Clinical trial NCT03870880
Conditions: Schizophrenia
Sponsor: Rovi Pharmaceuticals Laboratories
Start date: 2017-08-25; Completion date: 2020-01-08
Enrollment: 215 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is the long-term open label extension (OLE) of the study PRISMA-3 (NCT03160521). Those patients who complete participation in the main segment of the study (double blind) together with other clinically stable not previously enrolled (de novo patients) may opt to participate in this extension segment, where they will receive active Risperidone ISM® (75 mg or 100 mg)under open-label conditions every four weeks for approximately 12 months.

Detailed description:
Patients who have completed planned participation in the double-blind segment of the study PRISMA-3 (NCT03160521) through to the end of the treatment period, may be eligible to enter into this optional long-term extension segment of the study. During this extension, open-label Risperidone ISM® (i.e., either 75 or 100 mg) will be administered to all participating patients once every 4 weeks for approximately 12 months. Patients who enter into the extension segment of the study will begin participation in the extension segment immediately upon completion of the end-of-treatment visit assessments and procedures.

In addition to patients continuing from the double-blind segment of the study PRISMA-3 (rollover patients), clinically stable patients not previously enrolled in the study (de novo patients) may be eligible to enter the long-term extension segment of the study. These patients will be evaluated for eligibility at a screening visit and, if eligible, will be allocated to receive either 75 or 100 mg Risperidone ISM every 4 weeks for approximately 12 months.

Approximately 100 de novo patients are planned to be enrolled in the extension segment of the study, in addition to rollover patients.

Arms: arm 1: Patients assigned to this arm will receive 75 mg of Risperidone ISM during the open label extensión (OLE).

Patients enter the study as rollover patients from the study NCT03160521, along with newly enrolled de novo patients. arm 2: Patients assigned to this arm will receive 100 mg of Risperidone ISM during the open label extensión (OLE).

Patients enter the study as rollover patients from the study NCT03160521, along with newly enrolled de novo patients.
Interventions: intervention 1: Risperidone ISM 75 mg intervention 2: Risperidone ISM 100 mg
Intervention descriptions: intervention 1: Monthly (once every 4 weeks) intramuscular (IM) injection in the gluteal or deltoid muscle. intervention 2: Monthly (once every 4 weeks) IM injection in the gluteal or deltoid muscle.

Protocol documents:
ICF_002.pdf: 
COVER PAGE 
Subject Information Sheet (SIS) and Informed Consent 
Form (ICF) 
 
TITLE: Multicenter, Randomized, Double-Blind, Placebo-
Controlled Study to Evaluate the Efficacy and Safety of 
Intramuscular Injections of Risperidone ISM® in Patients 
with Acute Exacerbation of Schizophrenia (PRISMA-3) 
 
PROTOCOL NUMBER: ROV-RISP-2016-01 
 
NCT NUMBER: NCT03870880 
 
ICF VERSION 4.0 
DOCUMENT DATE: 13 APRIL 2018 
 
 


Subject Information Sheet and Consent Form 
Laboratorios Farmacéuticos ROVI, S.A. 
Protocol ROV-RISP-2016-01 (PRISMA-3) 
 
PRISMA-3_OLE Segment Master SIS-ICF_V4.0_13Apr2018_English 
 
 
 
 
 
Page 1 of 13 
 SUBJECT INFORMATION SHEET AND CONSENT FORM 
- OPEN-LABEL EXTENSION SEGMENT OF THE STUDY - 
 
Title:  Multicenter, Randomized, Double-Blind, Placebo-controlled Study to Evaluate the 
Efficacy and Safety of Intramuscular Injections of Risperidone ISM® in Patients with 
Acute Exacerbation of Schizophrenia (PRISMA-3) 
Protocol number: ROV-RISP-2016-01 
EudraCT number: (applicable to EU countries only) 
 
Sponsor Name: Laboratorios Farmacéuticos ROVI, S.A. 
Address of Sponsor:  C/ Julián Camarillo, 35.  28037 Madrid, Spain 
 
Principal Investigator: Insert Name, affiliation, location 
Telephone number 
Daytime: 
After Office Hours: 
 
Introduction and Purpose of the Study 
 
You are being asked to volunteer to take part in an extension segment of the study you 
were participating until now. You have completed the double-blind segment of this study 
and you are eligible to participate in an optional long-term extension segment of the 
study in which treatment with open-label Risperidone ISM® 75 or 100 mg  would begin 
immediately.  
 
 
If you decide to participate in the long-term extension segment, you should sign this 
Subject Information Sheet and the Informed Consent Form. If you are not willing to 
participate in the extension segment, a safety follow-up phone contact will occur in 
approximately 2 weeks.  
You can take as much time as you need to read and understand the information 
provided in this form and to ask questions. One of the research team members 
will go through the information sheet with you and answer any questions you 
have. Talk to others about the study if you wish.  
 
Since the open label extension segment is optional, it is not known how many subjects 
will participate in the long-term extension segment.   
 
Study Plan 
 
The study design includes 13 additional visits (beside the day 1) – every 4 weeks, for a 
total of one year, and one additional follow up visit on week 56. At each visit (except 
final visit 14 at week 52) you will receive Risperidone ISM® injection (either 75 or 100 
mg) and you may have laboratory tests done, ECG, vital signs assessments, physical 
examination, weight, injection site appearance and sensitivity examination and 


Subject Information Sheet and Consent Form 
Laboratorios Farmacéuticos ROVI, S.A. 
Protocol ROV-RISP-2016-01 (PRISMA-3) 
 
PRISMA-3_OLE Segment Master SIS-ICF_V4.0_13Apr2018_English 
 
 
 
 
 
Page 2 of 13 
questionnaires and scales completed the way you had during the double-blind segment 
of the trial (“double-blind” means that neither you nor your study doctor know what 
treatment you are receiving). 
 
Your visits to study center may take several hours. 
 
Eligibility 
 
To be eligible for participation in the open-label extension segment of the study, you 
must meet all of the inclusion criteria and none of the exclusion criteria defined in the 
study protocol. These criteria will be checked by your study doctor. 
 
You may be withdrawn from the study at any time if you, investigator or sponsor 
determines that it is not in your best interest to continue. Reasons for withdrawal may 
include, but are not limited to non-compliance, safety, development of a medical 
condition that requires treatment with a prohibited medication, a positive result on a 
pregnancy or urine drug screen test, or your withdrawal of consent without penalty or 
loss of benefits to which you are otherwise entitled. In addition, if your condition 
changes during the course of the study so that you no longer satisfy the inclusion and 
exclusion criteria, you may be withdrawn. 
 
Study Procedures 
 
Extension Visit 1: Day 1 
 
This visit may occur on the same day as visit 14 (+3 day window) of the double-blind 
segment, once all the assessments and procedures have been completed. 
 
If you qualify for open-label extension segment, at Visit 1 (Day 1) you will be 
administered a dose of Risperidone ISM® 75 mg or 100 mg by intramuscular injection, 
with examination of the injection site appearance and sensitivity on the same day. If you 
have received active Risperidone ISM® in the double-blind segment of the study, you 
will continue to receive active Risperidone ISM® at the same dose (ie, 75 or 100 mg) in 
the extension segment; if you had been receiving placebo in the double-blind segment 
of the study, you will be randomly (the study drug assignment will be done by chance, 
like tossing a coin) assigned to receive either 75 or 100 mg of Risperidone ISM® during 
the extension segment. “Open-label” means that you and your study doctor will know 
what treatment you will be receiving (Risperidone ISM® and not placebo).  
 
But, if you enter this extension segment of the study while some subjects are still in the 
double-blind stage, you will not know do you receive 75 or 100 mg of Risperidone ISM® 
until the completion of the double-blind stage of the study. At that time, you may ask 
your doctor to be informed on the treatment received.  
 


Subject Information Sheet and Consent Form 
Laboratorios Farmacéuticos ROVI, S.A. 
Protocol ROV-RISP-2016-01 (PRISMA-3) 
 
PRISMA-3_OLE Segment Master SIS-ICF_V4.0_13Apr2018_English 
 
 
 
 
 
Page 3 of 13 
At Day 1 the following tests and procedures will be done to determine if you are eligible 
for transition into the extension segment: 
 
• A set of standard questions/scales/questionnaires that will assess your physical 
sensations and symptoms, your quality of life and how it is affected by your 
schizophrenia, as well as assessment scales to assess your movements (the 
way you move and whether you have movements you cannot control) 
• Physical examination  
• Weight and body mass index 
• Vital signs (blood pressure, pulse rate, respiratory rate and body temperature) 
• ECG (electrocardiogram, which records heart function) 
• Review of your medications (including vitamins and herbal supplements) 
• Blood samples (about 2 teaspoons, approximately 10 mL) for laboratory testing 
which will show the function of your blood and vital organs (eg liver, kidney) 
• Blood sample (about 1/2 teaspoon, approximately 2.5 mL, will be taken from you 
for a pregnancy test if you are female able to have kids and if required by your 
study doctor 
• Urine samples for laboratory analysis, pregnancy test for females, and drug 
screen (if applicable) 
 
Results obtained at visit 14 for assessments performed for the end-of-treatment visit for 
the double-blind segment of the study may be used as the extension baseline values 
and do not need to be repeated for the extension baseline visit time point, if and only if 
the extension baseline visit occurs on the same day and date as the main study visit 
14/week 12/end-of-treatment visit. 
 
Blood testing (to the applicable visits) 
 
Your samples will be coded before being shipped to a central laboratory and will be 
stored there awaiting analysis. The central laboratory is experienced in handling and 
testing samples from research studies. All samples will be destroyed once all tests are 
complete. 
 
In case of a serious adverse event, an additional blood sample (about 4 mL) for 
pharmacokinetic testing will be taken. “Pharmacokinetic” testing is a procedure which is 
done to see what your body does to the drug and to show the levels of the drug in your 
blood. This sample will be processed in a same way as blood samples taken for visit 
related tests.   
 
The samples will only be used for study related purposes, and no other analyses than 
study related analyses will be performed without you and the ethics committee’s 
approval. 
 
 
 


Subject Information Sheet and Consent Form 
Laboratorios Farmacéuticos ROVI, S.A. 
Protocol ROV-RISP-2016-01 (PRISMA-3) 
 
PRISMA-3_OLE Segment Master SIS-ICF_V4.0_13Apr2018_English 
 
 
 
 
 
Page 4 of 13 
Extension Study Visits 2-14 (every 4 weeks) 
 
During each extension visit, you will receive Risperidone ISM® (75 or 100 mg) (except 
visit 14, week 52), your vital signs will be checked, a physical examination will be 
performed and questionnaires and assessment scales administered as it was done in 
double-blind segment of the study, to make sure it is safe for you to continue in the 
extension segment of the study. The injection site appearance and sensitivity will be 
examined. You will be asked if there have been any changes in your health and for any 
new medications you may have begun to take. A dipstick test will be done for pregnancy 
at each visit to applicable patients. 
 
Additionally, at visits 4 (week 12), 7 (week 24), 10 (week 36) and 14 (week 52) the study 
staff will perform laboratory tests (including blood and urine tests) and body weight. 
ECG will be done at visits 2 (week 4), 4 (week 12), 6 (week 20), 8 (week 28), 11 (week 
40) and 14 (week 52). 
 
Extension Study Visit 15 (week 56) 
 
This is a follow up visit where you will be asked if there have been any changes in your 
health and for any new medications you may have begun to take. 
 
Subject’s Responsibilities 
 
While you are in this extension segment of the study, you will be required to: 
 
• Come to the study clinic for all of your scheduled visits, complete all required 
study procedures, follow the instructions listed in this Subject Information Sheet 
and Informed Consent Form, and follow instructions given to you by the study 
staff. 
• Notify the study doctor of any changes in your health and medications or if your 
availability to take part in this study changes. ‘Medications’ include prescriptions 
and non-prescription drugs as well as vitamins or supplements. 
• Agree to continue to take your normal medications for your condition, as 
prescribed by your doctor, throughout this study. The study doctor will change 
your regular medication during this study only if it is necessary for your health. 
• Agree to not donate blood for at least 30 days after you leave the study. 
• For females able to have children, agree to use an acceptable form of birth 
control for the duration of the study and for ≥ 6 months after the last dose of IM 
study drug has been administered, such as intrauterine device (IUD), a condom 
(with or without spermicide), diaphragm or cervical cap with spermicide, oral 
contraceptive pills or other hormonal methods (patches, contraceptive implant or 
a vaginal ring). The study doctor or study staff will discuss this with you in more 
detail. 
• All male subjects must agree to use an acceptable barrier method of birth control 
for the duration of the study, such as a condom with or without spermicide. Men 


Subject Information Sheet and Consent Form 
Laboratorios Farmacéuticos ROVI, S.A. 
Protocol ROV-RISP-2016-01 (PRISMA-3) 
 
PRISMA-3_OLE Segment Master SIS-ICF_V4.0_13Apr2018_English 
 
 
 
 
 
Page 5 of 13 
with an exclusive surgically sterile female partner, as well as men who have 
themselves had a vasectomy (surgical sterilization), are exempt from the 
requirement to use contraception. The study doctor or study staff will discuss this 
with you in more detail. 
 
Avoid certain medicines, supplements, and beverages. Your study doctor will explain to 
you in detail which drugs/vitamins/supplements/herbal extracts/beverages you should 
not take. Please consult him/her prior to starting any new treatment. 
 
For your safety and the safety of others, it is important that you do not drink alcohol 
during the extension segment of the study, and especially you should not drink alcohol 
before or during any of the study visits. If you have any questions about any of these 
restrictions, medications or drugs, please ask the study doctor. 
 
 
Benefits and Risks 
 
In the outpatient clinical setting, non-compliance with prescribed oral antipsychotic 
medication regimens is frequently seen and has been associated with relapse and 
worsening of the disease. Long-acting formulations of antipsychotic medications, 
developed to promote treatment adherence, have helped to improve compliance and 
thus efficacy. Initially developed long-acting formulations of antipsychotic agents, which 
are known to be associated with a number of safety and tolerability concerns that limit 
their acceptability in current clinical practice. 
 
Risperidone ISM® formulation is an alternative long-acting injectable form of the atypical 
antipsychotic, risperidone. As a once monthly intramuscular injection, Risperidone ISM® 
provides rapid achievement (within 24 hours) of therapeutic levels of risperidone with 
sustained therapeutic levels in the blood for a period of up to 4 weeks without the initial 
need for daily oral risperidone supplementation.  
 
Your symptoms of schizophrenia may improve while participating in this extension 
segment of the study. Your participation will contribute to information about the study 
drug and may benefit other patients in the future. 
 
However, please note that your symptoms of schizophrenia may not improve and could 
even worsen during the extension segment of the study. 
 
Possible Side Effects of Risperidone 
 
Risperidone ISM® injection has been previously tested in 3 clinical trials. Adverse 
events reported in adult subjects so far include:  
 
• Endocrine disorders: hyperprolactinaemia - higher levels of prolactin in the blood. 
Prolactin is the hormone that controls the process of lactation 


Subject Information Sheet and Consent Form 
Laboratorios Farmacéuticos ROVI, S.A. 
Protocol ROV-RISP-2016-01 (PRISMA-3) 
 
PRISMA-3_OLE Segment Master SIS-ICF_V4.0_13Apr2018_English 
 
 
 
 
 
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• Gastrointestinal disorders: dry mouth, odynophagia (is painful swallowing, in the 
mouth or gullet) 
• General disorders and administration site conditions: injection site erythema 
(redness of the skin) and injection site pain 
• Nervous system disorders: dizziness, headache, oromandibular dystonia (this is 
a condition involving slow or sustained involuntary contraction of the muscles of 
the mouth, tongue or jaw), sedation, and somnolence 
• Psychiatric disorders: insomnia 
 
These side effects observed in previous clinical studies occurred in more than 5% of 
study subjects; nevertheless it does not mean that all of them were the side effects of 
the study drug. 
 
Frequency and severity of related side effects in previous studies: 
 
The most frequently reported related side effect was hyperprolactinaemia (27.7%); in 
4.0% it was moderate and in 96.0% it was mild. The second most frequently reported 
side effect was injection site pain (21.1%); in 3.9% was moderate and in 96.1% was 
mild. The third most frequently reported side effect was somnolence (6.3%); in 13.0% of 
cases it was moderate and in 87.0% it was mild. 
 
Description of serious side effects in previous studies: 
 
A total of 6 serious side effects related to Risperidone ISM® were observed in 4 subjects 
in previous studies. These serious side effects were 3 oromandibular dystonias (this is a 
condition involving slow or sustained involuntary contraction of the muscles of the 
mouth, tongue or jaw; 2 were severe and 1 was moderate), 2 tachycardias (is a heart 
rate that exceeds the normal resting rate; they were moderate) and 1 sedation which 
was moderate. In all of these cases the subjects recovered from the serious side effect. 
 
 
Possible Discomforts and Reactions Caused by Study Drug Injection 
Sometimes people have reactions at the spot where medications have been injected 
Reactions can include pain, tenderness, hardening of the area, swelling, redness, 
bruising, or itchiness. Very rarely a blood clot may form or an infection may occur. For 
your safety, call the study doctor right away if any of the following things happen at the 
injection site: intense pain, the area feels hard or has lumps, lots of swelling or blistering 
occurs, or if an open wound appears or a dark scab forms. 
 
Discomforts of Blood Tests and ECGs 
You may experience some discomfort, bruising, or slight bleeding on your arm where 
the blood samples are taken. Some people may feel faint or lightheaded for a few 
minutes after having blood taken. 
 


Subject Information Sheet and Consent Form 
Laboratorios Farmacéuticos ROVI, S.A. 
Protocol ROV-RISP-2016-01 (PRISMA-3) 
 
PRISMA-3_OLE Segment Master SIS-ICF_V4.0_13Apr2018_English 
 
 
 
 
 
Page 7 of 13 
The ECG may cause some discomfort or skin irritation where the adhesive (sticky) pads 
are applied to your body. 
 
Unknown/Unforeseeable Risks 
In addition to the risks or discomforts listed above, there may be other risks that are 
currently not known. Also, the risks or discomforts described may occur more often or 
be more severe than has been seen before. 
 
Reproduction Risks 
 
The effects of risperidone on a fetus are unknown. In animal studies, the risperidone 
has shown possible birth defects. Even with using an approved birth control method, a 
pregnancy can still occur. Also, pregnancy tests are not always accurate. There is 
always a possibility that a female is pregnant even if her pregnancy test results indicate 
that she is not pregnant. 
 
 
Sexually active females able to have children and men who are sexually active must 
use a medically acceptable birth control method while in this study and up to six months 
after the last study drug administration. Your study doctor will discuss this with you in 
more detail. Subjects who are abstinent (not sexually active) must agree to use an 
acceptable method of birth control if they become sexually active. 
 
Since the effects of the study drug on sperm are unknown, males are required to use a 
barrier birth control method, such as a condom with or without a spermicide, while being 
in this study. 
 
If you are a female and become pregnant during the study, you will be withdrawn from 
the study. If you think you or your partner might be pregnant at any time during the 
study, please inform the study doctor right away. A member of the research team will 
follow up on you throughout the pregnancy in order to collect information on the 
outcome of the pregnancy and development of the child after birth. Female subjects 
should not breast-feed during or for two months after the last study drug administration. 
 
New Findings 
 
Your study doctor will tell you of any information learned during the course of the study 
that might cause you to change your mind about taking part in the study. You may 
contact the study doctor at any time after your participation ends to find out if any new 
information about this study has become available. 
 
Possible Benefits 
 


Subject Information Sheet and Consent Form 
Laboratorios Farmacéuticos ROVI, S.A. 
Protocol ROV-RISP-2016-01 (PRISMA-3) 
 
PRISMA-3_OLE Segment Master SIS-ICF_V4.0_13Apr2018_English 
 
 
 
 
 
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Your symptoms of schizophrenia may improve while participating in this study. Your 
participation in the study will contribute to information about the study drug and may 
benefit other patients in the future. 
 
Costs  
 
Being in this study will not cost you or your insurance company.  Laboratorios 
Farmacéuticos ROVI, S.A. will pay for all charges for the study drugs.  It will also pay for 
all study-related procedures, like lab tests and ECGs. 
 
Alternative Treatments 
 
You do not have to take part in this extension segment of the study to receive treatment 
for your condition. If you decide not to participate, there are other treatments for 
schizophrenia available to you. Your doctor will discuss alternative treatments with you 
and their benefits and risks. 
 
 
Confidentiality and Data Protection 
 
This section provides information about how your medical records and health 
information (together, your "records") will be used and disclosed in the clinical study 
referenced above. Your records may include information about your blood samples, 
physical examinations, medical history, and any other data collected or reviewed during 
the course of the study as described in the consent form for the study. By signing this 
form, you authorize the study doctor identified in the consent form and the study staff to 
use your records to carry out the study described in the consent form. If you do not sign 
this form, you cannot participate in the study. 
 
Personal Data which will include the following general categories: name, contact details, 
date of birth, age, marital status; and the following sensitive categories: initials, gender, 
race, ethnic origin, health, sex life will be collected from you during the study and 
recorded in your medical notes by the Principal Investigator and/or the hospital/clinic 
staff. 
 
For most purposes, your personal data will be coded and Study records will identify you 
only by number, not by name. This coded personal data will be processed electronically 
by INC Research on behalf of the Study Sponsor. INC Research is a contract research 
organization specialized in organization and management of clinical studies which has 
been contracted by the Sponsor to conduct this project. The Investigator is responsible 
for keeping the code list which makes it possible to link your assigned unique number to 
your name. This will be kept in a safe place to ensure that in case of an emergency you 
can be identified and contacted. The code list may be retained until 15 years after the 
end of the research or 2 years after the treatment has received its last authorisation for 
sale or development has discontinued or as required by applicable law, whichever is 


Subject Information Sheet and Consent Form 
Laboratorios Farmacéuticos ROVI, S.A. 
Protocol ROV-RISP-2016-01 (PRISMA-3) 
 
PRISMA-3_OLE Segment Master SIS-ICF_V4.0_13Apr2018_English 
 
 
 
 
 
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longer. The information in your medical records, and the information you give to us, will 
be kept confidential (private) to the extent allowed by law. If any information from this 
study is published, your identity will not be disclosed, nor will your name be used in any 
way. Only coding or initials will appear on any records used. 
 
In addition, qualified representatives of (i) the Study Sponsor and its worldwide affiliates; 
and/or (ii) INC Research and its worldwide affiliates; and/or (iii) the Food and Drug 
Administration (FDA); and/or (iv) independent auditors; and/or (v) national and foreign 
regulatory authorities (including the European Medicines Agency and the Ethics 
Committee) may look at your medical notes (including uncoded personal data) if 
necessary for data analysis. If your personal data is transferred outside the country the 
Sponsor of the Study is responsible for taking appropriate steps to protect your personal 
data and keep it secure. 
 
With respect to data stored or processed in the United States by INC Research, INC 
Research will process personal data originating from Europe according to the relevant 
Safe Harbor Principles. INC Research subscribes to the "Safe Harbor Principles" issued 
by the U.S. Commerce Department on July 21, 2000. You can view INC Research’s 
certification 
of 
compliance 
with 
the 
Safe 
Harbor 
Principles 
at 
https://safeharbor.export.gov/list.aspx. 
 
By signing this form, you are consenting that the Principal Investigator and 
hospital/clinic staff can use your personal data for purposes of carrying out the Study, 
and can transfer and disclose your personal data to other members of the research 
team, as listed above. 
 
With your permission your general practitioner will also be informed of your participation 
in this Study. 
 
You have the right to access and correct the information collected about you during the 
Study and submit any queries or concerns about the collection or processing of your 
personal data by contacting the Principal Investigator at the address listed on page one 
of 
this 
document 
or 
INC 
Research’s 
Global 
Privacy 
Officer 
at 
data.privacy@incresearch.com. 
 
If you have personal insurance (eg, life insurance) your participation in this study may 
affect your policy. If necessary, before agreeing to take part in this study, you need to 
check this to ensure that your taking part does not affect your medical insurance or 
other personal insurance. 
 
If you decide that you no longer wish to have your personal data shared: 
• You must provide a written request to the Principal Investigator at the address listed 
on page one of this document and tell him or her that you no longer want to share 
your personal data. 


Subject Information Sheet and Consent Form 
Laboratorios Farmacéuticos ROVI, S.A. 
Protocol ROV-RISP-2016-01 (PRISMA-3) 
 
PRISMA-3_OLE Segment Master SIS-ICF_V4.0_13Apr2018_English 
 
 
 
 
 
Page 10 of 13 
• To ensure that the scientific integrity of the trial is not compromised, the research 
team may continue to process any of the personal data that they already have 
collected up until the date that you withdrew your consent. However, going forward, 
no additional personal data from you will be collected. 
• You will no longer be able to take part in this Study. 
• Your personal data may still be shared in accordance with applicable law if: (i) you 
have a bad reaction from the Study drug or device; and/or (ii) collection or further use 
of your personal is necessary to protect your vital interests; and/or it is legally 
required. 
 
Your decision to withdraw your consent to participate will not involve any penalty or loss 
of access to treatment or other benefits to which you are entitled. 
 
Your doctor, the sponsor company, or the regulatory authorities that have reviewed and 
approved the study has the right to stop your participation in the study at any time, with 
or without your consent, for any of the following reasons if: 
 
- 
you have an adverse effect from the study drugs 
- 
you need a treatment not allowed in this study  
 
- 
your study doctor thinks that it is in your best interest not to take part any longer 
in the study  
- 
you do not follow your study doctor’s instructions, and you do not take the study 
drug as instructed  
- 
you are a female and become pregnant 
- 
or the study is canceled by the regulatory authorities or the sponsor company.  
 
If this happens, the reason will be explained to you. 
 
This authorization for use of your personal data will not expire until the end of the trial 
and the final results are obtained, but you may revoke your authorization at any time, by 
writing to the Principal Investigator. 
 
Compensation 
 
If you take part in this extension segment of the study, you will not be paid or rewarded 
in any way but your travelling expenses due to your participation in the study and after 
providing receipts for expenses encountered like travel, parking and meals, will be 
reimbursed with a maximum. Your study doctor can give you the details about how to 
get reimbursed. [If the volunteer is to be reimbursed, clearly state the total amount to be 
paid, conditions for the payment(s) and when the payment(s) will be made.]. You will not 
be charged for the [study drug/device] or for any of the procedures connected with your 
participation in this extension segment of the study. 
 


Subject Information Sheet and Consent Form 
Laboratorios Farmacéuticos ROVI, S.A. 
Protocol ROV-RISP-2016-01 (PRISMA-3) 
 
PRISMA-3_OLE Segment Master SIS-ICF_V4.0_13Apr2018_English 
 
 
 
 
 
Page 11 of 13 
If you become ill or are injured as a direct result of being in this extension segment of 
the study, necessary and associated professional medical care will be provided at no 
cost to you. 
 
The sponsors of this extension segment of the study Laboratorios Farmacéuticos ROVI, 
S.A. will pay (name of hospital department or research fund) for including you in this 
extension segment of the study. This payment represents a compensation for study-
related tests and procedures completed, as required by the protocol. 
 
Contact Persons 
 
If you have any questions about this study, or about what to do if you become ill while in 
the study, please call Dr. [name of principal investigator] at [phone number] or [name of 
sub-investigator, research nurse etc.] at [phone number]. 
 
If you have any questions about your rights as a study subject, please call [subject 
representative, ombudsman local EC etc.] at [phone number]. 
 
 
 
Insurance  
 
In accordance with country regulation, the sponsor of the research has subscribed an 
insurance guaranteeing its civil liability, like that of the study doctors taking part in this 
research. A contract (enter policy number) was issued with the company 
Name and address of the insurance company: ................................................. 
Policy number: ................................  
 
If you experience any unexpected symptoms or injury, and if emergency medical 
treatment is required, please report immediately to your study doctor. 
 
Additional information 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov as 
required by the U.S. Law and on https://www.clinicaltrialsregister.eu/ in agreement with 
the Declaration of Helsinki that recommends public registry of clinical trials [add also 
any country specific public registry if applicable.].  These web sites will not include 
information that can identify you. At most, the Web site will include a summary of the 
results. You can search this web site at any time. 


Subject Information Sheet and Consent Form 
Laboratorios Farmacéuticos ROVI, S.A. 
Protocol ROV-RISP-2016-01 (PRISMA-3) 
 
PRISMA-3_OLE Segment Master SIS-ICF_V4.0_13Apr2018_English 
 
 
 
 
 
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INFORMED CONSENT FORM TEMPLATE 
 
- OPEN-LABEL EXTENSION SEGMENT OF THE STUDY - 
 
Title:  Multicenter, Randomized, Double-Blind, Placebo-controlled Study to Evaluate the 
Efficacy and Safety of Intramuscular Injections of Risperidone ISM® in Patients with 
Acute Exacerbation of Schizophrenia. (PRISMA-3). 
Protocol number: ROV-RISP-2016-01 
EudraCT number: (applicable to EU countries only) 
 
Sponsor name: Laboratorios Farmacéuticos ROVI, S.A. 
Address of Sponsor: C/ Julián Camarillo, 35. 28037 Madrid, Spain 
 
Principal Investigator: Insert Name, affiliation, location 
Telephone number 
Daytime: 
After Office Hours: 
 
 
 
 
 
 
 
Please initial each box to indicate  
 
 
 
 
 
 
 
 
 
your agreement 
1. I confirm that I have read and understand the information sheet for 
the above extension segment of the study. I confirm that the study 
has been explained to me and I have had the opportunity to ask 
questions and ample time to decide whether to participate. I know 
who to contact if I have any further questions. 
 
2. I confirm that I voluntarily agree to participate in this extension 
segment of the study, that I am aware of the conditions of 
participation and withdrawal and that I am free to leave the study at 
any time without giving a reason. I understand that I do not give up 
any of my legal rights by signing this Informed Consent Form. 
 
3. I understand that sections of my medical notes will be reviewed by 
representatives of INC Research, auditors and national and foreign 
regulatory authorities where it is relevant to my taking part in the 
study. I give permission for these individuals to have access to my 
medical records. 
 
4. I agree to the collection and transfer of my personal coded data 
including sensitive data initials, gender, race, ethnic origin, health, 
sex life, to Laboratorios Farmacéuticos ROVI, S.A. and to 
regulatory authorities both within and outside (insert country name), 
including to countries that may not have the same level of data 
protection as (insert country name), 
 
5. I agree that my personal coded data can be archived. 
 
6. I agree that my biological materials (blood, urine, etc) collected 
from me can be used for the purposes of this study. 
 


Subject Information Sheet and Consent Form 
Laboratorios Farmacéuticos ROVI, S.A. 
Protocol ROV-RISP-2016-01 (PRISMA-3) 
 
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7. My consent does not discharge the sponsor and the study doctor 
for their responsibilities. 
 
8. I agree to take part in this study. 
 
 
Do you agree to have your general practitioner informed about your 
participation in the extension segment of this study?         Yes   No 
 
An original or copy of the information sheet and signed consent form will be 
given to you to keep and an original will be placed in your subject’s file at site. 
 
Read and understood:  
 
______________________ 
Patient’s first and last Name 
 
__________________ 
Signature 
 
________ 
Date 
 
________ 
Time 
 
 
 
 
______________________ 
First and last Name of 
Investigator conducting consent 
 
 
__________________ 
Signature 
 
 
________ 
Date               
 
 
________ 
Time 
 

Prot_000.pdf: 
COVER PAGE 
Protocol 
 
TITLE: Multicenter, Randomized, Double-Blind, Placebo-
Controlled Study to Evaluate the Efficacy and Safety of 
Intramuscular Injections of Risperidone ISM® in Patients 
with Acute Exacerbation of Schizophrenia (PRISMA-3) 
 
PROTOCOL NUMBER: ROV-RISP-2016-01 
 
NCT NUMBER: NCT03870880 
 
PROTOCOL VERSION 7.0 
DOCUMENT DATE: 22 MARCH 2018 
 
 


 
Laboratorios Farmacéuticos ROVI, S.A. 
C/ Julián Camarillo 35, 28037 Madrid, Spain 
 
CLINICAL STUDY PROTOCOL 
Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of 
Intramuscular Injections of Risperidone ISM® in Patients with Acute Exacerbation of Schizophrenia 
(PRISMA-3) 
PROTOCOL NUMBER 
ROV-RISP-2016-01 
VERSION 7.0 
 
EudraCT No: 2016-002206-39 
 
CLINICAL DEVELOPMENT PHASE 
III 
 
DOCUMENT DATE 
 
22 March 2018 
 
CONFIDENTIAL 
 
 
This document and its contents are the property of and confidential to Laboratorios Farmacéuticos ROVI, 
S.A.  Any unauthorized copying or use of this document is prohibited. 


Laboratorios Farmacéuticos ROVI, S.A. 
 
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Synopsis 
Protocol Number: ROV-RISP-2016-01 
Title: Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and 
Safety of Intramuscular Injections of Risperidone ISM® in Patients with Acute Exacerbation of 
Schizophrenia (PRISMA-3) 
Active Study Drug: Risperidone ISM® 
Study Sites: Multinational multicenter  
Phase: III 
Objectives: 
Primary: 
 
To evaluate the efficacy of Risperidone ISM as compared with that of placebo in the treatment of 
patients with acute exacerbation of schizophrenia 
Secondary: 
 
To characterize safety and tolerability of Risperidone ISM as compared with that of placebo in 
patients with acute exacerbation of schizophrenia 
 
To quantify healthcare resource utilization (HRU), health-related quality of life (HRQL), and 
social functioning in patients treated with Risperidone ISM versus placebo for an acute 
exacerbation of schizophrenia  
 
To explore pharmacokinetic characteristics of Risperidone ISM and associations with efficacy 
Study Design:  
This is a multicenter, randomized, double-blind, placebo-controlled study designed to evaluate the 
efficacy and safety of Risperidone ISM, a new long-acting injectable form of the licensed drug 
Risperidone.  The study design includes a screening period, a 12-week treatment period, a follow-up 
period, and a 12-month open-label extension period.  Eligible patients will be randomly assigned, under 
double-blind conditions, to receive Risperidone ISM (75 or 100 mg) or placebo. 
If indicated for an individual patient, prohibited medications may be washed out during the screening 
period.  Patients who have never taken Risperidone must have a brief trial of oral Risperidone (2 mg/day 
for 3 days during the screening period) in order to ensure a lack of any clinically significant 
hypersensitivity reactions before the first dose of long-acting intramuscular (IM) study drug is 
administered.  Either of these circumstances may, at the investigators’ discretion, involve admitting the 
patient to the inpatient unit during the screening period.   
An ophthalmological examination, including slit-lamp biomicroscopy examination (eyelids, conjunctiva, 
iris, crystalline lens, sclera, and cornea), best corrected visual acuity, visual field, and intraocular 
pressure, should be done at any time during the screening period. The result of the ophthalmological 
examination must be available by study day -1.  These tests need to be done again at visit 14 or at early 
termination visit.     
Patients enrolled in the double-blind segment of the study will be admitted to the study site’s inpatient 
unit sometime during the screening period (from 1 to 8 days before study day 1).  It is generally 


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anticipated that patients may remain in the inpatient unit for at least 7 days after the first dose of study 
drug is administered, though inpatient duration for a given patient will be flexible.   
The IM study drug (double-blind active Risperidone ISM or placebo) will be administered in a deltoid or 
gluteal muscle for a total of 3 times, once every 4 weeks, during the 12-week treatment period (i.e., at 
study days 1, 29, and 57).  
Efficacy will be assessed by describing changes in scores on standard psychiatric assessment tools at each 
visit.  Safety assessments will also be conducted at each visit.   
Patients who complete planned double-blind study drug treatments and study evaluations may be eligible 
to participate in an optional long-term extension segment of the study, in which treatment with open-label 
Risperidone ISM 75 or 100 mg would begin immediately.  For patients who do not participate in the 
extension segment, a safety follow-up phone contact will occur approximately 2 weeks after the end-of-
treatment visit.  
In addition to patients continuing from the double-blind segment of the study (rollover patients), clinically 
stable patients not previously enrolled in the study (de novo patients) may be eligible to enter the 
long-term extension segment of the study.  These patients will be evaluated for eligibility at a screening 
visit and, if eligible, will be allocated to receive either 75 or 100 mg Risperidone ISM every 4 weeks for 
approximately 12 months. 
Number of Patients: Approximately 436 patients total randomized are planned (145 per arm) in the 
double-blind segment of the study.  Approximately 100 de novo patients are planned to be enrolled in the 
extension segment of the study, in addition to rollover patients. 
Interim Analysis: One unblinded interim analysis will be conducted when 196 (approximately 50%) 
randomized patients, for whom the blinding was not compromised, have either reached study day 85 or 
withdrawn from the study to re-estimate the sample size required for the final analysis up to 558 patients 
(186 patients per arm). 
Treatment: The active study drug is Risperidone ISM, and the comparator study drug (inactive) is 
placebo.  Eligible patients will be randomly assigned under double-blind conditions to receive the 
following study drug treatments in a 1:1:1 ratio during the double-blind treatment period: 
Risperidone ISM 75 mg, Risperidone ISM 100 mg, or placebo. 
During the treatment period of the double-blind segment of the study, treatment assignment for each 
individual patient will remain blinded for patients, investigators, and all study site staff, with the 
exception of certain identified individuals at each study site who will be unblinded in order to prepare and 
administer IM study drug for each patient at that study site.   
However, in the extension segment of the study, all participating patients will receive active Risperidone 
ISM under open-label conditions.  Patients who had been on active Risperidone ISM in the double-blind 
segment of the study will continue to receive active Risperidone ISM at the same dose (i.e., 75 or 100 mg) 
in the extension segment.  Patients who had been receiving placebo in the double-blind segment of the 
study will be randomly assigned to receive either 75 or 100 mg during the extension segment.  However, 
in order to preserve the blinding condition of the double-blind stage of the study, if a participating patient 
enters this OLE phase of the study prior to locking the database of the double-blind stage of the study, the 


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allocation to either 75 or 100 mg of this patient will still be blinded at least up to locking the 
aforementioned database.   
De novo patients participating in the extension segment of the study will receive either 75 or 100 mg 
Risperidone ISM depending on their previous oral risperidone dose.  Patients on 4 mg/day of oral 
risperidone will be assigned to 75 mg Risperidone ISM every 4 weeks, and patients on more than 4 
mg/day to a maximum of 6 mg/day of oral risperidone will be assigned to 100 mg Risperidone ISM every 
4 weeks. 
Duration of Patient Participation: Approximately 12 to 15 weeks in total is planned, including a 
screening period ranging from 1 day to 2 weeks (screening > 8 days requires medical monitor approval), a 
12-week treatment period, and a 2-week follow-up period (not applicable for patients who enter into the 
long-term extension study).  For rollover patients, the optional long-term extension segment of the study 
begins immediately upon completion of the end-of-treatment visit and continues for approximately 12 
months.  For de novo patients, a screening period of up to 8-day is planned, followed by a 12-month 
open-label treatment period.  There is a 4-week follow-up period for all patients in the extension segment 
of the study. 
Study Population: Selected main inclusion criteria for the double-blind segment of the study include the 
following: 
 
Current diagnosis of schizophrenia, according to the Diagnostic and Statistical Manual of Mental 
Disorders, Fifth Edition criteria (DSM-5) 
o Currently experiencing an acute exacerbation or relapse with onset < 2 months before screening 
o If inpatient at screening, has been hospitalized for < 2 weeks for the current exacerbation 
o ≥ 2 years have elapsed since initial onset of active-phase schizophrenia symptoms 
 
Has been able to achieve outpatient status for > 4 months during the past year 
 
Has previously had a clinically significant beneficial response (improvement in schizophrenia 
symptoms), as determined by the investigator, to treatment with an antipsychotic medication other 
than clozapine 
 
Agrees to discontinue prohibited medications as applicable and as clinically indicated according to 
investigator instructions 
 
Dosages of all permitted medications are considered to have been stable (with the exception of 
medication to be used on an as-needed basis) for ≥ 2 weeks prior to the baseline visit and to remain 
stable during participation in this study 
 
Positive and Negative Syndrome Scale (PANSS) results at the screening and baseline visits meets the 
following criteria: 
o Total score between 80 and 120, inclusive 
o Score of ≥ 4 (moderate or greater) for ≥ 2 of the following Positive Scale items: 
 
Item 1 (P1: delusions) 
 
Item 2 (P2: conceptual disorganization) 
 
Item 3 (P3: hallucinatory behavior) 
 
Item 6 (P6: suspiciousness/persecution) 
 
Clinical Global Impression – Severity (CGI-S) score of ≥ 4 (moderately ill or worse) 
 
Age ≥ 18 and ≤ 65 years 


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 
Resides in a stable living situation and is anticipated to return to that same stable living situation after 
discharge from the inpatient study unit, in the opinion of the investigator 
 
Has an identified reliable informant who is anticipated to remain the same after the patient is 
discharged from the inpatient study unit, in the opinion of the investigator 
 
To be eligible for rollover into the extension segment of the study, a patient must meet inclusion criteria 
including the following: 
 
Has completed scheduled participation in the main part of the study, through to the end of the 
treatment period and including the end-of-treatment visit 
 
Continues to require long-term treatment with an antipsychotic medication, in the opinion of the 
investigator 
Selected main inclusion criteria for clinically stable de novo patients in the extension segment of the study 
include the following: 
 
Subject is ≥ 18 and ≤ 65 years old, inclusive, at screening 
 
Subject is on a stable dose of oral risperidone from 4 to 6 mg daily as maintenance therapy for at least 
the last 4 weeks prior/before screening/baseline and would potentially benefit from conversion to an 
extended release injectable, in the opinion of the investigator 
 
Subject has a current diagnosis of schizophrenia, according to the DSM-5 criteria that is clinically 
stable as evidenced by: 
o No hospitalizations for acute exacerbations of schizophrenia and psychiatrically stable without 
significant symptom exacerbation over the last 3 months before screening based on the 
investigator’s judgment  
 
PANSS total score < 70 at screening 
 
CGI-S score of ≤ 3 (mild) at screening 
 
Subject has previously had a clinically significant beneficial response (improvement in schizophrenia 
symptoms), as determined by the investigator, to treatment with an antipsychotic medication other 
than clozapine 
 
Subject with ≥ 2 years elapsed since initial onset of active-phase schizophrenia symptoms 
 
Subject resides in a stable living situation, in the opinion of the investigator 
 
Subject has an identified reliable informant, in the opinion of the investigator 
 
The protocol includes a more extensive set of eligibility (inclusion and exclusion) criteria. 
Variables: 
Efficacy Variables 
Endpoint is defined as study day 85 or the last post-baseline double-blind assessment.   
Primary Efficacy Variable 
 
PANSS total score mean change from baseline to endpoint 


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Secondary Efficacy Variables 
Key Secondary Efficacy Variable 
 
CGI-S score mean change from baseline to endpoint 
 
Other Secondary Efficacy Variables 
 
Clinician Global Impression – Improvement (CGI-I) score mean at endpoint 
 
Overall response rate at endpoint 
o Overall response is defined as either of the following: 
 
PANSS total score ≥ 30% decrease (improvement of symptoms) from baseline to endpoint 
 
CGI-I score of 2 (much improved) or 1 (very much improved) at endpoint 
 
PANSS response rate at endpoint 
o PANSS response is defined as the following: 
 
PANSS total score ≥ 30% decrease (improvement of symptoms) from baseline 
 
Time to reach PANSS response 
 
PANSS total score mean change from baseline at each post-baseline assessment time point 
 
PANSS subscale score mean change from baseline at endpoint and at each post-baseline assessment 
time point for each of the positive, negative, and general psychopathology subscales 
 
Overall response rate at each post-baseline assessment time point 
 
Time to reach overall response 
 
PANSS response rate at each post-baseline assessment time point 
 
CGI-S score mean change from baseline at each post-baseline assessment time point 
 
CGI-I score mean at each post-baseline assessment time point 
 
Health Economics and Outcomes Research Variables 
Endpoint is defined as study day 85 or the last post-baseline double-blind assessment.  
 
 HRU and cost variables include the following: 
o For each item, total quantity of resources used within and outside the participating center at 
endpoint.  For each item, mean number at endpoint and rate of use per 3 months will be 
calculated 
o By-resource use category (e.g., inpatient services, outpatient services) and total direct medical 
costs (reflecting resources used within and outside the participating center) at endpoint and 
average cost per 3 months will be calculated. 
o For all resource use categories combined, total direct medical costs at endpoint and average cost 
per 3 months will be calculated. 
o Indirect costs (days absent from work due to illness) at endpoint 
 
Personal and Social Performance Scale (PSP) total score mean change from baseline at each post-
baseline assessment time point 
 
PSP domain  score mean change from baseline at each post-baseline assessment time point 
 
20-item Subjective Well-Being Under Neuroleptics Treatment Scale (SWN-20) total score mean 
change from baseline at each post-baseline assessment time point 
 
SWN-20 subscale score mean change from baseline at each post-baseline assessment time point 


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Safety Variables 
 
Occurrence, nature, duration, intensity, and relationship to study drug of injection site reactions: 
o Injection site pain, assessed by patients using a visual analog scale (VAS) after each dose 
o Injection site evaluation of redness, swelling, and induration, evaluated by designated study site 
personnel after each injection 
 
Occurrence (incidence), nature, onset time, duration, intensity, action taken, and relationship to study 
drug of treatment-emergent adverse events 
 
Occurrence, nature, time to onset, duration, seriousness criteria, relationship to study drug, and 
outcome of treatment-emergent serious adverse events 
 
Occurrence of extrapyramidal symptoms, as assessed using the Simpson-Angus Scale, Barnes 
Akathisia Rating Scale, and Abnormal Involuntary Movement Scale 
 
Columbia-Suicide Severity Rating Scale 
 
Physical examination, vital signs, weight, body mass index, clinical laboratory test results, and 
electrocardiogram findings 
 
Time to early termination 
Pharmacokinetic Variables (Double-Blind segment only) 
 
Summary plasma concentrations of Risperidone, its active metabolite (9-OH-Risperidone), and the 
active moiety (i.e., Risperidone plus 9-OH-Risperidone) by injection site (gluteal and deltoid) and by 
study drug dose level   
 
Trough concentrations and accumulation index for steady state based on minimum concentration 
values by injection site (gluteal and deltoid) and by study drug dose level   
 
Exploratory associations of pharmacokinetic results with efficacy results   
Genotype Sampling (Double-Blind segment only) 
A blood sample will be collected for evaluation of genotypes for cytochrome P450 enzymes and/or genes 
that are potentially related to efficacy response and/or adverse effects.   


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Table of Contents 
Synopsis .............................................................................................................................................................. 2 
1 
Introduction .............................................................................................................................................. 14 
2 
Objectives ................................................................................................................................................. 17 
2.1 
Primary Objective ............................................................................................................................ 17 
2.2 
Secondary Objectives ...................................................................................................................... 17 
3 
Investigational Plan ................................................................................................................................. 17 
3.1 
Overall Study Design and Plan ....................................................................................................... 17 
3.2 
Requirements and Restrictions ....................................................................................................... 29 
3.2.1 
Contraception and Pregnancy ................................................................................................. 29 
3.2.2 
Concomitant Therapy .............................................................................................................. 29 
4 
Patients ..................................................................................................................................................... 31 
4.1 
Eligibility ......................................................................................................................................... 31 
4.1.1 
Eligibility Criteria for Enrollment into the Double-Blind Segment of the Study ................ 31 
4.1.2 
Eligibility Criteria for Entry into Optional Extension Segment of the Study (Rollover 
Patients) .................................................................................................................................... 35 
4.1.3 
Eligibility Criteria for Entry into Optional Extension Segment of the Study (De Novo 
Patients) .................................................................................................................................... 36 
4.2 
Patient Withdrawal .......................................................................................................................... 39 
5 
Study Treatment ....................................................................................................................................... 39 
5.1 
Study Drugs ..................................................................................................................................... 40 
5.1.1 
Study Drugs ............................................................................................................................. 40 
5.1.2 
Preparation and Administration of Study Drug ..................................................................... 41 
5.2 
Study Site Inpatient Unit ................................................................................................................. 42 
5.3 
Treatment Assignment and Blinding .............................................................................................. 42 
5.3.1 
Treatment Assignment ............................................................................................................ 42 
5.3.2 
Blinding ................................................................................................................................... 43 
5.4 
Study Drug Accountability, Adherence, Handling, and Disposal................................................. 44 
6 
Procedures ................................................................................................................................................ 44 
6.1 
General ............................................................................................................................................. 45 
6.1.1 
Informed Consent .................................................................................................................... 45 
6.1.2 
Demographics, Medical History, and Psychiatric History .................................................... 45 


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6.1.3 
Concomitant Medication Review ........................................................................................... 45 
6.1.4 
MINI International Neuropsychiatric Interview for Schizophrenia and Psychotic Disorders 
Studies ...................................................................................................................................... 45 
6.2 
Efficacy Assessments ...................................................................................................................... 46 
6.2.1 
Positive and Negative Syndrome Scale and Clinician Global Impression ........................... 46 
6.3 
Health Economics and Outcomes Research Assessments ............................................................. 46 
6.3.1 
Healthcare Resource Utilization ............................................................................................. 46 
6.3.2 
Health-Related Quality of Life ............................................................................................... 46 
6.3.3 
Social Functioning .................................................................................................................. 47 
6.4 
Safety Assessments ......................................................................................................................... 47 
6.4.1 
Physical Examination, Body Height, Weight ........................................................................ 47 
6.4.2 
Ophthalmological Examination .............................................................................................. 47 
6.4.3 
Vital Signs ............................................................................................................................... 48 
6.4.4 
Electrocardiogram ................................................................................................................... 49 
6.4.5 
Laboratory Assessments ......................................................................................................... 49 
6.4.6 
Injection Site Reactions .......................................................................................................... 51 
6.4.7 
Extrapyramidal Symptoms Rating Scales .............................................................................. 51 
6.4.8 
Columbia-Suicide Severity Rating Scale ............................................................................... 51 
6.4.9 
Adverse Events ........................................................................................................................ 51 
6.5 
Pharmacokinetic Sample Collection ............................................................................................... 55 
6.6 
Genotype Sample Collection .......................................................................................................... 56 
6.7 
Outcome Variables .......................................................................................................................... 56 
6.7.1 
Efficacy Variables ................................................................................................................... 56 
6.7.2 
Health Economics and Outcomes Research Variables .......................................................... 57 
6.7.3 
Safety Variables ...................................................................................................................... 57 
6.7.4 
Pharmacokinetic Variables ..................................................................................................... 58 
6.7.5 
Genotype Sampling ................................................................................................................. 58 
7 
Statistics ................................................................................................................................................... 58 
7.1 
General Considerations ................................................................................................................... 58 
7.2 
Analysis Populations ....................................................................................................................... 58 
7.3 
Planned Analyses ............................................................................................................................. 59 
7.3.1 
Patient Disposition .................................................................................................................. 59 
7.3.2 
Demographics and Baseline Data ........................................................................................... 60 


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7.3.3 
Study Drug Administration ..................................................................................................... 60 
7.3.4 
Efficacy .................................................................................................................................... 60 
7.3.5 
Safety ....................................................................................................................................... 64 
7.3.6 
Pharmacokinetics .................................................................................................................... 66 
7.4 
Sample Size...................................................................................................................................... 66 
7.5 
Sample Size Re-estimation/Interim Analysis ................................................................................. 67 
8 
Data and Documentation ......................................................................................................................... 68 
8.1 
Data Handling and Record Keeping ............................................................................................... 68 
8.1.1 
Data Handling.......................................................................................................................... 68 
8.1.2 
Data Recording ........................................................................................................................ 68 
8.1.3 
Inspection of Records.............................................................................................................. 69 
8.1.4 
Retention of Records ............................................................................................................... 69 
8.1.5 
Use of Information and Publication Policy ............................................................................ 69 
8.2 
Source Materials Access ................................................................................................................. 69 
8.2.1 
Study Monitoring .................................................................................................................... 69 
8.2.2 
Institutional Review Board ..................................................................................................... 69 
8.2.3 
Audits and Inspections ............................................................................................................ 70 
9 
Quality Control and Assurance ............................................................................................................... 70 
9.1 
Data Collection ................................................................................................................................ 70 
9.2 
Confidentiality ................................................................................................................................. 70 
10 
Ethical Considerations ......................................................................................................................... 70 
10.1 
Ethics Review .................................................................................................................................. 70 
10.2 
Ethical Conduct of the Study .......................................................................................................... 71 
10.3 
Informed Consent ............................................................................................................................ 71 
10.4 
Patient Data Protection .................................................................................................................... 71 
11 
Indemnification .................................................................................................................................... 72 
12 
Further Requirements and General Information ................................................................................ 72 
12.1 
External Service Organizations....................................................................................................... 72 
12.1.1 
Interactive Voice Response System ....................................................................................... 72 
12.1.2 
Contract Research Organization ............................................................................................. 72 
12.1.3 
Central Laboratories for Laboratory Assessments ................................................................ 72 
12.1.4 
Central Facility for Other Assessments.................................................................................. 72 
12.2 
Study Committees ........................................................................................................................... 72 


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12.2.1 
Data Monitoring Committee ................................................................................................... 72 
12.3 
Changes to Final Study Protocol .................................................................................................... 73 
12.4 
Ethics Committee Notification of Study Completion or Termination .......................................... 73 
12.5 
Retention of Study Data .................................................................................................................. 73 
12.6 
Study Report Signatory ................................................................................................................... 73 
References ........................................................................................................................................................ 74 
Appendix A: Study Assessments and Procedures by Study Visit ............................................................. 76 
Appendix B: Prohibited Medications ........................................................................................................ 107 
Appendix C : Rating Scale and Interview Descriptions........................................................................... 108 
Appendix D: Visual Analog Scale (VAS) ................................................................................................ 110 
Appendix E: Risperidone ISM Investigator Brochure ............................................................................. 111 
Appendix F: Contact Information ............................................................................................................. 112 
Appendix G: Protocol Signatories ............................................................................................................ 113 
Appendix H : Investigator Agreement ...................................................................................................... 114 
 


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Abbreviations 
AE 
Adverse event 
AIMS 
Abnormal Involuntary Movement Scale 
ANCOVA 
Analysis of covariance 
AUCtau 
Area under the concentration-time curve for a dosing interval  
BARS 
Barnes Akathisia Rating Scale 
CGI-I 
Clinician Global Impression – Improvement  
CGI-S 
Clinician Global Impression – Severity  
Cmax 
Maximum concentration 
CRO 
Contract Research Organization 
C-SSRS 
Columbia-Suicide Severity Rating Scale  
Ctrough 
Trough concentration in plasma 
CHW 
Cui, Hung, Wang 
DMC 
Data Monitoring Committee 
DMSO 
Dimethyl sulfoxide 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
GCP 
Good Clinical Practice 
HRQL 
Health-related quality of life 
HRU 
Healthcare resource utilization 
ICH 
International Council for Harmonisation of Technical Requirements for Pharmaceuticals 
for Human Use 
IEC 
Independent Ethics Committee 
IM 
Intramuscular 
IOP 
Intraocular pressure 
IRB 
Institutional Review Board 
ISM 
In situ microparticle 
ITT 
Intent-to-treat 
mITT 
modified Intent-to-treat 
MMRM 
Mixed effect model with repeated measurements 
OLE 
Open-label extension 
PANSS 
Positive and Negative Syndrome Scale 
PLGA 
Poly lactic-co-glycolic acid 
PP 
Per-protocol 
mPP 
modified Per-Protocol 
PSP 
Personal and Social Performance Scale 
QTcB 
QT interval corrected for heart rate using Bazett’s formula 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
RO 
Receptor occupancy 
SAE 
Serious adverse event 
SAS 
Simpson-Angus Scale 
SWN-20 
20-item Subjective Well-Being Under Neuroleptics Treatment Scale 
THC 
Tetrahydrocannabinol 


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Tmax 
Time to maximum concentration 
VAS 
Visual analog scale 


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1 Introduction 
In the outpatient clinical setting, nonadherence with prescribed oral antipsychotic medication regimens is 
prevalent in patients with schizophrenia and has been associated with relapse and worsening of long-term 
functional and mental outcomes.1,2  Long-acting formulations of antipsychotic medications, developed to 
promote treatment adherence, have helped to improve compliance and thus efficacy.3  Initially developed 
long-acting formulations include typical antipsychotic agents, which are known to be associated with a 
number of safety and tolerability concerns that limit their acceptability in current clinical practice.  Long-
acting formulations also are available for certain atypical antipsychotics, including Risperidone (Risperdal 
Consta®) and paliperidone palmitate (Xeplion® and Invega Sustenna®).  Risperdal Consta has been shown 
to be efficacious in achieving and maintaining remission status, and studies have shown an overall 
reduction in healthcare costs associated with frequent relapse and hospitalization.4    
Clinical studies have shown that intramuscular (IM) paliperidone palmitate may be clinically useful in the 
treatment of patients with acute schizophrenia who were previously unsuccessfully treated with oral 
antipsychotics.5,6  However, the number of currently available long-acting atypical antipsychotic 
medication options is limited, and thus there is a clinical need for additional long-acting atypical 
antipsychotic medication options.   
Risperidone ISM® is an injectable IM in situ microparticle (ISM) long-acting formulation of risperidone 
currently in clinical development as a treatment for schizophrenia.  Risperidone ISM is intended for IM 
administration once every 4 weeks, without any supplementation with oral risperidone.  Previous studies 
of Risperidone ISM support its further clinical development.   
Two single-dose clinical phase I studies have been conducted to characterize the pharmacokinetic 
characteristics and to evaluate the safety and tolerability of Risperidone ISM in healthy volunteers 
(n = 17) and in subjects with schizophrenia or schizoaffective disorder (n = 36), respectively.   
In the phase I study in healthy volunteers (ROV-RISP-2009-01), single Risperidone ISM doses of 
25 mg (n = 8) and 37.5 mg (n = 9) were evaluated, and all subjects completed the study.  Risperidone, 
9-OH-risperidone, and the active moiety (risperidone and 9-OH-risperidone combined) plasma 
concentration profiles showed that while plasma concentrations were higher for the 37.5 mg dose than for 
the 25 mg dose, maximum concentration (Cmax) and area under the concentration-time curve values 
increases were not dose proportional.  All subjects had at least 1 treatment-emergent adverse event (AE).  
The most frequently reported AEs were somnolence (10.1%) and injection site pain (8.1%), all of which 
were considered to be of mild or moderate intensity.  Only 2 subjects, both in the second cohort (37.5 
mg), had a serious AE (SAE).  Each of these 2 subjects had 2 SAEs; the same 2 SAEs of tachycardia and 
oromandibular dystonia were reported by both subjects.  All subjects were considered to have recovered 
by the end of the study.   
In the phase I study in subjects with schizophrenia or schizoaffective disorder (ROV-RISP-2011-01 
[PRISMA-1]), the pharmacokinetic characteristics of risperidone after single Risperidone ISM doses of 
50 mg (n = 13), 75 mg (n = 12), and 100 mg (n = 11) were delineated.  Risperidone, 9-OH-risperidone, 
and the active moiety (risperidone and 9-OH-risperidone combined) plasma concentration profiles over 
time (up to 75 days after administration of Risperidone ISM) showed the following active moiety mean 


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concentrations in the 50 mg, 75 mg, and 100 mg groups, respectively (for 3 selected time points after 
injection of Risperidone ISM): 21.4 ng/mL, 24.6 ng/mL, and 29.6 ng/mL at 24 hours; 22.8 ng/mL, 
24.5 ng/mL, and 31.4 ng/mL at 48 hours; and 12.2 ng/mL, 17.3 ng/mL, and 20.0 ng/mL at 30 days).  
Estimated pharmacokinetic parameters of Risperidone ISM were in line with the results of the previous 
phase I study and with the literature on other marketed long-acting atypical antipsychotics, and overall, 
Risperidone ISM at all 3 tested dose strengths provided sustained release of risperidone and achieved 
therapeutic plasma levels within 1 day after injection.  Overall, 34 subjects (94.4%) had at least 1 
treatment-emergent AE during the study; the percentage of subjects reporting at least 1 treatment-
emergent AE was similar across the 3 dose groups (92.3%, 100%, and 90.9% in the 50 mg, 75 mg, and 
100 mg groups, respectively).   
A phase II multiple-dose study has also been conducted (ROV-RISP-2011-02 [PRISMA-2]).  Population 
pharmacokinetics modeling simulations were performed to guide the dose selection in this multicenter, 
open-label, 2-arm, parallel-design, repeat-dose clinical study to evaluate the pharmacokinetics, safety, and 
tolerability of 4 monthly IM injections of Risperidone ISM (75 mg) in subjects with schizophrenia.  
Risperidone ISM provided a sustained release of risperidone that achieved monthly therapeutic plasma 
levels within 1 day, without oral supplementation.   
The preliminary safety data of Risperidone ISM from the clinical studies mentioned above are consistent 
with the well-known safety profile of other marketed risperidone products in subjects with schizophrenia 
or schizoaffective disorder and have shown Risperidone ISM to be well tolerated in the subjects 
evaluated.   
Based on the pharmacokinetic results from the phase I study in healthy volunteers (ROV-RISP-2009-01), 
a population pharmacokinetic model was constructed to estimate plasma concentrations for therapeutic 
doses of Risperidone ISM.  For the phase I clinical study (ROV-RISP-2011-01 [PRISMA-1]), both 
overall exposures and an active moiety Cmax cutoff point of 80 ng/mL were considered in dose selection.  
A maximum dose of 100 mg was selected for use in the first part of the study, as the population 
pharmacokinetic model’s worst-case estimate was that this dose would provide an active moiety median 
Cmax value of approximately 80 ng/mL (i.e., assuming log-linear increases in bioavailability with 
ascending doses).  Data from the phase I and phase II studies were used to further refine the population 
pharmacokinetic model to support dose selection for this and other phase III clinical studies.   
Simulations and comparison of 5 multiple-dose regimens (37.5, 50, 75, 100, and 125 mg) showed that 
doses of 75 and 100 mg administered either in the gluteal or deltoid muscle resulted in predicted median 
Cmax and trough concentration in plasma (Ctrough) that stayed between thresholds of 7.5 and 80 ng/mL, 
thereby reducing the risk of extrapyramidal symptoms while maintaining plasma concentrations 
sufficiently high for efficacy. 
Plasma concentration-time profiles and steady-state pharmacokinetic parameters of the active moiety after 
4 doses (75 and 100 mg) Risperidone ISM were compared to commercially available Xeplion 
(paliperidone palmitate).  Paliperidone is the active metabolite of risperidone (i.e., 9-OH-risperdione) and 
is administered as initial doses of 150 and 100 mg, given 1 week apart, followed by a maintenance dosing 
regimen of 75 or 100 mg, given every 4 weeks.  There was a large overlap in pharmacokinetic profiles.  
In a number of patients, the predicted plasma concentrations of active moiety at the end of the 28-day 
treatment with 75 and 100 mg isperidone ISM were below the lower threshold of 7.5 ng/mL.7  Steady-


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state pharmacokinetic parameters varied between the 2 drugs with Cmax being slightly higher and Ctrough 
slightly lower after administration of Risperidone ISM. 
Furthermore, the same 2 doses (75 and 100 mg) of Risperidone ISM were compared to oral risperidone 
given daily at doses of either 4 mg/day or 6 mg/day.  Full adherence was assumed for oral risperidone.  
Compared to Risperidone ISM, 4 mg/day oral risperidone resulted in steady-state plasma concentrations 
of the active moiety above 7.5 ng/mL in almost all patients.  In addition, all simulated profiles did not 
reach the upper threshold of 80 ng/mL, which is considered to be a surrogate for safety.  For the higher 
dose of 6 mg/day, predicted plasma concentrations were higher than 80 ng/mL in a number of patients 
and over the entire dosing interval.  The 75 mg dose of Risperidone ISM resulted in similar area under the 
concentration-time curve within a dosing interval and average plasma concentration as the oral 4 mg/day 
dose.  However, it should be kept in mind that nonadherence to long-term oral medication is a well-
known therapeutic issue in schizophrenia.8,9  Hence, the simulated pharmacokinetic profiles after oral 
risperidone treatment are predicted to be higher than those that may be actually expected in patients with 
schizophrenia.  As a consequence, Ctrough values after oral treatment in patients with schizophrenia may 
well be in the same range or even lower than those predicted for Risperidone ISM. 
In an exploratory evaluation of predicted D2 receptor occupancy (RO), it was shown that after IM 
administration of a 100 mg and 125 mg dose of Risperidone ISM, median D2 RO stayed within the 65% 
to 80% window over the entire 4-week dosing interval, only slightly exceeding the upper limit in the first 
week after administration.  Comparison of Risperidone ISM with Xeplion showed that predicted median 
average RO values were comparable for both compounds after administration of a maintenance dose of 
75 or 100 mg.  However, predicted median Ctrough RO values were slightly lower and predicted median 
peak RO slightly higher after administration of Risperidone ISM.  When evaluating predicted D2 RO, it 
should be kept in mind that the correlation between D2 RO and clinical responses to an antipsychotic 
drug might be more complex and that patients might experience efficacy on much lower predicted D2 RO 
or might not experience any extrapyramidal symptoms at higher predicted D2 RO.10   
These doses are expected to produce therapeutic levels of risperidone within 24 hours of the first 
injection; these therapeutic levels will be maintained for 28 days and will provide sustained levels of 
risperidone throughout the duration of the study.  Thus, this study is designed to statistically demonstrate 
superior efficacy of Risperidone ISM to placebo. 


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2 Objectives 
2.1 Primary Objective 
The primary objective of this study is the following:  
 
To evaluate the efficacy of Risperidone ISM as compared with that of placebo in the treatment of 
patients with acute exacerbation of schizophrenia 
2.2 Secondary Objectives 
The secondary objectives of this study are the following:  
 
To characterize safety and tolerability of Risperidone ISM as compared with that of placebo in 
patients with acute exacerbation of schizophrenia 
 
To quantify healthcare resource utilization (HRU), health-related quality of life (HRQL), and social 
functioning in patients treated with Risperidone ISM versus placebo for an acute exacerbation of 
schizophrenia  
 
To explore pharmacokinetic characteristics of Risperidone ISM and associations with efficacy 
3 Investigational Plan 
3.1 Overall Study Design and Plan 
This is a multicenter, randomized, double-blind study designed to evaluate the efficacy and safety of 
Risperidone ISM, a new long-acting injectable form of the licensed drug risperidone.  Eligible patients 
will be randomly assigned, under double-blind conditions, to receive Risperidone ISM (75 or 100 mg) or 
placebo. 
The study design includes a screening period (planned duration 1 to 8 days) immediately preceding the 
baseline day (designated as study day 1), a treatment period (duration 12 weeks), a follow-up period 
(duration 2 weeks; not applicable for patients who enter into a long-term extension study), and an 
open-label extension period (duration 12 months).   
The screening period for a given patient generally should be as brief as is clinically feasible (e.g., target of 
3 days preferred) but may last up to 8 days (e.g., in order to safety washout any prohibited medications); 
an extension up 14 days maximum may be permitted with medical monitor approval.  Eligible patients 
should be admitted to the inpatient study unit upon completion of screening assessments at the initial 
screening visit.    
Patients will have a diagnosis of schizophrenia experiencing an acute exacerbation.  Following 
confirmation of eligibility, each patient will be randomly assigned under double-blind conditions to 
receive 1 of the following 3 study drug treatments: Risperidone ISM 75 mg, Risperidone ISM 100 mg, or 
placebo. 
The randomization scheme will ensure that an overall 1:1:1 ratio of assignments to each of these 3 study 
drug treatments is approximated.  


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Patients who have never taken risperidone must have a brief trial of oral risperidone 2 mg/day for 3 days 
during the screening period in order to ensure a lack of any clinically significant hypersensitivity 
reactions before the first dose of long-acting IM study drug is administered.  A trial of oral risperidone is 
not required for patients who have previously taken any formulation of risperidone. 
Patients enrolled in the double-blind segment of the study will be admitted to the study site’s inpatient 
unit sometime during the screening period (from 1 to 8 days before study day 1).  It is generally 
anticipated that patients may remain on the inpatient unit for at least 7 days after the first IM dose of long-
acting study drug is administered.  However, inpatient duration may vary for individual patients and 
potentially may range from 1 to 14 days.  If the investigator determines that a given patient should remain 
inpatient beyond study day 15, the medical monitor should be contacted to discuss the extension.   
Study drug will be administered as IM injections (see Section 5.1.2).  Treatment assignment for each 
individual patient will remain blinded for patients, investigators, and all study site staff, with the 
exception of identified individuals at each study site who will be unblinded in order to prepare and 
administer study drug for each patient at that study site.   
After initial dosing on study day 1, each study drug (Risperidone ISM or placebo) will be administered 
once every 4 weeks during the 12-week treatment period (i.e., at study days 29 and 57).   
Efficacy will be assessed by describing changes in scores on standard psychiatric assessment tools at each 
visit, and safety assessments will be conducted at each visit as well.   
Patients who complete planned participation in this study through to the end of the treatment period may 
be eligible to enter into an optional long-term extension segment of the study during which open-label 
Risperidone ISM (i.e., either 75 or 100 mg) will be administered to all participating patients once every 
4 weeks for approximately 12 months.  However, in order to preserve the blinding condition of the 
double-blind stage of the study, if a participating patient enters this OLE phase of the study prior to 
locking the database of the double-blind stage of the study, the allocation to either 75 or 100 mg of this 
patient will be still blinded at least up to locking the aforementioned database. Patients who enter into the 
extension segment of the study will begin participation in the extension segment immediately upon 
completion of the end-of-treatment visit assessments and procedures.  Patients who do not enter into the 
extension segment will have a final safety follow-up phone contact approximately 2 weeks after the end-
of-treatment visit.  
The planned total number of randomized patients in the double-blind segment of the study is 
approximately 436 patients total randomized planned (145 in each of the 3 treatment groups) (see Section 
7.4). Note: due to a potential accidental unblinding quality issue, it was considered that 43 patients were 
potentially compromised and therefore the sample size has been increased to compensate them. 
In addition to patients continuing from the double-blind segment of the study (rollover patients), patients 
not previously enrolled in the study (de novo patients) may be eligible to enter the long-term extension 
segment of the study.  These patients will be evaluated for eligibility at a screening visit and, if eligible, 
will be allocated to receive either 75 or 100 mg Risperidone ISM every 4 weeks for approximately 
12 months.   


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Approximately 100 de novo patients are planned to be enrolled in the extension segment of the study, in 
addition to rollover patients. 
The overall study design is depicted schematically in Figure 1.  A schedule of assessments and procedures 
is displayed by visit in Table 1, Table 2 and Table 3.   
Figure 1: Schematic of Study Design 
 
 
TREATMENT PERIOD 
  
 
 
 
Risperidone ISM 100 mg 
FOLLOW-UP 
VISIT a 
 
 
 
 
 
 
 
Risperidone ISM 75 mg 
Or 
SCREENING 
 
 
 
ENTER 
EXTENSION 
SEGMENT b,c 
 
 
Placebo 
 
 
Administer Study Drug: X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
Study Day: 1 
 
 
 
29 
 
 
 
57 
 
 
 
85 
 
 
Study Week: 
 
1 
 
 
4 
 
 
 
8 
 
 
 
12 
a If a patient does not enter the extension segment of the study, no additional doses of study drug will be administered to that 
patient.  
b Patients who complete planned participation through to the end of the treatment period may be eligible to enter into a 
long-term extension segment of the study, during which open-label Risperidone ISM (i.e., 75 or 100 mg) will be administered 
once every 4 weeks for approximately 12 months.  However, in order to preserve the blinding condition of the double-blind 
stage of the study, if a participating patient enters this OLE phase of the study prior to locking the database of the double-blind 
stage of the study, the allocation to either 75 or 100 mg of this patient will be still blinded at least up to locking the 
aforementioned database. Patients who enter into the extension segment will begin participation in the extension segment 
immediately upon completion of scheduled end-of-treatment assessments and procedures at the week 12 time point.  Patients 
who had been on active Risperidone ISM in the double-blind segment of the study will continue to receive active Risperidone 
ISM at the same dose (i.e., 75 or 100 mg) in the extension segment; patients who had been receiving placebo in the double-
blind segment of the study will be randomly assigned to receive either 75 or 100 mg during the extension segment.   
c De novo patients may also be eligible to enter the long-term extension segment of the study.  These patients will be evaluated 
for eligibility at a screening visit and, if eligible, will be allocated to receive either 75 or 100 mg Risperidone ISM every 4 
weeks for approximately 12 months.  De novo patients on 4 mg/day of oral risperidone will be assigned to 75 mg Risperidone 
ISM every 4 weeks, and patients on more than 4 mg/day to a maximum of 6 mg/day of oral risperidone will be assigned to 100 
mg Risperidone ISM every 4 weeks. 
 
 


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Table 1 
Schedule of Assessments and Procedures 
Screening Baseline 
Treatment Period (Double-Blind) 
Follow 
-up 
Study Visit Number:
1 
2 
3 
4 
5 
6 
71 
8 
9 
10 
11 
12 
13 
142 
153 
Study Day4:
-8 to -15 
1 
3 
4 
8 
15 
22 
29 
31 
43 
57 
59 
71 
85 
99 
Treatment Week:
 
 
 
 
1 
2 
3 
4 
 
6 
8 
 
10 
12 
 
Overall Dosing Sequence:
 
1 
 
 
 
 
 
2 
 
 
3 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening assessments6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility criteria review7 
X 
X 
 
 
 
 
 
 
Inpatient study unit8 
X 
X 
X 
X 
(X) 
(X) 
 
 
 
(Test oral risperidone)9 
(X) 
 
 
 
 
 
 
Randomization10 
X 
 
 
 
 
 
 
Inject IM study drug11 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
Efficacy scales:12 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PANSS 
X 
X 
 
X 
X 
X 
 
X 
 
 
X 
 
 
X 
CGI-S 
X 
X 
 
X 
X 
X 
 
X 
 
 
X 
 
 
X 
CGI-I 
 
X 
X 
X 
 
X 
 
X 
X 
 
X 
X 
Socio-demographic 
information 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
HRU data collection – 
center 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
HRU data collection – 
patient 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
Health outcome scales13 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PSP (clinician 
administered) 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
SWN-20 (patient 
reported) 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
Safety assessments: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AEs14 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant meds15 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination 
X 
 
 
 
X 
X 
 
 
 
 
 
 
 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight and body mass 
index 
X 
X 
 
 
X 
X 
 
X 
 
 
X 
 
 
X 
 
Vital signs16 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECG17 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Injection site evaluation18 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
Injection site pain VAS18 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
Safety scales:12 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AIMS 
X 
X 
 
X 
X 
X 
 
X 
 
X 
X 
 
X 
X 
BARS 
X 
X 
 
X 
X 
X 
 
X 
 
X 
X 
 
X 
X 
SAS 
X 
X 
 
X 
X 
X 
 
X 
 
X 
X 
 
X 
X 
C-SSRS 
X 
X 
 
 
X 
X 
 
X 
 
X 
 
X 
Ophthalmological 
examination19 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Blood sample for: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology panel20 
X 
X 
 
 
X 
X 
 
X 
 
X 
 
X 


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Screening Baseline 
Treatment Period (Double-Blind) 
Follow 
-up 
Study Visit Number:
1 
2 
3 
4 
5 
6 
71 
8 
9 
10 
11 
12 
13 
142 
153 
Study Day4:
-8 to -15 
1 
3 
4 
8 
15 
22 
29 
31 
43 
57 
59 
71 
85 
99 
Treatment Week:
 
 
 
 
1 
2 
3 
4 
 
6 
8 
 
10 
12 
 
Overall Dosing Sequence:
 
1 
 
 
 
 
 
2 
 
 
3 
 
 
 
Chemistry panel21 
X 
X 
 
 
X 
X 
 
X 
 
X 
 
X 
Prolactin  
X 
X 
 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
Pharmacokinetics22 
X 
X 
 
X23 
X23 X23 
X 
X 
X 
X 
X 
Genotype24 
X 
 
 
 
 
 
 
Serology panel25 
X 
 
 
 
 
 
 
Pregnancy test (serum) 
X 
 
 
 
 
 
 
Urine sample for: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test26 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
Urinalysis27 
X 
X 
 
 
X 
X 
 
X 
 
X 
 
X 
Drug screen28 
X 
X 
 
 
(X) 
(X) 
 
(X) 
 
(X) (X) 
 
(X) 
(X) 
AE = adverse event; AIMS = Abnormal Involuntary Movement Scale; BARS = Barnes Akathisia Rating Scale; CGI-I = Clinical 
Global Impression – Improvement; CGI-S = Clinical Global Impression – Severity; C-SSRS = Columbia-Suicide Severity Rating 
Scale; ECG = electrocardiogram; HRU = healthcare resource utilization; IM = intramuscular; ISM = in situ microparticle; 
PANSS = Positive and Negative Syndrome Scale; PSP = Personal and Social Performance Scale; SAS = Simpson-Angus Scale; 
SWN-20 = 20-item Subjective Well-Being Under Neuroleptics Treatment Scale; VAS = visual analog scale; (X) = assessment to 
be done as applicable.
                                                       
1  Study visit 7 (study day 22) is applicable to patients who participate in pharmacokinetic subgroup only. 
2  Visit 14, which is scheduled to occur at the week 12 time point, is the designated end-of-treatment visit.  However, if a patient 
withdraws or is withdrawn early from the study (i.e., before the week 12 time point), an early termination visit should occur at 
which time all assessments for the end-of-treatment visit (as listed for visit 14) will be performed.   
3  The follow-up visit will be conducted by telephone.  The follow-up visit is to occur 14 (± 3) days after the end-of-treatment 
visit (i.e., the week 12 time point or earlier in the case of an early termination).  This visit is not applicable for patients who 
enter into a long-term extension study. 
4 The study day 4 (visit 4) must occur 3 days after study day 1.  Allowable study visit time windows for treatment period study 
visits occurring after visit 4 (study day 4) are ± 1 day for study visit 5, ± 2 days for study visit 14, and ± 3 days for each of the 
other treatment period study visits (i.e., study visits 6 through 13, inclusive).   
5  If there is a valid reason for a given potential patient to extend the screening period duration beyond the designated 8 days, the 
investigator may contact the medical monitor to request an extension of up to 14 days; such an extension may be implemented 
only after medical monitor approval has been obtained.   
6  Screening assessments will include the following: informed consent, demographic data, medical and psychiatric history, and a 
diagnostic interview (which will include completion of the MINI International Neuropsychiatric Interview for Schizophrenia 
and Psychotic Disorders studies, version 7.0.2).  
7  Eligibility will be determined by the investigator, who will assess eligibility by confirming that that all inclusion criteria (see 
Section 4.1.1.1) have been met and that none of the exclusion criteria have been met (see Section 4.1.1.2).   
8  Patients who, after completion of all scheduled assessments on the screening visit day, are considered provisionally eligible 
will be admitted directly to the inpatient study that day.  Patients will subsequently remain in the inpatient study unit for the 
remainder of the screening period (i.e., through study day -1, inclusive).  Confirmed eligible patients will remain inpatient on 
study day 1.  No patient should be discharged from the inpatient before study day 2, and it is anticipated that most patients will 
remain on the inpatient unit through study day 8, and that thereafter patients will be discharged from the inpatient unit when 
the investigator has assessed the patient and determines that he or she is appropriately clinically stable and otherwise ready for 
safe discharge.  After study day 8, continuation of a patient on the inpatient unit from study day 9 through study day 15, 
inclusive, is an allowable option, as deemed clinically indicated.  If the investigator believes that a given patient should remain 
inpatient beyond study day 15, the investigator should contact the medical monitor to discuss the proposed inpatient duration 
extension.   
 


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9  Patients who have never taken risperidone must take oral risperidone 2 mg/day for 3 days sometime during the screening 
period to ensure a lack of clinically significant hypersensitivity before the first IM dose of study drug is administered; this oral 
risperidone trial is not required for patients who have previously taken any formulation of risperidone.   
10  A unique randomization number will be assigned via interactive voice or web response system accessed immediately after 
eligibility confirmation of a patient.  The randomization process will determine (under double-blind conditions) for each 
individual patient the study drug regimen: an individual patient will receive either active Risperidone ISM or IM placebo.   
11 All study drug doses will be administered by deep IM injection (deltoid muscle or gluteal muscle).  The IM study drug doses 
will be prepared and administered by a designated unblinded individual at the study site (see Section 5.1.2).  The IM study 
drug will contain either active Risperidone ISM (75 or 100 mg) or placebo (double blind).   
12 See Appendix C – Rating Scale and Interview Descriptions. 
13 Health economics and outcomes research evaluations.  To be administered prior to medication dose.    
14  Monitoring for AEs will occur throughout a patient’s participation in this study, starting from the patient’s signature of 
informed consent form; required details of identified AEs are to be recorded.   
15  Information regarding concomitant medications, including new medications and changes to existing medications, will be 
elicited and recorded.   
16  Vital signs will include blood pressure, pulse rate, respiratory rate, and body temperature .  At each identified time point, vital 
signs will be measured after the patient has been resting in a supine position for at least 5 minutes.  On days when patients 
receive an IM injection of study drug, vital signs are to be measured within 1 hour before and then again within 3 hours after 
the study drug injection; at each of these time points, orthostatic blood pressure and pulse rate will be measured (immediately 
after completion of supine vital sign measurements) after the patient has risen from the supine to the standing position and has 
remained standing for approximately 3 minutes (see Section 6.4.3).   
17  A 12-lead ECG will be performed at identified visits; on days when patients receive an injection of IM study drug, an ECG 
will be performed both before and after dosing.  Pre-dose ECG is to be completed within 1 hour prior to dosing.  The post-dose 
ECG is to be completed within 3 hours post-dose.  All scheduled ECGs are to be performed after the patient has rested quietly 
for at least 5 minutes in the supine position (see Section 6.4.4).   
18 The patient will perform and record self-assessment of pain at the injection site using the injection site pain VAS (see 
Appendix D) approximately 1 hour after each study drug injection.  The investigator will inspect the recent injection site and 
all injection sites where IM study drug has been injected on previous visits, also approximately 1 hour after each study drug 
injection. 
19 Ophthalmological examination will include slit-lamp biomicroscopy examination (eyelids, conjunctiva, iris, crystalline lens, 
sclera, and cornea), best corrected visual acuity, visual field, and intraocular pressure (see Section 6.4.2).  
20 The hematology panel includes the following tests: hematocrit, hemoglobin, red blood cell count, white blood cell count and 
differential count (absolute values for basophils, eosinophils, lymphocytes, monocytes, and neutrophils), and platelets. 
21  The chemistry panel will include standard tests as well as hemoglobin A1c, thyroid-stimulating hormone, and a lipid panel.   
22  Pharmacokinetic samples will be obtained for all patients in the study on days 1, 3, 29, 31, 57, 59, and 85 (visits 2, 3, 8, 9, 11, 
12, and 14, respectively).  Pharmacokinetic samples will also be collected from patients who have a serious AE.   
23 A subgroup of 75 study participants will have additional pharmacokinetic samples collected on days 8, 15, and 22 (visits 5, 6, 
and 7, respectively). 
24 Genotype samples will be obtained only from those patients who sign a separate consent form for genotype sample collection. 
In these patients, a blood sample for genotype testing may be collected at any time point after randomization (see Section 
6.7.5.)  
25 A blood sample for a serology panel testing for hepatitis B surface antigen, antihepatitis C antibodies, and human 
immunodeficiency virus will be performed at screening only.   
26 On study day 1 and at identified visits thereafter, onsite dipstick tests will be used for urine pregnancy tests.  On each study 
drug dosing day, the urine pregnancy test must be performed and a negative result confirmed before the schedule dose of study 
drug for that day is administered.   
27 The urinalysis includes the following tests: color, pH, specific gravity, ketones, protein, glucose, bilirubin, nitrite, urobilinogen, 
and occult blood.  Microscopic examination only if urinalysis dipstick results are abnormal. 
28  Urine drug screen is mandatory at screening and baseline and is optional thereafter.  On these timepoints, the sample will be 
sent to the laboratory for analysis (see Section 6.4.5.4.3).  The urine drug screen will include identification of the presence or 
absence of amphetamines, barbiturates, cocaine, methadone, opioids, and phencyclidine, as well as for tetrahydrocannabinol, 
alcohol, and benzodiazepines. In addition, onsite dipstick urine drug screen testing (with the exception of alcohol) may be 
optionally performed on the sample collected. 
 
 
 
 


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Table 2 
Schedule of Assessments and Procedures: Optional Open-label Extension Segment for 
Rollover Patients 
Extension 
Baseline 
Extension Segment Treatment Period (Open-Label) 
Extension 
Follow-up 
Extension Visit Number:
   11 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 12 
13 142 
153 
Extension Study Day4:
   15 
29 
57 
85 113 141 169 197 225 253 281 309 337 365 
393 
Extension Treatment Week:
 
4 
8 
12 16 
20 
24 28 
32 
36 
40 44 
48 
52 
56 
Extension Dosing Sequence:
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 12 
13 
 
 
Informed consent6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility criteria review7 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inject Risperidone ISM8 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Efficacy scales: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PANSS 
 X9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
CGI-S 
 X9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
CGI-I10 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Socio-demographic 
information 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
HRU data collection – center 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
HRU data collection – patient 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Health outcome scales:11 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PSP (clinician administered) 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
X 
 
SWN-20 (patient reported) 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
X 
 
Safety assessments: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AEs12 
 X9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant meds13 
 X9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination 
 X9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Weight and body mass index 
 X9 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
Vital signs14 
X8 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECG15 
X8 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
Injection site evaluation16 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Injection site pain VAS16 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Safety scales: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AIMS 
 X9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
BARS 
 X9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
SAS 
 X9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
C-SSRS 
 X9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Blood sample for: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology panel17 
 X9 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
Chemistry panel18 
 X9 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
Prolactin 
 X9 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
Pregnancy test19 (serum) 
(X) 
(X) (X) (X) (X) (X) (X) (X) (X) (X) (X) (X) (X) (X) 
 
Urine sample for: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test20 
 X9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Urinalysis21 
 X9 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
Drug screen22 
(X) 
(X) (X) (X) (X) (X) (X) (X) (X) (X) (X) (X) (X) (X) 
  
 
 


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22 Mar 2018 
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Page 24 of 114 
AE = adverse event; AIMS = Abnormal Involuntary Movement Scale; BARS = Barnes Akathisia Rating Scale; CGI-I = Clinical 
Global Impression – Improvement; CGI-S = Clinical Global Impression – Severity; C-SSRS = Columbia-Suicide Severity Rating 
Scale; ECG = electrocardiogram; HRU = healthcare resource utilization; IM = intramuscular; ISM = in situ microparticle; 
PANSS = Positive and Negative Syndrome Scale; PSP = Personal and Social Performance Scale; SAS = Simpson-Angus Scale; 
SWN-20 = 20-item Subjective Well-Being Under Neuroleptics Treatment Scale; VAS = visual analog scale; (X) = assessment to 
be done as applicable  
                                                       
1  The extension baseline visit may occur on the same day as visit 14 (+ 3-day window) of the main part of the study (i.e., the day 
on which the designated end-of-treatment visit for the double-blind treatment period of the main part of the study occurs), 
which is scheduled to occur at the week 12 time point of the main part of the study.  However, in order to be eligible for 
transition into the extension segment, a patient must first complete all assessments and procedures scheduled for the end-of-
treatment visit for the double-blind treatment period of the main part of the study.  Patients who withdraw or are withdrawn 
early from the main part of the study (i.e., before the scheduled week 12 time point) are not eligible for enrollment into the 
extension segment.   
2  Visit 14 is the designated end-of-treatment visit.  However, if a patient withdraws or is withdrawn early from the study, an 
early termination visit should occur at which time all assessments for the end-of-treatment visit (as listed for visit 14) plus all 
the socio-demographic information and HRU (center and patient) data collection will be performed. 
3  The follow-up visit will be conducted by telephone.  
4 The allowable study visit time window for each of the extension baseline visit is within 3 days after visit 14 of the main part of 
the study occurs; however, it is generally preferable to conduct the extension baseline visit assessments and procedures later in 
the day (i.e., after completion of all assessments and procedures scheduled for the end-of-treatment visit for the double-blind 
treatment period of the main part of the study) on the same day on which the main study visit 14 occurs.  The allowable study 
visit time window for each of the subsequent extension visits is ± 3 days (i.e., extension visits 2 through 15, inclusive).   
5  Extension day 1 (the extension baseline visit time point) is planned to be the same day and date as day 85 of the main part of 
the study, though a + 3-day window for extension day 1, as compared with the day and date of the end-of- treatment visit for 
the main study day 85, is allowable.   
6  A separate informed consent form for participation in the optional extension segment of the study must be signed before any 
assessments or procedures for the extension segment are performed for a given patient and before any dose of open-label 
Risperidone ISM is administered to that patient.   
7  Eligibility will be determined by the investigator, who will assess eligibility by confirming that that all extension segment 
inclusion criteria (see Section 4.1.2.1) have been met and that none of the extension segment exclusion criteria have been met 
(see Section 4.1.2.2).   
8  In the extension segment of the study, all participating patients will receive active Risperidone ISM under open-label 
conditions.  Patients who had been on active Risperidone ISM in the double-blind segment of the study will continue to receive 
Risperidone ISM at the same dose (i.e., 75 or 100 mg) in the extension segment; patients who had been receiving placebo in 
the double-blind segment of the study will be randomly assigned to receive either 75 or 100 mg during the extension segment.  
All Risperidone ISM doses will be administered by deep IM injection (deltoid muscle or gluteal muscle).    
9  For identified assessments at the extension baseline visit time point (on extension day 1), results obtained as part of the main 
study visit 14 (i.e., the designated assessments performed for the end-of-treatment visit for the double-blind treatment period 
[week 12 time point] of the main part of the study) may be used as the extension baseline values and do not need to be repeated 
for the extension baseline visit time point if and only if the extension baseline visit occurs on the same day and date as the 
main study visit 14/week 12/end-of-treatment visit.  If the extension baseline visit instead occurs on a day 1 to 3 days after the 
main study visit 14/week 12/end-of-treatment visit (see extension segment footnotes 2 and 3), all of the designated 
assessments must be performed separately on the day of the extension baseline visit, and the main study visit 14/week 12/end-
of-treatment visit assessment results cannot be used as substitutes.   
10  Although a CGI-I score in reference to baseline of the main part of the study will be reported as part of the assessments for the 
end-of-treatment visit for the double-blind treatment period (visit 14 of the main part of the study), no CGI-I score in reference 
to the extension segment will be reported at the extension baseline time point (which may be later on the same day as the visit 
14 of the main part of the study).  For all subsequent visits in the treatment period of the extension segment (i.e., extension 
segment visits 2 through 14, inclusive), the reference time point for the CGI-I scores will be that patient’s overall status at the 
extension baseline time point.   
11  Health economics and outcomes research evaluations. To be administered prior to medication dose.     
12  Monitoring for AEs will occur throughout a patient’s participation in the extension segment of the study, starting from the 
patient’s signature of informed consent form; required details of identified AEs are to be recorded.   
13  Information regarding concomitant medications, including new medications and changes to existing medications, will be 
elicited and recorded.   
14  Vital signs will include blood pressure, pulse rate, respiratory rate, and body temperature.  At each identified time point, vital 
signs will be measured after the patient has been resting in a supine position for at least 5 minutes.  At each scheduled visit, 
 


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Protocol ROV-RISP-2016-01 
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VERSION 7.0 
22 Mar 2018 
CONFIDENTIAL 
Page 25 of 114 
                                                                                                                                                                                 
vital signs are to be measured within 1 hour before and then again within 3 hours after the Risperidone ISM injection; at each 
of these time points, orthostatic blood pressure and pulse rate will be measured (immediately after completion of supine vital 
sign measurements) after the patient has risen from the supine to the standing position and has remained standing for 
approximately 3 minutes (see Section 6.4.3).   
15  A 12-lead ECG will be performed at identified visits, both before and after dosing of risperidone ISM (with the exception of 
visit 14 when only 1 ECG is applicable).  Each pre-dose ECG is to be completed within 1 hour before dosing.  Each post-dose 
ECG is to be completed within 3 hours post-dose.  All scheduled ECGs are to be performed after the patient has rested quietly 
for at least 5 minutes in the supine position (see Section 6.4.4).   
16 The patient will perform and record self-assessment of pain at the injection using the injection site pain VAS (see Appendix D) 
approximately 1 hour after each study drug injection. The investigator will inspect the recent injection site and all injection 
sites where IM study drug has been injected on previous visits, also approximately 1 hour after each study drug injection. 
17 The hematology panel includes the following tests: hematocrit, hemoglobin, red blood cell count, white blood cell count and 
differential count (absolute values for basophils, eosinophils, lymphocytes, monocytes, and neutrophils), and platelets. 
18  The chemistry panel will include standard tests as well as hemoglobin A1c, thyroid-stimulating hormone, and a lipid panel.   
19 A blood sample for a serum pregnancy test is not required, but the investigator may order a serum pregnancy test at any time 
according to the investigator’s judgment.   
20 On extension segment day 1 and at each identified visit thereafter, onsite dipstick tests will be used for urine pregnancy tests.  
At each applicable visit, the urine pregnancy test must be performed and a negative result confirmed before the schedule dose 
of study drug for that day is administered.   
21 The urinalysis includes the following tests: color, pH, specific gravity, ketones, protein, glucose, bilirubin, nitrite, urobilinogen, 
and occult blood. Microscopic examination only if urinalysis dipstick results are abnormal. 
22  Urine drug screen is optional at each study site visit. It will include identification of the presence or absence of amphetamines, 
barbiturates, cocaine, methadone, opioids, and phencyclidine, as well as for tetrahydrocannabinol, alcohol, and 
benzodiazepines.     
 


Laboratorios Farmacéuticos ROVI, S.A. 
 
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PRISMA-3 
VERSION 7.0 
22 Mar 2018 
CONFIDENTIAL 
Page 26 of 114 
Table 3 
Schedule of Assessments and Procedures: Open-label Extension Segment for De Novo 
Patients 
Screening Baseline 
Extension Segment Treatment Period (Open-Label) 
Extension 
Follow-up 
Extension Visit Number:
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 11 12 13 141 
15 
Extension Study Day2:
-8 to -13 
1 
29 57 85 113 141 169 197 225 253 281 309 337 365 
393 
Extension Treatment 
Week:
 
 
4 
8 
12 16 20 24 28 32 36 40 44 48 52 
56 
Extension Dosing
Sequence:
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 11 12 13 
 
 
Informed consent4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening assessment* 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility criteria review2 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Arm assignment5 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inject Risperidone ISM3 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Efficacy scales: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PANSS 
X 
 X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
CGI-S 
X 
 X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
CGI-I 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Socio-demographic 
information 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
HRU data collection – 
center 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
HRU data collection – 
patient 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Health outcome scales:6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PSP (clinician 
administered) 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
X 
 
SWN-20 (patient 
reported) 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
X 
 
Safety assessments: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AEs7 
X 
 X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant meds8 
X 
 X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination 
X 
 X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Weight and body mass 
index 
X 
 X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
Vital signs9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECG10 
X 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
Injection site 
evaluation9 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Injection site pain 
VAS11 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Safety scales: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AIMS 
X 
 X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
BARS 
X 
 X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
SAS 
X 
 X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
C-SSRS 
X 
 X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Blood sample for: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology panel12 
X 
 X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
Chemistry panel13 
X 
 X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
Prolactin 
X 
 X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
Serology panel** 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test14 
(serum) 
X 
(X) 
(X) (X) (X) (X) (X) (X) (X) (X) (X) (X) (X) (X) (X) 
 


Laboratorios Farmacéuticos ROVI, S.A. 
 
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VERSION 7.0 
22 Mar 2018 
CONFIDENTIAL 
Page 27 of 114 
Screening Baseline 
Extension Segment Treatment Period (Open-Label) 
Extension 
Follow-up 
Extension Visit Number:
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 11 12 13 141 
15 
Extension Study Day2:
-8 to -13 
1 
29 57 85 113 141 169 197 225 253 281 309 337 365 
393 
Extension Treatment 
Week:
 
 
4 
8 
12 16 20 24 28 32 36 40 44 48 52 
56 
Extension Dosing
Sequence:
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 11 12 13 
 
 
Urine sample for: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test15 
 
 X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Urinalysis16 
X 
 X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
Drug screen17 
X 
X 
(X) (X) (X) (X) (X) (X) (X) (X) (X) (X) (X) (X) (X) 
  
AE = adverse event; AIMS = Abnormal Involuntary Movement Scale; BARS = Barnes Akathisia Rating Scale; CGI I = Clinical 
Global Impression – Improvement; CGI-S = Clinical Global Impression – Severity; C-SSRS = Columbia-Suicide Severity Rating 
Scale; ECG = electrocardiogram; HRU = healthcare resource utilization; IM = intramuscular; ISM = in situ microparticle; 
PANSS = Positive and Negative Syndrome Scale; PSP = Personal and Social Performance Scale; SAS = Simpson-Angus Scale; 
SWN-20 = 20-item Subjective Well-Being Under Neuroleptics Treatment Scale; VAS = visual analog scale; (X) = assessment to 
be done as applicable. 
                                                       
1  Visit 14 is the designated end-of-treatment visit.  However, if a patient withdraws or is withdrawn early from the study, an 
early termination visit should occur at which time all assessments for the end-of-treatment visit (as listed for visit 14) plus all 
the socio-demographic information and HRU (center and patient) data collection will be performed. 
2 The allowable study visit time window for baseline visit 1 is + 4-day window and for each of the subsequent extension visits is 
± 3 days (i.e., extension visits 2 through 15, inclusive).   
3  If there is a valid reason for a given potential patient to extend the screening period duration beyond the designated 8 days, the 
investigator may contact the medical monitor to request an extension of up to 14 days; such an extension may be implemented 
only after medical monitor approval has been obtained. 
4 An informed consent form for participation in the extension segment of the study must be signed before any assessments or 
procedures for the extension segment are performed for a given patient and before any dose of open-label Risperidone ISM is 
administered to that patient. Eligibility will be determined by the investigator, who will assess eligibility by confirming that 
that all inclusion criteria have been met and that none of the exclusion criteria have been met. 
5  In the extension segment of the study, all participating patients will receive active Risperidone ISM under open-label 
conditions.  Patients on 4 mg of oral risperidone will be assigned to 75 mg Risperidone ISM every 28 days. Patients on more 
than 4 mg to a maximum of 6 mg of oral risperidone will be assigned to 100 mg Risperidone ISM every 28 days. All 
Risperidone ISM doses will be administered by deep IM injection (deltoid muscle or gluteal muscle).   
6  Health economics and outcomes research evaluations. To be administered prior to medication dose. 
7  Monitoring for AEs will occur throughout a patient’s participation in the extension segment of the study, starting from the 
patient’s signature of informed consent form; required details of identified AEs are to be recorded. 
8 Information regarding concomitant medications, including new medications and changes to existing medications, will be 
elicited and recorded. 
9 Vital signs will include blood pressure, pulse rate, respiratory rate, and body temperature.  At each identified time point, vital 
signs will be measured after the patient has been resting in a supine position for at least 5 minutes.  At each scheduled visit, 
vital signs are to be measured within 1 hour before and then again within 3 hours after the Risperidone ISM injection; at each 
of these time points, orthostatic blood pressure and pulse rate will be measured (immediately after completion of supine vital 
sign measurements) after the patient has risen from the supine to the standing position and has remained standing for 
approximately 3 minutes (see Section 6.4.3).   
10  A 12-lead ECG will be performed at identified visits, both before and after dosing of risperidone ISM (with the exception of 
visit 14 when only 1 ECG is applicable).  Each pre-dose ECG is to be completed within 1 hour before dosing.  Each post-dose 
ECG is to be completed within 3 hours post-dose.  All scheduled ECGs are to be performed after the patient has rested quietly 
for at least 5 minutes in the supine position (see Section 6.4.4).   
11 The patient will perform and record self-assessment of pain at the injection using the injection site pain VAS (see Appendix D) 
approximately 1 hour after each study drug injection. The investigator will inspect the recent injection site and all injection 
sites where IM study drug has been injected on previous visits, also approximately 1 hour after each study drug injection. 
12 The hematology panel includes the following tests: hematocrit, hemoglobin, red blood cell count, white blood cell count and 
differential count (absolute values for basophils, eosinophils, lymphocytes, monocytes, and neutrophils), and platelets. 
13 The chemistry panel will include standard tests as well as hemoglobin A1c, thyroid-stimulating hormone, and a lipid panel.   
14 A blood sample for a serum pregnancy test is not required, but the investigator may order a serum pregnancy test at any time 
according to the investigator’s judgment.  
 


Laboratorios Farmacéuticos ROVI, S.A. 
 
Protocol ROV-RISP-2016-01 
PRISMA-3 
VERSION 7.0 
22 Mar 2018 
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15 On extension segment day 1 and at each identified visit thereafter, onsite dipstick tests will be used for urine pregnancy tests.  
At each applicable visit, the urine pregnancy test must be performed and a negative result confirmed before the schedule dose 
of study drug for that day is administered.  
16 The urinalysis includes the following tests: color, pH, specific gravity, ketones, protein, glucose, bilirubin, nitrite, urobilinogen, 
and occult blood. Microscopic examination only if urinalysis dipstick results are abnormal. 
17 Urine drug screen is optional at each study site visit properly identified (X). It will include identification of the presence or 
absence of amphetamines, barbiturates, cocaine, methadone, opioids, and phencyclidine, as well as for tetrahydrocannabinol, 
alcohol, and benzodiazepines. 
* Screening assessments will include the following: informed consent, demographic data, medical and psychiatric history, and a 
diagnostic interview (which will include completion of the MINI International Neuropsychiatric Interview for Schizophrenia 
and Psychotic Disorders studies, version 7.0.2).  
**A blood sample for a serology panel testing for hepatitis B surface antigen, antihepatitis C antibodies, and human 
immunodeficiency virus will be performed at screening only. 


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3.2 Requirements and Restrictions 
3.2.1 
Contraception and Pregnancy 
All patients must agree to use an acceptable method of contraception for the duration of the study and 
for ≥ 6 months after the last dose of IM study drug has been administered.   
The following are considered acceptable methods:  
 
Condom (male or female) with or without a spermicidal agent 
 
Diaphragm or cervical cap with spermicide 
 
Intrauterine device 
 
Hormonal contraceptive (e.g., birth control pills or patches, vaginal ring, or contraceptive 
implant) 
Female patients who have had a hysterectomy, bilateral tubal ligation, or bilateral salpingo-
oophorectomy are considered surgically sterile and are thus are exempt from the requirement to use 
contraception.  Men with an exclusive female partner meeting 1 of these surgically sterile criteria, as 
well as men who have themselves had a vasectomy, are also exempt from the requirement to use 
contraception.   
Female patients who are postmenopausal are considered not of childbearing potential and thus exempt 
from the contraception requirement; for the purpose of this study, postmenopausal is defined as the 
permanent cessation of menstruation for at least 12 months prior to screening in women ≥ 45 years of 
age.   
Patients who are abstinent from sexual intercourse are eligible for participation in this study if they 
agree to use an acceptable contraceptive method should they engage in such sexual activity while 
participating in this study.   
If a female patient becomes pregnant while participating in the study, study drug must be discontinued 
immediately and early termination and safety follow-up visits should be scheduled.  Any pregnancy 
must be reported to the sponsor (see Section 6.4.9).   
3.2.2 
Concomitant Therapy 
All concomitant medications (including those used during ophthalmological examination, if any) and 
other therapies received during a patient’s participation in this study (i.e., from the date of the 
informed consent form is signed through to the date of the final study visit) should be recorded.   
The investigator may discontinue or adjust the dose of a concomitant medication to ensure patient 
safety; however, unnecessary changes in concomitant medications for reasons other than safety are 
generally discouraged to avoid confounding study evaluations.   
The medical monitor should be consulted for any questions concerning concomitant medications.   
3.2.2.1 Prohibited Therapy 
3.2.2.1.1 
Prohibited Medications 
3.2.2.1.1.1 Cytochrome P450 3A4 Inducers and Inhibitors and 2D6 Inhibitors 
Clinically significant inducers and inhibitors of cytochrome P450 3A4 and inhibitors of cytochrome 
P450 2D6 (whether prescription medications, over-the-counter medications, or dietary supplements) 
are prohibited during the course of the study and within 30 days before study day 1 (see Appendix B).   


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3.2.2.1.1.2 Antipsychotics 
Antipsychotic medications, other than the study drugs administered according to this protocol, are not 
permitted during a patient’s participation in the treatment period of this study.  Existing antipsychotic 
medication must be discontinued during the screening period (for patients in the double-blind segment 
of the study, this will be while the patient is admitted to the inpatient study unit), if deemed clinically 
appropriate by investigator judgment.  The same applies to de novo patents where all antipsychotic 
medication other than oral risperidone must be discontinued during the screening period.  The last 
dose of oral risperidone should be administered on the day preceding baseline visit. 
This restriction applies also for antipsychotics given as sleep aids.   
The duration of the antipsychotic medication washout period (e.g., approximately 3 to 5 times the 
half-life of an oral antipsychotic, if appropriate and feasible) will be at the discretion of the 
investigator, in consultation with the medical monitor when deemed indicated.   
If administration of an additional or different antipsychotic medication (other than protocol-defined 
study drug), or any other treatment for schizophrenia, is considered clinically indicated during a 
patient’s participation in the study, the investigator should contact the medical monitor to discuss the 
circumstance and determine a course of action for the given patient.   
3.2.2.1.1.3 Other Psychotropic Medications 
Monoamine oxidase inhibitors (e.g., phenelzine, tranylcypromine, selegiline, moclobemide) are 
strictly prohibited during a patient’s participation in this study and for ≥ 14 days before the screening 
visit.  All other antidepressant medications are also not permitted during the treatment period.  
Patients taking antidepressants may be considered for washout of these medications during the 
screening period.    
Lithium and mood stabilizers are not permitted during a patient’s participation in the treatment period 
of this study.   
Nicotine replacement therapy, including nicotine replacement patch and oral nicotine gum, is 
permitted.  However, varenicline (Chantix®) is not permitted.   
Otherwise, in general, use of psychotropic medications other than study drug is discouraged during a 
patient’s participation in the study, with the exception of medications specifically identified in this 
protocol as permissible.   
The medical monitor should be consulted for any questions about use of any psychotropic 
medications during a patient’s participation in this study.   
3.2.2.1.1.4 Drugs of Abuse 
Prohibited substances include amphetamines, barbiturates, cocaine, methadone, opioids, and 
phencyclidine.  If it is determined that a patient has been using any of these substances during 
participation in this study, the investigator should contact the medical monitor to discuss the course of 
action.   
Tobacco and/or caffeine use is allowable if use is anticipated to remain relatively stable throughout a 
patient’s participation in the study.   
While it is preferable that patients do not use any alcohol or tetrahydrocannabinol (THC)-containing 
substances (e.g., marijuana), in certain cases patients with occasional and stable use of small amounts 


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these substances may not be exclusionary if exclusion criterion 9 is not met, and only if the medical 
monitor provides approval (also see Section 6.4.5.4.3).   
3.2.2.1.2 
Prohibited Nonmedication Therapy 
Psychotherapy should not be started or changed during a patient’s participation in the study.  It is 
acceptable for a patient already receiving psychotherapy to participate in the study.   
While on the inpatient study unit during participation in the study, initiation of new augmenting 
psychotherapies (i.e., group therapy) is discouraged, though standard milieu-related activities are 
acceptable.   
Partial hospitalization after discharge from the inpatient study unit is discouraged, though the level of 
care after discharge from the inpatient study unit ultimately should be made based on investigator 
judgment.   
Psychiatric hospitalization during the treatment period after the patient has been discharged from the 
inpatient study unit could result in early withdrawal of that patient from the study (see Section 4.2).  
3.2.2.2 Permitted Therapy 
3.2.2.2.1 
Rescue Medication 
Permitted rescue medications for this study include the following:  
 
Benzodiazepines 
o Indications: agitation, anxiety, insomnia, and/or restlessness 
o Maximum dosage: 6 mg/day lorazepam or equivalent for other benzodiazepines 
o Notes:  
 
Short half-life benzodiazepines are preferable to longer half-life benzodiazepines due to 
the potential for lingering effects on daytime functioning and study assessments 
 
For treatment of agitation and/or anxiety, the dose benzodiazepines should be kept as 
stable as possible throughout the patient’s participation in study in order to avoid 
interference with daytime functioning and study assessments 
 
Anticholinergics 
o Indication: extrapyramidal symptoms 
o Maximum dosage: 4 mg/day benztropine or equivalent for other anticholinergics 
 
Propranolol 
o Indications: akathisia or tremor 
o Maximum dosage: 20 mg 3 times daily (60 mg/day total) 
4 Patients 
4.1 Eligibility 
To be eligible for participation in the study, at screening each patient must meet all of the inclusion 
criteria  and none of the exclusion criteria.   
4.1.1 
Eligibility Criteria for Enrollment into the Double-Blind Segment of the Study 
4.1.1.1 Inclusion Criteria 


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To be eligible for enrollment into the double-blind segment of the study, each patient must meet all of 
the following criteria at screening:  
1. Capable of providing informed consent 
a. A signed informed consent form must be provided before any study assessments are 
performed 
b. Patients must be fluent in the language that is spoken by the investigator and the study site 
staff (including raters) and must be able to read and understand the words in which the 
informed consent is written 
2. Age ≥ 18 and ≤ 65 years 
3. Body mass index 18.5 to 40.0 kg/m2 (inclusive) 
4. Current diagnosis of schizophrenia, according to the Diagnostic and Statistical Manual of Mental 
Disorders, Fifth Edition (DSM-5) criteria 
a. Currently experiencing an acute exacerbation or relapse with onset < 2 months before 
screening 
b. If inpatient at screening, has been hospitalized for < 2 weeks for the current exacerbation 
c. ≥ 2 years have elapsed since initial onset of active-phase schizophrenia symptoms 
5. Has been able to achieve outpatient status for > 4 months during the past year 
6. Has previously had a clinically significant beneficial response (improvement in schizophrenia 
symptoms), as determined by the investigator, to treatment with an antipsychotic medication other 
than clozapine 
7. Agrees to discontinue prohibited medications as applicable and as clinically indicated according 
to investigator instructions 
8. Dosages of all permitted medications are considered to have been stable (with the exception of 
medication to be used on an as-needed basis) for ≥ 2 weeks prior to the baseline visit and to 
remain stable during participation in this study 
9. Positive and Negative Syndrome Scale (PANSS) results at the screening and baseline visits meets 
the following criteria:  
a. Total score between 80 and 120, inclusive 
b. Score of ≥ 4 (moderate or greater) for ≥ 2 of the following Positive Scale items:  
i. 
Item 1 (P1: delusions) 
ii. 
Item 2 (P2: conceptual disorganization) 
iii. 
Item 3 (P3: hallucinatory behavior) 
iv. 
Item 6 (P6: suspiciousness/persecution) 
10. Clinical Global Impression – Severity (CGI-S) score of ≥ 4 (moderately ill or worse) 
11. Resides in a stable living situation and is anticipated to return to that same stable living situation 
after discharge from the inpatient study unit, in the opinion of the investigator 
12. Has an identified reliable informant who is anticipated to remain the same after the patient is 
discharged from the inpatient study unit, in the opinion of the investigator 
13. Meets the following criteria:  
a. If a sexually active, is using a medically accepted contraceptive method, and will continue to 
use such throughout participation in this study (and for ≥ 6 months after the last dose of IM 
study drug has been administered); acceptable methods include the following:  
i. 
Condoms (male or female) with or without a spermicidal agent 
ii. 
Diaphragm or cervical cap with spermicide 
iii. 
Intrauterine device 
iv. 
Hormonal contraceptive 
b. If not currently sexually active, then meets the following criteria:  


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i. 
Agrees that if sexual activity resumes while participating in this study, a medically 
accepted contraception method will be used 
14. Willing and able to be confined to an inpatient study unit for up to 2 weeks (or longer if clinically 
indicated), as applicable and as clinically indicated according to investigator instructions 
15. Agrees not to post any personal medical data related to the study or information related to the 
study on any website or social media site (e.g., Facebook, Twitter, and others) during the study 
duration 
4.1.1.2 Exclusion Criteria 
An individual who meets any of the following criteria at screening will not be permitted to enroll in 
the study:   
1. History of proven inadequate clinical response to treatment with therapeutic doses (with good 
compliance) of risperidone or paliperidone 
2. History of treatment resistance, defined as failure to respond to 2 discrete adequate trials (≥ 4 
weeks with an adequate dose) of 2 different antipsychotic medications; history of clozapine use 
(exception: use was not because of treatment resistance or refractory psychotic symptoms) 
3. Improvement in PANSS total score 20% or greater between the initial screening visit and first 
injection 
4. Known or suspected intolerance of or allergy or hypersensitivity to risperidone, paliperidone, or 
any of the excipients in the IM formulations of these 
5. History of neuroleptic malignant syndrome, clinically significant tardive dyskinesia, or tardive 
dystonia 
6. History of any other medical condition that is considered to pose any unjustifiable risk or interfere 
with study assessments 
7. Clinically significant extrapyramidal symptoms at screening or baseline 
8. Answer of “yes” on item 4 or on item 5 of the Columbia-Suicide Severity Rating Scale (C-SSRS) 
(ideation) with the most recent episode occurring within the past 2 months, or answer “yes” to any 
of the 5 items (behavior) with an episode occurring within the last year 
9. Current diagnosis or a history of substance use disorder according to DSM-5 criteria within 
6 months prior to the screening visit (with the exception of tobacco, mild cannabis, or mild 
alcohol use disorder) or a positive drug screen test (with the exception of cannabis) verified by 
repeat testing 
10. Lifetime history of diagnosis of schizoaffective disorder or bipolar disorder 
11. Clinically significant comorbid neuropsychiatric disorders including any of the following:  
a. Current untreated or unstable major depressive disorder 
b. Clinically significant cognitive difficulties including dementia, delirium, or amnesic 
syndrome, within the past 2 years and would interfere with participation in the study 
c. Any other psychiatric condition that would, in the judgment of the investigator, interfere with 
participation in the study 
12. Clinically significant or unstable medical illness/condition/disorder that would be anticipated, in 
the investigator’s opinion, to potentially compromise patient safety or adversely affect the 
evaluation of efficacy, including (but not necessarily limited to) the following:  
a. Clinically significant hypotension or hypertension not stabilized by medical therapy (diastolic 
blood pressure > 105 mmHg) 
b. Unstable thyroid dysfunction in the past 6 months 
c. Malignant tumor within the last 5 years 
d. Neurologic conditions including the following: 


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i. 
History of seizure disorder or condition associated with seizures 
ii. 
History of brain tumor, subdural hematoma, or other clinically significant neurological 
condition within the past 12 months 
iii. 
Head trauma with loss of consciousness within 12 months before screening 
iv. 
Active acute or chronic central nervous system infection 
v. 
Stroke within 6 months before screening 
e. Cardiac conditions including the following:  
i. 
Clinically significant cardiac arrhythmia, cardiomyopathy, or cardiac conduction defect 
ii. 
History of myocardial infarction or unstable angina within the last 3 months before 
screening, or clinically significant abnormality on screening or baseline 
electrocardiogram (ECG) including but not limited to the following: QT interval 
corrected for heart rate using Fridericia’s formula (QTcF) > 465 msec if male or > 485 
msec if female 
13. Laboratory abnormality that, in the opinion of the investigator, would compromise the well-being 
of the patient, or any of the following laboratory abnormalities at screening or baseline:  
a. Aspartate aminotransferase or alanine aminotransferase value ≥ 2 times the upper limit of the 
laboratory normal reference range 
b. Hemoglobin A1c > 9% 
c. Absolute neutrophil count ≤ 1.5 × 103 μL 
d. Platelet count ≤ 75 × 103 μL 
e. Creatinine clearance < 60 mL/min 
f. Positive test result for human immunodeficiency virus, hepatitis B surface antigen, or 
antihepatitis C virus antibody 
g. Positive pregnancy test result 
h. Urine drug screen at screening or baseline shows a positive result for any of the tested 
substances (potential exceptions: results positive for benzodiazepine may not be exclusionary 
if the investigator confirms that such medication was medically indicated and consults the 
medical monitor before enrolling a patient with such a finding; results positive for THC may 
not be exclusionary in certain cases only if exclusion criterion 9 is not met and only if the 
medical monitor provides approval) 
14. Pregnant, lactating, or breastfeeding 
15. Inadequate gluteal or deltoid musculature or excessive fat, as determined by the investigator, that 
would interfere with IM study drug injections 
16. Any contraindication for IM injections  
17. Receipt of any long-acting antipsychotic medication by IM injection within 60 days before 
screening 
18. Current involuntary hospitalization or incarceration 
19. Hospitalized for more than 30 days during the 90 days before screening 
20. Participation in another clinical study in which the patient received an experimental or 
investigational drug or agent within 6 months before screening 
21. Participation in a clinical study with Risperidone ISM within 12 months before screening 
22. Study site personnel and/or persons employed by the investigator or study site or is an immediate 
family member of such persons 
23. Patients taking any prohibited concomitant medication (see Section 3.2.2.1.1) at the time of 
randomization visit 
24. Clinically significant ocular disease or visual impairment interfering with the planned 
ophthalmological examinations or that in the investigator’s opinion could potentially compromise 
patients’ ocular safety 


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25. Patients with planned or anticipated need for ocular surgery during the treatment period of the 
trial 
4.1.2 
Eligibility Criteria for Entry into Optional Extension Segment of the Study (Rollover 
Patients) 
Participation in the open-label extension segment of the study is optional, and patients who complete 
participation in the main segment of the study may opt to not participate.  Patients who are interested 
in participating must meet all eligibility criteria in order to enter into the extension segment.  
4.1.2.1 Inclusion Criteria for Extension Segment 
To be eligible for entry into the extension segment of the study, a patient must meet all of the 
following criteria at the extension baseline time point (immediately upon completion of the end-of-
treatment visit assessments and procedures for the main part of the study): 
1. Has completed scheduled participation in the main part of the study, through to the end of the 
treatment period and including the end-of-treatment visit 
2. Continues to require long-term treatment with an antipsychotic medication, in the opinion of the 
investigator 
3. Continues to meet contraceptive requirements of the study (see Section 3.2.1) 
4. Is willing to participate in the extension segment of the study and remains capable of providing 
informed consent 
a. A signed informed consent form must be provided before any study assessments are 
performed for the extension segment 
5. Continues to reside in a stable living situation, in the opinion of the investigator 
6. Continues to have an identified reliable informant, in the opinion of the investigator 
4.1.2.2 Exclusion Criteria for Extension Segment 
An individual who meets any of the following criteria at the extension baseline time point 
(immediately upon completion of the end-of-treatment visit assessments and procedures for the main 
part of the study) will not be permitted to enter into the extension segment of the study:   
1. Missed more than 1 scheduled study visit during participation in the main part of the study 
2. Had an abnormal clinical laboratory value, vital sign, or ECG finding during participation in the 
main part of the study that, in the opinion of the investigator, was clinically relevant, related to 
study drug, and would compromise the well-being of the patient in the extension segment 
3. Had a clinically significant or unstable medical illness/condition/disorder during the main part of 
the study that would be anticipated, in the investigator’s opinion, to potentially compromise 
patient safety in the extension segment 
4. Is taking or is anticipated to require any prohibited concomitant medication (see Section 3.2.2.1.1)  
5. Pregnant, lactating, or breastfeeding 
6. Any contraindication for continued IM injections (e.g., treatment with anticoagulant) 
7. Inadequate gluteal or deltoid musculature or excessive fat, as determined by the investigator, that 
would interfere with IM study drug injections 
8. Study site personnel and/or persons employed by the investigator or study site or is an immediate 
family member of such persons 
 


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4.1.3 
Eligibility Criteria for Entry into Optional Extension Segment of the Study (De Novo 
Patients) 
4.1.3.1 Inclusion Criteria: de novo patients  
To be eligible for entry into the extension segment of the study, a de novo patient must meet all of the 
following criteria at the extension segment screening visit: 
1. Capable of providing informed consent 
a. A signed informed consent form must be provided before any study assessments are 
performed 
b. Patients must be fluent in the language that is spoken by the investigator and the study site 
staff (including raters) and must be able to read and understand the words in which the 
informed consent is written 
2. Age ≥ 18 and ≤ 65 years old, inclusive, at screening 
3. On a stable dose of oral risperidone from 4 to 6 mg daily as maintenance therapy for at least the 
last 4 weeks prior/before screening/baseline and would potentially benefit from conversion to an 
extended release injectable, in the opinion of the investigator 
4. Current diagnosis of schizophrenia, according to the Diagnostic and Statistical Manual of Mental 
Disorders, Fifth Edition (DSM-5) criteria that is clinically stable as evidenced by: 
 
No hospitalizations for acute exacerbations of schizophrenia and psychiatrically stable 
without significant symptom exacerbation over the last 3 months before screening based on 
the investigator’s judgment  
 
PANSS total score < 70 at screening 
 
CGI-S score of ≤ 3 (mild) at screening 
5. Has previously had a clinically significant beneficial response (improvement in schizophrenia 
symptoms), as determined by the investigator, to treatment with an antipsychotic medication other 
than clozapine 
6. At least 2 years elapsed since initial onset of active-phase schizophrenia symptoms 
7. Subject is outpatient; not hospitalized for worsening of schizophrenia within the last 3 months 
(hospitalization for social management within this time period is acceptable) 
8. Medically stable over the last month prior to screening based on the investigator’s judgment 
9. BMI of 18.5 to 40.0 kg/m2 (inclusive) at screening 
10. Agrees to discontinue prohibited medications as applicable and as clinically indicated according 
to investigator instructions 
11. Dosages of all permitted medications are considered to have been stable (with the exception of 
medication to be used on an as-needed basis) for ≥ 2 weeks prior to the baseline visit and to 
remain stable during participation in this study 
12. Resides in a stable living situation, in the opinion of the investigator 
13. Has an identified reliable informant, in the opinion of the investigator 
14. Meets the following contraceptive criteria: 
a.  If sexually active, is using a medically accepted contraceptive method, and will continue to 
use such throughout participation in this study (and for ≥ 6 months after the last dose of IM 
study drug has been administered); acceptable methods include the following: 
i.  Condoms (male or female) with or without a spermicidal agent 
ii.  Diaphragm or cervical cap with spermicide 
iii.  Intrauterine device 
iv.  Hormonal contraceptive 
b. If not currently sexually active, then meets the following criteria: 


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i.  Agrees that if sexual activity resumes while participating in this study, a medically 
accepted contraception method will be used 
15. Agrees not to post any personal medical data related to the study or information related to the 
study on any website or social media site (e.g., Facebook, Twitter, and others) during the study 
duration 
 
4.1.3.2 Exclusion criteria: de novo patients 
An individual who meets any of the following criteria at screening will not be permitted to enroll in 
the study:   
1. History of proven inadequate clinical response to treatment with therapeutic doses (with good 
compliance) of risperidone or paliperidone 
2. History of treatment resistance, defined as failure to respond to 2 discrete adequate trials (≥ 4 
weeks with an adequate dose) of 2 different antipsychotic medications; history of clozapine use 
(exception: use was not because of treatment resistance or refractory psychotic symptoms) 
3. Known or suspected intolerance of or allergy or hypersensitivity to risperidone, paliperidone, or 
any of the excipients in the IM formulations of these 
4. History of neuroleptic malignant syndrome, clinically significant tardive dyskinesia or tardive 
dystonia 
5. History of any other medical condition that is considered to pose any unjustifiable risk or interfere 
with study assessments  
6. Clinically significant extrapyramidal symptoms at screening or baseline 
7. At significant risk of suicidal, homicidal or violent ideation or behavior, by history or as clinically 
assessed by the investigator at screening visit 
8. Answer of “yes” on item 4 or on item 5 of the Columbia-Suicide Severity Rating Scale (C-SSRS) 
(ideation) with the most recent episode occurring within the past 2 months, or answer “yes” to any 
of the 5 items (behavior) with an episode occurring within the last year 
9. Current diagnosis or a history of substance use disorder according to DSM-5 criteria within 6 
months prior to the screening visit (with the exception of tobacco, mild cannabis, or mild alcohol 
use disorder) or a positive drug screen test (with the exception of cannabis) verified by repeat 
testing 
10. Lifetime history of diagnosis of schizoaffective disorder or bipolar disorder 
11. Clinically significant comorbid neuropsychiatric disorders including any of the following: 
a.  Current untreated or unstable major depressive disorder 
b.  Clinically significant cognitive difficulties including dementia, delirium, or amnesic 
syndrome, within the past 2 years and would interfere with participation in the study 
c.  Any other psychiatric condition that would, in the judgment of the investigator, interfere with 
participation in the study 
12. Clinically significant or unstable medical illness/condition/disorder that would be anticipated, in 
the investigator’s opinion, to potentially compromise patient safety or adversely affect the 
evaluation of efficacy, including (but not necessarily limited to) the following:  
a.  Clinically significant hypotension or hypertension not stabilized by medical therapy (diastolic 
blood pressure > 105 mmHg) 
b. Unstable thyroid dysfunction in the past 6 months 
c. Malignant tumor within the last 5 years 
d. Neurologic conditions including the following: 
i.  History of seizure disorder or condition associated with seizures 


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ii.  History of brain tumor, subdural hematoma, or other clinically significant neurological 
condition within the past 12 months 
iii.  Head trauma with loss of consciousness within 12 months before screening 
iv.  Active acute or chronic central nervous system infection 
v.  Stroke within 6 months before screening 
e. Cardiac conditions including the following:  
i. 
Clinically significant cardiac arrhythmia, cardiomyopathy, or cardiac conduction defect 
ii. History of myocardial infarction or unstable angina within the last 3 months before 
screening, or clinically significant abnormality on screening or baseline 
electrocardiogram (ECG) including but not limited to the following: QT interval 
corrected for heart rate using Fridericia’s formula (QTcF) > 465 msec if male or > 485 
msec if female 
13.  Laboratory abnormality that, in the opinion of the investigator, would compromise the well-being 
of the patient, or any of the following laboratory abnormalities at screening or baseline:  
a. Aspartate aminotransferase or alanine aminotransferase value ≥ 2 times the upper limit of the 
laboratory normal reference range 
b. Hemoglobin A1c > 9% 
c. Absolute neutrophil count ≤ 1.5 × 103 μL 
d. Platelet count ≤ 75 × 103 μL 
e. Creatinine clearance < 60 mL/min 
f. Positive test result for human immunodeficiency virus, hepatitis B surface antigen, or 
antihepatitis C virus antibody 
g. Positive pregnancy test result 
h. Urine drug screen at screening or baseline shows a positive result for any of the tested 
substances (potential exceptions: results positive for benzodiazepine may not be exclusionary 
if the investigator confirms that such medication was medically indicated and consults the 
medical monitor before enrolling a patient with such a finding; results positive for THC may 
not be exclusionary in certain cases only if exclusion criterion 9 is not met and only if the 
medical monitor provides approval) 
14. Pregnant, lactating, or breastfeeding 
15. Inadequate gluteal or deltoid musculature or excessive fat, as determined by the investigator, that 
would interfere with IM study drug injections 
16. Any contraindication for IM injections  
17. Receipt of any long-acting antipsychotic medication by IM injection within 60 days before 
screening 
18. Current involuntary hospitalization or incarceration 
19. Hospitalized for more than 30 days during the 90 days before screening 
20. Participation in another clinical study in which the patient received an experimental or 
investigational drug or agent within 6 months before screening 
21. Participation in a clinical study with Risperidone ISM within 12 months before screening 
22. Study site personnel and/or persons employed by the investigator or study site or is an immediate 
family member of such persons 
23. Patients taking or anticipated to require any prohibited concomitant medication (see 
Section 3.2.2.1.1)  


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4.2 Patient Withdrawal 
A patient may be withdrawn from the study at any time if the patient, investigator, or sponsor 
determines that it is not in the best interest of the patient to continue.   
Reasons for patient withdrawal may include, but are not limited to, noncompliance, safety, 
development of a medical condition that requires treatment with a prohibited medication, a positive 
result on a pregnancy or urine drug screen test, or patient withdrawal of consent.  In addition, if a 
patient’s condition changes during the course of the study so that he or she no longer satisfies the 
inclusion and exclusion criteria, he or she may be withdrawn.   
If psychiatric hospitalization for worsening, relapse, or exacerbation of schizophrenia symptoms 
occurs during the treatment period at a time point after the patient has been discharged from the 
inpatient study unit, the medical monitor should be contacted to discuss whether early withdrawal of 
that patient from the study may be indicated.   
All efforts should be made to perform an early termination visit for any patient who withdraws or is 
withdrawn from the study, except for patients who withdraw consent.   
If a patient is withdrawn because of an AE or other medical reason, the patient should be followed 
until the AE resolves or is deemed stable by the investigator or until the patient is deemed by the 
investigator to be lost to follow-up.   
If, in the opinion of the investigator, it is clinically indicated to monitor a patient beyond the early 
termination visit, subsequent clinical contacts (in addition to protocol-designated study visits) may be 
extended on an as-needed basis.  In such instances, the medical monitor should be contacted so that 
the sponsor or designee and the investigator can agree to an acceptable clinical follow-up schedule.   
In the event that a patient chooses to withdraw from the study, the investigator should make a 
reasonable effort to ascertain the reason for withdrawal while fully respecting the patient’s rights to 
withdraw.   
The investigator will determine the most appropriate post-study treatment for each withdrawn patient, 
which may include conferring with the patient’s treating psychiatrist. 
The investigator must maintain a record of all patients who withdraw from the study and the reasons 
for discontinuation.  The reason for discontinuation will be documented.  If a patient is lost to follow-
up, a reasonable attempt to contact the patient must be made and documented.   
5 Study Treatment 
The following 3 study drug treatments will be used in the study:  
 
Risperidone ISM 75 mg (Double-Blind and Open-label Segment) 
 
Risperidone ISM 100 mg (Double-Blind and Open-label Segment) 
 
Placebo (Double-Blind Segment only) 
In the double-blind segment of the study, the treatment assignment for each patient will remain 
blinded for patients, investigators, and all study site staff, with the exception of identified individuals 
at each study site who will be unblinded in order to prepare and administer IM study drug for each 
patient at that study site.  In the extension segment of the study, all participating patients will receive 


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active Risperidone ISM under open-label conditions. However, in order to preserve the blinding 
condition of the double-blind stage of the study, if a participating rollover patient enters this OLE 
phase of the study prior to locking the database of the double-blind stage of the study, the allocation to 
either 75 or 100 mg of this patient will be still blinded at least up to locking the aforementioned 
database. 
5.1 Study Drugs 
5.1.1 
Study Drugs 
Risperidone ISM is the active study drug being evaluated in this study.   
Risperidone ISM is a long-acting formulation of risperidone that uses ISM technology.  Laboratorios 
Farmacéuticos ROVI, S.A. is the manufacturer of Risperidone ISM.  The World Health Organization 
Anatomical Therapeutic Chemical class of risperidone is N05AX08 (other antipsychotics).   
The active moiety of Risperidone ISM is risperidone.   
The following excipients are contained in both, Risperidone ISM and placebo: poly lactic-co-glycolic 
acid (PLGA; copolymer of lactic and glycolic acids) and dimethyl sulfoxide (DMSO).  Risperidone 
ISM and placebo are formulated as a suspension and dissolution for injection, respectively.  
The manner in which Risperidone ISM and placebo study drugs are provided to study sites requires a 
reconstitution procedure to be performed at the study site for each dose to be administered.   
Risperidone ISM/placebo kits will be provided to study sites, and they will be stored refrigerated at a 
temperature between 2ºC and 8ºC.  Each kit includes 2 syringes, 1 of which contains the Risperidone 
ISM study drug (except for placebo) plus PLGA in the form of a solid powder, and the other of which 
contains DMSO solvent.   
Each kit will also contain 2 needles: a 2-inch 20 gauge safety needle and a 1-inch 21 gauge safety 
needle.   
Risperidone ISM study drug kits will be provided for the dose levels of 75 and 100 mg.  
Corresponding placebo study drug will also be provided.  Risperidone ISM and corresponding 
placebo kits will be labelled appropriately.   
5.1.1.1 Justification of Selected Doses 
Results from previously conducted phase I and phase II studies as well as pharmacokinetic modeling 
are considered to support the doses selected for this study (see Section 1).   
5.1.1.2 Oral Test Doses for Risperidone-Naïve Patients 
Patients who have never taken risperidone must have a brief trial of oral risperidone 2 mg/day for 3 
days during the screening period in order to ensure a lack of any hypersensitivity reactions before the 
first dose of IM study drug is administered.   
A trial of oral risperidone is not required or indicated for patients who have previously taken any 
formulation of risperidone. 
Risperidone tablets will be provided by study sponsor to all participating sites for risperidone-naïve 
patients testing. 


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5.1.2 
Preparation and Administration of Study Drug 
At each study site, during the double-blind treatment period (and until the Data Base lock of the 
Double-blind segment), each dose of study drug for each patient will be prepared individually by 1 or 
more identified members of the study site personnel; such designated individuals will be unblinded to 
the study drug identities and assignments to patients.  An unblinded individual will also administer the 
IM injections of study drug to each patient in a manner that maintains the blind.  The designated 
unblinded individuals must be considered appropriately experienced, trained, and qualified to perform 
these critical functions.   
The study days on which administration of double-blind study drug injections are scheduled are study 
day 1, study day 29 (treatment week 4), and study day 57 (treatment week 8). 
An unblinded study staff member will reconstitute the appropriate dosage of the study drug according 
to the instructions provided by the sponsor and will administer the study drug immediately after 
reconstitution.  
For a given patient, each of the IM injections of study drug should be administered at approximately 
the same time of day, if possible.  Generally, at a given study visit, the IM injection of study drug 
should be administered after efficacy evaluations have been performed and after any required blood 
samples (e.g., pharmacokinetic sample), if applicable at the given study visit, have been collected.   
For each injection, the study drug should be injected slowly, deep into the muscle.  Care should be 
taken to avoid inadvertent injection into a blood vessel.  Each individual dose is to be administered in 
a single injection; divided injections are not permitted.   
Generally, serial gluteal injections should be alternated between the 2 gluteal muscles, and serial 
deltoid injections should be alternated between the 2 deltoid muscles.  However, the investigator may 
determine which injection site is most appropriate for a given patient.  
The recommended needle size for administration of study drug into the gluteal muscle for most 
patients is the 2-inch 20 gauge needle.  The injection should be administered into the upper-outer 
quadrant of the gluteal muscle.   
The recommended needle size for administration of study drug into the deltoid muscle is 1-inch 21 
gauge needle.   
Risperidone ISM doses are summarized for each double-blind treatment group by study day in Table 
4. 


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Table 4 
Risperidone ISM Doses by Study Day 
Study Drug Treatment Group 
Study Day 1 
 
Study Day 29 
 
Study Day 57 
Risperidone 75 mg 
75 mg 
 
75 mg 
 
75 mg 
Risperidone 100 mg 
100 mg  
 
100 mg 
 
100 mg  
Placebo 
0 mg 
 
0 mg 
 
0 mg  
ISM = in situ microparticle. 
Note: During the conduct of the study, assignments of double-blind study drug treatments to patients will be under double-
blind conditions and will not be revealed to investigators, study staff (except for specifically identified unblinded individuals 
only), or patients. 
5.2 Study Site Inpatient Unit 
A patient who, after completion of all scheduled assessments on the screening visit day, is considered 
provisionally eligible for participation in the double-blind segment of this study will be admitted 
directly to the inpatient study unit that day.  Patients subsequently will remain on the inpatient study 
unit for the remainder of the screening period (i.e., through study day -1, inclusive).   
All confirmed eligible patients will remain inpatient on study day 1.  No patient should be discharged 
from the inpatient unit before study day 2, and it is anticipated that most patients will remain on the 
inpatient unit through study day 8, and that thereafter patients will be discharged from the inpatient 
unit when the investigator has assessed the patient and determines that he or she is appropriately 
clinically stable and otherwise ready for safe discharge.  After study day 8, continuation of a patient 
on the inpatient unit from study day 9 through study day 15, inclusive, is an allowable option, as 
deemed clinically indicated.  If the investigator believes that a given patient should remain inpatient 
beyond study day 15, the investigator should contact the medical monitor to discuss the proposed 
inpatient duration extension to discuss the extension.   
De novo patients entering the extension segment of the study are not planned to be admitted to the 
inpatient study unit. 
5.3 Treatment Assignment and Blinding 
5.3.1 
Treatment Assignment 
Upon confirmation of eligibility for a given patient to participate in the double-blind segment of the 
study, a unique randomization number for that patient will be assigned via an interactive voice or web 
response system that is to be accessed by study site personnel immediately after confirmation of 
patient eligibility has been recorded.   
The randomization number for a given patient will be used to identify the study drug (i.e., blinded 
Risperidone ISM 75 mg, Risperidone ISM 100 mg, or placebo) that will be administered to that 
patient.   
The randomization scheme will automatically ensure that the study drug assignment for a given 
patient is random and that an overall 1:1:1 ratio of assignments to each of the 3 study drug treatments 
is approximated.   
In addition, the randomization scheme will include the following stratification parameters to ensure 
balanced distribution of assignment to the 3 treatments: country where enrolled and PANSS total 
score (i.e., ≥ 95 versus < 95) at baseline/randomization.   


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An independent biostatistician will maintain the randomization scheme key, which will remain 
unavailable to all other individuals until after study completion and subsequent locking of the study 
database.   
Once a randomization number has been assigned, that number must not be used again for any other 
patient (e.g., when patient is withdrawn from the study, that patient’s randomization number must not 
be reused for any other patient).   
5.3.1.1 Extension Segment of the Study 
In the extension segment of the study, all participating patients will receive active Risperidone ISM 
under open-label conditions.  Patients who had been on active Risperidone ISM in the double-blind 
segment of the study will continue to receive active Risperidone ISM at the same dose (i.e., 75 or 
100 mg) in the extension segment; patients who had been receiving placebo in the double-blind 
segment of the study will be randomly assigned to receive either 75 or 100 mg during the extension 
segment. However, in order to preserve the blinding condition of the double-blind stage of the study, 
if a participating patient enters this OLE phase of the study prior to locking the database of the 
double-blind stage of the study, the allocation to either 75 or 100 mg of this patient will be still 
blinded at least up to locking the aforementioned database.   
De novo patients participating in the extension segment of the study will receive either 75 or 100 mg 
Risperidone ISM depending on their previous oral risperidone dose.  Patients on 4 mg of oral 
risperidone will be assigned to 75 mg Risperidone ISM, and patients on more than 4 mg to a 
maximum of 6 mg of oral risperidone will be assigned to 100 mg Risperidone ISM.  Upon 
confirmation of eligibility for a given de novo patient, the corresponding IMP kit will be assigned via 
an interactive voice or web response system that is to be accessed by study site personnel immediately 
after confirmation of patient eligibility has been recorded. 
5.3.2 
Blinding 
During the double-blind segment of the study, the IM study drug will be administered under double-
blind conditions so that investigators, site staff, and patients will not be aware about the identity of the 
study drug (i.e., blinded Risperidone ISM 75 mg, Risperidone ISM 100 mg, or placebo) administered 
to any given patient.   
The packaging and labelling for placebo or Risperidone ISM 75 or 100 mg will be identical during the 
whole study in order to keep the blinding.  The placebo and Risperidone ISM doses are practically 
indistinguishable before or after reconstitution.  Reconstitution follows same process for placebo or 
Risperidone ISM.  Any small differences in final volumes are not perceptible.  For de novo patients, 
the corresponding IMP kit will be assigned via an interactive voice or web response system based on 
the above described criteria (see Section 5.3.1.1) so that both investigator and patient can know the 
treatment administered, consistent with the open-label definition of this segment of the study. 
Nevertheless, the management of the study drug will be performed by different study personnel (see 
Section 5.4).  Only designated unblinded individuals at sites will be dealing with the study drug 
reconstitution and administration of the study drug to the patient, and will not be involved in any 
clinical evaluation.  These individuals will be appropriately qualified and trained to perform the 
required study drug reconstitution and study drug administration to patients.   
Oral risperidone test doses, if applicable for a given patient, will be administered under open-label 
conditions.   


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5.3.2.1 Breaking the Blind 
If an investigator deems it necessary to break the treatment assignment blind, he or she should 
promptly document and explain to the medical monitor or designee reason of the unblinding (e.g., 
accidental unblinding, unblinding due to an SAE) of study drug.   
Once it has been determined that breaking the blind is necessary, the investigator or other designated 
study site staff member will contact the interactive voice or web response system to obtain disclosure 
of the identified patient’s treatment assignment.   
Breaking the blind for a single patient will not affect the blind for the remaining patients.   
5.3.2.2 Extension Segment of the Study 
All patients who participate in the optional extension segment of the study will receive active 
Risperidone ISM (i.e., 75 or 100 mg; see Section 5.3.1.1) under open-label conditions.  However, in 
order to preserve the blinding condition of the double-blind stage of the study, if a participating 
rollover patient enters this OLE phase of the study prior to locking the database of the double-blind 
stage of the study, the allocation to either 75 or 100 mg of this patient will be still blinded at least up 
to locking the aforementioned database.  For de novo patients, the corresponding IMP kit will be 
assigned via interactive voice or web response system based on the above described criteria (=4 mg or 
>4 to 6 mg oral risperidonesee Section 5.3.1.1) so that both investigator and patient can know the 
treatment administered, consistent with the open-label definition of this segment of the study. 
 
5.4 Study Drug Accountability, Adherence, Handling, and Disposal 
The clinical site is required to maintain current drug dispensation and accountability logs throughout 
the study for study drug. 
The study drug injections will be reconstituted and administered directly by appropriately qualified 
and trained unblinded study site personnel until the Data Base lock of the Double-blind segment.  The 
date and time of each study drug administration will be recorded for each patient and as such will 
serve to document adherence.   
Unused supplies will be checked against study drug records periodically throughout the study.   
After completion and verification of accountability logs by the study monitor, all remaining study 
drug must be destroyed.  Packages may be destroyed on site according to Good Clinical Practice 
(GCP) and site practice; alternatively, the sponsor may arrange for destruction with a third-party 
vendor operating in accordance with GCP.   
The same procedure applies to risperidone tablets provided for risperidone-naïve patients testing, as 
applicable. 
6 Procedures 
The overall schedules of assessments and procedures by visit are displayed in Table 1, Table 2, and 
Table 3. 
A by-visit list of assessments and procedures is provided in Appendix A.   


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6.1 General 
6.1.1 
Informed Consent 
During the screening visit, the nature of the study and anticipated risks and benefits of participation 
will be explained to the patient by the investigator or designated study personnel.  Each patient will 
receive an informed consent form that summarizes pertinent study information and will be given 
ample time to read it and to ask questions about the study.  If a patient chooses to participate, the 
patient must sign the informed consent form before any study-specific procedures are conducted (see 
Section 10.3).   
Screen Failure patients (applicable for patients entering the double-blind segment and de novo 
patients entering the extension segment) can be considered to be allowed for Re-Screening purposes 
as long as they have previously been discussed between the Principal Investigator and the Medical 
Monitor. More than 14 days, from the initial ICF signature, should be elapsed and all the procedures 
required (except the Ophthalmological examination, if this is not the reason of the re-screening), 
including the signature of a new ICF, should be repeated within the established screening period. In 
these specific cases a new ID number will be assigned.   
6.1.2 
Demographics, Medical History, and Psychiatric History 
To determine eligibility during screening, the patient’s demographic data, medical history, and 
psychiatric history will be reviewed and documented.  At later visits, each patient’s medical and 
psychiatric history since the prior visit will be reviewed and any significant change will be recorded in 
the source documents and electronic case report form (eCRF) as an AE as appropriate.   
6.1.3 
Concomitant Medication Review 
At screening, patients will be asked about all medications they have taken in the last 30 days, 
including prescription and nonprescription medications, vitamins, and supplements.   
Patients will also be asked about any long-acting injectable antipsychotic medications taken in the last 
60 days (see inclusion criterion 6 in Section 4.1.1.1, exclusion criterion 17 in Section 4.1.1.2, 
inclusion criterion 5 in Section 4.1.3.1, and exclusion criterion 17 in Section 4.1.3.2) as well as any 
past use of risperidone (see exclusion criteria 1 and 4 in Section 4.1.1.2, and exclusion criteria 1 and 3 
in Section 4.1.3.2).  Patients will also be asked about any history of failure to respond to adequate 
trials of antipsychotic medications, as well as about any history of clozapine use (see exclusion 
criterion 2 in Section 4.1.1.2 and Section 4.1.3.2).  The investigator will record in the eCRF the use of 
all medications taken in a period of 30 days prior to the trial, and the use of any long-acting injectable 
antipsychotic medications taken in the period of 60 days prior to the trial. 
At each subsequent visit, enrolled patients will be asked about use of concomitant medications since 
the previous visit.  Any new medications or changes in previously recorded medications will be 
documented.  The investigator will record the following data on all medications used by the patient: 
medication name, dose, regimen, route of administration, start and stop dates, and the indication for 
use.   
6.1.4 
MINI International Neuropsychiatric Interview for Schizophrenia and Psychotic 
Disorders Studies 
The MINI International Neuropsychiatric Interview for Schizophrenia and Psychotic Disorders 
studies, version 7.0.2 (see Appendix C) will be completed at the screening visit to verify 
schizophrenia and any other psychiatric diagnoses according to the DSM-5 (see inclusion criterion 4 
and exclusion criterion 9 in Section 4.1.1 and Section 4.1.3).   


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6.2 Efficacy Assessments 
6.2.1 
Positive and Negative Syndrome Scale and Clinician Global Impression 
Efficacy assessments will include the PANSS, CGI-S, and Clinical Global Impression – Improvement 
(CGI-I).  The PANSS, CGI-S, and CGI-I are performed at scheduled time points throughout the 
treatment period as indicated in Table 1, Table 2 and Table 3.   
The investigator or qualified designee will complete these scale ratings.   
The PANSS total score is defined as the sum of scores on the PANSS positive, negative, and general 
psychopathology subscales.  The PANSS results will be used for the primary efficacy variable 
(Section 6.7.1.1) as well as secondary variables (Section 6.7.1.2).   
6.3 Health Economics and Outcomes Research Assessments 
6.3.1 
Healthcare Resource Utilization 
Healthcare resource utilization data will be collected in 2 ways: site-based reporting and patient-based 
(or informant-based) reporting. Study site staff will retrospectively record any HRU that occurred 
within the clinical trial center into the applicable forms of the eCRF.  Detailed resource use in 
following categories is collected: medication, emergency visits, inpatient services, outpatient services 
(specialist consultations and other outpatient hospital care contacts), and therapy.  During the double-
blind phase, clinician-reported data will be recorded once at 3 months (see Table 1).  During the open-
label extension, data will be recorded every 6 months for a total of 2 measurement points (see Table 2 
and Table 3). 
Study site staff will administer a survey to patients (or their informant) to report any HRU that 
occurred outside the clinical trial center.  The patient survey will be administered at the clinical trial 
center by designated study site staff (paper and pencil).  The information will subsequently be 
recorded into the applicable forms of the eCRF.  Detailed resource use in the following categories is 
collected: medication, emergency visits, inpatient services, outpatient services, therapy, community-
based day services, primary and community care contacts, criminal justice services, and days absent 
from work due to illness.  During the double-blind phase, patient- (or informant)-reported data will be 
administered every month for a total of 3 measurement points (see Table 1).  During the open-label 
extension, the survey will be administered every month for a total of 12 measurement points (see 
Table 2 and Table 3). 
Clinician-reported and patient- (or informant)-reported HRU will be combined for analysis.  For each 
item, total quantity of resources used will be calculated as the sum of resources both within and 
outside the participating center during the double-blind and open-label extension phases, respectively.  
This will define the secondary HRU variables (Section 6.7.2).  
6.3.2 
Health-Related Quality of Life 
Health-related Quality of Life will be assessed by the patient-completed 20-item Subjective Well-
Being Under Neuroleptics Treatment Scale (SWN-20).  The SWN is a 38-item instrument developed 
to measure subjective effects of neuroleptic medications in patients with schizophrenia and consists of 
20 positive statements and 18 negative statements.11  The short form of the SWN, the 20-item SWN-
20, was developed in order to allow for quick assessment of subjective side effects in a clinical 
setting.12  Like in the original SWN, with the SWN-20 the patient is asked to rate well-being items 
that have been identified as related to antipsychotic treatment on a 6-point scale ranging from “Not at 
all” to “Very much.”  The SWN-20 is scored on a scale ranging from 20 to 120, with higher scores 


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indicating better HRQL.  The SWN-20 contains five 4-item subscales: mental functioning, self-
control, emotional regulation, physical functioning, and social integration.  Each subscale score 
ranges from 4 to 24, with higher scores indicating better HRQL.  The SWN-20 will be performed at 
scheduled time points throughout the treatment period as indicated in Table 1, Table 2 and Table 3.  
The baseline administration of the SWN-20 should occur prior to the administration of the medication 
dose on study day 1 (double blind segment) or extension study day 1 (de novo patients in the 
extension segment). 
6.3.3 
Social Functioning 
Social functioning will be assessed by the clinician-administered Personal and Social Performance 
Scale (PSP).  The PSP is a 100-point single-item rating scale that is based on 4 areas: family and 
social functioning, self-care, work and socially useful activities, and disturbing and aggressive 
behaviors.13  Higher scores indicate better social functioning.  The PSP will be administered by a 
trained clinician, either the study investigator or a qualified designee.  The PSP will be performed at 
scheduled time points throughout the treatment period as indicated in Table 1, Table 2 and Table 3.  
The baseline administration of the PSP should occur prior to the administration of the medication dose 
on study day 1 (double blind segment) or extension study day 1 (de novo patients in the extension 
segment). 
6.4 Safety Assessments 
Safety assessments will include AEs, vital signs (blood pressure, pulse rate, respiratory rate, and body 
temperature), weight, body mass index, laboratory tests (i.e., hematology, chemistry [including 
prolactin], urinalysis, urine drug screen), ECGs, physical examinations, injection site reactions, and 
selected safety scales.  Safety scales will include the C-SSRS and the following 3 scales to assess 
extrapyramidal symptoms: the Abnormal Involuntary Movement Scale (AIMS), the Barnes Akathisia 
Rating Scale (BARS), and the Simpson-Angus Scale (SAS).   
6.4.1 
Physical Examination, Body Height, Weight 
A physical examination will be performed at time points identified in Table 1, Table 2 and Table 3.  
The physical examination will include assessment of the following: general appearance, skin, 
lymphatic, eyes, ears, nose, throat, neck, respiratory, cardiovascular, gastrointestinal, musculoskeletal, 
and neurological.   
Body height (cm) will be measured at screening only.  Body weight (kg) will be measured at time 
points identified in Table 1, Table 2 and Table 3. 
The body mass index value at each of these time points will be calculated; the body mass index value 
must be within the range of 18.5 to 40.0 kg/m2, inclusive, at screening.   
6.4.2 
Ophthalmological Examination 
The Risperidone ISM formulation is composed of risperidone and 2 excipients: PLGA and DMSO.  
Although DMSO is widely used in the pharmaceutical product formulations for topical, subcutaneous, 
and intravenous dosage forms and during pharmaceutical manufacturing processes, there have been 
published reports of toxicity to the eyes in animals treated with DMSO, including crystalline lens 
opacity.  Therefore, an ophthalmological examination of study patients is required.  All efforts should 
be made to have both examinations performed by the same ophthalmologist in order to get consistent 
data. 


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An ophthalmological examination will be performed at any time during the screening period of the 
double-blind segment of the study, and the result must be available by study day -1.  This examination 
needs to be done again at visit 14 or at an early termination visit during the Double-blind period.     
Ophthalmological examination includes best corrected visual acuity, visual field, intraocular pressure 
(IOP) measurements, and slit-lamp biomicroscopy examination of the eyelids, conjunctiva, iris, 
crystalline lens, sclera, and cornea.  
Slit-lamp examination must be performed prior to IOP measurements or instillation of the fluorescein 
agent. 
6.4.2.1 Best Corrected Visual Acuity Testing 
A standard procedure is to be used to obtain best corrected visual acuity measurements.  This activity 
may be performed by an optometrist, ophthalmologist, or certified ophthalmic technician. 
6.4.2.2. Slit-Lamp Examination (Biomicroscopy) 
A slit-lamp examination of the eyelids, conjunctiva, iris, crystalline lens, sclera, and cornea will be 
performed without pupil dilation (unless needed).  Any abnormalities will be graded as mild, 
moderate, or severe.  Any abnormality found during the slit-lamp examination should be noted. 
Presence of cataract (absent, mild, moderate, severe), aphakia, or intraocular lens (anterior chamber 
intraocular lens, posterior chamber intraocular lens, or iris clip) and status of the posterior lens capsule 
(intact, open, or absent) should be specified. Slit-lamp examination should precede IOP measurement.  
6.4.2.3. Intraocular Pressure  
The IOP will be measured by a routinely used applanation tonometer.  Study sites should calibrate the 
applanation tonometer according to the manufacturer’s instructions.  The IOP in both eyes will be 
measured, with the right eye preceding the left eye. If it is a routine practice at the site, a non-contact 
air-puff tonometry can also be used. 
6.4.2.4. Visual Fields 
The visual field will be examined using a standard procedure at the site.  The recommended visual 
fields examination is automated perimetry including Humphrey (24-2 full threshold, 24-2 SITA 
standard, 30-2 central threshold, [Note: 24-2 SITA fast not allowed]) and Octopus (GI dynamic 
strategy, GI normal strategy, 24-2 dynamic strategy, 24-2 normal strategy) perimetry.  
If this procedure was performed within the past 90 days and documented in the patient’s medical 
record, this procedure need not be repeated (unless the investigator suspects a change).  This may be 
performed by a trained certified ophthalmic assistant, certified ophthalmic technician, nurse, or 
research coordinator. 
6.4.3 
Vital Signs 
Vital signs will include blood pressure, pulse rate, respiratory rate, and body temperature.   
Vital signs will be measured at time points identified in Table 1, Table 2 and Table 3. 
At each of these time points, vital signs will be measured after the patient has been resting in a supine 
position for at least 5 minutes.   


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On days when patients receive IM injections of study drug, vital signs are to be measured within 1 
hour before and then again within 3 hours after the study drug injection; at each of these time points, 
orthostatic blood pressure and pulse rate will be measured (immediately after completion of supine 
vital sign measurements) after the patient has risen from the supine to the standing position and has 
remained standing for approximately 3 minutes.   
Efforts should be made to take all blood pressure and pulse rate measurements from the same arm 
(preferably the patient’s dominant arm) throughout the study.  The same blood pressure cuff should be 
used to measure blood pressure each time.  Automated measurement is preferred, but if measurements 
are performed manually, pulse rate will be measured in the brachial artery for at least 30 seconds.   
6.4.4 
Electrocardiogram 
A 12-lead ECG will be performed at the study visits identified in Table 1, Table 2 and Table 3. 
On days when patients receive injections of IM study drug, an ECG will be performed both within 1 
hour before dosing and within 3 hours post-dose.   
All scheduled ECGs must be performed after the patient has rested quietly for at least 5 minutes in the 
supine position.   
Absolute values for QT intervals should be automatically corrected for heart rate by the ECG machine 
using both Bazett’s fomula (QTcB) and Fridericia’s formula (QTcF).   
The ECGs will be evaluated by a central reader.  Additional details regarding recording and 
evaluation of ECGs will be described in a manual provided to the study site.   
6.4.5 
Laboratory Assessments 
Blood and urine samples for laboratory assessments will be collected at screening and at time points 
identified in in Table 1, Table 2 and Table 3. 
Samples will be collected in accordance with the study site’s usual procedures and analyzed by a 
central laboratory.   
In the event of abnormal laboratory test values, follow-up samples may be obtained for repeat testing 
if deemed clinically indicated by the investigator.   
Each out-of-range laboratory value will be assessed by the investigator as either clinically significant 
or not clinically significant.  Clinically significant values should be considered AEs and recorded as 
such.   
Additional details regarding laboratory sample collection and processing will be described in a 
manual provided to the study site.   
6.4.5.1 Hematology  
The hematology panel includes the following tests:  
 
Hematocrit, hemoglobin, red blood cell count, white blood cell count and differential count 
(absolute values for basophils, eosinophils, lymphocytes, monocytes, and neutrophils), and 
platelets 


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6.4.5.2 Chemistry  
The chemistry panel includes the following tests:  
 
Sodium, potassium, glucose, creatinine, creatinine clearance [Estimated Glomerular Filtration 
Rate (eGFR) using Modification of Diet in Renal Disease (MDRD) formula], total protein, blood 
urea nitrogen, albumin, total bilirubin, alanine aminotransferase, aspartate aminotransferase, lactic 
dehydrogenase, gamma-glutamyl transferase, alkaline phosphatase, and creatine phosphokinase 
 
Prolactin (see Section 6.4.9.3) 
 
Hemoglobin A1c  
 
Thyroid-stimulating hormone 
 
Lipid panel: low-density lipoprotein, high-density lipoprotein, total cholesterol, and triglycerides 
6.4.5.3 Urinalysis  
The urinalysis includes the following tests:  
 
Color, pH, specific gravity, ketones, protein, glucose, bilirubin, nitrite, urobilinogen, and occult 
blood 
 
Microscopic examination only if urinalysis dipstick results are abnormal 
6.4.5.4 Other Laboratory Tests 
6.4.5.4.1 
Serology 
A blood sample for a serology panel testing for hepatitis B surface antigen, antihepatitis C antibodies, 
and human immunodeficiency virus will be performed at screening only.   
6.4.5.4.2 
Pregnancy Testing 
A serum pregnancy test will be performed for all women at screening.  Results must be negative for 
initial study eligibility.  Urine pregnancy test (dipstick) will be performed on site for all women at 
baseline and subsequently at time points identified in Table 1, Table 2 and Table 3. Results at baseline 
must be negative for initial study eligibility.   
Results must be negative for continued participation.  On each IM study drug dosing day, the urine 
pregnancy test must be performed and a negative result confirmed before the scheduled dose of study 
drug for that day is administered.   
A serum pregnancy test is not required during the open-label extension stage but may be performed.  
The investigator may order a serum pregnancy test at any time according to her or his judgment. 
6.4.5.4.3 
Drug Screening 
A urine drug screen for prohibited substances will be performed at time points identified in Table 1 
and Table 3 (mandatory at screening and baseline) and on as-needed basis as indicated in Table 1, 
Table 2 and Table 3.  The urine drug screen will include identification of the presence or absence of 
amphetamines, barbiturates, cocaine, methadone, opioids, and phencyclidine, as well as for THC, 
alcohol, and benzodiazepines.   
 Urine drug screen will be performed at each scheduled timepoint and the collected sample will be 
sent to the central laboratory for analysis. In addition, onsite dipstick urine drug screen testing may be 
optionally performed on the sample collected. 


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Results at screening or baseline indicating the presence of a prohibited substance will exclude a 
patient from further participation in the study (see Section 3.2.2.1.1.4 and exclusion criterion 13.h in 
Section 4.1.1.2 and Section 4.1.3.2).   
If a patient has a positive result for benzodiazepines, the investigator should determine if 
benzodiazepine use was medically indicated; a positive benzodiazepine result may not be 
exclusionary if the investigator determines that the benzodiazepine use is clinically appropriate and is 
not indicative of abuse (see Section 4.1.1.2 and Section 4.1.3.2).   
A positive result for THC and/or alcohol generally is to be considered exclusionary; however, such a 
finding may not necessarily be exclusionary in certain cases only if exclusion criterion 9 is not met 
and only if the medical monitor provides approval.   
6.4.6 
Injection Site Reactions 
Approximately 1 hour after an injection, the investigator will inspect the injection site where the study 
drug has been administered for redness, swelling, and induration.  The investigator will also observe 
all injection sites where IM study drug has been injected on previous visits.  At the same time 
(approximately 1 hour after injection), the study patient will perform and record self-assessment of 
pain at the injection site using a visual analog ccale (VAS; see Appendix D).  If clinically significant, 
the injection site reaction will be recorded as an AE and the nature, duration, intensity, and 
relationship to the study drug will be recorded. 
Any injection site reaction that occurs outside the schedule established in Table 1, Table 2 and 
Table 3 will be recorded as AE. 
6.4.7 
Extrapyramidal Symptoms Rating Scales 
Extrapyramidal symptoms rating scales will include the AIMS, BARS, and SAS.  The investigator or 
designee will complete the set of abnormal movement rating scales at time points identified in Table 
1, Table 2 and Table 3.  Clinically significant changes from baseline in extrapyramidal symptoms are 
to be recorded as AEs.   
6.4.8 
Columbia-Suicide Severity Rating Scale 
The investigator or designee will complete the C-SSRS at time points identified in Table 1, Table 2 
and Table 3.   
At screening, the baseline version will be administered.  At subsequent visits, the since-last-visit 
version will be administered.   
The C-SSRS results for each patient should be reviewed by the investigator at each applicable visit.  If 
at any time the C-SSRS results for a given patient reveal potential suicidality, the investigator should 
assess the clinical significance of such results.  If a clinically significant risk of suicidality is identified 
for a patient, the investigator should consider further clinical evaluation of that patient and 
implementation of appropriate clinical measures as deemed indicated to help ensure patient safety.   
Clinically significant changes from baseline in the level of suicidality are to be recorded as AEs.   
6.4.9 
Adverse Events 
An AE is any symptom, physical sign, syndrome, or disease that either emerges during the study 
(from the informed consent form signature) or, if present at screening, worsens during the study, 


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regardless of the suspected cause of the event.  All medical and psychiatric conditions (except those 
related to the indication under study) that are present at screening will be documented on the 
appropriate page of the eCRF.  Changes in these conditions and new symptoms, physical signs, 
syndromes, or diseases are to be noted on the source documents and the AE page of the eCRF during 
the rest of the study.  Clinically significant laboratory abnormalities are also to be recorded as AEs.   
Collection of AE data will begin after a patient signs the informed consent form and will continue 
until completion of the final follow-up visit.  Any AE having an onset after the final safety follow-up 
visit will not be collected or reported unless the investigator feels that the event may be related to the 
IM study drug.   
Adverse events may be volunteered spontaneously by the patient, discovered as a result of general 
questioning by the study staff, or determined by physical examination.  At each study visit, the patient 
will be asked the open-ended question, “Have you experienced any health problems since your last 
visit?”  All AEs will be recorded on the source documents and the eCRF.  For all AEs, the 
investigator must pursue and obtain information that is adequate both to determine the outcome of the 
AE and to assess whether it meets the criteria for classification as an SAE requiring immediate 
notification.  If the AE persists, follow-up even after the date of therapy discontinuation is required 
until the event resolves or stabilizes at a level acceptable to the investigator.  Patients will be 
instructed to contact the investigator at any time after randomization if any symptoms develop.  
In order to avoid vague, ambiguous, or colloquial expressions, all AEs should be recorded in standard 
medical terminology rather than in the patient’s own words.  Each AE will also be described in terms 
of duration, frequency, intensity, association with the study drug, assessment of possible causes, 
actions taken, and outcome, using choices given on the eCRF.  Specific guidelines for classifying AEs 
by intensity and by relationship to study drug are given below:  
Classification of Adverse Events by Intensity 
The severity (or intensity) of an AE refers to the extent to which it affects the patient’s daily activities 
and will be classified as mild, moderate, or severe using the following criteria: 
 
Mild: An event that is easily tolerated by the patient, causing minimal discomfort and not 
interfering with everyday activities 
 
Moderate: An event that is sufficiently discomforting to interfere with normal everyday activities 
 
Severe: An event that prevents normal everyday activities 
When changes in the intensity of an AE occur within a day, the maximum intensity for that day 
should be noted.  If the intensity category changes over a number of days, those changes should be 
recorded separately (with distinct onset dates).   
Classification of Adverse Events by Relationship to Study Drug  
The investigator’s assessment of an AE’s relationship to study drug is part of the documentation 
process but is not a factor in determining what is or is not reported in the study. 
The investigator will assess causality (i.e., whether there is a reasonable possibility that the study drug 
caused the event) for all AEs and SAEs.  The relationship will be characterized using the following 
classification: 


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 
Suspected: The temporal relationship of the AE with the investigational medicinal product makes 
causality possible, and the AE cannot be due to another cause such as other drugs, a surgical 
intervention, or an underlying disease 
 
Not suspected: The temporal relationship of the AE with the investigational medicinal product 
makes causality improbable, and the AE may be due to another cause such as other drugs, surgical 
intervention, or underlying disease 
6.4.9.1 Serious Adverse Events 
An SAE is defined as any AE that meets 1 or more of the following criteria:  
 
The event is fatal or life threatening 
 
The event is permanently disabling (incapacitating or interfering with the ability to resume usual 
life patterns) 
 
The event results in unplanned inpatient hospitalization or prolongation of existing hospitalization 
 
The event is a congenital anomaly 
 
The event requires medical intervention of any kind in order to prevent any of the aforementioned 
outcomes 
Important medical events that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon appropriate medical judgment, they may jeopardize the 
patient and may require medical or surgical intervention to prevent 1 of the outcomes listed in this 
definition. Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse. 
An AE is considered “life threatening” if, in the view of either the investigator or sponsor, its 
occurrence places the patient at immediate risk of death. It does not include an AE that, had it 
occurred in a more severe form, might have caused death. 
An SAE is not necessarily severe; for example, an overnight hospitalization for a diagnostic procedure 
must be reported as an SAE even though the occurrence is not medically serious.  By the same token, 
a severe AE is not necessarily serious: nausea of several hours’ duration may be rated as severe but 
may not be considered serious.   
Protocol-allowed psychiatric inpatient stays (e.g., during the screening period and for up to 2 weeks 
during the first part [administration] of the treatment period or longer if needed) will not be reported 
as AEs.  Subsequent hospitalizations will be recorded and tracked as SAEs.   
6.4.9.2 Reporting Adverse Events  
The investigator is responsible for recording all AEs that are observed or reported during the study, 
regardless of their relationship to study drug or their clinical significance.  If there is any doubt as to 
whether a clinical observation is an AE, the event should be recorded. 
All AEs, regardless of causality and severity, occurring during the conduct of the clinical trial whether 
observed by the investigator or spontaneously reported by the patient or in response to an open-ended 
question about any medical problems since the last visit, must be recorded in the source document and 
in the relevant section of the eCRF.  Adverse events will be recorded from informed consent signature 
until completion of the final follow-up visit. 


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Any SAE due to any cause, whether or not related to the study drug, must be reported within 24 
hours of occurrence or when the investigator becomes aware of the event.  The investigator must 
send a preliminary report of the SAE to the ROVI Pharmacovigilance Department by fax/email within 
24 hours (see Appendix F), using an SAE Report Form.   
ROVI Pharmacovigilance Department 
Phone: +34 917617561/+34 911863678 
Fax: +34 912444421 
Email: farmacovigilancia@rovi.es 
The event must also be recorded on the standard AE eCRF page.  Preliminary reports of SAEs must 
be followed by detailed descriptions, including legible photocopies of hospital case reports, consultant 
reports, autopsy reports, and other documents when requested and applicable.  The SAE reports must 
be made whether or not the investigator considers the event to be related to the study drug. 
Appropriate remedial measures should be taken to treat the SAE, and the response should be recorded. 
Patients must be closely followed until sufficient information is obtained to indicate a return to normal 
status or until the event stabilizes at a level acceptable to the investigator.  
Clinical, laboratory, and diagnostic measures should be employed as needed in order to determine the 
etiology of the event.  For this purpose, additional blood samples (as needed) will be collected and 
analyzed whenever an SAE is identified until the event stabilizes at a level acceptable to the 
investigator.  The results must be reported promptly to the sponsor. 
During the double-blind part of the study and until Data Base lock (of the double-blind part), this 
process must be conducted in a manner that maintains blinding of study drug assignment.   
As information is available, a pregnancy diagnosed during a patient’s active participation in the study 
(and any voluntarily provided notice of a pregnancy that is received within 6 months after a patient’s 
last dose of study drug) as patients staff that is will be reported immediately to the sponsor or 
designee, including pregnancy in female partners of male patients.  The pregnancy may be followed to 
term and/or outcome, and this outcome may be reported to the sponsor.  Pregnancy, in and of itself, is 
not regarded as an AE or SAE unless the birth results in a congenital anomaly/birth defect or there is 
suspicion that the study drug may have interfered with the effectiveness of a contraceptive medication 
or method.   
6.4.9.3 Other Significant Adverse Events 
To ensure patient safety, the investigator should also notify the safety coordinator or medical monitor 
should any AE occur that is considered significant but does not meet the criteria for an SAE or that is 
considered unexpected.  An unexpected AE is an AE that is not identified in nature, intensity, or 
frequency in the reference safety information of the investigator brochure.  In addition, any field 
monitor who notes a significant AE or medical condition while reviewing eCRFs or source documents 
at the study site must immediately convey this information to the medical monitor.   
An increase in prolactin plasma levels should be considered an AE when any of the following criteria 
are present:  
 
Values above 1000 mIU/L for 3 consecutive determinations after randomization, although no 
clinical symptoms are present 


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 
Values above 530 mIU/L if clinical symptoms of hyperprolactinemia are present (e.g., headache, 
decreased libido, oligo-amenorrhea) 
However, where patients have prolactin concentrations above the upper limit of normal at screening, 
the following criteria could be used by the investigator as a guideline:  
 
For patients at screening with prolactin blood levels above the normal limit, an increase of 
prolactin from baseline (day 1, pre-dose) values is recommended to be considered as an AE when 
the patient presents 3 consecutive determinations with a prolactin value above 1000 mIU/L, if the 
increase is > 20% even though no other clinical symptoms are associated 
 
For patients at screening with prolactin blood levels above 1000 mIU/L, it is recommended to 
consider it as an AE when there is an increase > 20% of the baseline (day 1, pre-dose) level in 3 
consecutive determinations even though no other clinical symptoms are associated 
As a general rule, it should be considered that the “hyperprolactinemia” event has finished the day 
when a prolactin value lower to 1000 mIU/L is obtained, or when levels return to the basal value for 
patients with prolactin concentrations above the upper normal limit at screening.   
 
The day and time of the determination should be recorded in the eCRF.  It has to be noted that 
same date could be registered as the end of hyperprolactinemia for 1 event (AE #1) and the start 
of another hyperprolactinemia for another event (AE #2).  As an example: if the day when 4 
prolactin determinations are made matches that in the first determination the hyperprolactinemia 
has finished (AE #1) but after the injection of Risperidone ISM, a new event of 
hyperprolactinemia (AE #2) is considered as started (as per protocol), and that date should be 
registered as the date of the end of AE #1 and start date of AE #2.  The times of finalization and 
starting of both events should be recorded.   
To this end, the date of the third abnormal determination will be considered as the start date of the 
AE.   
Those patients with values out of range that are considered an AE will be monitored either until the 
values do not fulfill the aforementioned AE criteria or stabilize at a level acceptable to the 
investigator.   
6.5 Pharmacokinetic Sample Collection 
During the double-blind segment of the study, pharmacokinetic samples will be collected from all 
patients participating in the study in a manner that maintains the double-blind with respect to patient 
treatment assignment.  All patients will have pharmacokinetic samples collected on days 1, 3, 29, 31, 
57, 59, and 85 (visits 2, 3, 8, 9, 11, 12, and 14, respectively).  Additionally, 75 patients irrespective of 
randomized treatment will be selected to have additional sampling on days 8, 15, and 22 (visits 5, 6, 
and 7, respectively).  In addition, pharmacokinetic samples will be collected at the time of an SAE.   
In order to maintain study drug blinding, at the selected study sites, pharmacokinetic samples will be 
collected from all enrolled patients (regardless of treatment assignment); however, only samples from 
patients receiving active Risperidone ISM will be analyzed.   
A blood sample (approximately 4 mL each) for measurement of concentration in plasma of 
risperidone and its active metabolite (9-OH-risperidone) will be obtained at time points shown in 
Table 1.   


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These pharmacokinetic samples will be obtained before administration of study drug as applicable 
(i.e., on study days when pharmacokinetic samples and study drug administration both occur).  
Pharmacokinetic blood samples will be processed at the study site (e.g., centrifugation, separation of 
plasma, and freezing) according to instructions that will be provided to the study site in a manual.  
Contact information and sample handling and shipment instructions will be described in the manual.   
Pharmacokinetic samples from patients receiving active Risperidone ISM will be analyzed by a 
central laboratory; however, the samples from patients receiving placebo will not be analyzed (they 
are collected nevertheless in order to maintain the double-blind).  The process for this selective 
pharmacokinetic analysis will be performed in a manner than maintains the double-blind with respect 
to patient treatment assignment.   
6.6 Genotype Sample Collection 
Genotype samples will be collected from all patients who will sign the appropriate consent in the 
double-blind segment of the study.   
A separate informed consent form for participation genotype sample collection must be signed before 
any blood samples for genotype assessment sample are collected for a given patient.   
A single blood sample will be collected from each patient for evaluation of genotypes for cytochrome 
P450 enzymes and/or genes considered potentially related to response.  The blood sample for 
genotype testing may be collected at any time point after randomization during the Double-blind 
period.   
6.7 Outcome Variables 
6.7.1 
Efficacy Variables 
Efficacy variables are listed within this section.  In this context, endpoint is defined as study day 85 or 
the last post-baseline double-blind assessment.   
6.7.1.1 Primary Efficacy Variable 
The primary efficacy variable is the following:  
 
PANSS total score mean change from baseline to endpoint  
6.7.1.2 Secondary Efficacy Variables 
6.7.1.2.1 
Key Secondary Efficacy Variable 
The key secondary efficacy variable is the following:  
 
CGI-S score mean change from baseline to endpoint 
6.7.1.2.2 
Other Secondary Efficacy Variables 
Other secondary efficacy variables include the following:  
 
CGI-I score mean at endpoint 
 
Overall response rate at endpoint 
o Overall response is defined as either of the following:  
 
PANSS total score ≥ 30% decrease (improvement of symptoms) from baseline to 
endpoint 


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 
CGI-I score of 2 (much improved) or 1 (very much improved) at endpoint 
 
PANSS response rate at endpoint 
o PANSS response is defined as the following:  
 
PANSS total score ≥ 30% decrease (improvement of symptoms) from baseline at 
endpoint 
 
Time to reach PANSS response 
 
PANSS total score mean change from baseline at each post-baseline assessment time point 
 
PANSS subscale score mean change from baseline at endpoint and at each post-baseline 
assessment time point for each of the positive, negative, and general psychopathology subscales 
 
Overall response rate at each post-baseline assessment time point 
 
Time to reach overall response 
 
PANSS response rate at each post-baseline assessment time point 
 
CGI-S score mean change from baseline at each post-baseline assessment time point 
 
CGI-I score mean at each post-baseline assessment time point 
6.7.2 
Health Economics and Outcomes Research Variables 
Health economics and outcomes research variables are listed within this section.  In this context, 
endpoint is defined as study day 85 or the last post-baseline double-blind assessment.   
 
HRU and cost variables include the following: 
o For each item, total quantity of resources used within and outside the participating center at 
endpoint.  For each item, mean number at endpoint and rate of use per 3 months will be 
calculated 
o By-resource use category (e.g., inpatient services, outpatient services) and total direct medical 
costs (reflecting resources used within and outside the participating center) at endpoint and 
average cost per 3 months will be calculated. 
o For all resource use categories combined, total direct medical costs at endpoint and average 
cost per 3 months will be calculated. 
o Indirect costs (days absent from work due to illness) at endpoint 
 
PSP total score mean change from baseline at each post-baseline assessment time point 
 
PSP domain  score mean change from baseline at each post-baseline assessment time point 
 
SWN-20 total score mean change from baseline at each post-baseline assessment time point 
 
SWN-20 subscale score mean change from baseline at each post-baseline assessment time point 
6.7.3 
Safety Variables 
Safety variables include the following:  
 
Occurrence, nature, duration, intensity, and relationship to study drug of injection site reactions.  
o Injection site pain, assessed by patients using a VAS after each dose.  
o Injection site evaluation of redness, swelling, and induration, evaluated by designated study 
site personnel after each injection 
o Occurrence (incidence), nature, onset time, duration, intensity, action taken, and relationship 
to study drug of treatment-emergent AEs 
 
Occurrence, nature, time to onset, duration, seriousness criteria, relationship to study drug, and 
outcome of treatment-emergent SAEs 
 
Occurrence of extrapyramidal symptoms, as assessed using the SAS, BARS, and AIMS 
 
C-SSRS 


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 
Physical examination, vital signs, weight, body mass index, clinical laboratory test results, and 
ECG findings 
 
Time to early termination 
6.7.4 
Pharmacokinetic Variables 
The pharmacokinetic variables are the following:  
 
Summary plasma concentrations of risperidone, its active metabolite (9-OH-Risperidone), and the 
active moiety (i.e., risperidone plus 9-OH-risperidone) by injection site (gluteal and deltoid) and 
by study drug dose level 
 
Trough concentrations and accumulation index for steady state by injection site (gluteal and 
deltoid) and by study drug dose level 
 
Exploratory associations of pharmacokinetic results with efficacy results 
6.7.5 
Genotype Sampling  
For all study patients who consent to collecting genotype sample and sign a separate consent form, a 
blood sample will be collected for evaluation of genotypes for cytochrome P450 enzymes and/or 
genes that are potentially related to efficacy response and/or adverse effects.  The sample may be 
obtained at any point after randomization occurs during the Double-blind period.  The samples will be 
tested for all patients for correlation with pharmacokinetic and/or efficacy results.  
7 Statistics 
7.1 General Considerations 
The statistical analysis methods are described below and refer to the main (double-blind) part of the 
study.  Additional details will be provided in a separate Statistical Analysis Plan document, which will 
be finalized before database lock and unblinding of the study.  Analysis for the extension segment of 
the study will be descriptive only.   
In general, summary statistics (n, mean, standard deviation, median, minimum, and maximum values 
for continuous variables, and number and percentage of patients in each defined category for 
categorical variables) will be provided by treatment group for all variables.  Source data for the 
summary tables and statistical analyses will be presented as patient data listings.   
Baseline in the main (double-blind) part of the study will be defined as last non-missing observation 
before first dose of study drug.  Baseline in the extension segment of the study will be defined as last 
non-missing observation before first dose of Risperidone of the extension segment of the study. 
7.2 Analysis Populations 
The randomization population will consist of all patients that are randomized in the study. Analyses 
performed on the randomization population will be as randomized.  This population will be used for 
sensitivity analysis of the primary variable. 
The safety population will include all patients who receive at least 1 dose of study drug.  Analyses 
performed on the safety population will be as treated. 
The modified safety population will consist of all patients in the safety population for whom blinding 
was not potentially compromised. Analyses performed on the modified safety population will be as 
treated.  This population will be used for selected safety analyses.   


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The intent-to-treat (ITT) population will consist of all randomized patients who received at least 1 
dose of study drug with a baseline measurement and ≥ 1 post-baseline evaluation of the PANSS.  
Analyses performed on the ITT population will be as randomized.  The ITT population will be used 
for analyses of efficacy endpoints, including health economics and outcomes research endpoints. 
The modified intent-to-treat (mITT) population will consist of all patients in the ITT population for 
whom blinding was not potentially compromised. Analyses performed on the mITT population will 
be as randomized.  The mITT population will be used for analyses of efficacy endpoints. 
The per-protocol (PP) population will consist of patients from the ITT population who receive ≥ 2 
injections of study drug (active or placebo) during the treatment period and have no major protocol 
deviations that may impact the primary efficacy variable.  Patients will be analyzed according to 
assigned treatment.  The PP population will be used for supporting analyses of efficacy endpoints. 
The modified per-protocol (mPP) population will consist of all patients in the PP population for whom 
blinding was not potentially compromised. Analyses performed on the mPP population will be as 
treated.  This population will be used for selected efficacy analyses. 
The pharmacokinetic population will include patients in the safety population who have at least 
1 measured plasma concentration value.  In cases where a protocol deviation is identified to 
potentially affect plasma concentration data, the identified concentration values will be flagged and 
excluded from summarization as indicated, and in some cases may be excluded from the 
pharmacokinetic analysis overall; excluded concentration values will be identified before database 
lock based on a protocol deviations log and confirmed with sponsor. An intense pharmacokinetic 
subset of patients with additional samples measured after dose 1 will be used to evaluate non-
compartmental pharmacokinetic parameters during dosing interval after dose 1. 
Explanations for pharmacokinetic parameters that could not be estimated will be provided in the 
clinical study report as applicable.   
Genotyping data will be listed and summarized for all patients in safety population if available. 
A blinded data review meeting will be held before database lock and unblinding of the double-blind 
phase to clarify any open questions or doubts and agree upon the PP and pharmacokinetic 
populations.  Attendees will include appropriate individuals from the sponsor and Contract Research 
Organization (CRO).  All decisions will be documented.  Details regarding the data to be reviewed at 
the meeting will be documented in the Statistical Analysis Plan, and a separate blinded data review 
meeting plan. Prior consideration will be given to ensure that no data will be reviewed which has 
potential to present blinding issues (e.g., pharmacokinetic concentration data).  Reasons for excluding 
patients from the PP or pharmacokinetic population will be determined and documented before 
database lock.  All patients satisfying the ITT and mITT population definition will be included in the 
respective efficacy analyses. 
The open-label population will consist of all patients who received at least 1 dose of study drug in the 
extension segment of the study.  Analyses performed on the open-label population will be as treated, 
and by double-blind segment treatment arm and de novo entry at the time of OLE phase. 
7.3 
Planned Analyses 
7.3.1 
Patient Disposition 


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The number of patients who enter and complete the main (double-blind) part of the study will be 
tabulated.  Patients who fail to complete the main (double-blind) part of the study will be summarized 
and categorized by reason for termination.  Similarly, the description of the patients’ dispositions in 
the extension segment of the study (including whether the patient was a rollover or de novo patient) 
will be performed. 
In addition, the numbers of patients randomly assigned to each study drug treatment and the number 
of patients included in each analysis population (e.g., safety, modified safety, ITT, mITT, PP, mPP, 
open label, and pharmacokinetic) will be summarized by treatment group, along with reasons for 
exclusion as applicable.   
7.3.2 
Demographics and Baseline Data 
Demographics and baseline characteristics will be summarized by treatment group for safety, ITT, 
mITT, PP, mPP, open-label, and pharmacokinetic populations using descriptive statistics as described 
in Section 7.1.   
Cytochrome P450 2D6 inferred metabolic status will be summarized and details of the genotype will 
be listed and summarized by treatment group for safety modified safety, ITT, mITT, PP, mPP, open-
label, and pharmacokinetic populations using descriptive statistics.  Predicted phenotypes will be 
determined following the activity score system published by Gaedigk et al (2008).14  Patients with an 
activity score > 2 will be considered as ultra-rapid metabolizers, a value of 1.5 to 2 as extensive 
metabolizers, 0.5 to 1 as intermediate metabolizers, and a value of 0 as poor metabolizers. 
Medical and psychiatric history will be summarized by treatment group for the safety and open-label 
populations.   
7.3.3 
Study Drug Administration 
Study drug administration data will be summarized for all randomized patients by treatment group.  
Study drug administration data from the extension segment of the study will be similarly summarized 
for the open-label population. 
7.3.4 
Efficacy 
Results for efficacy variables will be summarized by treatment group for the mITT, ITT and PP 
populations using descriptive statistics (see Section 7.1) for data obtained during the main (double-
blind) part of the study. The analyses of primary and key secondary endpoints will also be provided 
for the mPP population. Although any confirmatory findings related to efficacy must be substantiated 
in both the mITT and ITT populations, the mITT will be used as the primary population to describe 
efficacy results in the CSR. For the primary and key secondary variables, results will also be 
summarized separately for stage 1 and stage 2 of the study (see Section 7.5).  
Efficacy variables (PANSS, CGI-S, CGI-I) from the extension segment of the study will be 
summarized similarly for the open-label population, as applicable, for descriptive purposes. 
To account for patients for whom the post-baseline endpoint (i.e., at the time when the last post-
baseline double-blind assessment was performed) occurs at a time point before study day 85, a mixed 
effect model with repeated measurements (MMRM) using an unstructured covariance matrix 
approach will be used as the primary method.  It is assumed that the majority of the missing values 
will be one of the following:  
 
“Missing Completely at Random” (i.e., probability of an observation being missing does not 
depend on observed or unobserved measurements) or 


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 
“Missing at Random” (i.e., probability of an observation being missing depends only on observed 
measurements) 
In such situations, likelihood-base methods like MMRM are appropriate17 and are already usual.16  
If a patient has a PANSS assessment recorded, but any of the 30 items are missing, the last non-
missing score for the respective item from previous assessments will be carried forward.22  If the total 
or subscale score has > 30% of the items missing at a particular visit, the respective total or subscale 
score at the visit will not be calculated and will be treated as missing data in the analysis.   
7.3.4.1 Primary Efficacy Variable Analyses 
The primary efficacy analysis is designed to show superiority of active treatment versus placebo in the 
primary efficacy variable (Section 6.7.1.1).   
Two hypotheses will be tested: 
a. 
H0,A: µRisperidone ISM   75 mg - µplacebo = 0 vs H1,A: µRisperidone ISM  75 mg - µplacebo ≠ 0 
b. H0,B: µRisperidone ISM 100 mg - µplacebo = 0 vs H0,B: µRisperidone ISM 100 mg - µplacebo ≠ 0   
with µ = PANSS total score mean change from baseline to endpoint for identified treatment group.   
An MMRM approach will be fitted for patients in the mITT population with country where enrolled, 
visit, treatment, and treatment-by-visit interaction as fixed effects and baseline PANSS total score as a 
covariate.  This model will be applied separately for patients in stage 1 and stage 2 of the study.  The 
treatment differences from the model at study day 85 will be evaluated to test the hypotheses above, 
maintaining a 2-sided type 1 error rate of 5%.  Model results from each stage will be presented. 
In order to maintain the type 1 error rate for the primary analysis, each hypothesis will be tested using 
a weighted test statistic in accordance with Cui, Hung, Wang18 (CHW) methodology which comprises 
of combining the z-statistics from the respective study day 85 treatment comparison at each stage.  
The weighting will be equal for each stage and pre-defined as sqrt (0.5). 
The nominal 2-sided p-value for each hypothesis will be calculated for the respective weighted CHW 
statistic using the cumulative normal distribution. 
To account for multiplicity of testing and to keep the type 1 error rate at 5%, the Hommel’s closed-
testing correction procedure19 as implemented in SAS software (PROC MULTTEST) will be used to 
provide adjusted p-values to assess for superiority of either dose.  
The primary efficacy analysis will be supported with sensitivity analyses.  All sensitivity analyses will 
use the CHW and Hommel adjustment to present p-values.  The MMRM (as above) and analysis of 
covariance (ANCOVA) models using both observed endpoint values and multiply imputed20 study 
day 85 values will be performed for the mITT population.  The ANCOVA models will include 
country where enrolled and treatment as fixed effects and baseline PANSS total score as a covariate.   
All analyses described above will be repeated for the ITT population. However, to account for extra 
43 patients included in Stage 1, the CHW statistic will be derived using weights of sqrt(0.55) and 
sqrt(0.45) for stage 1 and 2 respectively. 
Confirmatory findings from the Hommel adjusted CHW analyses will only remain so for a particular 
dose if p<0.05 in both the mITT and ITT analyses. 


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All analyses described above for the ITT and mITT population will also be repeated for the PP and 
mPP population respectively. 
The descriptive statistics summary will be presented for each country and by the baseline PANSS 
total score (< 95 v ≥ 95) for both the mITT and ITT population. In addition, the MMRM (without 
CHW or Hommel adjustments) will be repeated in the mITT and ITT population incorporating a 
treatment by country or baseline PANSS total score (< 95 v ≥ 95) interaction as a fixed effect in order 
to explore the treatment differences within each country and baseline PANSS total score (< 95 v ≥ 
95).  
The unadjusted LS means and standard errors of the change from baseline over time from the MMRM 
including all patients will be presented graphically both overall (from the primary analysis) and by the 
baseline PANSS total score (< 95 v ≥ 95) (from the interaction models). 
The effect of CYP2D6 phenotype on the primary efficacy variable will be assessed using subgroup 
analyses.  Summaries will be repeated by CYP2D6 phenotype groupings (using combined data across 
stages).  The MMRM applied to all data combined will be repeated with additional fixed effects for 
CYP2D6 phenotype and treatment-by-CYP2D6 phenotype interaction. 
7.3.4.2 Secondary Efficacy Variables Analyses 
7.3.4.2.1 
Key Secondary Efficacy Variable Analyses 
The key secondary variable will be analyzed at endpoint for the mITT and ITT population in a 
hierarchical order, taking multiplicity into account.  
If, and only if, the primary efficacy analysis shows the superiority of the Risperidone ISM treatment 
versus the IM placebo treatment for both doses will the confirmatory testing be performed 
sequentially on the mITT and ITT population with regard to the key secondary efficacy variable 
(Section 6.7.1.2.1).  Otherwise, all analyses for the key secondary efficacy variable will be deemed 
supportive/exploratory evidence.   
The CGI-S mean change will be analyzed using identical methods as described for the primary, 
sensitivity and subgroup analyses of the primary efficacy variable (Section 7.3.4.1).  The only 
exception to this will be that the baseline CGI-S will be used as a covariate in the MMRM/ANCOVA 
models instead of the baseline PANSS score.  
7.3.4.2.2 
Other Secondary Efficacy Variables Analyses 
The other secondary efficacy variables (see Section 6.7.1.2.2) will be displayed as described in 
Section 7.1, in each treatment group and at each applicable visit on the mITT, ITT and PP 
populations.  The analysis will be performed using only observed cases with both stages of the study 
combined. 
The mean scores and their changes from baseline will be displayed for PANSS, PANSS subscales, 
CGI-S and CGI-I at each applicable post-baseline visit and endpoint.  Treatments will be compared at 
each time point using a MMRM with country where enrolled, visit, treatment, and treatment-by-visit 
interaction as fixed effects and the respective baseline (PANSS will be used for CGI-I model) as a 
covariate.  Each dose level of Risperidone ISM will be compared to placebo at each study day.  
Unadjusted p-values and 95% confidence intervals will be presented. For PANSS and CGI-S, the 
models applied as part of the primary and key secondary variable sensitivity analyses (on all data 
patient data combined) will be used for these comparisons. 


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Overall and PANSS response rates will be shown with exact (Clopper-Pearson) 95% confidence 
intervals at each respective time point and endpoint.  Pairwise comparisons of each dose level of 
Risperidone ISM to placebo will be conducted using a Mantel-Haenzel test stratified by country 
where enrolled and baseline PANSS total score (≥ 95 or < 95). 
The time to reach the overall or the PANSS response will be displayed graphically using Kaplan-
Meier estimates.  Pairwise comparisons of each dose level of Risperidone ISM to placebo will be 
conducted using a log-rank test stratified by country where enrolled and baseline PANSS total score 
(≥ 95 or < 95). 
7.3.4.2.3 
Efficacy Variables Analyses in the Extension Segment of the Study 
The following efficacy parameters will be summarized in the extension segment of the study for the 
open-label population by treatment group and overall.  There will be no formal statistical testing. 
Durability of effect evaluations: 
 
PANSS total score 
 
Positive, negative, and general psychopathology subscale scores   
 
CGI-I score  
 
CGI-S score  
 
Overall response (as defined in 6.7.1.2.2) 
 
PANSS response (as defined in 6.7.1.2.2)  
 
Relapse, defined as 
o PANSS total score increase of ≥ 30% from baseline or  
o Re-hospitalization for psychotic symptoms or use of adjunctive antipsychotic medication 
after stabilization  
 
Remitters, defined as 
o The simultaneous attainment of a score of ≤ 3 for 6 months or  
o More on 8 main items of the PANSS  
 
Time to discontinuation  
Other evaluations include HRU, PSP, SWN-20, and concomitant antipsychotic medication use.  
7.3.4.3 Health Economics and Outcomes Research Variables Analyses 
Clinician-reported and patient-reported (or informant reported) HRU will be combined for analysis.  
When all data are missing for a time point, no imputation will take place.  Analyses will be performed 
by study phase (double-blind vs. open-label).  For analysis of each resource item and at each time 
point, non-zero missing data will be imputed using the Fully Conditional Specification procedure.  
Results for each HRU variable will be summarized by treatment group (placebo, two Risperidone 
ISM® arms, and all Risperidone ISM® combined) for the ITT and open-label populations using 
descriptive statistics, including 95% confidence limits.  For each HRU variable, an average rate of use 
per 3 months will be calculated by treatment group, and potential differences between treatment 
groups will be tested.  For analyses of the open-label population, de novo patients form a separate 
treatment group, and the rollover patients will be analyzed by their originally randomized treatment 
group in the double-blind segment. 
Country-specific unit costs will be assigned to each resource use item and costs across all items will 
be summed to yield a total direct medical cost.  Direct medical cost will be analyzed per individual 


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country for each resource use category and for all resource use categories combined for the ITT and 
open-label populations.  The average cost per 3 months by treatment group will be calculated, and 
differences between treatment groups will be tested.  Indirect costs (days absent from work due to 
illness) will also be analyzed per individual country.  Parametric and nonparametric methods for cost 
analyses will be assessed.  This may include bootstrapping technique to calculate 95% confidence 
intervals.  
Details of HRU and cost analyses will be specified in the Statistical Analysis Plan. 
The PSP and SWN-20 scores will be summarized by treatment group for the ITT and PP populations 
using descriptive statistics (see Section 7.1) for data obtained during the main double-blind segment 
of the study.  The PSP and SWN-20 scores from the extension segment of the study will be similarly 
summarized for the open-label population, as applicable, for descriptive purposes. 
Analyses of PSP and SWN-20 data will be according to instrument-specific guidance, as specified in 
the Statistical Analysis Plan. 
7.3.5 
Safety 
All safety variables will be displayed as described in Section 7.1 for the safety (and modified safety 
for selected endpoints) population in the main (double-blind) part of the study and the open-label 
population in the extension segment of the study.   
Safety and tolerability will be evaluated based on the incidence of treatment-emergent AEs, incidence 
of AEs leading to discontinuation, vital sign measurements, physical examination findings, weight, 
abnormal laboratory test results, ECG findings, abnormal movement scale results (AIMS, BARS, and 
SAS), C-SSRS results, use of concomitant medications, and injection site reactions.  Additionally, 
time to early termination results will be summarized descriptively.   
Descriptive statistics will be used to summarize the changes from baseline in vital signs, body weight, 
body mass index, and safety scales (e.g., C-SSRS, SAS, AIMS, and BARS) for each treatment group 
at each visit as described in Section 7.1.   
7.3.5.1 Adverse Events 
Events that occur after a patient provides informed consent but before the time of the first dose of 
study drug will be considered pretreatment AEs.  Treatment-emergent AEs are defined as events that 
are newly occurring or worsening from the time of the first dose of IM study drug.  All AEs will be 
listed by patient but only treatment-emergent AEs will be included in summary tables.  Reported AE 
terms will be coded using Medical Dictionary for Regulatory Activities preferred terms and system 
organ classes.   
The incidence of treatment-emergent AEs will be summarized by treatment group and overall, by 
severity, and by relationship to study drug (for both safety and modified safety populations 
separately).   
The summary tables will include the number and percentage of patients with treatment-emergent AEs 
together with the number of the respective treatment-emergent AE overall, by system organ class, and 
by preferred terms within each system organ class (for both safety and modified safety populations 
separately).  Treatment-emergent AEs resulting in treatment discontinuation or modification will be 
identified and summarized by treatment group (for both safety and modified safety populations 
separately).   


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7.3.5.2 Vital Signs and Physical Examinations 
Vital sign measurements (systolic and diastolic blood pressure [mmHg], pulse rate [beats/minute], 
respiration rate [breaths/minute], and body temperature [°C]) will be summarized by treatment group 
at each time point for the absolute value and for changes from baseline as described in Section 7.1.  
Orthostatic measurement data will also be summarized.  
7.3.5.3 Weight and Body Mass Index 
Weight (kg) and body mass index (kg/m2) measurements will be summarized by treatment group at 
each time point for the absolute value and for changes from baseline.   
7.3.5.4 Clinical Laboratory Tests  
Laboratory test results, including prolactin results, will be summarized by treatment group at each 
time point for the absolute value itself and for changes from baseline.  Tables showing the shift of 
clinically relevant abnormalities from baseline to endpoint will also be presented.   
7.3.5.5 Electrocardiograms  
QT, QTcB, and QTcF intervals will be calculated at each ECG assessment.  Interval data will be 
summarized by treatment group at each time point for the absolute value and for changes from 
baseline.  Additionally, QTcF values will be categorized and summarized, using the following QTcF 
value categories: increase from baseline > 30 msec, increase from baseline > 60 msec, as well as 
absolute values > 450 msec for males or > 470 msec for females.   
Other ECG variables that are collected will be listed.   
7.3.5.6 Extrapyramidal Symptoms Rating Scales 
For the SAS, AIMS, and BARS, total scores and subcategory scores, as applicable, will be 
summarized by treatment group at each time point for the absolute value and for changes from 
baseline.   
7.3.5.7 Columbia-Suicide Severity Rating Scale 
Individual items of the C-SSRS will be summarized by treatment group at each time point by the 
number and percentage of patients responding to that item.  Data will be summarized by treatment 
group.   
7.3.5.8 Concomitant Medications 
Concomitant medications will be categorized and presented using the World Health Organization 
Anatomical Therapeutic Chemical drug classification system.  The number and percentage of patients 
using concomitant medications will be summarized by treatment group.   
7.3.5.9 Injection Site Reactions 
Injection site reaction data will be summarized by treatment group.  The number and percentage of 
patients having reactions at each assessment time point will be presented.   
7.3.5.10 Time to Early Termination 
Time to early termination will be summarized by treatment group as described in Section 7.1.  
Additionally, Kaplan-Meier estimates will be displayed graphically.   


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7.3.5.11 Ophthalmological Examination 
Data will be summarized by treatment group.  The number and percentage of patients having changes 
from baseline will be presented. 
7.3.6 
Pharmacokinetics 
Descriptive statistics will be used to summarize plasma concentrations of risperidone, its active 
metabolite (9-OH-risperidone), and the active moiety (risperidone plus 9-OH-risperidone), whenever 
possible, at each sampling time point by injection site (gluteal and deltoid) and by study drug dose.   
Concentration values for all patients in the pharmacokinetic population will be listed.  
Pharmacokinetic parameters, including Ctrough, and accumulation index will be derived if possible, and 
results will be summarized as applicable.  Plasma concentrations will be presented graphically.   
A set of non-compartmental parameters will be estimated for a subset of patients after dose 1 (e.g., 
maximum concentration [Cmax], time to Cmax [Tmax], area under the concentration-time curve for a 
dosing interval [AUCtau], and others). 
Association of SAEs with the measured pharmacokinetic concentration either planned or outside the 
regular schedule will be evaluated. 
Comparisons of pharmacokinetic parameters between the gluteal and deltoid muscle injections will be 
performed.   
Effects of the CYP2D6 phenotype on pharmacokinetic parameters in the complete pharmacokinetic 
population and in a subset with intense pharmacokinetic sampling will be evaluated. 
A population pharmacokinetic analysis will be performed according to a separate pharmacokinetic 
analysis plan document.   
7.4 Sample Size  
The overall ratio for the random allocation of the 3 treatments to patients will be 1:1:1 (Risperidone 
ISM 75 mg: Risperidone ISM 100 mg: placebo) during the Double-blind period.  
The primary efficacy analysis will include all patients for whom the blinding was not compromised, 
who receive at least 1 dose of study drug and have both a baseline and at least 1 post-baseline PANSS 
evaluation (mITT population).  
The difference between the active treatments and placebo in the PANSS total score mean change from 
baseline to endpoint (primary efficacy variable; see Section 6.7.1.1) will be assumed as a 9-point 
decrease.   
Taking into account that each of the 2 Risperidone ISM groups (i.e., Risperidone ISM 75 mg and 
Risperidone ISM 100 mg) will be tested separately against the placebo group, a Bonferroni 
adjustment for the  level was performed.  A common standard deviation of 20 in 2-group t-tests was 
assumed.  
A sample size of 124 patients in the mITT population in each treatment group will have 90% power to 
detect a difference in means of 9 (standard deviation = 20, effect size = 0.45) with a 2.5% 2-sided 
significance level for a Risperidone ISM group versus the placebo group.  The power to show 
superiority of both Risperidone ISM doses to placebo using the above calculation would be at least 


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81%.  This will be higher due to a high correlation in pharmacokinetic data between doses (see 
Section 1) and use of a less conservative multiplicity adjustment than Bonferroni (i.e., Hommel – see 
Section 7.3.4.1).   
A relatively low post-randomization dropout rate is anticipated because it is surmised that most 
patients in the inpatient setting will reach study day 4 (patients who drop out before study day 4 will 
not be included in the mITT population); therefore, a 5% dropout rate is considered reasonable.  
Assuming this 5% dropout rate, a randomized sample size of 131 patients per treatment group, or 393 
patients total (all 3 treatment groups combined) for whom the blinding was not compromised, will be 
required. This assumption will be re-assessed at the interim analysis and used in re-estimating the 
total number of randomized patients required (see Section 7.5). 
Taking into account the 43 patients for whom blinding was potentially compromised, 436 randomized 
patients in total will be required. 
Assuming a screening failure rate of 35%, approximately 671 patients will need to be screened in 
order to achieve the initially planned 436 patients randomized.  
7.5 Sample Size Re-estimation/Interim Analysis 
One unblinded interim analysis will be conducted when 196 (approximately 50%) randomized 
patients, for whom the blinding was not compromised, have either reached study day 85 or withdrawn 
from the study; to re-estimate the sample size required for the final analysis up to 558 patients (186 
patients per arm) in the mITT population. The unblinded interim statistical analysis will be conducted 
by an independent statistical center. 
Those patients included in the interim analysis (as well as those for whom the blinding was 
compromised) will constitute stage 1 patients with all subsequent patients being stage 2 patients for 
purpose of the primary and key secondary variable analyses.  There will be no overlap of patients 
between stages. Only those patients meeting the criteria for inclusion in the mITT population will be 
included in the interim analysis for purpose of sample size re-estimation. 
For stage 1 patients meeting the criteria for inclusion in the mITT population, the effect size (mean 
difference/pooled standard deviation) will be calculated for each dose compared to placebo separately 
for the primary efficacy variable (change from baseline to endpoint in total PANSS score). The mean 
difference will be repesented by the difference between LS means from the primary MMRM model at 
Day 85 (see Section 7.3.4.1) and the pooled standard deviation will be derived from the standard error 
of the difference between LS means divided by sqrt(1/nr + 1/np) where nr and np are the sample size 
included in the interim analysis for the risperidone and placebo group respectively. 
If one or both of the effect sizes are less than the expected effect size of 0.45, the lowest effect size 
will be used to derive the new sample size per group for the mITT population (M2) as suggested by 
Cui et al. (1999)18 as follows: 
M2 = 124 * (0.45/lowest effect size) up to a maximum of 186 patients per group in the mITT 
population. 
If the lowest effect size is greater than or equal to 0.45, the target sample size for the mITT population 
will be maintained at 124 patients per arm. 


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The dropout rate at interim (from the randomization population to the ITT population) will be used to 
re-calculate the number of patients required to be randomized in stage 2 to meet the required total 
number in the mITT. 
From an ethical point of view, there will be an early stopping for futility for a particular dose when 
the conditional power21 at interim <10%. 
8 Data and Documentation 
8.1 Data Handling and Record Keeping 
8.1.1 
Data Handling 
The data obtained during the study should be transcribed faithfully from the source documents to the 
forms of the eCRF, as these data are considered valid information for further evaluation of the 
efficacy and safety of the treatment under investigation.   
The sponsor or designee will provide the site with eCRFs.  The investigator is to provide patient data 
according to the sponsor’s instructions, in the designated data collection form, compliant with GCP 
practices.  All data collection forms and the databases from the study are the exclusive property of the 
sponsor.   
The investigator must maintain records and data during the study in compliance with all applicable 
legal and regulatory requirements.  Records of the patient’s participation in this study will be held 
confidential except as disclosure is required by law or as described in the informed consent document.  
If the results of this study are published or presented at meetings, the patients will never ever be 
identified.  Each data point must be supported by a source document at the study site.  Any records or 
documents used as the source of information (called the “patient source data”) are to be retained for 
review by authorized representatives of the sponsor or a regulatory agency.  In this study, eCRFs will 
be used.  Further details may be provided in monitoring guidelines, as applicable.   
The investigator will ensure that there are sufficient time, staff, and facilities available for the duration 
of the study to conduct and record the study as described in this protocol and according to all 
applicable guidances, laws, and regulations.   
All data collection forms, such as eCRFs, should be completed as soon as possible after the evaluation 
has occurred.  All dates appearing on the sponsor’s patient data collection forms for laboratory tests, 
cultures, and other data collected must be the dates on which the specimens were obtained or the 
procedures performed.   
Within 1 week (or other agreed timeframe) of study completion by each patient, the investigator 
should agree to have the patient’s eCRF available for inspection by the field monitor.   
8.1.2 
Data Recording 
This study will use eCRFs for recording data.  All entries, corrections, and alterations will be made by 
the investigator or other authorized study personnel, and all data entries will be verified for accuracy 
and correctness.  The electronic data capture system will maintain an audit trail.   
Source documents will remain at the study site.   


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8.1.3 
Inspection of Records 
The sponsor or its representative will be allowed to conduct site visits to the investigational facilities 
for the purpose of monitoring any aspect of the study.  The investigator must agree to allow the 
unblinded or blinded monitor as applicable to inspect the drug storage area, study drug stocks, drug 
accountability records, patient charts and source documents, and other records relative to study 
conduct.   
8.1.4 
Retention of Records 
Retention and storage of essential clinical study documents (e.g., worksheets, drug accountability 
forms, and other administrative documentation) will be according to the clinical study agreement as 
applicable.   
Sponsor-specific essential documents should be retained until at least 25 years after the last approval 
of a marketing application in an International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use (ICH) region and until there are no pending or contemplated 
marketing applications in an ICH region or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the study drug.  These documents should be retained for a 
longer period, however, if required by the applicable regulatory requirements or if needed by the 
sponsor.   
Medical files should be retained in accordance with the applicable legislation and in accordance with 
the maximum period of time permitted by the hospital, institution, or private practice.   
8.1.5 
Use of Information and Publication Policy 
Data generated in this study are proprietary information that is the sole property of the sponsor.  
Results of the study are to be held in confidence by both the investigators and the sponsor.   
The clinical study report will be issued at 2 time points: the first will have the data from the double-
blind phase of the trial, and the second will be issued after the open-label extension phase of the study 
is completed and will contain all study data (both double blind and open label).  
Please refer to the clinical study agreement for details on the procedures for publishing and presenting 
data.   
8.2 Source Materials Access 
8.2.1 
Study Monitoring 
Monitoring of the study site (including, but not limited to, reviewing eCRFs for accuracy and 
completeness) will be performed by a study monitor.   
Blinded and unblinded monitors may be involved in the study site monitoring process, and each will 
interact with blinded and unblinded study site staff in a manner that maintains the blind for all blinded 
individuals until the Data Base lock of the Double-blind period.   
8.2.2 
Institutional Review Board 
The investigator must obtain Institutional Review Board (IRB) or Independent Ethics Committee 
(IEC) approval for the investigation.  Initial IRB/IEC approval as well as all materials approved by the 
IRB/IEC for this study, including the patient informed consent form and recruitment materials, must 
be maintained by the investigator and made available for inspection.   


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8.2.3 
Audits and Inspections 
Authorized representatives of the sponsor, a regulatory authority, and/or an IRB/IEC may visit the site 
to perform audits or inspections, including the drug storage area, study drug stocks, drug 
accountability records, patient charts and source documents, and other records relative to study 
conduct.  The purpose of a sponsor audit or inspection is to systematically and independently examine 
study-related activities and documents (e.g., laboratory reports, radiographs, workbooks, patients’ 
medical records) to determine if these activities were conducted and if data were recorded, analyzed, 
and accurately reported according to the protocol, ICH GCP guidelines, and any applicable regulatory 
requirements.   
The investigator should contact the sponsor and/or CRO immediately if contacted by a regulatory 
agency regarding an inspection.   
9 Quality Control and Assurance 
This study will be conducted under GCP and applicable regulatory requirements.  To ensure 
compliance, the sponsor may conduct a quality assurance audit.   
9.1 Data Collection 
The eCRFs will be completed by study site staff before review by the study monitor.  All eCRFs will 
be reviewed by the investigator, as noted by his or her electronic signature, after review by the 
sponsor monitor or designated representative.  The sponsor monitor or designated representative will 
review all source records onsite and compare them with the data collected on the eCRF.   
As specified in Section 6.2.2, study site staff will retrospectively record any HRU that occurred within 
the clinical trial center into the applicable forms of the eCRF.  Study site staff will administer a paper 
survey to patients (or their informant) to report any HRU that occurred outside the clinical trial center.  
The information will subsequently be recorded into the applicable forms of the eCRF. 
Results of the clinician-administered PSP will be collected on the eCRF.  Patients will complete the 
SWN-20 on paper, and the data will be entered into the eCRF by study site staff. 
9.2 Confidentiality 
The investigator must maintain in confidence information provided to him or her by the sponsor and 
will divulge such information to his or her respective IRB/IEC under an appropriate understanding of 
confidentiality with that body.   
All data are considered the sole property of the sponsor.   
10 Ethical Considerations 
10.1 Ethics Review 
The clinical site’s IRB/IEC must meet all relevant regulatory requirements.  The study protocol and 
informed consent form will be reviewed by the IRB/IEC before enrolling patients into the study; 
written approval from the committee must be received by the sponsor before study drug will be 
released to the investigator.  The protocol must be re-approved by the IRB/IEC upon receipt of 
amendments and annually, as local regulatory requirements require.   


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The investigator is responsible for submitting all protocol changes and SAE reports to the IRB/IEC 
according to local procedures.  At a minimum, all SAEs requiring an investigational new drug safety 
report must be immediately reported.  All relevant correspondence from the IRB/IEC will be 
forwarded by the study site to the sponsor in a timely manner.   
 
10.2 Ethical Conduct of the Study 
This study must be conducted in accordance with this protocol, GCP (ICH GCP Guidelines E6), and 
applicable regulatory requirements.  The sponsor is committed to complying with GCP standards to 
protect the rights, safety, and well-being of study patients, consistent with principles having their 
origin in the Declaration of Helsinki.   
10.3 Informed Consent 
The investigator (or authorized designee) at each study site will ensure that each patient is given full 
and adequate oral and written information about the nature, purpose, and possible risk and benefit of 
the study.  Each patient will receive an informed consent form that summarizes the pertinent study 
information and will be given ample time to read and ask questions about the study.  Patients must 
also be informed of their right to withdraw consent without prejudice at any time during the study.  If 
the patient chooses to participate, he or she must sign the informed consent form before any study-
specific procedures are conducted.   
All patients will be informed of their rights to privacy and will be made aware that the study data will 
be submitted to the sponsor and to regulatory authorities for review and evaluation for the duration of 
the study and until the project has been approved for marketing or is withdrawn from investigation.  
They will also be informed that the study monitor may inspect their medical records to verify the 
accuracy and completeness of the study records and results.   
Each consent form should contain an authorization allowing the Principal Investigator(s) and 
Laboratorios Farmacéuticos ROVI, S.A. to use and disclose private health information (i.e., patient-
identifiable health information) in compliance with local laws. 
 
Significant changes to the protocol or product safety information may cause a revision of the informed 
consent form, which must be reviewed and signed by all applicable study participants.  The 
investigator must maintain the original, signed, and dated informed consent form.  A copy of the 
signed and dated informed consent form, or a second original of a signed and dated informed consent 
form, must be given to the patient. 
10.4 Patient Data Protection 
The study patients should be informed by the investigator that complete confidentiality will be 
maintained concerning their identity.  On eCRFs, patients will be identified only by the assigned trial 
number. 
Prior to any testing under this protocol, including screening tests and assessments, candidates must 
also provide all authorizations required by local law (e.g., private health information authorization in 
North America). 
A signed written informed consent signifies the explicit acceptance by the individual that data from 
the study and clinical notes will be available to the investigator and his/her staff, the representatives of 
the sponsor and, if required, by the IRB/IEC and regulatory authorities.  However, all data contained 


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in the patients’ clinical notes will be considered as confidential. Laboratorios Farmacéuticos ROVI, 
S.A. will also treat data according to European Union Data Privacy Directive 95/46/EC. 
11 Indemnification 
The sponsor will contract a clinical study insurance policy in compliance with all applicable laws, 
rules, and regulations.   
12 Further Requirements and General Information 
12.1 External Service Organizations 
12.1.1 Interactive Voice Response System 
An external vendor will be selected to provide interactive voice or web response system support for 
this study.  Each site will be provided with appropriate training and a user manual before patients are 
screened or enrolled. 
12.1.2 Contract Research Organization 
A CRO will be responsible for all administrative aspects of the study including, but not limited to, 
regulatory submissions, study initiation, monitoring, data management and submissions of AE/SAE 
reporting.  Prior to enrollment of the first patient at each site, the CRO will review study 
responsibilities with the investigators and other site personnel, as appropriate.  The roles and 
responsibilities of all parties involved (CRO), third-party vendors, and the sponsor will be described 
in the Study Project Management Plan.  
12.1.3 Central Laboratories for Laboratory Assessments 
A central laboratory will be selected to analyze all hematology, blood chemistry, and urinalysis 
samples collected for this study.  Pharmacokinetic determinations will be done by another laboratory 
selected by Laboratorios Farmacéuticos ROVI, S.A.  Detailed procedures and instructions are 
included in the Laboratory Reference Guide. 
12.1.4 Central Facility for Other Assessments 
12.1.4.1 Electrocardiogram Reading Center 
An external vendor will be selected to evaluate all ECGs collected for this study.  Detailed procedures 
and instructions are included in an ECG Study Reference Guide. 
12.1.4.2 Central Training  
An external vendor will be selected to train the study raters before they perform any study 
assessments to ensure they understand and use the study scales consistency.  All raters will be 
required to pass an assessment on the use of the PANSS before to perform any efficacy assessments.  
Patients should be rated as much as possible by the same rater across the study.  
12.2 Study Committees 
12.2.1 Data Monitoring Committee 
A Data Monitoring Committee (DMC) will be formed to monitor patient accrual and to monitor 
compliance with the protocol at individual investigational sites, review any safety data (including 
individual AEs and SAEs), and alert and/or make recommendations to the sponsor about any existing 
or potential problems.  The DMC will be composed of a minimum of 3 voting members; they will not 


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be allowed to participate as investigators in this study and will not be affiliated in any way with 
Laboratorios Farmacéuticos ROVI, S.A.  Findings and conclusions will be reported to the 
Laboratorios Farmacéuticos ROVI, S.A. Medical Director.  Investigational sites will be notified of 
any relevant safety findings that may jeopardize patient safety.  The DMC will meet approximately 
twice a year.  A charter will be established between Laboratorios Farmacéuticos ROVI, S.A. and the 
DMC to outline the DMC’s responsibilities and procedures.  In one of their regular meetings, the 
DMC will receive from the unblinded statistician the results of outcome of the interim analysis for 
sample size re-estimation (blinded outcome only) performed as described in Section 7.5.  The DMC 
will communicate to the sponsor the blinded outcome from the interim analysis together with the 
conclusions from any other data review performed.  
12.3 Changes to Final Study Protocol 
All protocol amendments must be submitted to the IRB/IEC.  Protocol modifications that affect 
patient safety, the scope of the investigation, or the scientific quality of the study must be approved by 
the IRB/IEC before implementation of such modifications to the conduct of the study.  If required by 
local law, such modifications must also be approved by the appropriate regulatory agency prior to 
implementation.  However, Laboratorios Farmacéuticos ROVI, S.A., at any time, can amend this 
protocol to eliminate an apparent immediate hazard to a patient.  In this case, the appropriate 
regulatory authorities will be notified subsequent to the modification.  In the event of a protocol 
modification, the patient consent form may require similar modifications (see Sections 10.1 and 10.3). 
12.4 Ethics Committee Notification of Study Completion or Termination 
The Health Authority and the IRB/IEC in each country must be notified within 90 days of the 
completion of the study or within 15 days if the study is terminated early, unless any more restrictive 
period of time is specified by local applicable laws and regulations. 
12.5 Retention of Study Data 
The Principal Investigator(s) must maintain all essential documents (as listed in the ICH GCP 
Guidelines E6) until notified by Laboratorios Farmacéuticos ROVI, S.A. and in accordance with all 
local laws regarding retention of records. 
12.6 Study Report Signatory 
Laboratorios Farmacéuticos ROVI, S.A. will designate 1 of the participating study investigators as a 
signatory for the study report.  This determination will be made by several factors, including, but not 
limited to, the investigator’s experience and reputation in the studied indication; the investigator’s 
contribution to the study in terms of design, management, and/or patient enrollment; or other factors 
determined to be relevant by Laboratorios Farmacéuticos ROVI, S.A. 


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References 
1. Keith SJ, Kane JM. Partial compliance and patient consequences in schizophrenia: our patients 
can do better. J Clin Psychiatry. 2003;64(11):1308-15. 
2. Ascher-Svanum H, Faries DE, Zhu B, Ernst FR, Swartz MS, Swanson JW. Medication adherence 
and long-term functional outcomes in the treatment of schizophrenia in usual care. J Clin 
Psychiatry. 2006;67(3):453-60. 
3. Kane JM. Strategies for improving compliance in treatment of schizophrenia by using a long-
acting formulation of an antipsychotic: clinical studies. J Clin Psychiatry. 2003;64(Suppl 16):34-
40. 
4. Keith S. Use of long-acting risperidone in psychiatric disorders: focus on efficacy, safety and 
cost-effectiveness. Expert Rev Neurother. 2009;9(1):9-31. 
5. Hargarter L, Cherubin P, Bergmans P, Keim S, Rancans E, Bez Y, Parellada E, Carpiniello B, 
Vidailhet P, Schreiner A. Intramuscular long-acting paliperidone palmitate in acute patients with 
schizophrenia unsuccessfully treated with oral antipsychotics. Prog Neuropsychopharmacol Biol 
Psychiatry. 2015;58:1-7. 
6. Lauriello J, Lambert T, Andersen S, Lin D, Taylor CC, McDonnell D. An 8-week, double-blind, 
randomized, placebo-controlled study of olanzapine long-acting injection in acutely ill patients 
with schizophrenia. J Clin Psychiatry. 2008;69(5):790-9. 
7. Samtani MN, Gopal S, Gassmann-Mayer C, Alphs L, Palumbo JM. Dosing and switching 
strategies for paliperidone palmitate: based on population pharmacokinetic modelling and clinical 
trial data. CNS Drugs. 2011;25(10):829-45. 
8. Seeman P. Atypical antipsychotics: mechanism of action. Can J Psychiatry. 2002;47(1):27-38.  
9. Nakajima S, Uchida H, Bies RR, Caravaggio F, Suzuki T, Plitman E, Mar W, Gerretsen P, 
Pollock BG, Mulsant BH, Mamo DC, Graff-Guerrero A. Dopamine D2/3 receptor occupancy 
following dose reduction is predictable with minimal plasma antipsychotic concentrations: an 
open-label clinical trial. Schizophr Bull. 2016;42(1):212-9. 
10. Catafau AM, Penengo MM, Nucci G, Bullich S, Corripio I, Parellada E, García-Ribera C, 
Gomeni R, Merlo-Pich E; Barcelona Clinical Imaging in Psychiatry Group. Pharmacokinetics and 
time-course of D(2) receptor occupancy induced by atypical antipsychotics in stabilized 
schizophrenic patients. J Psychopharmacol. 2008;22(8):882-94. 
11. Naber D. A self-rating to measure subjective effects of neuroleptic drugs, relationships to 
objective psychopathology, quality of life, compliance and other clinical variables. Int Clin 
Psychopharmacol. 1995;10(Suppl 3):133-8. 
12. Naber D, Moritz S, Lambert M, Pajonk FG, Holzbach R, Mass R, Andresen B. Improvement of 
schizophrenic patients’ subjective well-being under atypical antipsychotic drugs. Schizophr Res. 
2001;50(1-2):79-88. 
13. Morosini PL, Magliano L, Brambilla L, Ugolini S, Pioli R. Development, reliability and 
acceptability of a new version of the DSM-IV Social and Occupational Functioning Scale 
(SOFAS) to assess routine social functioning. Acta Psychiatr Scand. 2000;101(4):323-9. 
14. Gaedigk A, Simon SD, Pearce RE, Bradford LD, Kennedy MJ, and Leeder JS. The CYP2D6 
Activity Score: Translating Genotype Information into a Qualitative Measure of Phenotype. 
Clinical Pharmacology and Therapeutics. 2008; 83(2):234-42. 
15. Nasser AF, Henderson DC, Fava M, Fudala PJ, Twumasi-Ankrah P, Kouassi A, Heidbreder C. 
Efficacy, safety, and tolerability of RBP-7000 once-monthly risperidone for the treatment of acute 
schizophrenia: an 8-week, randomized, double-blind, placebo-controlled, multicenter phase 3 
study. J Clin Psychopharmacol. 2016;36(2):130-40. 


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16. Kane JM, Peters-Strickland T, Baker RA, Hertel P, Eramo A, Jin N, Perry PP, Gara M, McQuade 
RD, Carson WH, Sanchez R.  Aripiprazole once-monthly in the acute treatment of schizophrenia: 
findings from a 12-week, randomized, double-blind, placebo-controlled study. J Clin Psychiatry. 
2014;75(11):1254-60. 
17. European Medicines Agency (EMA); Committee for Medicinal Products for Human Use 
(CHMP). Guideline on missing data in confirmatory clinical trials. EMA/CPMP/EWP/1776/99 
Rev. 1. 2 July 2010. 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/09/WC5000
96793.pdf. Accessed 12 May 2016 
18. Cui L, Hung HMJ, Wang SJ. Modification of sample-size in group sequential trials. Biometrics. 
1999;55:853-7. 
19. Hommel G. A stagewise rejective multiple test procedure based on a modified Bonferroni test.  
Biometrika. 1988;75(2):383-6. 
20. Ratitch B, O’Kelly M. Implementation of pattern-mixture models using standard SAS/STAT 
procedures. SUGI 2011. 
21. Chang M. Adaptive Design Theory and Implementation Using SAS and R. 2008: p144. 
22. NDA/Serial Number 200603 / S 000 Drug Name: Lurasidone Hydrochloride Indication: 
Schizophrenia   
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/200603Orig1s000StatR.pdf. Accessed 
2 January 2018 
 


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Appendix A: Study Assessments and Procedures by Study Visit 
The by-visit descriptive list of study assessments and procedures in this appendix reflects information 
in in the main body text of the protocol (Section 3.1) for the main (double-blind) part of the study, the 
optional open-label extension segment and the extension segment for de novo patients (Table 1, Table 
2 and Table 3, respectively). 
In order to ensure consistency and minimize inter-rater variability, all efforts should be made to have 
efficacy and safety scales assessments at all visits performed by the same investigator/rater. 


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Double-Blind Study 
Allowable study visit time windows for treatment period study visits occurring after study visit 3 
(study day 4) are as follows:  
 
± 1 day for study visit 5,  
 
± 2 days for study visit 14 
 
± 3 days for each of the other treatment period study visits (i.e., study visits 6 through 13, 
inclusive) 
The follow-up telephone visitis to occur 14 (± 3) days after the end-of-treatment visit (i.e., the week 
12 time point or earlier in the case of an early termination).  This visit is not applicable for patients 
who enter into a long-term extension study. 
 


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Study Visit 1: Screening Visit 
Study Day -8 to -1 
Obtain informed consent from the patient. 
 
Informed consent form must be signed and dated by the patient before any study-related 
procedures are performed (see protocol Section 6.1.1) 
Obtain the following information (see protocol Section 6.1.2): 
 
Demographic data 
 
Medical and psychiatric history data 
Diagnostic interview will be performed, including the following: 
 
MINI International Neuropsychiatric Interview for Schizophrenia and Psychotic Disorders studies 
will be completed (see protocol Section 6.1.4) 
Complete the following efficacy scales: 
 
PANSS (see protocol Section 6.2.1) 
 
CGI-S (see protocol Section 6.2.1.) 
Complete the following safety assessments: 
 
Physical examination (see protocol Section 6.4.1) 
 
Ophthalmological examination (see protocol Section 6.4.2) 
 
Height 
 
Weight and body mass index 
 
Vital signs (see protocol Section 6.4.3 for details) 
 
ECG (see protocol Section 6.4.4) 
 
Assess for AEs (see protocol Section 6.4.9) 
 
Review concomitant medications (see protocol Section 6.1.3) 
Complete the following safety scales: 
 
AIMS, BARS, SAS (see protocol Section 6.4.7) 
 
C-SSRS (see protocol Section 6.4.8) 
Blood samples for the following will be obtained: 
 
Hematology panel (see protocol Section 6.4.5.1) 
 
Chemistry panel (see protocol Section 6.4.5.2) 
 
Prolactin (see protocol Section 6.4.5.2) 
 
Serology panel (see protocol Section 6.4.5.4.1) 
 
Pregnancy test, serum (see protocol Section 6.4.5.4.2) 
Urine samples for the following will be obtained: 


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 
Urinalysis (see protocol Section 6.4.5.3) 
 
Urine drug screen (see protocol Section 6.4.5.4.3) 
Inclusion/exclusion criteria will be reviewed for patient eligibility. 
Patients who, after completion of all scheduled assessments on the screening visit day, are considered 
provisionally eligible will be admitted directly to the inpatient study that day.   
 
Patients will subsequently remain on the inpatient study unit for the remainder of the screening 
period (i.e., through study day -1, inclusive).     
Patients who have never taken risperidone must take oral risperidone 2 mg/day for 3 days sometime 
during the screening period, to ensure a lack of clinically significant hypersensitivity before the first 
IM dose of study drug is administered; this oral risperidone trial is not required for patients who have 
previously taken any formulation of risperidone. 
If there is a valid reason for a given potential patient to extend the screening period duration beyond 
the designated 8 days, the investigator may contact the medical monitor to request an extension of up 
to 14 days; such an extension may be implemented only after medical monitor approval has been 
obtained. 
 


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Study Visit 2: Baseline Evaluations and Administration of First Dose of Study Drug 
Study Day 1 
Patients must be already admitted to the inpatient study unit for study day 1; confirmed eligible 
patients will remain inpatient on study day 1 to complete the study day 1 assessments and procedures 
and to receive the first injection of IM study drug. 
The following baseline evaluations are to be completed before randomization occurs (and before the 
first dose of study drug is administered), with the exception of vital signs and ECG that should be 
checked within one hour before study drug administration: 
 
PANSS 
 
CGI-S 
Complete the following health economics and outcome research evaluations: 
 
Socio-demographic information 
 
PSP 
 
SWN-20 
Complete the following safety assessments: 
 
Weight and body mass index 
 
Vital signs  
 
ECG  
 
Assess for AEs 
 
Review concomitant medications 
Complete the following safety scales: 
 
AIMS, BARS, SAS 
 
C-SSRS 
Blood samples for the following will be obtained: 
 
Hematology panel 
 
Chemistry panel 
 
Prolactin 
 
Pharmacokinetic sample 
Urine samples for the following will be obtained: 
 
Urinalysis 
 
Pregnancy test, urine 
 
Urine drug screen 
Inclusion/exclusion criteria will be reviewed for patient eligibility. 


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 
Confirmation patient eligibility for continued participation in the study 
Randomization will be performed (for patients confirmed to be eligible) after all of the above baseline 
evaluations have been performed. 
 
Obtain assigned unique randomization number via interactive voice or web response system 
The following will be performed after randomization: 
 
First dose of IM study drug (i.e., double-blind Risperidone ISM 75 mg, Risperidone ISM 100 mg, 
or placebo) will be administered by IM injection 
o A designated unblinded individual at the study site will prepare and administer IM study drug 
in a manner that maintains the blind for investigators, other study site personnel, and the 
patient  
A blood sample for genotype sample may be collected at any point after randomization during a 
patient’s participation in the study (for patients who have given specific informed consent for 
genotyping). 
The following will be performed after administration of IM study drug 
 
Complete the following safety assessments: 
o Vital signs 
o ECG 
o Injection site evaluation by investigator approximately 1 hour after injection 
o Injection site pain VAS by study patient approximately 1 hour after injection 
All patients will remain on the inpatient study unit through the entire day of study day 1 and into 
study day 2. 
 


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Study Visit 3, Study Visit 9 and Study Visit 12 
Treatment Week 1, Treatment Week 4, and Treatment Week 8 (Study Day 3, Study Day 31 and Study 
Day 59) 
Complete the following safety assessments: 
 
Vital signs 
 
ECG 
 
Assess for AEs 
 
Review concomitant medications 
Blood sample for the following will be obtained: 
 
Pharmacokinetic testing  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Study Visit 4 
Study Day 4 
Complete the following efficacy scales: 
 
PANSS  
 
CGI-S and CGI-I 
Complete the following safety assessments: 
 
Vital signs 
 
ECG 
 
Assess for AEs  
 
Review concomitant medications 
Complete the following safety scales: 
 
AIMS, BARS, SAS 
No patient should be discharged from the inpatient study unit before study day 2, and it is anticipated 
that most patients will remain on the inpatient unit through study day 8, and that thereafter patients 
will be discharged from the inpatient unit when the investigator has assessed the patient and 
determines that he or she is appropriately clinically stable and otherwise ready for safe discharge.   
 


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Study Visit 5 and Study Visit 6 
Treatment Week 1 (Study Day 8) and Treatment Week 2 (Study Day 15) 
Complete the following efficacy scales: 
 
PANSS 
 
CGI-S and CGI-I 
Complete the following safety assessments: 
 
Physical examination 
 
Weight and body mass index 
 
Vital signs 
 
ECG 
 
Assess for AEs 
 
Review concomitant medications 
Complete the following safety scales: 
 
AIMS, BARS, SAS 
 
C-SSRS 
Blood samples for the following will be obtained: 
 
Hematology panel 
 
Chemistry panel  
 
Prolactin (visit 5 [study day 8] only) 
 
Pharmacokinetic sample (a subgroup of 75 study participants only) 
Urine samples for the following will be obtained: 
 
Urinalysis 
 
Optional: urine drug screen 
It is anticipated that most patients will remain on the inpatient unit through study day 8, and that 
thereafter patients will be discharged from the inpatient unit when the investigator has assessed the 
patient and determines that he or she is appropriately clinically stable and otherwise ready for safe 
discharge.   
After study day 8, continuation of a patient on the inpatient unit from study day 9 through study day 
15, inclusive, is an allowable option, as deemed clinically indicated.   
If the investigator believes that a given patient should remain inpatient beyond study day 15, the 
investigator should contact the medical monitor to discuss the proposed inpatient duration extension.


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Study Visit 7 (a subgroup of 75 study participants only) 
Treatment Week 3 (Study Day 22)  
Complete the following safety assessments: 
 
Vital signs 
 
ECG 
 
Assess for AEs 
 
Review concomitant medications 
Blood samples for the following will be obtained: 
 
Pharmacokinetic sample  
 


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 
Study Visit 8 and Study Visit 11: Study Drug Administration Visits 
Treatment Week 4 and Treatment Week 8 (Study Day 29 and Study Day 57) 
Complete the following efficacy scales: 
 
PANSS 
 
CGI-S and CGI-I 
Complete the following health economics and outcome research evaluations: 
 
Socio-demographic information 
 
HRU data collection – patient (or informant) 
 
PSP 
 
SWN-20 
Complete the following safety assessments: 
 
Weight and body mass index 
 
Vital signs 
 
ECG 
 
Assess for AEs 
 
Review concomitant medications 
Complete the following safety scales: 
 
AIMS, BARS, SAS 
 
C-SSRS 
Blood samples for the following will be obtained: 
 
Hematology panel 
 
Chemistry panel 
 
Prolactin 
 
Pharmacokinetic sample  
Urine samples for the following will be obtained: 
 
Pregnancy test, urine 
 
Urinalysis 
 
Optional: urine drug screen 
Study drug (i.e., double-blind Risperidone ISM or placebo) will be administered by IM injection 
 
Study drug doses 3 and 4 at study visit 8 and study visit 11, respectively 


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The following will be performed after administration of IM study drug: 
 
Complete the following safety assessments: 
o Vital signs  
o ECG  
o Injection site evaluation by investigator approximately one hour after injection 
o Injection site pain VAS by study patient approximately 1 hour after injection 
 
 


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Study Visit 10 and Study Visit 13 
Treatment Week 6 and Treatment Week 10 (Study Day 43 and Study Day 71) 
Complete the following efficacy scales: 
 
CGI-I 
Complete the following safety scales: 
 
AIMS, BARS, SAS 
Complete the following safety assessments: 
 
Vital signs 
 
ECG 
 
Assess for AEs 
 
Review concomitant medications 
Urine samples for the following will be obtained: 
 
Optional: urine drug screen 


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Study Visit 14: End-of-Treatment Visit 
Treatment Week 12 (Study Day 85) 
Complete the following efficacy scales: 
 
PANSS 
 
CGI-S and CGI-I 
Complete the following health economics and outcomes research evaluations: 
 
Socio-demographic information 
 
HRU data collection - center 
 
HRU data collection - patient (or informant) 
 
PSP 
 
SWN-20 
 Complete the following safety assessments: 
 
Physical examination 
 
Ophthalmological examination 
 
Weight and body mass index 
 
Vital signs 
 
ECG 
 
Assess for AEs 
 
Review concomitant medications 
Complete the following safety scales: 
 
AIMS, BARS, SAS 
 
C-SSRS 
Blood samples for the following will be obtained: 
 
Hematology panel 
 
Chemistry panel  
 
Prolactin 
 
Pharmacokinetic sample  
Urine samples for the following will be obtained: 
 
Pregnancy test, urine 
 
Urinalysis  
 
Optional: urine drug screen 


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Study Visit 15: Safety Follow-up Contact (Via Telephone) 
Study Day 99  
Complete the following safety assessments: 
 
Assess for AEs 
 
Review concomitant medications 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Optional Open-Label Extension Segment of the Study 
The allowable study visit time window for each of the extension baseline visit is within 3 days after 
visit 14 of the main part of the study occurs; however, it is generally preferable to conduct the 
extension baseline visit assessments and procedures later in the day (i.e., after completion of all 
assessments and procedures scheduled for the end-of-treatment visit for the double-blind treatment 
period of the main part of the study) on the same day on which the main study visit 14 occurs.  The 
allowable study visit time window for each of the subsequent extension visits is ± 3 days (i.e., 
extension visits 2 through 15, inclusive).   
The follow-up telephone visit is to occur 28 (± 3) days after the end-of-extension visit (i.e. the week 
52 time point, or earlier in the case of an early termination).   
 


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Extension Visit 0: Screening Visit (de novo patients only) 
Study Day -8 to -1 
Obtain informed consent from the patient. 
 
Informed consent form must be signed and dated by the patient before any study-related 
procedures are performed (see protocol Section 6.1.1) 
Obtain the following information (see protocol Section 6.1.2): 
 
Demographic data 
 
Medical and psychiatric history data 
Diagnostic interview will be performed, including the following: 
 
MINI International Neuropsychiatric Interview for Schizophrenia and Psychotic Disorders studies 
will be completed (see protocol Section 6.1.4) 
Complete the following efficacy scales: 
 
PANSS (see protocol Section 6.2.1) 
 
CGI-S (see protocol Section 6.2.1) 
Complete the following safety assessments: 
 
Physical examination (see protocol Section 6.4.1) 
 
Height 
 
Weight and body mass index 
 
Vital signs (see protocol Section 6.4.3 for details) 
 
ECG (see protocol Section 6.4.4) 
 
Assess for AEs (see protocol Section 6.4.9) 
 
Review concomitant medications (see protocol Section 6.1.3) 
Complete the following safety scales: 
 
AIMS, BARS, SAS (see protocol Section 6.4.7) 
 
C-SSRS (see protocol Section 6.4.8) 
Blood samples for the following will be obtained: 
 
Hematology panel (see protocol Section 6.4.5.1) 
 
Chemistry panel (see protocol Section 6.4.5.2) 
 
Prolactin (see protocol Section 6.4.5.2) 
 
Serology panel (see protocol Section 6.4.5.4.1) 
 
Pregnancy test, serum (see protocol Section 6.4.5.4.2) 
Urine samples for the following will be obtained: 


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 
Urinalysis (see protocol Section 6.4.5.3) 
 
Urine drug screen (see protocol Section 6.4.5.4.3) 
Inclusion/exclusion criteria will be reviewed for patient eligibility. 
Patients who, after completion of all scheduled assessments on the screening visit day, are considered 
provisionally eligible will be admitted directly to the study that day.   
If there is a valid reason for a given potential patient to extend the screening period duration beyond 
the designated 8 days, the investigator may contact the medical monitor to request an extension of up 
to 14 days; such an extension may be implemented only after medical monitor approval has been 
obtained. 


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Extension Visit 1: Baseline 
Extension Study Day 1 
Obtain informed consent from the prospective patient (rollover patients only) 
 
A separate informed consent form for participation in the optional extension segment of the study 
must be signed before any assessments or procedures for the extension segment are performed for 
a given patient, and before any dose of open-label Risperidone ISM is administered to that 
patient. 
Inclusion/exclusion criteria for extension segment will be reviewed for patient eligibility. 
Treatment arm assignment (de novo patients only) 
 
Patients on 4 mg of oral risperidone will be assigned to 75 mg (Risperidone ISM) every 28 days. 
Patients on more than 4 mg to a maximum of 6 mg of oral risperidone will be assigned to 100 mg 
(Risperidone ISM) every 28 days. 
ECG and vital signs assessments will be performed within one hour before study drug administration. 
A dose of IM study drug (Risperidone ISM 75 mg or Risperidone ISM 100 mg) will be administered 
by IM injection. Patients who had been receiving placebo in the double-blind segment of the study 
will be randomly assigned to receive either 75 or 100 mg of Risperidone ISM during the extension 
segment” 
The following will be performed after administration of IM study drug 
Complete the following safety assessments: 
 
Vital signs 
 
ECG 
 
Injection site evaluation by investigator approximately 1 hour after injection 
 
Injection site pain VAS by study patient approximately 1 hour after injection 
Collect socio-demographic information.  Complete the following health economics and outcome 
research evaluations (de novo patients only): 
 
HRU data collection – center  
 
HRU data collection – patient  
 
SWN-20 - patient reported  
 
PSP - clinician-administered  
For rollover patients, for assessments listed below results obtained as part of the main study 
visit 14 may be used as the extension baseline values and do not need to be repeated for the 
extension baseline visit time point if and only if the extension baseline visit occurs on the same 
day and date as the main study visit 14/week 12/end-of-treatment visit (rollover patients only).     
If the extension baseline visit instead occurs on a day 1 to 3 days after the main study visit 14/study 
week 12/study day 85/end-of-treatment visit, and for all de novo patients, all of the following 
assessments must be performed on the day of the extension baseline visit: 


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Complete the following efficacy scales: 
 
PANSS  
 
CGI-S  
Complete the following safety assessments: 
 
Physical examination  
 
Weight and body mass index  
 
Vital signs  
 
ECG  
 
Assess for AEs  
 
Review concomitant medications  
Complete the following safety scales: 
 
AIMS, BARS, SAS  
 
C-SSRS  
Blood samples for the following will be obtained: 
 
Hematology panel  
 
Chemistry panel  
 
Prolactin 
 
Pregnancy test, serum - optional 
Urine samples for the following will be obtained: 
 
Pregnancy testing  
 
Urinalysis  
 
Urine drug screen – optional for rollover patients, mandatory for de novo patients 
 


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Extension Visit 2, Extension Visit 6, and Extension Visit 11 
Extension Week 4, Extension Week 20, and Extension Week 40 
(Extension Day 29, Extension Day 141, and Extension Day 281)  
Complete the following efficacy scales: 
 
PANSS  
 
CGI-S  
 
CGI-I  
Complete the following health economics and outcome research evaluation: 
 
HRU data collection – patient  
Complete the following safety assessments: 
 
Physical examination 
 
Vital signs  
 
ECG  
 
Assess for AEs  
 
Review concomitant medications  
Complete the following safety scales: 
 
AIMS, BARS, SAS  
 
C-SSRS  
Blood samples for the following will be obtained: 
 
Pregnancy test, serum - optional 
Urine samples for the following will be obtained: 
 
Pregnancy testing  
 
Urine drug screen - optional 
A dose of IM study drug (Risperidone ISM 75 mg or Risperidone ISM 100 mg) will be administered 
by IM injection. 
The following will be performed after administration of IM study drug 
 
Complete the following safety assessments: 
o Vital signs  
o ECG  
o Injection site evaluation 
o 
Injection site pain VAS 


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Extension Visit 3, Extension Visit 5, Extension Visit 8, Extension Visit 9, and Extension Visit 12 
Extension Week 8, Extension Week 16, Extension week 28, Extension Week 32, and Extension Week 
44 
(Extension Day 57, Extension Day 113, Extension Day 197, Extension Day 225, and Extension Day 
309)  
Complete the following efficacy scales: 
 
PANSS  
 
CGI-S  
 
CGI-I  
Complete the following health economics and outcome research evaluation: 
 
HRU data collection – patient  
Complete the following safety assessments: 
 
Physical examination  
 
Vital signs  
 
ECG (at Extension Visit 8 only) 
 
Assess for AEs  
 
Review concomitant medications  
 Complete the following safety scales: 
 
AIMS, BARS, SAS  
 
C-SSRS  
Blood samples for the following will be obtained: 
 
Pregnancy test, serum - optional 
Urine samples for the following will be obtained: 
 
Pregnancy testing 
 
Urine drug screen - optional 
A dose of IM study drug (Risperidone ISM 75 mg or Risperidone ISM 100 mg) will be administered 
by IM injection. 


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The following will be performed after administration of IM study drug 
Complete the following safety assessments: 
 
Vital signs 
 
Injection site evaluation 
 
Injection site pain VAS 
 
ECG (at Extension Visit 8/Extension Day 197 only) 
 


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Extension Visit 4 
Extension Week 12 (Extension Day 85) 
Complete the following efficacy scales: 
 
PANSS  
 
CGI-S  
 
CGI-I  
Collect socio-demographic information. 
Complete the following health economics and outcome research evaluations: 
 
HRU data collection – patient  
 
SWN-20 - patient reported  
 
PSP - clinician-administered  
Complete the following safety assessments: 
 
Physical examination  
 
Weight and body mass index  
 
Vital signs  
 
ECG  
 
Assess for AEs  
 
Review concomitant medications  
Complete the following safety scales: 
 
AIMS, BARS, SAS  
 
C-SSRS  
Blood samples for the following will be obtained: 
 
Hematology panel  
 
Chemistry panel  
 
Prolactin 
 
Pregnancy test, serum - optional 
Urine samples for the following will be obtained: 
 
Pregnancy testing  
 
Urinalysis  
 
Urine drug screen - optional 
A dose of IM study drug (Risperidone ISM 75 mg or Risperidone ISM 100 mg) will be administered 
by IM injection. 
The following will be performed after administration of IM study drug 
Complete the following safety assessments: 


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 
Vital signs  
 
ECG  
 
Injection site evaluation 
 
Injection site pain VAS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Extension Visit 7 
Extension Week 24 (Extension Day 169) 
Complete the following efficacy scales: 
 
PANSS  
 
CGI-S  
 
CGI-I  
Collect socio-demographic information.Complete the following health economics and outcome 
research evaluations: 
 
HRU data collection – center  
 
HRU data collection – patient  
 
SWN-20 - patient reported  
 
PSP - clinician-administered  
Complete the following safety assessments: 
 
Physical examination  
 
Weight and body mass index  
 
Vital signs  
 
Assess for AEs  
 
Review concomitant medications  
Complete the following safety scales: 
 
AIMS, BARS, SAS  
 
C-SSRS  
Blood samples for the following will be obtained: 
 
Hematology panel  
 
Chemistry panel  
 
Prolactin 
 
Pregnancy test, serum - optional 
Urine samples for the following will be obtained: 
 
Pregnancy testing  
 
Urinalysis  
 
Urine drug screen - optional 
A dose of IM study drug (Risperidone ISM 75 mg or Risperidone ISM 100 mg) will be administered 
by IM injection. 
The following will be performed after administration of IM study drug 
Complete the following safety assessments: 


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 
Vital signs  
 
Injection site evaluation 
 
Injection site pain VAS 
 
 


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Extension Visit 10 
Extension Week 36 (Extension Day 253) 
Complete the following efficacy scales: 
 
PANSS  
 
CGI-S  
 
CGI-I  
Collect socio-demographic information. 
Complete the following health economics and outcome research evaluations: 
 
HRU data collection – patient  
Complete the following safety assessments: 
 
Physical examination  
 
Weight and body mass index  
 
Vital signs  
 
Assess for AEs  
 
Review concomitant medications  
 Complete the following safety scales: 
 
AIMS, BARS, SAS  
 
C-SSRS  
Blood samples for the following will be obtained: 
 
Hematology panel  
 
Chemistry panel  
 
Prolactin 
 
Pregnancy test, serum - optional 
Urine samples for the following will be obtained: 
 
Pregnancy testing  
 
Urinalysis  
 
Urine drug screen - optional 
A dose of IM study drug (Risperidone ISM 75 mg or Risperidone ISM 100 mg) will be administered 
by IM injection. 
The following will be performed after administration of IM study drug 
Complete the following safety assessments: 
 
Vital signs  
 
Injection site evaluation 
 
Injection site pain VAS 


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Extension Visit 13 
Extension Week 48 (Extension Day 337) 
Complete the following efficacy scales: 
 
PANSS  
 
CGI-S  
 
CGI-I  
Complete the following health economics and outcome research evaluation: 
 
Collect socio-demographic information. 
 
HRU data collection – center  
 
HRU data collection – patient  
Complete the following safety assessments: 
 
Physical examination  
 
Vital signs  
 
Assess for AEs  
 
Review concomitant medications  
 Complete the following safety scales: 
 
AIMS, BARS, SAS  
 
C-SSRS  
Blood samples for the following will be obtained: 
 
Pregnancy test, serum - optional 
Urine samples for the following will be obtained: 
 
Pregnancy testing  
 
Urine drug screen - optional 
A dose of IM study drug (Risperidone ISM 75 mg or Risperidone ISM 100 mg) will be administered 
by IM injection. 
The following will be performed after administration of IM study drug 
Complete the following safety assessments: 
 
Vital signs  
 
Injection site evaluation 
 
Injection site pain VAS 


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Extension Visit 14 
Extension Week 52 (Extension Day 365) 
Complete the following efficacy scales: 
 
PANSS  
 
CGI-S  
 
CGI-I  
Complete the following health economics and outcome scales: 
 
SWN-20 - patient reported  
 
PSP - clinician-administered  
Complete the following safety assessments: 
 
Physical examination  
 
Weight and body mass index  
 
Vital signs  
 
ECG  
 
Assess for AEs  
 
Review concomitant medications  
 Complete the following safety scales: 
 
AIMS, BARS, SAS  
 
C-SSRS  
Blood samples for the following will be obtained: 
 
Hematology panel  
 
Chemistry panel  
 
Prolactin 
 
Pregnancy test, serum - optional 
Urine samples for the following will be obtained: 
 
Pregnancy testing  
 
Urinalysis  
 
Urine drug screen - optional 


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Extension Visit 15: Extension Follow-up Visit (Conducted by Telephone) 
Extension Week 56 (Extension Day 393) 
Complete the following safety assessments: 
 
Assess for AEs  
 
Review concomitant medications  


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Appendix B: Prohibited Medications 
 
Cytochrome P450 3A4 Inducers and Inhibitors and 2D6 Inhibitors 
http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm2923
62.pdf 
Also see the following SAMPLE TABLE: 
Prohibited Medications Affecting Cytochrome P450 3A4 (Inducers and Inhibitors) or 2D6 
(Inhibitors) 
3A4 Inducers 
3A4 Inhibitors 
2D6 Inhibitors 
 Carbamazepine 
 Barbiturates  
(e.g., phenobarbital) 
 Phenytoin 
 Rifampin 
 Hyperforin  
(e.g., St. John’s Wort) 
 Modafinil 
 Cyproterone (e.g., antiandrogen, 
progestin, Diane-35) 
 Non-nucleotide reverse 
transcriptase inhibitors (e.g., 
efavirenz, nevirapine, etravirine) 
 Ketoconazole 
 Itraconazole 
 Fluconazole 
 Clarithromycin 
 Erythromycin 
 Telithromycin 
 Nefazodone 
 Fluvoxamine 
 Protease inhibitors  
(ritonavir, indinavir, nelfinavir) 
 Verapamil 
 Grapefruit juice 
 Bergamottin  
 Quercetin 
 Quinidine 
 Selective serotonin reuptake 
inhibitors  
(e.g., fluoxetine, paroxetine, 
citalopram) 
 Duloxetine Bupropion MDMA  
(3,4-methylenedioxymeth-
amphetamine; ecstasy) 
 Terbinafine 
 Goldenseal  
(Hydrastis canadensis) 
 
 


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Appendix C : Rating Scale and Interview Descriptions 
 
MINI  
The MINI International Neuropsychiatric Interview for Schizophrenia and Psychotic Disorders 
Studies is a short, structured diagnostic interview that was developed for DSM-V and ICD-10 
psychiatric disorders that has been validated against the Structured Clinical Interview for DSM 
diagnoses (SCID).  It will be used to assess for excluded psychiatric conditions outlined in the study 
entry criteria. 
PANSS 
The Positive and Negative Syndrome Scale (PANSS), is a 30-item clinician-rated instrument for 
assessing the symptoms of schizophrenia and will be used as the primary efficacy endpoint measure. 
The positive scale consists of 7 items which measure delusions, conceptual disorganization, 
hallucinations, grandiosity, and suspiciousness/persecution.  The negative subscale consists of items 
which measure blunted affect, emotional withdrawal, poor rapport, passive/apathetic social 
withdrawal, difficulty in abstract thinking, lack of spontaneity and flow of conversation, and 
stereotyped thinking.  The general psychopathology scale consists of 16 items which measure somatic 
concern, 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. The 
change from baseline in the PANSS total score at 12 weeks is the primary efficacy endpoint. 
CGI-S 
The Clinical Global Impression Severity of Illness (CGI-S) is a 7-point clinician-rated scale for 
assessing the global severity of the illness. The change in CGI-S score from baseline to 12 weeks will 
be used as a secondary efficacy endpoint. Also the change in PANSS positive subscale response 
change from baseline to 12 weeks will be included as a secondary endpoint. The PANSS positive 
subscale assesses features such as delusions and hallucinations. 
CGI-I 
The CGI-I consists of a single 7-point rating score total improvement, regardless of whether or not the 
change it is due entirely to drug treatment. Raters select one response based on the following question, 
“Compared to your patient’s condition at the beginning of treatment, how much has your patient 
changed?” Scores are: 1, Very much improved; 2, Much improved; 3, Minimally improved; 4, No 
change; 5, Minimally worse; 6, Much worse; or 7, Very much worse.  For the CGI-I Scale, the 
patient’s condition at the Day 1 (baseline) visit will be the criterion for judging improvement at 
subsequent visits. 
AIMS 
The Abnormal Involuntary Movement Scale (AIMS) will be used to document occurrences of 
dyskinesias in patients, specifically tardive dyskinesia. The scale incorporates observation and brief 
examination of the patient and consists of 12 items. Items 1-4 assess the severity of orofacial 
movements.  Items 5-7 assess extremity and truncal dyskinesias. Items 8-10 rate global severity of 


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VERSION 7.0 
22 Mar 2018 
CONFIDENTIAL 
Page 109 of 114 
movements as indicated by the examiner’s judgment of the severity of abnormal movements (item 8), 
the examiner’s judgment of the patient’s incapacitation due to the movements (item 9), and the 
patient’s awareness of the movements and associated distress (item 10).  Items 11 12 concern the 
patient’s dental status 
BARS 
The Barnes Akathisia Rating Scale (BARS) will be administered to assess akathisia. The scale is 
designed to rate akathisia through observation of restless behavior and questioning of the patient to 
determine the degree of subjective restlessness and distress associated with restlessness. A global 
clinical rating completes the assessment. The first 3 items of the BARS (Objective, Subjective, and 
Distress related to restlessness) are rated on a 4 point scale (0-3). The fourth item, the global clinical 
assessment of akathisia, uses a 6 point scale (0-5). Only the global clinical assessment measure from 
this scale will be analyzed.  Higher scores indicate increased severity. All ratings are anchored. The 
BARS takes approximately 10 minutes to administer 
SAS 
The Simpson Angus Scale (SARS) will be administered to assess parkinsonian symptoms and related 
extrapyramidal side effects through observation of the patient. The scale contains 10 items, including 
gait, arm dropping, shoulder shaking, elbow rigidity, wrist rigidity, leg pendulousness, glabellar tap, 
tremor, and salivation.  The head rotation item (from the modified SAS) will be substituted for the 
original #7 item, head dropping. Seven of the 10 items measure parkinsonian rigidity. Each item is 
rated on an anchored 5-point scale, with 0 = the absence of the condition or normal and 4 = the most 
extreme form of the condition. A total score is obtained by adding all of the scores of the individual 
items. The SAS takes approximately 10 minutes to administer. 
C-SSRS 
The Columbia Suicide Severity Rating Scale (C-SSRS) is an interview-based rating scale to 
systematically assess suicidal ideation and suicidal behavior. Versions are available for screening 
/baseline and follow-up visits. 
PSP 
This operationalized, 100-point scale consists of 4 main areas: socially useful activities, personal and 
social relationships, self-care, and disturbing and aggressive behavior. Each of the 4 domains is rated 
in 6 degrees of severity (absent, mild, manifest, marked, severe, very severe).  A difference of 8 points 
can be classified as a clinically highly relevant difference.  
SWN-20 
The Subjective Well-being Under Neuroleptic Treatment Scale (SWN) is used to assess well-being in 
patients with schizophrenia undergoing antipsychotic treatment. The 20-item version of the SWN 
scale consists of 20 items referring to the last 7 days.  The total score ranges from a minimum of 20 
(poor) to a maximum of 120 (excellent). 10 items are formulated positively and 10 items are 
formulated negatively, describing each complaint in a positive and negative phrase. The SWN-20 
measures subjective experience in 5 subscales: emotional regulation, self-control, mental functioning, 
social integration and physical functioning.   
 


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22 Mar 2018 
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Page 110 of 114 
 
Appendix D: Visual Analog Scale (VAS) 
 
 VISUAL ANALOG SCALE  
 
 
On the scale of zero to ten, where zero means no pain and ten equals the worst possible pain, 
what is the level of the pain right now at the injection site? Please circle the number that 
corresponds to it.  
 
 
 
 
10
Worst 
possible 
pain
9
No pain
6
7
8
0
1
2
3
4
5
 
 
 


Laboratorios Farmacéuticos ROVI, S.A. 
 
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PRISMA-3 
VERSION 7.0 
22 Mar 2018 
CONFIDENTIAL 
Page 111 of 114 
 
Appendix E: Risperidone ISM Investigator Brochure 
 
Due to the size of the document, the most updated version of the Investigator’s Brochure for 
Risperidone ISM® is available as a separate document.  
 


Laboratorios Farmacéuticos ROVI, S.A. 
 
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PRISMA-3 
VERSION 7.0 
22 Mar 2018 
CONFIDENTIAL 
Page 112 of 114 
 
Appendix F: Contact Information 
 
ROVI Pharmacovigilance Department 
Phone: +34 917617561/+34 911863678 
Fax: +34 912444421 
Email: farmacovigilancia@rovi.es 
Laboratorios Farmacéuticos ROVI S.A. (SAEs) 
ROVI Pharmacovigilance Department 
Fax number: +34 912444421 
E-mail: farmacovigilancia@rovi.es 
Phone number: +34 917617561/+34 911863678 
 
INC Research – (SUSARs only) 
Milan Matković MD, Senior Project Manager 
Fax number: +381 11 240 25 70 
E-mail: milan.matkovic@syneoshealth.com 
Phone number: +381 11 715 8058 
Enrique Comesaña MD, MBA 
Executive Medical Director - Medical Affairs 
E-mail: enrique.comesana@syneoshealth.com 
Moble Phone number: +1 (512) 367 0592 
 
 
 
 
 
 
 
 




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Page 114 of 114 
 
Appendix H : Investigator Agreement  
 
Laboratorios Farmacéuticos ROVI, S.A. 
Multicenter, Randomized, Double-Blind, Placebo-controlled Study to Evaluate the Efficacy and 
Safety of Intramuscular Injections of Risperidone ISM® in Patients with Acute Exacerbation of 
Schizophrenia (PRISMA-3) 
Protocol No. ROV-RISP-2016-01, Version No. 7.0  
Date: 22 March 2018 
Amendment No.: 4.0 
PRINCIPAL INVESTIGATOR COMMITMENT: 
I will provide copies of the protocol, any subsequent protocol amendments and access to all information 
provided by the Sponsor to the study personnel under my supervision.  I will discuss this material with 
them to ensure that they are fully informed about the investigational drug and the study protocol. 
I agree to conduct this clinical trial according to the attached protocol, except when mutually agreed to 
in writing.  I also agree to conduct this study in compliance with all federal, state and local regulations, 
Good Clinical Practices (GCP), as well as with the requirements of the appropriate Institutional Review 
Board(s) (IRB)/Independent Ethics Committee(s) (IEC) and any other institutional requirements. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name of Principal Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Principal Investigator 
 
 
 
 
 
 
 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Institution 
 

SAP_001.pdf: 
COVER PAGE  
Statistical Analysis Plan (SAP) 
 
TITLE: Multicenter, Randomized, Double-Blind, Placebo-
Controlled Study to Evaluate the Efficacy and Safety of 
Intramuscular Injections of Risperidone ISM® in Patients 
with Acute Exacerbation of Schizophrenia (PRISMA-3) 
 
PROTOCOL NUMBER: ROV-RISP-2016-01 
 
NCT NUMBER: NCT03870880 
 
SAP VERSION 4.0 
DOCUMENT DATE: 15 February 2019 
 
 


 
 
This document is confidential. 
SAP Version: V4.0 15-FEB-2019 
Controlled Document ID: 3903C.00, Effective Date 30-Apr-2018 
Page 1 of 95 
Statistical Analysis Plan  
 
Sponsor Name: Laboratorios Farmacéuticos ROVI, S.A. 
 
Protocol Number: ROV-RISP-2016-01 
 
Protocol Title: Multicenter, Randomized, Double-Blind, Placebo-controlled Study to Evaluate the 
Efficacy and Safety of Intramuscular Injections of Risperidone ISM® in Patients with Acute 
Exacerbation of Schizophrenia (PRISMA-3). 
 
Protocol Version and Date: (DD-Mmm-YYYY): 7.0 (22-MAR-2018) 
 
Syneos Health Project Code: 1004855 
 
Author:  
Gary Smith, Principal Biostatistician 
 
 
 
 
 
 
 
Notice of Confidential and Proprietary Information: 
The information contained in this document is confidential belonging to Laboratorios 
Farmacéuticos ROVI, S.A. Acceptance of this document constitutes agreement by the recipient that 
no information contained herein will be published or disclosed without prior written authorization 
from an official of Laboratorios Farmacéuticos ROVI, S.A. However, this document may be 
disclosed to appropriate Institutional Review Board and Ethics Committees or duly authorized 
representatives of a national regulatory authority under the condition that they are requested to 
keep it confidential. In the event of an actual or suspected breach of this obligation, Syneos Health 
should be notified promptly. 
 
 
 


Statistical Analysis Plan for Interventional Studies 
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Revision History 
 
Version # 
Date 
(dd-mmm-yyyy) 
Document 
Owner 
Revision Summary 
1.0 
28-JUL-2017 
Gary Smith 
First Version 
2.0 
03-JAN-2018 
Gary Smith 
- Update in line with latest protocol V6.0  
- Update to detail potential accidental unblinding issue 
and corresponding actions: 
 
Define mITT, mPP and mSAF populations 
(Section 5) 
 
Detail of updated confirmatory testing 
procedures and additional analysis of new 
analysis populations (Section 8) 
- Clarify how to determine the effect size for purpose of 
sample size re-estimation (Section 12) 
- Provide more detail on the conditional power 
calculation to assess futility (Section 12) 
3.0 
23-FEB-2018 
Gary Smith 
- Update to CHW analysis using z instead of t as per the 
reference (Section 8.1.1). 
- Update to conditional power formula in line with the 
formula used in the reference (Section 12) 
- Clarify the outputs to be provided to DMC for sample 
size re-estimation (Section 12) 


Statistical Analysis Plan for Interventional Studies 
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Version # 
Date 
(dd-mmm-yyyy) 
Document 
Owner 
Revision Summary 
4.0 
15-FEB-2019 
Gary Smith 
- Rebranding of INC Research to Syneos Health (all 
sections). 
- Added detail of interim analyses 2 and 3 (sections 2.3 
and 12) 
- Update study overview text (section 3) based on 
Protocol V7 updates for inclusion of de novo subjects. 
- Added Modified Randomized Population for multiple 
imputation sensitivity analyses (section 5.5). 
- Updated PP population definition following blind data 
review (Section 5.8)) 
- Added PK evaluable windowing definitions relative to 
dosing rather than study visits (Sections 5.10 and 9) 
- Added PGx population (Section 5.11) 
- Updated the definition for treatment exposure (section 
6.2.8) 
- Ensure that disposition listings and summaries include 
de novo patients (section 7.1). 
- Update treatment groupings for OLE summaries 
(sections 5.10 / 6.1 / 8.2.3) and clarify treatment 
groups/sorting for listings (section 6.1). 
- Update definition of concomitant medication to 
exclude medications taken after treatment 
discontinuation. The term prior medication replaced with 
off-treatment medication and definition updated (section 
7.4). 
- Added additional interaction terms including visit into 
MMRM models for subgroup analyses to enable within 
subgroup treatment comparisons at each visit (Section 
8.1.1) 
- Added approach to Simpson Angus Scale data 
collected on the incorrect scale (section 11.7.3) 
- Clarified baseline for change from baseline endpoints 
for the C-SSRS (section 11.8) 


19 FEB 2019, 9:30 am EST


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TABLE OF CONTENTS 
1. 
GLOSSARY OF ABBREVIATIONS ................................................................................... 10 
2. 
PURPOSE ............................................................................................................................... 13 
2.1 
Responsibilities ........................................................................................................................ 13 
2.2 
Standards ................................................................................................................................. 13 
2.3 
Timings of Analyses ................................................................................................................ 13 
3. 
STUDY OVERVIEW ............................................................................................................ 15 
3.1 
Primary Objective .................................................................................................................. 15 
3.2 
Secondary Objective(s) ........................................................................................................... 15 
3.3 
Brief Description ..................................................................................................................... 15 
3.4 
Patient Selection ...................................................................................................................... 16 
3.4.1 
Eligibility Criteria for Enrollment into the DB Phase of the Study .................................................... 16 
3.4.2 
Eligibility Criteria for Entry into the OLE Phase of the Study (Rollover Patients) ............................ 16 
3.4.3 
Eligibility Criteria for Entry into the OLE Phase of the Study (De Novo Patients)............................ 17 
3.5 
Determination of Sample Size ................................................................................................ 17 
3.6 
Treatment Assignment & Blinding ....................................................................................... 18 
3.6.1 
Treatment Assignment ........................................................................................................................ 18 
3.6.2 
Blinding .............................................................................................................................................. 19 
3.6.3 
Potential Unblinding ........................................................................................................................... 20 
3.7 
Administration of Study Medication .................................................................................... 21 
3.8 
Study Procedures and Flowchart .......................................................................................... 22 
4. 
VARIABLES .......................................................................................................................... 33 
4.1 
Primary Efficacy Variables ................................................................................................... 33 
4.2 
Secondary Efficacy Variables ................................................................................................ 33 
4.3 
Efficacy Variables in the OLE Phase of the Study .............................................................. 34 


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4.4 
Health Economics and Outcomes Research (HEOR) Variables ........................................ 34 
4.5 
Safety Variables ...................................................................................................................... 35 
4.6 
Pharmacokinetic Variables .................................................................................................... 36 
4.7 
Other Variables ....................................................................................................................... 36 
5. 
ANALYSIS POPULATIONS ................................................................................................ 37 
5.1 
Screened Population ............................................................................................................... 37 
5.2 
Safety Population .................................................................................................................... 37 
5.3 
Modified Safety Population ................................................................................................... 37 
5.4 
Randomized Population ......................................................................................................... 37 
5.5 
Modified Randomized Population ......................................................................................... 38 
5.6 
Intent-to-Treat Population ..................................................................................................... 38 
5.7 
Modified Intent-to-Treat Population .................................................................................... 38 
5.8 
Per Protocol Population ......................................................................................................... 38 
5.9 
Modified Per Protocol Population ......................................................................................... 39 
5.10 
Pharmacokinetic Population .................................................................................................. 39 
5.11 
Pharmacogenomic Population ............................................................................................... 40 
5.12 
Modified Pharmacogenomic Population .............................................................................. 40 
5.13 
Open-label Population ............................................................................................................ 40 
6. 
GENERAL ASPECTS FOR STATISTICAL ANALYSIS................................................. 41 
6.1 
General Methods ..................................................................................................................... 41 
6.2 
Key Definitions ........................................................................................................................ 42 
6.2.1 
DB and OLE Phases ........................................................................................................................... 42 
6.2.2 
Stage 1 and Stage 2 ............................................................................................................................. 42 
6.2.3 
First Dose Date ................................................................................................................................... 42 
6.2.4 
Double-Blind Study Day .................................................................................................................... 42 
6.2.5 
Open-Label Extension Study Day ...................................................................................................... 43 


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6.2.6 
Baseline Values .................................................................................................................................. 43 
6.2.7 
Last Dose Date .................................................................................................................................... 43 
6.2.8 
Duration of Exposure .......................................................................................................................... 43 
6.2.9 
End of Study ....................................................................................................................................... 43 
6.2.10 
Endpoint ......................................................................................................................................... 43 
6.3 
Missing Data ............................................................................................................................ 44 
6.4 
Visit Windows ......................................................................................................................... 44 
6.5 
Pooling of Centers ................................................................................................................... 44 
6.6 
Subgroups ................................................................................................................................ 44 
7. 
DEMOGRAPHIC, OTHER BASELINE CHARACTERISTICS AND MEDICATION 46 
7.1 
Patient Disposition and Withdrawals ................................................................................... 46 
7.2 
Demographic and Baseline Characteristics .......................................................................... 46 
7.3 
Medical, Surgical and Psychiatric History ........................................................................... 46 
7.4 
Medication ............................................................................................................................... 47 
7.4.1 
Off-Treatment Medication .................................................................................................................. 47 
7.4.2 
Concomitant Medication ..................................................................................................................... 47 
8. 
EFFICACY ............................................................................................................................. 49 
8.1 
Primary Efficacy Variables and Analysis ............................................................................. 49 
8.1.1 
Primary Efficacy Analyses ................................................................................................................. 50 
8.1.2 
Sensitivity Analyses ............................................................................................................................ 53 
8.2 
Secondary Efficacy Variables and Analyses ........................................................................ 54 
8.2.1 
Key Secondary Efficacy Variable Analyses ....................................................................................... 54 
8.2.2 
Other Secondary Efficacy Variables Analyses ................................................................................... 55 
8.2.3 
Efficacy Variables Analyses in the Open-Label Extension Phase of the Study .................................. 57 
8.2.4 
Health Economics and Outcomes Research (HEOR) Variables Analyses ......................................... 58 
9. 
ANALYSIS OF PHARMACOKINETICS .......................................................................... 66 
9.1 
Plasma PK endpoint ............................................................................................................... 66 
9.2 
Collection Schedule and Allowed Windows for Sampling of Cmax, Trough Levels and 
Dense Pharmacokinetics for risperidone and 9-OH-risperidone .................................................... 67 
9.3 
Handling of Missing Data ...................................................................................................... 68 


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9.4 
Listing and Presentation of Individual PK data .................................................................. 68 
9.5 
Summary of PK concentrations in plasma ........................................................................... 69 
9.6 
PK Parameters Derivation ..................................................................................................... 70 
9.7 
PK parameters summarization ............................................................................................. 72 
9.8 
Planned Statistical Models for PK Parameters and Concentrations ................................. 72 
9.9 
PK / PD Exploratory Analysis ............................................................................................... 73 
10.  EXPLORATORY ANALYSIS OF PHARMACOGENOMICS ........................................ 74 
10.1 
CYP2D6 Activity Score .......................................................................................................... 74 
10.2 
Efficacy Subgroup Analyses .................................................................................................. 75 
10.3 
PK Subgroup Analyses ........................................................................................................... 75 
11.  SAFETY .................................................................................................................................. 76 
11.1 
Extent of Exposure ................................................................................................................. 76 
11.2 
Adverse Events ........................................................................................................................ 76 
11.3 
Laboratory Evaluations ......................................................................................................... 78 
11.4 
Vital Signs ................................................................................................................................ 80 
11.5 
ECG.......................................................................................................................................... 80 
11.6 
Physical Examination ............................................................................................................. 81 
11.7 
Abnormal Movement Scales .................................................................................................. 81 
11.7.1 
Abnormal Involuntary Movement Scale (AIMS) .......................................................................... 81 
11.7.2 
Barnes Akathisia Rating Scale (BARS) ......................................................................................... 82 
11.7.3 
Simpson-Angus Scale .................................................................................................................... 82 
11.8 
Columbia Suicide-Severity Rating Scale (C-SSRS) ............................................................. 82 
11.9 
Injection Site Reactions .......................................................................................................... 84 
11.10 
Other Safety Variables ........................................................................................................... 84 


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12.  INTERIM ANALYSES ......................................................................................................... 85 
13.  CHANGE FROM ANALYSIS PLANNED IN PROTOCOL ............................................ 87 
14.  REFERENCE LIST ............................................................................................................... 88 
15.  PROGRAMMING CONSIDERATIONS ............................................................................ 90 
15.1 
General Considerations .......................................................................................................... 90 
15.2 
Table, Listing, and Figure Format ........................................................................................ 90 
15.2.1 
General ........................................................................................................................................... 90 
15.2.2 
Headers .......................................................................................................................................... 91 
15.2.3 
Display Titles ................................................................................................................................. 91 
15.2.4 
Column Headers ............................................................................................................................. 91 
15.2.5 
Body of the Data Display ............................................................................................................... 92 
15.2.6 
Footnotes ........................................................................................................................................ 94 
16.  QUALITY CONTROL .......................................................................................................... 95 
17.  MOCK-UPS ............................................................................................................................ 95 
 
 


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1. 
GLOSSARY OF ABBREVIATIONS 
Abbreviation 
Description 
AE 
Adverse Event 
AIMS 
Abnormal Involuntary Movement Scale 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of Covariance 
ATC 
Anatomical Therapeutic Chemical 
AST 
Aspartate aminotransferase 
BARS 
Barnes Akathisia Rating Scale 
BCVA 
Best Corrected Visual Activity 
BDRM 
Blind Data Review Meeting 
BMI 
Body Mass index 
CGI-I 
Clinician Global Impression – Improvement scale 
CGI-S 
Clinician Global Impression – Severity scale 
CI 
Confidence Interval 
Cmax 
maximum concentration 
Cmin 
minimum concentration 
CP 
Conditional Power 
CRF 
Case Report Form 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CSR 
Clinical Study Report 
CV 
Coefficient of Variation 
DB 
Double-blind 
DMC 
Data Monitoring Committee 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition 
ECG 
Electrocardiogram 
eGFR 
Estimated Glomerular Filtration Rate 
EMA 
European Medicines Agency 
ET 
End of Study Visit 


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Abbreviation 
Description 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HEOR 
Health Economics and Outcomes Research 
HRQL 
Health-Related Quality of Life 
HRU 
Healthcare Resource Utilization 
ICH 
International Conference on Harmonization 
ITT 
Intent-to-Treat 
IM 
intramuscular 
ISM® 
In situ microparticle 
IVRS 
Interactive Voice Randomization System 
IWRS 
Interactive Web Randomization System 
MAR 
Missing at Random 
Max 
Maximum 
MDRD 
Modification of Diet in Renal Disease 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Multiple Imputation 
Min 
Minimum 
MINI 
MINI International Neuropsychiatric Interview 
mITT 
Modified Intent-to-Treat 
MMRM 
Mixed Model Repeated Measurement 
MNAR 
Missing Not at Random 
mPP 
Modified Per-protocol 
mSAF 
Modified Safety Population 
N/A 
Not Applicable 
NA 
Not Applicable 
NCI 
National Cancer Institute 
OC 
Observed Cases 
OLE 
Open-label extension phase 
OLP 
Open-label Population 


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Abbreviation 
Description 
PANSS 
Positive and Negative Syndrome Scale 
PK 
Pharmacokinetic 
PMM 
Pattern Mixture Model 
PP 
Per-protocol 
PSP 
Personal and Social Performance scale 
PT 
Preferred Term 
QC 
Quality Control 
QTc 
Corrected QT Interval 
QTcB 
QT interval corrected for heart rate using Bazett’s formula 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
SAE 
Serious Adverse Event 
SAF 
Safety Population 
SAP 
Statistical Analysis Plan 
SAS 
Simpson-Angus Scale 
SD 
Standard Deviation 
SE 
Standard Error 
SI 
Standard International System of Units 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SWN-20 
Subjective Well-being Under Neuroleptics – Short Form 
TEAE 
Treatment Emergent Adverse Event 
TLF 
Table, Listing and Figure 
VAS 
Visual Analogue Scale 
WHO 
World Health Organization 
 
 


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2. 
PURPOSE 
The purpose of this statistical analysis plan (SAP) is to ensure that the data listings, summary tables 
and figures which will be produced, and the statistical methodologies that will be used, are complete 
and appropriate to allow valid conclusions regarding the study objectives.   
2.1 
RESPONSIBILITIES 
Syneos Health will perform the statistical analyses and are responsible for the production and quality 
control of all tables, figures and listings. Laboratorios Farmacéuticos ROVI, S.A. will review and 
approve the final tables, figures and listings. 
From 4th January 2018, INC Research was re-branded to Syneos Health. Syneos Health will always be 
referred to in this version of the SAP, even when discussing past activities prior to this date. 
2.2 
STANDARDS 
Statistical analyses are planned and conducted in accordance with the principles outlined by the ICH 
E9 guidelines. Creation and validation of the clinical database, management of data, and transfer of 
laboratory data are conducted in accordance with 21 CFR Part 11 and Guidance for Industry on 
Computerized Systems Used in Clinical Trials.  
2.3 
TIMINGS OF ANALYSES 
The primary analysis of safety, efficacy, and pharmacokinetics is to be conducted when all patients 
have either completed or terminated early from the DB phase of the study. Unless otherwise specified, 
the analysis will include all data collected in the database through the time of the database lock for the 
DB phase, which will also include open label extension (OLE) analyses on incomplete data. A follow-
up analysis will be performed when all patients have completed or discontinued from the OLE phase 
of the study. 
An interim analysis to evaluate sample size assumptions will be conducted when 196 randomized 
patients, for whom the blinding is not compromised (see Section 3.6.3), have either reached day 85 or 
withdrawn from the DB phase of the study.  Only data from these patients will be used in this analysis. 
An independent statistical center will perform the analyses (as described in Sections 8.1 and 12 of this 
SAP) to maintain the blinding of the study. 
Two further interim analyses will be conducted following the unblinding of the DB phase when 
approximately 65 and 100 patients are known to have been exposed to either of the active arms for at 
least 337 days respectively.  
A Data Monitoring Committee (DMC) will be formed to monitor patient accrual and to monitor 
compliance with the protocol at individual investigational sites, review any safety data (including 


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individual AEs and SAEs), alert and /or make recommendations to the sponsor about any existing or 
potential problems. The DMC meetings will take place as follows: 
DMC Safety Review Meetings will be scheduled as follows: 
 Approximately 4 – 6 weeks after: 
o 
10% patients have completed (i.e. reached day 85) the DB phase  
o 
25%, 50% (including interim analysis*) and 75% of the randomized patients have 
either completed (i.e. reached day 85) or terminated early from the DB phase of the study. 
 After the DB phase is completed, meetings will be planned to review 25%, 50%, 75% of patients 
completed as applicable (OLE) phase  
 Ad hoc at the request of the DMC or Laboratorios Farmacéuticos ROVI, S.A. (e.g. in the event of 
unexpected SAEs)  
 
* Note: Due to potential accidental unblinding, it was considered that 43 patients were potentially 
compromised and therefore the interim analysis sample size re-estimation will only include the 196 
non-compromised patients (see Section 12) whereas the safety outputs provided for the 50% DMC 
will include both the 196 non-compromised and 43 compromised patients. 
 


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3. 
STUDY OVERVIEW 
3.1 
PRIMARY OBJECTIVE 
The primary objective of this study is to evaluate the efficacy of Risperidone ISM® as compared with 
that of placebo in the treatment of patients with acute exacerbation of schizophrenia. 
3.2 
SECONDARY OBJECTIVE(S) 
The secondary objectives of this study are the following:  
 
To characterize safety and tolerability of Risperidone ISM as compared with that of placebo in 
patients with acute exacerbation of schizophrenia 
 
To quantify healthcare resource utilization (HRU), health-related quality of life (HRQL), and 
social functioning in patients treated with Risperidone ISM versus placebo for an acute 
exacerbation of schizophrenia 
 
To explore pharmacokinetic characteristics of Risperidone ISM and associations with efficacy 
3.3 
BRIEF DESCRIPTION 
This is a multicenter, randomized, double-blind, placebo-controlled study designed to evaluate the 
efficacy and safety of Risperidone ISM, a new long-acting injectable form of the licensed drug 
risperidone.  Eligible patients will be randomly assigned, under double-blind conditions, to receive 
Risperidone ISM (75 or 100 mg) or placebo. 
The study design includes a screening period (planned duration 1 to 8 days) immediately preceding the 
DB phase baseline day (designated as DB phase study day 1), a DB phase treatment period (duration 
12 weeks), an OLE period (duration 12 months) and a follow-up period (duration 2 weeks [DB] or 4 
weeks [OLE]).   
The initial planned total number of randomized patients in the DB phase of the study is approximately 
393 patients (131 in each of the 3 treatment groups) for whom the blinding is not compromised (see 
Section 3.6.3). Following confirmation of eligibility, each patient will be randomly assigned under 
double-blind conditions to receive 1 of the following 3 study drug treatments: Risperidone ISM 75 mg, 
Risperidone ISM 100 mg, or placebo, with an overall 1:1:1 ratio. 
Patients who have never taken risperidone must have a brief trial of oral risperidone 2 mg/day for 3 
days during the screening period in order to ensure a lack of any clinically significant hypersensitivity 
reactions before the first dose of long-acting IM study drug is administered.  A trial of oral risperidone 
is not required for patients who have previously taken any formulation of risperidone. 
Study drug will be administered as IM injections.  Treatment assignment for each individual patient 
will remain blinded for patients, investigators, and all study site staff, with the exception of identified 


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individuals at each study site who will be unblinded in order to prepare and administer study drug for 
each patient at that study site.   
After initial dosing on study day 1, study drug (Risperidone ISM or placebo) will be administered 
once every 4 weeks during the 12-week treatment period (i.e., at study days 29 and 57).   
Patients who complete planned participation in this study through to the end of the DB phase treatment 
period may be eligible to enter into an optional OLE phase of the study, during which open-label 
Risperidone ISM (i.e. either 75 or 100 mg) will be administered to all participating patients once every 
4 weeks for approximately 12 months. Patients who enter into the OLE phase of the study will begin 
participation in that phase immediately upon completion of the DB phase end-of-treatment visit 
assessments and procedures. Patients who do not enter into the OLE phase will have a final safety 
follow-up phone contact approximately 2 weeks after the DB phase end-of-treatment visit. 
In addition to patients continuing from the DB phase of the study (rollover patients), patients not 
previously enrolled in the study (de novo patients) may be eligible to enter the long-term OLE phase 
of the study.  These patients will be evaluated for eligibility at a screening visit and, if eligible, will be 
allocated to receive either 75 or 100 mg Risperidone ISM every 4 weeks for approximately 12 months.  
Approximately 100 de novo patients are planned to be enrolled in the OLE phase of the study, in 
addition to rollover patients. 
3.4 
PATIENT SELECTION 
To be eligible for participation in the study, at screening each patient must meet all of the inclusion 
criteria and none of the exclusion criteria. 
3.4.1 
Eligibility Criteria for Enrollment into the DB Phase of the Study 
3.4.1.1 Inclusion Criteria 
Inclusion criteria for enrollment in the DB phase of the study are defined in the Study Protocol Section 
4.1.1.1. 
3.4.1.2 Exclusion Criteria 
Exclusion criteria for enrollment in the DB phase of the study are defined in the Study Protocol 
Section 4.1.1.2. 
3.4.2 
Eligibility Criteria for Entry into the OLE Phase of the Study (Rollover Patients) 
Participation in the OLE phase of the study is optional, and patients who complete participation in the 
DB phase of the study may opt to not participate.  Patients who are interested in participating must 
meet all eligibility criteria in order to enter into the OLE phase.  


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3.4.2.1 Inclusion Criteria  
Inclusion criteria for the OLE phase for rollover patients are defined in the Study Protocol Section 
4.1.2.1. 
3.4.2.2 Exclusion Criteria  
Exclusion criteria for the OLE phase for rollover patients are defined in the Study Protocol Section 
4.1.2.2. 
3.4.3 
Eligibility Criteria for Entry into the OLE Phase of the Study (De Novo Patients) 
To be eligible for entry into the OLE phase of the study, a de novo patient must meet all of the 
eligibility criteria at the OLE screening visit. 
3.4.3.1 Inclusion Criteria  
Inclusion criteria for the OLE phase for de novo patients are defined in the Study Protocol Section 
4.1.3.1. 
3.4.3.2 Exclusion Criteria  
Exclusion criteria for the OLE phase for de novo patients are defined in the Study Protocol Section 
4.1.3.2. 
 
3.5 
DETERMINATION OF SAMPLE SIZE 
The overall ratio for the random allocation of the 3 treatments to patients will be 1:1:1 (Risperidone 
ISM 75 mg: Risperidone ISM 100 mg: placebo) during the DB phase.  
The primary efficacy analysis will include all patients for whom the blinding was not compromised 
(see Section 3.6.3), who receive at least 1 dose of study drug and have both a baseline and at least 1 
post-baseline PANSS evaluation (modified intent-to-treat [mITT]) population).  
The primary efficacy variable is the PANSS total score mean change from baseline to endpoint, which 
is assumed to differ between Risperidone ISM and placebo groups by 9 points. The primary efficacy 
analysis is designed to show superiority of the active treatment groups versus placebo, according to the 
closed testing procedure (see Section 8.1). 
Taking into account that each of the 2 Risperidone ISM groups (i.e. Risperidone ISM 75 mg and 
Risperidone ISM 100 mg) will be tested separately against the placebo group, a Bonferroni adjustment 
for the α level was performed. A common standard deviation of 20 in 2-group t-tests was assumed.  
A sample size of 124 patients in the mITT population in each treatment-group will have 90% power to 
detect a difference in means of 9 (standard deviation = 20, effect size = 0.45) with a 2.5% 2-sided 


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significance level in both Risperidone ISM groups versus the placebo group. The power to show 
superiority of both Risperidone ISM doses to placebo using the above calculation would be at least 
81%. This will be higher due to a high correlation in pharmacokinetic data between doses (see Study 
Protocol - Section 1) and use of a less conservative multiplicity adjustment than Bonferroni (i.e., 
Hommel – see Section 8.1.1).. 
A relatively low post-randomization dropout rate is anticipated because it is surmised that most 
patients in the inpatient setting will reach study day 4 (patients who drop out before study day 4 will 
not be included in the mITT population); therefore, a 5% dropout rate is considered reasonable.  
Assuming this 5% dropout rate, a randomized sample size of 131 patients per treatment group, or 393 
patients total (all 3 treatment groups combined) for whom the blinding was not compromised (see 
Section 3.6.3), will be required. This assumption will be re-assessed at the interim analysis and used in 
re-estimating the total number of randomized patients required (see Section 12). 
Taking into account the 43 patients for whom blinding was potentially compromised (see Section 
3.6.3), 436 randomized patients in total will be required for the DB phase of the study. 
Assuming a screening failure rate of 35%, approximately 671 patients will need to be screened in 
order to achieve the planned 436 patients randomized in the DB phase of the study.  
3.6 
TREATMENT ASSIGNMENT & BLINDING 
3.6.1 
Treatment Assignment 
Upon confirmation of eligibility for a given patient to participate in the DB phase study, a unique 
randomization number for that patient will be assigned via an interactive voice or web response 
system (IVRS/IWRS) that is to be accessed by study site personnel immediately after confirmation of 
patient eligibility has been recorded.   
The randomization number for a given patient will be used to identify the study drug (i.e., blinded 
Risperidone ISM 75 mg, Risperidone ISM 100 mg, or placebo) which will be administered to that 
patient.   
The randomization scheme will automatically ensure that the study drug assignment for a given patient 
is random, and that an overall 1:1:1 ratio of assignments to each of the 3 study drug treatments is 
approximated.   
In addition, the randomization scheme will include the following stratification parameters to ensure 
balanced distribution of assignment to the 3 treatments: country where enrolled and PANSS total score 
(i.e., ≥ 95 versus < 95) at baseline/randomization.   
An independent biostatistician will maintain the randomization scheme key, which will remain 
unavailable to all other individuals until after completion of the DB phase and subsequent locking of 
the DB phase data at this point.   


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Once a randomization number has been assigned, that number must not be used again for any other 
patient (e.g. when patient is withdrawn from the study, that patients’s randomization number must not 
be reused for any other patient).   
In the OLE phase of the study, all participating patients will receive active Risperidone ISM under 
open-label conditions. However, in order to preserve the blinding condition of the double-blind stage 
of the study, if a participating patient enters this OLE phase of the study prior to locking the database 
of the double-blind stage of the study, the allocation to either 75 or 100 mg of this patient will be still 
blinded at least up to locking the aforementioned database. Patients who had been on active 
Risperidone ISM in the DB phase of the study will continue to receive active Risperidone ISM at the 
same dose (i.e., 75 or 100 mg) in the OLE phase. Patients who had been receiving placebo in the DB 
phase of the study will be randomly assigned to receive either 75 or 100 mg during the OLE phase. 
De novo patients participating in the OLE phase of the study will receive either 75 or 100 mg 
Risperidone ISM depending on their previous oral risperidone dose.  Patients on 4 mg of oral 
risperidone will be assigned to 75 mg Risperidone ISM, and patients on more than 4 mg to a 
maximum of 6 mg of oral risperidone will be assigned to 100 mg Risperidone ISM. Upon 
confirmation of eligibility for a given de novo patient, the corresponding IMP kit will be assigned via 
IVRS/IWRS which will be accessed by study site personnel immediately after confirmation of patient 
eligibility has been recorded 
3.6.2 
Blinding 
During the double-blind phase of the study, the IM study drug will be administered under double-blind 
conditions so that investigators, site staff, and patients will not be aware about the identity of the study 
drug (i.e., blinded Risperidone ISM 75 mg, Risperidone ISM 100 mg, or placebo) administered to any 
given patient.   
The packaging and labelling for placebo or Risperidone ISM 75 or 100 mg will be identical. The 
placebo and Risperidone ISM doses are practically indistinguishable before or after reconstitution. 
Reconstitution will follow the same process for placebo or Risperidone ISM. Any small differences in 
final volumes are not perceptible.  
For de novo patients, the corresponding IMP kit will be assigned via IVRS/IWRS based on the criteria 
stated in Section 3.6.1 (i.e., 4 mg or >4 to 6 mg oral risperidone) so that both investigator and patient 
will know the treatment administered, which is consistent with the open -label definition of this phase 
of the study. 
Nevertheless, the management of the study drug will only be performed by designated unblinded 
individuals at sites who will be dealing with the study drug reconstitution and administration of the 
study drug to the patient, and will not be involved in any clinical evaluation. These individuals will be 


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appropriately qualified and trained to perform the required study drug reconstitution and study drug 
administration to patients.  
Oral risperidone test doses of 2mg per day for 3 days, if applicable for a given patient, will be 
administered under open-label conditions during the screening period.   
If an investigator deems it necessary to break the treatment assignment blind, he or she should 
promptly document and explain to the medical monitor or designee the reason of the unblinding (e.g. 
accidental unblinding, unblinding due to an SAE) of study drug.   
Once it has been determined that breaking the blind is necessary, the investigator or other designated 
study site staff member will contact the IVRS/IWRS to obtain disclosure of the identified patient’s 
treatment assignment.   
Breaking the blind for a single patient will not affect the blind for the remaining patients.   
All patients who participate in the optional OLE phase of the study will receive active Risperidone 
ISM (i.e., 75 or 100 mg) under open-label conditions. However, in order to preserve the blinding 
condition of the double-blind stage of the study, if a participating rollover patient enters this OLE 
phase of the study prior to locking the database of the double-blind stage of the study, the allocation to 
either 75 or 100 mg of this patient will still be blinded at least up to locking the aforementioned 
database.   
One unblinded interim analysis will be conducted when 196 randomized patients have either reached 
day 85 or withdrawn from the DB phase.  This interim statistical analysis will be conducted by a 
designated Syneos Health unblinded team located in a different country to the Syneos Health blinded 
team.  All designated blinded study personnel will remain blinded.  
3.6.3 
Potential Unblinding  
On 28th September 2017, due to a noted error in the IWRS system, potential accidental unblinding of 
treatment allocation to patients for blinded personnel was reported. 
At an ad-hoc DMC meeting on 8th November 2017, it was concluded that there were 43 patients for 
whom the blinding was potentially compromised due to this error. The following decisions pertaining 
to the analysis of the study were also agreed: 
 
Add 43 replacement patients  
 
Create a modified ITT (mITT) population which will comprise of the ITT population without 
the compromised patients. 
 
The mITT population will become the primary analysis population for efficacy. The reasoning 
would be that this will be the most conservative patient group to demonstrate efficacy. The 
full ITT analysis would still have to meet the significance levels also in the final analysis. 


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 
Perform the sample size re-estimation at interim based on the mITT analysis (i.e. perform 
original study plan as if the compromised patients did not exist) 
 
Keep the planned analysis weightings for the final analysis of the mITT that were in place for 
the ITT (i.e. 50/50 between pre/post IA) and same analysis methods 
 
Modify the weightings for the ITT analysis to account for likely greater percentage of patients 
at interim but otherwise keep all planned analyses. 
 
Repeat all ITT efficacy analyses using the mITT. 
 
Add a modified PP (mPP) population to support mITT results (selected endpoints). 
 
Add a modified SAF (mSAF) population to support SAF results (selected endpoints). 
 
PK populations and analysis unaffected due to objective data. 
These actions were recommended by the Syneos Health Biostatistics team and agreed by ROVI and 
DMC members prior to first receipt of the unblinded randomization list by Syneos Health Unblinded 
Statistical personnel (for DMC analyses). This was received on 17th November 2017. 
 
3.7 ADMINISTRATION OF STUDY MEDICATION 
The preparation and administration of the study drugs are described in Section 5.1.2 of the Study 
Protocol. 


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3.8 STUDY PROCEDURES AND FLOWCHART 
The overall study design is depicted schematically in Figure 1.  A schedule of assessments and 
procedures is displayed by visit in Table 1, Table 2 and Table 3.  
Figure 1 
Schematic of Study Design 
 


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Table 1  
Schedule of Assessments and Procedures During the Double-Blind Phase 
Screening 
DB 
BL 
Treatment Period (DB Phase) 
FU 
DB Phase Visit Number:
1 
2 
3 
4 
5 
6 
71 
8
9 
10 
11 
12 
13 
142
153 
DB Phase Study Day4: -8 to -15 
1 
3 
4 
8 
15 
22 
29 
31 
43 
57 
59 
71 
85 
99 
DB Phase Treatment 
Week:
 
 
 
 
1 
2 
3 
4 
 
6 
8 
 
10 
12 
 
DB Phase Overall Dosing 
Sequence: 
1 
 
 
 
 
 
2 
 
 
3 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening assessments6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility criteria review7 
X 
X 
 
 
 
 
 
 
Inpatient study unit8 
X 
X 
X 
X 
(X)
(X)
 
 
 
(Test oral risperidone)9 
(X) 
 
 
 
 
 
 
Randomization10 
X 
 
 
 
 
 
 
Inject IM study drug11 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
Efficacy scales:12 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 PANSS 
X 
X 
 
X 
X 
X 
 
X 
 
 
X 
 
 
X 
 CGI-S 
X 
X 
 
X 
X 
X 
 
X 
 
 
X 
 
 
X 
 CGI-I 
 
X 
X 
X 
 
X 
 
X 
X 
 
X 
X 
 Socio-demographic 
information 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 HRU data collection – 
center 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 HRU data collection – 
patient 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
Health outcome scales13 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 PSP (clinician 
administered) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 SWN-20 (patient 
reported) 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
Safety assessments: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 AEs14 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 Concomitant meds15 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 Physical examination 
X 
 
 
 
X 
X 
 
 
 
 
 
 
 
X 
 
 Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Weight and body mass 
index 
X 
X 
 
 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 Vital signs16 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 ECG17 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 Injection site  
evaluation18 
 
X 
 
 
X 
X 
 
X 
 
X 
X 
 
X 
X 
 
 Injection site pain  
VAS18 
 
X 
 
 
X 
X 
 
X 
 
X 
X 
 
X 
X 
 
 Safety scales:12 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  AIMS 
X 
X 
 
X 
X 
X 
 
X 
 
X 
X 
 
X 
X 
  BARS 
X 
X 
 
X 
X 
X 
 
X 
 
X 
X 
 
X 
X 
  SAS 
X 
X 
 
X 
X 
X 
 
X 
 
X 
X 
 
X 
X 
  C-SSRS 
X 
X 
 
 
X 
X 
 
X 
 
X 
 
X 


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Screening 
DB 
BL 
Treatment Period (DB Phase) 
FU 
DB Phase Visit Number:
1 
2 
3 
4 
5 
6 
71 
8
9 
10 
11 
12 
13 
142
153 
DB Phase Study Day4: -8 to -15 
1 
3 
4 
8 
15 
22 
29 
31 
43 
57 
59 
71 
85 
99 
DB Phase Treatment 
Week:
 
 
 
 
1 
2 
3 
4 
 
6 
8 
 
10 
12 
 
DB Phase Overall Dosing 
Sequence: 
1 
 
 
 
 
 
2 
 
 
3 
 
 
 
Ophthalmological 
examination19 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Blood sample for: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Hematology panel20 
X 
X 
 
 
X 
X 
 
X 
 
X 
 
X 
 Chemistry panel21 
X 
X 
 
 
X 
X 
 
X 
 
X 
 
X 
 Prolactin  
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 Pharmacokinetics22 
X 
X 
 
X23
X23
X23
X 
X 
X 
X 
X 
 Genotype24 
X 
 
 
 
 
 
 
 Serology panel25 
X 
 
 
 
 
 
 
 Pregnancy test (serum) 
X 
 
 
 
 
 
 
Urine sample for: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Pregnancy test26 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 Urinalysis27 
X 
X 
 
 
X 
X 
 
X 
 
X 
 
X 
 Drug screen28 
X 
X 
 
 
(X)
(X)
 
(X) 
 
(X)
(X) 
 
(X) (X)
AE = adverse event; AIMS = Abnormal Involuntary Movement Scale; BARS = Barnes Akathisia Rating Scale;  
BL = Baseline; CGI-I = Clinical Global Impression – Improvement; CGI-S = Clinical Global Impression – Severity;  
C-SSRS = Columbia-Suicide Severity Rating Scale; ECG = electrocardiogram; FU = Follow-up;  
HRU = healthcare resource utilization; IM = intramuscular; ISM = in situ microparticle;  
PANSS = Positive and Negative Syndrome Scale; PSP = Personal and Social Performance Scale;  
SAS = Simpson-Angus Scale; SWN-20 = 20-item Subjective Well-Being Under Neuroleptics Treatment Scale;  
VAS = visual analog scale; (X) = assessment to be done as applicable.  
 
1. Study visit 7 (study day 22) is applicable to patients who participate in pharmacokinetic subgroup only. 
2. Visit 14, which is scheduled to occur at the week 12 time point, is the designated end-of-treatment visit. However, if a 
patient withdraws or is withdrawn early from the study (ie, before the week 12 time point), an early termination visit 
should occur at which time all assessments for the end-of-treatment visit (as listed for visit 14) will be performed. 
3. The follow-up visit will be conducted by telephone. The follow-up visit is to occur 14 (± 3) days after the end-of-
treatment visit (ie, the week 12 time point or earlier in the case of an early termination). This visit is not applicable for 
patients who enter into the OLE phase. 
4. The study day 4 (visit 4) must occur 3 days after study day 1. Allowable study visit time windows for treatment period 
study visits occurring after visit 4 (study day 4) are ± 1 day for study visit 5, ± 2 days for study visit 14, and ± 3 days for 
each of the other treatment period study visits (ie, study visits 6 through 13, inclusive). 
5. If there is a valid reason for a given potential patient to extend the screening period duration beyond the designated 8 
days, the investigator may contact the medical monitor to request an extension of up to 14 days; such an extension may 
be implemented only after medical monitor approval has been obtained. 
6. Screening assessments will include the following: informed consent, demographic data, medical and psychiatric history, 
and a diagnostic interview (which will include completion of the MINI International Neuropsychiatric Interview for 
Schizophrenia and Psychotic Disorders studies, version 7.0.2). 
7. Eligibility will be determined by the investigator, who will assess eligibility by confirming that that all inclusion criteria 
(see Study Protocol Section 4.1.1.1) have been met and that none of the exclusion criteria have been met (see Study 
Protocol Section 4.1.1.2). 
 


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8. Patients who, after completion of all scheduled assessments on the screening visit day, are considered provisionally 
eligible will be admitted directly to the inpatient study that day. Patients will subsequently remain on the inpatient study 
unit for the remainder of the screening period (ie, through study day -1, inclusive). Confirmed eligible patients will 
remain inpatient on study day 1. No patient should be discharged from the inpatient before study day 2, and it is 
anticipated that most patients will remain on the inpatient unit through study day 8, and that thereafter patients will be 
discharged from the inpatient unit when the investigator has assessed the patient and determines that he or she is 
appropriately clinically stable and otherwise ready for safe discharge. After study day 8, continuation of a patient on the 
inpatient unit from study day 9 through study day 15, inclusive, is an allowable option, as deemed clinically indicated. If 
the investigator believes that a given patient should remain inpatient beyond study day 15, the investigator should contact 
the medical monitor to discuss the proposed inpatient duration extension. 
9. Patients who have never taken risperidone must take oral risperidone 2 mg/day for 3 days sometime during the screening 
period to ensure a lack of clinically significant hypersensitivity before the first IM dose of study drug is administered; this 
oral risperidone trial is not required for patients who have previously taken any formulation of risperidone. 
10. A unique randomization number will be assigned via interactive voice or web response system accessed immediately 
after eligibility confirmation of a patient. The randomization process will determine (under double-blind conditions) for 
each individual patient the study drug regimen: an individual patient will receive either active Risperidone ISM or IM 
placebo. 
11. All study drug doses will be administered by deep IM injection (deltoid muscle or gluteal muscle). The IM study drug 
doses will be prepared and administered by a designated unblinded individual at the study site (see Study Protocol 
Section 5.1.2). The IM study drug will contain either active Risperidone ISM (75 or 100 mg) or placebo (double blind). 
12. See Protocol Appendix C – Rating Scale and Interview Descriptions. 
13. Health economics and outcomes research evaluations. To be administered prior to medication dose. 
14. Monitoring for AEs will occur throughout a patient’s participation in this study, starting from the patient’s signature of 
informed consent form; required details of identified AEs are to be recorded. 
15. Information regarding concomitant medications, including new medications and changes to existing medications, will be 
elicited and recorded. 
16. Vital signs will include blood pressure, pulse rate, respiratory rate, and body temperature. At each identified time point, 
vital signs will be measured after the patient has been resting in a supine position for at least 5 minutes. On days when 
patients receive an IM injection of study drug, vital signs are to be measured within 1 hour before and then again within 3 
hours after the study drug injection; at each of these time points, orthostatic blood pressure and pulse rate will be 
measured (immediately after completion of supine vital sign measurements) after the patient has risen from the supine to 
the standing position and has remained standing for approximately 3 minutes (see Study Protocol Section 6.4.3). 
17. A 12-lead ECG will be performed at identified visits; on days when patients receive an injection of IM study drug, an 
ECG will be performed both before and after dosing. Pre-dose ECG is to be completed within 1 hour prior to dosing. The 
post-dose ECG is to be completed within 3 hours post-dose. All scheduled ECGs are to be performed after the patient has 
rested quietly for at least 5 minutes in the supine position (see Study Protocol Section 6.4.4). 
18. The patient will perform and record self-assessment of pain at the injection site using the injection site pain VAS (see 
Protocol Appendix D) approximately 1 hour after each study drug injection. The investigator will inspect the recent 
injection site and all injection sites where IM study drug has been injected on previous visits, also approximately 1 hour 
after each study drug injection. 
19. Ophthalmological examination will include slit-lamp biomicroscopy examination (eyelids, conjunctiva, iris, crystalline 
lens, sclera, and cornea), best corrected visual acuity, visual field, and intraocular pressure (see Study Protocol Section 
6.4.2). 
20. The hematology panel includes the following tests: hematocrit, hemoglobin, red blood cell count, white blood cell count 
and differential count (absolute values for basophils, eosinophils, lymphocytes, monocytes, and neutrophils), and 
platelets. 
21. The chemistry panel will include standard tests as well as hemoglobin A1c, thyroid-stimulating hormone, and a lipid 
panel. 
22. Pharmacokinetic samples will be obtained for all patients in the study on days 1, 3, 29, 31, 57, 59, and 85 (visits 2, 3, 8, 9, 
11,12, and 14, respectively). Pharmacokinetic samples will also be collected from patients who have a serious AE. 
23. A subgroup of 75 study participants will have additional pharmacokinetic samples collected on days 8, 15, and 22 (visits 
5, 6,and 7, respectively). 
24. Genotype samples will be obtained only from those patients who sign a separate consent form for genotype sample 
collection. In these patients, a blood sample for genotype testing may be collected at any time point after randomization 
(see Study Protocol Section 6.7.5.) 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Laboratorios Farmacéuticos ROVI, S.A.; Protocol No.: ROV-RISP-2016-01 / 1004855 
 
This document is confidential. 
SAP Version: V4.0 15-FEB-2019 
Controlled Document ID: 3903C.00, Effective Date 30-Apr-2018 
Page 26 of 95 
25. A blood sample for a serology panel testing for hepatitis B surface antigen, antihepatitis C antibodies, and human 
immunodeficiency virus will be performed at screening only. 
26. On study day 1 and at identified visits thereafter, onsite dipstick tests will be used for urine pregnancy tests. On each 
study drug dosing day, the urine pregnancy test must be performed and a negative result confirmed before the schedule 
dose of study drug for that day is administered. 
27. The urinalysis includes the following tests: color, pH, specific gravity, ketones, protein, glucose, bilirubin, nitrite, 
urobilinogen, and occult blood. Microscopic examination only if urinalysis dipstick results are abnormal. 
28. Urine drug screen is mandatory at screening and baseline and is optional thereafter. On these timepoints the sample will 
also be sent to the laboratory for analysis (see Study Protocol Section 6.4.5.4.3). The urine drug screen will include 
identification of the presence or absence of amphetamines, barbiturates, cocaine, methadone, opioids, and phencyclidine, 
as well as for tetrahydrocannabinol, alcohol, and benzodiazepines. In addition, onsite dipstick urine drug screen testing 
(with the exception of alcohol) may be optionally performed on the sample collected. 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Laboratorios Farmacéuticos ROVI, S.A.; Protocol No.: ROV-RISP-2016-01 / 1004855 
 
This document is confidential. 
SAP Version: V4.0 15-FEB-2019 
Controlled Document ID: 3903C.00, Effective Date 30-Apr-2018 
Page 27 of 95 
 
Table 2 
Schedule of Assessments and Procedures: Optional Open-label Extension Phase for 
Rollover Patients 
 
OLE 
Baseline 
OLE Treatment Period (Open-Label) 
OLE 
Follow-up
OLE Phase Visit Number:
 11 
2
3
4
5 
6 
7 
8 
9 
10 
11 
12 
13 
142
153
OLE Phase Study Day4: 
 15 
29 57 85 113
141
169
197
225
253
281 309 337 365
393 
OLE Phase Treatment Week:
 
4
8
12
16 
20 
24 
28 
32 
36 
40 
44 
48 
52 
56 
OLE Phase Dosing Sequence:
1 
2
3
4
5 
6 
7 
8 
9 
10 
11 
12 
13 
 
 
Informed consent6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility criteria review7 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inject Risperidone ISM8 
X 
X
X
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Efficacy scales: 
 
 
 
 
 PANSS 
 X9 
X
X
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 CGI-S 
 X9 
X
X
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 CGI-I10 
 
X
X
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 Socio-demographic 
information 
 
 
 
X
 
 
X 
 
 
X 
 
 
X 
 
 
 HRU data collection - center 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 HRU data collection – patient 
 
 
 
X
 
 
X 
 
 
X 
 
 
X 
 
 
Health outcome scales:11 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 PSP (clinician administered) 
    
 
 
X
 
 
X 
 
 
 
 
 
 
X 
 
 SWN-20 (patient reported) 
 
 
 
X
 
 
X 
 
 
 
 
 
 
X 
 
Safety assessments: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 AEs12 
X9 
X
X
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 Concomitant meds13 
X9 
X
X
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 Physical examination 
X9 
X
X
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 Weight and body mass index 
X9 
 
 
X
 
 
X 
 
 
X 
 
 
 
X 
 
 Vital signs14 
X9 
X
X
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 ECG15 
X9 
X
 
X
 
X 
 
X 
 
 
X 
 
 
X 
 
 Injection site evaluation16 
X9 
X
X
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 Injection site pain VAS16 
X9 
X
X
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 Safety scales: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  AIMS 
X9 
X
X
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
  BARS 
X9 
X
X
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
  SAS 
X9 
X
X
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
  C-SSRS 
X9 
X
X
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Blood sample for: 
 
 
 
 
 Hematology panel17 
X9 
 
 
X
 
 
X 
 
 
X 
 
 
 
X 
 
 Chemistry panel18 
X9 
 
 
X
 
 
X 
 
 
X 
 
 
 
X 
 
 Prolactin 
X9 
 
 
X
 
 
X 
 
 
X 
 
 
 
X 
 
 Pregnancy test19 (serum) 
(X) 
(X) (X) (X) (X)
(X)
(X)
(X)
(X)
(X)
(X) (X) (X) (X)
 
Urine sample for: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Pregnancy test20 
X9 
X
X
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 Urinalysis21 
X9 
 
 
X
 
 
X 
 
 
X 
 
 
 
X 
 
 Drug screen22 
(X) 
(X) (X) (X) (X)
(X)
(X)
(X)
(X)
(X)
(X) (X) (X) (X)
  
 
AE = adverse event; AIMS = Abnormal Involuntary Movement Scale; BARS = Barnes Akathisia Rating Scale;  
CGI-I = Clinical Global Impression – Improvement; CGI-S = Clinical Global Impression – Severity;  


Statistical Analysis Plan for Interventional Studies 
Sponsor: Laboratorios Farmacéuticos ROVI, S.A.; Protocol No.: ROV-RISP-2016-01 / 1004855 
 
This document is confidential. 
SAP Version: V4.0 15-FEB-2019 
Controlled Document ID: 3903C.00, Effective Date 30-Apr-2018 
Page 28 of 95 
C-SSRS = Columbia-Suicide Severity Rating Scale; ECG = electrocardiogram; HRU = healthcare resource utilization; IM = 
intramuscular; ISM = in situ microparticle; PANSS = Positive and Negative Syndrome Scale;  
PSP = Personal and Social Performance Scale; SAS = Simpson-Angus Scale; SWN-20 = 20-item Subjective Well-Being 
Under Neuroleptics Treatment Scale; VAS = visual analog scale; (X) = assessment to be done as applicable  
 
1. The OLE phase baseline visit may occur on the same day as visit 14 (+ 3-day window) of the main part of the study (i.e., 
the day on which the designated end-of-treatment visit for the double-blind treatment period of the main part of the study 
occurs), which is scheduled to occur at the week 12 time point of the main part of the study. However, in order to be 
eligible for transition into the OLE phase, a patient must first complete all assessments and procedures scheduled for the 
end-oftreatment visit for the double-blind treatment period of the main part of the study. Patients who withdraw or are 
withdrawn early from the main part of the study (i.e., before the scheduled week 12 time point) are not eligible for 
enrollment into the OLE phase. 
2. Visit 14 is the designated end-of-treatment visit.  However, if a patient withdraws or is withdrawn early from the study, 
an early termination visit should occur at which time all assessments for the end-of-treatment visit (as listed for visit 14) 
plus all the socio-demographic information and HRU (center and patient) data collection will be performed. 
3. The follow-up visit will be conducted by telephone. 
4. The allowable study visit time window for each of the OLE baseline visit is within 3 days after visit 14 of the main part 
of the study occurs; however, it is generally preferable to conduct the OLE baseline visit assessments and procedures 
later in the day (i.e., after completion of all assessments and procedures scheduled for the end-of-treatment visit for the 
double-blind treatment period of the main part of the study) on the same day on which the main study visit 14 occurs. The 
allowable study visit time window for each of the subsequent OLE visits is ± 3 days (i.e., OLE visits 2 through 15, 
inclusive). 
5. Extension day 1 (the OLE baseline visit time point) is planned to be the same day and date as day 85 of the main part of 
the study, though a + 3-day window for OLE day 1, as compared with the day and date of the end-of- treatment visit for 
the main study day 85, is allowable. 
6. A separate informed consent form for participation in the optional OLE phase of the study must be signed before any 
assessments or procedures for the OLE phase are performed for a given patient and before any dose of open-label 
Risperidone ISM is administered to that patient. 
7. Eligibility will be determined by the investigator, who will assess eligibility by confirming that that all OLE phase 
inclusion criteria (see Study Protocol Section 4.1.2.1) have been met and that none of the OLE phase exclusion criteria 
have been met (see Study Protocol Section 4.1.2.2). 
8. In the OLE phase of the study, all participating patients will receive active Risperidone ISM under open-label conditions. 
Patients who had been on active Risperidone ISM in the DB phase of the study will continue to receive Risperidone ISM 
at the same dose (i.e., 75 or 100 mg) in the OLE phase; patients who had been receiving placebo in the DB phase of the 
study will be randomly assigned to receive either 75 or 100 mg during the OLE phase. All Risperidone ISM doses will be 
administered by deep IM injection (deltoid muscle or gluteal muscle). 
9. For identified assessments at the OLE baseline visit time point (on OLE day 1), results obtained as part of the main study 
visit 14 (i.e., the designated assessments performed for the end-of-treatment visit for the double-blind treatment period 
[week 12 time point] of the main part of the study) may be used as the OLE baseline values and do not need to be 
repeated for the OLE phase baseline visit time point if and only if the OLE baseline visit occurs on the same day and date 
as the main study visit 14/week 12/end-of-treatment visit. If the OLE baseline visit instead occurs on a day 1 to 3 days 
after the main study visit 14/week 12/end-of-treatment visit, all of the designated assessments must be performed 
separately on the day of the OLE baseline visit, and the main study visit 14/week 12/endof- treatment visit assessment 
results cannot be used as substitutes. 
10. Although a CGI-I score in reference to baseline of the main part of the study will be reported as part of the assessments 
for the end-of-treatment visit for the double-blind treatment period (visit 14 of the main part of the study), no CGI-I score 
in reference to the OLE phase will be reported at the OLE baseline time point (which may be later on the same day as the 
visit 14 of the main part of the study). For all subsequent visits in the treatment period of the OLE phase (i.e., OLE phase 
visits 2 through 14, inclusive), the reference time point for the CGI-I scores will be that patient’s overall status at the 
OLE baseline time point. 
11. Health economics and outcomes research evaluations. To be administered prior to medication dose. 
12. Monitoring for AEs will occur throughout a patient’s participation in the OLE phase of the study, starting from the 
patient’s signature of informed consent form; required details of identified AEs are to be recorded. 
13. Information regarding concomitant medications, including new medications and changes to existing medications, will be 
elicited and recorded. 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Laboratorios Farmacéuticos ROVI, S.A.; Protocol No.: ROV-RISP-2016-01 / 1004855 
 
This document is confidential. 
SAP Version: V4.0 15-FEB-2019 
Controlled Document ID: 3903C.00, Effective Date 30-Apr-2018 
Page 29 of 95 
14. Vital signs will include blood pressure, pulse rate, respiratory rate, and body temperature. At each identified time point, 
vital signs will be measured after the patient has been resting in a supine position for at least 5 minutes. At each 
scheduled visit, vital signs are to be measured within 1 hour before and then again within 3 hours after the Risperidone 
ISM injection; at each of these time points, orthostatic blood pressure and pulse rate will be measured (immediately after 
completion of supine vital sign measurements) after the patient has risen from the supine to the standing position and has 
remained standing for approximately 3 minutes (see Study Protocol Section 6.4.3). 
15. A 12-lead ECG will be performed at identified visits, both before and after dosing of risperidone ISM (with the exception 
of visit 14 when only 1 ECG is applicable). Each pre-dose ECG is to be completed within 1 hour before dosing. Each 
post-dose ECG is to be completed within 3 hours post-dose. All scheduled ECGs are to be performed after the patient has 
rested quietly for at least 5 minutes in the supine position (see Study Protocol Section 6.4.4). 
16. The patient will perform and record self-assessment of pain at the injection using the injection site pain VAS (see 
Protocol Appendix D) approximately 1 hour after each study drug injection. The investigator will inspect the recent 
injection site and all injection sites where IM study drug has been injected on previous visits, also approximately 1 hour 
after each study drug injection. 
17. The hematology panel includes the following tests: hematocrit, hemoglobin, red blood cell count, white blood cell count 
and differential count (absolute values for basophils, eosinophils, lymphocytes, monocytes, and neutrophils), and 
platelets. 
18. The chemistry panel will include standard tests as well as hemoglobin A1c, thyroid-stimulating hormone, and a lipid 
panel. 
19. A blood sample for a serum pregnancy test is not required, but the investigator may order a serum pregnancy test at any 
time according to the investigator’s judgment. 
20. On OLE phase day 1 and at each identified visit thereafter, onsite dipstick tests will be used for urine pregnancy tests. At 
each applicable visit, the urine pregnancy test must be performed and a negative result confirmed before the schedule 
dose of study drug for that day is administered. 
21. The urinalysis includes the following tests: color, pH, specific gravity, ketones, protein, glucose, bilirubin, nitrite, 
urobilinogen, and occult blood. Microscopic examination only if urinalysis dipstick results are abnormal 
22. Urine drug screen is optional at each study site visit. It will include identification of the presence or absence of 
amphetamines, barbiturates, cocaine, methadone, opioids, and phencyclidine, as well as for tetrahydrocannabinol, 
alcohol, and benzodiazepines. 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Laboratorios Farmacéuticos ROVI, S.A.; Protocol No.: ROV-RISP-2016-01 / 1004855 
 
This document is confidential. 
SAP Version: V4.0 15-FEB-2019 
Controlled Document ID: 3903C.00, Effective Date 30-Apr-2018 
Page 30 of 95 
Table 3 
Schedule of Assessments and Procedures: Open-label Extension Phase for De Novo 
Patients 
 
Screening 
OLE 
Baseline
OLE Treatment Period (Open-Label) 
OLE 
Follow
-up 
OLE Visit Number:
0 
1 
2
3
4
5 
6 
7 
8 
9 
10 
11 
12 
13 
141
15 
OLE Study Day2: -8 to -13 
1 
29 57 85 113
141
169
197
225
253
281 309 337 365
393 
OLE Treatment Week:
 
 
4
8
12
16 
20 
24 
28 
32 
36 
40 
44 
48 
52 
56 
OLE Dosing Sequence:
 
1 
2
3
4
5 
6 
7 
8 
9 
10 
11 
12 
13 
 
 
Informed consent4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening assessment* 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility criteria 
review2 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Arm assignment5 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inject Risperidone ISM3 
 
X 
X
X
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Efficacy scales: 
 
 
 
 
 
 PANSS 
X 
 X 
X
X
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 CGI-S 
X 
 X 
X
X
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 CGI-I 
 
 
X
X
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 Socio-demographic 
information 
 
X 
 
 
X
 
 
X 
 
 
X 
 
 
X 
 
 
 HRU data collection – 
center 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 HRU data collection – 
patient 
 
X 
X
X
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Health outcome scales:6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 PSP (clinician 
administered) 
 
X 
 
 
X
 
 
X 
 
 
 
 
 
 
X 
 
 SWN-20 (patient 
reported) 
 
X 
 
 
X
 
 
X 
 
 
 
 
 
 
X 
 
Safety assessments: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 AEs7 
X 
 X 
X
X
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 Concomitant meds8 
X 
 X 
X
X
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 Physical examination 
X 
 X 
X
X
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 Weight and body mass 
index 
X 
 X 
 
 
X
 
 
X 
 
 
X 
 
 
 
X 
 
 Vital signs9 
X 
X 
X
X
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 ECG10 
X 
X 
X
 
X
 
X 
 
X 
 
 
X 
 
 
X 
 
 Injection site 
evaluation11 
 
X 
X
X
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 Injection site pain 
VAS11 
 
X 
X
X
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 Safety scales: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  AIMS 
X 
 X 
X
X
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
  BARS 
X 
 X 
X
X
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
  SAS 
X 
 X 
X
X
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
  C-SSRS 
X 
 X 
X
X
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Blood sample for: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Hematology panel12 
X 
 X 
 
 
X
 
 
X 
 
 
X 
 
 
 
X 
 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Laboratorios Farmacéuticos ROVI, S.A.; Protocol No.: ROV-RISP-2016-01 / 1004855 
 
This document is confidential. 
SAP Version: V4.0 15-FEB-2019 
Controlled Document ID: 3903C.00, Effective Date 30-Apr-2018 
Page 31 of 95 
 
Screening 
OLE 
Baseline
OLE Treatment Period (Open-Label) 
OLE 
Follow
-up 
OLE Visit Number:
0 
1 
2
3
4
5 
6 
7 
8 
9 
10 
11 
12 
13 
141
15 
OLE Study Day2: -8 to -13 
1 
29 57 85 113
141
169
197
225
253
281 309 337 365
393 
OLE Treatment Week:
 
 
4
8
12
16 
20 
24 
28 
32 
36 
40 
44 
48 
52 
56 
OLE Dosing Sequence:
 
1 
2
3
4
5 
6 
7 
8 
9 
10 
11 
12 
13 
 
 
 Chemistry panel13 
X 
 X 
 
 
X
 
 
X 
 
 
X 
 
 
 
X 
 
 Prolactin 
X 
 X 
 
 
X
 
 
X 
 
 
X 
 
 
 
X 
 
 Serology panel** 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Pregnancy test14 
(serum) 
X 
(X) 
(X) (X) (X) (X)
(X)
(X)
(X)
(X)
(X)
(X) 
(X) 
(X) 
(X)
 
Urine sample for: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Pregnancy test15 
 
 X 
X
X
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 Urinalysis16 
X 
 X 
 
 
X
 
 
X 
 
 
X 
 
 
 
X 
 
 Drug screen17 
X 
X 
(X) (X) (X) (X)
(X)
(X)
(X)
(X)
(X)
(X) 
(X) 
(X) 
(X)
  
AE = adverse event; AIMS = Abnormal Involuntary Movement Scale; BARS = Barnes Akathisia Rating Scale; CGI I = 
Clinical Global Impression – Improvement; CGI-S = Clinical Global Impression – Severity; C-SSRS = Columbia-Suicide 
Severity Rating Scale; ECG = electrocardiogram; HRU = healthcare resource utilization; IM = intramuscular; ISM = in situ 
microparticle; PANSS = Positive and Negative Syndrome Scale; PSP = Personal and Social Performance Scale; SAS = 
Simpson-Angus Scale; SWN-20 = 20-item Subjective Well-Being Under Neuroleptics Treatment Scale; VAS = visual analog 
scale; (X) = assessment to be done as applicable. 
 
1. Visit 14 is the designated end-of-treatment visit.  However, if a patient withdraws or is withdrawn early from the study, 
an early termination visit should occur at which time all assessments for the end-of-treatment visit (as listed for visit 14) 
plus all the socio-demographic information and HRU (center and patient) data collection will be performed. 
2. The allowable study visit time window for baseline visit 1 is + 4-day window and for each of the subsequent OLE visits 
is ± 3 days (i.e., OLE visits 2 through 15, inclusive).   
3. If there is a valid reason for a given potential patient to extend the screening period duration beyond the designated 8 
days, the investigator may contact the medical monitor to request an extension of up to 14 days; such an extension may 
be implemented only after medical monitor approval has been obtained. 
4. An informed consent form for participation in the OLE phase of the study must be signed before any assessments or 
procedures for the OLE phase are performed for a given patient and before any dose of open-label Risperidone ISM is 
administered to that patient. Eligibility will be determined by the investigator, who will assess eligibility by confirming 
that that all inclusion criteria have been met and that none of the exclusion criteria have been met. 
5. In the OLE phase of the study, all participating patients will receive active Risperidone ISM under open-label conditions.  
Patients on 4 mg of oral risperidone will be assigned to 75 mg Risperidone ISM every 28 days. Patients on more than 4 
mg to a maximum of 6 mg of oral risperidone will be assigned to 100 mg Risperidone ISM every 28 days. All 
Risperidone ISM doses will be administered by deep IM injection (deltoid muscle or gluteal muscle).   
6. Health economics and outcomes research evaluations. To be administered prior to medication dose. 
7. Monitoring for AEs will occur throughout a patient’s participation in the extension segment of the study, starting from 
the patient’s signature of informed consent form; required details of identified AEs are to be recorded. 
8. Information regarding concomitant medications, including new medications and changes to existing medications, will be 
elicited and recorded. 
9. Vital signs will include blood pressure, pulse rate, respiratory rate, and body temperature.  At each identified time point, 
vital signs will be measured after the patient has been resting in a supine position for at least 5 minutes.  At each 
scheduled visit, vital signs are to be measured within 1 hour before and then again within 3 hours after the Risperidone 
ISM injection; at each of these time points, orthostatic blood pressure and pulse rate will be measured (immediately after 
completion of supine vital sign measurements) after the patient has risen from the supine to the standing position and has 
remained standing for approximately 3 minutes (see Study Protocol Section 6.4.3).   
10. A 12-lead ECG will be performed at identified visits, both before and after dosing of risperidone ISM (with the exception 
of visit 14 when only 1 ECG is applicable).  Each pre-dose ECG is to be completed within 1 hour before dosing.  Each 
post-dose ECG is to be completed within 3 hours post-dose.  All scheduled ECGs are to be performed after the patient 
has rested quietly for at least 5 minutes in the supine position (see Study Protocol Section 6.4.4).   


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11. The patient will perform and record self-assessment of pain at the injection using the injection site pain VAS (see Study 
Protocol Appendix D) approximately 1 hour after each study drug injection. The investigator will inspect the recent 
injection site and all injection sites where IM study drug has been injected on previous visits, also approximately 1 hour 
after each study drug injection. 
12. The hematology panel includes the following tests: hematocrit, hemoglobin, red blood cell count, white blood cell count 
and differential count (absolute values for basophils, eosinophils, lymphocytes, monocytes, and neutrophils), and 
platelets. 
13. The chemistry panel will include standard tests as well as hemoglobin A1c, thyroid-stimulating hormone, and a lipid 
panel.   
14. A blood sample for a serum pregnancy test is not required, but the investigator may order a serum pregnancy test at any 
time according to the investigator’s judgment.  
15. On OLE phase day 1 and at each identified visit thereafter, onsite dipstick tests will be used for urine pregnancy tests.  At 
each applicable visit, the urine pregnancy test must be performed and a negative result confirmed before the schedule 
dose of study drug for that day is administered.  
16. The urinalysis includes the following tests: color, pH, specific gravity, ketones, protein, glucose, bilirubin, nitrite, 
urobilinogen, and occult blood. Microscopic examination only if urinalysis dipstick results are abnormal. 
17. Urine drug screen is optional at each study site visit properly identified. It will include identification of the presence or 
absence of amphetamines, barbiturates, cocaine, methadone, opioids, and phencyclidine, as well as for 
tetrahydrocannabinol, alcohol, and benzodiazepines. 
*  Screening assessments will include the following: informed consent, demographic data, medical and psychiatric history, 
and a diagnostic interview (which will include completion of the MINI International Neuropsychiatric Interview for 
Schizophrenia and Psychotic Disorders studies, version 7.0.2).  
** A blood sample for a serology panel testing for hepatitis B surface antigen, antihepatitis C antibodies, and human 
immunodeficiency virus will be performed at screening only.


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4. 
VARIABLES 
4.1 
PRIMARY EFFICACY VARIABLES 
Positive and Negative Syndrome Scale (PANSS)1 total score mean change from baseline to endpoint.  
In this context, endpoint is defined as study day 85 or the last post-baseline double-blind assessment.   
4.2 
SECONDARY EFFICACY VARIABLES 
Key Secondary Efficacy Variable: 
 
Clinician Global Impression – Severity scale (CGI-S) score mean change from baseline to 
endpoint 
 
Other Secondary Efficacy Variables: 
 
CGI-I score mean at endpoint 
 
Overall response rate at endpoint 
o Overall response is defined as either of the following: 
 
PANSS total score ≥ 30% decrease (improvement of symptoms) from baseline to endpoint 
 
Clinician Global Impression – Improvement scale (CGI-I) score of 2 (much improved) or 
1 (very much improved) at endpoint 
 
PANSS response rate at endpoint 
o PANSS response is defined as the following: 
 
PANSS total score ≥ 30% decrease (improvement of symptoms) from baseline at endpoint 
 
Time to reach PANSS response 
 
PANSS total score mean change from baseline at each post-baseline assessment time point 
 
PANSS subscale score mean change from baseline at endpoint and at each post-baseline 
assessment time point for each of the positive, negative and general psychopathology subscales 
 
Overall response rate at each post-baseline assessment time point 
 
Time to reach overall response 
 
PANSS response rate at each post-baseline assessment time point 
 
CGI-S score mean change from baseline at each post-baseline assessment time point 
 
CGI-I score mean at each post-baseline assessment time point 


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4.3 
EFFICACY VARIABLES IN THE OLE PHASE OF THE STUDY 
The following efficacy parameters will be summarized in the OLE phase of the study for the Open –
Label Population (OLP – see section 5.13) by treatment group and overall. 
Durability of effect evaluations: 
 
Positive and Negative Syndrome Scale (PANSS) total score 
 
Positive, negative, and general psychopathology subscale scores   
 
CGI-I score  
 
CGI-S score  
 
Overall response (as defined in Section 4.2) 
 
PANSS response (as defined in Section 4.2)  
 
Relapse, defined as 
o PANSS total score increase of ≥ 30% from baseline or  
o Re-hospitalization for psychotic symptoms or use of adjunctive antipsychotic 
medication after stabilization  
 
Remitters, defined as 
o The simultaneous attainment of a score of ≤ 3 for 6 months or more on 8 main items 
of the PANSS (delusions, conceptual disorganization, hallucinations, blunted affect, 
passive apathetic social withdrawal, lack of spontaneity and flow of conversations, 
mannerisms and posturing, unusual thought content)   
 
Time to discontinuation.  
Other evaluations include HRU, PSP, SWN-20 and concomitant antipsychotic medication use.  
All analyses of data from the OLE phase of the study will be of descriptive nature only. 
 
4.4 
HEALTH ECONOMICS AND OUTCOMES RESEARCH (HEOR) VARIABLES 
Endpoint is defined as study day 85 or the last post-baseline double-blind assessment.  
 
HRU data will be collected both inside and outside the treating center with the aim to establish 
resource use patterns that are as complete as possible and to generate more accurate cost estimates. 
HRU categories include: 
o Medication 
o Inpatient hospital services 
o Emergency/A&E visits 
o Outpatient hospital services (i.e. specialist outpatient visits and day hospital visits) 
o Outpatient hospital care contacts (i.e. other allied healthcare professional contacts) 


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o Community-based day services (patient-reported only) 
o Primary and community care contacts (patient-reported only) 
o Therapy 
o Criminal justice services (patient-reported only) 
 
HRU and cost variables include the following: 
o For each item, total quantity of resources used within and outside the participating center at 
endpoint. For each item, the mean number at endpoint and rate of use per 3 months will be 
calculated. 
o By resource use category (e.g. inpatient services, outpatient services) and total direct medical 
costs (reflecting resources used within and outside the participating center) at endpoint and 
average cost per 3 months will be calculated. 
o For all resource use categories combined, total medical costs at endpoint and average cost per 
3 months will be calculated. 
o Indirect costs (days absent from work due to illness) at endpoint. 
 
Personal and Social Performance Scale (PSP) score mean change from baseline at each post-
baseline assessment time point. 
 
PSP2 domain score mean change from baseline at each post-baseline assessment time point. 
 
Subjective Well-being Under Neuroleptics – Short Form (SWN-20) total score mean change from 
baseline at each post-baseline assessment time point. 
 
SWN-20 subscale score mean change from baseline at each post-baseline assessment time point. 
 
4.5 
SAFETY VARIABLES  
Safety variables include the following:  
 
Occurrence, nature, duration, intensity, and relationship to study drug of injection site reactions:  
o Injection site pain, assessed by patients using a visual analog scale (VAS) after each dose 
o Injection site evaluation of redness, swelling, and induration, evaluated by designated study 
site personnel after each injection 
 
Occurrence (incidence), nature, onset time, duration, intensity, action taken, and relationship to 
study drug of treatment-emergent AEs 
 
Occurrence, nature, time to onset, duration, seriousness criteria, relationship to study drug, and 
outcome of treatment-emergent SAEs 
 
Occurrence of extrapyramidal symptoms, as assessed using the SAS3, BARS, and AIMS 
 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
 
Physical examination, vital signs, weight, body mass index, clinical laboratory test results, and 
ECG findings 


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 
Time to early termination 
 
4.6 
PHARMACOKINETIC VARIABLES 
Pharmacokinetic variables include the following: 
 
Summary plasma concentrations of risperidone, its active metabolite (9 OH-risperidone), and the 
active moiety (ie, risperidone plus 9-OH-risperidone) by injection site (gluteal and deltoid) and by 
study drug dose level   
 
Trough and estimated Cmax concentrations and accumulation index for steady state by injection site 
(gluteal and deltoid) and by study drug dose level  
 
Estimated Cmax for all doses (days 3, 31 and 59) 
 
Cmin for all doses (days 29, 57 and 85) including Css after last dosing interval (day 85) 
 
Css/D after last dosing interval (day 85) 
 
RCmin and RCmax 
 
Exploratory associations of pharmacokinetic results with efficacy results 
 
Non-compartmental PK parameters will be derived for a subset of patients: 
 
Derived Cmax for dose 1 
 
Derived Cmax/D for dose 1 
 
tmax for dose 1 
 
Tlast for dose 1 
 
Clast for dose 1 
 
AUClast for dose 1 
 
AUCtau for dose 1  
 
AUCtau/D for dose 1 
 
Cavg for dose 1 
 
t1/2 for dose 1 
 
AUCinf for dose 1 
 
CL/F for dose 1 
 
V/F for dose 1   
 
4.7 
OTHER VARIABLES 
Genotypes for cytochrome P450 enzymes, and/or genes that are potentially related to efficacy 
response and/or adverse effects. These will be used to provide subgroup analyses for PK and efficacy 
and will be of exploratory nature only for both. 
 


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5. 
ANALYSIS POPULATIONS 
Protocol deviations will be captured throughout the study. Those that may significantly impact the 
completeness, accuracy, and/or reliability of the study data or may significantly affect a patient's 
rights, safety, or well-being will be classed as an important protocol deviation. 
A blinded data review meeting (BDRM) will be held before database lock and unblinding of the DB 
phase to clarify any open questions or doubts and agree upon the exclusions from the PP and 
Pharmacokinetic (PK) populations and analyses as defined below. All patients satisfying the ITT and 
mITT population definitions will be included in the respective efficacy analyses. Attendees will 
include appropriate individuals from the sponsor and contract research organization.  Additional 
details will be provided in a separate blinded data review meeting plan document.  Reasons for 
excluding patients from the PP or PK population will be determined and documented before database 
lock, except mistakes regarding randomization procedures or based on non-quantifiable PK 
concentrations which are not available before unblinding. All decisions will be documented.  
 
5.1 
SCREENED POPULATION 
The screened population will include all patients that signed the informed consent form. The screened 
population will include screen failures.  Unless specified otherwise, this set will be used for patient 
listings and summaries of patient disposition. 
 
5.2 
SAFETY POPULATION  
The safety population (SAF) will include all patients who receive at least 1 dose of study drug.  
Analyses performed on the safety population will be as treated.  The safety population will be used for 
analyses of all safety endpoints and all patient listings unless specified otherwise. 
 
5.3 
MODIFIED SAFETY POPULATION 
The modified safety population (mSAF) will consist of all patients in the SAF population for whom 
blinding was not compromised (see Section 3.6.3). Analyses performed on the mSAF population will 
be as treated.  This population will be used for selected safety analyses. 
 
5.4 
RANDOMIZED POPULATION 
The randomization population will consist of all patients that are randomized in the study. Analyses 
performed on the randomization population will be as randomized.  This population will be used for 


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sensitivity analysis of the primary variable and for summaries/listings of patient disposition post-
screening. 
 
5.5 
MODIFIED RANDOMIZED POPULATION 
The modified randomized population will consist of all patients in the randomized population for 
whom blinding was not compromised (see Section 3.6.3). This population will be used for sensitivity 
analysis of the primary variable. 
 
5.6 
INTENT-TO-TREAT POPULATION  
The intent-to-treat (ITT) population will consist of all randomized patients who receive at least 1 dose 
of study drug with a baseline measurement and ≥ 1 post-baseline evaluation of the PANSS.  Analyses 
performed on the ITT population will be as randomized. The ITT population will be used for analyses 
of efficacy endpoints. 
 
5.7 
MODIFIED INTENT-TO-TREAT POPULATION 
The modified intent-to-treat (mITT) population will consist of all patients in the ITT population for 
whom blinding was not compromised (see Section 3.6.3). Analyses performed on the mITT population 
will be as randomized.  The mITT population will be used for analyses of efficacy endpoints, 
including health economics and outcomes research endpoints. 
 
5.8 
PER PROTOCOL POPULATION 
The per-protocol (PP) population will consist of patients from the ITT population who receive ≥ 2 
injections of study drug (active or placebo) during the DB phase and have no important protocol 
deviations that may impact the primary efficacy variable (PANSS).   
Additionally, if a patient receives < 2 injections due to early treatment discontinuation with a reason 
related to an adverse event or lack of efficacy (i.e.  insufficient clinical response, hospitalization for 
worsening, relapse, or exacerbation of Schizophrenia symptoms or other reason related to lack of 
efficacy or worsening, relapse, or exacerbation of Schizophrenia symptoms) then they will not be 
excluded from the PP population for this reason.  
Additionally, if a patient has a protocol deviation which is deemed to have only affected the PANSS 
data following the third dose, then only the affected data will be excluded from the PP analysis and the 
patient will not be excluded from the PP population for this reason.  


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Analyses performed on the PP population will be as treated. The PP population will be used for 
supporting analyses of all efficacy endpoints. 
Table 4 provides examples of important protocol deviation for which the patient would be excluded 
from the PP population. Patients to be excluded from the PP population will be determined prior to 
database lock. 
Table 4  Examples of Important Protocol Deviations that would result in exclusion from PP 
population 
Type of deviation 
Description of Deviation 
Failed 
inclusion/exclusion 
Patient failed to meet at least 1 inclusion criterion, or met at least 1 exclusion 
criterion for the DB phase of the study. 
Dosing error 
Patient received incorrect study medication during the DB phase of the study 
Other investigational 
drug 
Patient took any experimental or investigational drug or agent after enrollment 
in the current study, other than investigational treatment for Study ROV-RISP-
2016-01 during the DB phase of the study 
Substance abuse 
Patient took prohibited substances include amphetamines, barbiturates, cocaine, 
methadone, opioids, and phencyclidine during the DB phase of the study. 
Prohibited Therapy 
Patient took one of the following prohibited medications during participation in 
the DB phase of the study: 
 Cytochrome P450 3A4 Inducers and Inhibitors and 2D6 Inhibitors are 
prohibited during the course of the study and within 30 days before 
study day 1 
 Antipsychotic medications, other than the study drugs administered 
according to this protocol, are not permitted during a patient’s 
participation in the DB phase of this study.  Existing antipsychotic 
medication must be discontinued during the screening period (while the 
patient is admitted to the inpatient study unit), if deemed clinically 
appropriate by investigator judgment.  
 Monoamine oxidase inhibitors 
 Lithium and mood stabilizers 
 Nicotine replacement therapy varenicline (Chantix®) is not permitted.   
 Prohibited non-medication therapy 
 
5.9 
MODIFIED PER PROTOCOL POPULATION 
The modified per-protocol (mPP) population will consist of all patients in the PP population for whom 
blinding was not compromised (see Section 3.6.3). Analyses performed on the mPP population will be 
as treated.  This population will be used for selected efficacy analyses. 
5.10 
PHARMACOKINETIC POPULATION   
Out of 393 patients randomized into the study, approximately 262 will receive active treatment of 
Risperidone ISM 75 or 100 mg. Such patients will be considered for the Pharmacokinetic (PK) 


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population. Patients on placebo treatment will also have PK samples taken to prevent unblinding but 
will not have the plasma analyzed and will not be included in the PK population. 
The PK population will include patients in the safety population who have at least 1 measured plasma 
concentration value. In cases where a protocol deviation is identified to potentially effect plasma 
concentration data, or if the sample was taken out of the required window (see section 9.2) the 
identified concentration values will be flagged and excluded from summarization as indicated, and in 
some cases may be excluded from the pharmacokinetic analysis overall; excluded concentration values 
will be identified before database lock based on a protocol deviations log and a listing of sample times 
verus dosing  and confirmed with sponsor. Actual PK concentrations will not be reviewed by any 
blinded study personnel until after database lock of the DB phase. 
This population will be used for the analysis of trough and estimated Cmax concentrations over the DB 
phase. 
Intense PK Subset 
The PK population will consist of a further subset of patients defined as the intense PK subset. 
A subset of 75 patients will be identified (in eCRF) to undergo additional PK sampling on days 8, 15, 
22. This will include approximately 50 patients from the PK population (i.e. those who receive active 
treatment) though the exact number will not be known. The patients will be included in the intense PK 
subset. 
This population will be used for the analysis of non-compartmental PK parameters over the DB phase. 
 
5.11 
PHARMACOGENOMIC POPULATION 
The pharmacogenomic (PGx) population will consist of all patients in the SAF who have a blood 
sample taken for genotyping in the DB phase. 
 
5.12 
MODIFIED PHARMACOGENOMIC POPULATION 
The modified pharmacogenomic (mPGx) population will consist of all patients in the PGx population 
for whom blinding was not compromised (see Section 3.6.3). 
5.13 
OPEN-LABEL POPULATION 
The OLP will consist of all patients who received at least 1 dose of study drug in the OLE phase of the 
study and will be used for presentation of OLE analyses and listings.  Analyses performed on the OLP 
will be as treated, and by DB phase treatment arm / de novo entry at time of the OLE phase (see 
section 6.1). 


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6. 
GENERAL ASPECTS FOR STATISTICAL ANALYSIS 
6.1 
GENERAL METHODS 
Statistical methodology and analyses are in accordance with the principles outlined by the ICH E9 
guidelines.  All statistical analyses will be done using SAS statistical software version 9.3 or higher.  
Tables, listings and figures (TLFs) will be produced in accordance with the principles outlined by the 
International Conference on Harmonization (ICH) E3 guidelines.  For most summary statistics, data 
from the DB phase will be analyzed by the following treatment groups: Placebo, Risperidone ISM 75 
mg, Risperidone ISM 100 mg, and All Risperidone ISM. The treatment groupings to be employed for 
OLE efficacy and safety summaries (excluding adverse events, see Section 11.2) will be as follows in 
respect to DB/OLE treatments:  
1) 
Placebo / Risperidone ISM 75mg 
2) 
Risperidone ISM 75mg / Risperidone ISM 75mg 
3) 
De novo / Risperidone ISM 75mg 
4) 
All / Risperidone ISM 75mg 
5) 
Placebo / Risperidone ISM 100mg 
6) 
Risperidone ISM 100mg / Risperidone ISM 100mg 
7) 
De novo / Risperidone ISM 100mg 
8) 
All / Risperidone ISM 100mg 
9) 
All / Risperidone ISM 
 
All available data for all patients from the relevant analysis population will be presented in the patient 
listings.  Unless stated otherwise, listings will be sorted by treatment group and then patient number. 
Listings showing only data from the DB phase will be sorted by the DB treatment groups only, whilst 
all other listings will be sorted by the DB/OLE combination group (i.e. 1, 2, 3, 5, 6 and 7 from above, 
and Risperidone ISM 75mg / NA or Risperidone ISM 100mg / NA for patients not dosed in the OLE 
phase).   
With regards to HRU, PSP, and SWN-20 endpoints, data will be analyzed for All Risperidone ISM 
doses pooled. The reason for this is (1) HEOR data are not primary endpoints in this study and the 
study is not powered to detect differences between risperidone doses in these endpoints; (2) there is no 
hypothesis stated in the protocol and study design around the higher dose of risperidone having a 
significant influence on HEOR endpoints compared to the lower dose; (3) pooling of the two 
risperidone arms will increase the sample size and therefore the precision around the estimates. This in 
turn will have an influence on finding statistically significant differences in HEOR endpoints 
compared to placebo, i.e. lower p-values; and finally, (4) often HEOR endpoints are even pooled 
between treatment arms (i.e. pooling of risperidone and placebo) for use in economic models when no 
difference is found between the arms. Economic modelling always differentiates the efficacy by 
treatment arm and treatment dose, but once a specific health state is reached (for example a health 


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state based on the PANSS), patients incur the same “utility value” and incur the same type of follow-
up care (i.e. same costs). So, pooling between the two risperidone doses is acceptable. 
In general, summary statistics (n, mean, standard deviation, median, minimum, and maximum values 
for continuous variables, and number and percentage of patients in each defined category for 
categorical variables) will be provided by treatment group for all variables.  Unless otherwise 
specified, the denominator for percentages will be the number of patients in the treatment group. 
Source data for the summary tables and statistical analyses will be presented as patient data listings.   
Scheduled visit assessment data will appear in summary tables and figures.  Unscheduled visit 
assessment data will not be summarized.  Both scheduled and unscheduled visit assessment data will 
appear in the patient listings.  
In the case of multiple or repeat assessments at a scheduled visit, the latest value at the visit will be 
used for summarization and analyses unless otherwise specified.  
No data imputation will be applied for missing values, unless otherwise specified (e.g. HEOR 
endpoints, see Section 8.2.4).  
6.2 
KEY DEFINITIONS 
6.2.1 
DB and OLE Phases 
The terms DB and OLE will be used to represent the item of interest in the DB and OLE phases 
respectively. 
6.2.2 
Stage 1 and Stage 2 
Those patients included in the interim analysis (see section 12) will constitute stage 1 patients with all 
subsequent patients being stage 2 patients for purpose of the primary and key secondary efficacy 
analyses. 
 
6.2.3 
First Dose Date 
Two “first dose dates” will be required – one for the DB phase and one for the OLE phase.  The first 
dose date for the DB phase will be the date that the first dose of randomized, double-blind study 
medication is administered, and the first dose date for the OLE phase will be the date of the first 
administration of Risperidone ISM in the OLE phase. Both first dose dates will be obtained from the 
CRF.   
6.2.4 
Double-Blind Study Day 
Patients will be randomized and the first dose of randomized, double-blind study medication will be 
administered on Day 1.  There is no study day 0.  Study day for event dates prior to the date of the first 
dose will be determined as Study Day = Event Date –DB First Dose Date.  Study day for event dates 


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on or after the date of first dose will be determined as Study Day = Event Date – DB First Dose Date + 
1.  
6.2.5 
Open-Label Extension Study Day 
The first dose of medication in the OLE phase will be administered on OLE day 1. OLE study day for 
event dates during the OLE phase will be determined as OLE Study Day = Event Date – OLE First 
Dose Date + 1. 
6.2.6 
Baseline Values 
Unless otherwise specified, baseline values are the last non-missing measurement or assessment prior 
to the first dose of study medication in each phase. The DB baseline will be used for summaries during 
the DB phase and the OLE baseline will be used for summaries during the OLE phase.   
For rollover patients, OLE baseline is planned to be the same day as day 85 of the DB phase of the 
study; in which case, DB Day 85 assessments will serve as the OLE baseline.  A ± 3 days window for 
OLE day 1 is allowed.  If the OLE baseline visit occurs later than the date of Visit 14 (see Section 3.8, 
Table 1) of the DB phase, all the designated assessments must be repeated. 
6.2.7 
Last Dose Date 
Two “last dose dates” will be required – one for the DB phase and one for the OLE phase.  The last 
dose date for the DB phase will be the date on which a patient takes the last dose of randomized, 
double-blind study medication.  Last dose date for OLE phase will be the date on which a patient takes 
the last dose of the open-label study medication.   
6.2.8 
Duration of Exposure 
Duration of DB treatment will be determined as DB Duration = Last DB Dose Date – First DB Dose 
Date + 28.  Duration of OLE treatment will be determined as OLE Duration = Last OLE Dose Date – 
First OLE Dose Date + 28.  Duration of Risperidone ISM treatment = Date of last administration of 
Risperidone ISM – Date of first administration of Risperidone ISM +1. 
6.2.9 
End of Study 
Two ‘end of study’ dates will be required. The end of DB study is defined as the date of early 
termination or the date of completion of DB treatment through Day 85. The end of OLE phase is 
defined as the date of early termination or the date of completion of OLE treatment through OLE Day 
365. 
6.2.10 Endpoint 
For the DB phase, endpoint is defined as study day 85 or the last post-baseline DB assessment.  For 
the OLE phase, endpoint is defined as study day 365 or the last post-baseline OLE assessment. 


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6.3 
MISSING DATA 
No imputation of missing data will be used unless specified in the subsequent sections.   
6.4 
VISIT WINDOWS 
The screening period is planned for Days -8 to -1, and the randomization is planned for Day 1, Visit 2. 
Visit 4 must occur 3 days immediately after study day 1.  The allowable study visit time windows for 
DB phase study visits occurring after Visit 4 are as follows: 
 
± 1 day for study visit 5,  
 
± 2 days for study visit 14 and  
 
± 3 days for each of the other DB phase study visits (i.e. study visits 6 through 13, inclusive) 
The follow-up telephone visit is to occur 14 (± 3) days after the DB phase end-of-treatment visit (i.e. 
the week 12 time point, or earlier in the case of an early termination) for patients who do not enter the 
OLE phase.  
For rollover patients, the OLE phase day 1 is planned to be the same day and date as Visit 14 of the 
DB phase though a +3-day window for OLE phase day 1, as compared with the Visit 14 of the DB 
phase of the study is allowable.  The allowable study visit time window for each of the subsequent 
visits is ± 3 days.  
For de novo patients, the allowable study visit time window for baseline visit 1 is + 4-day window and 
for each of the subsequent extension visits is ± 3 days (i.e., extension visits 2 through 15, inclusive). 
Nominal visit will be used for all efficacy and visit-wise safety data. No visit mapping will be used.  
For patients withdrawing early, the end of study data (ET visit) will be mapped to the closest planned 
scheduled visit, based on the day of assessmement relative to first dose in the corresponding phase 
(DB or OLE) for summarization and analysis. If the closest planned scheduled visit was actually 
already performed then for efficacy analyses, the result will be mapped to the next scheduled visit (to 
enable inclusion of the endpoint result in the MMRM analyses), whilst for safety analyses the result 
will not be mapped to a scheduled visit (although this result will be used in end of treatment 
summaries).  
6.5 
POOLING OF CENTERS 
The randomization used in this study is stratified by country. Patients will not be pooled based on 
center size, but rather by country, to ensure a sufficient number of patients per treatment arm per 
country in both ITT and PP populations for analysis stratified by country.   
6.6 
SUBGROUPS 
The primary and key secondary efficacy analysis will be repeated to assess the treatment differences 
within country and baseline PANSS total score (≥ 95 versus < 95). 


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There will be an exploratory evaluation of genotypes for cytochrome P450 enzymes and/or genes 
considered potentially related to response and the correlation with primary efficacy, key secondary 
efficacy and PK outcomes (see Section 10).   


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7. 
DEMOGRAPHIC, OTHER BASELINE CHARACTERISTICS AND MEDICATION 
7.1 
PATIENT DISPOSITION AND WITHDRAWALS 
A disposition table will presented by treatment group and overall, the number and/or percentage of 
patients who signed the informed consent and entered the study (i.e. were screened, screen failed, and 
randomized), completed the study with post-baseline efficacy assessments, and withdrew early from 
the study after randomization. The reasons for early withdrawal after randomization and the duration 
until completion or withdrawal from the double blind phase will be summarized.  A separate table will 
display the number of patients who were not randomized with a summary of the reasons for non-
randomization. Similar tables will be repeated for the OLE phase (including whether the patient was a 
rollover or de novo patient). 
Assignment to the analysis populations (SAF, mSAF, ITT, mITT, PP, mPP, PK, and OLP [rollovers 
only]) will be summarized for the Randomized population. The assignment to the OLP in terms of 
rollover / de novo patients will be summarized. A listing will be provided for patient disposition 
including all patients that are either in the Randomized population or are a de novo patient. 
A CONSORT figure showing all patient disposition during the study will be provided in the CSR. 
All protocol deviations will be listed and important protocol deviations will be summarized by 
category and whether they lead to exclusion from the PP or PK population. 
7.2 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS 
Demographic and personal characteristics will be summarized by treatment group and overall.  Sex, 
race, ethnicity, country, age (years), height (cm), weight (kg) and body mass index (BMI, kg/m2). BMI 
(kg/m2) is calculated as BMI = 1002 x Weight (kg)/ [Height (cm) 2].  
Age will be calculated as the number of complete years between the date of birth and the informed 
consent date. For the OLE phase summary, age will be derived using the respective date of informed 
consent for that phase. 
Demographic and baseline characteristics will be summarized for the SAF, ITT, mITT, PP, mPP, PK, 
Intense PK subset and OLP populations and listed. The details of diagnosis of schizophrenia will be 
summarised (years since diagnosis and weeks since Acute Exacerbation or relapse) and listed. 
Socio-demographic data will be displayed as per Section 8.2.4.8.   
7.3 
MEDICAL, SURGICAL AND PSYCHIATRIC HISTORY 
Medical, surgical and psychiatric history will be collected. Each condition will be recorded along with 
verbatim term, date of onset, date resolved, and a checkbox that indicates ongoing conditions.  
Medical, surgical and psychiatric history and concomitant diseases will be coded using the most up to 
date version of MedDRA at the time of data analysis. 


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Medical, surgical and psychiatric history and concomitant diseases will be summarized for the safety 
population by treatment group, system organ class, and MedDRA preferred term, overall and by 
country. The SOC and preferred terms will be displayed in alphabetical order and patients will be 
counted only once for each SOC and preferred term.  
7.4 
MEDICATION 
Medications (off-treatment and concomitant) will be coded based on the most up to date version of 
World Health Organization (WHO) Drug dictionary and Anatomical Therapeutic Chemical (ATC) 
codes at the time of data analysis; the version number will be given in a footnote to the applicable 
displays.   
Medication summaries based on ATC classes 1 and 3 and the preferred term will be produced for the 
Safety Population.  Summaries will present the frequency and percentage of patients who used any 
medication in an ATC classes 1 and 3, or any medication based on a single preferred term, by 
treatment group. Medications will be sorted alphabetically and patients will be counted only once for 
each distinct medication class and preferred term.  
For patient listings, medications will be reported based on ATC classes 1 and 3 and preferred term; 
multiple medications for an individual patient will be listed by start date and then by stop date, from 
earliest to latest medications. 
Concomitant medications and medications taken whilst off-treatment will be presented together in a 
single listing and flagged to identify the classification. Off-treatment medications will be presented 
separately from concomitant medications in summary tables.   
7.4.1 
Off-Treatment Medication 
A medication will be classed as off-treatment if either 1) it has a confirmed stop date prior or equal to 
the first dose date of study drug in the study or 2) a start date equal to or after the day of treatment 
discontinuation in the study. In the case of a partial stop date, missing day will be considered as the 
last day of the month, missing month will be considered as December, and missing month and day will 
be considered as December 31st. In the case of a partial start date, missing day will be considered as 
the first day of the month, missing month will be considered as January, and missing month and day 
will be considered as January 1st. 
7.4.2 
Concomitant Medication 
A medication will be classed as concomitant during the DB/OLE phase if 1) it had a confirmed stop 
date after the first dose date of study drug in the DB/OLE phase or a missing stop date and 2) the start 
date was prior to the day of treatment discontinuation in the DB/OLE phase   
In the case of a partial stop date, missing day will be considered as the last day of the month, missing 
month will be considered as December, and missing month and day will be considered as December 


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31st. In the case of a partial start date, missing day will be considered as the first day of the month, 
missing month will be considered as January, and missing month and day will be considered as 
January 1st. 
 


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8. 
EFFICACY 
Efficacy variables from the double-blind part of the study will be summarized by treatment group for 
the mITT, ITT and PP populations using descriptive statistics. The analyses of primary and key 
secondary endpoints will also be provided for the mPP population. Although any confirmatory 
findings related to efficacy must be substantiated in both the mITT and ITT populations (see sections 
8.1.1 and 8.2.1), the mITT will be used as the primary population to describe efficacy results in the 
CSR.   
Efficacy variables from the OLE phase of the study will be summarized similarly for the OLP, as 
applicable, for descriptive purposes.  
All efficacy assessments will be listed. 
With regard to efficacy variables that refer to endpoint, to account for post-baseline endpoints 
occurring before study day 85 (i.e. at the time when the last post-baseline double-blind assessment was 
performed) a mixed model for repeated measurements (MMRM) using an unstructured covariance 
matrix approach will be used as the primary method and the estimates from the model at day 85 will 
be used for the primary efficacy analysis.  It is assumed that a majority of the missing values will be 
the following 
 
“Missing Completely At Random”, i.e., probability of an observation being missing does not 
depend on observed or unobserved measurements. or 
 
 “Missing At Random”, i.e. probability of an observation being missing depends only on observed 
measurements. 
In such situations, likelihood-base methods like MMRM are appropriate (EMA, 20104), and already 
were use previously as per Kane et al (2014)5 and Nasser et al (2016)6.  
8.1 
PRIMARY EFFICACY VARIABLES AND ANALYSIS 
The primary efficacy variable is PANSS total score mean change from baseline to endpoint. The 
PANSS will be performed at screening, DB phase study days 1 (pre-dose), 4, 8, 15, 29, 57, and 85 and 
OLE phase study days 1, 29, 57, 85, 113, 141, 169, 197, 225, 253, 281, 309, 337, and 365.  
The PANSS is a well-known and validated rating scale used in numerous drug evaluation trials. This 
30-item scale provides a total score (sum of the scores of all 30 items) and scores for 3 subscales. The 
subscales include the positive subscale (7 items), negative subscale (7 items), and general 
psychopathology subscale (16 items). The severity of each of the 30 items of the PANSS is rated on a 
scale of 1 (absent) to 7 (extreme). Higher scores represent greater symptom severity. The maximum 
total score equals 210 and the total minimum score equals 30, when all items are completed.  
If a patient has a PANSS assessment recorded, but any of the 30 items are missing, the last nonmissing 
score for the respective item from previous assessments will be carried forward. If the total or subscale 


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score has > 30% of the items missing at a particular visit, the respective total or subscale score at the 
visit will not be calculated and will be treated as missing data in the analysis. 
  
8.1.1 
Primary Efficacy Analyses 
The primary efficacy analysis is designed to show superiority of active treatment versus placebo in the 
PANSS total score mean change from baseline to endpoint.   
Two hypotheses will be tested: 
a. 
H0,A: µRisperidone 75 mg  - µplacebo = 0 vs H1,A: µRisperidone 75 mg  - µplacebo ≠ 0 
b. H0,B: µRisperidone 100 mg - µplacebo = 0 vs H0,B: µRisperidone 100 mg - µplacebo ≠ 0   
with µ = PANSS total score mean change from baseline for the identified treatment group.  
An MMRM will be fitted for patients in the mITT population with country where enrolled, visit, 
treatment, and treatment-by visit interaction as fixed effects and baseline PANSS total score as a 
covariate. This model will be applied separately for patients in stage 1 and stage 2 of the study (see 
Section 12) as well as overall patients. The treatment differences from the model at study day 85 will 
be evaluated to test the hypotheses above, maintaining a 2-sided type 1 error rate of 5%. Model results 
from each stage and overall will be presented. 
In order to maintain the type 1 error rate for the primary efficacy analysis, each hypothesis will be 
tested using a weighted test statistic in accordance with Cui, Hung, Wang7 (CHW) methodology which 
comprises of combining the z-statistics from the respective study day 85 treatment comparison at each 
stage. The weighting will be equal for each stage and pre-defined as sqrt (0.5) such that: 
ZCHW = 
 
where zn is the cumulative normal density function for the two-sided p-value divided by 2 (i.e. one-
sided p-value) from the study day 85 treatment comparison at stage n,  n=1 and n=2. 
The nominal 2-sided p-value for each hypothesis will be calculated for the respective weighted CHW 
statistic using the cumulative normal distribution.  
Point estimates and 95% CI will be obtained using methodology suggested by Hung and Lawrence8: 
 
Point estimate: 
 
where  
t1 = 0.5 


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t* = (Re-estimated sample size per group for analysis)/124 
 
 
95% CI: 
 
 
To account for multiplicity of testing and to keep the type 1 error rate at 5%, the Hommel’s closed 
testing correction procedure9 as implemented in SAS software (PROC MULTTEST) will be used to 
provide adjusted p-values to assess for superiority of either dose.  
For the MMRM, an unstructured covariance structure shared across treatment groups will be used to 
model the within-patient errors and the Kenward-Rogers10 correction to degrees of freedom will be 
applied.  Model assumptions will be checked.  
In case of difficulties with initially fitting this unstructured (UN) covariance matrix, the following 
approaches will be undertaken to improve chances of convergence with the UN structure:  1) 
Covariance matrix estimated from empty model with no covariance will feed into the full model as the 
initial values; 2) Fisher scoring will be used to begin the iterative fitting (by specifying a SCORING=5 
option in the PROC MIXED statement); 3) initial values for the covariance parameters will be 
specified based on covariance estimates from a simpler covariance structure. For the last approach, the 
simpler covariance structure will be compound symmetry (TYPE=CS option in the REPEATED 
statement) and the corresponding estimates of the covariance parameters will be captured in the ODS 
Output dataset CovParms from PROC MIXED. These estimates will then be passed as the initial 
values for the estimation of the UN structure using the PARMS statement in PROC MIXED. In the 
event the convergence cannot be attained with these approaches, the following alternative structures 
will be attempted in the specified order: heterogeneous Toeplitz structure (TOEPH), heterogeneous 
autoregressive(1) (ARH(1)), heterogeneous compound symmetry (CSH), No Diagonal Factor Analytic 
(FA0(q), with q equal to the number of time points), Toeplitz structure (TOEP), autoregressive(1) 
(AR(1)), and compound symmetry (CS). If either ARH(1) or AR(1) structure is used, a random patient 
intercept will also be included in the model (using RANDOM INT statement in PROC MIXED). 


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Sample SAS code for MMRM analysis: 
proc mixed data=all3 covtest; 
title1 “MMRM with PANSS” 
    class country trt visit subjid ; 
    model panss = country trt visit trt*visit baseline / s chisq ddfm=kr;              
    repeated visit / type=un subject=subjid r;  
    lsmeans trt*visit / cl diff; 
run;  
 
Sample SAS code to compute Hommel’s adjusted p-value: 
proc multtest inpvalues=xx hommel; 
run; 
 
The results from the MMRM using all patients will be presented with least squares means and 
differences between active and placebo least squares means (with 95% confidence intervals (CI) and 
p-value) for each timepoint. The Day 85 contrast will include the CHW adjusted p-values for each 
comparison (and Lawrence-Hung estimate for the treatment differences with 95% CIs) and the 
Hommel adjusted p-values for each comparison (to assess superiority). 
The results from the MMRM for each stage will also be presented separately with least squares means 
and differences between active and placebo least squares means (with 95% confidence intervals (CI) 
and p-value) for each timepoint. 
Descriptive statistics of the absolute values and change from baseline (n, mean, median, standard 
deviation, minimum, and maximum) will be reported by treatment group and visit.  
All analyses described above will be repeated for the ITT population. However, to account for extra 43 
patients included in Stage 1, the CHW statistic will be derived as: 
ZCHW = 
 
and in the Hung and Lawrence calculations: 
t1 = 0.55 
t* = (Re-estimated sample size per group for mITT analysis + 14)/138 
Confirmatory findings from the Hommel adjusted CHW analyses will only remain so for a particular 
dose if p<0.05 in both the mITT and ITT analyses. 
All analyses described above for the ITT and mITT population will also be repeated for the PP and 
mPP population respectively. 
The descriptive statistics summary will be presented for each country and by the baseline PANSS total 
score (< 95 v ≥ 95) for both the mITT and ITT population. In addition, the MMRM (without CHW or 


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Hommel adjustments) will be repeated in the mITT and ITT population incorporating all main effects 
and interactions between treatment, visit and the subgroup (i.e. country or baseline PANSS total score 
[< 95 v ≥ 95]) in order to explore the treatment differences within subgroups. The model assessing 
treatment differences within the baseline PANSS total score (< 95 v ≥ 95) will have the continuous 
baseline PANSS covariate removed. 
The LS means and standard errors of the change from baseline over time from the MMRM including 
all patients will be presented graphically both overall (from the primary analysis) and by the baseline 
PANSS total score (< 95 v ≥ 95) (from the interaction models).   
8.1.2 
Sensitivity Analyses 
Sensitivity analyses will include: 
 
Analysis of PANSS total score mean change from baseline to endpoint, in the mITT 
population using observed cases (OC) only (i.e. when the last post-baseline double-blind 
assessment was performed). For this analysis, change from baseline at endpoint will be 
analyzed using an Analysis of Covariance (ANCOVA) model with country where enrolled 
and treatment as fixed effects and baseline PANSS total score as a covariate.  
 
Analysis of the PANSS total score mean change from baseline to day 85, in the modified 
randomized population using an ANCOVA model with country where enrolled and treatment 
as fixed effects and baseline PANSS total score as a covariate. Missing data from patients with 
the last post-baseline double-blind assessment performed prior to day 85 (or no post-baseline 
double-blind assessment) will be imputed using a standard multiple imputation (MI) analysis.  
Imputed data for the PANSS total score in each step will always be rounded to the nearest 
integer corresponding to a possible PANSS total score (i.e. 30 to 210). Data will be imputed in 
the framework of a pattern mixture model (PMM) for missing visits, following a general 
three-step approach as outlined below (Ratitch B and O’Kelly M, 201111): 
1. 
Non-monotone (intermediate visits) missing data will be imputed first using the Monte 
Carlo Markov Chain method under the Missing at Random (MAR) assumption in all 
treatment arms (using the MCMC statement in PROC MI). Multiple chains option 
(CHAIN=MULTIPLE option in the MCMC statement of PROC MI) will be used. For 
the non-monotone imputation of the PANSS missing data, a multivariate normal model 
will be used including variables for the PANSS at baseline and all post-baseline visits 
within each treatment group and the randomization stratification variables (country 
where enrolled, as well as PANSS total score [ie, ≥ 95 versus < 95] at 
baseline/randomization). One hundred imputations will be generated. 
2. 
After the non-monotone missing data have been imputed, the remaining monotone 
missing data will be imputed under the Missing Not at Random (MNAR) assumption that 


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patients who withdraw from the Risperidone ISM treatment groups (75 mg and 100 mg) 
will have correlations with future (post-withdrawal) visits similar to patients in the 
placebo group, adjusted for baseline covariates and observed outcomes prior to 
withdrawal. Monotone missing data of withdrawn patients from the placebo group will 
be imputed under the MAR assumption and will follow the pattern of placebo 
completers. In other words, monotone missing values of the PANSS will be imputed for 
all patients who withdrew from the study (regardless of treatment group) using an 
imputation model at each time point estimated from patients with available data in the 
placebo group only. A regression imputation model for the PANSS at each time point 
will include the stratification factors at randomization and PANSS at all previous time 
points, including baseline.  The input dataset will include all placebo patients and only 
those patients from Risperidone ISM groups that have values at that time point missing. 
Imputations will be performed using a sequence of regression-based imputations (using 
PROC MI statement MONOTONE REG) for each post-baseline time point suggested by 
Ratitch B and O’Kelly M, 201111.  
3. 
Imputed data in each of the multiple imputed datasets will be analyzed using an 
ANCOVA model. The model will include country where enrolled and treatment as fixed 
effects and baseline PANSS score as a covariate. The results from all imputed datasets 
will be combined using the Rubin’s combination rule (PROC MIANALYZE).  
The sensitivity analyses described above will employ the same CHW and Hommel adjustments and 
results will be presented both by stage (Stage 1 and 2) and with both stages combined. Each analysis 
will also be repeated for the ITT (randomized for MI analysis), PP and mPP population. The weighting 
for the CHW and Hung and Lawrence calculations for the modified populations will be the same as 
the mITT, whilst the non-modified poulations will be the same as the ITT population. 
8.2 
SECONDARY EFFICACY VARIABLES AND ANALYSES 
8.2.1 
Key Secondary Efficacy Variable Analyses  
The key secondary variable is mean change from baseline to endpoint in CGI-S during the DB phase. 
The CGI-S will be performed at Screening, DB phase study days 1 (pre-dose), 4, 8, 15, 29, 57, 85 and 
OLE phase study days 1, 29, 57, 85, 113, 141, 169, 197, 225, 253, 281, 309, 337, and 365.   
The CGI-S severity of illness scale requires the clinician to rate the severity of illness on a 7-point 
ordinal scale (0=Not assessed, 1= Normal, not at all ill; 2=Borderline mentally ill; 3=Mildly ill; 
4=Moderately ill; 5=Markedly ill; 6=Severely ill; 7=Among the most extremely ill patients).  
Similar analyses and summary as for the primary efficacy variable will be performed.   


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As per the primary efficacy analysis, the CGI-S will be analyzed taking the interim assessment into 
account by using CHW methodology and the multiplicity of testing into account using Hommel’s 
closed-testing correction procedure as implemented in SAS (PROC MULTTEST).  
CGI-S will be analyzed using hierarchical ordering such that if, and only if, the primary efficacy 
analysis shows the superiority of both doses of Risperidone ISM treatment versus the IM placebo 
treatment at day 85 in both the mITT and ITT, then the confirmatory testing will be performed 
sequentially on the mITT and ITT population with regard to the key secondary efficacy variable at day 
85. In similar fashion to the primary efficacy variable, only the testing of these hypotheses for the key 
secondary efficacy variable from the MMRM (with CHW and Hommel adjustments) will provide 
confirmatory evidence of efficacy (if proven in both mITT and ITT populations) with all other 
analyses providing exploratory or supporting evidence only.  
OC and MI will be conducted as sensitivity analyses and all analyses will be repeated for the ITT, PP 
and mPP populations in a similar fashion to the primary efficacy variable. 
Descriptive statistics of the absolute values and change from baseline (n, mean, median, standard 
deviation, minimum, and maximum) and the distribution across categories will be reported by 
treatment group and visit.  
8.2.2 
Other Secondary Efficacy Variables Analyses 
Other secondary efficacy variables will be summarized and tested in the mITT, ITT and PP 
populations.  The nominal p-values without adjustment for interim assessment or multiple 
comparisons will be used and they will only be considered as exploratory analysis.   
8.2.2.1 CGI-I score at each post-baseline assessment and endpoint 
The CGI-I will be performed at DB phase study days 4, 8, 15, 29, 43, 57, 71, 85 and OLE phase study 
days 29, 57, 85, 113, 141, 169, 197, 225, 253, 281, 309, 337, and 365.   
The CGI-I global improvement scale requires the clinician to assess how much the patient's illness has 
improved or worsened relative to a baseline state at the beginning of the intervention. The clinician 
rates the degree of change observed on a 7-point ordinal scale (1= Very much improved; 2= Much 
improved; 3= Minimally improved; 4= No change; 5= Minimally worse; 6= Much worse; or 7= Very 
much worse). This CGI degree of change scores will be dichotomized into 2 categories, Improved and 
Not Improved, with scores of 1 (very much improved) and 2 (much improved) in the Improved 
category and scores of 3 (minimally improved) to 7 (very much worse) in the Not Improved category.   
Descriptive statistics of the absolute values and change from baseline (n, mean, median, standard 
deviation, minimum, and maximum) and the distribution across categories will be reported by 
treatment group and visit.  


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Analysis will be conducted using the MMRM model in Section 8.1.1 as a template.  The fixed effects 
will include country where enrolled, visit, treatment, and treatment-by-visit interaction and baseline 
CGI-S score will be used as a covariate.  
8.2.2.2 Overall and PANSS Response Rate 
PANSS response is defined as PANSS total score ≥ 30% decrease (improvement of symptoms) from 
baseline. 
The overall response is defined as satisfying either criterion below: 
 
Response on PANSS or 
 
CGI-I score of 2 (much improved) or 1 (very much improved) 
The response rate at each visit will be presented twice using differing approaches for a patient that has 
withdrawn early from treatment: 1) will be considered as a non-responder at all time points following 
early withdrawal, 2) will be excluded from the analysis at all relevant time points following early 
withdrawal. 
The overall and PANSS response will be presented by treatment for each visit and at endpoint using 
frequency of responses, rate in percentage, along with the exact (Clopper-Pearson) 95% confidence 
limits. Pairwise comparisons of each dose level of Risperidone ISM to placebo will be conducted 
using a Mantel-Haenzel test stratified by country where enrolled and baseline PANSS total score [≥ 95 
or < 95]. The 95% stratified Newcombe CIs will also be presented. 
8.2.2.3 Time to Reach Overall or PANSS Response 
Time to reach overall or PANSS response will be presented by cumulative frequencies and 
percentages of patients achieving a response up to each assessment for both DB and OLE phases 
separately.  The median and 95% confidence limits for median will be estimated using Kaplan-Meier 
method.  Kaplan-Meier plots will be presented by treatment group. If the patient does not achieve a 
response, the time of response will be censored at the date of treatment discontinuation in the DB 
phase. A log-rank test between the treatment groups will be performed, adjusted on the stratification 
factors at randomization. 
8.2.2.4 PANSS subscale score mean change from baseline at endpoint and at each post-baseline 
assessment time point 
The PANSS subscales include the positive subscale (7 items; range 7 - 49), negative subscale (7 items; 
range 7 - 49), and general psychopathology subscale (16 items; range 16 -112).  Descriptive statistics 
of the subscale scores and change from baseline (n, mean, median, standard deviation, minimum, and 
maximum) will be presented. 


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Analysis will be conducted using the MMRM model in Section 8.1.1 as a template.  The fixed effect 
will include country where enrolled, visit, treatment, and treatment-by-visit interaction and appropriate 
baseline score will be used as a covariate.  
8.2.3 
Efficacy Variables Analyses in the Open-Label Extension Phase of the Study 
Efficacy scales PANSS, CGI-S are collected at baseline and all efficacy scales (PANSS, CGI-S, and 
CGI-I) are collected at all post-baseline time point during the OLE phase. All efficacy analyses in the 
OLE phase of the study will use the OLP.   
Efficacy variables PANSS, PANSS subscale scores, CGI-I, CGI-S, Overall response, PANSS response 
in the OLE phase of the study will be summarized and listed similarly as in the DB phase of the study, 
although none of the formal testing between treatment groups will be conducted.   
Relapse in the OLE phase is defined as either a PANSS total score increase of  ≥ 30% from baseline, 
re-hospitalization for psychotic symptoms or use of adjunctive antipsychotic medication after 
stabilization.  
Remitters in the OLE phase are defined as the simultaneous attainment of a score of ≤ 3 for 6 months 
or more on 8 main items of the PANSS (delusions, conceptual disorganization, hallucinations, blunted 
affect, passive apathetic social withdrawal, lack of spontaneity and flow of conversations, mannerisms 
and posturing, unusual thought content). 
Relapse and remitters will be analyzed two ways: by rate during the OLE phase and by time to relapse 
or remittance.  Similar summary statistics will be provided as for overall response and time to reach 
overall response (including Kaplan Meier methods) in DB phase.   
The frequency of responses and percentage rate for patients with the following during the OLE 
phasewill be presented:  
- PANSS total score increase of  ≥ 30% from baseline 
- Re-hospitalization for psychotic symptoms 
- Use of adjunctive antipsychotic medication after stabilization 
Time to discontinuation will be summarized by n, mean, standard deviation, median, and 95% 
confidence limits for median estimated from Kaplan-Meier method.  They will be displayed 
graphically by treatment group. 


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8.2.4 
Health Economics and Outcomes Research (HEOR) Variables Analyses 
8.2.4.1 General comments 
All HEOR data will be used and analyzed by ITT – no patients or measurements will be discarded 
from the analysis. The analysis will include all data from the start of the study until the end of the 
study. 
All analyses are exploratory in nature and not hypothesis driven, therefore no adjustment will be made 
to the threshold of significant value for multiple testing.  
Additionally, the analyses will document missing data for select outcomes as a proportion of all 
responses collected, and the analysis method will take incomplete data (i.e., partially completed 
instruments) into account. 
8.2.4.2 Exploration of missing data 
It is expected there will be some missing data due to missed visits, non-completion of HRU and SWN-
20 and PSP forms, loss to follow-up and due to the patient being in an exacerbation and unable to 
complete the instruments.  Missing data can impact on the validity of the analysis, especially if  
(1) the missingness is related to the occurrence of an exacerbation (= not missing at random): in 
this case missingness will lead to an under-estimation of resources and also to a missed ‘drop’ 
in the SWN-20 and PSP instruments which will affect the estimated impact of an exacerbation 
in terms of costs and quality of life. 
AND 
(2) the frequency of exacerbations is treatment-related: when comparing total costs and quality of 
life between treatments the estimated difference between treatments will be smaller than the 
true difference, with fewer statistically significant results found between arms. 
The number of patients in the study at each visit will be summarized. Similarly, completeness of HRU 
and SWN-20 and PSP data will be summarized by visit, as the number of patients with responses at 
each visit. We will also estimate the total follow-up time of each patient in the study: overall and by 
treatment phase. 
Furthermore, the relationship between the missingness in resource use and SWN-20 and PSP 
instruments and the occurrence of a relapse will be investigated, in order to assess whether the data are 
missing at random or not. For this particular assessment, the focus will be on fully missed visits only 
(i.e. all of the HRU items reported by the patient or all of the SWN-20 or PSP items for a visit are 
missing). This will be done with a logistic regression, with missingness as a dependent variable, and 
exacerbation as an independent variable, as well as treatment arm, age, gender, education, living 
situation and employment indicators. 


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Regarding missing data in resource utilization: When analyzing cost data particular attention needs 
to be given to the fact that total costs are composed of many individual cost items, each with their 
variation and with a different pattern of missing data. When analyzing the sum of these costs it is 
important to acknowledge that not imputing missing items in this total cost will result in under-
estimation. Therefore, the amount and the pattern of missing data for each item need to be investigated 
and an imputation procedure needs to be selected that will result in correct estimation of the missing 
values. This relates only to the case where a few items for an assessment time point are missing; in 
case all HRU items reported by the patient are missing for a particular time point then no imputation 
will take place for that time point. 
Regarding SWN-20 and PSP instruments: The impact on analysis of  a missing item in a 
questionnaire (incompletion) will be different from missing a visit  (missed assessment). A missing 
observation at the item level still allows the other items and domain scores to be documented. A 
missing observation at the patient level implies that none of the questions and domains was scored. No 
imputation is planned for SWN-20 and PSP instruments. Changes from baseline and distribution of 
patients across levels of the SWN-20 and the PSP will be calculated based on available data only. 
8.2.4.3 Healthcare Resource Utilization (HRU) 
Healthcare Resource Utilization data will be collected in two ways: site-based reporting and patient- 
(or proxy/caregiver)-based reporting.  
Study site staff will retrospectively record any HRU that occurred within the clinical trial center into 
the applicable forms of the eCRF. Detailed resource use will be collected in the categories detailed in 
Section 4.4. During the DB phase, clinician-reported data will be recorded once at the end of that 
phase (at 12 weeks). During the OLE phase, data will be recorded every six months for a total of two 
measurement points (at weeks 36 and 60 counted from the start of the study). 
Study site staff will administer a survey to patients (or their proxy/caregiver) to report any HRU that 
occurred outside the clinical trial center. The patient survey will be administered at the clinical trial 
site by designated study site staff. Detailed resource use will be collected in the categories detailed in 
Section 4.4. During the DB phase, patient (or proxy/caregiver)-reported data will be administered 
every month for a total of three measurement points (weeks 4, 8 and 12). During the OLE phase, the 
survey will be administered every three months for a total of four measurement points (weeks 12, 24, 
36 and 48 counted from the start of the study). 
The number of days missed from work will be recorded at the end of the DB phase and at the end of 
the OLE phase. The data will be summarized by treatment group. 
Clinician-reported HRU (within the participating site) and patient (or proxy/caregiver)-reported HRU 
(outside the center) will be cross-validated and combined for analysis. 


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The patients are hospitalized at the start of the study for at least 2 days after which they can be 
discharged at the discretion of the treating specialist. It may be possible that patients on Risperidone 
ISM have a different length of hospitalization than placebo patients; therefore, this resource use, 
although protocol-driven, will also be included in the analysis and added to the total health care 
utilization. 
Depending on the amount of missing data, missing values for time points where some categories of 
resources are missing may be imputed. When all data are missing for a time point; however, no 
imputation will take place. Reliable imputation is only possible, if a distinction was made during the 
data collection phase between a missing value (i.e., we do not know whether the patients used a 
category of resources) and a zero value (i.e., we know the patient did not use this category). 
Otherwise, the resources will be over-estimated due to the imputation process. It is therefore important 
at data collection to distinguish, to the extent possible, between “0” and “missing”. 
For each resource category and each time period, the non-zero missing data will be imputed. Data will 
be imputed using the Fully Conditional Specification procedure. This imputation method for missing 
data uses a regression approach to provide an estimate for the missing value on a specific item of 
resources. The missing value for each category of resources will be predicted using the patient’s health 
state (based on PANSS) and his use of other categories of medical resources use data, plus a random 
term.  
Data will be analyzed by the following treatment groups: Placebo and all Risperidone ISM.  The steps 
and objectives of the HRU analysis are the following: 
1. Describe the types and amounts of resources used by patients per study Phase (DB phase 
versus OLE phase) expressed as a rate per 3 months  
2. Report indirect costs (days absent from work due to illness) per study Phase 
3. Test for differences in resource utilization between treatment groups  
 
For each resource use item separately 
4. Calculate total costs for each Phase of the study (DB phase and OLE phase) and generate 
confidence intervals 
 
For each resource use item separately 
 
By resource use category (e.g. inpatient hospital services, outpatient services, drugs) 
 
For all resources combined (i.e. total medical costs) 
5. Test for differences in total costs between treatment arms 


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8.2.4.4 Statistical analysis of healthcare resource utilization 
Combining resource use: 
Results for each HRU variable will be summarized by treatment group for the ITT populations using 
descriptive statistics, including 95% confidence interval.  
Clinician-reported and patient (or proxy/caregiver-) reported HRU will be combined for analysis. For 
each individual item of resources, total quantity used will be calculated as the sum of resources both 
within and outside the participating center during the DB and OLE phases, respectively. Patient’s 
exposure time will be calculated and a “rate of use per 3 months” will be computed for all types of 
resources, per patient. This rate will then be averaged across all patients per treatment arm. A general 
linear model with the rate as dependent variable, treatment as independent variable and a log link and 
gamma distribution will be estimated to test for differences between treatment arms. 
The reason for choosing a rate as the “unit of measurement” for reporting resource utilization and 
testing for differences between groups is that (1) resources are measured at different intervals during 
the study: the physician is reporting HRU at 3 months whereas patients are reporting HRU on a 
monthly basis in the DB phase. In the OLE phase, the physician is reporting HRU every 6 months and 
the patient every 3 months. The resources reported for the longer units of time cannot reliably be 
distributed over the shorter periods. (2) In addition, some patients will have missed visits and therefore 
the observation time will be different for each patient. The analysis needs to take into account that 
longer observation times inevitably imply accumulation of more resources, and not taking observation 
time into account would bias against treatments that keep patients longer in the study (longer follow-
up time and fewer drop-outs). Reporting resources in 3-monthly rates remediates both problems: it 
rescales all resources to the same time period and it divides total resources by the total patient-years of 
follow-up which takes the length of observation into account. 
Calculating total costs: 
For the comparison of Total Costs, patient-level all resource counts will be multiplied with their unit 
cost, summed up and then divided by the patient’s exposure time to obtain a total cost per 3 months. 
The average cost per 3 months by treatment arm will be calculated and non-parametric confidence 
intervals around the mean cost per treatment arm will be generated using bootstrapping. Bootstrapping 
is the suitable method for generating non-symmetrical confidence intervals around total costs, this 
variable taking only non-negative values and being highly skewed to the right.  
Statistical comparison between groups will be done with a general linear model with a log link and 
gamma distribution, where “total cost per patient per 3 months” is the dependent variable, and 
treatment allocation the independent variable.  
Analysis by country: 


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Analyses by country may be considered in light of potential country clustering due to differences in 
disease management patterns. Country will be included as a covariate in the regression analysis when 
testing for differences in the rate of resource use. 
8.2.4.5 Social Functioning  
Social functioning will be assessed by the clinician-administered Personal and Social Performance 
Scale (PSP). The PSP will be evaluated at time points: at the DB phase study days 1, 29, 57, 85 and 
OLE phase study days 1, 85, 365. 
The PSP score (Morosini 20002) is a 100-point single-item rating scale, subdivided into 10 equal 
intervals. The ratings are based mainly on the assessment of patient’s functioning in four main areas: 
1) socially useful activities; 2) personal and social relationships; 3) self-care; and 4) disturbing and 
aggressive behaviors. Operational criteria to rate the levels of disabilities have been defined for the 
above-mentioned areas.   
The steps for analysis of the PSP are as follows: 
1. Describe the distribution of patients at baseline across the items and domains of the PSP, 
provide baseline summary scores 
2. Describe changes from baseline in PSP at each post-baseline assessment time point: describe 
the distribution of patients across the levels of PSP, as well as the summary scores over time 
3. Test for difference between treatment arms in the total scores of the PSP at each time point 
jointly 
Analyses of the PSP scale will be according to instrument-specific guidance, as specified by the 
licensing agencies. Domain scores and total scores will be calculated for each assessment point. For 
the PSP the scoring is as follows:  
 
Family and social functioning: Absent, Mild, Manifest, Marked, Severe, Very Severe 
 
Self-care: Absent, Mild, Manifest, Marked, Severe, Very Severe 
 
Work and socially useful activities: Absent, Mild, Manifest, Marked, Severe, Very Severe 
 
Disturbing and aggressive behaviours: Absent, Mild, Manifest, Marked, Severe, Very Severe 
 
Overall score: ranges from 0 to 100, where scores from 0-30 reflect a poorly functioning 
patient requiring intensive support or supervision, scores from 31-70 reflect varying degrees 
of disability, and scores from 71-100 reflect only mild difficulties 
8.2.4.6 Health-related Quality of Life (HRQL) 
Health-related Quality of Life will be assessed by the patient-completed Subjective Well-being Under 
Neuroleptics – Short Form (SWN-20).  Within the SWN-20 the patient is asked to rate well-being 
items that have been identified as related to antipsychotic treatment on a 6-point scale ranging from 


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“Not at all” to “Very much.” The SWN-20 is scored on a scale ranging from 20 to 120, with higher 
scores indicating better HRQL.  
The SWN-20 contains five 4-item sub-scales: mental functioning, self-control, emotional regulation, 
physical functioning, and social integration. Each sub-scale score ranges from 4 to 24, with higher 
scores indicating better HRQL. The SWN-20 will be performed at scheduled time points throughout 
the treatment period as indicated in Table 1. 
The baseline administration of the SWN-20 should occur prior to the administration of the medication 
dose on Study Day 1 of the DB phase. 
The steps for analysis of the SWN-20 are as follows: 
1. Describe the distribution of patients at baseline across the items and domains of the SWN-20, 
provide baseline summary scores 
2. Describe changes from baseline in SWN-20 at each post-baseline assessment time point: 
describe the distribution of patients across the levels of SWN-20, as well as the summary 
scores over time 
3. Test for difference between treatment arms in the total scores of the SWN-20 at each time 
point jointly 
Analyses of the SWN-20 data will be according to instrument-specific guidance, as specified by the 
licensing agencies. Domain scores and total scores will be calculated for each assessment point. For 
the SWN-20 the domain scores are calculated as follows: Rating categories scores for items with a ` + 
': not at all (1), a little (2), somewhat (3), noticeable (4), much (5), very much (6); for items with a `-' 
scores have to be reversed, i.e. 6 =1, 5 =2, 4 =3, 3 =4, 2 =5, 1 =6.  
Subscales: combining the following items:  
 
Mental functioning: 3 (+), 7 (+), 11 (-), 17 (-)  
 
Self-control: 15 (+), 19 (+), 1 (-), 12 (-)  
 
Emotional regulation: 18 (+), 20 (+), 4 (-), 10 (-)  
 
Physical functioning: 2 (+), 5 (+), 9 (-), 16 (-)  
 
Social integration: 8 (+), 13 (+), 6 (-), 14 (-) 
 
Total score: sum of all items 
8.2.4.7 Statistical Analysis of the SWN-20 and the PSP  
PSP and SWN-20 scores will be summarized by treatment group for the ITT population and using 
descriptive statistics for data obtained during the DB phase of the study.  PSP and SWN-20 scores 
from the OLE phase of the study will be summarized similarly for the OLP, as applicable, for 
descriptive purposes. 
At baseline: 


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At first, univariable analyses will be presented, cross-tabulating the SWN-20 and PSP summary scores 
at baseline by quantiles of the PANSS and CGI-S values at baseline. In addition, these summary 
scores will be presented by patient age, gender, country, by history of exacerbations (any other 
covariates that might be of interest).  
Frequency tables will show the proportion of patients falling in each response category for each 
question of the SWN-20 and the PSP. The denominator for calculating the frequencies will be the 
number of patients with non-missing data for each variable. Statistical difference between the 
treatment groups of the summary scores at baseline will be estimated with a general linear model 
(GLM) with the summary score as dependent and treatment allocation as independent variable. The 
GLM will have an identity or log link and a normal distribution and gamma distribution will be fitted. 
The best-fitting model parameterization will be determined by the AICC statistic. 
Evolution over time: 
In a second step, the values of these summary scores will be summarized (means) by treatment group 
over time. The evolution of the summary scores will be plotted over time by treatment arm (including 
95% confidence intervals). Furthermore, changes from baseline to each assessment point of the 
summary scores will be tabulated as well. 
P-values for differences between treatment groups over time will be estimated with a repeated 
measurement model which takes the inter-patient as well as the intra-patient correlation into account.  
A repeated measurement regression framework takes into the account the repeated measures structure 
of the data and, if appropriate, additionally allows regression coefficients to vary across specified 
subgroups. We will initially try to fit a random effects model, which is designed to estimate a 
population level intercept and hence provides distilled estimates of the coefficient. The model will 
initially be fitted with 3 random effects (intercept, slope and slope²). We will gradually test for the 
inclusion of the three random effects in the model using a Likelihood Ratio test. The model will also 
specify the correlation matrix of the repeated measurements by estimating the most efficient 
VARCOV matrix. The correlation of the measurements over time will be modelled through the 
specification of that variance-covariance matrix. It is assumed that the residual errors are 
homoscedastic and uncorrelated. We will start with an unstructured matrix and test for more reduced 
version of the variance-covariance matrix such as Toeplitz, compound symmetry and the independent 
structure. 
Furthermore, the analysis will test for different distributions and link functions that would fit the data, 
such as: 
 
Normal model: Link = ID, distribution = normal 
 
Lognormal model: Link = log, distribution = normal 
 
Gamma model: Link = log, distribution = gamma 


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These different specifications will be tested against each other using the Likelihood Ratio test. 
Depending on convergence of the model and on goodness-of-fit, specific random effects may be 
retained and a more structured version of the variance-covariance matrix possibly with a non-normal 
distribution will be considered. These type of models tend to have problems with convergence due to 
the unbalanced nature of the data and non-convergence will lead to more simplified models whilst still 
retaining the repeated measurement nature of the data. 
8.2.4.8 Socio-demographic Variables  
The objectives of the socio-demographic analysis are as follows: 
1. By treatment group and per study phase (DB phase versus OLE phase), document the 
distribution of patients for education, living arrangement, housing and employment at 
baseline 
2. By treatment group and per study phase (DB phase versus OLE phase), document changes 
from baseline in education, living arrangement, housing and employment at the end of the DB 
phase and the OLE phase. 
All data will be summarized for each visit as follows: n, mean, standard deviation, median, min, max, 
and normal approximation 95% confidence limits. 
 


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9. 
ANALYSIS OF PHARMACOKINETICS 
9.1 
PLASMA PK ENDPOINT 
The pharmacokinetic endpoints for all patients on Risperidone ISM 75 mg or 100 mg (PK population) 
will be the following:  
 
Summary plasma concentrations of risperidone, its active metabolite (9 OH-risperidone), and the 
active moiety (ie, risperidone plus 9-OH-risperidone) by injection site (gluteal and deltoid) and by 
study drug dose level 
 
Trough concentrations and accumulation index for steady state by injection site (gluteal and 
deltoid) and by study drug dose level 
 
Cmin for all doses (days 29, 57 and 85 including Css after last dosing interval (day 85) 
 
Css/D after last dosing interval 
 
RCmin and RCmax 
 
Estimated Cmax by injection site (gluteal and deltoid) and by study drug dose level – measured on 
days 3, 31 and 59 
Additionally, data from the patients in the intense PK subset with additional PK sampling points on 
days 8, 15, 22 will be used to derive the following non-compartmental parameters by injection site 
(gluteal and deltoid) and by study drug dose level: 
 
Derived Cmax for dose 1 
 
Derived Cmax/D for dose 1 
 
tmax for dose 1 
 
Tlast for dose 1 
 
Clast for dose 1 
 
AUClast for dose 1 
 
AUCtau for dose 1  
 
AUCtau/D for dose 1 
 
Cavg for dose 1   
 
t1/2 for dose 1 
 
AUCinf for dose 1 
 
CL/F for dose 1 
 
V/F for dose 1 
In addition, there will be exploratory associations of pharmacokinetic results with efficacy results. 
 
 


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9.2 
COLLECTION SCHEDULE AND ALLOWED WINDOWS FOR SAMPLING OF 
CMAX, TROUGH LEVELS AND DENSE PHARMACOKINETICS FOR 
RISPERIDONE AND 9-OH-RISPERIDONE  
Venous blood samples with corresponding sampling times are shown relative to dosing days and dose 
number in the DB phase in Table 5 below. 
 
Table 5 Venous blood samples with corresponding times post-dose 
DB Phase Day 
1 
3 
8 
15 
22 
29 
31 
57 
59 
85 
Dose number 
1 
 
 
 
 
2 
 
3 
 
 
Day relative to dosing 
1 
3 
8 
15 
22 
29 
3 
29 
3 
29 
Inject IM Study drug 
+ 
 
 
 
 
+ 
 
+ 
 
 
All patients 
+ 
+ 
 
 
 
+ 
+ 
+ 
+ 
+ 
Subset of patients with intense PK sampling 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
 
The samples at days 29, 57 and 85 are planned to be used to represent the trough concentrations. In 
order for a sample to be evaluable as a trough concentration corresponding to a particular dose, the day 
relative to dosing must lie between days 26 and 32 inclusive. If multiple samples lie within this 
window then the closest sample to day 29 (later sample if two are same proximity either side) will be 
used. 
 
The samples at days 3, 31 and 59 (2 days after dosing) are planned to be used to represent the 
estimated Cmax. In order for a sample to be evaluable as a Cmax concentration corresponding to a 
particular dose, the day relative to dosing must lie between days 2 and 4 inclusive. If multiple samples 
lie within this window then the closest sample to day 3 (later sample if two are same proximity either 
side) will be used. This may be different to the derived Cmax for dose 1 for those patients undertaking 
the intense sampling regime. 
 
For the intense PK samples, all samples collected relative to Dose 1 between days 1 and 32 will be 
evaluable for PK parameter derivations, apart from Cmax which must lie between days 2 and 4 inclusive 
similar to the sparse PK Cmax to be evaluable. For summaries over time, the sample must be collected 
within +/- 2 days of the respective planned day 8, 15, 22 time point (later sample if two are same 
proximity either side), with the same window as above for the days 3 and 29 time points.  


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Visit 14 concentrations from patients that discontinue early from treatment will be included in the 
above mapping considerations but only patients identified in the Intense PK subset from the eCRF will 
be included in Intense PK analyses. 
 
9.3 
HANDLING OF MISSING DATA  
Missing concentration data for all patients who are administered scheduled study treatments will be 
considered as non-informative missing and will not be imputed. No concentration estimates will be 
provided for missing sample values. 
For the derivation of AUC and related parameters, the following rules will apply: 
 
The sampling time of pre-dose samples relative to dosing will be treated as zero; 
 
BLQ values for pre-dose 1 concentration and before the 1st quantifiable concentration will be 
set to 0 
 
All below limit of quantification (BLQ) values after the 1st quantifiable point will be set to 
missing. 
 
If the actual time of sampling is missing, the planned time may be used. 
 
Samples taken outside the sampling windows may be excluded from by-time point summary 
statistics; this will be determined prior to unblinding. 
For the plasma concentration summary and for the individual concentration versus time curves and 
mean concentration versus time graphs, the following rules will apply: 
 
Plasma concentration BLQ values in all samples will be set to zero except when they are 
flanked by quantifiable concentrations. 
 
BLQ values when they are flanked by quantifiable concentration will be set to missing. 
 
No further imputation will be applied to any missing values. 
9.4 
LISTING AND PRESENTATION OF INDIVIDUAL PK DATA 
The actual sampling time of PK blood sample collection will be listed for all patients in the PK 
population and will include the deviation in time from the protocol scheduled time, if applicable. 
Individual patient plasma risperidone, 9-OH-risperdone and active moiety (risperidone + 9-OH 
risperidone) concentration data will be listed by patient, time point and treatment for patients in the PK 
population.  
Individual plasma trough (day 29 following dosing) and estimated Cmax (day 3 following dosing) 
concentration profiles vs dose number will be presented for each patient in the PK population with the 


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three analytes combined in the same figure on linear and log-linear scales. Profiles will be grouped 
according to injection site and dose level.  
Individual plasma concentration profiles vs actual time for dose 1 (days 3, 8, 15, 22 and 29) will be 
presented for each patient in the intense PK subset with three analytes combined in the same figure on 
linear and log-linear scales. Profiles will be grouped according to injection site and dose level. 
 
9.5 
SUMMARY OF PK CONCENTRATIONS IN PLASMA 
Summaries of plasma concentrations over time for dose 1 (days 3, 8, 15, 22 and 29) will be presented 
by dose level (75 mg and 100 mg) and injection site (deltoid, gluteal and overall) for patients in the 
intense PK sampling subset. Imputation rules for summary statistics of PK concentrations are 
described in Section 9.3. 
Summarization of PK parameters from trough and estimated Cmax concentration values are described 
in the Section 9.6 of the SAP 
Samples taken outside the allowed time windows for scheduled time points may be excluded from 
summarization. This will be determined prior to database lock. 
The following conventions will be used for the presentation of the descriptive statistics of plasma 
concentrations for patients in the intense PK sampling subset: 
Variable 
Summarized with: 
Plasma concentration at each 
nominal time point 
n, number BLQ, arithmetic mean, SD, coefficient of 
variance (CV) %, minimum, median, and maximum 
 


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PK Reporting Precision: 
Statistics 
Degree of Precision 
Minimum, Maximum 
3 significant digits or as needed based on actual measured 
values (for example PK concentrations) 
Mean (arithmetic and geometric), 
Median 
4 significant digits or as needed based on actual measured 
values (for example PK concentrations) 
Standard deviation 
5 significant digits or as needed based on actual measured 
values (for example PK concentrations) 
CV% and Geometric CV% 
1 decimal point or as needed based on actual measured values 
(for example PK concentrations) 
Mean ± SD plasma concentrations for patients in the intense PK sampling subset will be presented by 
time point relative to start of the 1st dose up to day 29. Curves for the three analytes will be combined 
on the same figure, separately for injection site (deltoid, gluteal and overall)  and dose level (75 mg 
and 100 mg).  
9.6 
PK PARAMETERS DERIVATION 
For all patients in the PK population, the following parameters will be derived for risperidone, 9-OH 
risperidone and active moiety (risperodone + 9-OH risperidone): 
PK population 
Estimated Cmax 
Maximum observed plasma concentration for all doses measured on day 3 
relative to each dose 
Estimated Cmax/D 
Maximum observed plasma concentration dose normalized for all doses 
measured on day 3 relative to each dose 
RCmin and RCmax 
Accumulation ratios based on trough concentrations and estimated Cmax 
Cmin 
Trough concentration after each dose (1, 2, 3), same as Css for dose 3 
Cmin/D 
Trough concentration after each dose (1, 2, 3), same as Css for dose 3, dose 
normalized 
Css 
Trough concentration at steady state (after last dosing interval) 
Css/D 
Trough concentration at steady state (after last dosing interval), dose 
normalized 
  
For patients in the intense PK sampling subset (as data allow), the following parameters will be 
derived for risperidone, 9-OH risperidone and active moiety (risperodone + 9-OH risperidone): 
Intense PK subset 
Derived Cmax 
Maximum observed plasma concentration for dose 1only 
Derived Cmax/D 
Maximum observed plasma concentration dose normalized for dose 1only 


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tmax 
Time of maximum observed concentration during dosing interval for dose 
1 
AUCtau 
Area under the plasma concentration-time curve from time zero to the end 
of dosing interval for dose 1 only 
AUCtau/D 
Area under the plasma concentration-time curve from time zero to the end 
of dosing interval for dose 1, dose normalized 
Cavg 
AUCtau divided by tau for dose 1 
t1/2 
Terminal elimination half-life 
AUCinf 
Area under the plasma concentration-time curve from time zero 
extrapolated to infinity 
λz 
Elimination constant 
CL/F 
Apparent terminal plasma clearance 
V/F 
Apparent volume of distribution 
 
The PK parameters will be estimated as follows: 
 
AUCs will be calculated using the linear/log trapezoidal rule. 
 
The apparent Cmax and the corresponding tmax will be read directly from the concentration-time 
plot (observed data, not predicted data by a program); 
Elimination parameters (t1/2, AUCinf, CL/F, V/F) may be estimated if data allow with all applicable PK 
acceptance criteria included to judge the reliability of the resulting parameters: 
 
number of points excluding Cmax to calculate λz ≥3 
 
R2 adjusted >0.85  
 
interval for λz calculation > than t1/2 
 
AUCextrap >25%.  
Unreliable elimination PK parameters, if calculated, will be flagged and will be excluded from 
summarization and statistical analyses. Secondary PK parameters R2adj, number of points to calculate 
λz, upper and lower limits of interval for the calculation of λz, AUCextrap% will be listed but not 
summarized. 


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9.7 
PK PARAMETERS SUMMARIZATION 
Pharmacokinetic parameters and plasma concentration data will be summarized by injection site 
(deltoid, gluteal and overall) and dose level (75 mg and 100 mg) using the following descriptive 
statistics: 
Variable 
Summarized with: 
AUCtau, AUCtau/D, AUCinf, Cmax (estimated 
and derived), Cmax /D (estimated and 
derived), Cavg, Css, Css /D, RCmin, RCmax, Cmin, 
Cmin /D 
n, arithmetic mean, SD, CV%, minimum, median, 
maximum, geometric mean, and geometric CV%  
t1/2, λZ, CL/F, V/F 
n, arithmetic mean, SD, CV%, minimum, median, 
and maximum 
tmax (actual time) 
n, minimum,Q1, median, Q3, and maximum 
Note: CV% = SD/mean in %.  
 
Dose normalized parameters for dose 1 will additionally be summarized just by injection site and 
overall. 
Mean ± SD plasma trough (day 29 relative to dosing) and estimated Cmax (day 3 relative to dosing) 
concentrations vs dose number will be presented for all patients in the PK population combining the 
curves for the three analytes within the same figure, on linear and log-linear scales separately for each 
injection site (deltoid and gluteal) and dose level (75 mg and 100 mg).   
Box-plots will be presented showing dose normalized PK parameters with a bar for each injection site 
(deltoid and gluteal) and analyte (risperidone, 9-OH risperidone and active moiety) on the same plot 
(i.e. 6 bars). 
 
 
9.8 
PLANNED STATISTICAL MODELS FOR PK PARAMETERS AND 
CONCENTRATIONS 
The PK parameters of risperidone, 9-OH risperidone and active moiety related to steady state 
(estimated Cmax/D from dose 1 and Css/D for all active patients, derived Cmax/D and  AUCtau/D for 
intense sampling PK subset) will be compared between injection sites and dose levels using an 
ANOVA model with injection site (deltoid or gluteal), dose level (75 mg or 100 mg) and injection site 
by dose level interaction as fixed effects, based on existing guidance on bioequivalence from EMA13  
and FDA [Food and Drug Administration (FDA)]14: 
The following hypotheses will be tested: 


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H01: µT/µR ≤ 80% vs. HA1: µT/µR > 80% and H02: µT/µR ≥ 125% vs. HA2: µT/µR < 125%where T and R 
are the two groups being compared. 
The following 6 contrasts involving the interaction between injection site (deltoid, gluteal) and dose 
level (75 mg, 100 mg) will be evaluated: 
1) Deltoid v Gluteal overall 
2) Deltoid v Gluteal within each dose level 
3) 75 mg v 100 mg overall 
4) 75 mg v 100 mg within each injection site  
 
PROC MIXED DATA =data_set_name;  
CLASS injection_site dose_level;  
MODEL PK_Parameter = injection_site|dose_level/ddfm=kr;  
LSMEANS injection_site / CL diff alpha=0.1; 
LSMEANS dose_level / CL diff alpha=0.1; 
LSMEANS injection_site*dose_level / CL diff alpha=0.1; 
RUN; 
 
9.9 
PK / PD EXPLORATORY ANALYSIS 
The relationship between the time matched trough concentrations for risperidone, 9-OH risperidone 
and active moiety (risperidone + 9-OH risperidone) and the change from baseline in the Total PANSS 
score at DB phase study days 29, 57 and 85 will be assessed. A scatter plot with regression line will be 
presented for each visit and analyte (9 plots). The Pearson and Spearman correlation (r coefficient with 
95% CI and p-value) will be presented, along with the ratio between the Pearson and Spearman 
correlation coefficients.  
The relationship between Cmax concentrations (sparse sampling) and the change from baseline in the 
Total PANSS score in the DB phase for the same doses on different study days will be assessed using 
the same methods as follows: 
 
Cmax for dose 1 on day 3 relative to dosing will be compared to the available PANSS scores 
for the dose 1 on days 4, 8, 15 and 29 
 
Cmax for dose 2 on day 3 relative to dosing will be compared to the available PANSS score for 
the dose 2 on day 57 (pre-dose 3) 
 
Cmax for dose 3 on day 3 relative to dosing will be compared to the available PANSS score for 
the dose 3 on day 85 (end of dosing) 
Total 18 plots will be produced for 6 comparison points and 3 analytes. 


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10. 
EXPLORATORY ANALYSIS OF PHARMACOGENOMICS 
10.1 
CYP2D6 ACTIVITY SCORE 
The results of pharmacogenetics testing will be listed for PGx population. Any exploratory analyses of 
efficacy and PK in subsequent sections will be based on patients in both the corresponding analysis 
populations and the PGx population. 
The results will include listing of alleles of CYP2D6 per subject with corresponding activity score 
derived based on the following Table 6 using the methods stated by Gaedigk et al (2008)15 to produce 
an activity score (AS) for the patient. The AS will be categorized into one of four phenotypic classess 
as follows: AS = 0 (Poor Metabolizer),  AS of 0.5 to 1 (Intermediate metabolizer), AS of 1.5 to 2 
(Extensive metabolizer) and AS > 2 (Ultra Metabolizer). 
Table 6 Activity Score Values Assigned to CYP2D6 
 
In case of alleles which were not characterized to their activity score the investigation of the latest 
literature data will be performed to relate the allele to activity of CYP2D6. The results will be 
recorded in a separate document with related references and described in the Clinical Study Report 
(CSR). The results will be also included in the listing with the explanation in the footnote. 
The AS and phenotypic classification will be summarized by treatment group, injection site and 
overall for SAF, mSAF, ITT, mITT, PP, mPP, PK and OP populations as well as the Intense PK 
subset. 


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10.2 
EFFICACY SUBGROUP ANALYSES 
The primary and key secondary endpoint will be summarized within each phenotypic classification 
defined above. In addition, an MMRM model will be fitted as per the primary and key secondary 
analyses (see Section 8.1) with the addition of fixed effects for the CYP2D6 phenotype class and a 
term for each of the treatment by visit by CYP2D6 phenotype class interaction levels. The LS mean of 
each treatment and treatment contrasts of interest (Risperidone ISM v placebo) will be presented 
within each CYP2D6 phenotype class. 
For the primary and key secondary endpoint, the relevant change from baseline at endpoint within 
each phenotypic classification will be presented using box-plots.  
10.3 
PK SUBGROUP ANALYSES  
Correlation between CYP2D6 and bioavailability of oral risperidone and risperidone ISM may be 
explored graphically on box plots for molar ratio of risperidone to 9-OH risperidone. Bioavailability 
PK parameters for different activity groups will be summarized separately and compared if sufficient 
number of data will be available for different activity scores. Effect of CYP2D6 metabolism on 
bioavailability of oral risperidone and risperidone ISM will be compared using descriptive statistics as 
described in Novalbos et al 201016. 
The dose normalized PK parameters of risperidone, 9-OH risperidone and active moiety related to 
steady state (estimated Cmax/D for dose 1 and Css/D for all active patients, AUCtau/D and derived 
Cmax/D for the intense sampling PK subset) will be compared between phenotype classifications. An 
ANOVA model as described in section 9.8 will be fitted but with additional fixed effects for 
phenotype class and the additional interaction terms between phenotype class, injection site and dose 
level . 
The following contrasts will be explored within each of the 9 combinations of injection site (deltoid, 
gluteal and overall) and dose level (75 mg, 100 mg and overall): 
 
Poor metabolizers (AS=0) vs extensive metabolizers (AS=1.5-2) 
 
Intermediate metabolizers (AS=0.5-1) vs extensive metabolizers (AS=1.5-2) 
 
Ultrafast metabolizers (AS=>2) vs extensive metabolizers (AS=1.5-2) 


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11. 
SAFETY 
All safety variables will be displayed as described in Section 4.5 separately for the SAF (and mSAF 
for selected endpoints) population in the main (double-blind) part of the study, and the OLP in the 
OLE phase of the study.   
Safety and tolerability will be evaluated based on the incidence of treatment-emergent AEs, incidence 
of AEs leading to discontinuation, vital sign measurements, physical examination findings, weight, 
abnormal laboratory test results, ECG findings, abnormal movement scale results (AIMS, BARS, and 
SAS), C-SSRS results, use of concomitant medications, and injection site reactions.  Additionally, 
time to early termination results will be summarized descriptively.   
11.1 
EXTENT OF EXPOSURE 
Exposure to study drug and duration of exposure will be summarized by treatment group separately 
for the DB phase and OLE phase as well as over both phases. 
A listing including study drug administration information from the CRF will be presented. Since all 
IM study drug is administered in clinic under supervision, no compliance summary is needed. 
11.2 
ADVERSE EVENTS 
Collection of AE data will begin after a patient signs the informed consent form and will continue 
until completion of the final follow-up visit.  Any AE having an onset after the final safety follow-up 
visit will not be collected or reported unless the investigator feels that the event may be related to the 
IM study drug.   
Preferred AE terms (PT) and system organ class (SOC) will be coded using terminology from the most 
up to date version of the Medical Dictionary for Regulatory Activities (MedDRA) at the time of data 
analysis.  Summaries will be presented by SOC and then PT in alphabetical order. 
A treatment-emergent adverse event (TEAE) is defined as an AE that is first identified, or is identified 
to have worsened in intensity, at a time point occurring on or after first dose date.  All reported 
adverse events will be listed, but only TEAEs will be summarized in tables.  
Completely missing or partially missing AE start dates will be imputed as described in Table 7  below 
after due diligence to obtain accurate AE information has failed.  The imputed dates will be used to 
determine TEAEs.    
TEAE onset day is calculated as (date of TEAE start – date of latest dose + 1).  The onset day will be 
missing if the start date is missing or partially missing.    
The duration of a TEAE will be calculated from the start date and time until the end date and time of 
the TEAE.   


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All summaries of AEs will be provided separately for the DB and OLE phases as well as over both 
phases combined (for active treatment only). 
An overall summary table will provide, by treatment group and overall (both SAF and mSAF 
populations separately), the number and percentage of patients who reported:   
 
Any TEAE 
 
Any severe TEAEs 
 
Any treatment-related TEAE (causal relationship suspected) 
 
Any treatment-related and severe TEAEs 
 
Any SAE 
 
Any serious treatment-related adverse event 
 
Any adverse event leading to study drug discontinuation 
 
Any adverse events leading to death. 
Separate summaries of TEAEs by SOC and PT will be presented for all TEAEs, treatment-related 
TEAEs, TEAEs leading to study drug discontinuation, and serious TEAEs (for both SAF and mSAF 
populations separately).  Each will include the number of TEAEs and the number and percentage of 
patients reporting each TEAE at least once. These SAF population summaries (excluding serious 
TEAEs) will be repeated separately for each dose (i.e. 1, 2 or 3), site of administration (i.e. deltoid or 
gluteus) and day of onset (≤ 7, 8-14, 15-21, ≥ 22). 
In addition, TEAEs will be summarized separately by severity and relationship to study drug. An 
additional table of TEAEs will be provided for PT’s that occurred in ≥2% of patients who received any 
Risperidone ISM during the respective period. 
In the summary tables, patients may be counted under multiple system organ classes and preferred 
terms, but for each system organ class and preferred term, patients are only counted once. If a patient 
has the same adverse event on multiple occasions, the highest severity (severe> moderate > mild) or 
drug relationship (Causal relationship suspected > Causal relationship not suspected) recorded for the 
event will be presented.   
Listings will be provided for all AEs, SAEs, AEs leading to drug discontinuation, and deaths. All 
reported AEs (including non-treatment-emergent adverse events) will be listed.  
No formal hypothesis-testing analysis of AE incidence rates will be performed. 


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Table 7 Imputation of Missing Adverse Event Data 
Missing Data Element 
Imputed Value 
Intensity/severity 
Severe 
Relationship to study drug 
Causal relationship suspected   
 
Action taken 
No imputation 
Serious? 
No 
Date of Onset 
Missing day 
 
If different month from the date of first dose of study drug, then impute last 
day of the month; else if same month as the date of first dose of study drug, 
then impute as date of first dose of study drug    
 
Missing day and month  
If different year from the date of first dose of study drug then impute 31st 
December; else if same year as the date of first dose of study drug then impute 
as date of first dose of study drug     
 
Completely missing  
Impute as date of first dose of study drug;  
If the stop date is prior to this, use the 31st December of the year in the stop 
date 
 
[Note: Any imputed date of onset must fall on or prior to the corresponding 
event stop date.] 
Treatment emergent 
Yes, if imputed start date >= first dose date 
Date of outcome 
No imputation 
Outcome 
Not recovered/ not resolved 
 
 
11.3 
LABORATORY EVALUATIONS 
Laboratory tests of hematology panel, chemistry panel, and urinalysis testing will be performed at the 
following time points:  at the screening visit (Day - 8 to Day -1), on DB phase study days 8, 15, 29, 57 
and 85, and OLE phase study days 1, 85, 169, 253, and 365. Prolactin assessments will be performed 
at the screening visit (Day - 8 to Day -1), on DB phase study days 8, 29, 57, and 85, and OLE phase 
study days 1, 85, 169, 253, and 365.  On days when study drug is administered, assessment sample 
will be taken pre-dose.  Baseline assessment are scheduled on Day 1 of each phase of the study; if 
a Day 1 value is not available then baseline will be the latest value obtained prior to Day 1.  Change 
from baseline for all continuous parameters will be calculated as the post-baseline value minus the 
baseline value. 


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Comparison to the normal ranges and assignment of a flag that will indicate a high, normal, or low 
value will be accomplished by the central laboratory. Each out-of-range laboratory value will be 
assessed by the investigator as either clinically significant or not clinically significant.  Clinically 
significant values should be considered AEs and recorded as such.  Partial dates/times related to the 
occurrence of clinically important abnormalities will use the same rules as imputation of TEAE start 
dates (see Section 11.2). 
All scheduled and unscheduled results will be considered in tables that assess maximum grade or 
toxicity.   
Observed values (in SI units) and change from baseline over time will be summarized by treatment 
group using descriptive statistics (n, mean, median, standard deviation, minimum and maximum) for 
each continuous clinical laboratory parameter.   
All laboratory data will be listed.  For hematology and chemistry, columns will be included for normal 
ranges and individual abnormal laboratory values will be flagged and clinical significance will be 
indicated.  A listing for the microscopic examination will be provided for patients who have a positive 
result from the urinalysis dipstick evaluation.  
The hematology panel includes hematocrit, hemoglobin, red blood cell count, white blood cell count 
and differential count (absolute values for basophils, eosinophils, lymphocytes, monocytes, and 
neutrophils), and platelets. The chemistry panel includes sodium, potassium, glucose, creatinine, 
creatinine clearance [Estimated Glomerular Filtration Rate (eGFR) using Modification of Diet in 
Renal Disease (MDRD) formula], total protein, blood urea nitrogen, albumin, total bilirubin, ALT, 
AST, lactic dehydrogenase, gamma-glutamyl transferase, alkaline phosphatase, creatine 
phosphokinase, prolactin, HbA1c, thyroid stimulating hormone, lipid panel low-density lipoprotein, 
high-density lipoprotein, total cholesterol, and triglycerides.  The urinalysis includes color, pH, 
specific gravity, ketones, protein, glucose, bilirubin, nitrite, urobilinogen, occult blood, and 
microscopic examination only if urinalysis dipstick results are abnormal.  Prolactin will be 
summarized with chemistry panel. 
Hematology and chemistry test will be summarized by treatment and overall at each time point for the 
absolute value itself and for changes from baseline. Tables showing the shift in terms of the 
Low/Normal/High indication (minimum and maximum) from baseline will also be presented. 
Other lab tests include serology, serum/urine pregnancy testing, and drug screening. Serology, serum 
pregnancy testing will be conducted at the screening visit.  Urine drug screen is mandatory at 
screening and baseline, and is optional thereafter.  Urine pregnancy test will be performed prior to 
dose administration on study days 1, 29, 57, and 85, and all time points in OLE phase of the study.   
The complete laboratory test results will be listed. In these listings, values outside the reference range 
will be flagged. Pregnancy testing and drug testing will be listed separately. 


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11.4 
VITAL SIGNS  
Vital signs will include blood pressure, pulse rate, respiratory rate, and body temperature and will be 
measured at each of the following time points:  at the screening visit, on DB phase study days 1, 3, 4, 
8, 15, 22 (Intense PK subset only), 29, 31, 43, 57, 59, 71, 85, and OLE phase study days 1, 29, 57, 85, 
113, 141, 169, 197, 225, 253, 281, 309, 337, and 365.  At each of these time point, vital signs will be 
measured after the patient has been resting in a supine position for at least 5 minutes.  On days when 
patient receive IM injections of study drug, vital signs are to be measured within 1 hour before and 
then again within 3 hours after the study drug injection; at each of these time points, orthostatic blood 
pressure and pulse rate will be measured (immediately after completion of supine vital sign 
measurements) after the patient has risen from the supine to the standing position and has remained 
standing for approximately 3 minutes.   
For blood pressure (supine, standing and orthostatic change), pulse rate (supine, standing and 
orthostatic change), respiration rate, body temperature and body weight, observed values and change 
from baseline will be summarized by treatment group and nominal visit using descriptive statistics (n, 
mean and median, standard deviation, minimum and maximum).  For assessments 3 hours post-dose, 
baseline will be the pre-dose values at the respective visit, otherwise, baseline will be the latest value 
obtained prior to the first dose of the study drug in each phase. 
Body weight and BMI will be measured at the screening visit, DB phase study days 1, 8, 15, 29, 57, 
and 85, and OLE phase study days 1, 85, 169, 253, and 365. On days when the patient receives IM 
injections, weight will be measured pre-dose. Height (cm) will be measured at the screening visit only.  
Weight and BMI will be summarized at each time point for the absolute value and for changes from 
baseline by treatment group and overall. 
All vital sign measurements will be included in patient listings. 
11.5 
ECG  
The standard 12-lead ECG will be obtained at each of the following time points: at the screening visit, 
on DB phase study days 1, 3, 4, 8, 15, 22 (Intense PK subset only), 29, 31, 57, 59, 85, and OLE phase 
study days 1, 29, 85, 141, 197, 281 and 365. For assessments 3 hours post-dose, baseline will be the 
pre-dose values at the respective visit, otherwise, baseline will be the latest value obtained prior to the 
first dose of the study drug in each phase.  
The following ECG parameters will be recorded:  heart rate (bpm), PR interval (msecs), QRS interval 
(msecs), QT interval (msecs), and corrected QT (QTc) intervals (msecs).  QT will be corrected for 
heart rate using Bazett’s (QTcB) interval and Fridericia’s (QTcF) interval.  On days when patients 
receive injections of IM study drug, an ECG will be performed both within 1 hour before dosing and 
within 3 hours after dosing.  All scheduled ECGs must be performed after the patient has rested 
quietly for at least 5 minutes in the supine position.   


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Interval data will be summarized at each time point for the absolute value and for changes from 
baseline by treatment group and overall. Overall assessment of ECG will also be summarized by 
treatment group using counts and percentage.  Additionally, QTcF values will be categorized and 
summarized, using the following QTcF value categories: 
 
Increase from baseline >30 msec; 
 
Increase from baseline >60 msec; 
 
Absolute values > 450 msec for males or > 470 msec for females. 
All ECG data will be listed. 
11.6 
PHYSICAL EXAMINATION 
A physical examination will be performed at time point: at the screening visit, on study days 8, 15, and 
85 during the DB phase, and OLE phase study days 1, 29, 57, 85, 113, 141, 169, 197, 225, 253, 281, 
309, 337, and 365.  The physical examination will include assessment of the following: skin, 
lymphatic, eyes, ears, nose, throat, neck, respiratory, cardiovascular, gastrointestinal, musculoskeletal, 
and neurological.  Physical examination will be listed. 
11.7 
ABNORMAL MOVEMENT SCALES 
Abnormal movement scales will include the following: Abnormal Involuntary Movement Scale 
(AIMS), Barnes Akathisia Rating Scale (BARS), and Simpson-Angus Scale (SAS)3. All abnormal 
movement scales will be completed at screening, and on DB phase study days 1, 4, 8, 15, 29, 43, 57, 
71, 85, and OLE phase study days 1, 29, 57, 85, 113, 141, 169, 197, 225, 253, 281, 309, 337, and 365. 
After administration of the first dose of study drug, if a patient complains of extrapyramidal symptoms 
on days when the abnormal movement scales are not scheduled to be performed, an unscheduled 
assessment will be performed.   
For all abnormal movement scales, total scores and subscale scores will be summarized by treatment 
group and overall at each visit for the absolute value and for changes from baseline. 
A listing will be provided for every abnormal movement scale. 
11.7.1 Abnormal Involuntary Movement Scale (AIMS) 
The Abnormal Involuntary Movement Scale (AIMS) is composed of 12 items and used to assess 
dyskinesia. Items related to severity of orofacial, extremity, and trunk movements, global judgment 
about incapacitation, and patient awareness are rated using a 5-point scale (0=none to 4=severe). Two 
items related to dental status are scored using “yes” or “no” responses. Overall AIMS scores range 
from 0 to 42.   


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11.7.2 Barnes Akathisia Rating Scale (BARS) 
The Barnes Akathisia Scale (BARS) is a tool used for diagnosis of drug-induced akathisia (Barnes, et. 
al, 2004).  The BARS consists of items that assess the objective presence and frequency of akathisia, 
the level of an individual’s subjective awareness and distress, and global severity. The objective rating 
is made using a 4-point scale (0=normal limb movement, 1=restlessness for less than half the time 
observed, 2=restlessness for at least half of the time observed, 3=constant restlessness). The BARS 
subjective component consists of two items, both rated using 4-point scales. One is Awareness of 
Restlessness (0=absent, 1=non-specific sense, 2=complaints of inner restlessness, 3=strong desire to 
move most of the time) and the other is Distress Related to Restlessness (0=none, 1=mild, 
2=moderate, 3=severe). The BARS Global Clinical Assessment of Akathisia is rated using a 6-point 
scale (0=absent, 1=questionable, 2=mild, 3=moderate, 4=marked, 5=severe).  The BARS will be 
summarized and listed. 
11.7.3 Simpson-Angus Scale 
The SAS is a brief clinician administered rating scale taking approximately 10 minutes and measuring 
EPS in patients (Simpson and Angus, 1970).  The 1970 version of this scale was later updated and 
modified by the authors to include the following 10 items:  gait, arm dropping, shoulder shaking, 
elbow rigidity, wrist rigidity, head rotation, glabella tap, tremor, salivation, and akathisia. Item scores 
range from 0 to 4 with higher scores representing more severe symptoms. The total score is calculated 
as the sum of the 10 item scores; the range of possible total scores is 0 to 40, with 0 representing 
a normal response on all items.  The modified SAS is typically used in schizophrenia studies to 
measure the presence of side effects in patients taking antipsychotic medications.  The SAS will be 
summarized and listed. 
During the study, it was noted that 26 patients were administered the incorrect SAS scales which 
included “Head dropping” instead of “Head rotation” and “Leg pendulousness” instead of “Akathisia”. 
For such patients, across all assessments, these items will be imputed as the mean of the other 8 item 
scores for calculating the total score.   
11.8 
Columbia Suicide-Severity Rating Scale (C-SSRS) 
The C-SSRS will be completed at screening, and on DB phase study days 1, 8, 15, 29, 57, 85, and 
OLE phase study days 1, 29, 57, 85, 113, 141, 169, 197, 225, 253, 281, 309, 337, and 365. 
The C-SSRS is a suicidal ideation rating scale used for assessment of suicidal ideation and behavior in 
clinical and research settings. The C-SSRS defines 4 types of suicidal behavior (actual, interrupted, 
and aborted attempts, and preparatory acts or behavior) and an overall suicidal behavior assessment.  
The C-SSRS also defines 5 types of suicidal ideation (death wish, active thoughts, active ideation 
without intention to act, active ideation with some intent to act without a plan, and active ideation with 
a specific plan and intent) and an overall suicidal ideation, defined as a ‘yes’ response to any of the 5 


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types.   
The investigator or qualified designee will complete the Columbia Suicide-Severity Rating Scale (C-
SSRS). A “baseline” version of the C-SSRS will be administered at screening. At subsequent visits, a 
“since last visit” version of the C-SSRS will be administered.  
For each behavior type, the frequency and percent of patients with a ‘yes’ response to each behavior 
type will be reported at each time point.  The denominator for percent will be the number of patients 
with a C-SSRS assessment at the time point.  Patients with a ‘yes’ response at any post baseline time 
point will be given a ‘yes’ response for the behavior type over the full treatment phase, which will also 
be summarized. 
For each ideation type, the frequency and percent of patients with a ‘yes’ response to each behavior 
type will be reported at each time point. The denominator for percent will be the number of patients 
with a C-SSRS assessment at the time point.  Patients with a ‘yes’ response at any post baseline time 
point will be given a ‘yes’ response for the ideation type over the full treatment phase, which will also 
be summarized. 
As recommended in the C-SSRS manual for evaluation of safety, the following items will be derived 
from the C-SSRS based on data collected throughout the study and reported in a table: 
 
The number and percent of patients who had treatment-emergent suicidal behavior 
 
The number and percent of patients who had treatment-emergent suicidal ideation 
 
The number and percent of patients who had treatment-emergent suicidal behavior or suicidal 
ideation 
 
The number and percent of patients whose suicidal behavior worsened from baseline (lifetime) 
 
The number and percent of patients whose suicidal ideation worsened from baseline (past 2 
months) 
 
The number and percent of patients whose suicidal behavior or suicidal ideation worsened 
from baseline 
 
The number of suicide attempts, aborted attempts, and interrupted attempts 
 
The mean of the per- patient lethality total scores 
 
Mean changes from baseline in per-patient lethality total scores 
 
The mean of the per-patient suicidal ideation intensity score 
 
Mean changes from baseline (past 2 months) in per-patient suicidal ideation intensity scores. 
 


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For OLE rollover patients, any worsening from baseline in suicidal behaviour recorded during the DB 
phase will be used as the OLE baseline for suicidal behaviour. For suicidal ideation, the maximum 
suicidal ideation and suicidal ideation intensity score from the DB days 57 and 85 will be considered 
as the OLE baseline.    
Summary tables will be produced for the SAF population (DB phase) and OLP (OLE phase) by 
treatment group, by country and overall.  
Data, as collected, will be included in patient listings. 
11.9 
INJECTION SITE REACTIONS 
The injection site and surrounding area will be evaluated on DB phase study days 1, 8, 15, 29, 43, 57, 
71 and 85, and OLE phase study days 1, 29, 57, 85, 113, 141, 169, 197, 225, 253, 281, 309, 337, and 
365. 
Injection site reactions (overall and by specific reaction subtype) and pain VAS score will be 
summarized for the mSAF and SAF populations (DB phase) and OLP (OLE phase) by treatment 
group and overall at each visit. The number and percentage of patients having reactions at each visit 
and at any visit within the respective phase will be presented. The pain VAS score at each visit will be 
summarised as both a categorical and continuous variable (additionally including 95% CI and inter-
quartile range). An additional summary of the maximum VAS score recorded for the patient across the 
respective phase will be presented.  
 
11.10 OTHER SAFETY VARIABLES 
Ophthalmological examination including slit lamp biomicroscopy examination (eyelids, conjunctiva, 
iris, crystalline lens, sclera and cornea), visual field, best correction visual acuity (BCVA), 
and intraocular pressure will be performed at any time during screening period and at study day 85 (or 
early termination) of the DB phase.  They will be summarized and listed. 


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12. 
INTERIM ANALYSES 
An unblinded interim analysis will be conducted when 196 (approximately 50%) randomized patients, 
for whom the blinding was not compromised (see Section 3.6.3), have either reached study day 85 or 
withdrawn from the study; to re-estimate the sample size required for the final analysis up to 558 
patients (186 patients per arm) in the mITT population.  Only data collected up to and including the 
date that the Data Management function become aware of this event from the database will be used in 
the interim analysis. 
Those patients included in the interim analysis (as well as those for whom the blinding was 
compromised) will constitute stage 1 patients with all subsequent patients being stage 2 patients for 
purpose of the primary and key secondary variable analyses. There will be no overlap of patients 
between stages. Only those patients meeting the criteria for inclusion in the mITT population will be 
included in the interim analysis for purpose of sample size re-estimation. 
For stage 1 patients meeting the criteria for inclusion in the mITT population, the effect size (mean 
difference/pooled standard deviation) will be calculated for each dose compared to placebo separately 
for the primary efficacy variable (change from baseline to endpoint in total PANSS score). The mean 
difference will be repesented by the difference between LS means from the primary MMRM model at 
Day 85 (see Section 8.1.1) and the pooled standard deviation will be derived from the standard error of 
the difference between LS means divided by sqrt(1/nr + 1/np) where nr and np are the sample size 
included in the interim analysis for the risperidone and placebo group respectively. 
If one or both of the effect sizes are less than the expected effect size of 0.45, the lowest effect size 
will be used to derive the new sample size per group for the mITT population (M2) as suggested by 
Cui et al. (1999)7 as follows: 
M2 = 124 * (0.45/lowest effect size) up to a maximum of 186 patients per group in the mITT 
population. 
If the lowest effect size is greater than or equal to 0.45, the target sample size for the mITT population 
will be maintained at 124 patients per arm. 
The dropout rate at interim (from the randomization population to the ITT population) will be used to 
re-calculate the number of patients required to be randomized in stage 2 to meet the required total 
number in the mITT. 
From an ethical point of view, there will be an early stopping for futility for a particular dose when the 
conditional power17 at interim <10%. The conditional power (cp) will be calculated for each 
risperidone dose as follows: 


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where p1 is the two-sided p-value from the primary analysis (MMRM Day 85 comparison) for stage 1 
(interim), δ and σ are the difference between least square means and the corresponding standard error 
divided by sqrt(1/nr + 1/np) respectively from stage 1 (na and np are the sample sizes for risperidone and 
placebo in the interim analysis), and 
 is the normal cumulative density function.  
The DMC will receive one of the following from the unblinded statistician in a letter relative to each 
risperidone group comparison to placebo: 
1. The number of patients to be randomized per group in stage 2 
2. Confirmation that the conditional power <10% 
The DMC will receive an analysis table (ensuring that the blinding of the DMC is not compromised) 
detailing the MMRM results compared to placebo, including the effect sizes and conditional powers. 
The DMC will communicate to the sponsor this decision from the interim analysis. 
Two further interim analyses will be conducted following the unblinding of the DB phase when 
approximately 65 and 100 patients are known to have been exposed to either of the active arms for at 
least 337 days respectively.  
 


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13. 
CHANGE FROM ANALYSIS PLANNED IN PROTOCOL 
The following updates have been made to section 7.2 Analysis Populations from the Protocol V7.0 
(22nd March 2018) in this version of the SAP: 
- The protocol section 7.3.4 states that the MI sensitivity analyses will be performed on the mITT and 
ITT populations. This SAP clarifies that these analyses will be performed to test the sensitivity of the 
mITT and ITT analyses using MI techniques for the Modified Randomized and Randomized 
populations respectively. This was the intention of the Randomized population as stated in the 
Analysis Populatons section 7.2 of the protocol. The use of MI allows the implementation of the true 
ITT principle and ability to impute missing data for all randomized patients  in the study in an 
unbiased manner. The addition of the mITT population in the updated protocol requires a Modified 
Randomization Population also to present sensitivity analyses for the mITT analyses, so this was 
added to this SAP. 
- The definition of the PP analysis was updated following the blind data review meeting such that:  
1) those patients with < 2 doses would not be excluded if they withdrew early due to lack of 
efficacy and/or AE.  
2) those patients with protocol deviations deemed to have affected the PANSS after the third 
dose will remain in the PP population but any data following the third dose will be excluded 
from the PP analysis.  
- The PK population and Intense PK subset will not be finalized until after database lock of the DB 
data when it can be checked if a patient has at least 1 measured plasma concentration value. 
Evaluability of PK concentrations due to protocol deviations and allowed sample windows will be 
conducted and agreed prior to data lock.   
- Additional interaction terms including visit by subgroup and visit by treatment by subgroup were 
added into the MMRM models for subgroup analyses. Only the treatment by subgroup interaction was 
mentioned in the protocol but as this is an MMRM model, in order to compare treatments within each 
subgroup at each visit, such interactions in the model are required.  
  
 
 


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14. 
REFERENCE LIST 
1. Kay, SR, Fiszbein A, Opler LA.  The positive and negative syndrome scale (PANSS) for 
schizophrenia.  Schizophr Bulletin 1987; 13:261-276. 
2. Morosini P-L, Magliano L, Brambilla L, Ugolini S, Pioli R. Development, reliability and 
acceptability of a new version of the DSMIV Social and Occupational Functioning Assessment 
Scale (SOFAS) to assess routine social funtioning. Acta Psychiatr Scand 2000: 101: 323-329. 
3. Simpson GM, Angus JW.  A rating scale for extrapyramidal side effects.  Acta Psychiatr Scand 
Suppl. 1970; 212:11-9. 
4. EMA: Guideline on Missing Data in Confirmatory Clinical Trials, Committee for Medicinal 
Products for Human Use (CHMP), EMA/CPMP/EWP/1776/99 Rev. 1, 2 July 2010 
5. Kane JM, Peters-Strickland T, Baker RA, Hertel P, Eramo A, Jin N, Peryy PP, Gara M, McQuade 
RD, Carson WH, Sanchez R: Aripiprazole once Monthly in the Acute Treatment of 
Schizophrenia: Findings from a 12-Week, Randomized, Double-Blind, Placebo-Controlled Study, 
J Clin Psychiatry, 2014 
6. Nasser AF, Henderson DC, MD, Fava M, Fudala PJ, Twumasi-Ankrah P, Kouassi A, Heidbreder 
C: Efficacy, Safety, and Tolerability of RBP-7000 Once-Monthly Risperidone for the Treatment 
of Acute Schizophrenia, An 8-Week, Randomized, Double-Blind, Placebo-Controlled, Multicenter 
Phase 3 Study, Journal of Clinical Psychopharmacology • Volume 36, Number 2, April 2016 
7. Cui L, Hung HM, Wang SJ.  Modification of sample size in group sequential clinical trials. 
Biometrics, 1999, 55:853-857. 
8. Lawrence J, Hung H.M. Estimation and Confidence after Adjusting the Maximum Information”. 
Biometrical Journal, 2003, 45, 143–152  
9. Hommel G: A stagewise rejective multiple test procedure based on a modified Bonferroni test, 
Biometrika, 1988, 75, 383-386 
10. Kenward, M. G. and Roger, J. H. Small Sample Inference for Fixed Effects from Restricted 
Maximum Likelihood,” Biometrics, 1997, 53, 983–997. 
11. Ratitch B., and O’Kelly M., Implementation of pattern-mixture models using standard SAS/STAT 
procedures, SUGI 2011. 
12. Xin Yan and Xiao Gang (2010). Stratified Wilson and Newcombe Confidence Intervals for 
Multiple Binomial Proportions. Statistics in Biopharmaceutical Research, 2:3, 329-335. 
13. EMA: Questions & Answers: positions on specific questions addressed to the Pharmacokinetics 
Working Party (PKWP), EMA/618604/2008 Rev. 13, 19 November 2015 
14. FDA Guidance for Industry: Statistical Approaches to Establishing Bioequivalence, January 2001 
15. A Gaedigk, SD Simon, RE Pearce, LD Bradford, MJ Kennedy and JS Leeder. The CYP2D6 
Activity Score: Translating Genotype Information into a Qualitative Measure of Phenotype 
Clinical Pharmacology & Therapeutics, 2008, 83 (2), 235 


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16. Novalbos J, López-Rodríguez R, Román M, Gallego-Sandín S, Ochoa D, Abad-Santos F. Effects 
of CYP2D6 genotype on the pharmacokinetics, pharmacodynamics, and safety of risperidone in 
healthy volunteers. J Clin Psychopharmacol. 2010 Oct;30(5):504-11. 
17. Chang, M. (2014). Adaptive Design Theory and Implementation using SAS and R - Second 
Edition (Chapter 9; p. 192). Boca Raton, FL; Taylor and Francis Group 
 


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15. 
PROGRAMMING CONSIDERATIONS 
All tables, data listings, figures (TLFs), and statistical analyses will be generated using SAS® for 
Windows, Release 9.3 (SAS® Institute Inc., Cary, NC, USA). Computer-generated table, listing and 
figure output will adhere to the following specifications.   
15.1 
GENERAL CONSIDERATIONS 
 
A separate SAS program will be created for each output. 
 
Each output will be stored in a separate file. 
 
Output files will be delivered in Word format. 
 
Numbering of TFLs will follow ICH E3 guidance 
15.2 
TABLE, LISTING, AND FIGURE FORMAT 
15.2.1 General 
 
All TLFs will be produced in landscape format, unless otherwise specified. 
 
All TLFs will be produced using the Courier New font, size 8  
 
The data displays for all TLFs will have a minimum 1-inch margin on all 4 sides. This area should 
be completely blank. 
 
Headers and footers for figures will be in Courier New font, size 8. 
 
Legends will be used for all figures with more than 1 variable, group, or item displayed. 
 
TLFs will be in black and white (no color), unless otherwise specified 
 
Specialized text styles, such as bolding, italics, borders, shading, and superscripted and 
subscripted text, will not be used in the TLFs, unless otherwise specified. On some occasions, 
superscripts 1, 2, or 3 may be used (see below). 
 
Only standard keyboard characters will be used in the TLFs. Special characters, such as non-
printable control characters, printer-specific, or font-specific characters, will not be used. 
Hexadecimal-derived characters will be used, where possible, if they are appropriate to help 
display math symbols (e.g., μ). Certain subscripts and superscripts (e.g., cm2, Cmax) will be 
employed on a case-by-case basis. 
 
Mixed case will be used for all titles, footnotes, column headers, and programmer-supplied 
formats, as appropriate. 


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15.2.2 Headers 
 
All output should have the following header at the top left of each page: 
< Laboratorios Farmacéuticos ROVI, S.A.> Protocol ROV-RISP-2016-01 (1004855)      
          
Draft/Final Run < date in DD-MMM-YYYY format> 
 
All output should have Page n of N at the top or bottom right corner of each page. TLFs should be 
internally paginated in relation to the total length (i.e., the page number should appear sequentially 
as page n of N, where N is the total number of pages in the table). 
 
The date output was generated should appear along with the program name as a footer on each 
page. 
15.2.3 Display Titles 
 
Each TLF should be identified by the designation and a numeral. (i.e., Table 14.1.1). ICH E3 
numbering is strongly recommended but sponsor preferences should be obtained prior to final 
determination. A decimal system (x.y and x.y.z) should be used to identify TLFs with related 
contents. The title is centered. The analysis set should be identified on the line immediately 
following the title. The title and table designation are single spaced. A solid line spanning the 
margins will separate the display titles from the column headers. There will be 1 blank line 
between the last title and the solid line. 
Table x.y.z 
First Line of Title 
Second Line of Title if Needed 
(ITT Analysis Set) 
 
15.2.4 Column Headers 
 
Column headings should be displayed immediately below the solid line described above in initial 
upper-case characters.  
 
In the case of efficacy tables, the variable (or characteristic) column will be on the far left 
followed by the treatment group columns and total column (if applicable). P-values may be 
presented under the total column or in separate p-value column (if applicable). Within-treatment 
comparisons may have p-values presented in a row beneath the summary statistics for that 
treatment. 
 
For numeric variables, include “unit” in column or row heading when appropriate. 


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 
Analysis set sizes will be presented for each treatment group in the column heading as (N=xx) (or 
in the row headings if applicable). This is distinct from the ‘n’ used for the descriptive statistics 
representing the number of patients in the analysis set. 
 
The order of treatments in the tables and listings will be Placebo first in the case of placebo 
controlled studies and Active comparators first in the case of active comparator trials, followed by 
a total column (if applicable). 
15.2.5 Body of the Data Display 
15.2.5.1 General Conventions 
Data in columns of a table or listing should be formatted as follows: 
• 
alphanumeric values are left-justified; 
• 
whole numbers (e.g., counts) are right-justified; and 
• 
numbers containing fractional portions are decimal aligned. 
15.2.5.2 Table Conventions 
 
Units will be included where available 
 
If the categories of a parameter are ordered, then all categories between the maximum and 
minimum category should be presented in the table, even if n=0 for all treatment groups in a given 
category that is between the minimum and maximum level for that parameter. For example, the 
frequency distribution for symptom severity would appear as: 
Severity Rating 
N
severe 
0 
moderate 
8 
mild 
3 
 
Where percentages are presented in these tables, zero percentages will not be presented and so any 
counts of 0 will be presented as 0 and not as 0 (0%). 
 
If the categories are not ordered (e.g., Medical History, Reasons for Discontinuation from the 
Study, etc.), then only those categories for which there is at least 1 patient represented in 1 or more 
groups should be included. 
 
An Unknown or Missing category should be added to any parameter for which information is not 
available for 1 or more patients.  
 
Unless otherwise specified, the estimated mean and median for a set of values should be printed 
out to 1 more significant digit than the original values, and standard deviations should be printed 


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out to 2 more significant digits than the original values. The minimum and maximum should 
report the same significant digits as the original values. For example, for systolic blood pressure: 
N 
  XX 
Mean (SD) 
XXX.X (XXX.XX) 
Median 
XXX.X 
Minimum 
XXX 
Maximum 
XXX 
95% CI 
XXX.X, XXX.X 
 
P-values should be output in the format: “0.xxx”, where xxx is the value rounded to 3 decimal 
places. Any p-value less than 0.001 will be presented as <0.001. If the p-value should be less than 
0.0001 then present as <0.0001. If the p-value is returned as >0.999 then present as >0.999 
 
Percentage values should be printed to one decimal place, in parentheses with no spaces, one 
space after the count (e.g., 7 (12.8%), 13 (5.4%)). Pre-determine how to display values that round 
down to 0.0.  A common convention is to display as '<0.1', or as appropriate with additional 
decimal places. Unless otherwise noted, for all percentages, the number of patients in the analysis 
set for the treatment group who have an observation will be the denominator. Percentages after 
zero counts should not be displayed and percentages equating to 100% should be presented as 
100%, without any decimal places.  
 
Tabular display of data for medical history, prior / concomitant medications, and all tabular 
displays of adverse event data should be presented by the body system, treatment class, or SOC in 
alphabetical order, assuming all terms are coded. Within the body system, drug class and SOC, 
medical history (by preferred term), drugs (by ATC1 code), and adverse events (by preferred term) 
should be displayed in alphabetical order. If incidence for more than 1 term is identical, they 
should then be sorted alphabetically. Missing descriptive statistics or p-values which cannot be 
estimated should be reported as “-”. 
 
The percentage of patients is normally calculated as a proportion of the number of patients 
assessed in the relevant treatment group (or overall) for the analysis set presented. However, 
careful consideration is required in many instances due to the complicated nature of selecting the 
denominator, usually the appropriate number of patients exposed. Describe details of this in 
footnotes or programming notes. 
 
For categorical summaries (number and percentage of patients) where a patient can be included in 
more than one category, describe in a footnote or programming note if the patient should be 
included in the summary statistics for all relevant categories or just 1 category and the criteria for 
selecting the criteria. 
 
Where a category with a subheading (such as system organ class) has to be split over more than 
one page, output the subheading followed by “(cont)” at the top of each subsequent page.  The 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Laboratorios Farmacéuticos ROVI, S.A.; Protocol No.: ROV-RISP-2016-01 / 1004855 
 
This document is confidential. 
SAP Version: V4.0 15-FEB-2019 
Controlled Document ID: 3903C.00, Effective Date 30-Apr-2018 
Page 94 of 95 
overall summary statistics for the subheading should only be output on the first relevant page. 
15.2.5.3 Listing Conventions 
 
Listings will be sorted for presentation in order of treatment groups as above, patient number, 
visit/collection day, and visit/collection time. 
 
Missing data should be represented on patient listings as either a hyphen (“-”) with a 
corresponding footnote (“- = unknown or not evaluated”), or as “N/A”, with the footnote “N/A = 
not applicable”, whichever is appropriate. 
 
Dates should be printed in SAS® DATE9.format (“ddMMMyyyy”: 01JUL2000). Missing 
portions of dates should be represented on patient listings as dashes (--JUL2000). Dates that are 
missing because they are not applicable for the patient are output as “N/A”, unless otherwise 
specified. 
 
All observed time values must be presented using a 24-hour clock HH:MM or HH:MM:SS format 
(e.g., 11:26:45, or 11:26). Time will only be reported if it was measured as part of the study. 
 
Units will be included where available 
15.2.5.4 Figure Conventions 
 
Unless otherwise specified, for all figures, study visits will be displayed on the X-axis and 
endpoint (e.g., treatment mean change from Baseline) values will be displayed on the Y-axis. 
15.2.6 Footnotes 
 
A solid line spanning the margins will separate the body of the data display from the footnotes.  
 
All footnotes will be left justified with single-line spacing immediately below the solid line 
underneath the data display. 
 
Footnotes should always begin with “Note:” if an informational footnote, or 1, 2, 3, etc. if a 
reference footnote. Each new footnote should start on a new line where possible. 
 
Patient specific footnotes should be avoided, where possible. 
 
Footnotes will be used sparingly and must add value to the table, figure, or data listing. If more 
than six lines of footnotes are planned, then a cover page may be used to display footnotes, and 
only those essential to comprehension of the data will be repeated on each page.  
 
The last line of the footnote section will be a standard source line that indicates the name of the 
program used to produce the data display, date the program was run, and the listing source (i.e., 
‘Program : myprogram.sas    Listing source: 16.x.y.z’). 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Laboratorios Farmacéuticos ROVI, S.A.; Protocol No.: ROV-RISP-2016-01 / 1004855 
 
This document is confidential. 
SAP Version: V4.0 15-FEB-2019 
Controlled Document ID: 3903C.00, Effective Date 30-Apr-2018 
Page 95 of 95 
16. 
QUALITY CONTROL 
SAS programs are developed to produce output such as analysis data sets, summary tables, data 
listings, figures or statistical analyses. Syneos Health SOPs Developing Statistical Programs (3907) 
and Quality Deliveries (SDTM, ADaM, TLF) (3908) describes the quality control procedures that are 
performed for all SAS programs and output. Quality control is defined here as the operational 
techniques and activities undertaken to verify that the SAS programs produce the output by checking 
for their logic, efficiency and commenting and by review of the produced output.   
 
17. 
MOCK-UPS 
Table, listing and figure mock ups will be presented in a separate document.