subjects with no viral load, no acute inflammation and no clinical
necessity for therapy will be allowed, at the discretion of the Investigator.
21. Subjects with a history of an allergic hypersensitivity to antipsychotic agents.
22. Subjects with a history of significant intolerance or who are refractory to antipsychotic
agents.
23. Subjects with a history of neuroleptic malignant syndrome.


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24. Subjects with clinically significant tardive dyskinesia at screening [any one AIMS item
(1-7) with a score >2].
25. Subjects likely to require prohibited concomitant therapy during the trial (see Section
8.6.1).
26. Subjects who require current use of agents that are strong inhibitors (e.g. quinidine) and
inducers (e.g. carbamazepine, phenytoin, rifampin, and phenobarbital) of cytochrome
P450 2D6.
27. Subjects who have received any investigational agent in a clinical trial within 30 days
prior to screening; for investigational drugs with an elimination half-life greater than 15
days, this time period will be extended to 60 days.
28. Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for
treatment of either a psychiatric or physical (e.g., infectious disease) illness, or who have
ongoing legal issues that could affect their ability to continue to participate in this trial.
29. Subjects who have been hospitalized, including hospitalization for psychosocial reasons,
for more than 30 days total in the last 60 days prior to entry into the Screening Phase.
30. Electroconvulsive therapy within 180 days prior to entry into the Screening Phase.
31. Any other finding that, in the Investigator’s opinion, would present undue risk to the
subject or may confound the interpretation of study results.
7.3.
Qualification Criteria
Each subject will receive a subject identification number after they have signed informed
consent. The number will consist of seven digits, where the first two digits are the country
number, the second set of two digits is the site number, and the third set of three digits is the
patient number. Every subject must sign informed consent prior to any study procedures being
conducted. All subjects who are consented will also have their data entered into the electronic
data capture (EDC) system. Subjects who are screen failures will only need to have informed
consent information, demographics, and reason for screen fail entered.
Subjects will enter either the Conversion or Maintenance Phase after all screening procedures
have been performed and eligibility to continue in the study is confirmed.  Eligibility will be
assessed again at the Baseline Visit for the Maintenance Phase (the end of the Conversion Phase
Visit can also serve as the Baseline Visit for the Maintenance Phase).  Once eligibility is
confirmed, all subjects will receive two or three Risperidone Implants on entry into the
Maintenance Phase.
7.4.
Removal of Subjects from Therapy or Assessment
A subject is free to withdraw his/her consent and discontinue participation in the study at any
time for any reason.
A subject should be considered for withdrawal from the study in the instance of occurrence of
psychotic symptom exacerbation/impending relapse in the 48-week Maintenance Treatment
Phase, defined as meeting any of the following 4 criteria:


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C O N FI D E N TI A L
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Pa ge 2 9 of 6 7
1) Cli nical G l o bal I m pressi o n of I m pr o ve me nt ( C GI-I) of ≥ 5 ( mi ni mall y w orse)
A N D

a n i ncrease o n a n y of t he f oll o wi n g i n di vi d ual P ositi ve a n d Ne gati ve S y n dr o me Scale ( P A N S S)
ite ms (c o nce pt ual dis or ga nizati o n, hall uci nat or y be ha vi or, s us pici o us ness, u n us ual t h o u g ht
c o nt e nt, h ostilit y) t o a sc ore > 4 wit h a n a bs ol ute i ncrease of ≥ 2 o n t hat s pecific ite m si nce
baseli ne O R

a n i ncrease o n a n y of t he f oll o wi n g i n di vi d ual P A N S S ite ms (c o nce pt ual dis or ga nizati o n,
hall uci nat or y be ha vi or, s us pici o us ness, u n us ual t h o u g ht c o nte nt, h ostilit y) t o a sc ore > 4 a n d a n
a bs ol ute i ncrease of ≥ 4 o n t he c o m bi ne d fi ve P A N S S ite ms (c o nce pt ual dis or ga nizati o n,
hall uci nat or y be ha vi or, s us pici o us ness, u n us ual t h o u g ht c o nte nt, h ostilit y) si nce baseli ne O R
2 ) H os pitalizati o n d ue t o w orse ni n g of ps yc h otic s y m pt o ms (i ncl u di n g partial h os pitalizati o n
pr o gra ms), b ut e xcl u di n g h os pitalizati o n f o r ps yc h os ocial reas o ns O R
3) Cli nicall y si g nifica nt s uici dal i deati o n or be ha vi or i n I n vesti gat or ’s j u d g me nt O R
4) Vi ole nt be ha vi or res ulti n g i n cli nicall y rele va nt self -i nj ur y, i nj ur y t o a n ot her pers o n, or pr o pert y
da ma ge
N O T E: If t he i n vesti gat or belie ves t his is n ot a tr ue e x acer b ati o n of sc hiz o p hre nia , u p o n
c o ns ultati o n wit h t he me dical m o nit or t he s u bject ma y b e c o nti n ue d a n d br o u g ht bac k f or a n
a d diti o nal assess me nt of sta bilit y wit hi n 7 da ys. If t he af ore me nti o ne d criteria persist after 7
da ys , t he s u bj ect s h o ul d be wit h dra w n. A d diti o nall y, a n y s u bject wit h dra w n f or lac k of efficac y
i n t he Mai nte na nce P has e per t he Pri nci p al I n vesti gat or h as t o meet at least o ne of t he criteria f or
e x acer bati o n of ps yc h oti c s y m pt o ms/i m pe n di n g rela pse.
A s u bject ma y als o be disc o nti n ue d fr o m t he st u d y, at t he discreti o n of t he
In vesti gat or a n d/ or
s p o ns or, f or a n y of t h e f oll o wi n g reas o ns:

E ntere d t he st u d y i n vi olati o n of t he pr ot oc ol;

Safet y reas o ns, i ncl u di n g a d verse e ve nt(s) ( A Es);

Use of u nacce pt a ble c o n c o mita nt me dicati o n(s);

N o n -c o m plia nce or maj or pr ot oc ol vi olati o n;

It is n ot c o nsi dere d i n t he best i nterest of t he s u bject t o c o nti n ue;

Pre g n a nc y; ( N O T E: All p ositi ve uri ne pre g na n c y test res ults are c o nfir me d b y a 2 n d uri ne
pre g na nc y t est. Treate d s u bjects wit h 2 p ositi ve uri ne tests will disc o nti n ue treat me nt, be
wit h dra w n fr o m t he tri al, a n d a n i m me diatel y re p orta ble e ve nt f or m will be c o m plete d).

M ulti ple p ositi ve uri ne dr u g s cree n or breat h alc o h ol tests.  I n vesti gat or will use cli nical
j u d g me nt a n d s h o ul d dis c uss wit h me dical m o nit or. O ne p ositi ve dr u g s cree n f or dr u gs of
a b use wit h o ut a pres cri pti o n, e x cl u di n g marij ua na, d uri n g t he st u d y will be disc usse d
wit h t he me dical m o nit or. If t he s u bject has a sec o n d p ositi ve dr u g scree n, t he s u bject wil l
be e x cl u de d fr o m t he trial ;

A d mi nistrati ve reas o ns (e. g., t er mi nati o n of e nr oll me nt or st u d y).
T he In vesti gat or m ust mai ntai n a rec or d of all s u bjects w h o disc o nti n ue fr o m t he st u d y pri or t o
c o m pleti o n; t he reas o n(s) f or st u d y disc o nti n uati o n will be d o c u me nte d. I n t he e ve nt t hat a
s u bject c h o oses t o wit h dra w fr o m t he st u d y, t h e In vesti gat or s h o ul d ma k e a reas o na bl e atte m pt t o


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Version: Final 4.0, 15JUL2016
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obtain and record the reason(s) for withdrawal, if possible, although the subject is not obligated
to provide such a reason.
In the event that a subject is discontinued while at the clinical site, the early termination
procedures shown in the Schedule of Assessments (Table 3) should be performed prior to
discharge from the study site. For any case of early discontinuation (whether or not the subject is
at the clinical site), the Investigator should ask the subject to return for the Follow-up visit
procedures, provided that the subject has not withdrawn consent for those procedures. If a
subject refuses to complete early termination procedures and/or the Follow-up visit, this
information will be recorded. The implants should be removed whenever possible from all
subjects who discontinue in the study
7.5.
Study Restrictions
In addition to the inclusion/exclusion criteria described in Section 7, the subject must agree to
abide by the following study restrictions:

Fasting the evening prior to blood tests

No recreational drug use

Limiting alcohol use

No blood donations


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8.
TREATMENTS
8.1.
Treatment Administration
Following confirmation of a signed informed consent document, eligibility and entry into the
Conversion Phase or Maintenance Phase:

Conversion Phase - Subjects will be converted from their current antipsychotic to oral
risperidone 4 mg/day over a minimum of 2 and a maximum of 6 weeks.

Maintenance Phase – approximately 25% of the subjects will receive 2-360 mg and
approximately 75% 3-300 mg Risperidone Implants at Baseline (Implant Day) and week
24.
Subjects meeting the criteria to enter the Maintenance Phase will receive Risperidone Implants
twice for up to 48 weeks of treatment total.
8.1.1.
Implant Insertion and Removal Procedures
All Risperidone implants will be implanted and removed by trained clinicians. The Sponsor will
institute the Risperidone Implant Clinical and Procedure Training and Evaluation program to
ensure that clinicians who perform the implant insertion and removal procedures meet
competency standards. The Sponsor will also provide an Implant Insertion/Removal Instruction
for Use slide deck and live training on the instructions for aseptic subdermal insertion and
removal of Risperidone implants. Following each implantation the physician will complete a
User Input Survey to assess the performance of the investigational Insertion Tool.
Prior to Maintenance Phase, Baseline (Implant Day), subjects will take their oral antipsychotic
that day as prescribed and for one day after. In addition, subjects should discontinue any non-
steroidal anti-inflammatory (NSAID) or aspirin-containing medications one week prior to and
bathe the day of insertion and removal of implants.
Details on Insertion/Removal procedures and training will be provided in the Instructions for
User (IFU) and live implant training. Subjects should be monitored closely for AEs and vital
signs for at least 30 minutes following insertion by medically qualified study staff.
Subjects will have their implants removed at the end of the Maintenance Phase. If the subject
withdraws early or completes the study the implants will be removed during the End of
Treatment Visit or as soon as explantation can be scheduled. Should the subject choose to leave
the study early and has not had their implants removed due to inability to contact the subject and
schedule an appointment, or for whatever reason, the sponsor may utilize a third party to locate
the subject to ensure the implants can be removed. Implant removal procedures are described in
detail in the IFU. If, upon removal, the Implanting Clinician has difficulty locating the implants,
ultrasound may be used to facilitate their localization.


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Version: Final 4.0, 15JUL2016
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8.2.
Identity of Investigational Product(s)
The Risperidone Implant is a sterile subcutaneous implant composed of 6, 60 mg USP grade
risperidone pellets (360 mg implant) or 5, 60 mg USP grade risperidone pellets (300 mg
implant), Tecoflex EG-80A, an aliphatic, polyether-based polyurethane membrane that controls
the rate of risperidone release. The dimensions of the implant are approximately 38 mm long
with an outside diameter of approximately 4 mm.  The release rate of two 360 mg Risperidone
Implants (720 mg total dose) is expected to result in comparable Cmin steady-state trough levels
from a 4 mg/day oral dose of risperidone. The release rate of three 300 mg Risperidone Implants
(900 mg total dose) is expected to result in comparable Cavg steady-state trough levels from a 4
mg/day oral dose of risperidone.
Each implant is individually packaged in a foil-lined, heat-sealed pouch. Pouched implants are
labeled and packaged into an individual Subject Kit (Box).  All Implant Kits used in the
Maintenance Phase will contain 2, 360 mg or 3, 300 mg Risperidone Implants. Commercially
available oral risperidone 2 mg and 4 mg will be provided to subjects in the Conversion Phase.
All containers/packages /boxes of study drug will be clearly labeled with study-specific
information meeting all the applicable regulatory/institutional requirements.
8.2.1.
Handling, Storage, and Accountability
All study drugs will be transported, received, stored, and handled strictly in accordance with the
container or product label, the instructions provided to the research site, and applicable
regulations.
All Subject Kits should be stored at room temperature (15–25°C / 59–77°F) in a secured area and
in accordance with applicable laws, regulations and institutional requirements.
Detailed drug accountability records must be maintained, including the dates shipments are
received, the quantity of material received, the dates dispensed, the running inventory, and the
unused quantities returned to the Sponsor’s drug supply vendor at the end of the trial. All unused
supplies will be checked against the drug accountability records during the study and/or at the
end of the study. Subjects will be instructed to return all unused study drugs to the clinical site
(oral risperidone; Conversion Phase).
Following implant removal, appropriate disposal of all implants is outlined in the Study IFU.
8.2.2.
Dispensing and Administration
The study drug will be dispensed or administered according to applicable standard operating
procedures. Details regarding the preparation and administration of the study drugs will be
outlined in a study-specific procedure. Only eligible subjects participating in the study will
receive the study drug. Only authorized research site staff may supply or administer the study
drugs. Once dispensed, study drug may not be relabeled or reassigned for use by other subjects.


Clinical Trial Protocol
Braeburn Pharmaceuticals
BB-RSP-301
CONFIDENTIAL
Version: Final 4.0, 15JUL2016
Page 33 of 67
8.3.
Selection of Doses
Approximately 25% of the total number of subjects enrolled will have two, 360 mg Risperidone
Implants inserted. The approximate remaining 75% of the total number of subjects enrolled will
have three, 300 mg Risperidone Implants inserted. Two 360 mg Risperidone Implants (720 mg
total dose) will deliver, over 24 weeks, comparable Cmin plasma levels of oral risperidone 4
mg/day.  Three 300 mg Risperidone Implants (900 mg total dose) will deliver, over 24 weeks,
comparable Cavg plasma levels of oral risperidone 4 mg/day. Risperidone 4 mg/day is considered
a therapeutic dose in the long-term treatment of schizophrenia.  Based on the CATIE study the
average daily dose of risperidone is 3.9 mg per day (Lieberman et al, 2005; Lehman, et al.,
2004).  The study was initiated by implanting patients with two, 360 mg (720 mg total dose)
Risperidone Implants with the understanding that the 720 mg Risperidone Implants would
deliver, over 24 weeks, comparable Cmin plasma levels of oral risperidone 4mg/day.  After
thorough PK modeling, it was later determined, after the study was initiated, that three, 300 mg
(900 mg total dose), over 24 weeks, would deliver approximately Cavg plasma levels of oral
risperidone 4 mg/day.  The target dose of the Risperidone Implants is to deliver approximate Cavg
plasma levels of oral risperidone 4 mg/day and that dose is three, 300 mg (900 mg total dose).
Oral risperidone 1 mg to 4 mg/day will be administered at the investigator’s discretion in the
Conversion Phase.
8.4.
Selection and Timing of Dose
During the Conversion Phase subjects will be tapered off their current antipsychotic and titrated
to oral Risperidone 4 mg/day administered in the morning without regard to meals.  On Baseline
of the Maintenance Phase each subject will have two or three Risperidone Implants inserted in
the upper portion of one arm. Baseline procedures and insertion of the Risperidone Implants
may take place over 24 hours if necessary, but it is preferable that all Baseline procedures occur
on the same day as insertion of the Risperidone Implants. On week 24/Day 168 (±4 days) of the
Maintenance Phase, the currently inserted Risperidone Implants will be removed and subjects
will receive two or three new Risperidone Implants in the opposite arm depending on what dose
they received originally.
8.5.
Blinding
The entire study is open-label so subjects, physicians, and sponsors will know what product the
patients are administered during the course of the study.
8.6.
Prior and Concomitant Therapy
All non-study medications, including prescription, over-the-counter, or herbal therapies, used by
the subject will be documented for the 45 days prior to Screening and throughout the study. The
Investigator will determine if the prior/concomitant medication(s) affect the patient’s/subject’s
eligibility to participate or continue to participate in the study. Any medication the patient takes
between Screening and the end of the study, other than the study drug, is considered to be a


Cli nical Trial Pr ot oc ol
Brae b ur n P har mace uticals
B B -R S P -3 0 1
C O N FI D E N TI A L
Versi o n: Fi nal 4 . 0, 1 5J U L 2 0 1 6
Pa ge 3 4 of 6 7
c o nc o mita nt me dicati o n. All c o nc o mita nt me dicati o ns m ust be rec or d e d i n t he electr o ni c cas e
re p ort f or m (e C R F). A n y c ha n ges i n t he d osa ge or re gi me n of a c o nc o mita nt me dicati o n m ust be
rec or d e d i n t he e C R F.
8. 6. 1.
Per mitte d , Pr o hi bite d, a n d Restricte d c o nc o mit a nt me dic ati o ns
Me dicati o ns Pr o hi bite d D uri n g t h e Trial

P ote nt C yt oc hr o me P 4 5 0 2 D 6 i n hi bit ors (fl u o x eti ne, par o x eti ne, b u pr o pi o n, q ui ni di ne,
ci nacal cet, rit o na vir) a n d i n d ucers (e. g. car ba maze pi ne, p he n yt oi n, rifa m pi n, a n d
p he n o bar bital) are pr o hi bite d d uri n g a n y P has e of t he st u d y. ( N O T E: A n y fl u o x eti ne
c o ntai ni n g c o m p o u n d m ust be was he d o ut f or 4 2 d a ys)

T he use of i n vesti gati o nal dr u gs will be restricte d f or at least 3 0 da ys ( or 5 -ti mes t he half-
life of t he dr u g, if k n o w n a n d l o n ger) pri or t o first st u d y dr u g a d mi nistrati o n a n d
t hr o u g h o ut t he st u d y. N O T E: f or i n vesti gati o nal dr u gs wit h a n eli mi nati o n half-life
greater t ha n 1 5 da ys, t his ti me peri o d will be e xte n de d t o 6 0 da ys

M o o d sta bilizers will be ta pere d a n d disc o nti n ue d i n t he Scree ni n g Peri o d at least 7 da ys
pri or t o eit her t he C o n versi o n or Mai nte na nce P hase.  M o o d sta bilizers are n ot per mitte d
d uri n g a n y of t he P hases of t he st u d y.

N utriti o nal s u p ple me nts a n d n o n prescri pti o n her b al pre parati o ns wit h ce ntral ner v o us
s yste m effects (e .g ., St. J o h n’s W ort, o me ga -3 fatt y aci ds, ka va e xtracts, ga m ma -
a mi n o b ut yric s h o ul d be t a pere d a n d disc o nti n ue d at least 1 4 da ys pri or t o t he e n d of t he
Scree ni n g Peri o d a n d are n ot per mitte d i n a n y of t he P hases of t he st u d y.
Me dicati o ns Restricte d D uri n g t he Tri al

Be nz o diaze pi nes are all o we d d uri n g all P hases of t he st u d y u p t o a m a xi m u m of 6
m g/ da y of l oraze pa m or e q ui vale nt.

A ntic h oli ner gi cs ≤ 4 m g/ da y b e nztr o pi ne or e q ui v ale nt f or E P S are p er mitte d d uri n g all
P hases of t he st u d y.

Pr o pra n ol ol (f or a kat hisia or tre m or) u p t o a ma xi m u m of 6 0 m g/ da y is per mitte d d uri n g
all P hases of t he st u d y.

S u bjects s h o ul d disc o nti n ue a n y n o n -ster oi dal a nti-i nfla m mat or y ( N S AI D) or as piri n-
c o ntai ni n g me di cati o ns o ne wee k pri or t o i nserti o n a n d re m o val of Ris peri d o ne i m pla nts.

A nt i ps yc h otics are all o w e d d uri n g t he Scree ni n g Peri o d b ut are ta p ere d off a n d c o n vert e d
t o oral ris peri d o ne d uri n g t he C o n versi o n P hase.  N o a nti ps yc h otics, ot her t ha n t he
Ris peri d o ne I m pl a nts are per mitte d d uri n g t h e Mai nte na nce P hase , wit h t he f oll o wi n g
e x ce pti o n:
I n t he i nsta n ce t hat t he i n vesti gat or b elie ves t hat t he s u bject is n ot e x perie nci n g a tr ue
e x acer bati o n of sc hiz o p hre nia (see Secti o n 7. 4 a b o ve), a s u p ple me nt al a nti ps yc h otic
ma y b e use d f or a ma xi m u m of 7 da ys u p o n c o ns ultati o n wit h t he me dical
m o nit or.
Me dicati o ns Per mitte d D uri n g t he Trial

N o n -be nz o diaze pi ne slee p ai ds are p er mitte d d uri n g all P hases of t he st u d y


Cli nical Trial Pr ot oc ol
Brae b ur n P har mace uticals
B B -R S P -3 0 1
C O N FI D E N TI A L
Versi o n: Fi nal 4 . 0, 1 5J U L 2 0 1 6
Pa ge 3 5 of 6 7

N o n -se dati n g a nti hista mi nes (e. g., l orat a di ne, cetirizi ne ) are t he treat me nt of c h oice f or
aller gies.
O n a cas e -b y -case b asis, t he In v esti gat or is per mitte d t o all o w t he use of s o me c o nc o mita nt
me dicati o ns, f or e x a m ple, t o treat a n A E, as l o n g as t he
In v esti gat or deter mi nes t hat t he
me dicati o n will n ot affect t he patie nt ’s/s u bject’s s afet y or st u d y i nte grit y (e. g., t o pical
me dicati o ns) . W he ne ver
p ossi ble, t he In v esti gat or s h o ul d o btai n a p pr o val fr o m t he s p o ns or ’s
me dical m o nit or pri or t o a d mi nisteri n g t he me dicati o n.
8. 7.
Tre at me nt C o m pli a nce
S u bjects will recei ve i m pla nts t wice d uri n g t he st u d y.  S u bjects will recei v e 2 -3 6 0 m g or 3 -3 0 0
m g Ris peri d o ne I m pla nts at t he Bas eli ne of t he M ai nte na nce P hase a n d will recei ve 2
or 3
Ris peri d o ne I m pl a nts aft er a p pr o xi matel y 1 6 8 d a ys ( +/- 4 da ys) i n t he M ai nte na nce P has e. T he
i m pla nts are i nserte d i nt o t he s u bject’s ar m, alter n ati n g ar ms, b y a trai ne d st u d y staff me m ber.
D uri n g t h e C o n versi o n P hase s u bjects will be dis p e nse d a s ufficie nt q ua ntit y of oral ris peri d o ne
t o last u ntil t he ne xt sc he d ule d st u d y visit ( +/- 3 d a ys) . C o m plia nc e wit h oral st u d y me dicati o n
will be m o nit ore d b y ta bl et c o u nts. S u bj ects w h o are n o nc o m plia nt wit h oral st u d y me dicati o n, i n
t he In v esti gat or ’s j u d g me nt, are t o be c o u ns ele d o n t he i m p orta nce of a d heri n g t o t he dail y
a d mi nistrati o n sc he d ule.


Clinical Trial Protocol
Braeburn Pharmaceuticals
BB-RSP-301
CONFIDENTIAL
Version: Final 4.0, 15JUL2016
Page 36 of 67
9.
STUDY PROCEDURES AND ASSESSMENTS
All study assessments will be performed at the visits and time points outlined in the Schedule of
Assessments (Table 1, Table 2, Table 3); the following sections outline the details and procedures
associated with the assessments. Other logistical considerations (e.g., sequence of events,
assessment windows) will be outlined in study-specific procedures.


Cli nical Trial Pr ot oc ol
Brae b ur n P har mace uticals
B B -R S P -3 0 1
C O N FI D E N TI A L
Versi o n: Fi nal 4 . 0, 1 5J U L 2 0 1 6
Pa ge 3 7 of 6 7
Ta ble 1 : Sc he d ule of Assess me nts – Scree ni n g a n d C o n versi o n P h ase
Pr oce d ure
Scree ni n g
(-4 5 d a ys) a
C o n versi o n P h ase b, c (3 d a ys)
C o n versi o n
D a y 1 o
Wee k 1
( Da y 7)
Wee k 2
( Da y 1 4)
Wee k 3
o
( Da y 2 1)
Wee k
4 o
( Da y 2 8)
Wee k
5 o
( Da y 3 5)
Wee k
6 o
( D a y 4 2) /
B aseli ne
M ai nte n a nce
P h ase
Writte n i nf or me d c o nse nt
d
X
I ncl usi o n/ E xcl usi o n Criteria
X
X
Me dical
/ Ps yc hiatric hist or y
X
A nti ps yc h otic me dicati o n hist or y e
X
Assess me nt of s u bsta nce de pe n de nce
X
P h ysical e xa mi nati o n f
X
X
Hei g ht
X
W ei g ht, B MI
g
X
X
X
Vital si g ns h
X
X
X
X
X
X
X
X
He mat ol o g y a n d c he mistr y i
X
X
X
Uri nal ysis
X
X
X
HI V, He patitis B/ C
X
Pre g na nc y test j
X
X
X
Uri ne dr u g scree n k
X
X
X
X
X
Breat h alc o h ol test k
X
X
X
X
X
1 2 -Lea d E C G l
X
C o nc o mita nt me dicati o ns
X
X
X
X
X
X
X
X
A d verse E ve nts m
X
X
X
X
X
X
X
X
C -S S R S ( B aseli ne) n
X
C -S S R S ( Si nce Last Visit) n
X
X
X
X
X
X
X


Cli nical Trial Pr ot oc ol
Brae b ur n P har mace uticals
B B -R S P -3 0 1
C O N FI D E N TI A L
Versi o n: Fi nal 4 . 0, 1 5J U L 2 0 1 6
Pa ge 3 8 of 6 7
Pr oce d ure
Scree ni n g
(-4 5 d a ys) a
C o n versi o n P h ase b, c (3 d a ys)
C o n versi o n
D a y 1 o
Wee k 1
( Da y 7)
Wee k 2
( Da y 1 4)
Wee k 3
o
( Da y 2 1)
Wee k
4 o
( Da y 2 8)
Wee k
5 o
( Da y 3 5)
Wee k
6 o
( D a y 4 2) /
B aseli ne
M ai nte n a nce
P h ase
4 m g oral ris peri d o ne a d mi nistrati o n
X
X
X
X
X
X
X
Pitts b ur g h Slee p Q ualit y I n de x
( P S QI)
X
X
S A S
X
X
X
X
X
B ar nes A kat h isia Scale
X
X
X
X
X
AI M S
X
X
X
X
X
P A N S S p
X
X
X
X
X
C GI -S
X
X
X
X
X
C GI -I
X q
a Scree ni n g pr oce d ures c o ul d be p erf or me d a n y ti me bet wee n Da y −4 5 a n d Da y 1 of t he C o n versi o n P hase or B aseli ne of t he Mai nte na nce P hase.
b S u bj ects w h o are recei vi n g m o n ot hera p y wit h pr ot oc ol acce pte d d oses of oral ris peri d o ne, l o n g acti n g ris peri d o ne i nj ecti o n, I n ve ga ® or I n ve ga ® S uste n na ® as
t heir c urre nt a nti ps yc h otic treat me nt at scree ni n g ca n pr ocee d directl y t o baseli ne of t he Mai nte na nce
P hase after scree ni n g.
c T he last visit i n t he C o n versi o n P hase will ser ve as t he Bas eli ne visit f or t he Mai nte na n ce P hase.
d I nf or me d c o nse nt will be o btai ne d pri or t o a n y trial -relate d pr oce d ures.
e All a nti ps yc h otic me dicati o ns use d wit hi n 4 5 da ys of scree ni n g a n d a n y a p pr o ve d l o n g -a cti n g a nti ps yc h otic de p ot f or m ulati o ns gi ve n wit hi n t he o ne c ycle pl us
1 4 da ys pri o r t o scree ni n g (e.g ., 2-wee k c ycle pl us a n a d diti o nal 1 4 da ys f or ris peri d o ne l o n g-acti n g i nj ecti o n) or i n vesti gati o nal l o n g -acti n g a nti ps yc h otics
gi ve n wit hi n 6 0 da ys of scree ni n g w ill be rec or de d. I n a d diti o n, t he In vesti gat or will rec or d details of t he cr oss -titrati o n t hat will occ ur d uri n g t he C o n versi o n
P hase t o bri n g a b o ut a sta ble tra nsiti o n fr o m pre vi o us a nti ps yc h otic treat me nt(s) t o oral ris peri d o ne.
f A f ull p h ysical e xa mi nati o n will be perf or me d wit h t he e xce pti o n of t he ge nit o uri nar y ( G U) b o d y s yste m.
g B MI will be calc ulate d i n k g/ m 2 fr o m t he scree ni n g hei g ht a n d baseli ne wei g ht usi n g o ne of t he f oll o wi n g f or m ulae, as a p pr o priate: W ei g ht ( k g) ÷ [ H ei g ht
( m)]2 or W ei g ht (l b) ÷ [ Hei g ht (i n)]2 x 7 0 3.
h Vital si g n meas ure me nts i ncl u des b o d y te m perat ure, s yst oli c a n d diast olic bl o o d press ure, res pirat or y rate a n d p ulse rate. Bl o o d press ure c uff s h o ul d b e use d o n
t he o p p osite ar m of t he i m pla nt f or at least 2 wee ks after i m pla nt da y.
iS u bj ects s h o ul d fast f or a mi ni m u m of 1 0 h o urs pri or t o bl o o d dra ws f or scree ni n g la b orat or y assess me nts. If n o fasti n g bl o o d sa m ples are o btai ne d i nitiall y f or
deter mi ni n g eli gi bilit y f or t he trial, a fasti n g bl o o d sa m ple s h o ul d be dra w n pri or t o e nr oll me nt.
j A ser u m pre g na nc y test f or β h C G is perf or me d at scree ni n g f or all w o me n of c hil d beari n g p ote ntial. S u bj ects wit h a p ositi ve res ult are e xcl u de d fr o m t he trial.
Uri ne pre g na nc y tests c o ul d be perf or me d at a n y p oi nt d uri n g t he trial if pre g na nc y is s us pecte d. All p ositi ve uri ne pre g na nc y test res ults are c o nfir me d b y a 2 n d


Clinical Trial Protocol
Braeburn Pharmaceuticals
BB-RSP-301
CONFIDENTIAL
Version: Final 4.0, 15JUL2016
Page 39 of 67
urine pregnancy test. Treated subjects with 2 positive urine tests will discontinue treatment, be withdrawn from the trial, and an immediately reportable event
form will be completed.
k A urine drug screen and a breath alcohol test are required at the designated times, but either or both can be conducted at any time during the Phase at the
discretion of the Investigator.
l ECG recordings will be obtained and evaluated at the investigational site to determine the subject’s eligibility and to monitor safety.
m Adverse events will be recorded starting at the screening visit.
n The C-SSRS (Baseline Version) will be completed for all subjects at the baseline visit; the C-SSRS (Since Last Visit Version) will be completed for all subjects
at all subsequent visits as scheduled.
o These weekly visits are not required if subject is stable on oral risperidone and meets eligibility requirements for the Maintenance Phase.
p PANSS is required at the designated times, but can be conducted at any time during the Phase at the discretion of the Investigator.
q Reference point for CGI-I is the baseline of the Maintenance Phase (i.e., last visit of the Conversion Phase or Screening Phase).


Cli nical Trial Pr ot oc ol
Brae b ur n P har mace uticals
B B -R S P -3 0 1
C O N FI D E N TI A L
Versi o n: Fi nal 4 . 0, 1 5J U L 2 0 1 6
Pa ge 4 0 of 6 7
Ta ble 2 : Sc he d ule of Assess me nts – Mai nte na nce P hase: Bas eli ne
– Wee k 2 4
Pr oce d ure
M ai nte n a nce P h ase ( Vi sits 4 d a ys) k
B aseli n
e a
W k
1
W k
2
W k
3
W k
4
W k
6
W k
8
W k
1 0
W k
1 2
W k
1 6
W k
2 0
W k
2 2
W k
2 4
I ncl usi o n/ E xcl usi o n
Criteria
X
P h o ne c o ntact b
X
X
X
Assess criteria f or
e xacer bati o n of
ps yc h otic
s y m pt o ms/i m pe n di n g
rela pse
X
X
X
X
X
X
X
P h ysical e xa mi nati o n c
X
X
W ei g ht, B MI
d
X
X
X
Vital si g ns e
X
X
X
X
X
X
X
X
He mat ol o g y a n d
ser u m c he mistr yf
X
X
X
Uri nal ysis
X
X
X
Uri ne pre g na nc y test g
X
X
X
X
X
X
X
Uri ne dr u g scree nh
X
X
X
Breat h alc o h ol test h
X
X
X
1 2 -Lea d E C G
C o nc o mita nt
me dicati o ns
X
X
X
X
X
X
X
X
X
X
A d verse E ve nts
X
X
X
X
X
X
X
X
X
X
I m pla nt pal pati o n a n d
site e xa mi nati o n
X
X
X
X
X
X
X
X
X
C -S S R S ( Si nce Last
Visit)
X
X
X
X
X
X
X
X


Cli nical Trial Pr ot oc ol
Brae b ur n P har mace uticals
B B -R S P -3 0 1
C O N FI D E N TI A L
Versi o n: Fi nal 4 . 0, 1 5J U L 2 0 1 6
Pa ge 4 1 of 6 7
Pr oce d ure
M ai nte n a nce P h ase ( Vi sits 4 d a ys) k
B aseli n
e a
W k
1
W k
2
W k
3
W k
4
W k
6
W k
8
W k
1 0
W k
1 2
W k
1 6
W k
2 0
W k
2 2
W k
2 4
4 m g oral ris peri d o ne
a d mi nistrati o n
X L
St u d y dr u g
i m pla ntati o n /
e x pla ntati o n
X m
X m
S A S
X
X
X
X
X
X
X
B ar nes A kat h isia Scale
X
X
X
X
X
X
X
AI M S
X
X
X
X
X
X
X
P A N S S i
X
X
X
C GI -S
X
X
X
X
X
X
X
X
C GI -Ij
X
X
X
X
X
X
X
X
Pitts b ur g h Slee p
Q ualit y I n de x ( P S QI)
X
X
X
X
X
X
X
a T he e n d of t he C o n versi o n P hase visit will ser ve as t he Baseli ne f or t he Mai nte na nce P hase; t heref ore, all e val uati o ns n ote d f or “E n d of t he C o n versi o n P hase or
B aseli ne Mai nte na nce P hase ” will be perf or me d o n t he da y of a d mi nistrati o n pri or t o i nserti o n o f t he Ris peri d o ne I m pla nts. T he baseli ne pr oce d ures pri or to
i m pla nti n g ca n occ ur o ver 2 4 h o urs if necessar y, alt h o u g h it is preferre d t hat all pr oce d ures occ ur o n t he sa me da y as i nserti o n of t he Ris peri d o ne I m pla nts.
b P h o ne c o ntacts ca n be ma de t o t he patie nt at t he discreti o n of t he I n vesti gat or t hr o u g h o ut t he c o urse of t he st u d y. At W ee k 6, 1 0, 2 2, a n d 3 0 i n lie u of a p h o ne
call, a n o n -site visit ca n be ma de t o perf or m t he f oll o wi n g pr oce d ures: C-S S R S, A E a n d c o nc o mita nt me dicati o n assess me nt, i m pla nt pal pati o n a n d site
e xa mi nati o n, vital si g ns c ollecti o n, assess criteria f or e xacer bati o n of ps yc h otic s y m pt o ms/i m pe n di n g rela ps e.
c A f ull p h ysical e xa mi nati o n will be perf or me d wit h t he e xce pti o n of t he ge nit o uri nar y ( G U) b o d y s yste m.
d B MI will be calc ulate d i n k g/ m 2 fr o m t he scree ni n g hei g ht a n d baseli ne wei g ht usi n g o ne of t he f oll o wi n g f or m ulae, as a p pr o priate: W ei g ht ( k g) ÷  [ Hei g ht
( m)]2 or W ei g ht (l b) ÷ [ Hei g ht (i n)] 2 x 7 0 3.
e Vital si g n meas ure me nts i ncl u des b o d y te m perat ure, s yst oli c a n d diast olic bl o o d press ure, res pirat or y rate a n d p ulse rate. Bl o o d press ure c uff s h o ul d b e o n t he
o p p osite ar m of t he i m pla nt f or at least 2 wee ks after i m pla nt da y.
f S u bj ects s h o ul d fast f or a mi ni m u m of 1 0 h o urs pri or t o bl o o d dra ws f or la b orat or y assess me nts.
g Uri ne pre g na nc y tests c o ul d be perf or me d at a n y p oi nt d uri n g t he trial if pre g na nc y is s us pecte d. All p ositi ve uri ne pre g na nc y test res ults are c o nfir me d b y a 2 n d
uri ne pre g na nc y test. Treate d s u bj ects wit h 2 p ositi ve uri ne t ests will disc o nti n ue treat me nt, be wit h dra w n fr o m t he trial, a n d a n i m me diatel y re p orta ble e ve nt
f or m will be c o m plete d.
h A uri ne dr u g scree n a n d a breat h alc o h ol test are re q uire d at t h e desi g nate d ti mes, b ut eit her or b ot h ca n be c o n d ucte d at a n y ti me d uri n g t he P hase at t he
discreti o n of t he In vesti gat or.


Cli nical Trial Pr ot oc ol
Brae b ur n P har mace uticals
B B -R S P -3 0 1
C O N FI D E N TI A L
Versi o n: Fi nal 4 . 0, 1 5J U L 2 0 1 6
Pa ge 4 2 of 6 7
i P A N S S is re q uire d at t he desi g nate d ti mes, b ut ca n be c o n d ucte d at a n y ti me d uri n g t he P hase at t he discreti o n of t he In vesti gat or .  If rela pse occ urs or PI
s us pects t hat patie nt will rela pse, P A N S S s h o ul d be c o n d uct e d.
j Refere nce p oi nt f or C GI -I is t he baseli ne of t he Mai nte na nc e P hase (i.e., last visit of t he C o n versi o n P hase or Scree ni n g P hase).
k B aseli ne is Da y 1 of t he Mai nte n a nce P hase. Wee k 2 is Da y 1 4, Wee k 4 is Da y 2 8, Wee k 6 is Da y 4 2, Wee k 8 is Da y 5 6, Wee k 1 2 is Da y 8 4, etc.
L Oral ris peri d o ne ( 4 m g) s h o ul d be a d mi nistere d o n baseli ne da y a n d f or o ne da y after i m pla ntati o n.
m S u bj ects s h o ul d re mai n o n site f or at least 3 0 mi n utes after t he i m pla nt has bee n i nserte d.
Ta ble 3 : Sc he d ule of Assess me nts – M ai nte n a nce P h ase: Wee k 2 6 – F oll o w -U p
Pr oce d ure
M ai nte n a nce P h ase ( Visits
4 d a ys) k
W k
2 5
W k
2 6
W k
2 7
W k
2 8
W k
3 0
W k
3 2
W k
3 6
W k
4 0
W k
4 4
W k
4 8 E T/
I m pe n di n g
rela pse
F oll o w -U p
Visit + 1 4 t o
+ 2 8 da ys after
W k
4 8
I ncl usi o n/ E xcl usi o n
Criteria
P h o ne c o ntact b
X
Assess criteria f or
e xacer bati o n of
ps yc h otic
s y m pt o ms/i m pe n di n g
rela pse
X
X
X
X
X
X
X
P h ysical e xa mi nati o n c
X
W ei g ht, B MI
d
X
X
Vital si g ns e
X
X
X
X
X
X
X
He mat ol o g y a n d
ser u m c he mistr yf
X
X
Uri nal ysis
X
X
Uri ne pre g na nc y test g
X
X
X
X
X
X


Cli nical Trial Pr ot oc ol
Brae b ur n P har mace uticals
B B -R S P -3 0 1
C O N FI D E N TI A L
Versi o n: Fi nal 4 . 0, 1 5J U L 2 0 1 6
Pa ge 4 3 of 6 7
Pr oce d ure
M ai nte n a nce P h ase ( Visits
4 d a ys) k
W k
2 5
W k
2 6
W k
2 7
W k
2 8
W k
3 0
W k
3 2
W k
3 6
W k
4 0
W k
4 4
W k
4 8 E T/
I m pe n di n g
rela pse
F oll o w -U p
Visit + 1 4 t o
+ 2 8 da ys after
W k
4 8
Uri ne dr u g scree n h
X
X
Breat h alc o h ol test h
X
X
1 2 -Lea d E C G
X
C o nc o mita nt
me dicati o ns
X
X
X
X
X
X
X
X
X
X
A d verse E ve nts
X
X
X
X
X
X
X
X
X
X
I m pla nt pal pati o n a n d
site e xa mi nati o n
X
X
X
X
X
X
X
X
X
X
C -S S R S ( Si nce Last
Visit)
X
X
X
X
X
X
X
St u d y dr u g e x pla ntati o n
X
S A S
X
X
X
X
X
X
B ar nes A kat h isia Scale
X
X
X
X
X
X
AI M S
X
X
X
X
X
X
P A N S S i
X
X
C GI -S
X
X
X
X
X
X
X
C GI -Ij
X
X
X
X
X
X
X
Pitts b ur g h Slee p
Q ualit y I n de x ( P S QI)
X
X
X
X
X
X
a T he e n d of t he C o n versi o n P hase visit will ser ve as t he Baseli ne f or t he Mai nte na nce P hase; t heref ore, all e val uati o ns n ote d f or “E n d of t he C o n versi o n P hase or
B aseli ne Mai nte na nce P hase ” will be perf or me d o n t he da y of a d mi nistrati o n pri or t o i nserti o n o f t he Ris peri d o ne I m pla nts.
b P h o ne c o ntacts ca n be ma de t o t he patie nt at t he discreti o n of t he I n vesti gat or t hr o u g h o ut t he c o urse of t he st u d y. At W ee k 6 , 1 0, 2 2, a n d 3 0 i n lie u of a p h o ne
call, a n o n -site visit ca n be ma de t o perf or m t he f oll o wi n g pr oce d ures: C-S S R S, A E a n d c o nc o mita nt me dicati o n assess me nt, i m pla nt pal pati o n a n d site
e xa mi nati o n, vital si g ns c ollecti o n, assess criteria f or e xacer bati o n of ps yc h otic s y m pt o ms/i m pe n di n g rela pse.
c A f ull p h ysical e xa mi nati o n will be perf or me d wit h t he e xc e pti o n of t he ge nit o uri nar y ( G U) b o d y s yste m.


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d BMI will be calculated in kg/m2 from the screening height and baseline weight using one of the following formulae, as appropriate: Weight (kg) ÷ [Height
(m)]2 or Weight (lb) ÷ [Height (in)]2 x 703.
e Vital sign measurements includes body temperature, systolic and diastolic blood pressure, respiratory rate and pulse rate. Blood pressure cuff should be used on
the opposite arm of the implant for at least 2 weeks after implant day.
f Subjects should fast for a minimum of 10 hours prior to blood draws for laboratory assessments.
g Urine pregnancy tests could be performed at any point during the trial if pregnancy is suspected. All positive urine pregnancy test results are confirmed by a 2nd
urine pregnancy test. Treated subjects with 2 positive urine tests will discontinue treatment, be withdrawn from the trial, and an immediately reportable event
form will be completed.
h A urine drug screen and a breath alcohol test are required at the designated times, but either or both can be conducted at any time during the Phase at the
discretion of the Investigator.
i PANSS is required at the designated times, but can be conducted at any time during the Phase at the discretion of the Investigator. If relapse occurs or PI
suspects that patient will relapse, PANSS should be conducted.
j Reference point for CGI-I is the baseline of the Maintenance Phase (i.e., last visit of the Conversion Phase or Screening Phase).


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9.1.
Demographics and Other Baseline Characteristics
9.1.1.
Informed Consent
The nature of the study and its risks and benefits will be explained to the participant by the
Investigator or designated study personnel. The participant must provide written informed
consent on an ethics-approved informed consent form (ICF), prior to performing any study-
related procedures.
9.1.2.
Demographics
The following demographics will be recorded: age (birthdate), sex, race, and ethnicity.
9.1.3.
Medical History
A complete medical history will be taken for each patient at Screening (Visit 1) in accordance
with the Schedule of Assessments (Flow Chart Table 1).  General medical history information
will be recorded in the eCRF and will include information relating to any prior or existing
medical conditions.
9.1.4.
Medication History and Alcohol/Drug Use
All medications (prescription and non-prescription, herbal medications/natural health products,
or investigational drugs) taken by the subjects during the 45 days prior to Screening will be
recorded in the source documentation as medication history.
All antipsychotic medications used within 45 days of screening and any approved long-acting
antipsychotic depot formulations given within the one cycle plus 14 days prior to screening (e.g.,
2-week cycle plus an additional 14 days for risperidone long-acting injection) or investigational
long-acting antipsychotics given within 60 days of screening will be recorded. In addition, the
Investigator will record details of the cross-titration that will occur during the Conversion Phase
to bring about a stable transition from previous antipsychotic treatment(s) to oral risperidone.
DSM-5 modules will be included as a part of drug/alcohol use history and used to screen for
substance use disorders.
9.2.
Eligibility Review and Randomization
Prior to conversion and implantation, subjects must meet all inclusion and not meet any
exclusion criteria as outlined in Section 7.1 and 7.2.
The Investigator or designee must document that the subjects meet each individual criterion via a
signed note or eligibility and clinical stability checklist during Screening. Signatures on these
documents must be dated on or before the date of study drug administration in the Maintenance
Phase.


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9.3.
Study Assessments
9.3.1.
Primary Endpoints
1) 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 Severity Scale assessments (C-SSRS), Abnormal
Involuntary Movement Scale (AIMS), Simpson-Angus Scale (SAS), and Barnes Akathisia Scale
(BARS), and adverse event (AE) monitoring.
2) Time to discontinuation due to all causes
3) Mean change from baseline to endpoint in PANSS Total Score
4) Mean change from baseline to endpoint in Clinical Global Impression of Severity (CGI-S)
5) Mean change from baseline to endpoint in PANSS positive and negative subscales
6) Mean CGI-I score at endpoint
9.3.1.1.
Positive and Negative Symptom Scale
The PANSS consists of 3 subscales containing a total of 30 symptom constructs. For each
symptom construct, severity is rated on a 7-point scale, with a score of 1 indicating the absence
of symptoms and a score of 7 indicating extremely severe symptoms. The symptom constructs
for each subscale are as follows:
1) Positive Subscale (7 positive symptom constructs: delusions, conceptual disorganization,
hallucinatory behavior, excitement, grandiosity, suspiciousness/persecution, and hostility)
2) Negative Subscale (7 negative symptom constructs: blunted affect, emotional withdrawal,
poor rapport, passive/apathetic withdrawal, difficulty in abstract thinking, lack of
spontaneity and flow of conversation, stereotyped thinking)
3) General Psychopathology Subscale (16 symptom constructs: somatic concerns, anxiety,
guilt feelings, tension, mannerisms and posturing, depression, motor retardation,
uncooperativeness, unusual thought content, disorientation, poor attention, lack of
judgment and insight, disturbance of volition, poor impulse control, preoccupation, and
active social avoidance)
All efforts will be made to ensure that the same rater administered the PANSS for a given subject
and the number of raters within each trial center is kept to a minimum. Instructions for
administering this instrument will be provided to the site. All raters will be required to
demonstrate interrater reliability before rating subjects in this trial. A copy of the PANSS
assessment with complete rating criteria is required as source documentation. Qualified raters
will be required to demonstrate rating proficiency on the PANSS prior to being certified to rate
subjects in the trial to ensure continued interrater reliability through the duration of the trial.
PANSS is required at the designated times, but can be conducted at any time during the Phase at
the discretion of the Investigator.  If relapse occurs or PI suspects that patient will relapse,
PANSS should be conducted.


Cli nical Trial Pr ot oc ol
Brae b ur n P har mace uticals
B B -R S P -3 0 1
C O N FI D E N TI A L
Versi o n: Fi nal 4 . 0, 1 5J U L 2 0 1 6
Pa ge 4 7 of 6 7
9. 3. 1. 2.
Cli nic al Gl o b al I m pressi o n – Se verit y
T h e se verit y of ill ness f or eac h s u bj ect will be rat e d usi n g t he C GI-S scale. T o assess C GI -S, t he
rater or In vesti gat or will a ns wer t he f oll o wi n g q u esti o n: “ C o nsi deri n g y o ur t otal cli nical
e x perie nce wit h t his parti c ular p o p ulati o n, h o w me ntall y ill is t he patie nt at t his ti me? ” Res p o nse
c h oices i ncl u de d: 0 = n ot assesse d; 1 = n or m al, n ot ill at all; 2 = b or derli ne me ntall y ill; 3 =
m il dl y ill; 4 = m o deratel y ill; 5 = mar ke dl y ill; 6 = se verel y ill; a n d 7 = a m o n g t he m ost
e xtre mel y ill patie nts.
9. 3. 1. 3.
Cli nic al Gl o b al I m pressi o n – I m pr o ve me nt
T he efficac y of trial me dicati o n will be rate d f or eac h s u bj ect usi n g t he C GI-I scale. T he rater or
In vesti gat or will rate t he s u bj ect’s t otal i m pr o ve me nt w het her or n ot it is d ue e ntirel y t o dr u g treat me nt.
All res p o nses w ill be c o m pare d t o t he s u bject ’s c o n diti o n at baseli ne of t he a p pr o priate P hase. I n ot h er
w or ds, t he refere nce p oi nt i s t he e n d of t he C o n versi o n P hase/ baseli ne of t he Mai nte na nce
P hase f or
assess me nts ma de d uri n g t he Mai nte na nce P hase . Res p o nse c h oices i ncl u de d: 0 = n ot assesse d, 1 = ver y
m uc h i m pr o ve d, 2 = m uc h i m pr o ve d, 3 = mi ni mall y i m pr o ve d, 4 = n o c ha n ge, 5 = mi ni mall y w orse, 6 =
m uc h w orse, a n d 7 = ver y m uc h w orse.
9. 3. 2.
Sec o n d ar y E n d p oi nt
T he sec o n d ar y e n dp oi nt of t he trial will be t he i nci de nce of ps yc h otic s y m pt o m
e x acer bati o n/ i m pe n di n g rela pse i n t he 4 8 -wee k M ai nte na nce Treat me nt P hase, defi n e d as
meeti n g a n y of t he f oll o wi n g 4 cri teria:
1)
Cli nical Gl o bal I m pressi o n of I m pr o ve me nt ( C GI -I) of ≥ 5 ( mi ni mall y w orse)
A N D

a n i ncrease o n a n y of t he f oll o wi n g i n di vi d ual P ositi ve a n d Ne gati ve S y n dr o me Scale
( P A N S S) ite ms (c o nce pt ual dis or ga nizati o n, hall uci nat or y be ha vi or, s us pici o us ness,
u n us ual t h o u g ht c o nte nt , h ostilit y) t o a s c ore > 4 wit h a n a bs ol ute i ncrease of ≥ 2 o n t hat
s pecific ite m si nce b aseli ne O R

a n i ncrease o n a n y of t he f oll o wi n g i n di vi d ual P A N S S ite ms (c o nce pt ual dis or ga nizati o n,
hall uci nat or y be ha vi or, s us pici o us ness, u n us ual t h o u g ht c o nte nt , h ostilit y) t o a sc ore > 4
a n d a n a bs ol ute i ncreas e of ≥ 4 o n t he c o m bi ne d fi ve P A N S S ite ms (c o nce pt ual
dis or ga nizati o n, hall uci n at or y b e ha vi or, s us pici o us ness, u n us ual t h o u g ht c o nte nt ,
h ostilit y ) si nce baseli ne O R
2)
H os pitalizati o n d ue t o w orse ni n g of ps yc h otic s y m pt o ms (i ncl u di n g partial
h os pitalizati o n pr o gra ms), b ut e x cl u di n g h os pitalizati o n f or ps yc h os o cial reas o ns O R
3)
Cli nicall y si g nifica nt s uici dal i deati o n or be h a vi or i n I n v esti gat or’s j u d g m e nt
O R
4)
Vi ole nt be ha vi or res ulti n g i n cl i nicall y rele va nt self-i nj ur y, i nj ur y t o a n ot h er pers o n, or
pr o pert y da ma ge


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BB-RSP-301
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Version: Final 4.0, 15JUL2016
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9.3.3.
Exploratory Endpoint
1) Pittsburgh Sleep Quality Index (PSQI)
9.4.
Safety Assessments
Safety monitoring will be performed throughout the study for all subjects.
9.4.1.
Adverse Events (AEs) and Serious Adverse Events (SAEs)
The Investigator and research site staff are responsible for the detection, documentation,
classification, reporting, and follow-up of events meeting the definition of an AE or serious
adverse event (SAE). An AE can be any unfavorable and unintended sign (including a clinically
significant laboratory abnormality), symptom, or disease temporally associated with the use of an
investigational product, whether or not related to the investigational product.
All AEs will be recorded in the AE eCRF, regardless of causality or severity, following informed
consent (at Screening) until the end of the Follow-up period of the study. Pre-existing
conditions, diseases, or disorders are not considered AEs unless there is a change in intensity,
frequency, or quality.
Appropriate medical intervention should be provided and, if necessary, implants may be removed
as clinically indicated.
9.4.1.1.
Adverse Event Reporting
All AEs must be entered on the AE CRF, regardless of causality or severity. AEs include new
AEs, worsening baseline conditions, clinically significant laboratory findings, disease-related
signs and symptoms that were not present at baseline, and any events or findings that the
Investigator feels are clinically significant.
Disease-related signs and symptoms that are present at baseline should not be recorded as AEs
unless they worsen in severity or increase in frequency.
Information collected concerning AEs will include the following:

Name of the event

Onset date

Resolution date

Severity (i.e., mild, moderate, or severe)

Relationship to study drug

Action and outcome

Relationship to insertion / removal procedure

Seriousness of event


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Version: Final 4.0, 15JUL2016
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All AEs will be documented and followed from the time the subject has signed the ICF until 14
days after the End of Treatment Visit (i.e., implant removal). All unresolved AEs will be
followed for a minimum of 14 days after the participant’s final study visit, unless the
Investigator’s judgment dictates otherwise, the event has resolved or stabilized before the 14-day
period, or the participant is lost to follow-up. Serious AEs and AEs that have been designated as
possibly related to study drug will be followed until resolution or stabilization.
9.4.1.2.
Serious Adverse Events and Serious Unexpected Adverse Events
An SAE is any untoward medical occurrence that at any dose:

Results in death;

Is life-threatening (at the time of the event);

Requires inpatient hospitalization or prolongation of existing hospitalization;

Results in persistent or significant disability/incapacity; or

Is a congenital anomaly/birth defect.

An Important medical event that may not result in death, be life-threatening, or require
hospitalization may be considered an SAE when, based upon appropriate medical
judgment, the event may jeopardize the subject and/or may require medical or surgical
intervention to prevent one of the outcomes listed in this definition.
A serious and unexpected AE is an SAE that is not identified in nature, intensity, or frequency in
the risk information set out in the Investigator’s Brochure/Product Monograph of the drug.
All AEs requiring hospitalization or prolongation of a pre-existing hospitalization should be
reported as SAEs unless they occur greater than 30 days after the End of Treatment Visit. Date
and time of hospitalization should be captured.
9.4.1.2.1. Serious Adverse Event Reporting
Serious Adverse Events (SAEs) must be reported to the Sponsor or designee within 24 hours of
knowledge of the event. All SAEs that occur while a subject is receiving study drug and within
30 days following the End of Treatment Visit are reportable within 24 hours.
The procedure for reporting an SAE is as follows:

Within 24 hours of knowledge of the event, the site must contact the Sponsor (or
designee) by telephone or facsimile to report the event.

The initial report should include all information known at the time of the report
(additional information can be reported as discovered). Do not delay the initial reporting
in order to obtain resolution or follow-up information.

The site will enter into the electronic database (or fax, if the database cannot be accessed
for any reason) an SAE report, or similar form, that includes the following information,
as available:


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Version: Final 4.0, 15JUL2016
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o
Subject ID
o
Basic demographic information (age, gender, weight)
o
Outcomes attributed to the event (death, life-threatening hospitalization [new or
prolonged], disability, congenital anomaly, required medical intervention to
prevent permanent impairment/damage, etc.)
o
Onset date and severity of the event
o
Brief description of the event including frequency and severity of symptoms
leading to diagnosis
o
List of relevant test results and lab data
o
Any other relevant history
o
Dates of implantation and removal, if applicable
o
Whether the study drug was discontinued
o
Investigator’s assessment of causality
The Medical Monitor or another representative of the Sponsor may contact the Investigator to
request additional information regarding the event or to confirm information. All SAEs will be
entered on the AE eCRF. The same nomenclature should be used on both the SAE report and the
AE eCRF.
Specific instructions for SAE reporting and a copy of an SAE report form will be provided to the
sites.
The Investigator is responsible for the complete and timely reporting of all SAEs to the Sponsor
(or designee), reporting pertinent follow-up information on the SAE, and notifying the
appropriate IRB / Independent Ethics Committee (IEC) of the occurrence of and details
surrounding the event. In the event there is a question as to whether the AE is serious, the event
should be reported.
9.4.2.
Pregnancy
Urine pregnancy tests could be performed at any point during the trial if pregnancy is suspected.
All positive urine pregnancy test results are confirmed by a 2nd urine pregnancy test. Treated
subjects with 2 positive urine tests will discontinue treatment, be withdrawn from the trial, and
an immediately reportable event form will be completed.
Pregnancies among trial participants should be reported to the Sponsor or designee as soon as
possible after learning of the event. Follow-up information will be obtained where possible (with
the consent of the participant or their partner) regarding the course and outcome of the
pregnancy, including any post-natal sequelae in the infant (30 days post-birth).


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9.4.3.
Clinical Laboratory Assessments
All protocol-specified laboratory tests on blood and urine samples will be performed at a selected
central laboratory, with the exception of urine pregnancy tests that are conducted at the study
site. The central lab will generate laboratory reports and forward them to the clinical site in a
timely manner. It is the responsibility of the Investigator to review and sign all lab reports
expeditiously, in order to document appropriate safety monitoring of study subjects. The
Investigator should sign and date each lab report concurrent with her or his review, and should
indicate the clinical significance of each abnormal/flagged value by noting “NCS” (not clinically
significant) or “CS” (clinically significant), for example. Notations indicating that a value is
clinically significant should also include a brief description of the underlying disease or
condition that is associated with the value, e.g., “CS/mild anemia.” In general, abnormal,
clinically significant laboratory values are expected to be associated with an item recorded in
medical history or with an AE.
Blood and urine samples will be collected, processed, and shipped according to instructions from
the safety laboratory. Additional laboratory samples may be taken at the discretion of the
Investigator if the results of any tests fall outside reference ranges or clinical symptoms
necessitate testing to ensure safety. Specific hematology, coagulation, biochemistry, and
urinalysis assessments are listed in Table 4.


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Version: Final 4.0, 15JUL2016
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Table 4: Clinical Laboratory Assessments
Hematology
Biochemistry
Urinalysis
Hemoglobin
Hematocrit
Red blood cell (RBC) count
White blood cell (WBC) count
White blood cell differential
Platelet count
Sodium
Potassium
Calcium
Glucose (fasting)
Carbon Dioxide
Chloride
Creatinine
Total protein
Blood urea nitrogen
Phosphorus
Albumin
Total bilirubin
Alanine aminotransferase (ALT)
Aspartate aminotransferase (AST)
Gamma-glutamyl transferase (GGT)
Lactic dehydrogenase (LDH)
Alkaline phosphatase
Triglycerides
Total cholesterol
HDL (high-density lipoprotein)
LDL (low-density lipoprotein)
HDL/Total Cholesterol
Follicle stimulating hormone a
pH
Specific gravity
Ketones
Protein
Glucose
Urobilinogen
Blood
Microscopic examination of
sediment, only if urinalysis
dipstick results are abnormal
a Postmenopausal women at Screening only.
In addition to the clinical laboratory tests, pregnancy testing for the presence of β-human
chorionic gonadotropin will be performed for all women of childbearing potential. Serum
pregnancy tests will be performed at the screening visit, and must be negative prior to study
entry. Results of all scheduled urine pregnancy tests will be reported and determined to be
negative prior to study continuation and/or dosing.
A blood sample for a serology panel testing for hepatitis B surface antigen, anti-hepatitis C
antibodies, and HIV will be performed for all subjects. Only subjects with negative viral
serology tests will be eligible for the study. Positive results will be managed according to local
regulatory requirements and the site’s standard operating procedures.
Any value outside the normal range will be flagged for the attention of the Investigator, who will
indicate whether or not a flagged value is of clinical relevance. If one or more values are


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q uesti o na ble, t he test(s) ma y b e re p eate d. If t he res ult of a n y test ( or re p eat test, if d o ne) is
i n dicate d as cli nicall y rele va nt i n t he sa m ples ta ke n d uri n g t he Scree ni n g P eri o d, t he s u bject will
n ot be e nr olle d i nt o t he trial wit h o ut t he per missi o n of t he me dical m o nit or. I n a d diti o n, f oll o w-
u p u nsc he d ule d la b orat or y ass ess me nts are p erf or me d o n cli nicall y rele v a nt a b n or malities.
U nsc he d ule d la b orat or y t ests ma y b e re p eate d at a n y ti me at t he discreti o n of t he In vesti gat or f or
a p pr o priate m e dical care.
T he f oll o wi n g l a b orat or y test res ults were e x cl usi o nar y:
1) Platelet c o u nt ≤7 5, 0 0 0/ m m 3
2) He m o gl o bi n ≤ 9 g/ d L
3) Ne utr o p hil c o u nt, a bs ol ute ≤1 0 0 0/ m m 3
4) As partate a mi n o tra nsferase ( A S T) > 3 x u p per li mit of n or mal
5) Ala ni ne a mi n otra nsferase ( A L T) > 3 x u p per li mit of n or mal
6) Creati n i ne ≥ 2 m g/ d L
I n a d diti o n, s u bjects are e x cl u de d if t he y h a ve a n y ot her a b n or mal la b orat or y test res ult at
scree ni n g t hat, i n t he In v esti gat or ’s j u d g m e nt, is me dicall y si g nifica nt i n t hat it w o ul d i m pact t he
safet y of t he s u bject or t h e i nter pret ati o n of t he trial res ults.
9. 4. 4.
Uri ne Dr u g Scree n a n d Bre at h Alc o h ol Testi n g
Uri ne dr u g scree ns will test f or t he f oll o wi n g dr u gs of a b use: bar bit urates, o pi ates,
a m p heta mi nes, c ocai ne, p he nc ycli di ne ( P C P) a n d be nz o diaze pi nes.
Breat h alc o h ol testi n g will be perf or me d acc or di n g t o t he site's sta n dar d o p erati n g pr oce d ures. If
t here is a n y d o u bt or c o n cer n re gar di n g alc o h ol us e, researc h site staff ma y re q uest a breat h test
f or alc o h ol meas ures at a n y ti me d uri n g t he st u d y.
9. 4. 5.
Vit al Si g ns
T he f oll o wi n g vital si g ns will be assesse d i n acc or da nce wit h t he Sc h e d ule of Assess me nts (s ee
Ta ble 1 , Ta bl e 2 , Ta ble 3 ):

B l o o d press ure, sitti n g (s yst olic a n d diast olic; m m H g);

P ulse rate ( beats per mi n ute) , sitti n g;

B o d y te m perat ure ( oral ° C).

R es pirat or y rate ( breat hs/ mi n),
Vital si g ns will be meas ure d at all st u d y visits after all o wi n g t he p atie nt t o rest i n a sitti n g
p ositi o n f or at least fi ve mi n utes.
T he bl o o d press ure c uff s h o ul d be p ut o n t he o p p osite ar m of
t he i m pla nt f or at least 2 wee ks after i m pla nt da y.


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9.4.6.
12-Lead Electrocardiograms
Twelve-lead electrocardiograms (ECGs) will be performed in accordance with the Schedule of
Assessments (Table 1, Table 2, and Table 3). ECGs will be performed after the subject has been
resting in a semi-supine position for at least 5 minutes. The ECG variables will include
ventricular heart rate and the PR, QRS, QT, QTcB and QTcF intervals. The ECGs will be signed
and dated by a medically-qualified individual to confirm review of the ECG and verify whether
any abnormalities are clinically significant. In general, abnormal, clinically significant ECGs are
expected to be associated with an item recorded in medical history or with an AE.
Additional 12-lead ECGs may be obtained at the Investigator’s discretion and are always to be
obtained in the event of an early termination. The ECGs are evaluated at the investigational site
to determine the subject’s eligibility and to monitor safety during the trial. The ECG should be
repeated if any results are considered to be clinically relevant.
A screening ECG finding of QTc > 470 msec for females and QTc > 450 msec for males using
the QTcF (Fridericia) correction is exclusionary (see exclusion criterion #18 in Section 7.2). In
addition, subjects are excluded if they had any other abnormal ECG finding at screening that, in
the Investigator’s judgment, are medically significant in that it would impact the safety of the
subject or the interpretation of the trial results.
9.4.7.
Physical Examination
Physical examinations will be performed in accordance with the Schedule of Assessments (Table
1, Table 2, and Table 3).  A complete physical examination will be conducted with the exception
of the genitourinary (GU) body system at Visit 1 (Screening) and the End of Study Visit.
9.4.8.
Physical Measurements
Height will be measured at Screening while body weight/BMI will be recorded at Screening, and
at scheduled time points (Table 1, Table 2, and Table 3) throughout the Conversion and
Maintenance Phases. The following guidelines will aid in the standardization of these
measurements:
• The same scale should be used to weigh a given patient throughout the study.
• Scales should be calibrated and reliable; scales should be zeroed just prior to each patient’s
weigh-in session.
• Weight should be recorded before a patient’s meal (if applicable) and at approximately the
same time each day.
• A patient should be minimally clothed (i.e., no shoes or heavy over garments).
The BMI (kg/m2) will be calculated from the screening height and the weight at the current visit
using one of the following formulae, as appropriate: Weight (kg) ÷ [Height (m)]2 or Weight (lb)
÷ [Height (in)]2 x 703.


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9.4.9.
Implant Site Examination and Wound Care
Subjects will receive written instructions that explain how to care for the surgical site after
implant insertion and removal. Subjects should be informed about care of the implant site and
implant site safety, educated about situations where they should seek medical attention, and
queried about implant-related AEs. Copies of the wound care information sheets must be
reviewed and approved by each site’s IRB, prior to providing them to subjects.
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 Assessments (Table 2, Table 3). Clinically significant infection, as deemed by the
Investigator, resulting from the implant site assessment will be recorded as AEs. If there is
scarring, abnormal bleeding, infection etc., at the implant location, non-identifying pictures of
the implant location may be taken. 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 regimen.  Additionally, ultrasounds may be performed at the
discretion of the Investigator to confirm implant location.
If there is any evidence of removal or attempted removal of the implants, or if the subject
confirms the removal of some or all of the implants, the subject will be withdrawn from study
and any remaining implant will be removed.
If an expulsion of an implant(s) occurs, and the subject appears to be compliant and wants to
continue with the study, the current implant site will have all implants removed and new
implants (same dosage strength as original) will be implanted into the opposite arm. If an
expulsion occurs, sites are to contact the medical monitor to discuss if oral risperidone should be
given to the patient prior to the following implantation.
The Investigator will inform the Sponsor’s Medical Monitor of any clinically significant findings
related to implant assessments.
9.4.10.
Other Assessments
9.4.10.1.
Columbia Suicide Severity Rating Scale (C-SSRS)
Suicidality will be monitored throughout the trial using the Columbia Suicide Severity Rating
Scale (C-SSRS). The C-SSRS scale consists of a baseline evaluation that assesses the lifetime
experience of the subject with suicide events and suicidal ideation and a post baseline ”Since
Last Visit” evaluation that focuses on suicidality since the last trial visit. The baseline C-SSRS
form will be completed at Screening. The “Since Last Visit” C-SSRS form will be completed at
all subsequent visits.
9.4.10.2.
Simpson-Angus Scale (SAS)
The SAS consists of a list of 10 symptoms of parkinsonism (gait, arm dropping, shoulder
shaking, elbow rigidity, wrist rigidity, head rotation, glabella tap, tremor, salivation, and
akathisia). Each item is rated on a 5-point scale, with a score of one representing absence of


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symptoms, and a score of 5 representing a severe condition. The SAS Total Score is the sum of
the scores for all 10 items.
9.4.10.3.
Abnormal Involuntary Movement Scale (AIMS)
The AIMS assessment consists of 10 items describing symptoms of dyskinesia. Facial and oral
movements (items 1 through 4), extremity movements (items 5 and 6), and trunk movements
(item 7) are observed unobtrusively while the subject is at rest (e.g., in the waiting room), and
the Investigator also makes global judgments on the subject’s dyskinesias (items 8 through 10).
Each item is rated on a 5-point scale, with a score of 0 representing absence of symptoms (for
item 10, no awareness), and a score of 4 indicating a severe condition (for item 10,
awareness/severe distress). For this scale, the subject is to be sitting on a hard, firm chair. In
addition, the AIMS includes 2 yes/no questions that addresses the subject’s dental status. The
AIMS Movement Rating Score is defined as the sum of items 1 through 7 (i.e., items 1 through
4, facial and oral movements; items 5 through 6, extremity movements; and item 7, trunk
movements).
9.4.10.4.
Barnes Akathisia Rating Scale (BARS)
The BARS consists of 4 items related to akathisia: objective observation of akathisia by the
Investigator, subjective feelings of restlessness by the subject, subject distress due to akathisia,
and global evaluation of akathisia. The first 3 items are rated on a 4-point scale, with a score of 0
representing absence of symptoms and a score of 3 representing a severe condition. The global
clinical evaluation is made on a 6-point scale, with 0 representing absence of symptoms and a
score of 5 representing severe akathisia. To complete this scale, subjects are observed while they
were seated and then standing for a minimum of 2 minutes in each position. Symptoms observed
in other situations (e.g., while engaged in neutral conversation or engaged in activity on the
ward) are also rated. Subjective phenomena are to be elicited by direct questioning.
9.4.10.5.
Pittsburgh Sleep Quality Index (PSQI)
The Pittsburgh Sleep Quality Index (PSQI) is a self-rated questionnaire which assesses sleep
quality and disturbances over a 1-month time interval. Nineteen individual items generate seven
“component” scores: subjective sleep quality, sleep latency, sleep duration, habitual sleep
efficiency, sleep disturbances, use of sleeping medication, and daytime dysfunction. The sum of
scores for these seven components yields one global score. (Buysse et al., 1989)


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10.
DATA QUALITY ASSURANCE
This study will be conducted under Good Clinical Practice (GCP) and all applicable regulatory
requirements. To ensure compliance, the sponsor or designee may conduct a quality assurance
audit, as outlined in Section 10.2.
Actions to ensure the accuracy and reliability of data include the selection of qualified
Investigators and appropriate study centers; the review of protocol procedures with the
Investigator and study personnel prior to study start; the design of suitable source documents
with appropriate instructions for use (where applicable); the internal audit of source data
according to GCP and internal procedures to ensure their accuracy, completeness, and
verifiability; as well as the periodic site monitoring by the sponsor. Written instructions will be
provided for collection, preparation, and shipment of blood, plasma, and urine samples. The
sponsor or designee will review source documents for accuracy and completeness during on-site
monitoring visits and after their return to the sponsor; any discrepancies will be resolved with the
Investigator, as appropriate.
Significant and/or repeated non-compliance will be investigated and remedial action instituted
when appropriate. Failure to comply with remedial actions may result in Investigator site
termination and regulatory authority notification.
10.1.
Data Collection
Source documents include but are not limited to original documents, data and records such as
hospital/medical records (including electronic health records), clinic charts, lab results,
participant diaries, data recorded in automated instruments, microfilm or magnetic media, and
pharmacy records, etc. This study will use electronic data capture (EDC). At a minimum, all data
required by the protocol should have supporting source documentation for entries in the EDC
system, unless that data can be recorded directly in the EDC system or other device.
All CRFs will be completed by the site staff prior to review by the sponsor’s monitor or
designated representative. The sponsor’s monitor or designated representative will review all
source records on-site and compare them to the data collected on the CRF.  All entries,
corrections, and alterations will be made by the Investigator or other authorized study personnel.
All data entries will be verified for accuracy and correctness by independent monitors. The
electronic data capture system maintains a full audit trail.
10.2.
Study Auditing and Monitoring
Monitoring of the study site (including, but not limited to, reviewing CRFs for accuracy and
completeness) will be performed by the sponsor’s monitor or designee. The extent, nature, and
frequency of on-site visits will be based on such considerations as the study objectives and/or
endpoints, the purpose of the study, study design complexity, and enrollment rate. By signing the
protocol, the Investigator agrees that, within local regulatory restrictions and institutional and
ethical considerations, authorized representatives of the sponsor, a regulatory authority, and/or an
institutional review board (IRB) may visit the site to perform audits or inspections, including the


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drug storage area, study drug stocks, drug accountability records, participant charts and source
documents, and other records related to study conduct. The purpose of the sponsor audit or
inspection is to systematically and independently examine all study-related activities and
documents to determine whether the study-related activities were conducted, and data recorded,
analyzed, and accurately reported according to the protocol, the site’s standard operating
procedures, GCP guidelines of the International Conference on Harmonisation (ICH), and any
applicable regulatory requirements.  The Investigator should contact the sponsor immediately if
contacted by a regulatory agency regarding an inspection.


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11.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
11.1.
Statistical and Analytical Plans
Complete details of the statistical analyses to be performed will be documented in a statistical
analysis plan, which will be completed prior to database lock. This document will include more
detail of analysis populations, summary strategies, and analysis methodologies. Changes to the
statistical analysis plan in the methodologies used for the clinical study report (CSR) will be
discussed in the clinical study report.
11.2.
Analysis Populations
The study analysis populations will consist of

Enrolled Population: All subjects enrolled into the study.

Safety Population: All subjects who received at least one dose of study medication

Intent-to-treat population: All enrolled subjects.
11.3.
Planned Analyses
11.3.1.
Subject disposition
Subject disposition will be summarized for the enrolled population, including the number and
percent of subjects who are included in each population, who completed the study, and who drop
out the study prematurely with the reasons for early termination.
11.3.2.
Demographics and Other Baseline Characteristics
Demographic and baseline characteristics will be summarized for the enrolled population as well
as for the safety population.
11.3.3.
Prior and concomitant medication
Prior and concomitant medication will be summarized for the safety population.
11.3.4.
Analysis of Safety Assessments (Primary Endpoints)
Study drug exposure will be summarized for the safety population.  The following safety
measures will be summarized over time:
1) Columbia Severity Scale assessments (C-SSRS), Abnormal Involuntary Movement Scale
(AIMS), Simpson-Angus Scale (SAS), Barnes Akathisia Scale (BARS) and Pittsburgh Sleep
Quality Index (PSQI).
2) Time to discontinuation due to all causes
3) Mean change from baseline to endpoint in PANSS Total Score
4) Mean change from baseline to endpoint in Clinical Global Impression of Severity (CGI-S)


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Pa ge 6 0 of 6 7
5)
Mea n c ha n ge fr o m
baseli ne t o e n d p oi nt i n P A N S S p ositi ve a n d ne gati ve s u bscales
6)
Mea n C GI -I sc ore at e n d p oi nt
Treat me nt e mer gi n g a d verse e ve nts are A Es t hat o cc urre d o n or after t he first d ose of st u d y
me dicati o n a n d o n or bef ore t he last d ose of st u d y me dicati o n.  S A Es t hat occ urr e d wit hi n 4
wee ks after t he last d ose of st u d y me dicati o n will als o be i ncl u de d.
A d verse e ve nts will be c o de d b y pri mar y s yste m or ga n class ( S O C) a n d preferre d ter m acc or di n g
t o t he Me dical Dicti o nar y f or Re g ulat or y Acti vities ( Me d D R A), a n d s u m marize d b y nu m ber a n d
perce nt of s u bjects i n eac h pri mar y S O C a n d preferre d ter m. S u m maries of t hese A E s u bs ets will
be prese nt e d f or relati o ns hi p t o trial dr u g, i nte nsit y, seri o us ness, A Es or S A Es lea di n g t o
disc o nti n uati o n. Fre q ue n cies f or deat hs a n d h os pitalizati o n s will als o be s u m marize d.
Data f or cli nical la b orat or y tests, E C G, vital si g ns, a n d p h ysi cal a n d i m pla nt site e x a mi nati o ns
will be s u m marize d usi n g sta n dar d des cri pti ve a n d c ha n ge fr o m baseli ne st atistics. S hift ta bles
a n d ta b ular s u m maries of a b n or maliti es will be pr o vi de d, w here a p pr o priate.
Me dicati o ns will be c o de d usi n g t he Worl d Healt h Or ga nizati o n Dr u g dicti o nar y a n d s u m marize d
usi n g descri pti ve statistics.
B y -s u bject listi n gs will be pr o vi de d f or all safet y data.
1 1. 3. 5.
Effic ac y assess me nt
T he sec o n d ar y en d p oi nt of t he trial will be t he i nci de nce of ps yc h otic s y m pt o m
e x acer bati o n/i m pe n di n g rela pse i n t he 4 8 -wee k M ai nte na nce Treat me nt P h ase, defi n e d as
meeti n g a n y of t he f oll o wi n g 4 criteria:
1)
Cli nical Gl o bal I m pressi o n of I m pr o ve me nt ( C GI -I) of ≥ 5 ( mi ni mall y w orse)
A N D

a n i ncrease o n a n y of t he f oll o wi n g i n di vi d ual P ositi ve a n d Ne gati ve S y n dr o me Scale
( P A N S S) ite ms (c o nce pt ual dis or ga nizati o n, hall uci nat or y be ha vi or, s us pici o us ness,
u n us ual t h o u g ht c o nte nt, h ostilit y) t o a s c ore > 4 wit h a n a bs ol ute i ncreas e of ≥ 2 o n t hat
s pecific ite m si nce b aseli ne O R

a n i ncrease o n a n y of t he f oll o wi n g i n di vi d ual P A N S S ite ms (c o nce pt ual dis or ga nizati o n,
hall uci nat or y be ha vi or, s us pici o us ness, u n us ual t h o u g ht c o nte nt, h ostilit y) t o a sc ore > 4
a n d a n a bs ol ute i ncreas e of ≥ 4 o n t he c o m bi ne d fi ve P A N S S ite ms (c o nce pt ual
dis or ga nizati o n, hall uci nat or y b e ha vi or, s us pici o us ness, u n us ual t h o u g ht c o nte nt,
h ostilit y) si nce baseli ne O R
2)
H os pitalizati o n d ue t o w orse ni n g of ps yc h otic s y m pt o ms (i ncl u di n g partial
h os pitalizati o n pr o gra ms), b ut e x cl u di n g h os pitalizati o n f or ps yc h os o cial reas o ns
O R
3)
Cli nicall y si g nifica nt s uici dal i deati o n or be h a vi or i n I n v esti gat or ’s j u d g m e nt O R
4)
Vi ole nt be ha vi or res ulti n g i n cli nicall y rele va nt self -i nj ur y, i nj ur y t o a n ot her pers o n, or
pr o pert y da ma ge


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11.4.
Determination of Sample Size
The sample size of approximately 140 subjects will enter the Maintenance Phase to achieve the
goal of having 100 subjects with 48 week exposure.


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12.
STUDY ADMINISTRATION AND INVESTIGATOR
RESPONSIBILITIES
Additional details may be outlined in the Clinical Study Agreement (CSA) between the sponsor
and the investigational site.
12.1.
Regulatory and Ethical Considerations
12.1.1.
Ethical Conduct of the Study
The Investigator will conduct the study in accordance with GCP and all applicable regulations,
including, where applicable, the Declaration of Helsinki. The study will also be carried out in
keeping with applicable national and local laws and regulations. This may include an inspection
by the sponsor’s representatives and/or regulatory authority’s representatives at any time.
12.1.2.
Regulatory Authority and Ethics Approval
The investigational site’s IRB must meet all relevant regulatory requirements. The study protocol
and ICF will be reviewed by the IRB prior to enrolling participants into the study; written
approval from the committee must be received by the sponsor before drug will be released to the
Investigator. The Investigator is responsible for submitting all protocol or ICF changes and SAE
reports to the IRB according to local procedures. At a minimum, all SAEs requiring an
investigational new drug safety report must be immediately reported.
In accordance with applicable local regulatory requirements, the Investigator may be obligated to
provide periodic safety updates on the conduct of the study at his or her research site and
notification of study closure to the IRB. Such periodic safety updates and notifications are the
responsibility of the Investigator and not of the sponsor. The sponsor will be provided with
copies of all notifications sent to the IRB.
All relevant correspondence from the IRB will be forwarded by the respective study site to the
sponsor in a timely fashion.
In accordance with applicable local regulations, the sponsor or designee will obtain approval
from the appropriate regulatory agency prior to a site initiating the study in that country or
jurisdiction.
12.1.3.
Subject Informed Consent
The Investigator (or authorized designee) will ensure that the participant is given full and
adequate oral and written information about the nature, purpose, potential and possible risks and
benefits of the study. Each prospective subject will receive an IRB-approved ICF that
summarizes the pertinent study information and will be given ample time to read the form and
ask questions about the study. All information is to be provided in a language understandable to
the participant and must not include any language that waives the participant’s legal rights.
Prospective participants must also be informed of their right to withdraw consent without
prejudice at any time during the study. If the participant chooses to participate, he/she must sign
the ICF before any study-related procedures are performed.


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Significant changes to the protocol or product safety information may require a revision of the
ICF, which must be reviewed and signed by all applicable study participants.
The time that informed consent is obtained must be documented. The Investigator must maintain
the original, signed ICF in the participant’s source documents. A copy of the signed ICF must be
given to the study participant.
12.2.
Privacy and Confidentiality
The Investigator is responsible for complying with applicable privacy regulations, per his or her
jurisdiction. Only information identified in this protocol will be collected. The information
collected will only be used for the purposes identified in this protocol.
To ensure anonymity and to limit disclosure, participants will be assigned a unique identifier at
their first assessment. This identifier will be cross-referenced in the participant’s chart. The
identifier will not contain any potentially identifiable information. An identifier log will be
maintained, linking each participant’s name to the corresponding identifier. This log will be
stored at the research site in a secure location.
The knowledge gained through this study is the property of the sponsor. The sponsor,
representatives and affiliated companies of the sponsor, the IRB, and regulatory agencies (such
as the United States Food and Drug Administration [FDA]) may inspect medical records related
to the study to check the validity and accuracy of the data gathered in this study. Participant
medical records (with participant’s initials and/or date of birth) may be copied. Confidentiality of
participant records will be maintained except where release of information is required by law.
The results of this study will be reported in such a manner that participants will not be
identifiable in any way. Published reports or presentations will refer to grouped data or coded
individual data and not to any identifiable individuals. Study reports sent to the sponsor or drug
regulatory agencies will not include participant names.
By signing the ICF, the participant consents to the collection, access, use, and disclosure of his or
her information as described in the ICF document. If a participant withdraws consent, some of
the subject’s information may still be collected, used, and disclosed by those involved in this
study, per applicable laws.
By signing this protocol, the Investigator affirms that he or she will maintain in confidence
information furnished to him or her by the sponsor and will divulge such information to his or
her respective IRB or IEC under an appropriate understanding of confidentiality with such board.
All data will be considered the sole property of the sponsor. Please refer to the Clinical Study
Agreement (CSA) for details.
12.3.
Study and Site Closure
Upon completion of the study, all study data will be provided to the sponsor following review of
site study records for completeness, and data clarifications and resolutions. Accounting,


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reconciliation, and final disposition of used and unused study drugs, treatment codes, and
emergency code break envelopes will be performed, as applicable.
In addition, the sponsor reserves the right to temporarily suspend or prematurely discontinue this
study at any time and for any reason. If such action is taken, the sponsor will discuss this with
the Investigator (including the reasons for taking such action) at that time. The sponsor will
promptly inform any other Investigators and/or institutions conducting the study, if the study is
suspended or terminated for safety reasons and will inform the regulatory authorities of the
suspension or termination of the study and the reason(s) for the action. If required by applicable
regulations, the Investigator will inform the IRB promptly and provide the study participants
with the reason for the suspension or termination. If the study is prematurely discontinued, all
study data will be returned to the sponsor.
12.4.
Regulatory Documents and Records Retention
The Investigator is responsible for creating and/or maintaining all study documentation required
by 21 CFR 50, 54, 56 and 312, ICH E6 section 8, as well as any other documentation defined in
the protocol or CSA. The Investigator must provide key documents to the sponsor prior to the
start of the study.  A complete list of required regulatory documents will be supplied by the
sponsor or its representative.
Federal and local regulations require that the Investigator retain a copy of all regulatory
documents and records that support the data for this study for whichever of the following is the
longest period of time:

A period of 2 years following the final date of approval by the FDA or other regulatory
agency of the study drug for the purposes that were the subject of the investigation; or

A period of 5 years following the date on which the results of the investigation were
submitted to the FDA or other regulatory agency in support of, or as part of, an
application for a research or marketing permit for the study drug for the purposes that
were the subject of the investigation.
The sponsor will notify Investigators once one of the above 2 timeframes has been satisfied.
If the investigation does not result in the submission of the data in support of, or as part of, an
application for a research or marketing permit, records must be retained for a period of 2 years
following notification by the sponsor that the entire clinical investigation (not merely the
Investigator’s portion) is completed, terminated, or discontinued or 2 years following withdrawal
of the Investigational New Drug application/Clinical Trial Authorization or request for marketing
approval (New Drug Application/Marketing Authorization Application).
If the 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. The sponsor must be notified in writing of the name and address of the new
custodian. Study records should not be destroyed without consultation with the sponsor.


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Version: Final 4.0, 15JUL2016
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12.5.
Delegation of Responsibilities and Adequate Resources
The Investigator should have adequate time to conduct the study properly and should have an
adequate number of qualified staff to assist with the conduct of the study.
The term “Investigator” used throughout this protocol refers to the principal Investigator and/or
qualified sub-Investigators. However, the Investigator may delegate responsibilities to other
investigational site personnel. The Investigator shall delegate tasks only to individuals qualified
by education, training and experience to perform the delegated tasks. The Investigator shall have
direct oversight of all delegated activities and shall document delegation of responsibilities. The
Investigator is responsible for ensuring all delegated staff have been properly trained on the
protocol and their assigned study responsibilities. A delegation log identifying all delegated
duties and the individual to whom they have been delegated will be maintained at the
investigational site.
12.6.
Protocol Amendments
Approval of a protocol amendment by the Investigator’s IRB must be obtained before
implementation of the protocol amendment, unless a change is necessary to eliminate an
apparent immediate hazard to the participant or when the change involves logistical or
administrative aspects of the study. The protocol amendment must be signed and dated by both
the sponsor and the Investigator. The sponsor or designee will submit protocol amendments to
the appropriate regulatory authorities, if required.
12.7.
Financial Disclosure
Clinical Investigators are required to provide financial disclosure information for the submission
of certification or disclosure statements required under 21 CFR § 54. As defined in 21 CFR §
54.2, a clinical Investigator is a listed or identified Investigator or sub-Investigator who is
directly involved in the treatment or evaluation of research participants. The term also includes
the spouse and each dependent child of the Investigator. In addition, Investigators must promptly
update financial disclosure information if any relevant changes occur during the course of the
investigation and for 1 year following completion of the study.


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Version: Final 4.0, 15JUL2016
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13.
INVESTIGATOR PROTOCOL AGREEMENT PAGE
A ONE YEAR, OPEN-LABEL, STUDY TO EVALUATE THE SAFETY AND TOLERABILITY OF
RISPERIDONE IMPLANTS AS A MAINTENANCE TREATMENT IN PATIENTS WITH
SCHIZOPHRENIA
Version: 4.0
Date: 15-JUL-2016
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.
Principal Investigator’s
Name
(please print or type)
Principal Investigator’s Signature
Date


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Version: Final 4.0, 15JUL2016
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14.
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