Conditions: Parkinson Disease
Keywords: Parkinson Disease Dyskinesia ropinirole implant ProNeura movement disorders dopamine agonist extended-release Parkinsonian disorders brain diseases central nervous system diseases Neurodegenerative Diseases Antiparkinson agents Anti-dyskinesia agents dopamine agents neurotransmitter agents REQUIP subdermal
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 6
Healthy volunteers: no

Brief summary:
Subjects stable on L-Dopa and oral ropinirole will have their ropinirole replaced with the Ropinirole Implant(s). The Ropinirole Implant was designed using the ProNeura™ implant technology where the implant is inserted under the skin. This study will measure how much ropinirole is released in the blood during 12 weeks of ropinirole implant treatment, and evaluate the side effects of this new formulation.

Detailed description:

Arms:
arm 1: Requip; One Ropinirole Implant arm 2: Requip; Two Ropinirole Implants arm 3: Requip; Three Ropinirole Implants arm 4: Requip; Four Ropinirole Implants

Interventions: intervention 1: Ropinirole oral product intervention 2: Ropinirole Implant
Intervention descriptions: intervention 1: oral immediate-release ropinirole intervention 2: ropinirole hydrochloride/ethylene vinyl acetate

Protocol document:
Prot_000.pdf: 
Titan Pharmaceuticals, Inc. 
Ropinirole Implant, Amendment 1 
ROP-001-A1 
07Jun2017 
Confidential 
1 
CLINICAL STUDY PROTOCOL 
Title:  An Open-Label, Relative Bioavailability Study Evaluating the Safety, 
Tolerability, and Pharmacokinetics of Ropinirole Implants in Patients with 
Parkinson’s Disease Switched from Oral Immediate-Release Ropinirole While on 
L-Dopa
Protocol Number:  ROP-001 
10 January 2017 
Amendment 1: 
07Jun2017 
Investigational Drug: 
Ropinirole Implant 
IND Applicant/Product Sponsor: 
Titan Pharmaceuticals, Inc. 
400 Oyster Point Blvd., Suite 505 
South San Francisco, CA 94080 
Authorized Signatory: 
Executive Vice President,  
Chief Development Officer 
Titan Pharmaceuticals, Inc. 
400 Oyster Point Blvd., Suite 505 
South San Francisco, CA 94080 
Study Contact: 
Vice President, Clinical Operations 
Titan Pharmaceuticals, Inc. 
400 Oyster Point Blvd, Suite 505 
South San Francisco, CA 94080 
Phone:  
Confidentiality Statement 
The confidential information in this document is provided to you as an investigator or consultant for review by you, your staff, 
and the applicable Institutional Review Board.  Your acceptance of this document constitutes agreement that you will not 
disclose the information contained herein to others without written authorization from the sponsor. 
NCT03250117


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SUMMARY OF CHANGES 
Amendment 1, Description of changes: 
1. Section 2.2: Addition of secondary objectives related to analyses of ropinirole metabolites 
2. Section 2.3:  Addition of exploratory objectives related to Ropinirole Implant Applicator. 
3. Figure 1:  Updated study schematic and language throughout to change “Group” to 
“Cohort”. 
4. Sections 3.1 and 14.4:  Revisions to dose escalation committee review requirements, 
including addition of pharmacokinetic (PK) profile data review for Cohorts 1and 2, and 
extending the period for safety and PK data from 4 weeks to 12-weeks for Cohort 1. 
5. Sections 3.1.1, 5.2.1, and Table 2:  Adjustment in screening period to 2-4 weeks.  Overall 
duration of the subject participation revised to up to 17.5-19.5 weeks. 
6. Section 3.1.2 – Clarification that enrolled subjects who withdraw early will not be replaced. 
7. Sections 3.1.3.1: Clarification regarding L-Dopa dosing 
8. Sections 3.1.3.1, 5.2.2.3, and Table 3:  Clarification that on Day -1, immediate release 
ropinirole must be administered 8 hours apart. 
9. Sections 3.1.3.3 and 5.2.4: Clarification that subjects should not transition back to oral 
ropinirole until after the 18-hour PK sample has been collected. 
10. Section 3.1.3.5:  Addition of section on investigator training. 
11. Section 3.2.1:  Clarification of safety assessments for AEs and SAEs, and addition of the 
Scales for Outcomes in Parkinson’s disease–Psychiatric Complications (SCOPA-PC) as a 
safety assessment. 
12. Sections 3.2.5, 3.2.6, 5.2.3.1, 5.2.4, 5.2.5.2, 6.9.1, 6.9.2, 6.10, and Table 2  Addition of 
assessments, including implant depth ultrasound, implant palpability, implant applicator 
complaints, failures, and malfunctions, and Implanting Physician and patient satisfaction 
surveys. 
13. Section 4.1, Inclusion Criteria: 
• 
Clarification that age of eligible subjects is 30 to 80, inclusive, and that this should be 
assessed at time of informed consent. 
• 
Clarification on the timeframe for practicing acceptable methods of contraception 
(females of childbearing potential). 
• 
Clarification of the requirement for subjects with clinically stable Parkinson’s Disease 
(PD). 
14. Section 4.2, Exclusion Criteria: 
• 
Clarification of the location for prohibited scarring or tattoos. 
• 
Addition of exclusion criterion for BMI ≤19 and skin to fascia depth ≤3 mm at the 
bicipital groove of the brachium. 


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• 
Clarification of eligibility of subjects with Parkinson’s disease-related psychosis. 
• 
Revision to exclude subjects with current impulse control disorder or symptoms. 
• 
Revision to exclude subjects using nicotine replacement products. 
• 
Addition of prilocaine, chlorhexidine, and adhesive dressing to exclusion criterion 
regarding hypersensitivity. 
15. Sections 4.2, 4.3, 5.2.1, 6.7.2, and Table 2:  Clarification that urine drug screens are for 
drugs of abuse, and positive drug screens cannot be repeated.  Positive alcohol breath tests 
can only be repeated during the screening period.   
16. Section 4.3:  Correction to implantation criterion 3 (change OR to AND) 
17. Section 4.4:  Addition of abuse of non-study assigned ropinirole as a subject withdrawal 
criterion.  Clarification language added for recording reasons for discontinuation/removal. 
18. Section 5.2.1:  Clarification that screening assessments may be conducted across more than 
one visit during the screening period.   
19. Sections 5.2 (Screening Period, Visit P1, Visit Day-2, Day 3 Visit, Day 4 Visit, and Weeks 
1 through 14), 6.4.8, and Table 2:  Addition of SCOPA-PC  
20. Sections 5.2, 6.4.4, and Table 2:  Height and weight separated from vital signs in Schedule 
of Events and in visit descriptions. 
21. Section 5.2.1 and Table 2:  Addition of Hauser Diary concordance training. 
22. Section 5.2.2.2 (Visit Day -2):  Correction of serum to urine pregnancy test. 
23. Section 5.2.2.3 and Table 3:  Addition of low fat meal requirement and recommended 
windows for PK sample collection. 
24. Section 5.2.3.1 and Table 2:  Respiratory rate and oral body temperature added to vital 
signs assessments. 
25. Sections 5.2.4, 6.9.2, and Table 2:  Addition of ultrasound prior to implant removal at 
Week 12 Visit. 
26. Table 3:  Addition of rows to clarify the required PK timepoints on Day -1.  Removal of a 
redundant footnote. 
27. Sections 7.1 and 7.2: Update of implant drug content range per Investigator’s Brochure. 
28. Section 7.2: Update of safety margin calculation and total drug content 
29. Section 7.3: Change in Investigational Product packaging configuration 
30. Section 8.1:  Addition of language prohibiting use of marijuana. 
31. Section 9.1.1.2:  Clarification of SAE definition as related to unplanned hospitalizations 
related to implant placement or removal. 
32. Section 9.1.3, Table 4:  Addition of category for “Possibly Related” and revision of  
existing definition of “Related” to adverse event attribution table 


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33. Section 9.1.5.1:  Addition of SAE reporting element for relationship to insertion/removal 
procedure.  Addition of pharmacovigilance contact information. 
34. Section 9.1.5.5:  Collection and reporting of male subject partner pregnancies removed. 
35. Section 9.1.5.6:  Addition of section for reporting of implant applicator malfunction or 
failure 
36. Section 10.2:  Revision of definition of efficacy evaluable population. 
37. Section 10.3.2.1: Addition of pharmacokinetic analyses for N-despropyl ropinirole and 7-
hydroxy ropinirole. 
38. Section 10.3.3:  Clarification of planned AE listings. 
39. Section 15.2:  Clarifications for record retention requirements following study closure. 
40. Administrative  and grammatical edits were made throughout the protocol 
 
 


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INVESTIGATOR’S SIGNATURE 
 
I have received and read the investigator’s brochure for Ropinirole implants.  I have read protocol 
ROP-001 Amendment 1 and agree to conduct the study as outlined.  I agree to maintain the 
confidentiality of all information received or developed in connection with this protocol. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Title of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Date 




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TABLE OF CONTENTS  
SUMMARY OF CHANGES ...........................................................................................................2 
TABLE OF CONTENTS .................................................................................................................7 
LIST OF TABLES .........................................................................................................................12 
LIST OF FIGURES .......................................................................................................................12 
LIST OF ABBREVIATIONS ........................................................................................................13 
1. 
INTRODUCTION ......................................................................................................15 
2. 
OBJECTIVES .............................................................................................................17 
2.1. 
Primary Objectives .....................................................................................................17 
2.2. 
Secondary Objective ...................................................................................................17 
2.3. 
Exploratory Objectives ...............................................................................................17 
3. 
INVESTIGATIONAL PLAN .....................................................................................18 
3.1. 
Overall Study Design ..................................................................................................18 
3.1.1. 
Study Duration ............................................................................................................19 
3.1.2. 
Subject Participation ...................................................................................................19 
3.1.3. 
Methodology and Dosing ...........................................................................................19 
3.1.3.1. 
Period 1 .......................................................................................................................19 
3.1.3.2. 
Ropinirole Implant Insertion and Period 2 (Maintenance Phase) ...............................20 
3.1.3.3. 
Ropinirole Implant Removal and Follow-up ..............................................................20 
3.1.3.4. 
Ropinirole Implant Insertion and Removal Procedures..............................................20 
3.1.3.5. 
Investigator Training ..................................................................................................20 
3.2. 
Study Endpoints ..........................................................................................................21 
3.2.1. 
Safety and Tolerability Assessments ..........................................................................21 
3.2.2. 
Pharmacokinetic Assessments ....................................................................................21 
3.2.3. 
Efficacy Assessments .................................................................................................21 
3.2.4. 
Exploratory Assessments ............................................................................................22 
3.2.5. 
Other Assessments ......................................................................................................22 
3.2.6. 
Satisfaction Surveys ....................................................................................................22 
4. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................23 
4.1. 
Inclusion Criteria ........................................................................................................23 
4.2. 
Exclusion Criteria .......................................................................................................23 
4.3. 
Implantation Criteria ...................................................................................................26 


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4.4. 
Subject Withdrawal Criteria .......................................................................................26 
4.5. 
Clinical Management ..................................................................................................27 
5. 
STUDY SCHEDULE AND PROCEDURES ............................................................28 
5.1. 
Study Schedule ...........................................................................................................28 
5.2. 
Study Visits .................................................................................................................28 
5.2.1. 
Screening Period / Visit S1 (2 - 4 Weeks) ..................................................................28 
5.2.2. 
Period 1 (Pre-Implantation Baseline) .........................................................................29 
5.2.2.1. 
Period 1 / Visit P1 .......................................................................................................29 
5.2.2.2. 
Period 1 / Visit Day -2 ................................................................................................29 
5.2.2.3. 
Period 1 / Visit Day -1 ................................................................................................30 
5.2.3. 
Period 2 (Post-Implantation) .......................................................................................31 
5.2.3.1. 
Period 2 / Implant Visit (Day 1) .................................................................................31 
5.2.3.2. 
Period 2 / Day 2 Visit .................................................................................................32 
5.2.3.3. 
Period 2 / Day 3 Visit .................................................................................................32 
5.2.3.4. 
Period 2 / Day 4 Visit .................................................................................................32 
5.2.3.5. 
Period 2 / Weeks 1 – 10 ..............................................................................................33 
5.2.3.6. 
Weeks 1, 2 and 3 .........................................................................................................33 
5.2.3.7. 
Week 4 ........................................................................................................................33 
5.2.3.8. 
Week 6 ........................................................................................................................34 
5.2.3.9. 
Week 8 ........................................................................................................................34 
5.2.3.10. 
Week 10 ......................................................................................................................35 
5.2.4. 
End of Treatment / Week 12 or Early Withdrawal Visit ............................................35 
5.2.5. 
Follow-up Period ........................................................................................................36 
5.2.5.1. 
Follow-up Period / Week 13 .......................................................................................36 
5.2.5.2. 
Follow-Up Period / Week 14 ......................................................................................37 
5.2.6. 
Unscheduled Visits .....................................................................................................37 
6. 
ASSESSMENTS.........................................................................................................44 
6.1. 
Informed Consent .......................................................................................................44 
6.2. 
Eligibility Review .......................................................................................................44 
6.2.1. 
United Kingdom Brain Bank Diagnostic Criteria ......................................................44 
6.2.2. 
Mini Mental State Examination (MMSE) ..................................................................44 
6.3. 
Demographics and Medical and Medications History ................................................44 
6.4. 
Safety and Tolerability Assessments ..........................................................................44 


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6.4.1. 
Adverse Events ...........................................................................................................44 
6.4.2. 
Physical and Neurological Examination and Abbreviated Review of Systems .........45 
6.4.3. 
Implant Site Examination/Treatment Compliance .....................................................45 
6.4.4. 
Height and Weight ......................................................................................................45 
6.4.5. 
Vital Signs ..................................................................................................................45 
6.4.6. 
Electrocardiography (ECG) ........................................................................................45 
6.4.7. 
Columbia Suicide Severity Rating Scale (C-SSRS) ...................................................46 
6.4.8. 
Scale for Outcomes of Parkinson’s Disease-Psychiatric Complications 
(SCOPA-PC)...............................................................................................................46 
6.5. 
Efficacy Assessments .................................................................................................46 
6.5.1. 
Movement Disorder Society-Sponsored Revision of the Unified Parkinson’s 
Disease Rating Scale (MDS-UPDRS) ........................................................................46 
6.5.2. 
Parkinson’s Disease Sleep Scale (PDSS-2) ................................................................46 
6.5.3. 
Epworth Sleepiness Scale (ESS) ................................................................................46 
6.5.4. 
Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease-
Rating Scale (QUIP-RS) .............................................................................................46 
6.5.5. 
Awake “On and Off” Time Diary (Hauser Diary) ......................................................46 
6.6. 
Concomitant Medications/Therapies ..........................................................................47 
6.7. 
Laboratory Assessments .............................................................................................47 
6.7.1. 
Serum Chemistry, Hematology, Coagulation Profile, Urinalysis, and Virus 
Serology ......................................................................................................................47 
6.7.2. 
Urine Drug and Cotinine Screen and Breath Alcohol Test ........................................48 
6.8. 
Pharmacokinetic Assessments ....................................................................................48 
6.9. 
Other Assessments ......................................................................................................48 
6.9.1. 
Palpation of Implant(s) ...............................................................................................48 
6.9.2. 
Ultrasound for Depth of Implant(s) ............................................................................48 
6.10. 
Satisfaction Surveys ....................................................................................................48 
7. 
INVESTIGATIONAL DRUG INFORMATION AND MANAGEMENT ...............49 
7.1. 
Investigational Drug Dose Regimen ...........................................................................49 
7.2. 
Dose Rationale ............................................................................................................49 
7.3. 
Investigational Drug Packaging and Labeling ............................................................49 
7.4. 
Investigational Drug Storage ......................................................................................50 
7.5. 
Investigational Drug Administration ..........................................................................50 
7.6. 
Investigational Drug Accountability ...........................................................................50 


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8. 
TREATMENT OF SUBJECTS ..................................................................................51 
8.1. 
Concomitant Medication ............................................................................................51 
8.2. 
Other Restrictions .......................................................................................................51 
8.3. 
Treatment Compliance ................................................................................................51 
8.4. 
Treatment Identification Card .....................................................................................51 
8.5. 
Wound Care Information Sheet ..................................................................................51 
9. 
ADVERSE EVENTS..................................................................................................52 
9.1. 
Adverse and Serious Adverse Events .........................................................................52 
9.1.1. 
Definitions of Adverse Events ....................................................................................52 
9.1.1.1. 
Adverse Event (AE) ....................................................................................................52 
9.1.1.2. 
Serious Adverse Event (SAE) ....................................................................................52 
9.1.1.3. 
Adverse Reaction (AR) and Suspected Adverse Reaction (SAR) ..............................53 
9.1.1.4. 
Unexpected Adverse Reaction (UAR) ........................................................................53 
9.1.2. 
Severity of AEs/SAEs .................................................................................................54 
9.1.3. 
Relationship to Investigational Product ......................................................................54 
9.1.4. 
Collecting and Recording Adverse Events .................................................................55 
9.1.4.1. 
Period of Collection ....................................................................................................55 
9.1.4.2. 
Methods of Collection ................................................................................................55 
9.1.4.3. 
Recording Method ......................................................................................................56 
9.1.5. 
Reporting Adverse Events or Ropinirole Implant Applicator Incidents ....................56 
9.1.5.1. 
Reporting SAEs to Titan .............................................................................................56 
9.1.5.2. 
Reporting SAEs to Health Authorities .......................................................................57 
9.1.5.3. 
Reporting SAEs to IRB(s) ..........................................................................................57 
9.1.5.4. 
Reporting SAEs to the DSMB ....................................................................................57 
9.1.5.5. 
Reporting Pregnancy ..................................................................................................57 
9.1.5.6. 
Ropinirole Implant Applicator Malfunction or Failure and Reporting ......................58 
10. 
STATISTICS ..............................................................................................................59 
10.1. 
Power and Sample Size Determination ......................................................................59 
10.2. 
Analysis Populations ..................................................................................................59 
10.3. 
Pharmacokinetics and Safety Analyses ......................................................................59 
10.3.1. 
Background and Demographic Characteristics ..........................................................59 
10.3.2. 
Pharmacokinetic Analyses ..........................................................................................59 
10.3.2.1. 
Pharmacokinetic Analyses and Presentations .............................................................59 


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10.3.3. 
Safety Analyses ..........................................................................................................60 
10.3.4. 
Prior and Concomitant Medications; Concomitant Therapies ....................................61 
10.4. 
Efficacy and Exploratory Analyses ............................................................................61 
10.5. 
Other Statistical Considerations .................................................................................61 
10.5.1. 
Missing Data ...............................................................................................................61 
10.5.2. 
Visit Windows ............................................................................................................61 
11. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................62 
11.1. 
Study Monitoring ........................................................................................................62 
11.2. 
Source Documents ......................................................................................................62 
11.3. 
Data Collection and Management ..............................................................................62 
12. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................63 
13. 
ETHICS ......................................................................................................................64 
13.1. 
Ethics Review .............................................................................................................64 
13.2. 
Ethical Conduct of the Study ......................................................................................64 
13.3. 
Written Informed Consent ..........................................................................................64 
13.3.1. 
Subject Information and Informed Consent ...............................................................64 
13.3.2. 
Provision of New and Important Information Influencing Subject’s Consent 
and Revision of the Written Information ....................................................................64 
13.4. 
Subject Confidentiality ...............................................................................................65 
14. 
ADMINISTRATIVE PROCEDURES .......................................................................66 
14.1. 
Publications of the Clinical Study ..............................................................................66 
14.2. 
Protocol Amendments and Deviations .......................................................................66 
14.3. 
Data and Safety Monitoring Board (DSMB) ..............................................................66 
14.4. 
Dose Escalation Committee (DEC) ............................................................................66 
15. 
DATA HANDLING AND RECORD KEEPING ......................................................67 
15.1. 
Inspection of Records .................................................................................................67 
15.2. 
Retention of Records ..................................................................................................67 
16. 
REFERENCES ...........................................................................................................68 
 


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LIST OF TABLES 
Table 1: 
Period 1 Dosing Schedule and Conversion from Ropinirole Extended-
Release Formulation ...................................................................................................19 
Table 2: 
Study Schedule of Events ...........................................................................................38 
Table 3: 
Schedule of PK Blood Sample Collection ..................................................................42 
Table 4: 
Attribution of Adverse Events ....................................................................................55 
LIST OF FIGURES 
Figure 1: 
ROP-001 Study Design Schematic .............................................................................18 
 


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LIST OF ABBREVIATIONS 
The following abbreviations are used in this study protocol. 
 
Abbreviation or specialist term 
Explanation 
AE 
adverse event 
AR 
adverse reaction 
AUC0-t 
area under the plasma concentration versus time curve from time 0 to 
time of last measureable concentration 
AUC0-24 
area under the plasma concentration versus time curve from time 0 to 
24 hours 
BLOQ 
below the limit of quantitation 
BP 
blood pressure 
CDS 
continuous dopaminergic stimulation 
CFR 
Code of Federal Regulations 
Cmax 
maximum measured plasma concentration 
Cmin 
minimum measured plasma concentration 
CRU 
Clinical Research Unit 
CS 
clinically significant 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CYP 
cytochrome P450 
DBP 
diastolic blood pressure 
DEC 
dose escalation committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EE 
efficacy evaluable 
EOT 
end of treatment 
ESS 
Epworth Sleepiness Scale 
EVA 
ethylene vinyl acetate 
GCP 
Good Clinical Practice 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 


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IR 
immediate-release 
IRB 
institutional review board 
λz 
first-order terminal elimination rate constant  
L-Dopa 
levodopa 
MDS-UPDRS 
Movement Disorder Society-sponsored revision of the 
Unified Parkinson’s Disease Rating Scale  
MMSE 
Mini-Mental State Examination 
MOP 
Manual of Procedures 
NCS 
not clinically significant 
PD 
Parkinson’s disease 
PDSS-2 
Parkinson’s Disease Sleep Scale 
PK 
pharmacokinetic(s) 
QUIP-RS 
Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s 
Disease-Rating Scale 
Ropinirole 
ropinirole hydrochloride 
SAE 
serious adverse event 
SAR 
suspected adverse reaction 
SBP 
systolic blood pressure  
SCOPA-PC 
Scale for Outcomes of Parkinson’s disease – Psychiatric 
Complications 
SOP 
standard operating procedure 
t½ 
terminal elimination half-life 
t.i.d. 
3 times daily 
Tmax 
time to maximum plasma concentration 
UAR 
unexpected adverse reaction 
WHO 
World Health Organization 
 


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1. 
INTRODUCTION 
Parkinson’s disease (PD) is a progressively debilitating neurological disorder affecting around 1 million 
or more people in the United States and about 5 million people worldwide.  This disease of the central 
nervous system is marked by various motor impairments including tremor, muscular rigidity, slowness of 
movement, decreased dexterity, and imbalance.  Chiefly affecting middle-aged and elderly people, it is 
associated with degeneration of the basal ganglia of the brain and a regional deficiency of the 
neurotransmitter dopamine. 
Treatment for PD is primarily based on a dopamine replacement strategy.  While dopaminergic drugs are 
highly beneficial in the early stages of treatment, benefits are limited by the development of motor 
complications and other problems not related to dopamine deficiency, such as non-motor features.  Higher 
doses of dopaminergic medication are often associated with an increased risk of motor fluctuations and 
dyskinesia as well as sedation and hallucinations (Olanow et al., 2013). 
Ropinirole hydrochloride (ropinirole) is a dopamine agonist that provides anti-parkinsonian benefits 
similar to those of levodopa but with a lower risk of inducing motor complications (Rascol et al., 2000).  
It is currently marketed in immediate-release and extended-release (once-daily) formulations.  Oral 
dosing with ropinirole typically provides an initial peak blood level of the drug, which declines relatively 
rapidly, reaching subtherapeutic trough levels after several hours, thus necessitating repeat dosing for 
maintenance of therapeutic effect.  High maximum serum concentration levels in the initial period 
following dosing may contribute to side effects experienced with ropinirole in over one-third of PD 
patients; these include nausea, dizziness, hypotension, dyskinesias, and drowsiness 
Titan Pharmaceuticals, Inc. (Titan) has developed an implant to provide sustained-release of ropinirole 
following subdermal insertion.  Titan plans to develop this implant as a potential therapy for the signs and 
symptoms of idiopathic Parkinson’s disease.  This implant is based on the ProNeura™ technology 
utilized in Probuphine®, a buprenorphine hydrochloride implant.  Pharmacokinetic (PK) studies of 
Probuphine demonstrated an early, brief pulse of buprenorphine release followed by sustained low plasma 
levels for 6 months.  The ProNeura implant technology may offer a far more consistent and durable 
sustained-release profile as compared to biodegradable polymer formulations and there is no risk of 
unintended release that can sometimes occur with reservoir-based implants.  When implanted 
subdermally, a ropinirole implant allows for the drug substance to be slowly and continuously released 
through the process of dissolution-controlled diffusion, resulting in sustained release of ropinirole over a 
3-month period.  Continuous dopaminergic stimulation (CDS) is a major aim for pharmacotherapy in PD, 
as there is strong evidence that it can provide substantial improvement for long-term outcomes 
(Fernandez et al., 2015 and Zulli et al., 2016).  One important goal that CDS may provide is delay in the 
onset of levodopa-induced dyskinesias as well as their duration and severity if they do develop.  
Continuous dopaminergic stimulation via the ProNeura subdermal drug delivery system could mitigate 
the problems of pulsatile delivery of oral dopamine-replacement therapy, while simultaneously avoiding 
technical and tolerability problems associated with infusion pumps (currently used for apomorphine and 
carbidopa-levodopa gel suspension).  Data from non-human primate models of PD using dopaminergic 
agonist-containing implants using the ProNeura platform have shown management of parkinsonian signs 
without skin irritation and inflammation, and with improvements in motor function, and attenuation of 
levodopa-induced dyskinesias (Bibbiani et al., 2005; Sreedharan et al., 2015). 


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This study will be conducted in compliance with the protocol, Good Clinical Practice (GCP), and all 
applicable regulatory requirements.  


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2. 
OBJECTIVES 
2.1. 
Primary Objectives 
• 
To assess the relative bioavailability of ropinirole implants versus oral immediate-
release (IR) ropinirole as determined by plasma ropinirole AUC0-24 in subjects with PD. 
• 
To assess the safety and tolerability of ropinirole implants over a 3-month course of 
treatment. 
2.2. 
Secondary Objective 
• 
To assess the efficacy of ropinirole implants in controlling motor fluctuations and drug-
induced dyskinesias. 
• 
To assess plasma pharmacokinetics for major metabolites of ropinirole, N-despropyl 
ropinirole and 7-hydroxyl ropinirole, for ropinirole implants versus oral IR ropinirole. 
2.3. 
Exploratory Objectives 
• 
To assess the efficacy of ropinirole implants on clinical features of PD. 
• 
To assess the safety and effectiveness of the Ropinirole Implant Applicator for the 
subdermal placement of ropinirole implants. 
• 
To assess Implanting Physician satisfaction with the design and functionality of the 
Ropinirole Implant Applicator for the subdermal placement of ropinirole implants. 
 


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3. 
INVESTIGATIONAL PLAN 
3.1. 
Overall Study Design 
This study is a phase 1/2 open-label relative bioavailability study evaluating the safety, tolerability, and 
PK of 4 dose levels of ropinirole implants.  The doses will be administered sequentially in patients with 
PD.  The study design schematic is shown in Figure 1; the study consists of 4 parts:  Screening, Period 1, 
Period 2, and Follow-Up.   
Figure 1: 
ROP-001 Study Design Schematic 
 
   
IR = immediate release; PK = blood draw for pharmacokinetic assessments; S = screening; MDS-UPDRS =  
Movement Disorder Society-sponsored revision of the Unified Parkinson’s Disease Rating Scale 
Cohort 1: 4.5 – 6.0 mg/day, IR; 1 ropinirole implant 
Cohort 2: 7.5- 9.0 mg/day, IR; 2 ropinirole implants 
Cohort 3: 12.0 – 14.25 mg/day, IR; 3 ropinirole implants 
Cohort 4: 15.0 – 17.25 mg/day, IR; 4 ropinirole implants 
The study will enroll approximately 20 subjects across 1-3 sites in the U.S in 4 cohorts based on the fixed 
dose of IR ropinirole that the subject is currently taking, or if the subject is taking the extended-release 
product, they must convert to the IR formulation as shown in Table 1. 
• 
Cohort 1:  Subjects on a fixed dose in the range of 4.5 to 6.0 mg/day of IR ropinirole;  
• 
Cohort 2:  Subjects on a fixed dose in the range of 7.5 to 9.0  mg/day IR ropinirole;  
• 
Cohort 3:  Subjects on a fixed dose in the range of 12.0 to 14.25 mg/day IR ropinirole; 
and 
• 
Cohort 4:  Subjects on a fixed dose in the range of 15.0 to 17.25 mg/day IR ropinirole.   
Enrollment will initially be restricted to Cohort 1 until the determination is made to open enrollment to 
Cohort 2 based on an evaluation of safety and characterization of the PK profile of approximately 5 
subjects over the full 12-week period for Cohort 1 by both an independent data safety monitoring board 
(DSMB) and Titan, which make up the dose escalation committee (DEC).  Prior to commencement of 


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enrollment for Cohort 3, review of Cohort 2 safety and PK data through the Week 4 Visit will be 
required, in addition to ongoing safety review of currently enrolled subjects.  Prior to commencement of 
enrollment for Cohort 4, review of Cohort 3 safety data through the Week 4 Visit will be required, in 
addition to ongoing safety review of currently enrolled subjects. 
Subjects who have provided written informed consent will undergo initial screening to determine 
eligibility.  Screening data from each subject will be reviewed, and a determination on the suitability of 
the subject for the study will be made by the investigator prior to initiation of IR ropinirole or ropinirole 
implant study drug.   
3.1.1. 
Study Duration 
Subjects will be seen for approximately 18 visits over a period of up to 17.5-19.5 weeks (Table 2):  
Screening, P1, Day -2, Day -1, Implant (Day 1), Post-implant Day 2, Day 3, Day 4, Treatment (Weeks 1, 
2, 3, 4, 6, 8, and 10), End of Treatment (EOT) (Week 12), and 2 Follow-up (Weeks 13 and 14).  
Additional visits may be necessary for unscheduled assessments due to adverse events (AEs). 
3.1.2. 
Subject Participation 
This study will enroll approximately 20 subjects (5 per cohort) meeting diagnostic criteria for idiopathic 
PD and the United Kingdom (UK) Brain Bank Diagnostic Criteria, aged 30 to 80 years, clinically stable 
on levodopa (L-Dopa) and ropinirole.  Enrolled subjects who withdrawal early [prior to 12 weeks on 
implant(s)] will not be replaced. 
3.1.3. 
Methodology and Dosing 
3.1.3.1. 
Period 1 
Subjects will enter screening having been on a fixed dose of 4.5 to 17.25 mg/day IR ropinirole and remain 
on their maintenance dose until implantation of ropinirole implants. 
If subjects enter screening taking the extended-release formulation of ropinirole, their medication will be 
switched to the IR formulation, to be administered 3 times daily (t.i.d.) until implantation of ropinirole 
implants, as shown in Table 1.  Period 1 will last up to 10 days, the last 7 consecutive days of which will 
be at a fixed dose.  Tablet counts will be done at every visit and subjects will complete diary cards to log 
their awake “On and Off” periods and track medication compliance.  
Table 1: 
Period 1 Dosing Schedule and Conversion from Ropinirole Extended-Release 
Formulation 
Cohort 
Ropinirole XL (once 
daily) 
Total Daily Dose 
IR Ropinirole 
1 
4 mg 
4.5 mg 
2 
8 mg 
7.5 mg 
3 
12 mg 
12 mg 
4 
16 mg 
15 mg 
IR = immediate-release; XL = extended-release; 
 


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Two days prior to the Implantation Visit (Day -2), subjects will be admitted to the Clinical Research Unit 
(CRU) in preparation for the first inpatient PK sampling visit.  Pharmacokinetic samples will be taken the 
day prior to implantation (Day -1), at the Implantation Visit (Day 1), and at the Post-implant Visit 
(Day 2).  The subjects will then be discharged on Day 2.  An additional inpatient PK visit will occur at the 
EOT Visit. 
On Day -1, each dose of IR ropinirole should be administered 8 hours apart.  Dosing times may vary in 
the preceding days, however doses must be taken t.i.d. 
Subjects will continue their L-Dopa medication as prescribed throughout the entire study. 
3.1.3.2. 
Ropinirole Implant Insertion and Period 2 (Maintenance Phase) 
Subjects meeting Implantation Criteria (Section 4.3) will undergo an in-office procedure to insert the 
ropinirole implant(s) at the start of Period 2.  Subjects completing Period 1 in the 4.5 to 6.0 mg/day IR 
ropinirole dose range will have 1 implant inserted, subjects at an IR ropinirole dose of 7.5 to 9.0 mg/day 
will receive 2 implants, subjects at a dose of 12.0 to 14.25 mg/day will receive 3 implants, and subjects at 
a dose of 15.0 to 17.25 mg/day will receive 4 implants.  Following implantation, subjects will be followed 
on treatment for 12 weeks (Period 2). 
 
  The Ropinirole Implant Applicator is similar in design to the commercially approved 
applicators currently used for the insertion of Probuphine® and other implantable drugs, such as 
Implanon® (please see the study Manual of Procedures [MOP] for details regarding the insertion 
procedure).  Subjects will be monitored closely for AEs and vital signs for at least 30 minutes following 
insertion by medically qualified study staff.   
Subjects will return intermittently for assessments of safety, PK sampling, and/or motor symptoms 
(Table 2).   
3.1.3.3. 
Ropinirole Implant Removal and Follow-up 
Ropinirole implants will be removed at the Week 12 EOT Visit in an in-office procedure.  See the Study 
MOP for Insertion/Removal Instructions and additional details regarding the removal procedure.  Subjects 
will be admitted to the CRU the day prior in preparation for inpatient PK sampling.  Following removal 
of the implant(s) and PK sampling, subjects will be transition to their pre-study treatment and will be 
followed for 2 weeks.  The transition back to oral ropinirole may be initiated after the 18-hour PK sample 
has been collected at the EOT Visit.  Subjects who are discontinued early from the study will attend the 
EOT Visit and the Follow-up Visits. 
3.1.3.4. 
Ropinirole Implant Insertion and Removal Procedures 
 
   
Implants are removed through a skin incision under local anesthesia using sterile technique.  Detailed 
insertion and removal procedures are described in the MOP provided to the investigator. 
3.1.3.5. 
Investigator Training 
All study investigators and appropriate clinical staff will be trained prior to study start, including training 
in the correct ultrasound technique for the localization of the implants.   The sponsor has developed an 


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extensive hands-on training program for Implanting Physicians that will include training on implant 
insertion and removal techniques. 
3.2. 
Study Endpoints 
3.2.1. 
Safety and Tolerability Assessments 
Safety assessments will include: 
• 
Adverse events (AEs) and serious adverse events (SAEs) related to the study drug 
• 
AEs and SAEs related to the insertion/removal procedure 
• 
Physical and neurological examinations 
• 
Vital signs including positional blood pressure measurements 
• 
12-lead electrocardiograms (ECGs) 
• 
Clinical laboratory tests (hematology, chemistry, coagulation, and urinalysis)  
• 
Implant site examinations/treatment compliance 
• 
Change from Baseline in the Columbia Suicide Severity Rating Scale (C-SSRS) 
• 
Change from Baseline in the Scales for Outcomes in Parkinson’s disease–Psychiatric 
Complications (SCOPA-PC) 
3.2.2. 
Pharmacokinetic Assessments 
The following noncompartmental PK parameters will be derived from ropinirole, N-despropyl ropinirole, 
and 7-hydroxy ropinirole plasma concentration versus time curves as appropriate:  
• 
Maximum measured plasma concentration (Cmax) 
• 
Minimum measured plasma concentration (Cmin) 
• 
Time to maximum plasma concentration (Tmax) 
• 
Area under the plasma concentration versus time curve from time 0 to time of last 
measureable concentration (AUC0-t) 
• 
Area under the plasma concentration versus time curve from time 0 to 24 hours after 
dosing (AUC0-24) 
• 
First-order terminal elimination rate constant (λz) 
• 
Terminal elimination half-life (t½) 
Additional PK parameters may be calculated if deemed appropriate. 
3.2.3. 
Efficacy Assessments 
The following endpoints will be used to evaluate the efficacy of ropinirole implants in controlling motor 
fluctuations and drug-induced dyskinesias: 
• 
Change from baseline in the Movement Disorder Society-sponsored revision of the 
Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) total score 


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• 
Change from baseline in hours of awake “On and Off” time 
3.2.4. 
Exploratory Assessments 
The following assessments will be used to evaluate the efficacy of ropinirole implants on clinical features 
of PD: 
• 
Change from baseline in Parkinson’s Disease Sleep Scale (PDSS-2) total score 
• 
Change from baseline in Epworth Sleepiness Scale (ESS) score 
• 
Change from baseline in Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s 
Disease-Rating Scale (QUIP-RS) total score 
3.2.5. 
Other Assessments 
• 
Depth of the implant(s) measured by ultrasound 
• 
Palpability of the implant(s) 
• 
Any Applicator complaints, failures and malfunctions during a procedure (whether or not 
associated with an AE) 
3.2.6. 
Satisfaction Surveys 
• 
Implanting Physician Satisfaction Survey to assess satisfaction with the design and functionality 
of the Ropinirole Implant Applicator  
• 
Patient Satisfaction Survey to assess satisfaction with the study treatment and insertion and 
removal procedures 


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4. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
4.1. 
Inclusion Criteria 
A subject must meet all of the following inclusion criteria at Screening (i.e., the answer to all of these 
questions must be “YES”) to be eligible to enroll in the study: 
1. Has the subject voluntarily provided written informed consent prior to the conduct of any 
study-related procedures? 
2. Is the subject 30 to 80 years (inclusive) of age at the time of informed consent? 
3. If female of child-bearing potential, does the subject agree to practice a clinically accepted 
method of contraception from time of informed consent to the last Follow-up Visit (as 
defined in Section 6.2)?  
4. Has the subject been on a fixed dose of L-Dopa and a fixed dose of ropinirole immediate 
release 4.5 to 17.25 mg/day (or ropinirole extended-release 4 to 16 mg/day) for at least 30 
days, and have their PD deemed clinically stable and at baseline, in the opinion of the 
investigator, for at least 2 weeks immediately prior to the Screening Visit? 
5. If the subject is taking a COMT inhibitor, MAO-B inhibitor, or amantadine medication, 
have they been on a fixed dose for at least 1 month prior to screening and are willing to 
remain at that dose for the duration of the study? 
6. Does the subject meet diagnostic criteria for idiopathic PD and the UK Brain Bank 
Criteria? 
7. Does the subject score ≥26 on the Mini-Mental State Examination (MMSE) at the 
Screening Visit? 
8. Is the subject willing and able to comply with all study requirements (protocol, clinic visits, 
procedures, diaries, and medication administration), and is the subject sufficiently 
proficient in English to understand and complete study instruments? 
9. If the subject is, or was, on hormone replacement therapy or therapy with any drug known 
to substantially inhibit cytochrome P450 (CYP) 1A2 (e.g., ciprofloxacin, fluvoxamine, 
cimetidine, ethinyl estradiol) or induce CYP1A2 (e.g., nicotine,  omeprazole):  
a. Did the subject remain on a stable dose (i.e., did not withdraw, introduce, or change 
doses) in the 14 days prior to the Screening Visit?, and  
b. Is the subject willing to remain on a stable dose from the Screening Visit through 
the Follow-up Visit? 
4.2. 
Exclusion Criteria 
Subjects are not eligible for the study if any of the following criteria are met at screening (i.e., the answer 
to all of the following questions must be “NO”):  
1. If the subject is female, is the subject pregnant, breastfeeding, or planning to become 
pregnant during the study or within 1 month after completion of the study? 


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2. Does the subject have a systolic blood pressure (SBP)  ≥180 mmHg or ≤90 mmHg OR 
diastolic blood pressure (DBP) ≥110 mmHg or ≤50 mmHg at the Screening Visit (either 
supine or erect)? 
3. Has the subject had any episodes of moderate to severe dizziness or syncope within the last 
6 months, or does the subject exhibit orthostatic hypotension, defined as a fall in blood 
pressure (BP) after rising from the supine to standing posture of >20 mmHg for systolic 
pressure and >10 mmHg for diastolic pressure during the screening assessments? 
4. Is the subject taking any dopamine agonists other than L-Dopa or ropinirole? 
5. Has the subject undergone electroconvulsive therapy in the 90 days prior to the Screening 
Visit? 
6. Does the subject have scarring or tattoos on his/her inner upper arms within 6 months prior 
to the Screening Visit or a history of keloidal scarring? 
7. Does the subject have a BMI of ≤19, and if so, do they have a skin to fascia depth of 
≤3 mm at the bicipital groove of the brachium on ultrasound? 
8. Has the subject donated or lost greater than 400 mL of blood within 1 month prior to the 
Screening Visit? 
9. Does the subject have a lifetime history of any suicide attempt (including an active attempt, 
interrupted attempt, or aborted attempt) or have had suicidal ideation in the past 6 months 
as indicated by a positive response (“Yes”) to either Question 4 or Question 5 of the 
C-SSRS at screening? 
10. Does the subject have active epilepsy (i.e., occurrence of a seizure) within the past year 
prior to the Screening Visit? 
11. Does the subject have a history of or any current non-Parkinson’s-related psychosis? 
12. If the subject has Parkinson’s disease related psychosis, in the opinion of the investigator, 
are they likely to alter the risk-benefit of study participation or to interfere with study 
conduct or interpretation of results? 
13. Does the subject have a history of or any current impulse control disorder or symptoms 
thereof? 
14. Does the subject have severe clinical dementia, e.g., scoring 4 on MDS-UPDRS item 
1.1 [Cognitive Impairment]? 
15. Does the subject have cognitive impairment in the judgment of the investigator that 
excludes him/her from understanding consent or participating in the study? 
16. Has the subject undergone deep brain stimulation or have a history of brain surgery or 
serious brain injury? 
17. Does the subject have a history of any melanoma? 
18. Does the subject have a history of alcohol or substance use disorder within the prior 
12 months, according to investigator judgment? 
19. Does the subject have a positive urine drug screen for drugs of abuse or breath alcohol test 
at the Screening Visit?  Positive urine drug  screens may not be repeated.   


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20. Does the subject use tobacco or nicotine replacement products, or have a positive urine 
cotinine test at the Screening Visit? 
21. Does the subject have a definite or suspected personal history of clinically significant 
adverse reactions or hypersensitivity to ropinirole (or to drugs with a similar chemical 
structure) or ethylene vinyl acetate (EVA) that would preclude implantation with 
ropinirole/EVA? 
22. Does the subject have a hypersensitivity to lidocaine , prilocaine, chlorhexidine, 
epinephrine, or adhesive dressing?  
23. Does the subject have a history of wound healing problems? 
24. Does the subject have a history of coagulopathy within the past 90 days; current 
anti-coagulant therapy, such as warfarin or any non-over the counter anti-coagulant; or any 
other medications or condition that in the opinion of the investigator would pose an 
increased risk of bleeding during a surgical procedure? 
25. In the investigator’s opinion, is the subject at risk of prolonged bleeding times based on 
history, prothrombin time, partial thromboplastin time, or platelet count? 
26. Does the subject have an atypical parkinsonian syndrome or secondary parkinsonism 
(e.g., due to drugs, metabolic disorders, encephalitis, cerebrovascular disease, or 
degenerative disease) or has the subject used medications within 6 months prior to the 
Screening Visit that may cause secondary parkinsonism, including but not limited to:  
dopamine antagonists (other than quetiapine [up to 100 mg/day] or pimavanserin [at doses 
labelled for treatment of PD]), antipsychotic or neuroleptic medications, metoclopramide, 
alpha-methyldopa, flunarizine, cinnarizine, reserpine, or stimulant medications such as 
methylphenidate or amphetamine?  
27. Does the subject have a history of neuroleptic malignant syndrome? 
28. Has the subject used any other investigational drug within 60 days or 5 half-lives 
(whichever is longer) prior to the Screening Visit, or have plans to take such a drug any 
time during the study (through the end of the Follow-up period)? 
29. Does the subject have a positive test for human immunodeficiency virus (HIV), hepatitis C 
virus (HCV), or hepatitis B virus (HBV) at screening? 
30. Does the subject have aspartate aminotransferase (AST) levels >2X the upper limit of 
normal (ULN), alanine aminotransferase (ALT) >2X ULN, total bilirubin >1.5X ULN 
(unless only from Gilbert’s syndrome), or serum creatinine >1.5X ULN, or other significant 
abnormalities in laboratory or ECG tests at screening that in the investigator’s opinion 
unfavorably alters the risk-benefit of study participation? 
31. Does the subject have any clinically significant medical, surgical, psychiatric, or social 
condition(s) other than PD, or is taking a concomitant medication that, in the opinion of the 
investigator, unfavorably alters the risk-benefit of study participation or is likely to interfere 
with study participation or accurate data collection? 


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4.3. 
Implantation Criteria 
Prior to implantation at the Implant Visit, subjects must meet the following criteria (i.e., the answer to all 
of these questions must be “YES”):  
1. Does the subject continue to satisfy all inclusion and exclusion criteria? 
2. Does the subject have a negative urine drug screen for drugs of abuse, cotinine and breath 
alcohol test at the Day -2 Visit?  Positive urine drug and breath alcohol screens may not be 
repeated.  Subjects should be informed that no alcohol should be consumed within 24 hours 
of any visit. 
3. Does the subject have a supine or erect SBP of <180 mmHg or >90 mmHg AND DBP 
<110 mmHg or >50 mmHg at the Implant Visit? 
4. Has the subject been compliant in taking his/her assigned IR ropinirole study medication? 
5. Did the subject complete Period 1 with at least 7 consecutive days at the assigned fixed 
treatment dose of oral ropinirole tablets just prior to implantation? 
4.4. 
Subject Withdrawal Criteria 
Every subject has the right to refuse participation in treatment or the study at any time and without 
providing reasons.  A subject’s participation must be terminated immediately upon his/her request and 
reason(s) for discontinuation documented accordingly in the corresponding eCRF.  
Any subject who meets one or more of the following criteria will be removed from study drug treatment 
without prejudice: 
• 
Subject request 
• 
Subject noncompliance, defined as refusal or inability to adhere to the study protocol or 
any other instances determined by the investigator  
• 
Subject refusal to receive implants  
• 
Evidence of implant removal or attempted removal of the implant 
• 
A medically significant infection or other medically significant AE at the implant site 
• 
Unacceptable or intolerable treatment-related AE    
• 
Pregnancy 
• 
Use of or abuse of non-study assigned ropinirole 
• 
Use of dopamine antagonists other than quetiapine (up to 100 mg/day) or pimavanserin 
(at doses labelled for treatment of PD) 
• 
Deep brain stimulation 
• 
Use of any investigational treatment  
• 
Intercurrent illness or circumstances that would, in the judgment of the investigator, 
affect assessments of clinical status to a significant extent, require discontinuation of 
drug, or both 


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• 
At request of Titan, regulatory agencies, or an institutional review board (IRB) of 
record 
• 
Lost to follow-up 
Any subject who meets the above criteria should be seen for an EOT Visit during which implant(s) will 
be removed.  The reason for discontinuation/removal shall be documented.  The implant(s) will not be 
replaced, and follow-up clinical evaluations will be performed as outlined in Section 5.2.5, where possible. 
Titan retains the right to end the study at any time.  In case of premature termination or suspension of the 
study, Titan will promptly inform the investigator/institutions and regulatory authorities, of the 
termination or suspension and the reason for termination/suspension.  
4.5. 
Clinical Management  
Based on preclinical data, a temporary increase in ropinirole plasma concentrations is expected to occur 
following insertion of the ropinirole implant and to last approximately 8-12 hours.   Maximum measured 
plasma concentration (Cmax ) during this period may briefly reach a level corresponding to approximately 
two times the Cmax following the subject’s baseline oral dose.  During this period, subjects may 
experience symptoms similar to those associated with mild ropinirole overdose.  Such symptoms reported 
during clinical trials with ropinirole included vomiting, increased coughing, fatigue, syncope, vasovagal 
syncope, dyskinesia, agitation, chest pain, orthostatic hypotension, somnolence, and confusional state 
(Requip Label).  These symptoms will be managed at the investigator’s discretion. 


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5. 
STUDY SCHEDULE AND PROCEDURES 
5.1. 
Study Schedule 
The study schedule can be found in Table 2, and the PK blood sample collection schedule can be found in 
Table 3.  Detailed information on study assessments is provided in Section 6.   
5.2. 
Study Visits 
5.2.1. 
Screening Period / Visit S1 (2 - 4 Weeks)  
Screening (Visit S1) will begin within 4 weeks prior to the start of Period 1.  Written informed consent 
must be obtained before any study-specific procedure is performed.  Subjects must meet all eligibility 
criteria before being enrolled in the study (see Section 4).  Screening assessments may be conducted 
across more than one visit during the screening period.  
The following information will be collected and procedures performed: 
• 
Obtain written informed consent 
• 
Eligibility criteria review 
• 
Demographics 
• 
Obtain medical and medications history (including history of PD and PD medications) 
• 
Urine drug and cotinine screen and alcohol breath test (to be performed prior to cognitive and 
motor assessments).  Subjects with a positive alcohol breath test at the S1 Visit should be 
rescheduled to return to complete the remaining procedures along with another alcohol breath test.  
During the S1 Visit, and onward, subjects should be instructed not to consume alcohol within 24 
hours of any subsequent visit. 
• 
Clinical chemistry, hematology, coagulation profile, urinalysis  
• 
Neurological examination  
• 
UK Brain Bank Diagnostic Criteria 
• 
MMSE 
• 
Hoehn and Yahr scale 
• 
MDS-UPDRS 
• 
C-SSRS 
• 
SCOPA-PC 
• 
QUIP-RS 
• 
Serum pregnancy test (females of childbearing potential only) 
• 
Standard 12-lead ECG 
• 
Height 


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• 
Weight  
• 
Vital signs (supine and standing BP [orthostatic measurements], pulse rate, respiratory rate, and 
oral body temperature) 
o Two sets of measurements of supine/erect BP should be obtained at least 15 minutes 
apart.  These measurements will be recorded in the eCRF.  Subjects with any readings 
that are exclusionary will not be eligible for the study. 
• 
Physical examination 
• 
Virus serology:  HBV, HCV, HIV (Ensure that the subject has been properly consented and was 
counseled prior to drawing blood for testing; HBV, HCV, and HIV testing is required unless a 
site’s IRB or country-specific laws/regulations prohibit such testing.) 
• 
Dispense subject diary cards 
• 
Hauser Diary concordance training 
5.2.2. 
Period 1 (Pre-Implantation Baseline)  
5.2.2.1. 
Period 1 / Visit P1  
The Period 1 (P1) Visit should occur as soon as all eligibility criteria have been satisfied following 
Visit S1.  Period 1 will last up to 10 days, the last 7 consecutive days of which will be at a fixed dose of 
oral ropinirole.  Refer to Section 3.1.3.1 for additional details on dosing during Period 1. 
The following information will be collected and procedures performed: 
• 
C-SSRS 
• 
SCOPA-PC 
• 
Weight 
• 
Vital signs (supine and standing BP [orthostatic measurements], pulse rate, respiratory rate, and 
oral body temperature) 
• 
Dispense and collect subject diary cards 
• 
Dispense oral ropinirole tablets 
• 
Record AEs 
• 
Review concomitant medications 
5.2.2.2. 
Period 1 / Visit Day -2 
Two days prior to the Implantation Visit (Day -2), subjects will be admitted to the CRU in preparation for 
the first inpatient PK sampling visit beginning the following morning.  Subjects will be confined to the 
CRU from the time of check-in on Day -2 until discharge following all scheduled procedures on Day 2.  
Subjects should be reminded to bring their unused study drug or empty packaging to this visit, and also 
that no alcohol is allowed within 24 hours of any study visit. 
The following information will be collected and procedures performed: 
• 
C-SSRS 


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• 
SCOPA-PC 
• 
PDSS-2 
• 
ESS 
• 
Urine pregnancy test (females of childbearing potential only) 
• 
Standard 12-lead ECG 
• 
Weight 
• 
Vital signs (supine and standing BP [orthostatic measurements], pulse rate, respiratory rate, and 
oral body temperature) 
• 
Clinical chemistry, hematology, coagulation profile, urinalysis 
• 
Urine drug and cotinine screen and alcohol breath test 
• 
Collect subject diary cards 
• 
Treatment compliance (tablet counts) 
• 
Record AEs 
• 
Review concomitant medications 
5.2.2.3. 
Period 1 / Visit Day -1 
On Day -1, the following information will be collected and procedures performed: 
• 
Low fat meals should be provided to each subject at mealtime on this day.  Low fat meals are 
meals where ≤30% of calories are from fat. 
• 
Vital signs (supine and standing BP [orthostatic measurements], pulse rate, respiratory rate, and 
oral body temperature) 
• 
PK blood sample collection: 
o Each dose of ropinirole should be administered with 8 ounces of water, dosing should be 
observed, a hand/mouth check should be performed, and the time of dosing should be 
recorded.  On Day -1, each dose of IR ropinirole should be administered 8 hours apart.  
Dosing times may vary in the preceding days, however doses must be taken t.i.d.  The 
second and third doses of ropinirole are to be taken immediately following the 8-hour and 
16-hour PK draws, respectively. 
o PK sampling will be done predose (0 hours), and postdose at 0.5 hours, 1 hour, 1.5 hours, 
2 hours, 4 hours, 8 hours,8.5 hours, 9 hours, 9.5 hours, 10 hours, 12 hours, 16 hours, 16.5 
hours, 17 hours, 17.5 hours, 18 hours, 20 hours, and 24 hours as specified in Table 3. 
o Sites are encouraged to collect the inpatient PK samples within a ±2 minute window.  
Collections falling outside this window, unless the difference in time is inordinately large, 
will not be considered a protocol deviation. 
 
o The nondominant arm will be selected for blood draws, and implantation, so that the 
opposite arm will be available for BP readings and activities such as eating. 


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• 
Treatment compliance (tablet counts) 
• 
Record AEs 
• 
Review concomitant medications 
5.2.3. 
Period 2 (Post-Implantation) 
5.2.3.1. 
Period 2 / Implant Visit (Day 1) 
Following the completion of the PK sample collection occurring on Day -1, the following baseline 
procedures will be performed on Day 1, prior to implantation.  The subject will be served breakfast at 
least 1 hour prior to implantation. 
Prior to Implantation: 
• 
Eligibility criteria review, including Implantation Criteria in Section 4.3  
• 
Neurological examination  
• 
Vital signs (supine and standing BP [orthostatic measurements], pulse rate, respiratory rate, and 
oral body temperature) 
o Subjects with any BP readings that do not meet Implantation Criteria will not be 
implanted and will be withdrawn from study. 
• 
Abbreviated review of systems  
• 
Urine drug and cotinine screen and alcohol breath test  
• 
Implant site examination/treatment compliance (tablet counts) 
• 
PK blood sample collection (0 hour time point) 
 
Implant Insertion: 
• 
Insertion of ropinirole implant(s) 
• 
Palpation of implant(s) as detailed in the MOP 
• 
Vital signs (supine and standing BP [orthostatic measurements], pulse rate, respiratory rate, and 
oral body temperature) 
o Orthostatic hypotension measures (supine and standing BP and 60 second pulse rate) will 
be taken at the following post-implantation time points:  0.5 hours, 1 hour, 2 hours, and 
4 hours.  
o Respiratory rate and body temperature will be collected at 15 minutes and 30 minutes 
following implant insertion. 
• 
PK blood sample collection at 1 hour, 2 hours, 4 hours, 8 hours, 12 hours, and 20 hours 
postimplantation as specified in Table 3  
• 
Standard 12-lead ECG at 3 hours [±15 minutes] 
• 
Dispense treatment identification card 
• 
Provide wound care information sheet 


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• 
Record AEs (monitor AEs for at least 30 minutes after removal) 
• 
Review concomitant medications  
• 
Insertion Procedure Assessment Form 
• 
Implanting Physician Satisfaction Survey 
5.2.3.2. 
Period 2 / Day 2 Visit 
This visit will occur the day after the Implant Visit, while the subject is still an inpatient.  The following 
assessments and evaluations will occur at this visit: 
• 
Vital signs (supine and standing BP [orthostatic measurements], pulse rate, respiratory rate, and 
oral body temperature) 
• 
Dispense subject diary cards 
• 
Implant site examination/treatment compliance 
• 
Record AEs 
• 
Review concomitant medications 
• 
PK blood sample collection at 24 hours and 36 hours post-implantation, as specified in Table 3  
• 
Following collection of the, 36-hour PK sample on Day 2, subjects will be discharged from the 
CRU and instructed to return for Day 3 
5.2.3.3. 
Period 2 / Day 3 Visit 
The following assessments and evaluations will occur at this visit: 
• 
C-SSRS 
• 
SCOPA-PC 
• 
Vital signs (supine and standing BP [orthostatic measurements], pulse rate, respiratory rate, and 
oral body temperature) 
• 
Implant site examination/treatment compliance 
• 
Record AEs 
• 
Review concomitant medications 
• 
PK blood sample collection at 0 hours (collected at the same time of day relative to the time of 
implantation) 
5.2.3.4. 
Period 2 / Day 4 Visit 
The following assessments and evaluations will occur at this visit: 
• 
C-SSRS 
• 
SCOPA-PC 
• 
Weight 


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• 
Vital signs (supine and standing BP [orthostatic measurements], pulse rate, respiratory rate, and 
oral body temperature) 
• 
Implant site examination/treatment compliance 
• 
Record AEs 
• 
Review concomitant medications 
• 
PK blood sample collection at 0 hours (collected at the same time of day relative to the time of 
implantation) 
5.2.3.5. 
Period 2 / Weeks 1 – 10 
Weeks 1-10 Visits should occur ±1 day relative to the projected time point as measured from the Implant 
Visit.  All visits are outpatient.  The following information will be collected and procedures performed at 
visits during Period 2. 
5.2.3.6. 
Weeks 1, 2 and 3 
• 
C-SSRS 
• 
SCOPA-PC 
• 
Weight 
• 
Vital signs (supine and standing BP [orthostatic measurements], pulse rate, respiratory rate, and 
oral body temperature) 
• 
Dispense and collect subject diary cards 
• 
Implant site examination/treatment compliance 
• 
Record AEs 
• 
Review concomitant medications 
• 
PK blood sample collection at 0 hours (collected at the same time of day relative to the time of 
implantation) 
5.2.3.7. 
Week 4  
• 
MDS-UPDRS 
• 
C-SSRS  
• 
SCOPA-PC 
• 
PDSS-2  
• 
ESS  
• 
QUIP-RS 
• 
Urine pregnancy test (females of childbearing potential only) 
• 
Standard 12-lead ECG 
• 
Weight 


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• 
Vital signs (supine and standing BP [orthostatic measurements], pulse rate, respiratory rate, and 
oral body temperature) 
• 
Abbreviated review of systems 
• 
Clinical chemistry, hematology, coagulation profile, urinalysis 
• 
Urine drug and cotinine screen and alcohol breath test  
• 
Dispense and collect subject diary cards 
• 
Implant site examination/treatment compliance 
• 
Record AEs 
• 
Review concomitant medications 
• 
PK sampling will be done at the following time points: 0 hours (collected at the same time of day 
relative to the time of implantation), 12 hours, and 24 hours as specified in Table 3  
5.2.3.8. 
Week 6 
• 
C-SSRS 
• 
SCOPA-PC 
• 
Weight 
• 
Vital signs (supine and standing BP [orthostatic measurements], pulse rate, respiratory rate, and 
oral body temperature) 
• 
Dispense and collect subject diary cards 
• 
Implant site examination/treatment compliance 
• 
Record AEs 
• 
Review concomitant medications 
• 
PK blood sample collection at 0 hours (collected at the same time of day relative to the time of 
implantation) 
5.2.3.9. 
Week 8 
• 
MDS-UPDRS 
• 
C-SSRS 
• 
SCOPA-PC 
• 
PDSS-2 
• 
ESS  
• 
QUIP-RS  
• 
Urine pregnancy test (females of childbearing potential only) 
• 
Weight 


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• 
Vital signs (supine and standing BP [orthostatic measurements], pulse rate, respiratory rate, and 
oral body temperature) 
• 
Abbreviated review of systems 
• 
Dispense and collect subject diary cards 
• 
Implant site examination/treatment compliance 
• 
Record AEs 
• 
Review concomitant medications 
• 
PK blood sample collection at 0 hours (collected at the same time of day relative to the time of 
implantation), 12 hours, and 24 hours as specified in Table 3  
5.2.3.10. Week 10 
• 
C-SSRS 
• 
SCOPA-PC 
• 
Weight 
• 
Vital signs (supine and standing BP [orthostatic measurements], pulse rate, respiratory rate, and 
oral body temperature) 
• 
Dispense and collect subject diary cards 
• 
Implant site examination/treatment compliance 
• 
Record AEs 
• 
Review concomitant medications 
• 
PK blood sample collection at 0 hours (collected at the same time of day relative to the time of 
implantation) 
5.2.4. 
End of Treatment / Week 12 or Early Withdrawal Visit 
The EOT Visit should occur no less than 12 weeks from the Implant Visit, except in cases of early 
withdrawal.  Subjects will report to the CRU for admission during the evening of the day prior to the 
Week 12 Visit or early termination, in preparation for implant removal and PK sampling beginning the 
following morning.  Subjects should be reminded that no alcohol is allowed within 24 hours of any study 
visit.  The subject will be served breakfast at least 1 hour prior to removal of the implant(s).  The morning 
of the Week 12 Visit, prior to the implant removal procedure, the following procedures are performed. 
Prior to Implant Removal: 
• 
Palpation of implant(s) as detailed in the MOP 
• 
Ultrasound 
• 
Neurological examination 
• 
MDS-UPDRS 
• 
C-SSRS 


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• 
SCOPA-PC 
• 
PDSS-2 
• 
ESS  
• 
QUIP-RS  
• 
Standard 12-lead ECG 
• 
Weight 
• 
Vital signs (supine and standing BP [orthostatic measurements], pulse rate) 
• 
Abbreviated review of systems 
• 
Clinical chemistry, hematology, coagulation profile, urinalysis 
• 
Implant site examination/treatment compliance 
• 
Collect subject diary cards 
• 
PK blood sample collection (0 hour time point) 
Implant Removal: 
• 
Removal of ropinirole implant(s)  
• 
Serum pregnancy test (females of childbearing potential only) 
• 
Vital signs (supine and standing BP [orthostatic measurements], pulse rate, respiratory rate, and 
oral body temperature) 
o Orthostatic hypotension measures (supine and standing BP and 60-second pulse rate) will 
be taken at the following time points post implantation removal:  0.5 hours, 1 hour, 
2 hours, and 4 hours  
• 
Urine drug and cotinine screen and alcohol breath test  
• 
Record AEs (monitor for AEs in the clinic for at least 30 minutes after removal) 
• 
Review concomitant medications 
• 
Provide wound care information 
• 
Removal Procedure Assessment Form 
• 
PK sampling will be done at the following time points relative to implant removal: 6 hours, 
12 hours, and 18 hours.  Any transition back to oral ropinirole should not occur until after the last 
PK sample has been collected.  
• 
Subjects will be discharged from the CRU following collection of the 18 hour PK sample 
5.2.5. 
Follow-up Period 
5.2.5.1. 
Follow-up Period / Week 13 
The following assessments and evaluations will occur at this visit: 
• 
C-SSRS 


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• 
SCOPA-PC 
• 
Weight 
• 
Vital signs (supine and standing BP [orthostatic measurements], pulse rate, respiratory rate, and 
oral body temperature) 
• 
Implant site examination 
• 
Record AEs 
• 
Review concomitant medications 
5.2.5.2. 
Follow-Up Period / Week 14 
The following assessments and evaluations will occur at this visit: 
• 
C-SSRS 
• 
SCOPA-PC 
• 
Urine pregnancy test (females of childbearing potential only) 
• 
Weight 
• 
Vital signs (supine and standing BP [orthostatic measurements], pulse rate, respiratory rate, and 
oral body temperature) 
• 
Implant site examination 
• 
Patient Satisfaction Survey 
• 
Record AEs 
• 
Review concomitant medications 
5.2.6. 
Unscheduled Visits 
Subjects may experience AEs that necessitate an unscheduled visit.  There may also be situations in 
which the investigator asks a subject to report for an unscheduled visit following the report of an AE or 
SAE.  Should emergency removal of the implants be necessary during the study, subjects should be 
instructed to contact the 24-hour emergency contact number for the investigator, as listed on the treatment 
identification card (Section 8.4).  All assessments, AEs, or SAEs associated with the unscheduled 
emergency visit will be recorded in the eCRF.  If the subject is unable to see the investigator or seeks care 
elsewhere in a situation that requires emergency removal of the implants, the subject should present their 
treatment identification card to the health care provider, indicating that they are receiving ropinirole as 
part of the study.  Follow-up care will be provided by the investigator, and the subject should complete an 
Early Withdrawal visit and Follow-Up Visits, where possible.  Additional examinations may be 
conducted at these visits as necessary to ensure the safety and well-being of subjects during the study.  
Electronic case report forms should be completed for each unscheduled visit. 


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Table 2: 
Study Schedule of Events  
Event 
Screening 
(up to 4 
weeks) 
Period 1 
(up to 10 days) 
Period 2 
 
EOT or 
EWD 
Follow-up 
Visits1 
S1 
P1 Day 
-2 
Day 
-1 
Implant 
 Visit 
(Day 1) 
Day 
2 
Day 
3 
Day 
4 
Week 
1 
Week 
2 
Week 
3 
Week 
4 
Week 
6 
Week 
8 
Week 
10 
Week 12 
Week 
13 
Week 
14 
Written Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility Criteria Review 
X 
 
 
 
X2 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical and Medications 
History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Neurological Examination  
X 
 
 
 
X2 
 
 
 
 
 
 
 
 
 
 
X3 
 
 
UK Brain Bank Diagnostic 
Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MMSE 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hoehn and Yahr 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MDS-UPDRS 
X 
 
 
 
 
 
 
 
 
X 
 
X 
 
X3 
 
 
C-SSRS 
X 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X3 
X 
X 
SCOPA-PC 
X 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X3 
X 
X 
PDSS-2 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
 
X3 
 
 
ESS 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
 
X3 
 
 
QUIP-RS 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
X3 
 
 
Pregnancy Test4 
X 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
12-Lead ECG 
X 
 
X 
 
X5 
 
 
 
 
 
 
X 
 
 
 
X3 
 
 
Implantation Criteria 
 
 
 
 
X2 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Event 
Screening 
(up to 4 
weeks) 
Period 1 
(up to 10 days) 
Period 2 
 
EOT or 
EWD 
Follow-up 
Visits1 
S1 
P1 Day 
-2 
Day 
-1 
Implant 
 Visit 
(Day 1) 
Day 
2 
Day 
3 
Day 
4 
Week 
1 
Week 
2 
Week 
3 
Week 
4 
Week 
6 
Week 
8 
Week 
10 
Week 12 
Week 
13 
Week 
14 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs6 
X7 
X 
X 
X 
X8, 9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X8 
X 
X 
Physical Examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviated Review of 
Systems 
 
 
 
 
X2 
 
 
 
 
 
 
X 
 
X 
 
X3 
 
 
Chemistry, Hematology, 
Coagulation Profile, 
Urinalysis 
X 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X3 
 
 
Urine Drug and Cotinine 
Screen and Breath Alcohol 
Test10 
X 
 
X 
 
X2 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
HBV, HCV, HIV 
X11 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hauser Diary concordance 
training 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense Subject Diary 
Cards12  
X 
X 
 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Collect Subject Diary Cards12 
 
X 
X 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X3 
 
 
Insertion Procedure  
 
 
 
 
X13 
 
 
 
 
 
 
 
 
 
 
 
 
 
Palpation of Implant(s)14 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Ultrasound 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X3 
 
 
Dispense Oral Study 
Medication 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK Blood Sample Collection 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Implant Site Examination / 
Treatment Compliance15 
 
 
X 
X 
X2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X3 
X 
X 


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Event 
Screening 
(up to 4 
weeks) 
Period 1 
(up to 10 days) 
Period 2 
 
EOT or 
EWD 
Follow-up 
Visits1 
S1 
P1 Day 
-2 
Day 
-1 
Implant 
 Visit 
(Day 1) 
Day 
2 
Day 
3 
Day 
4 
Week 
1 
Week 
2 
Week 
3 
Week 
4 
Week 
6 
Week 
8 
Week 
10 
Week 12 
Week 
13 
Week 
14 
Dispense Treatment 
Identification Card  
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Removal Procedure 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Wound Care Information 
Sheet 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Patient Satisfaction Survey 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Implanting Physician 
Satisfaction Survey 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications / 
Procedures 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
BP = blood pressure; C-SSRS = Columbia Suicide Severity Rating Scale; DBP = diastolic blood pressure; ECG = electrocardiogram; eCRF = electronic case 
report form; EOT = End of Treatment; ESS = Epworth Sleepiness Scale; EWD = early withdrawal; HBV = hepatitis B virus; HCV = hepatitis C virus; 
HIV = human immunodeficiency virus; IRB = Institutional Review Board; MDS-UPDRS = Movement Disorder Society-sponsored revision of the Unified 
Parkinson’s Disease Rating Scale; MMSE = Mini Mental State Examination; P = period; PD = Parkinson’s disease; PDSS-2 = Parkinson’s Disease Sleep Scale; 
PK = pharmacokinetic(s); QUIP-RS = Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease-Rating Scale; S = screening; SBP = systolic 
blood pressure; SCOPA-PC = Scale for Outcomes of Parkinson’s disease–Psychiatric Complications 
 
1 Visit windows:  The P1 Visit should occur once all screening assessments and eligibility criteria are met.  Weeks 1-10 Visits should occur ±1 day relative to the 
projected time point as measured from the Implant Visit.  The EOT Visit should occur no less than 12 weeks from the Implant Visit, except in cases of early 
withdrawal.  The Week 13 Follow-up Visit should occur 1 week ±2 days from EOT visit.  The Week 14 Follow-up Visit should occur 2 weeks ±2 days from 
last implant removed. 
2 To be performed prior to implantation. 
3 Measures to be completed prior to implant removal. 
4 For females of child-bearing potential, a serum pregnancy test will be performed at the Screening Visit and the EOT Visit (Week 12 or early withdrawal).  An 
"in-office" urine pregnancy test will be required at Day -2, Week 4, Week 8, and Week 14 Follow-up Visit. 
5 Implant Visit ECG to be completed 3 hours (±15 minutes) following implant insertion. 
6 Vital signs include supine BP and standing BP, pulse rate, respiratory rate, and oral body temperature.  Measurements for orthostatic hypotension will be taken 
at every study visit.  Orthostatic measurements (supine and standing BP and 60 seconds of pulse rate) can be measured manually or using an automated BP 
machine; the same method of measurement should, however, be used throughout the study for a particular subject.  The subject’s BP and pulse rate will be 


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measured after the subject has been supine for approximately 5 minutes.  The subject will be instructed to rise to a standing position, and a BP measurement 
will be taken after the subject has been standing for 1 minute.  Orthostatic hypotension is defined as a reduction of SBP of >20 mmHg or DBP >10 mmHg 
within 3 minutes of quiet standing. 
7 At screening, two sets of measurements of supine/erect BP should be obtained at least 15 minutes apart.  These measurements will be recorded in the eCRF.  
Subjects with any exclusionary readings will not be eligible for the study. 
8 Measures for orthostatic hypotension will be taken for:  Implant Visit at 0 (prior to implantation), 0.5, 1, 2, and 4 hours postimplantation; EOT Visit at 0 
(pre-implant removal), 0.5, 1, 2, and 4 hours post-implantation removal.  
9 Respiration rate and body temperature will be collected prior to implantation, and at 15 and 30 minutes following implant insertion. 
10 Subjects will also provide 3 random urines (to test for drugs of abuse and cotinine) and breath alcohol tests to be collected at any 3 non-PK inpatient stay study 
visits, with at least 2 collected during Period 2. 
11 It is the investigator's responsibility to understand and comply with all laws and regulations that apply to HIV, HBV, and HCV testing of blood.  HIV, HBV, 
and HCV testing is required unless a site's IRB prohibits such testing. 
12 Awake “On and Off” time diaries will be completed for 2 consecutive days prior to Visit P1 and Day -2, and 2 consecutive days prior to each visit for Weeks 1 
through 12.   
13 Prior to implant insertion, the Implantation Criteria must be met. 
14 As specified in the Manual of Procedures (MOP). 
15The implant site will be visually inspected.  If there is any evidence of removal or attempted removal of the implants, the subject will be withdrawn from the 
study and all implants will be removed.  Tablet counts will be conducted to track compliance. 
 
 


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Table 3: 
Schedule of PK Blood Sample Collection 
 
Inpatient1 
Outpatient4 
Outpatient4 
Inpatient1 
Hour 
Day -12, 3 
Implant 
Visit 
(D1) 
Day 2 
(D2) 
Days 3, 4 
(D3, D4) 
Weeks 
1, 2, 3 
Week 
4  
Week 
6 
Week 
8 
Week 
10 
EOT / Week 12 
(or EWD) 
04 
X5 
X6 
X7 
X 
X 
X 
X 
X 
X 
X5, 6 
0.5 
X 
 
 
 
 
 
 
 
 
 
1 
X 
X 
 
 
 
 
 
 
 
 
1.5 
X 
 
 
 
 
 
 
 
 
 
2 
X 
X 
 
 
 
 
 
 
 
 
4 
X 
X 
 
 
 
 
 
 
 
 
6 
 
 
 
 
 
 
 
 
 
X 
8 
X 
X 
 
 
 
 
 
 
 
 
8.5 
X 
 
 
 
 
 
 
 
 
 
9 
X 
 
 
 
 
 
 
 
 
 
9.5 
X 
 
 
 
 
 
 
 
 
 
10 
X 
 
 
 
 
 
 
 
 
 
12 
X 
X 
X7 
 
 
X 
 
X 
 
X 
16 
X 
 
 
 
 
 
 
 
 
 
16.5 
X 
 
 
 
 
 
 
 
 
 
17 
X 
 
 
 
 
 
 
 
 
 
17.5 
X 
 
 
 
 
 
 
 
 
 
18 
X 
 
 
 
 
 
 
 
 
X 
20 
X 
X 
 
 
 
 
 
 
 
 
24 
X 
 
 
 
 
X 
 
X 
 
 
CRU = clinical research unit; D = day; EOT = End of Treatment; EWD = early withdrawal; PK = pharmacokinetic(s) 
1 Sites are encouraged to collect their inpatient PK samples within a ±2 minute window.  Collections falling outside this window, unless the difference in time is 
inordinately large, will not be considered a protocol deviation. 


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2 Each dose of oral ropinirole should be administered with 8 ounces of water, dosing should be observed, a hand/mouth check should be performed, and the time 
of dosing should be recorded.  .  Each dose of IR ropinirole should be administered 8 hours apart on Day -1.  The second and third doses of ropinirole are to be 
taken immediately following the 8-hour and 16-hour PK draws, respectively.. 
3 The nondominant arm will be selected for blood draws and implantation, so that the opposite arm will be available for blood pressure readings and activities 
such as eating. 
4 Zero hour PK sampling time points are collected prior to each dosing on Day -1, on the Implant Visit prior to implantation, and at EOT Visit prior to implant 
removal.  For all other days, it should be collected at the same time of day relative to the time of implantation ±3 hours. 
5 Subjects will check-in to the CRU the day prior to begin their inpatient stay. 
6 Breakfast will be served at least 1 hour prior to implantation and prior to removal of the implant(s). 
7 Zero-hour and 12-hour collections on Day 2 correspond to the 24-hour and 36-hour sample collections post-implantation 
 


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6. 
ASSESSMENTS  
6.1. 
Informed Consent 
Subjects must voluntarily provide written informed consent before any study-related procedure or 
assessment is performed (see Section 13.3 for additional details).   
6.2. 
Eligibility Review 
Prior to initiating dosing with study drug at Visit P1, subjects must meet all eligibility criteria as outlined 
in Sections 4.1 and 4.2.   
To satisfy inclusion criterion 3, a clinically accepted method of contraception for females of childbearing 
potential includes being surgically sterile via bilateral tubal ligation or hysterectomy, has a male partner 
who is surgically sterilized, use of oral contraceptive (combined or progesterone only), use of any 
intrauterine device with published data showing that the lowest expected failure rate is less than 1% per 
year, use of a double-barrier method (any combination of physical and chemical barriers), use of implants 
of levonorgestrel, and use of any other methods with published data showing that the lowest expected 
failure rate for that method is less than 1% per year. 
Prior to implant insertion, subjects must meet the criteria outlined in Section 4.3.   
6.2.1. 
United Kingdom Brain Bank Diagnostic Criteria 
Potential subjects will be evaluated against the UK Brain Bank diagnostic criteria for PD at the Screening 
Visit to determine eligibility (Hughes et al., 1992). 
6.2.2. 
Mini Mental State Examination (MMSE) 
The MMSE will be performed at screening to assess eligibility (Folstein et al., 1975).  The subject must 
have a score ≥26 on the MMSE at the Screening Visit to be eligible for the study. 
6.3. 
Demographics and Medical and Medications History 
Information relating to the subject’s sex, age, race, height, and weight will be recorded at screening on the 
appropriate eCRF page.  A complete medical history and history of prior medications (including PD 
history and PD medication history) each subject will be collected at the Screening Visit and recorded on 
the appropriate eCRF page.  The Hoehn and Yahr scale will also be used at the Screening Visit to assess 
PD severity (Hoehn and Yahr, 1967).  The medical history will include any significant, previously 
diagnosed acute or chronic medical conditions, including any surgeries.  The medication history will 
capture medications taken up to 30 days prior to signing informed consent.  This history will also include 
any abnormalities found during the physical examination conducted at the Screening Visit.     
6.4. 
Safety and Tolerability Assessments 
6.4.1. 
Adverse Events 
All AEs that occur between the time the subject signs the ICF and 30 days after study drug treatment has 
been discontinued must be documented in the eCRF.  Adverse events that have been designated by the 


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investigator as related to study drug, and all serious AEs, will be followed until resolution or stabilization.  
Adverse events that are reported by the subject at times other than specified in the Schedule of Events 
(Table 2) should also be recorded.  Details regarding AE definitions, collection, recording, and reporting 
are found in Section 9. 
6.4.2. 
Physical and Neurological Examination and Abbreviated Review of Systems 
A complete physical examination of all major body systems (excluding genitourinary exam) will be 
performed at the Screening Visit.  At the Implant Visit and EOT Visit, an abbreviated review of systems 
will be performed to capture changes since screening.  Additionally, a neurological exam will be 
performed at the Screening Visit, Day 1, and Week 12. 
6.4.3. 
Implant Site Examination/Treatment Compliance 
The implant site will be visually inspected for evidence of erythema, edema, itching, pain, infection, 
bleeding, abnormal healing, and any other abnormalities.  If there is any evidence of removal and the 
subject confirms the removal of some or all of the implants, the subject will be withdrawn from study and 
all implants will be removed.   
6.4.4. 
Height and Weight 
Height will be recorded at the Screening Visit only.  Weight will be recorded at the visits listed in Table 2. 
6.4.5. 
Vital Signs 
Vital signs include supine BP and standing BP, pulse rate, respiratory rate, and oral body temperature.    
Measurements for orthostatic hypotension will be taken at every study visit and at specific time points as 
described in Table 2. 
Orthostatic measurements (supine and standing BP and 60 seconds of pulse rate) can be measured 
manually or using an automated BP machine; the same method of measurement should, however, be used 
throughout the study for a particular subject.  The subject’s BP and pulse rate will be measured after the 
subject has been supine for approximately 5 minutes.  The subject will be instructed to rise to a standing 
position, and a BP measurement will be taken after the subject has been standing for 1 minute 
At the Screening Visit, two sets of measurements of supine/erect BP should be obtained at least 15 
minutes apart.  These measurements will be recorded in the eCRF.  Subjects with any readings that are 
exclusionary per section 4.2 are not eligible for the study. 
Orthostatic hypotension is defined as a reduction of SBP of >20 mmHg or DBP >10 mmHg within 
3 minutes of quiet standing. 
6.4.6. 
Electrocardiography (ECG) 
A 12-lead ECG will be recorded and assessed at the Screening Visit, Day -2 Visit, Implant Visit, Week 4 
Visit, and EOT Visit by the investigator or other designated, qualified individual from the study research 
team.  At the Implant Visit, the ECG will be conducted 3 hours (±15 minutes) following implantation.  
The ECG will be signed and dated by a medically qualified individual to confirm review of the ECG and 
verify whether any abnormalities are clinically significant.  In general, abnormal, clinically significant 
ECGs are expected to be associated with an item recorded in medical history or with an AE.  


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6.4.7. 
Columbia Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS Baseline/Screening version will be used to assess suicidality of the subject at the Screening 
Visit; the “Since Last Visit” version will subsequently be completed at Visit P1, Visit Day -2, Post-
implant Visit Day 3, Post-implant Visit Day 4, and at Weeks 1 through 14 (Posner et al., 2008) . 
6.4.8. 
Scale for Outcomes of Parkinson’s Disease-Psychiatric Complications 
(SCOPA-PC) 
The SCOPA-PC is a semistructured questionnaire that has been validated to assess both psychotic and 
compulsive complications of therapy in PD (Visser et al., 2007).  The SCOPA-PC assesses the severity of 
each of the 7 items on a scale from 0 (no symptoms) to 3 (severe symptoms).  The  SCOPA-PC will be 
completed at the Screening Visit; Visit P1, Visit Day -2, Post-implant Visit Day 3, Post-implant Visit Day 
4, and at Weeks 1 through 14. 
6.5. 
Efficacy Assessments 
6.5.1. 
Movement Disorder Society-Sponsored Revision of the Unified Parkinson’s 
Disease Rating Scale (MDS-UPDRS) 
The MDS-UPDRS is a 4-part rating scale used to evaluate non-motor experiences of daily living (Part I), 
motor experiences of daily living (Part II), motor examination (Part III), and motor complications (Part 
IV) (Goetz et al., 2008).  The MDS-UPDRS assessment will be performed at the Screening Visit, and 
Weeks 4, 8, and 12.  The MDS-UPDRS must take place prior to implant removal at the Week 12 Visit. 
6.5.2. 
Parkinson’s Disease Sleep Scale (PDSS-2) 
The PDSS-2 is used to quantify the quality of sleep and level of sleep disruption experienced by the 
subject in the past week (Trenkwalder et al., 2011).  Subjects will complete this assessment on Day -2, 
and Weeks 4, 8, and 12. 
6.5.3. 
Epworth Sleepiness Scale (ESS) 
The ESS is a self-administered questionnaire used to evaluate daytime sleepiness (Johns, 1991).  In 
reference to the prior month, the subject will be asked to rate on a scale of 0 to 3 the chance of dozing in 
8 situations of daily life.  Subjects will complete this assessment on Day -2, and Weeks 4, 8, and 12. 
6.5.4. 
Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease-
Rating Scale (QUIP-RS) 
The QUIP is a self-rated screening instrument developed and validated for the detection of impulse 
control disorders and related behaviors in PD.  The QUIP-RS assesses the severity of the same behaviors 
with a Likert scale (Weintraub et al., 2012).  Subjects will complete this assessment at the Screening 
Visit, and Weeks 4, 8, and 12. 
6.5.5. 
Awake “On and Off” Time Diary (Hauser Diary) 
In order to evaluate patterns in motor function, awake “On” and “Off” time will be assessed using a 
subject diary (Hauser et al., 2000).  The diary will be used to record motor state in half-hour intervals over 
a 24-hour period (during waking hours) for 2 consecutive days prior to Visit P1, Day -2, and Weeks 1 


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through 12.  Subjects will receive training on diary completion and rater concordance by the investigator 
or designee during the Screening Visit. 
6.6. 
Concomitant Medications/Therapies 
All concomitant medications/therapies collected throughout the study must be recorded on the 
Concomitant Medication eCRF.  The prohibited concomitant medications/therapies for the study are 
discussed in Section 8.1. 
6.7. 
Laboratory Assessments 
6.7.1. 
Serum Chemistry, Hematology, Coagulation Profile, Urinalysis, and Virus 
Serology 
All protocol-specified laboratory tests on blood and urine samples will be performed at a selected central 
laboratory, with the exception of urine pregnancy tests, urine drug and cotinine screens, and breath 
alcohol tests.  The central lab will generate laboratory reports and forward them to the clinical site in a 
timely manner.  It is the responsibility of the investigator to review and sign all lab reports expeditiously, 
in order to document appropriate safety monitoring of study subjects.  The investigator should sign and 
date each lab report concurrent with her or his review, and should indicate the clinical significance (CS or 
not CS [NCS]) of each abnormal/flagged value by noting “NCS” or “CS,” for example.  Notations 
indicating that a value is clinically significant should also include a brief description of the underlying 
disease or condition that is associated with the value, e.g., “CS/mild anemia.”  In general, abnormal, 
clinically significant laboratory values are expected to be associated with an item recorded in medical 
history or with an adverse event. 
Please refer to the appropriate central laboratory instruction manuals provided for information on the 
collection and shipment of study samples.    
The following blood and urine samples will be collected during the specified clinic visits in Table 2: 
Hematology 
Hematocrit, hemoglobin, red blood cells (RBC), mean corpuscular volume 
(MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin 
concentration (MCHC), RBC morphology, white blood cells (WBC) with 
differential, and platelet count 
Chemistry 
(including liver 
profile) 
Blood urea nitrogen, calcium, bicarbonate, chloride, creatinine, glucose, 
potassium, sodium, albumin, alkaline phosphatase, AST (SGOT), ALT (SGPT), 
total bilirubin, total cholesterol, total protein 
Coagulation 
Profile 
Prothrombin time (PT), international normalized ratio (INR), partial 
thromboplastin time (PTT) 
Urinalysis 
Routine urinalysis 
Other 
Plasma ropinirole levels, hepatitis B virus (HBV), hepatitis C virus (HCV), 
human immunodeficiency virus (HIV) 


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It is the investigator’s responsibility to understand and comply with all laws and regulations that apply to 
the testing of blood for HIV, HBV, and HCV.  These laws and regulations may include state laws related 
to written consent, separate from the ROP-001 ICF, and pre- and post-test counseling. 
6.7.2. 
Urine Drug and Cotinine Screen and Breath Alcohol Test 
A routine urine drug screen (for drugs of abuse), cotinine screen, and breath alcohol test will be 
conducted at screening, Day -2, Implant Visit (preimplantation), Week 4 Visit, and the EOT Visit.  
Subjects will also provide 3 random urines (to test for drugs of abuse and cotinine) and breath alcohol 
tests to be collected at any 3 non-PK inpatient stay study visits, with at least 2 collected during Period 2. 
6.8. 
Pharmacokinetic Assessments 
Plasma for ropinirole quantification will be collected on the days and time points presented in Table 3.  
Following implantation, venous blood samples should be drawn from the nondominant arm.  Instructions 
for processing, storage, and shipping of PK samples will be provided to each site. 
6.9. 
Other Assessments 
6.9.1. 
Palpation of Implant(s) 
Palpation will be performed and recorded on the eCRF to confirm the presence of each of the 
implant(s) at the Implant Visit immediately after insertion and at the EOT Visit prior to implant removal, 
in accordance with the detailed instructions in the MOP. 
6.9.2. 
Ultrasound for Depth of Implant(s) 
At the EOT Visit prior to implant removal, an ultrasound will be performed to measure placement depth 
of the implant(s).  Evaluation of the depth of the implant to be conducted prior to removal by measuring 
and recording, in millimeters, the depth of each implant , using ultrasound with high frequency linear 
array transducer (10MHz or greater).  These measurements will be reviewed by a centralized reader.  
Additional ultrasounds, at other visits, may be performed if imaging is necessary to localize the 
implant(s).   
6.10. 
Satisfaction Surveys 
An Implanting Physician satisfaction questionnaire related to functionality, design, technical aspects and 
safety of the Applicator will be completed after the insertion procedure with questions specific to the 
Ropinirole Applicator as used in the insertion procedure.  
A Patient Satisfaction Survey will be administered at the Week 14 Visit. Each subject will rate their 
satisfaction with treatment across multiple domains including the implant insertion/removal procedures. 
In instances where the survey was not completed at the Week 14 Visit, a post visit phone contact may be 
conducted to obtain responses. 
 


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7. 
INVESTIGATIONAL DRUG INFORMATION AND 
MANAGEMENT 
7.1. 
Investigational Drug Dose Regimen 
Below is a brief description of the products and treatments to be used for this study.  Please refer to the 
Requip Label for more information regarding IR ropinirole. 
Ropinirole implants are designed to deliver a sustained dose of ropinirole for 3 months after subdermal 
implantation for the treatment of the signs and symptoms of PD.  This formulation of the ropinirole 
implant is based on ProNeura technology, which is an EVA-based non-biodegradable solid matrix 
subdermal implant. The ropinirole implant is 3.5 mm in diameter and 60 mm in length, and contains 
60% ropinirole HCl/40% EVA in the core and 3% ropinirole HCl/97% EVA in the shell.  Each washed 
and terminally sterilized implant contains a nominal 200 mg ± 10% of ropinirole.  
7.2. 
Dose Rationale 
The dose selection for the ropinirole implant is based on the approved dose range of IR ropinirole 
described in the Prescribing Information for the RLD (Requip Label).  
 
 
 
 
 
 
 
 
 
  
 
7.3. 
Investigational Drug Packaging and Labeling 
The IR ropinirole to be used in this study will be obtained from a commercial source.    
Ropinirole implants are individually packaged in a foil-laminate, heat-sealed pouch.  Pouches are then 
sterilized using radiation.  Ropinirole implants will be packaged into bulk cartons, each containing 
1 sterile pouched implant.  A label will be applied to each implant pouch as well as the bulk carton.  The 
bulk cartons will not be subject specific.   
All investigational products used in this study will be prepared, packaged, and labeled in accordance with 
the standard operating procedures (SOPs) of the manufacturers, Good Manufacturing Practice guidelines, 
International Conference on Harmonisation (ICH) guidelines for GCP, and applicable regulations.  


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7.4. 
Investigational Drug Storage 
All ropinirole implant Patient Kits should be stored at room temperature (15 to 25°C / 59 to 77°F) in a 
secured area and in accordance with applicable laws, regulations, and institutional requirements.   
Oral IR ropinirole should be stored at controlled room temperature (20° to 25°C / 68° to 77°F) and 
protected from light and moisture (Requip Label). 
7.5. 
Investigational Drug Administration 
An applicator consisting of a thin-walled cannula and obturator will be supplied for use in the subdermal 
insertion of the ropinirole implant(s).  Each applicator is intended for a single insertion procedure of the 
implant(s) into a single subject and must be disposed after use. 
Applicators will be provided sterile in a Tyvek pouch, with one Applicator per carton.  Both the 
Applicator pouch and carton will be labeled. 
Additional details on investigational product administration are provided in the Investigator Brochure and 
study MOP. 
7.6. 
Investigational Drug Accountability 
Detailed drug accountability records must be maintained, including the dates shipments are received, the 
quantity of material received, the dates dispensed, the running inventory, and the unused quantities 
returned to Titan’s drug supply vendor at the end of the study.  Please refer to the study MOP for more 
information.  
Following implant removal, all removed implants should be packaged and shipped to appropriate 
laboratory vendor, as outlined in the MOP. 


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8. 
TREATMENT OF SUBJECTS 
8.1. 
Concomitant Medication 
Prohibited medications for this study include medications that may cause secondary parkinsonism, 
including but not limited to dopamine antagonists (other than quetiapine [up to 100 mg/day] or 
pimavanserin [at doses labelled for treatment of PD]), antipsychotic or neuroleptic medications, 
metoclopramide, alpha-methyldopa, flunarizine, cinnarizine, and reserpine; stimulant medications such as 
methylphenidate or amphetamine; anti-coagulant therapies (such as warfarin and platelet inhibitors), 
aspirin (greater than 162 mg/day); and any investigational drugs.  Use of marijuana, including medical 
marijuana, and other compounds that interfere with study participation or accurate data collection are also 
prohibited. 
8.2. 
Other Restrictions 
No alcohol should be consumed within 24 hours of any visit post-screening and subjects should be 
reminded of this restriction prior to all alcohol testing. 
8.3. 
Treatment Compliance 
The implant site will be visually inspected by the investigator.  If there is any evidence of removal (or 
attempted removal), subjects will be withdrawn from study and have implants removed (if applicable). 
Treatment compliance with oral dosing of ropinirole will be evaluated by tablet counts. 
8.4. 
Treatment Identification Card 
Subjects will receive a wallet card indicating that they are receiving ropinirole as part of the study.  This 
card should be presented to health care providers by the subject in the event of an emergency.  Sample 
wallet cards will be provided for IRB submission. 
8.5. 
Wound Care Information Sheet 
Subjects will receive written instructions that explain how to care for the surgical site after implant 
insertion and removal.   


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9. 
ADVERSE EVENTS 
9.1. 
Adverse and Serious Adverse Events 
This section defines the types of AEs and outlines the procedures for appropriately collecting, grading, 
recording, and reporting them.  Information in this section complies with 21 Code of Federal Regulations 
(CFR) 312, ICH Guideline E2A: Clinical Safety Data Management: Definitions and Standards for 
Expedited Reporting, and ICH Guideline E-6: Guidelines for Good Clinical Practice. 
The investigator is responsible for the detection and documentation of AEs regardless of treatment group 
or suspected causal relationship to the investigational product.  For all AEs, the investigator must pursue 
and obtain information adequate to determine the outcome of the AE and to assess whether the AE meets 
the criteria for classification as an SAE or AE of special interest requiring immediate notification to Titan 
or its designated representative. 
9.1.1. 
Definitions of Adverse Events 
9.1.1.1. 
Adverse Event (AE) 
An AE is defined as any untoward or unfavorable medical occurrence associated with the subject’s 
participation in the research, whether or not considered related to the subject’s participation in the 
research (ICH E6 Guidelines for GCP).  Any medical condition that is present at the time that the subject 
is screened will be considered as medical history and not recorded as an AE; however, if the condition 
worsens at any time during the study, it will be recorded and reported as an AE. 
9.1.1.2. 
Serious Adverse Event (SAE) 
An AE is considered “serious” if, in the view of either the investigator or Titan, it results in any of the 
following outcomes (21 CFR 312.32(a)): 
• 
Death:  A death that occurs during the study or that comes to the attention of the 
investigator during the protocol-defined follow-up period must be reported to Titan 
whether it is considered treatment related or not. 
• 
A life-threatening event:  An AE or suspected adverse reaction (SAR) is considered 
“life-threatening” if, in the view of either the investigator or Titan, its occurrence places 
the participant at immediate risk of death.  It does not include an AE or SAR that, had it 
occurred in a more severe form, might have caused death. 
• 
Inpatient hospitalization or prolongation of existing hospitalization. 
• 
Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions. 
• 
An important medical event that may not result in death, be life threatening, or require 
hospitalization may be considered an SAE when, based on appropriate medical 
judgment, it may jeopardize the participant and may require medical or surgical 
intervention to prevent one of the outcomes listed above.  Examples of such medical 
events include allergic bronchospasm requiring intensive treatment in an emergency 


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room or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of investigational product dependency or abuse. 
• 
Congenital anomaly or birth defect. 
If an event meets any of the above definitions, regardless of the severity or relationship of the event to the 
study product, the event must be reported to Titan as described in Section 9.1.5. 
Adverse events reported from clinical studies associated with hospitalization or prolongation of 
hospitalization are considered serious.  Any hospital admission to an inpatient unit (excludes strictly 
observational admissions of less than 24 hours) meets these criteria.  Admission also includes transfer 
within the hospital to an acute/intensive care unit (e.g., from the medical floor to the intensive care unit). 
Hospitalization does not include the following: 
• 
Rehabilitation facilities, hospice facilities, or respite care (e.g., caregiver relief) 
• 
Nursing homes or skilled nursing facilities 
• 
Emergency room visits 
• 
Same day surgeries (as outpatient/same day/ambulatory procedures) 
Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical AE is not in 
itself an SAE.  Examples include: 
• 
Admission for treatment of a preexisting condition that did not worsen 
• 
Protocol-specified admission (e.g., for a procedure required by the study protocol), 
unless it is an unplanned hospitalization related to implant insertion or removal AE 
• 
Hospitalizations for cosmetic elective surgery, social, and/or convenience admissions 
• 
Pre-planned treatments or surgical procedures should be noted in the baseline 
documentation for the individual subject 
• 
Diagnostic and therapeutic procedures, such as surgery, should not be reported as AEs; 
however, the medical condition for which the procedure was performed should be 
reported if it occurs during the reporting period and meets the definition of an AE.  For 
example, an acute appendicitis that begins during the AE reporting period should be 
reported as an AE, and the resulting appendectomy should be recorded as treatment of 
the AE. 
9.1.1.3. 
Adverse Reaction (AR) and Suspected Adverse Reaction (SAR) 
An adverse reaction (AR) means any AE caused by a drug.   
Suspected AR means any AE for which there is a reasonable possibility that the drug caused the AE.  For 
the purposes of safety reporting, “reasonable possibility” means there is evidence to suggest a causal 
relationship between the drug and the AE.  Suspected AR implies a lesser degree of certainty about 
causality than an AR (21 CFR 312.32(a)).  
9.1.1.4. 
Unexpected Adverse Reaction (UAR) 
Titan is responsible for assessing AEs for expectedness.  With regards to reporting to the Health 
Authority, an AE is considered “unexpected” when its nature (specificity), severity, or rate of occurrence 


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is not consistent with applicable product information as described in the safety information provided in 
the protocol/package insert/investigator’s brochure/prescribing information for the study drugs.  
“Unexpected” as used in this definition, also refers to AEs or SARs that are mentioned in the 
investigator’s brochure as occurring with a class of drugs or as anticipated from the pharmacological 
properties of the drug but are not specifically mentioned as occurring with the particular drug under 
investigation (21 CFR 312.32(a)).  
For IR ropinirole, the expectedness of an AE will be determined by whether or not it is listed in the 
Requip Prescribing Information. 
9.1.2. 
Severity of AEs/SAEs 
The study site will grade the severity of AEs experienced by study participants using the categories noted 
below. This assessment is subjective and the investigator should use medical judgment to compare the 
reported AE to similar events observed in clinical practice. 
• 
Grade 1 = mild; usually transient; requires no special treatment and does not interfere with the 
subject’s daily activities 
• 
Grade 2 = moderate; produces a low level of inconvenience to the subject and may interfere with 
daily activities.  These events are usually ameliorated by simple therapeutic measures. 
• 
Grade 3 = severe; interrupts daily activity and requires systemic drug therapy or other medical 
treatment.  
• 
Grade 4 = life-threatening consequences; urgent intervention indicated. 
• 
Grade 5 = death related to AE. 
Note:  The terms serious and severe are not synonymous.  Serious criteria as defined in Section 9.1.1.2 
above serve as a guide for defining regulatory reporting obligations.  The term severe is often used to 
describe the intensity (severity) of a specific event (as in mild, moderate, or severe headache); the event 
itself, however, may be of relatively minor medical significance.  This is not the same as serious, which is 
based on subject/event outcome or action criteria usually associated with events that pose a threat to a 
subject’s life or functioning.  Therefore, an AE of severe headache might not be considered serious, but a 
moderate infection for which a subject is hospitalized should be reported as an SAE. 
9.1.3. 
Relationship to Investigational Product 
An investigator’s causality assessment is the determination of whether there exists a reasonable 
possibility that the investigational product (drug, procedure) caused or contributed to an AE and must be 
provided for all AEs (serious and non-serious).  
Titan’s determination of attribution will be used for reporting to the appropriate health authorities.  The 
relation of an AE to study participation will be determined using the descriptors and definitions provided 
in Table 4. 


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Table 4: 
Attribution of Adverse Events 
Not Related 
The AE is clearly or most probably caused by other etiologies such as participant’s 
underlying condition, illness or injury or identifiable cause, or therapeutic intervention 
or concomitant therapy; or the delay between administration and the onset of the AE is 
incompatible with a causal relation; or the AE started before administration (screening 
phase).  Therefore, there is not a reasonable possibility that the AE was caused by the 
investigational drug, or procedure. 
Possibly 
Related 
An adverse event that follows a reasonable temporal sequence from administration of 
the investigational product or procedure, follows a known or expected response pattern 
to the suspected investigational product or procedure, but that could readily have been 
produced by a number of other factors. 
Related 
The adverse event is clearly related to the investigational product or procedure – i.e. an 
event that follows a reasonable temporal sequence from administration of the 
investigational product or procedure, follows a known or expected response pattern to 
the suspected investigational product or procedure, that is confirmed by improvement 
on stopping and reappearance of the event on repeated exposure and that could not be 
reasonably explained by the known characteristics of the subject’s clinical state 
The investigator should decide whether, in his or her medical judgment, there is a reasonable possibility 
that the event may have been caused by the investigational product.  Any AE that is suspected to be 
related to the investigational product will be classified as an AR.   
9.1.4. 
Collecting and Recording Adverse Events 
9.1.4.1. 
Period of Collection 
All AEs will be documented and followed from the time the subject has signed the ICF until 30 days after 
study drug treatment has been discontinued.  Serious AEs and AEs that have been designated as possibly 
related to study drug will be followed until resolution or stabilization.  All AEs and SAEs should be 
treated as medically appropriate.   
9.1.4.2. 
Methods of Collection 
Adverse events may be collected as follows: 
• 
Observing the participant 
• 
Questioning the participant in an unbiased and non-leading manner 
• 
Receiving an unsolicited complaint from the participant 
An abnormal value or result from a clinical or laboratory evaluation or an ECG can also indicate an AE if 
it is determined by the investigator to be clinically significant.  If this is the case, it must be recorded in 
the source document and as an AE on the appropriate AE form(s).  The evaluation that produced the value 
or result should be repeated until that value or result returns to normal or is stabilized and the participant’s 
safety is not at risk. 


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9.1.4.3. 
Recording Method 
9.1.4.3.1. Adverse Events 
All AEs occurring during this clinical study will be recorded by the investigator on the appropriate eCRF 
in precise medical terms, along with the date and time of onset and the date and time of resolution.  To 
avoid vague, ambiguous, or colloquial expressions, the AE should be recorded in standard medical 
terminology rather than the subject’s own words.  Whenever possible, the Investigator should combine 
signs and symptoms into a single term that constitutes a single diagnosis.  Each AE is to be evaluated for 
duration, severity, seriousness, and relatedness to study drug or procedure.  The severity of the AE and its 
relationship to the study drug or procedure will be assessed by the investigator. 
The investigator will treat participants experiencing AEs appropriately and observe them at suitable 
intervals until their symptoms resolve or their status stabilizes.  If any medication is administered in 
response to the AE, this medication should be noted on the concomitant medication eCRF as a 
concomitant medication administered.  The action taken and the outcome must also be recorded.  Adverse 
events will be followed until resolution or until 30 days after a participant terminates from the study, 
whichever comes first.  The terms of AE resolution (i.e., resolved, resolved with sequelae, improved, 
worsened, lost to follow-up) should also be recorded.   
9.1.4.3.2. Serious Adverse Events 
Serious adverse events will be recorded on the AE eCRF and on the SAE eCRF, and health authorities 
will be notified as outlined in Section 9.1.5.2. 
9.1.5. 
Reporting Adverse Events or Ropinirole Implant Applicator Incidents 
9.1.5.1. 
Reporting SAEs to Titan 
The following process for reporting an SAE ensures compliance with 21 CFR 312 and ICH guidelines.  
After learning that a participant has experienced an SAE, the investigator or designee is responsible for 
reporting the SAE, regardless of relationship or expectedness, within 24 hours of becoming aware of the 
event.  The initial SAE report should include as much information as possible, but at a minimum must 
include the following: 
• 
Reporter 
• 
Subject ID 
• 
Study product or intervention 
• 
Serious AE term 
• 
Relationship to study medication(s) 
• 
Relationship to insertion/removal procedure 
• 
Reason why the event is serious 
Supplemental eCRF pages should be current at the time of SAE reporting:  medical history, concomitant 
medications, demographics, study drug administration, and death as applicable.  
Unavailable details of the event should not delay submission of the known information.  As additional 
details become available, the SAE eCRF should be updated and re-submitted via the electronic data 


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capture system.  Every time the SAE eCRF is submitted, it should be signed by the investigator or 
subinvestigator.  
For additional information regarding SAE reporting, contact: 
 
 
 
  
9.1.5.2. 
Reporting SAEs to Health Authorities 
Titan will report Investigational New Drug (IND) Safety Reports to the FDA and investigators in 
accordance with the FDA regulations detailed in 21 CFR 312.32. 
Final study report  
A complete summary of safety information is included in the final study report submitted at the closure of 
the protocol.  This option applies if the AE is classified as one of the following:  
• 
Serious, SAR 
• 
Serious and not an SAR 
9.1.5.3. 
Reporting SAEs to IRB(s) 
It is the responsibility of the investigators to promptly notify their respective IRB(s) of IND Safety 
Reports or other matters involving risk to subjects as mandated by the IRBs. 
9.1.5.4. 
Reporting SAEs to the DSMB 
All SAEs will be reported to the DSMB as described in the DSMB charter. 
9.1.5.5. 
Reporting Pregnancy 
During the study, all subjects should be instructed to contact the investigator immediately if they suspect 
they might be pregnant (e.g., missed or late menstrual period).  If pregnancy is confirmed, the subject will 
be withdrawn from the study and followed until the pregnancy comes to term.   
The investigator is responsible for reporting all available pregnancy information on the pregnancy eCRF 
within 24 hours of becoming aware of the event, although pregnancy itself if not considered an AE.  The 
investigator should counsel the participant and discuss the risks of continuing with the pregnancy and the 
possible effects on the fetus.  Monitoring of the participant should continue until the conclusion of the 
pregnancy.  Follow-up information detailing the outcome of the pregnancy should be reported as it 
becomes available.   
Any pregnancy complication or premature terminations including miscarriage, spontaneous abortion or 
elective termination of a pregnancy for medical reasons will be reported as an SAE, as described in 
Section 9.1.5.  Should the pregnancy result in a congenital abnormality or birth defect, a separate SAE 
report must be submitted.  Furthermore, all neonatal deaths that occur within 30 days of the birth should 
be reported as SAEs, without regard to causality.  In addition, any infant death that occurs after the 


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30-day reporting period that the investigator suspects is related to the in-utero exposure to the study 
treatment should also be reported.  
9.1.5.6. 
Ropinirole Implant Applicator Malfunction or Failure and Reporting  
Applicator complaint, malfunction, or failure and/or requests to the Sponsor for replacement Applicators 
due to mechanical problems during a procedure will be recorded (including all relevant applicator 
information) by the investigational site on the Implant Insertion Procedure Assessment Form and 
forwarded within 24 hours to the Sponsor for evaluation, regardless of whether or not a medical/adverse 
event was associated with the applicator malfunction or failure. 
The details of the malfunction and medical circumstances will be captured on the Implant Insertion 
Procedure Assessment Form and in the eCRF by the investigator.  Failed applicators will be inventoried 
and returned to the sponsor for investigation.  The final determination of reportability for applicator 
malfunctions is made by the sponsor and the investigational site based on the medical circumstances 
surrounding the event. 
 


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10. 
STATISTICS 
10.1. 
Power and Sample Size Determination 
The sample size for this study is not based on a formal power calculation as the study is not intended to 
demonstrate bioequivalence, but has been determined to be adequate to meet the PK and safety objectives 
of the study. 
10.2. 
Analysis Populations 
The analysis populations are defined as follows: 
• 
The safety population is defined as all subjects who receive at least 1 ropinirole implant.  The 
safety analyses will be performed on the safety population. 
• 
The PK population is defined as all subjects who received at least 1 ropinirole implant and for 
whom at least 1 PK parameter of interest can be calculated.  In general, on a parameter-by-
parameter basis, an individual subject’s data may be excluded from analysis if insufficient data 
are available for that subject to calculate the specific parameter in question. 
• 
The Efficacy Evaluable (EE) population will include all subjects who receive at least 1 ropinirole 
implant and complete at least 1 post-implantation efficacy assessment. 
10.3. 
Pharmacokinetics and Safety Analyses 
10.3.1. 
Background and Demographic Characteristics 
Demographic and baseline characteristics (i.e., age, sex, race, and body mass index) will be analyzed 
using the safety population.  Summary statistics (i.e., n, mean, median, standard deviation, standard error 
of the mean, coefficient of variation, minimum, and maximum) will be reported for each demographic 
and baseline characteristic. 
10.3.2. 
Pharmacokinetic Analyses 
10.3.2.1. Pharmacokinetic Analyses and Presentations 
The PK analyses will be performed using the PK population.  The following PK noncompartmental 
parameters will be determined (as appropriate) from the plasma ropinirole concentration-time data 
collected on Day -1, Day 1, Day 2, Week 4, Week 8, and Week 12 (EOT): 
Cmax 
Maximum measured drug concentration. 
Cmin 
Minimum measured drug concentration. 
Tmax 
Observed time of the maximum drug concentration (obtained 
without interpolation). 
λz 
Apparent terminal elimination rate constant calculated as the 
negative of the slope of the linear regression of the natural 
logarithm of concentration versus time for at least 3 data points 
that are decreasing in the terminal phase. 


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t½ 
Apparent elimination half-life calculated as ln (2)/ λz. 
AUC0-t 
Area under the drug concentration-time curve calculated using 
log/linear trapezoidal summation from time zero to time t, 
where t is the time of the last measurable concentration. 
AUC0-24 
Area under the drug concentration-time curve calculated using 
log/linear trapezoidal summation from time zero to 24 hours 
Plasma AUC0-24 and AUC0-t will be calculated using the log/linear trapezoidal rule.  Plasma 
concentrations below the limit of quantitation (BLOQ) prior to the first quantifiable concentration will be 
set at BLOQ and not used in the calculation of the pharmacokinetic parameters.  Plasma concentrations 
BLOQ after the first quantifiable concentration will be set at the lower limit of quantitation/2 for purposes 
of parameter estimation.   
Additionally, plasma concentrations at steady state, and peak and total exposure to ropinirole will be 
compared between Week 4, Week 8, and Day -1 using descriptive statistics.  No formal hypothesis testing 
or inferential statistical analyses will be performed. 
Descriptive statistics including arithmetic and geometric mean, standard deviation, coefficient of variation, 
standard error of the mean, median, minimum, and maximum will be calculated for all PK parameters.  
Geometric means will only be calculated for sampling times with at least 80% of the concentrations not 
missing.  Additionally, for AUC0-t, AUC0-24, and Cmax, geometric mean ratios and 90% confidence 
intervals will be calculated.  Actual sampling times, rather than scheduled sampling times, will be used in 
all plasma PK parameter computations involving sampling times.  For ease of presentation, scheduled 
sampling times will be used to present results in tables and figures.  Additional analyses of N-despropyl 
ropinirole and 7-hydroxy ropinirole metabolites will be specified. 
10.3.3. 
Safety Analyses 
Safety analyses will be performed using the safety population.  Adverse events will be coded for preferred 
term and system organ class using the most recent version of the Medical Dictionary for Regulatory 
Activities (MedDRA).   
A by-subject AE data listing including onset and resolution dates, verbatim term, preferred term, 
treatment, severity, relationship to treatment, action taken, and outcome will be provided for 
treatment-emergent AEs, drug-related and insertion/removal procedure-related AEs, SAEs, and premature 
discontinuations due to AEs..  Additionally, treatment-emergent AEs (i.e., any AEs recorded during or 
following implantation) will be summarized by treatment group and categorized by severity and 
relationship to the study procedures and to the investigational product. 
If a subject has more than 1 occurrence of the same AE, he/she will be counted only once within that 
preferred term in the summary tables.  The most severe occurrence of an AE, as well as the most extreme 
relationship of the AE to the study procedures and study drug, will be indicated in cases of multiple 
occurrences of the same AE.  Serious AEs and AEs of special interest also will be summarized separately.  
All AEs will be presented in a listing.  Additionally, listings of SAEs and AEs leading to discontinuation 
will be generated.  All SAEs will be evaluated to determine whether they are UARs.  
Vital signs, ECGs, and clinical laboratory values will be summarized by time of collection.  The C-SSRS 
and SCOPA-PC will be summarized by visit. Summary statistics (n, mean, median, standard deviation, 


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minimum, and maximum) will be calculated for quantitative safety data and frequency counts will be 
compiled for classification of qualitative safety data.  In addition, mean change from baseline data will be 
included for vital signs and clinical laboratory results and a shift table that describes out of normal range 
shifts will be provided for clinical laboratory results.   
Changes in physical and neurological examinations will be described in the text of the final study report. 
10.3.4. 
Prior and Concomitant Medications; Concomitant Therapies  
Prior and concomitant medications will be coded using the World Health Organization (WHO) Drug 
Dictionary, and will be summarized by drug class and preferred name, and listed by subject. 
Concomitant therapies will be coded using the WHO Drug Dictionary, and will be summarized by 
therapeutic intervention and listed by subject. 
10.4. 
Efficacy and Exploratory Analyses 
The EE population will be used for all efficacy and exploratory analyses.  Descriptive statistical 
summaries (n, mean, median, standard deviation, minimum, and maximum) for quantitative data and 
frequency counts for qualitative data, will presented for the following efficacy endpoints: 
• 
Change from baseline in MDS-UPDRS total score  
• 
Change from baseline in PDSS-2 total score 
• 
Change from baseline in ESS score 
• 
Change from baseline in QUIP-RS total score 
• 
Change from baseline in hours of awake “On and Off” time 
10.5. 
Other Statistical Considerations 
10.5.1. 
Missing Data 
Adverse events with missing start dates will be considered treatment emergent.  Adverse events with 
missing relationship or severity grades will be considered related and severe as applicable.  Missing PK 
concentration data will not be imputed. 
10.5.2. 
Visit Windows 
All data collected during the study up will be displayed and analyzed according to the actual visit data in 
the eCRF.  Assessments should be performed on the day when they are scheduled.  Weeks 1-10:  Visits 
should occur ±1 day relative to the projected time point as measured from the Implant Visit.  The Week 
13 Follow-up Visit should occur 1 week ±2 days from EOT Visit.  The Week 14 Follow-up Visit should 
occur 2 weeks ±2 days from last implant removed.   


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11. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
11.1. 
Study Monitoring 
According to ICH GCP guidelines, the sponsor of the study is responsible for ensuring the proper conduct 
of the study with regard to protocol adherence and validity of data recorded on the eCRFs.  The sponsor is 
responsible for assigning the study monitor(s) to this study.  The study monitor’s duties are to aid the 
investigator and Titan (or designee) in the maintenance of complete, accurate, legible, well-organized, 
and easily retrievable data.  The study monitor will advise the investigator of the regulatory necessity for 
study-related monitoring, audits, IRB(s) or Ethics Committee(s) reviews, and inspection by providing 
direct access to the source data/documents.  In addition, the study monitor will explain to and interpret for 
the investigator all regulations applicable to the clinical evaluation of an investigational product as 
documented in ICH guidelines. 
It is the study monitor’s responsibility to inspect the eCRFs and source documentation throughout the 
study to protect the rights of the subjects; to verify adherence to the protocol; to verify completeness, 
accuracy, and consistency of the data; and to confirm adherence of study conduct to any local regulations.  
Details will be outlined in the study monitoring plan. 
11.2. 
Source Documents 
Titan requires that the investigator prepare and maintain adequate and accurate records for each subject 
treated with the investigational product.  Source documents such as any hospital, clinic, or office charts 
and the signed informed consent forms are to be included in the investigator’s files with the subject’s 
study records. 
Study data will be captured electronically.  Study site personnel will record eCRF data from source 
documents.  If any data are first recorded onto documents such as laboratory reports, these documents will 
be considered source.  
11.3. 
Data Collection and Management 
This study will be conducted in compliance with the ICH document “Guidance for Industry-E6 Good 
Clinical Practice:  Consolidated Guidance,” dated April 1996.  This study will also be conducted in 
accordance with the Declaration of Helsinki (2013). 
This study will use electronic data collection (techniques to collect data directly from the investigational 
site using eCRFs).  The data will be stored centrally in a fully validated clinical database.  The 
investigator is responsible for ensuring that all sections of each eCRF are completed promptly and 
correctly and that entries can be verified against any source data.   
Study monitors will perform 100% source document verification to ensure there are no inconsistencies 
between the eCRFs and source documents.  Discrepancies will be resolved in accordance with the 
principles of GCP and the study monitoring plan. 
Data management will be coordinated by the data managers of Titan (or designee) in accordance with 
their SOPs for data management and a formal study data management plan.   


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12. 
QUALITY CONTROL AND QUALITY ASSURANCE 
Quality assurance includes all the planned and systematic actions that are established to ensure that the 
clinical study is performed and the data are generated, documented (recorded), and reported according to 
ICH GCP and local/regional regulatory standards. 
A quality assurance representative from Titan (or designee), who is independent of and separated from 
routine monitoring, may periodically arrange inspections/audits of the clinical study by reviewing the data 
obtained and procedural aspects.  These inspections may include on-site inspections/audits and source 
data checks.  Direct access to source documents is required for the purpose of these periodic 
inspections/audits.  


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13. 
ETHICS 
13.1. 
Ethics Review 
The investigator will not start this study, nor will investigational drugs be shipped to the investigator’s 
site, before providing Titan with evidence of IRB approval.  The investigator will promptly report to the 
IRB all changes in the research activity and all unanticipated problems involving risks to subjects.  The 
investigator will not make any changes in the research without IRB approval, except where necessary to 
eliminate apparent immediate hazards to the subjects.  The investigator will provide progress reports to 
the IRB as required by the IRB.  The investigator will provide a final report to the IRB after completion 
of participation in the study.  
13.2. 
Ethical Conduct of the Study 
The investigator should conduct the study in accordance with this protocol, the Declaration of Helsinki, 
and ICH GCP guidelines.  The investigator and Titan (or designee) will sign the protocol and study 
contract to confirm agreement.  The investigator will not implement any amendment (deviation or 
changes of the protocol) without agreement by Titan and the IRB approval/information, except where 
necessary to eliminate immediate hazards to study subjects or when changes involve only logistical or 
administrative aspects of the study. 
13.3. 
Written Informed Consent 
13.3.1. 
Subject Information and Informed Consent 
The informed consent document will be approved by the IRB that is appropriate for each study site.  The 
investigator is responsible for ensuring that the subject fully understands the nature and purpose of the 
study.  Information should be given in both oral and written form whenever possible.  No subject should 
be obliged to participate in the study.  Subjects must be given ample opportunity to inquire about details 
of the study.  The information must make clear that refusal to participate in the study or withdrawal from 
the study at any stage is without any prejudice to the subject’s subsequent care.  Subjects must be allowed 
sufficient time to decide whether they wish to participate. 
The subject must be made aware of and give consent to direct access to his/her source medical records by 
study monitors, auditors, the IRB(s), and regulatory authorities.  The subject should be informed that such 
access will not violate subject confidentiality or any applicable regulations.  The subject should also be 
informed that he/she is authorizing such access by signing the informed consent form. 
Each subject will be given a signed copy of the informed consent form to keep for his/her records.   
13.3.2. 
Provision of New and Important Information Influencing Subject’s Consent and 
Revision of the Written Information 
When any new and important information that may be relevant to the subject’s consent is obtained, the 
investigator and Titan (or designee) will consult with each other on how to deal with the information.  
When Titan (or designee) and a responsible investigator judge it necessary, the investigator must 
immediately provide the subjects with such information, revise the written information and other 
explanatory documents based on the new information, and obtain approval from the IRB.  In this instance, 


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the investigator should also immediately inform subjects currently participating in the clinical study of 
such information, confirm their intention to continue participation, re-explain the study to them using the 
revised written information and other explanatory documents, and obtain written consent to continue 
participation based on their voluntary decision.  
13.4. 
Subject Confidentiality 
Individual subject medical information obtained as a result of this study is considered confidential, and 
disclosure to third parties is prohibited.  Information will be accessible to authorized parties or personnel 
only.  Medical information may be given to the subject’s physician or to other appropriate medical 
personnel responsible for the subject’s well-being.  Each subject will be asked to complete a form 
allowing the investigator to notify the subject’s primary health care provider of his/her participation in 
this study. 


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14. 
ADMINISTRATIVE PROCEDURES 
14.1. 
Publications of the Clinical Study 
The clinical study plan and the results of the study will be published on www.ClinicalTrials.gov in 
accordance with 21 CFR 50.25(c).  The results of and data from this study belong to Titan 
Pharmaceuticals, Inc.   
14.2. 
Protocol Amendments and Deviations 
No change or amendment to this protocol may be made by the investigator or Titan after the protocol has 
been agreed to and signed by all parties unless such change(s) or amendment(s) has (have) been agreed 
upon by the investigator and Titan.  Any change agreed upon will be recorded in writing, and the written 
amendment will be signed by the investigator and Titan.  Institutional review board approval is required 
prior to the implementation of an amendment, unless overriding safety reasons warrant immediate action, 
in which case the IRB(s) will be promptly notified. 
No deviation from the protocol or investigational plan will be made except to protect the life or physical 
well-being of a subject in an emergency.  Except in such emergencies, prior approval of Titan, and the 
regulatory authorities (e.g., FDA) or the IRB if applicable, is required before deviations from the planned 
protocol.  All protocol deviations that occur during the study will be documented and reported to Titan (or 
designee) and to the IRB(s), if applicable, according to regulations.  Further details about the 
documentation, evaluation, and follow-up of protocol deviations are detailed in this study’s clinical 
monitoring plan.  
14.3. 
Data and Safety Monitoring Board (DSMB) 
An independent Data and Safety Monitoring Board (DSMB) will be established to safeguard the interests 
and safety of the study participants.  A DSMB charter will be prepared by Titan, defining the primary 
responsibilities, membership, purpose, and operations of the DSMB.  The charter also provides the 
procedures for ensuring confidentiality and proper communication, the statistical monitoring guidelines to 
be implemented by the DSMB, and an outline of the content of the reports that will be provided to the 
DSMB.  Any decision to interrupt or stop the study will be made by Titan based on recommendations of 
the independent DSMB.   
14.4. 
Dose Escalation Committee (DEC) 
The DSMB members and 2 representatives from Titan will comprise the DEC.  Enrollment will initially 
be restricted to Cohort 1 until evaluation of safety and characterization of the PK profile over the full 
12-week period for Cohort 1 is completed by the DEC and the determination is made to open enrollment 
to Cohort 2.  Prior to commencement of enrollment for Cohort 3, review of Cohort 2 safety and PK data 
through the Week 4 Visit will be required, in addition to ongoing safety review of currently enrolled 
subjects.  Prior to commencement of enrollment for Cohort 4, review of Cohort 3 safety data through the 
Week 4 Visit will be required, in addition to ongoing safety review of currently enrolled subjects.. 
Dose escalation policies and procedures will be described in the DSMB charter. 


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15. 
DATA HANDLING AND RECORD KEEPING 
15.1. 
Inspection of Records 
Titan, their designee(s), the IRB(s), or regulatory authorities will be allowed to conduct site visits to the 
investigational facilities for the purpose of monitoring or inspecting any aspect of the study.  The 
investigator agrees to allow Titan, their designee(s), the IRB(s), or regulatory authorities to inspect the 
investigational product storage area, investigational product stocks, investigational product records, 
subject charts and study source documents, and other records relative to study conduct.  
15.2. 
Retention of Records 
The principal investigator should retain all documentation relating to the study for a period of at least 
2 years after the last marketing application approval or, if not approved, 2 years following the 
discontinuance of the test article for investigation.  If this requirement differs from any local regulations, 
the local regulations will take precedence unless the local retention policy is less than 2 years.  Following 
study closure, the Investigator must inform Titan if the location for study records storage is changed (e.g. 
the Investigator leaves the institution where the study was conducted). In order to ensure that documents 
are not inadvertently destroyed prematurely, please contact Titan prior to the destruction of any 
study-related documents. 


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16. 
REFERENCES 
Bibbiani F, Costantini LC, Patel R, Chase TN. Continuous dopaminergic stimulation reduces risk of 
motor complications in parkinsonian primates. Exp Neurology. 2005 Mar;192(1):73-8. 
Fernandez HH, Standaert DG, Hauser RA, Lang AE, Fung VS, Klostermann F, et al. Levodopa-carbidopa 
intestinal gel in advanced Parkinson's disease: final 12-month, open-label results. Mov Disord. 2015 
Apr;30(4):500-9. 
Folstein MF, Folstein SE, McHugh PR. "Mini-mental state". A practical method for grading the cognitive 
state of patients for the clinician. J Psychiatr Res. 1975 Nov;12(3):189-98. 
Goetz CG, Tilley BC, Shaftman SR, Stebbins GT, Fahn S, Martinez-Martin P, et al. Movement Disorder 
Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS): scale 
presentation and clinimetric testing results. Mov Disord. 2008 Nov 15;23(15):2129-70.  
Hauser RA, Friedlander J, Zesiewicz TA, Adler CH, Seeberger LC, O'Brien CF, et al. A home diary to 
assess functional status in patients with Parkinson's disease with motor fluctuations and dyskinesia. Clin 
Neuropharmacol. 2000 Mar-Apr;23(2):75-81. 
Hoehn MM, Yahr MD. Parkinsonism: onset, progression and mortality. Neurology. 1967 May;17(5):427–
442. 
Hughes AJ, Daniel SE, Kilford L, Lees AJ. Accuracy of clinical diagnosis of idiopathic Parkinson's 
disease: a clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry. 1992 Mar; 55(3): 181–
184. 
Johns MW. A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep. 1991 
Dec;14(6):540-5. 
Olanow CW, Kieburtz K, Rascol O, Poewe W, Schapira AH, Emre M, et al. Factors predictive of the 
development of Levodopa-induced dyskinesia and wearing-off in Parkinson’s disease. Mov Disord. 2013 
Jul;28(8):1064-71. 
Posner K, Brent D, Lucas,C, Gould M, Stanley B, Brown G, et al. The Columbia-Suicide Severity Rating 
Scale. The Research Foundation for Mental Hygiene, Inc. 2008. 
Rascol O, Brooks DJ, Korczyn AD, De Deyn PP, Clarke CE, Lang AE. A five-year study of the incidence 
of dyskinesia in patients with early Parkinson’s disease who were treated with ropinirole or levodopa. N 
Engl J Med. 2000 May 18;342(20):1484-91. 
Requip® [ropinirole tablets, for oral use]. GlaxoSmithKline 2016. 
Sreedharan S, Bankiewicz K, Patel R. Continuous delivery of ropinirole by subdermal ProNeura™ 
implants [abstract]. Mov Disord. 2015;30 Suppl 1:1119. 
Trenkwalder C, Kies B, Rudzinska M, Fine J, Nikl J, Honczarenko K, et al. Rotigotine effects on early 
morning motor function and sleep in Parkinson's disease: a double-blind, randomized, placebo-controlled 
study (RECOVER). Mov Disord. 2011 Jan;26(1):90-9. 
Visser M, Verbaan D, van Rooden SM, Stiggelbout AM, Marinus J, van Hilten JJ. Assessment of 
Psychiatric Complications in Parkinson’s Disease: The SCOPA-PC. Mov Disord. 2007 Nov;22(15):2221-
8. 


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Weintraub D, Mamikonyan E, Papay K, Shea JA, Xie SX, Siderowf A. Questionnaire for Impulsive-
Compulsive Disorders in Parkinson's Disease-Rating Scale.  Mov Disord. 2012 Feb;27(2):242-7. 
Zulli C, Sica M, De Micco R, Del Prete A, Amato MR, Tessitore A, et al. Continuous intra jejunal 
infusion of levodopa-carbidopa intestinal gel by jejunal extension tube placement through percutaneous 
endoscopic gastrostomy for patients with advanced Parkinson's disease: a preliminary study. Eur Rev 
Med Pharmacol Sci. 2016 Jun;20(11):2413-7. 
 

SAP_001.pdf: 
NCT03250117


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CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. ROP-001 
 
11MAY2018 
Version:  1.0 
 
Page 2 of 39 
DOCUMENT VERSION CONTROL 
Version Number 
Date 
Comments/Changes 
1.0 
11 May 2018 
Initial SAP 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




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CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. ROP-001 
 
11MAY2018 
Version:  1.0 
 
Page 4 of 39 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS .............................................................................................. 6 
1. 
PURPOSE OF THE ANALYSES ............................................................................... 7 
2. 
PROTOCOL SUMMARY ........................................................................................... 8 
2.1 
Study Objectives ............................................................................................ 8 
2.2 
Overall Study Design and Plan ...................................................................... 8 
2.3 
Study Population .......................................................................................... 10 
2.4 
Treatment Regimens .................................................................................... 10 
2.5 
Treatment Group Assignments or Randomization ....................................... 10 
2.6 
Sample Size Determination .......................................................................... 10 
3. 
GENERAL ANALYSIS AND REPORTING CONVENTIONS .................................. 11 
3.1 
Software ....................................................................................................... 11 
3.2 
Definition of Baseline .................................................................................... 12 
4. 
ANALYSIS POPULATIONS .................................................................................... 13 
5. 
STUDY PATIENTS .................................................................................................. 14 
5.1 
Disposition of Patients .................................................................................. 14 
5.2 
Protocol Deviations ...................................................................................... 14 
6. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ......................... 15 
6.1 
Demographic and Baseline Characteristics ................................................. 15 
6.2 
Medical History ............................................................................................. 15 
7. 
EFFICACY EVALUATION ....................................................................................... 16 
7.1 
Overview of Efficacy Analysis Issues ........................................................... 16 
7.1.1 
Handling of Dropouts or Missing Data ................................................ 16 
7.1.2 
Multicenter Studies ............................................................................. 16 
7.1.3 
Assessment Time Windows ................................................................ 16 
7.2 
Efficacy Variables ......................................................................................... 16 
7.2.1 
MDS-UPDRS ...................................................................................... 16 
7.2.2 
PDSS-2 ............................................................................................... 17 
7.2.3 
ESS ..................................................................................................... 17 
7.2.4 
QUIP-RS ............................................................................................. 17 
7.2.5 
Hauser Diary ....................................................................................... 17 
7.3 
Analysis Methods ......................................................................................... 18 
7.3.1 
Primary Efficacy Analyses .................................................................. 18 
7.3.2 
Efficacy Analyses ................................................................................ 18 
7.3.3 
Exploratory Efficacy Analyses ............................................................. 18 
7.4 
Examination of Subgroups ........................................................................... 18 
8. 
SAFETY EVALUATION ........................................................................................... 19 
8.1 
Overview of Safety Analysis Methods .......................................................... 19 
8.2 
Measurements of Treatment Compliance and exposure ............................. 19 
8.3 
Adverse Events ............................................................................................ 19 
8.4 
Deaths, Serious Adverse Events, and Other Significant Adverse Events .... 20 
8.5 
Clinical Laboratory Evaluation ...................................................................... 20 
8.6 
Vital Signs, Physical Findings, and Other Observations Related to Safety .. 21 
8.6.1 
Vital Signs ........................................................................................... 21 
8.6.2 
Physical Examinations ........................................................................ 21 


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8.6.3 
Electrocardiograms ............................................................................. 21 
8.6.4 
Columbia Suicide Severity Rating Scale (C-SSRS) ............................ 21 
8.6.5 
Scales for Outcomes in Parkinson’s Disease – Psychiatric 
Complications ..................................................................................... 21 
8.6.6 
Prior and Concomitant Medications .................................................... 22 
9. 
PHARMACOKINETIC EVALUATION ..................................................................... 23 
10. ROPINIROLE IMPLANT PROCEDURES AND ROPINIROLE IMPLANT 
APPLICATOR .......................................................................................................... 24 
11. INTERIM ANALYSES AND DATA MONITORING .................................................. 25 
12. CHANGES TO THE ANALYSES PLANNED IN THE PROTOCOL ........................ 26 
13. REFERENCES ......................................................................................................... 27 
14. LIST OF PLANNED TABLES .................................................................................. 28 
15. LIST OF PLANNED FIGURES ................................................................................ 31 
16. LIST OF PLANNED DATA LISTINGS .................................................................... 32 
17. APPENDICES .......................................................................................................... 34 
17.1 
Imputation Algorithm for Partial and Missing Dates ..................................... 34 
17.2 
MDS-UPDRS Scoring .................................................................................. 34 
17.3 
Schedule of Events ...................................................................................... 36 
 


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LIST OF ABBREVIATIONS 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
BP 
Blood Pressure 
CSR 
Clinical Study Report 
C-SSRS 
Columbia Suicide Severity Rating Scale 
DEC 
Dose Escalation Committee 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EE 
Efficacy Evaluable 
EOT 
End of Treatment 
ESS 
Epworth Sleepiness Scale 
ICD 
International Classification of Diseases 
ICH 
International Conference on Harmonisation 
IR 
Immediate Release 
IRB 
Institutional Review Board 
L-Dopa 
Levodopa 
MDS-UPDRS 
Movement Disorder Society-Sponsored Revision of the Unified 
Parkinson’s Disease Scale 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMSE 
Mini Mental State Examination 
PD 
Parkinson’s Disease 
PDSS-2 
Parkinson’s Disease Sleep Scale 
PK 
Pharmacokinetic 
QUIP-RS 
Questionnaire for Impulsive-Compulsive Disorder in Parkinson’ 
Disease Rating Scale 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SCOPA-PC 
Scales for Outcomes in Parkinson’s Disease – Psychiatric 
Complications 
TEAE 
Treatment-Emergent Adverse Event 
WHODrug 
World Health Organization Drug Dictionary 
 


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1. PURPOSE OF THE ANALYSES 
The statistical analysis plan (SAP) is being developed for Study ROP-001 protocol 
Amendment 1, dated 07Jun2017.  The SAP is to be developed in two stages.  The 
purpose of the initial SAP is to allow 
 to start programming earlier in the process for 
the interim analysis.  Versions of the SAP up to initial Titan approval will be known as 
SAP 1.0. Changes following approval of SAP 1.0 will be tracked in the SAP Change Log 
and a last version of the SAP, known as SAP 2.0, will be issued for Titan approval prior 
to database lock. 
The purpose of the analyses is to evaluate the safety, tolerability, and pharmacokinetics 
(PK) of ropinirole implants in patients with Parkinson’s disease (PD).  The bioanalytical 
analysis of the concentrations of ropinirole, 7-hydroxy ropinirole, and N-despropyl 
ropinirole in human plasma is outlined in a separate document. 
The SAP contains detailed information to aid in the implementation of the statistical 
analysis and reporting of the study data for use in the clinical study report (CSR).  This 
SAP is being written with due consideration of the recommendations outlined in the most 
recent International Conference on Harmonisation (ICH) E9 Guideline entitled Guidance 
for Industry:  Statistical Principles for Clinical Trials, and the most recent ICH E3 
Guideline, entitled Guidance for Industry: Structure and Content of Clinical Study 
Reports. 
This SAP describes the analysis sets that will be analyzed, the subject characteristics 
parameters, the efficacy parameters, and the safety parameters.  The details of the specific 
statistical methods that will be used will be provided.  If additional analyses are required 
to supplement the planned analyses described in this SAP, they may be completed and 
will be identified in the CSR.  Table, figure, and listing specifications are provided in 
separate documents. 
 


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2. PROTOCOL SUMMARY 
2.1 Study Objectives 
Primary Objectives 
• To assess the relative bioavailability of ropinirole implants versus oral 
immediate-release (IR) ropinirole as determined by plasma ropinirole 
24-hour area under the curve (AUC0-24) in subjects with PD. 
• To assess the safety and tolerability of ropinirole implants over a 
3-month course of treatment. 
Secondary Objectives 
• To assess the efficacy of ropinirole implants in controlling motor 
fluctuations and drug-induced dyskinesias. 
• To assess plasma PK for major metabolites of ropinirole, N-despropyl 
ropinirole, and 7-hydroxy ropinirole, for ropinirole implants versus oral 
IR ropinirole.  
Exploratory Objectives 
• To assess the efficacy of ropinirole implants on clinical features of PD. 
• To assess the safety and effectiveness of the Ropinirole Implant 
Applicator for the subdermal placement of ropinirole implants. 
• To assess Implanting Physician satisfaction with the design and 
functionality of the Ropinirole Implant Applicator for the subdermal 
placement of ropinirole implants. 
Plasma samples will be collected in order to assess ropinirole, 7-hydroxy ropinirole, and 
N-despropyl ropinirole concentrations.  Pharmacokinetic collection times for each patient 
will be summarized by cohort and overall and presented in a listing.  The analysis of 
these data is outside of the scope of this analysis plan and will be addressed in a separate 
document. 
2.2 Overall Study Design and Plan 
This study is a phase 1/2, open-label, relative bioavailability study evaluating the safety, 
tolerability, and PK in patients implanted with 1 of 4 dose levels of ropinirole implants.  
The study compares the oral dose period to the implant period that follows.  The doses 
will be administered sequentially by cohort in patients with PD.  The study design 
schematic is shown in Figure 1; the study consists of 4 parts:  Screening, Period 1, 
Period 2, and Follow-Up.   


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Figure 1: 
ROP-001 Study Design Schematic 
 
IR = immediate release; MDS-UPDRS = Movement Disorder Society-sponsored revision of the Unified 
Parkinson’s Disease Rating Scale; PK = blood draw for pharmacokinetic assessments; S = screening 
Cohort 1: 4.5 – 6.0 mg/day, IR; 1 ropinirole implant 
Cohort 2: 7.5 – 9.0 mg/day, IR; 2 ropinirole implants 
Cohort 3: 12.0 – 14.25 mg/day, IR; 3 ropinirole implants 
Cohort 4: 15.0 – 17.25 mg/day, IR; 4 ropinirole implants 
 
The study will enroll approximately 20 subjects across 1 to 3 sites in the United States in 
4 cohorts based on the fixed dose of IR ropinirole that the subject is currently taking; if 
the subject is taking the extended-release product, they must convert to the IR 
formulation as shown in Table 1 of the protocol. 
• Cohort 1:  Subjects on a fixed dose in the range of 4.5 to 6.0 mg/day of 
IR ropinirole;  
• Cohort 2:  Subjects on a fixed dose in the range of 7.5 to 9.0 mg/day IR 
ropinirole;  
• Cohort 3:  Subjects on a fixed dose in the range of 12.0 to 14.25 mg/day 
IR ropinirole;  
• Cohort 4:  Subjects on a fixed dose in the range of 15.0 to 17.25 mg/day 
IR ropinirole.   
Enrollment will initially be restricted to Cohort 1 until the determination is made to open 
enrollment to Cohort 2 based on an evaluation of safety and characterization of the PK 
profile of approximately 3 to 5 subjects over the full 12-week period for Cohort 1 by both 
an independent data safety monitoring board (DSMB) and Titan, which make up the dose 
escalation committee (DEC).  Prior to commencement of enrollment for Cohort 3, review 
of Cohort 2 safety and PK data through the Week 4 Visit will be required, in addition to 
ongoing safety review of currently enrolled subjects.  Prior to commencement of 
enrollment for Cohort 4, review of Cohort 3 safety data through the Week 4 Visit will be 
required, in addition to ongoing safety review of currently enrolled subjects. 


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2.3 Study Population 
This study will enroll approximately 20 subjects (5 per cohort) meeting diagnostic criteria 
for idiopathic PD and the United Kingdom (UK) Brain Bank Diagnostic Criteria, aged 30 
to 80 years, clinically stable on levodopa (L-Dopa) and ropinirole.  Enrolled subjects who 
withdraw early (prior to 12 weeks on implant[s]) will not be replaced.  The full list of 
inclusion and exclusion criteria can be found in the protocol. 
2.4 Treatment Regimens 
Subjects will enter screening having been on a fixed dose of 4.5 to 17.25 mg/day IR 
ropinirole and remain on their maintenance dose through Period 1 until implantation of 
ropinirole implants. 
Subjects meeting implantation criteria, as specified in the protocol, will undergo an 
in-office procedure to insert the ropinirole implant(s) at the start of Period 2.  Subjects 
completing Period 1 in the 4.5 to 6.0 mg/day IR ropinirole dose range will have 1 implant 
inserted (Cohort 1), subjects at an IR ropinirole dose of 7.5 to 9.0 mg/day will receive 
2 implants (Cohort 2), subjects at a dose of 12.0 to 14.25 mg/day will receive 3 implants 
(Cohort 3), and subjects at a dose of 15.0 to 17.25 mg/day will receive 4 implants 
(Cohort 4).  Following implantation, subjects will be followed on treatment for 12 weeks 
(Period 2). 
Ropinirole implants will be removed at the Week 12 End of Treatment (EOT) Visit in an 
in-office procedure.   
2.5 Treatment Group Assignments or Randomization 
There is no randomization for this open-label study.  Enrollment is carried out 
sequentially by cohort, starting with Cohort 1.  There will be no crossover of subjects 
between cohorts.  Corresponding safety and PK data reviews for each applicable cohort 
will be performed prior to commencement of enrollment into the next cohort as detailed 
in Section 3.1 of the protocol and DSMB related documentation. 
2.6 Sample Size Determination 
The sample size for this study is not based on a formal power calculation as the study is 
not intended to demonstrate bioequivalence, but has been determined to be adequate to 
meet the PK and safety objectives of the study. 
 
 


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3. GENERAL ANALYSIS AND REPORTING CONVENTIONS 
This SAP documents the planned analyses described in the Statistics section of the 
protocol (Amendment 1 [07 June 2017]) for study ROP-001 with the exception of the 
pharmacokinetic analyses section.  The analysis of PK data is outside of the scope of this 
analysis plan and will be addressed in a separate document. 
By-patient data listings will be prepared for all data collected in the electronic case report 
form (eCRF).  All tables and listings will be produced as rich text format (RTF) files.  
Individual files will be created for each table and each listing output. 
All tables, listings, and graphs will have a header and footer showing the sponsor 
company name, protocol number, DSMB database cut date, file name, run date/time, and 
page number. 
Summary tables and data listings:  
• Data in summary tables will be presented by cohort: 
− Cohort 1: 4.5 – 6.0 mg/day, IR; 1 ropinirole implant 
− Cohort 2: 7.5 – 9.0 mg/day, IR; 2 ropinirole implants 
− Cohort 3: 12.0 – 14.25 mg/day, IR; 3 ropinirole implants 
− Cohort 4: 15.0 – 17.25 mg/day, IR; 4 ropinirole implants 
• A Cohort column will be empty until data are available for at least one patient in 
that group. 
• Categorical variables will be summarized using count and percentage and will be 
presented in the format ‘nn (pp.p%)’.  All percentages will be based on the 
population count unless otherwise specified.   
• Continuous variables will be summarized using number of observations (n), 
mean, standard error, 95% confidence interval (CI) of the mean, median, 
minimum, and maximum. 
• Minimum and maximum will be reported to the same level of precision as the 
original data.  Mean and median will be reported to 1 more significant digit than 
the original data.  Standard error will be reported to 2 more significant digits than 
the original data.  
• Only nominal/scheduled visit data will be reported in the tables.  All visits, 
including unscheduled, will be presented in the listings. 
• Data listings will be sorted in order of cohort, patient ID, and time of assessment, 
if applicable.  Dates will be presented in YYYY-MM-DD format.  If applicable, 
times will be presented in ISO format. 
3.1 
Software 
All statistical programing will be performed using SAS version 9.4 or later. 


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All statistical deliverables will be produced, validated, and reviewed for accuracy/ 
consistency in accordance with 
standard operating procedures and the processes 
described in the Statistical Validation and Quality Control Plan. 
3.2 
Definition of Baseline 
Unless otherwise stated, the last observed measurement on Day 1 / Implant Visit, 
conducted prior to implantation, will be considered the baseline measurement. 


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4. ANALYSIS POPULATIONS 
The analysis populations are defined as follows: 
• The safety population is defined as all subjects who receive at least 1 ropinirole 
implant.  The safety analyses will be performed on the safety population. 
• The efficacy evaluable (EE) population will include all subjects who receive at 
least 1 ropinirole implant and complete at least 1 post-baseline efficacy 
assessment.  The efficacy analyses will be performed on the EE population. 
 
 


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5. STUDY PATIENTS 
5.1 Disposition of Patients 
Disposition will be presented for all subjects who enter the study, and will include date 
and name of last visit, date of disposition, weeks implanted, completion status, and 
primary reason for early withdrawal (if applicable).  The number and percentage of 
subjects in each study population as well as the number and percentage of subjects who 
discontinued the study and the reason for discontinuation will be summarized by cohort.  
Discontinuation reasons include: subject request, subject noncompliance, subject refusal 
to receive implants, evidence of implant removal or attempted removal, medically 
significant infection or other medically significant adverse event (AE) at the implant site, 
unacceptable or intolerable treatment-related AE, pregnancy, use or abuse of 
nonstudy-assigned ropinirole, use of dopamine antagonists other than quetiapine (up to 
100 mg/day) or pimavanserin (at doses labeled for treatment of PD), deep brain 
stimulation, use of any investigational treatment, intercurrent illness or circumstances, 
request of Titan, regulatory agencies, or an institutional review board (IRB), lost to 
follow-up, or other.  All disposition data will be presented in subject listings.  
A screen failure will be defined as any subject who does not receive an implant.  The 
number of screen failures occurring in Screening, during Period 1/prior to implant, and 
overall will be summarized.  Failed criteria will also be summarized. 
A study completer will be defined as any subject completing the 12-Week study visit 
schedule on their assigned treatment, with removal of implants at EOT /Week 12 Visit. 
5.2 Protocol Deviations 
All protocol deviations will be recorded.  Major protocol violations will be identified 
prior to database lock, and reported in the listings by cohort.     
 
 


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6. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
6.1 
Demographic and Baseline Characteristics 
Demographic and baseline characteristics will be analyzed using the safety population.  
Demographic variables to be summarized include age, gender, race, body mass index at 
baseline, ethnicity, and baseline clinical characteristics.  Summary statistics (i.e., n, mean, 
median, standard error of the mean, coefficient of variation, minimum, and maximum) 
will be reported for each demographic and baseline characteristic. 
Age will be calculated based on the following conditional algorithm: 
• Has the patient had their birthday that year? 
o Yes, then AGE = (year of informed consent) – (year of birth). 
o No, then AGE = (year of informed consent) – (year of birth) – 1. 
Baseline clinical characteristics will include dose of levodopa/carbidopa, prestudy dose 
of oral ropinirole, percentage of subjects who entered on Requip XL formulation, age at 
PD onset, duration of PD (years), age (years) at PD diagnosis, duration of current L-dopa 
therapy, baseline Mini Mental State Evaluation (MMSE) score, and Hoehn and Yahr 
stage at screening. 
An identical summary will be created for subjects who were screen failures. 
6.2 
Medical History 
Medical history will be coded using Medical Dictionary for Regulatory Activities (MedDRA) 
Version 20.0.  It will be presented by system organ class and preferred term.  A medical history 
listing will be presented. 


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7. EFFICACY EVALUATION 
7.1 Overview of Efficacy Analysis Issues 
7.1.1 
Handling of Dropouts or Missing Data 
All available data will be used.  No imputations will be made for missing data unless 
otherwise specified.  Calculation of rating scale data, as well as handling of missing 
rating scale data, will follow instructions received from the scale authors and/or their 
relevant publications. 
7.1.2 
Multicenter Studies 
Subjects will be enrolled at approximately 1 to 3 sites.  No adjustments will be made for 
multiple centers. 
7.1.3 
Assessment Time Windows 
All data collected during the study will be displayed and analyzed according to the actual 
visit data in the eCRF.  Assessments should be performed on the day when they are 
scheduled.  Weeks 1-10:  Visits should occur ±1 day relative to the projected time point 
as measured from the Implant Visit.  The EOT Visit should occur no less than 12 weeks 
from the Implant Visit, except in cases of early withdrawal.  The Week 13 Follow-up 
Visit should occur 1 week ±2 days from the EOT Visit.  The Week 14 Follow-up Visit 
should occur 2 weeks ±2 days from removal of the last implant. 
7.2 Efficacy Variables 
Efficacy and exploratory endpoints consist of the following: 
• Change from baseline in Movement Disorder Society-Sponsored Revision of the 
Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) total score  
• Change from baseline in hours of awake “On and Off” time (Hauser Diary) 
• Change from baseline in Parkinson’s Disease Sleep Scale (PDSS-2) total score 
• Change from baseline in Epworth Sleepiness Scale (ESS) score 
• Change from baseline in Questionnaire for Impulsive-Compulsive Disorder in 
Parkinson’s Disease-Rating Scale (QUIP-RS) total score 
7.2.1 
MDS-UPDRS 
The MDS-UPDRS is a 4-part rating scale used to evaluate non-motor experiences of 
daily living (NM-EDL) (Part I), motor experiences of daily living (M-EDL) (Part II), 
motor examination (Part III), and motor complications (Part IV) (Goetz et al., 2008).  The 
MDS-UPDRS assessment will be performed at the Screening Visit, and at Weeks 4, 8, 
and 12.  The MDS-UPDRS must take place prior to implant removal at the Week 12 


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Visit.  The change from baseline in Part I score, , Part II score, Part III score, Part IV 
score, MDS-UPDRS total score, and Part II plus Part III score will be summarized by 
cohort and visit.  Information on how to calculate the MDS-UPDRS score is presented in 
Appendix 17.2. 
7.2.2 
PDSS-2 
The PDSS-2 is used to quantify the quality of sleep and level of sleep disruption 
experienced by the subject in the past week (Trenkwalder et al., 2011).  Subjects will 
complete this assessment on Day -2, and at Weeks 4, 8, and 12.  The total score will be 
calculated by adding all the individual items in the scale.  If one or two items are missing, 
then the item(s) will be imputed by averaging all the non-missing items.  If more than 
two items are missing, the non-missing items will be summarized, but a total score will 
not be calculated.  The PDSS-2 will be summarized by cohort and visit.   
7.2.3 
ESS 
The ESS is a self-administered questionnaire used to evaluate daytime sleepiness 
(Johns, 1991).  In reference to the prior month, the subject will be asked to rate on a scale 
of 0 to 3 the chance of dozing in 8 situations of daily life.  The total score is calculated by 
summing the scores for each of the eight responses, with a possible range of 0 to 24.  If 
one or more item-scores are missing, then the total score will not be computed.  Subjects 
will complete this assessment on Day -2, and at Weeks 4, 8, and 12.  The ESS score will 
be summarized by cohort and visit. 
7.2.4 
QUIP-RS 
The QUIP-RS is a self-rated screening instrument developed and validated for the 
detection of impulse control disorders and related behaviors in PD.  The QUIP-RS 
assesses the severity of these behaviors with a 5-point Likert scale (Weintraub et al., 
2012).  Individual responses, the total International Classification of Diseases (ICD) 
score (gambling, sex, buying, eating), and total QUIP-RS score will be recorded on the 
eCRF.  The total ICD score can have values from 0 through 64.  The total QUIP-RS score 
can have values from 0 through 112.  Subjects will complete this assessment at the 
Screening Visit, and at Weeks 4, 8, and 12.  The QUIP-RS total score will be summarized 
by cohort and visit. 
7.2.5 
Hauser Diary 
In order to evaluate patterns in motor function, awake “on” and “off” time will be 
assessed using a subject diary (Hauser et al., 2000).  The diary will be used to record 
motor state in half-hour intervals over a 24-hour period (during waking hours) for 
2 consecutive days prior to Visit P1, Day -2, and Weeks 1 through 12.  If more than 
4 half-hour segments are missing, then the data from that 24-hour period will not be used.  
Daily totals for waking hours will be normalized to a 16 hour waking day and averaged 
across the 2 consecutive days prior to each visit.  Awake time “on” without troublesome 
dyskinesia is comprised of “on without dyskinesia” and “on with non-troublesome 


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dyskinesia.  The data from the Hauser Diary will be summarized by cohort and visit for 
the variables below: 
Variable 
Units 
Awake time “on” 
Number of hours per 24-hour period 
Awake time “on” 
% of hours per 24-hour period 
Awake time without troublesome dyskinesia Number of hours per 24-hour period 
Awake time without troublesome dyskinesia % of hours per 24-hour period 
Awake time “off” 
Number of hours per 24-hour period 
Awake time “off” 
% of hours per 24-hour period 
 
7.3 Analysis Methods 
The EE population will be used for all efficacy and exploratory analyses.  Descriptive 
statistical summaries (n, mean, median, standard error, minimum, and maximum) for 
quantitative data and frequency counts for qualitative data will presented. 
7.3.1 
Primary Efficacy Analyses 
The primary endpoints for this study are PK and safety.  There are no primary efficacy 
endpoints. 
7.3.2 
Efficacy Analyses 
The efficacy endpoints for this study are change from baseline in MDS-UPDRS total 
score and change from baseline in hours of awake time spent “on” and “off.”  Descriptive 
statistics will be provided by cohort and visit.  Figures of mean MDS-UPDRS total score, 
percentage awake time spent “on”, percentage awake time without troublesome 
dyskinesia, and percentage awake time “off” will be presented by cohort and visit.  All 
data will be presented in subject listings.   
7.3.3 
Exploratory Efficacy Analyses 
The exploratory endpoints include change from baseline in PDSS-2 total score, change 
from baseline in ESS score, and change from baseline in QUIP-RS total score.  
Descriptive statistics will be provided by cohort and visit.  All data will be presented in 
subject listings. 
7.4 Examination of Subgroups 
There will be no subgroup analysis. 


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8. SAFETY EVALUATION 
8.1 Overview of Safety Analysis Methods 
Safety analyses will be performed using the safety population.  Descriptive statistical 
summaries (mean, standard error, 95% CI of the mean, median, minimum, and 
maximum) will be presented for quantitative data, and frequency counts will be presented 
for qualitative data. 
8.2 Measurements of Treatment Compliance and exposure 
For Period 1 (oral dose), the time on dose, total dose, percentage of expected doses taken, 
and the dose at Day -1 will be summarized by cohort.  For Period 2 (implantation), the 
total dose will be summarized by cohort.  Throughout the study, sites will be checking to 
determine whether subjects have removed or attempted to remove the implant.  The 
number and percentage of subjects who removed or attempted to remove the implant at 
any time during the study will be summarized.  The number of days between 
implantation and implant removal will be summarized. 
8.3 Adverse Events 
Adverse events will be coded for preferred term and system organ class using the most 
recent version of the MedDRA.   
Adverse events with missing start dates will be considered treatment emergent.  Adverse 
events with missing relationship or severity grades will be considered related and severe, 
as applicable.  Handling of missing or partial dates is presented in Appendix 17.1. 
Treatment-emergent AEs (TEAEs) will be defined as any AE occurring during or 
following implantation or an AE that worsens after implantation.  Implant site and 
non-implant site TEAEs will be summarized by cohort.  Tables categorizing by severity 
and relationship to the insertion or removal procedures and to the investigational product 
will also be created. 
In order to separate reactions specific to the insertion or removal of ropinirole implants 
from those specific to the drug substance and excipient, TEAEs will be categorized as 
either implant site related or non-implant site related.  Implant site TEAEs are defined as 
TEAEs associated with the implant site (either spatially or temporally, according to the 
investigator).  In contrast, non-implant site TEAEs are TEAEs not associated with the 
implant site. 
Non-treatment-emergent adverse events will be summarized by cohort. 
A by-subject AE data listing including onset and resolution dates, verbatim term, system 
organ class, preferred term, treatment, severity, relationship to treatment, action taken, 
and outcome will be provided for all TEAEs; drug-related, insertion procedure-related, 
and removal procedure-related AEs; serious adverse events (SAEs); and premature 
discontinuations due to AEs. 


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If a subject has multiple occurrences of the same AE, he/she will be counted only once 
within that system organ class and preferred term in the summary tables.  The most 
severe occurrence of an AE, as well as the most extreme relationship of the AE to the 
study procedures and study drug, will be indicated in cases of multiple occurrences of the 
same AE.   
Additionally, a listing of AEs leading to study discontinuation will be generated. 
8.4 Deaths, Serious Adverse Events, and Other Significant Adverse 
Events 
Deaths or hospitalizations, SAEs, and AEs of special interest (AESI) will be summarized 
separately.  The AESI for this study include somnolence, sleep attacks, narcolepsy, 
syncope, hypotension, orthostatic hypotension, hallucinations, psychotic-like behavior, 
impulse control/compulsive disorder, cardiac events, and protrusion/extrusion or 
expulsion of the implant.  Reported preferred terms and system organ class will be 
examined for terms related to the AESI and will be finalized prior to database lock.  In 
addition, orthostatic hypotension will defined as a reduction of systolic blood pressure 
(BP) of >20 mmHg or diastolic BP >10 mmHg within 3 minutes of quiet standing as 
collected in the vital signs data. 
All deaths, SAEs, and AESI will be presented in subject listings.  All SAEs will be 
evaluated to determine whether they are unexpected adverse reactions (UARs). 
8.5 Clinical Laboratory Evaluation 
The clinical laboratories to be collected are presented below.  
Hematology 
Hematocrit, hemoglobin, red blood cells, mean corpuscular volume, mean 
corpuscular hemoglobin, mean corpuscular hemoglobin concentration, red blood 
cell morphology, white blood cells with differential, and platelet count 
Chemistry 
(including liver 
profile) 
Blood urea nitrogen, calcium, bicarbonate, chloride, creatinine, glucose, 
potassium, sodium, albumin, alkaline phosphatase, aspartate transaminase, 
alanine transaminase, total bilirubin, total cholesterol, total protein 
Coagulation 
Profile 
Prothrombin time, international normalized ratio, partial thromboplastin time 
Urinalysis 
Routine urinalysis (color, nitrite, leukocyte esterase, clarity, specific gravity, pH, 
blood, protein, glucose, urobilinogen, ketones, microscopic and bilirubin) 
Clinical laboratory values will be summarized by time of collection.  Summary statistics 
(n, mean, median, standard error, minimum, and maximum) will be calculated for 
quantitative laboratory data and frequency counts will be compiled for classification of 
qualitative laboratory data (urinalysis).  Summary statistics will be presented by cohort.  
In addition, mean change from baseline value will be included for clinical laboratory 


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results and a shift table that describes out-of-normal range shifts will be provided.  
Listings of all laboratory data will be provided. 
8.6 Vital Signs, Physical Findings, and Other Observations Related to 
Safety 
8.6.1 
Vital Signs 
Vital signs include supine and standing BP, pulse rate, respiratory rate, and oral body 
temperature.  Measurements for orthostatic hypotension will be taken at every study visit 
and at specific time points as described in the schedule of events. 
Vital signs values will be summarized by time of collection.  Summary statistics (n, 
mean, median, standard error, minimum, and maximum) for mean change from baseline 
will be presented by cohort.  In addition, summaries of the number and percentage of 
abnormal clinically significant vital sign values by cohort and visit will be provided.  All 
vital sign data will be reported in listings.  
8.6.2 
Physical Examinations 
Abnormal values for neurological examination data will be summarized by cohort and 
visit.  Listings will be provided for all physical and neurological examination data. 
8.6.3 
Electrocardiograms  
Electrocardiogram (ECG) values will be summarized by time of collection.  Summary 
statistics (n, mean, median, standard error, minimum, and maximum) for mean change 
from baseline will be presented by cohort and visit.  In addition, summaries of the 
number and percentage of abnormal clinically significant ECG values cohort and visit 
will be provided.  All ECG data will be reported in listings. 
8.6.4 
Columbia Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS Baseline/Screening version will be used to assess suicidality of the subject 
at the Screening Visit; the “Since Last Visit” version will subsequently be completed at 
Visit P1, Day -2, Day 3, Day 4, and at Weeks 1 through 14 (Posner et al., 2008).  The 
C-SSRS will be summarized by cohort and visit.  All C-SSRS data will be presented in 
subject listings. 
8.6.5 
Scales for Outcomes in Parkinson’s Disease – Psychiatric 
Complications  
The Scales for Outcomes in Parkinson’s Disease – Psychiatric Complications 
(SCOPA-PC) is a semistructured questionnaire that has been validated to assess both 
psychotic and compulsive complications of therapy in PD (Visser et al., 2007).  The 
SCOPA-PC assesses the severity of each of the 7 items on a scale from 0 (no symptoms) 
through 3 (severe symptoms).  The change from baseline in SCOPA-PC will be 
summarized by cohort and visit.  SCOPA-PC data will be presented in subject listings. 


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8.6.6 
Prior and Concomitant Medications 
Prior and concomitant medications will be coded using the World Health Organization 
Drug Dictionary (WHODrug), version 2017, Q1 version, and will be summarized by drug 
class and preferred name, and listed by subject. 
Prior medications are defined as medications with stop dates occurring before the date of 
first administration of any study treatment 
Concomitant medications/therapies are defined as medications/therapies with start dates 
occurring on or after the date of first administration of any study treatment and no more 
than 30 days after the last administration of any study treatment.  Medications with start 
and stop dates that bracket the date of first administration of any study treatment 
component will be summarized as both prior and concomitant medications. 
Concomitant therapies will be coded using WHODrug, and will be summarized by 
therapeutic intervention and listed by subject. 
Medications with missing dates will be considered concomitant.  Handling of partial and 
missing dates is presented in Appendix 17.1. 


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9. PHARMACOKINETIC EVALUATION 
The analysis of PK data is outside of the scope of this analysis plan and will be addressed 
in a separate document. 
 


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10. ROPINIROLE IMPLANT PROCEDURES AND ROPINIROLE IMPLANT 
APPLICATOR 
Data on functioning of the Ropinirole Implant Applicator prior to the insertion procedure 
and the presence of failure or malfunction during the insertion procedure will be 
presented.   
Data from the insertion procedure will be summarized by cohort, including length of 
procedure, length of incision, number of palpable implants after insertion, whether an 
additional implant was used due to damage, whether an additional implant was used due 
to contamination, cannula and obturator correct function, total volume of anesthetic used, 
applicator failure or malfunction and whether the subject experienced insertion 
procedure-related AEs. 
Data from the removal procedure will be summarized by cohort, including whether it was 
the first attempt to remove the implant(s), number of fractured implants, length of 
procedure, percentage of procedures that used 
, percentage of implants 
completely removed, and whether the subject experienced removal procedure-related 
AEs. 
Central ultrasound reader evaluation of the depth of the implant by ultrasound will be 
summarized, including skin-to-fascia and skin-to-implant measurements.  When values 
from the central ultrasound reader are not available for a given measure, the site’s value 
will be used. 
 


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11. INTERIM ANALYSES AND DATA MONITORING 
An independent DSMB will be established to safeguard the interests and safety of the 
study participants.  A DSMB charter will be prepared by Titan, defining the primary 
responsibilities, membership, purpose, and operations of the DSMB.  The charter also 
provides the procedures for ensuring confidentiality and proper communication, the 
statistical monitoring guidelines to be implemented by the DSMB, and an outline of the 
content of the reports that will be provided to the DSMB.  Any decision to interrupt or 
stop the study will be made by Titan based on recommendations of the DSMB.  
In addition to the DSMB, there will be a dose escalation committee (DEC).  The DEC 
comprises the DSMB members and 2 representatives from Titan.  Enrollment will 
initially be restricted to Cohort 1 until evaluation of safety and characterization of the PK 
profile over the full 12-week period for Cohort 1 is completed by the DEC and the 
determination is made to open enrollment to Cohort 2.  Prior to commencement of 
enrollment for Cohort 3, review of Cohort 2 safety and PK data through the Week 4 Visit 
will be required, in addition to ongoing safety review of currently enrolled subjects.  Prior 
to commencement of enrollment for Cohort 4, review of Cohort 3 safety data through the 
Week 4 Visit will be required, in addition to ongoing safety review of currently enrolled 
subjects. 
Dose escalation policies and procedures will be described in the DSMB charter. 
Planned displays for the DSMB and the DEC are noted in Sections 14, 15, and 16. 


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12. CHANGES TO THE ANALYSES PLANNED IN THE PROTOCOL 
There are no changes to the analyses planned in the protocol. 
 


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13. REFERENCES 
Goetz CG, Tilley BC, Shaftman SR, Stebbins GT, Fahn S, Martinez-Martin P, et al. 
Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease 
Rating Scale (MDS-UPDRS): scale presentation and clinimetric testing results. Mov 
Disord. 2008 Nov 15;23(15):2129-70. 
Hauser RA, Friedlander J, Zesiewicz TA, Adler CH, Seeberger LC, O'Brien CF, et al. A 
home diary to assess functional status in patients with Parkinson's disease with motor 
fluctuations and dyskinesia. Clin Neuropharmacol. 2000 Mar-Apr;23(2):75-81. 
Johns MW. A new method for measuring daytime sleepiness: the Epworth sleepiness 
scale. Sleep. 1991 Dec;14(6):540-5.  http://epworthsleepinessscale.com/ 
Posner K, Brent D, Lucas,C, Gould M, Stanley B, Brown G, et al. The Columbia-Suicide 
Severity Rating Scale. New York: The Research Foundation for Mental Hygiene, Inc. 
2008. 
Trenkwalder C, Kies B, Rudzinska M, Fine J, Nikl J, Honczarenko K, et al. Rotigotine 
effects on early morning motor function and sleep in Parkinson's disease: a double-blind, 
randomized, placebo-controlled study (RECOVER). Mov Disord. 2011 Jan;26(1):90-9. 
Visser M, Verbaan D, van Rooden SM, Stiggelbout AM, Marinus J, van Hilten JJ. 
Assessment of psychiatric complications in Parkinson’s disease: The SCOPA-PC. Mov 
Disord. 2007 Nov;22(15):2221-8. 
Weintraub D, Mamikonyan E, Papay K, Shea JA, Xie SX, Siderowf A. Questionnaire for 
Impulsive-Compulsive Disorders in Parkinson's Disease-Rating Scale. Mov Disord. 2012 
Feb;27(2):242-7. 
 


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14. LIST OF PLANNED TABLES 
Table 
Identifier 
Table No. 
Title 
DS-T01 
14.x 
Summary of Subject Disposition by Cohort 
DS-T02 
14.x 
Summary of Screen Failures 
DM-T01 
14.x 
Summary of Demographic and Baseline Characteristics 
by Cohort 
DM_T02 
14.x 
Summary of Demographic and Baseline Characteristics 
for Screen Failures 
MH-T01 
14.x 
Summary of Medical History by Cohort 
CM-T01 
14.x 
Summary of Prior Medications by Cohort 
CM-T02 
14.x 
Summary of Concomitant Medications and Therapies by 
Cohort 
EX-T01 
14.x 
Summary of Study Drug Exposure and Compliance by 
Cohort 
EX-T02 
14.x 
Summary of Insertion Procedure and Ropinirole Implant 
Applicator 
EX-T03 
14.x 
Summary of Removal Procedure 
EF-T01 
14.x 
Summary of Mean and Mean Change from Baseline 
MDS-UPDRS by Cohort and Visit 
EF-T02 
14.x 
Summary of Mean and Mean Change from Baseline 
PDSS-2 by Cohort and Visit 
EF-T03 
14.x 
Summary of Mean and Mean Change from Baseline 
ESS by Cohort and Visit 
EF-T04 
14.x 
Summary of Mean and Mean Change from Baseline 
QUIP-RS Total Score by Cohort and Visit 
EF-T05 
14.x 
Summary of Awake Time Spent “On” by Cohort and 
Visit 
EF-T06 
14.x 
Summary of Awake Time Without Troublesome 
Dyskinesia by Cohort and Visit 
EF-T07 
14.x 
Summary of Awake Time Spent “Off” by Cohort and 
Visit 
AE-T01 
14.x 
Summary of All Treatment-Emergent Adverse Events 
by Cohort 
AE-T02  
14.x 
Summary of All Non-Treatment-Emergent Adverse 
Events by Cohort, System Organ Class, and Preferred 
Term 


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AE-T03 
14.x 
Summary of All Treatment-Emergent Adverse Events 
by Cohort, System Organ Class, and Preferred Term 
AE-T04 
14.x 
Summary of Treatment-Emergent Implant Site Adverse 
Events by Cohort, System Organ Class, and Preferred 
Term 
AE-T16 
14.x 
Summary of Treatment-Emergent Non-Implant Site 
Adverse Events by Cohort, System Organ Class, and 
Preferred Term 
AE-T05 
14.x 
Summary of All Treatment-Emergent Adverse Events 
Related to Study Drug by Cohort, System Organ Class, 
and Preferred Term 
AE-T06 
14.x 
Summary of All Treatment Emergent Adverse Events 
Related to Insertion or Removal Procedure by Cohort, 
System Organ Class, and Preferred Term 
AE-T07 
14.x 
Summary of All Treatment-Emergent Adverse Events 
Leading to Study Discontinuation by Cohort, System 
Organ Class, and Preferred Term 
AE-T08 
14.x 
Summary of All Treatment-Emergent Adverse Events 
by Cohort, System Organ Class, Preferred Term and 
Intensity 
AE-T09 
14.x 
Summary of Treatment-Emergent Implant Site Adverse 
Events by Cohort, System Organ Class, Preferred Term 
and Intensity 
AE-T10 
14.x 
Summary of Treatment-Emergent Non-Implant Site 
Adverse Events by Cohort, System Organ Class, 
Preferred Term and Intensity 
AE-T11 
14.x 
Summary of All Treatment-Emergent Serious Adverse 
Events by Cohort, System Organ Class, and Preferred 
Term 
AE-T12 
14.x 
Summary of Treatment-Emergent Serious Implant Site 
Adverse Events by Cohort, System Organ Class, and 
Preferred Term 
AE-T13 
14.x 
Summary of Treatment-Emergent Serious Non-Implant 
Site Adverse Events by Cohort, System Organ Class, 
and Preferred Term 
AE-T14 
14.x 
Summary of All Treatment-Emergent Adverse Events 
Leading to Death or Hospitalization by Cohort, System 
Organ Class, and Preferred Term 
AE-T15 
14.x 
Summary of Treatment-Emergent Adverse Events of 
Special Interest by Cohort, System Organ Class, and 
Preferred Term 


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LB-T01 
14.x 
Summary of Mean and Mean Change from Baseline in 
Hematology Values by Cohort and Visit 
LB-T02 
14.x 
Shift from Baseline in Laboratory Test: Hematology by 
Cohort and Visit 
LB-T03 
14.x 
Summary of Mean and Mean Change from Baseline in 
Serum Chemistry Values by Cohort and Visit 
LB-T04 
14.x 
Shift from Baseline in Laboratory Test: Serum 
Chemistry Results by Cohort and Visit 
LB-T05 
14.x 
Summary of Mean and Mean Change from Baseline in 
Coagulation Values by Cohort and Visit 
LB-T06 
14.x 
Shift from Baseline in Laboratory Test: Coagulation 
Results by Cohort and Visit 
LB-T07 
14.x 
Summary of Urinalysis Values by Cohort and Visit 
SC-T01 
14.x 
Summary of Mean and Mean Change from Baseline 
SCOPA-PC Total Score by Cohort and Visit 
ECG-T01 
14.x 
Summary of Mean and Mean Change from Baseline in 
ECG Values by Cohort and Visit 
ECG-T02 
14.x 
Summary of 12-Lead ECG Conclusions 
VS-T01 
14.x 
Summary of Mean and Mean Change from Baseline in 
Vital Sign Values by Cohort and Visit 
VS-T02 
14.x 
Potential Orthostatic Hypotension by Cohort and Visit 
CS-T01 
14.x 
Summary of C-SSRS by Cohort and Visit 
UL-T01 
14.x 
Summary of Ultrasound 
 
 


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15. LIST OF PLANNED FIGURES 
Figure 
Identifier 
Figure 
No. 
Title 
EF-T01 
 
Mean Change from Baseline in Awake Time Spent 
“On” by Cohort and Visit 
EF-T02 
 
Mean Change from Baseline in Awake Time Without 
Troublesome dyskinesia by Cohort and Visit 
EF-T03 
 
Mean Change from Baseline Awake Time Spent “Off” 
by Cohort and Visit 
EF-T04 
 
Mean Change from Baseline in MDS-UPDRS Total 
Score by Cohort and Visit 
EF-T05 
 
Mean Change from Baseline in ESS Total Score by 
Cohort and Visit 
EF-T06 
 
Mean Change from Baseline in Total QUIP-RS Score 
by Cohort and Visit 
 
 


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16. LIST OF PLANNED DATA LISTINGS 
Listing 
Identifier 
Listing 
No. 
Title 
DS-L01 
16.x 
Listing of Subject Disposition 
DS-L02 
16.x 
Listing of Subject Eligibility 
DS-L03 
16.x 
Listing of UK Brain Bank Diagnostic Criteria 
DM-L01 
16.x 
Listing of Subject Demographic and Baseline 
Characteristics 
MH-L01 
16.x 
Listing of Medical History 
CM-L01 
16.x 
Listing of Prior Medications 
CM-L02 
16.x 
Listing of Concomitant Medications and Therapies 
EX-L05 
16.x 
Listing of Oral Ropinirole Dosing Log 
EX-L03 
16.x 
Listing of Implantation Eligibility 
EX-L01 
16.x 
Listing of Implant Site Examination 
EX-L02 
16.x 
Listing of Implantation Procedure 
EX-L04 
16.x 
Listing of Implant Removal 
EF-L01 
16.x 
Listing of MDS-UPDRS Individual Items 
EF-L06 
16.x 
Listing of MDS-UPDRS Sub-scores and Total Score 
EF-L02 
16.x 
Listing of PDSS-2 
EF-L03 
16.x 
Listing of ESS 
EF-L04 
16.x 
Listing of QUIP-RS 
EF-L05 
16.x 
Listing of Hauser Diary Data 
AE-L01 
16.x 
Listing of All Adverse Events 
AE-L02 
16.x 
Listing of All Treatment-Emergent Serious Adverse 
Events 
AE-L03 
16.x 
Listing of All Treatment-Emergent Adverse Events 
Leading to Death or Hospitalization 
AE-L04 
16.x 
Listing of All Treatment-Emergent Adverse Events 
Leading to Study Drug Discontinuation 
AE-L05 
16.x 
Listing of Preferred Terms Included in Adverse 
Events of Special Interest 
LB-L01 
16.x 
Listing of Hematology Results 
LB-L02 
16.x 
Listing of Serum Chemistry Results 
LB-L03 
16.x 
Listing of Coagulation Results 
LB-L04 
16.x 
Listing of Urinalysis Results 
LB-L05 
16.x 
Listing of Urine Drug and Cotinine, and 
Breathalyzer Results 


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LB-L06 
16.x 
Listing of Pregnancy Results 
LB-L07 
16.x 
Listing of Virus Serology 
EG-L01 
16.x 
Listing of Electrocardiogram Values 
VS-L01 
16.x 
Listing of Vital Signs 
QS-L01 
16.x 
Listing of C-SSRS 
QS-L02 
16.x 
Listing of SCOPA-PC 
QS-L03 
16.x 
Listing of Mini Mental State Examination 
PE-L02 
16.x 
Listing of Neurological Examination Results 
PE-L01 
16.x 
Listing of Physical Examination Results 
UT-L01 
16.x 
Listing of Ultrasound Results 
PD-L01 
16.x 
Listing of Protocol Deviations 
 


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17. APPENDICES 
17.1 Imputation Algorithm for Partial and Missing Dates 
Adverse Events  
Note that if any of the imputations below result in an onset date that is after AE end date, 
then onset date will be set to AE end date. 
If onset date is completely missing, onset date is set to date of first dose. 
If (year is present and month and day are missing) or (year and day are present and month 
is missing): 
• If year = year of first dose, then set month and day to month and day of first dose 
• If year < year of first dose, then set month and day to December 31. 
• If year > year of first dose, then set month and day to January 1. 
If month and year are present and day is missing: 
• If year=year of first dose and 
o If month = month of first dose then set day to day of first dose 
o If month < month of first dose then set day to last day of month 
o If month > month of first dose then set day to first day of month 
• If year < year of first dose then set day to last day of month 
• If year > year of first dose then set day to first day of month 
For all other cases, set onset date to date of first dose 
 
Concomitant Medications 
Start Date: 
If start date is completely missing and end date is not prior to first dose, then the 
medication will be classified as concomitant.  If start date is completely missing and end 
date is prior to first dose, then the medication will be classified as prior. 
If (year is present and month and day are missing) or (year and day are present and month 
is missing) then set month and day to January 1. 
If year and month are present and day is missing then set day to first day of month. 
 
End Date: 
If end date is completely missing then the medication will be classified as concomitant.  
If (year is present and month and day are missing) or (year and day are present and month 
is missing) then set month and day to December 31. 
If year and month are present and day is missing then set day to last day of the month. 
Note that if both start and end dates are missing then the medication will be classified as 
concomitant. 
 
17.2 MDS-UPDRS Scoring 
Subscores 
Part I – All 13 items with scores (excludes 1.A Source of Information, 1.6A Who is 
filling out questionnaire) 
Part II – All 13 items 


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Part III – All 33 items with scores (excludes 3a, 3b, 3c, 3.C1, Were dyskinesias present, 
Did these movements interfere with ratings, Hoehn and Yahr Stage) 
Part IV – All 6 items  
Total Score = Sum of All Scores 
 
Missing Data Rules 
Part I subscore – 13 items with scores 
• If missing > 1, then subscore = missing 
• If missing <= 1, sum of the non-missing items X (total number of items)/ (number 
of items non-missing) 
Part II subscore – 13 items with scores 
• If missing > 2, then subscore = missing 
• If missing <= 2, sum of the non-missing items X (total number of items)/ (number 
of items non-missing) 
Part III subscore – 33 items with scores 
• If missing > 7, then subscore = missing 
• If missing <= 7, sum of the non-missing items X (total number of items)/ (number 
of items non-missing) 
Part IV subscore – 6 items with scores 
• If missing > 0, then subscore = missing 
 
 
 
 


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17.3 Schedule of Events 
Event 
Screening 
(up to 4 
weeks) 
Period 1 
(up to 10 days) 
Period 2 
 
EOT or 
EWD 
Follow-up 
Visits1 
S1 
P1 Day 
-2 
Day 
-1 
Implant 
 Visit 
(Day 1) 
Day 
2 
Day 
3 
Day 
4 
Week 
1 
Week 
2 
Week 
3 
Week 
4 
Week 
6 
Week 
8 
Week 
10 
Week 12 
Week 
13 
Week 
14 
Written Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility Criteria Review 
X 
 
 
 
X2 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical and Medications 
History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Neurological Examination  
X 
 
 
 
X2 
 
 
 
 
 
 
 
 
 
 
X3 
 
 
UK Brain Bank Diagnostic 
Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MMSE 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hoehn and Yahr 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MDS-UPDRS 
X 
 
 
 
 
 
 
 
 
X 
 
X 
 
X3 
 
 
C-SSRS 
X 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X3 
X 
X 
SCOPA-PC 
X 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X3 
X 
X 
PDSS-2 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
 
X3 
 
 
ESS 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
 
X3 
 
 
QUIP-RS 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
X3 
 
 
Pregnancy Test4 
X 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 


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Event 
Screening 
(up to 4 
weeks) 
Period 1 
(up to 10 days) 
Period 2 
 
EOT or 
EWD 
Follow-up 
Visits1 
S1 
P1 Day 
-2 
Day 
-1 
Implant 
 Visit 
(Day 1) 
Day 
2 
Day 
3 
Day 
4 
Week 
1 
Week 
2 
Week 
3 
Week 
4 
Week 
6 
Week 
8 
Week 
10 
Week 12 
Week 
13 
Week 
14 
12-Lead ECG 
X 
 
X 
 
X5 
 
 
 
 
 
 
X 
 
 
 
X3 
 
 
Implantation Criteria 
 
 
 
 
X2 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs6 
X7 
X 
X 
X 
X8, 9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X8 
X 
X 
Physical Examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviated Review of 
Systems 
 
 
 
 
X2 
 
 
 
 
 
 
X 
 
X 
 
X3 
 
 
Chemistry, Hematology, 
Coagulation Profile, 
Urinalysis 
X 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X3 
 
 
Urine Drug and Cotinine 
Screen and Breath Alcohol 
Test10 
X 
 
X 
 
X2 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
HBV, HCV, HIV 
X11 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hauser Diary Concordance 
Training 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense Subject Diary 
Cards12  
X 
X 
 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Collect Subject Diary Cards12 
 
X 
X 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X3 
 
 
Insertion Procedure  
 
 
 
 
X13 
 
 
 
 
 
 
 
 
 
 
 
 
 
Palpation of Implant(s)14 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 


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Event 
Screening 
(up to 4 
weeks) 
Period 1 
(up to 10 days) 
Period 2 
 
EOT or 
EWD 
Follow-up 
Visits1 
S1 
P1 Day 
-2 
Day 
-1 
Implant 
 Visit 
(Day 1) 
Day 
2 
Day 
3 
Day 
4 
Week 
1 
Week 
2 
Week 
3 
Week 
4 
Week 
6 
Week 
8 
Week 
10 
Week 12 
Week 
13 
Week 
14 
Ultrasound 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X3 
 
 
Dispense Oral Study 
Medication 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK Blood Sample Collection 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Implant Site Examination / 
Treatment Compliance15 
 
 
X 
X 
X2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X3 
X 
X 
Dispense Treatment 
Identification Card  
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Removal Procedure 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Wound Care Information 
Sheet 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Patient Satisfaction Survey 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Implanting Physician 
Satisfaction Survey 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications / 
Procedures 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
BP = blood pressure; C-SSRS = Columbia Suicide Severity Rating Scale; DBP = diastolic blood pressure; ECG = electrocardiogram; eCRF = electronic case 
report form; EOT = End of Treatment; ESS = Epworth Sleepiness Scale; EWD = early withdrawal; HBV = hepatitis B virus; HCV = hepatitis C virus; 
HIV = human immunodeficiency virus; IRB = Institutional Review Board; MDS-UPDRS = Movement Disorder Society-sponsored revision of the Unified 
Parkinson’s Disease Rating Scale; MMSE = Mini Mental State Examination; P = period; PD = Parkinson’s disease; PDSS-2 = Parkinson’s Disease Sleep Scale; 
PK = pharmacokinetic(s); QUIP-RS = Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease-Rating Scale; S = screening; SBP = systolic 
blood pressure; SCOPA-PC = Scale for Outcomes of Parkinson’s disease–Psychiatric Complications 
 
1 Visit windows:  The P1 Visit should occur once all screening assessments and eligibility criteria are met.  Weeks 1-10 Visits should occur ±1 day relative to the 
projected time point as measured from the Implant Visit.  The EOT Visit should occur no less than 12 weeks from the Implant Visit, except in cases of early 


Titan Pharmaceuticals, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. ROP-001 
 
11MAY2018 
Version:  1.0 
Page 39 of 39 
withdrawal.  The Week 13 Follow-up Visit should occur 1 week ±2 days from EOT visit.  The Week 14 Follow-up Visit should occur 2 weeks ±2 days from 
last implant removed. 
2 To be performed prior to implantation. 
3 Measures to be completed prior to implant removal. 
4 For females of child-bearing potential, a serum pregnancy test will be performed at the Screening Visit and the EOT Visit (Week 12 or early withdrawal).  An 
"in-office" urine pregnancy test will be required at Day -2, Week 4, Week 8, and Week 14 Follow-up Visit. 
5 Implant Visit ECG to be completed 3 hours (±15 minutes) following implant insertion. 
6 Vital signs include supine BP and standing BP, pulse rate, respiratory rate, and oral body temperature.  Measurements for orthostatic hypotension will be taken 
at every study visit.  Orthostatic measurements (supine and standing BP and 60 seconds of pulse rate) can be measured manually or using an automated BP 
machine; the same method of measurement should, however, be used throughout the study for a particular subject.  The subject’s BP and pulse rate will be 
measured after the subject has been supine for approximately 5 minutes.  The subject will be instructed to rise to a standing position, and a BP measurement 
will be taken after the subject has been standing for 1 minute.  Orthostatic hypotension is defined as a reduction of SBP of >20 mmHg or DBP >10 mmHg 
within 3 minutes of quiet standing. 
7 At screening, two sets of measurements of supine/erect BP should be obtained at least 15 minutes apart.  These measurements will be recorded in the eCRF.  
Subjects with any exclusionary readings will not be eligible for the study. 
8 Measures for orthostatic hypotension will be taken for:  Implant Visit at 0 (prior to implantation), 0.5, 1, 2, and 4 hours post-implantation; EOT Visit at 0 
(pre-implant removal), 0.5, 1, 2, and 4 hours post-implantation removal.  
9 Respiration rate and body temperature will be collected prior to implantation, and at 15 and 30 minutes following implant insertion. 
10 Subjects will also provide 3 random urines (to test for drugs of abuse and cotinine) and breath alcohol tests to be collected at any 3 non-PK inpatient stay study 
visits, with at least 2 collected during Period 2. 
11 It is the investigator's responsibility to understand and comply with all laws and regulations that apply to HIV, HBV, and HCV testing of blood.  HIV, HBV, 
and HCV testing is required unless a site's IRB prohibits such testing. 
12 Awake “On and Off” time diaries will be completed for 2 consecutive days prior to Visit P1 and Day -2, and 2 consecutive days prior to each visit for Weeks 1 
through 12.   
13 Prior to implant insertion, the Implantation Criteria must be met. 
14 As specified in the Manual of Procedures (MOP). 
15The implant site will be visually inspected.  If there is any evidence of removal or attempted removal of the implants, the subject will be withdrawn from the 
study and all implants will be removed.  Tablet counts will be conducted to track compliance.