Clinical trial NCT03007888
Conditions: Advanced Parkinson's Disease
Keywords: IPX203 (carbidopa-levodopa) Extended-Release capsules
Sponsor: Impax Laboratories, LLC
Start date: 2016-11-14; Completion date: 2017-08-01
Enrollment: 28 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
Primary Objective:

To compare the pharmacokinetics (PK) of single and multiple doses of IPX203 with Immediate release carbidopa-levodopa (IR CD-LD) in subjects with advanced Parkinson's disease (PD).

Secondary Objectives:

To compare the pharmacodynamics of single and multiple doses of IPX203 with IR CD-LD.

To compare the efficacy of IPX203 with IR CD-LD following multiple doses.

To evaluate the safety of IPX203.

Detailed description:
IPX203 is an investigational product containing CD-LD.

IPX203-B16-01 Study Design:

A randomized, open-label, rater-blinded, multicenter, 2-treatment, 2-period, multiple-dose crossover study.

Approximately 30 qualified IR CD-LD-experienced advanced PD subjects will be randomized.

The study duration will be approximately 8 weeks, including the screening period.

Arms: arm 1: Participants first received IPX203 ER CD-LD Capsules for 15 days After a Washout Period of 7 days; participants then received Sinemet (IR CD-LD) Tablet for 15 days Study drug doses were determined based on the subject's prestudy IR CD-LD regimen The typical IPX203 dosing regimen was 3 times a day, dosed approximately every 7 to 8 hours. arm 2: Participants first received Sinemet Capsules for 15 days After a Washout Period of 7 days; participants then received IPX203 ER CD-LD Capsules for 15 days Study drug doses were determined based on the subject's prestudy IR CD-LD regimen The typical IPX203 dosing regimen was 3 times a day, dosed approximately every 7 to 8 hours.
Interventions: intervention 1: Sinemet intervention 2: IPX203
Intervention descriptions: intervention 1: Immediate Release Tablet containing carbidopa-levodopa flexible dosing intervention 2: Extended Release capsules containing carbidopa-levodopa flexible dosing

Protocol documents:
Prot_000.pdf: 
Protocol No. IPX203-B16-01 
CONFIDENTIAL 
Amendment 2: October 5, 2016 
Impax Laboratories, Inc. 
Page 1 of 136 
IPX203 (CARBIDOPA-LEVODOPA) 
EXTENDED RELEASE 
IPX203-B16-01 
A RANDOMIZED, MULTIPLE DOSE STUDY TO 
ASSESS THE PHARMACOKINETICS AND 
PHARMACODYNAMICS OF IPX203 IN SUBJECTS 
WITH ADVANCED PARKINSON’S DISEASE 
SPONSOR 
Impax Laboratories, Inc., 
acting through its Impax Specialty Pharma division (Impax) 
30831 Huntwood Ave. 
Hayward, CA 94544 
Original Protocol, August 8, 2016 
Amendment 1, September 1, 2016 
Amendment 2, October 5, 2016 
CONFIDENTIALITY STATEMENT 
All information provided is the property of Impax Laboratories, Inc. and may not be divulged, 
published or otherwise disclosed without written consent of Impax.  All information provided to 
the Investigator by the Sponsor, including clinical observations at the investigative site, shall be 
held strictly confidential and confined to the clinical personnel involved in conducting the study, 
under the supervision of the Investigator.  This includes but is not limited to preclinical data, 
protocols, case report forms, and verbal or written communications.  This information may be 
related in confidence to the Institutional Review Board or other committees functioning in a 
similar capacity.  All reports, subject samples, data published or submitted to third parties will be 
identified by a coded number and initials only in order to maintain subject confidentiality. 


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Impax Laboratories, Inc. 
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SIGNATURE PAGE 
Reviewed and approved by: 
 
 


Protocol No. IPX203-B16-01 
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Impax Laboratories, Inc. 
Page 3 of 136 
INVESTIGATOR’S AGREEMENT 
 
Protocol No.: 
IPX203-B16-01 
Protocol Title: 
A Randomized, Multiple Dose Study to Assess the Pharmacokinetics and 
Pharmacodynamics of IPX203 in Subjects with Advanced Parkinson’s 
Disease 
 
 
I have read this protocol and agree to conduct the study as outlined herein, complying with the 
obligations and requirements of clinical investigators and all other requirements of International 
Conference on Harmonization (ICH), Good Clinical Practice (GCP), and the appropriate 
regulatory authority. 
I will provide copies of the protocol and all pertinent information to all individuals responsible to 
me who assist in the conduct of this clinical study.  I will discuss this material with them to 
ensure that they are fully informed regarding the study medication, the conduct of the study, and 
the obligations of confidentiality. 
 
 
_________________________________________ 
___________________ 
Principal Investigator’s signature 
Date 
 
 
_________________________________________ 
Principal Investigator’s printed name 
 


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Page 4 of 136 
STUDY CONTACT INFORMATION 
Changes in Impax study personnel listed on this page do not require a protocol amendment. 
Role  
Name and Contact Information 
Sponsor 
Impax Laboratories, Inc. acting through its Impax 
Specialty Pharma division (Impax) 
30831 Huntwood Avenue 
Hayward, CA 94544-7037 
(510) 240-6000 
FAX:  (510) 240-6113 and (510) 240-6114 
Medical Monitor 
Robert Rubens, MD, MBA 
Senior Director, Clinical Research & Development 
Mobile:  (510) 303-8207 
Office:  (510) 240-6012 
E-mail:  rrubens@impaxlabs.com 
Statistician 
Phillip Dinh, PhD 
Director, Statistics   
(510) 240-6402 
E-mail:  Phillip.Dinh@impaxlabs.com 
Clinical Pharmacology 
Aravind Mittur, PhD 
Director, Clinical Pharmacology 
(510) 240-6437 
E-mail:  amittur@impaxlabs.com 
Clinical Research Associates 
Barbara Pruitt, RN, BS 
Associate Director, Clinical Operations 
Office:  (510) 240-6003 
Mobile:  (510) 329-8489 
E-mail:  bpruitt@impaxlabs.com 
 
Weiru Hong, MS 
Senior CRA, Clinical Operations 
Office: (510) 240-6078 
Mobile: (510) 731-8309 
E-mail: whong@impaxlabs.com 
Serious Adverse Event 
Reporting 
FAX:  (866) 954-2061 


Protocol No. IPX203-B16-01 
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Amendment 2: October 5, 2016 
Impax Laboratories, Inc. 
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1. 
SYNOPSIS 
Name of Sponsor/Company:  Impax Laboratories, Inc. acting through its Impax Specialty 
Pharma division (Impax) 
Name of Investigational Product:  IPX203 (carbidopa-levodopa) Extended-Release Capsules 
Name of Active Ingredient:  carbidopa (CD), levodopa (LD) 
Protocol Title:  A Randomized, Multiple Dose Study to Assess the Pharmacokinetics and 
Pharmacodynamics of IPX203 in Subjects with Advanced Parkinson’s Disease 
Protocol No.:  IPX203-B16-01 
Study center(s):  Multicenter 
Phase of Development:  Phase 2 
Study Duration:  Approximately 8 weeks including Screening 
Objectives: 
Primary:  To compare the pharmacokinetics (PK) of single and multiple doses of IPX203 
with immediate release (IR) CD-LD in subjects with advanced Parkinson’s disease (PD). 
Secondary: 
 To compare the pharmacodynamics of single and multiple doses of IPX203 with 
IR CD-LD 
 To compare the efficacy of IPX203 with IR CD-LD following multiple doses 
 To evaluate the safety of IPX203. 
Methodology:  This is a randomized, open-label, rater-blinded, multicenter, 2-treatment, 
2-period, multiple-dose crossover study.  Approximately 30 advanced PD subjects will be 
randomized to 1 of 2 dosing sequences.  The study duration will be approximately 8 weeks, 
including the screening period. 
This study will consist of 4 study visits after Screening:  Day 1 of each treatment period 
(Visits 1 and 3), and Day 15 of each treatment period (Visits 2 and 4).  Study Exit procedures 
will be done at the end of Visit 4 or within 3 days of Visit 4 or during an early withdrawal.  
Subjects may continue to take allowed non-CD-LD based PD medications throughout the 
study if documented in their prestudy regimen and if dosing regimens have been stable for at 
least 4 weeks prior to Visit 1.  During the 1-week (± 2 days) washout period between treatment 
periods, subjects will return to their prestudy PD medication regimen. 
Within 2 weeks following Screening, eligible subjects will complete their PD and Dosing 
diaries, and will wear the Kinesia 360 sensor bands on the more affected side at home 
immediately after waking on each of the 3 days prior to Visit 1.  Subjects will be instructed to 
take their last dose of CD-LD no later than 10:00 PM on the evening prior to Visits 1 and 3.  
The first morning dose of study medication will be administered at the study site.  The “first 
morning dose” is defined as the subject’s first LD dose upon awakening for the day 
immediately following the subject’s usual nocturnal sleep period intended to achieve an “on” 


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state.  On Day 1 of the IR CD-LD treatment period, subjects will start with a single dose of 
their usual prestudy first morning IR CD-LD dose.  On Day 1 of the IPX203 treatment period, 
subjects will start with a single dose of IPX203 based on their usual prestudy first morning 
IR CD-LD dose.  Pharmacokinetic and pharmacodynamic measures will be assessed in the 
clinic for up to 8 hours postdose during Visits 1 and 3.  If subject experiences an “off” state for 
≥ 3 consecutive hours after dosing, the subject may receive rescue medication, (by taking an 
additional dose of study medication for that period).  PK blood sampling and 
pharmacodynamic assessments will be continued throughout the 8-hour PK/pharmacodynamic 
study period including in those subjects who receive rescue medication. 
Day 1 (Visits 1 and 3) blood samples (6 mL) for PK analysis will be collected predose and at 
0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 5.5, 6, 6.5, 7, 7.5, and 8 hours postdose. 
The following pharmacodynamic measures will be conducted during Visits 1 and 3 by 
qualified clinical staff who are blinded to dosing: 
 Assessment of Subject’s Motor State (“on” and “off,” and state of dyskinesia) at –1, –0.5, 
0, and at half-hourly intervals postdose for up to 8 hours. 
 MDS-UPDRS Part III (Motor Examination) at predose and hourly for up to 8 hours 
postdose. 
Following the completion of Visits 1 and 3, subjects will be discharged from the clinic and 
instructed to take their assigned study drug at home for the remainder of Day 1 through 
Day 14 of each treatment period and return to the clinic on Day 15 (of each treatment period) 
for Visits 2 and 4. 
During the IR CD-LD treatment period, the initial dosing regimen of IR CD-LD will be the 
same as the subject’s stable prestudy regimen unless they were taking a single daily bedtime 
dose of CR CD-LD, either alone or in combination with IR CD-LD, in which case, the 
CR CD-LD dose will be discontinued and substituted with a 1:1 milligram-equivalent 
IR CD-LD dose.  A “bedtime dose” is defined as a dose of CR CD-LD taken within 1 hour of 
the subject’s normal nighttime sleep period.  During the IPX203 treatment period, the initial 
doses of IPX203 will be based on the subject’s prestudy stable LD regimen and the initial 
response to IPX203.  The typical dosing regimen for IPX203 will be three times a day, dosed 
approximately every 7 to 8 hours.  Some subjects may require more or less frequent dosing to 
optimize therapeutic effect (minimize “off” time without causing troublesome dyskinesia or 
other dopaminergic side effects). 
During Days 1 through 9 of both treatment periods, investigators may adjust each subject’s 
study medication regimen if necessary to optimize efficacy and safety.  Site staff should 
follow-up on the subject’s status (dosing, response and adverse events) every 1-3 days by 
telephone. 
On Days 10 through 14 of each treatment period, subjects should be on a stable dosing 
regimen.  Subjects may continue to take permitted non-CD-LD based PD medications 
throughout the study if documented in their prestudy regimen and if dosing regimens have 
been stable for at least 4 weeks prior to Visit 1.  Subjects will complete their Dosing and PD 
Diaries and wear the Kinesia 360 sensor bands on the more affected side at home immediately 
after waking in the morning on each of the 3 days prior to Visits 2 and 4 (Days 12-14 of each 
treatment period). 
For the Day 15 clinic visits, the subjects will be instructed to withhold their study medication 


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for at least 5 hours before arriving at the study site.  The first morning dose of study 
medication will be administered at the study site.  This first morning dose and subsequent 
doses administered in the clinic will be the same as the dosing regimen recorded in the dosing 
diary for Days 12-14 of the current treatment period. 
Pharmacokinetic and pharmacodynamic measures will then be assessed in the clinic for up to 
10 hours postdose during Visits 2 and 4.  PK blood sampling and pharmacodynamic 
assessments will be continued throughout the 10-hour PK/pharmacodynamic study period. 
Day 15 (Visits 2 and 4) blood samples (6 mL) for PK analysis will be collected predose and at 
0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, and 10 hours postdose. 
The following pharmacodynamic measures will be conducted during Visits 2 and 4 by 
qualified clinical staff who are blinded to dosing: 
 Assessment of Subject’s Motor State (“on” and “off,” and state of dyskinesia) at –1, –0.5, 
0, and half-hourly intervals postdose for up to 10 hours. 
 MDS-UPDRS Parts I, II, and IV will be assessed at predose 
 MDS-UPDRS Part III (Motor Examination) will be assessed at predose and hourly for up 
to 10 hours postdose.  
When the subject leaves the clinic after Visit 2 for wash-out and after Visit 4 (end of treatment 
period 2), he/she will revert to his/her prestudy dosing regimen. 
Number of subjects (planned):  Approximately 30 subjects will be randomized to complete 
26. 
Diagnosis and main criteria for inclusion:  
 Male or female subjects diagnosed with idiopathic PD at age ≥40 years who are currently 
being chronically treated with stable regimens of CD-LD but experiencing motor 
complications.  Idiopathic PD is defined by United Kingdom Parkinson’s Disease Society 
Brain Bank Diagnostic Criteria. 
 Hoehn and Yahr Stages 2, 3, or 4 (part of MDS-UPDRS Part III) 
 Montreal Cognitive Assessment (MoCA) score ≥24 at Screening Visit in the “on” state. 
 For the 4 weeks prior to Screening, the subject experiences daily “wearing-off” episodes 
with periods of bradykinesia and rigidity, and experiences an “off” state upon awakening 
on most mornings by history. 
 At Visit 1, review of the 3-day PD diary confirms the following:  that the subject is able to 
properly complete the diary with valid entries; and that the subject has an average of at 
least 2.5 hours per day of “off” time during the waking hours over the 3 days with at least 
1.5 hours “off” time on each day.  Inability to properly complete the diary is indicated 
when more than 1 day of the diary is not returned or when more than 2 hours (4 half-hour 
periods) of one 24-hour diary day are missing. 
 Responsive to CD-LD therapy and currently being treated on a stable regimen with 
CD-LD for at least 4 weeks prior to Visit 1 and: 
o requires 100 to 250 mg (in units of 50 mg) of IR CD-LD for the morning dose 
o requires a total daily dose of at least 400 mg of IR CD-LD 
o takes a maximum total daily dose of 1800 mg LD, comprising IR CD-LD alone or 


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IR CD-LD in combination with a single daily bedtime dose of CR CD-LD. 
o has a dosing frequency of 4 to 9 times daily of CD-LD 
o typically experiences an “on” response with the first dose of IR CD-LD of the day (by 
subject history) 
o By history, efficacy of the first morning dose of IR CD-LD lasts less than 4 hours, 
typically wearing “off” prior to the next dose; or subject takes the second dose of PD 
medications prior to 4 hours to avoid an “off.” 
 Has not used doses of controlled-release (CR) CD-LD apart from a single daily bedtime 
dose for at least 4 weeks prior to Visit 1. 
 Has not used any doses of Rytary for the past 4 weeks prior to Visit 1. 
 At Screening, the MDS-UPDRS Part III total score in the “off” state is: 
o at least 20 units  
o at least 25% or 10 units greater than in the “on” state 
 Exclusions: 
o History of medical conditions or of a prior surgical procedure that would interfere with 
LD absorption, such as gastrectomy or proximal small-bowel resection. 
o Liver enzyme values ≥2.5 times the upper limit of normal; or history of severe hepatic 
impairment; or serum creatinine level ≥1.75 times the upper limit of normal; or 
requires dialysis at the time of Screening. 
o History of drug or alcohol abuse within the 12 months prior to Screening. 
o Received within 4 weeks of Visit 1 or planning to take during participation in the 
clinical study:  any doses of a controlled-release (CR) LD apart from a single bedtime 
dose or any doses of Rytary, additional CD (eg, Lodosyn) or benserazide (eg, 
Serazide), or catechol-O-methyl transferase inhibitors (entacapone or tolcapone) or 
medications containing these inhibitors (Stalevo).  Received within 4 weeks of Visit 1 
or planning to take during participation in the clinical study: nonselective MAO 
inhibitors, apomorphine, or dopaminergic blocking agents including antiemetics. 
o History of psychosis within the past 10 years.  Mild PD-associated illusions are not 
exclusionary provided that they do not occur more than once per week and the subject 
does not lose insight 
o Treatment with any dopamine antagonist antipsychotics within the last 2 years. 
o Based on clinical assessment, subject does not adequately comprehend the terminology 
needed to complete the PD diary. 
Investigational product, dosage and mode of administration: IPX203 (carbidopa-levodopa) 
Extended-Release capsules, containing 180 mg and 270 mg of LD, for oral administration. 
Reference therapy, dosage and mode of administration:  Immediate-release carbidopa-
levodopa (IR CD-LD) tablet containing 100 mg of LD for oral administration. 
Criteria for evaluation: 
Efficacy:  
 Primary: Percent “off” time during waking hours, based on subject PD diaries for the last 


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3 days collected at the end of each treatment period 
 Secondary:  
o Subject PD diaries for the last 3 days collected at the end of each treatment period:  
 Average of (1) total “off” time (2) total “on” time with no troublesome dyskinesia 
[good on] (3) total “on” time with no dyskinesia (4) total “on” time with 
troublesome dyskinesia (5) total “on” time with non-troublesome dyskinesia 
(6) total time asleep 
 Proportion of subjects with an improvement of at least 0.5, 1, 1.5, 2, and 3 hours 
from baseline in the total “off” time based on PD Diaries 
 Proportion of subjects in “off” state within the first 30 minutes of awakening for the 
day immediately following the subject’s usual nocturnal sleep period. 
 Average total “off” time and total “on” time with no troublesome dyskinesia 
normalized for 16 waking hours 
o Change in the dyskinesia, mobility, and tremor measures obtained using the 
Kinesia 360 
o MDS-UPDRS collected predose on Day 15 of each treatment period – Average of  
 total MDS-UPDRS score for the sum of Parts I to IV 
 total scores for each of the 4 parts of the MDS-UPDRS 
 total MDS-UPDRS score for the sum of Parts II and III 
Pharmacodynamics: 
 Subject Motor Assessment - Day 1 and Day 15 of each treatment period 
o average of (1) total off time (2) total “on” time with no troublesome dyskinesia [good 
on] (3) total “on” time with no dyskinesia (4) total “on” time with troublesome 
dyskinesia (5) total “on” time with non-troublesome dyskinesia (6) total time asleep,  
o proportion of subjects who are “off” and proportion of subjects “on” without 
troublesome dyskinesia will be presented at each time point 
 MDS-UPDRS Part III - Day 1 and Day 15 of each treatment period 
o average of change in MDS-UPDRS Part III score from Day 1 predose value at each 
time point 
o average of the area under the curve (AUC) of change in MDS-UPDRS Part III motor 
score value from predose value on Day 1 
o average duration of effect estimated using the time point at which an improvement of at 
least (1) 4 points (2) 7 points (3) 13 points in the MDS-UPDRS Part III score from 
predose value on Day 1 is first observed and continuing until the time point at which 
the improvement is no longer observed. 
o Individual and average of change in sum of questions 4 through 8 and question 14 
MDS-UPDRS Part III score from Day 1 predose value at each time point to assess 
bradykinesia. 
Pharmacokinetics (Visits 1 – 4):  
The following PK parameters will be calculated from the CD and LD plasma concentration-
time profiles after each treatment:   


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 fluctuation index (Visits 2 and 4) 
 accumulation (Visits 2 and 4) 
 observed maximum plasma concentration (Cmax) and time to maximum concentration 
(Tmax) on Day 1 
 area under the plasma concentration-time curve from time zero to the last measurable 
concentration (AUC0-t), and from time zero to infinity (AUC0-∞) on Day 1 
 apparent elimination half-life (t1/2) on Day 1 
 bioavailability of IPX203 relative to IR CD-LD on Day 1 
 time to 50% Cmax of LD on Day 1 
 duration > 50% Cmax of LD on Day 1. 
Safety:   
 electrocardiograms (ECGs), clinical laboratory tests, physical examinations, C-SSRS, and 
vital signs 
 adverse events and concomitant medications evaluated throughout the course of the study. 
Statistical methods:  
Pharmacokinetics:  
Descriptive statistics will be presented by treatment group for the PK parameters for 
IR CD-LD and IPX203.  Following natural logarithm transformation, analyses of variance 
(ANOVA) will be performed on CD and LD AUC and Cmax normalized for dose.  
Additionally, duration of LD plasma concentration above 50% of Cmax values will be analyzed 
using ANOVA.  Comparisons will be performed using a mixed-effect ANOVA model that 
includes treatment, period, and sequence as fixed effects and subject-within-sequence as a 
random effect for the following treatments: IPX203 versus IR CD-LD. 
Efficacy: 
 Descriptive statistics and frequency distributions will be displayed for all endpoints 
 Primary:  The primary efficacy parameter for this study will be the average percent “off” 
time during waking hours based on subject PD diaries collected at the end of each 
treatment period.  For each day it will be calculated as the number of half-hour intervals in 
which “off” is checked.  The average percent “off” time will be defined as the average of 
percent “off” time (total “off” time divided by the total time not “asleep” (ie, waking 
hours) from the subject PD diaries completed for the 3 days immediately prior to the visit.  
The difference between the average percent “off” time between treatments will be analyzed 
using a standard mixed-model analysis of variance at a 0.05 level of significance.  This 
model will include the fixed-effect factors of treatment, and period and the random-effect 
inter- and intra-subject factors. 
 Secondary:  The continuous efficacy endpoints will be evaluated for differences between 
treatments using a standard mixed-model analysis of variance at a 0.05 level of 
significance.  This model will include the fixed-effect factors of treatment, sequence and 
period and the random-effect inter- and intra-subject factors.  The categorical endpoints 
will be analyzed using generalized estimating equations methods.  The model will include 
treatment and period. All comparisons of secondary endpoint will be tested at 5% 
significance level without any multiplicity correction. 


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Pharmacodynamics: 
 Descriptive statistics and frequency distributions will be displayed for all 
pharmacodynamic endpoints. 
 The continuous endpoints will be evaluated for differences between treatments using a 
standard mixed-model analysis of variance at a 0.05 level of significance.  This model will 
include the fixed-effect factors of treatment, sequence and period and the random-effect 
inter- and intra-subject factors.  The categorical endpoints will be analyzed using 
generalized estimating equations methods.  The model will include treatment and period.  
All comparisons of secondary endpoint will be tested at 5% significance level without any 
multiplicity correction. 
Safety: 
Quantitative data for safety will be summarized using descriptive statistics.  Qualitative safety 
data will be summarized by count per category and number and percentage of subjects where 
appropriate. 


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2. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES 
TABLE OF CONTENTS 
1. 
SYNOPSIS ...................................................................................................................5 
2. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............12 
3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................17 
4. 
INTRODUCTION ......................................................................................................19 
5. 
TRIAL OBJECTIVES ................................................................................................21 
5.1. 
Primary Objective .......................................................................................................21 
5.2. 
Secondary Objectives .................................................................................................21 
6. 
INVESTIGATIONAL PLAN .....................................................................................22 
6.1. 
Overall Study Design ..................................................................................................22 
6.2. 
Number of Subjects ....................................................................................................23 
6.3. 
Treatment Assignment ................................................................................................23 
6.4. 
Dosing and Dose Determination Criteria ...................................................................24 
6.4.1. 
Day 1 In-Clinic Dosing at Visit 1 and at Visit 3 .........................................................24 
6.4.2. 
Study Drug Regimen following First In-Clinic Dose at Visits 1 and 3 ......................24 
6.5. 
Dose Adjustment Criteria ...........................................................................................26 
6.6. 
Criteria for Study Termination ...................................................................................27 
7. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................28 
7.1. 
Subject Inclusion Criteria ...........................................................................................28 
7.2. 
Subject Exclusion Criteria ..........................................................................................29 
7.3. 
Subject Withdrawal Criteria .......................................................................................31 
8. 
STUDY PROCEDURES ............................................................................................32 
8.1. 
Screening Visit ............................................................................................................34 
8.2. 
Visits 1 and 3 ..............................................................................................................35 
8.2.1. 
Prior to Visit 1 ............................................................................................................35 
8.2.2. 
Prior to Visits 1 and 3 .................................................................................................35 
8.2.3. 
Predose at Visit 1 ........................................................................................................36 
8.2.4. 
Predose at Visits 1 and 3 .............................................................................................36 
8.2.5. 
Postdose at Visits 1 and 3 ...........................................................................................36 


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8.3. 
Days 2-14 (Visits 1 and 3) ..........................................................................................38 
8.4. 
Washout Period (Between Visit 2 and 3) ...................................................................38 
8.5. 
Visits 2 and 4 ..............................................................................................................38 
8.5.1. 
Prior to Visits 2 and 4 .................................................................................................38 
8.5.2. 
Predose at Visits 2 and 4 .............................................................................................39 
8.5.3. 
Postdose at Visits 2 and 4 ...........................................................................................39 
8.6. 
Study Exit/Early Withdrawal Procedures ...................................................................40 
8.7. 
Early Withdrawal ........................................................................................................40 
8.8. 
Blood Volume .............................................................................................................40 
9. 
TREATMENT OF SUBJECTS ..................................................................................41 
9.1. 
Description of Study Drug ..........................................................................................41 
9.2. 
Concomitant Medications ...........................................................................................41 
9.2.1. 
Permitted PD Medications ..........................................................................................41 
9.2.2. 
Prohibited PD Medications .........................................................................................41 
9.3. 
Treatment Compliance ................................................................................................42 
9.4. 
Randomization and Blinding ......................................................................................42 
10. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................43 
10.1. 
Study Drug ..................................................................................................................43 
10.2. 
Study Drug Packaging and Labeling ..........................................................................43 
10.3. 
Study Drug Storage .....................................................................................................43 
10.4. 
Study Drug Administration.........................................................................................43 
10.5. 
Study Drug Dispensing and Accountability ...............................................................44 
10.6. 
Study Drug Handling and Disposal ............................................................................44 
11. 
ASSESSMENT OF EFFICACY ................................................................................45 
11.1. 
Primary Efficacy Endpoint .........................................................................................45 
11.2. 
Secondary Efficacy Endpoints ....................................................................................45 
12. 
PHARMACOKINETIC AND PHARMACODYNAMIC ASSESSMENTS ............46 
12.1. 
Pharmacokinetic Assessments ....................................................................................46 
12.1.1. 
Blood Sample Collection Schedule in Each Study Period .........................................46 
12.1.2. 
Samples per Subject ....................................................................................................46 
12.1.3. 
Pharmacokinetic Blood Sample Collection and Processing .......................................46 
12.2. 
Pharmacodynamic Assessments Endpoints ................................................................47 
12.2.1. 
MDS-UPDRS .............................................................................................................47 


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12.2.2. 
Assessment of Subject’s Motor State .........................................................................47 
13. 
ASSESSMENT OF SAFETY .....................................................................................48 
13.1. 
Safety Parameters .......................................................................................................48 
13.2. 
Adverse Events ...........................................................................................................48 
13.2.1. 
Definition of Adverse Event .......................................................................................48 
13.2.2. 
Recording Adverse Events .........................................................................................48 
13.2.3. 
Follow-up ....................................................................................................................48 
13.2.4. 
Relationship to Study Drug ........................................................................................49 
13.2.5. 
Assessment of Severity ...............................................................................................49 
13.3. 
Serious Adverse Events ..............................................................................................49 
13.3.1. 
Definition of Serious Adverse Event ..........................................................................49 
13.3.2. 
Reporting Serious Adverse Events .............................................................................50 
13.4. 
Pregnancy ...................................................................................................................50 
13.5. 
Other Safety Parameters and Related Information .....................................................50 
14. 
STATISTICS ..............................................................................................................51 
14.1. 
Study Design and Sample Size Estimation .................................................................51 
14.2. 
Demographics/Baseline Comparability ......................................................................51 
14.3. 
Analysis of Pharmacokinetic Data ..............................................................................51 
14.4. 
Analysis of Efficacy Data ...........................................................................................52 
14.4.1. 
Primary Efficacy Endpoint .........................................................................................52 
14.4.2. 
Secondary Efficacy Endpoint .....................................................................................52 
14.5. 
Analysis of Pharmacodynamics Data .........................................................................54 
14.6. 
Analysis of Dosing Data .............................................................................................55 
14.7. 
Population Analysis and Handling of Dropouts .........................................................55 
14.8. 
Safety ..........................................................................................................................56 
15. 
ADMINISTRATIVE PROCEDURES .......................................................................57 
15.1. 
Guidelines for Good Clinical Practice ........................................................................57 
15.2. 
Institutional Review Board Approval .........................................................................57 
15.3. 
Informed Consent .......................................................................................................57 
15.4. 
Study Monitoring ........................................................................................................57 
15.5. 
Protocol Amendments ................................................................................................57 
15.6. 
Termination of Study ..................................................................................................58 
15.7. 
Case Report Forms .....................................................................................................58 


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15.8. 
Investigator’s Final Conduct Report ...........................................................................58 
15.9. 
Records Retention .......................................................................................................58 
16. 
PUBLICATION POLICY ..........................................................................................59 
17. 
LIST OF REFERENCES ............................................................................................60 
18. 
APPENDICES ............................................................................................................61 
APPENDIX A. SINEMET PRESCRIBING INFORMATION ..................................................61 
APPENDIX B. UNITED KINGDOM PARKINSON’S DISEASE SOCIETY BRAIN 
BANK DIAGNOSTIC CRITERIA FOR PARKINSON’S DISEASE ......................72 
APPENDIX C. MONTREAL COGNITIVE ASSESSMENT (MOCA) ....................................73 
APPENDIX D. MDS-UPDRS ....................................................................................................79 
APPENDIX E. COMPONENTS OF IPX203 ...........................................................................112 
APPENDIX F. COLUMBIA-SUICIDE SEVERITY RATING SCALE .................................113 
APPENDIX G. KINESIA 360 SYSTEM .................................................................................120 
APPENDIX H. PARKINSON’S DISEASE DIARY ................................................................129 
APPENDIX I. ASSESSMENT OF SUBJECT’S MOTOR STATE .........................................130 
APPENDIX J. CLINICAL LABORATORY STUDIES ..........................................................131 
APPENDIX K. BLOOD SAMPLE LABELING, PROCESSING, STORAGE AND 
SHIPMENT ..............................................................................................................133 
APPENDIX L. EXAMPLES OF PROTEIN CONTENT .........................................................135 
 


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LIST OF TABLES 
Table 1: 
Abbreviations and Specialist Terms ...........................................................................17 
Table 2: 
Randomization Schedule for IPX203-B16-01 ............................................................23 
Table 3: 
Day 1 In-clinic Dosing — First Morning Dose of Study Medication ........................24 
Table 4: 
Initial IPX203 LD Dosing Regimen Subsequent to IPX203 Morning Dose 
Based on Prestudy Regimen of LD ............................................................................25 
Table 5: 
Events Schedule for Impax Study IPX203-B16-01 ....................................................32 
Table 6: 
Study Drugs for Study IPX209-B16-01 .....................................................................41 
 
LIST OF FIGURES 
Figure 1: 
Study Flow Chart ........................................................................................................23 
 


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3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
Table 1: 
Abbreviations and Specialist Terms 
Abbreviation or Specialist Term 
Explanation 
AADC 
aromatic amino acid decarboxylase 
AE 
adverse event 
ANCOVA 
analysis of covariance 
ANOVA 
analysis of variance 
AUC 
area under the curve 
AUC0-t 
area under the plasma concentration-time curve from time zero to 
the last measurable concentration 
AUC0-inf or AUC0-∞ 
area under the plasma concentration time curve from time 0 to 
time infinity 
CD 
Carbidopa 
CR 
controlled release 
CRF 
case report form 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
ECG 
electrocardiogram 
ENTA 
Entacapone 
ER 
extended release 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
IEC 
independent ethics committee 
IR 
immediate release 


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Abbreviation or Specialist Term 
Explanation 
IRB 
institutional review board 
LD 
Levodopa 
MDS-UPDRS 
Movement Disorders Society version of the Unified Parkinson’s 
Disease Rating Scale 
MoCA 
Montreal Cognitive Assessment 
PD 
Parkinson’s disease 
PK 
pharmacokinetic (adjective)  
pharmacokinetics (singular noun) 
PI 
principal investigator 
SAE 
serious adverse event 
TEAE 
treatment-emergent adverse event 
Tmax 
time to maximum concentration 
t1/2 
apparent elimination half-life 
 


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4. 
INTRODUCTION 
Parkinson’s disease (PD) is a progressive neurodegenerative disorder of the extrapyramidal 
nervous system.  Levodopa (LD) used in combination with carbidopa (CD) is considered the 
gold standard for the symptomatic treatment of PD.  LD is a dopamine precursor converted to 
dopamine by aromatic amino acid decarboxylase (AADC).  Carbidopa is an AADC inhibitor that 
does not cross the blood-brain barrier.  When used in combination with LD, CD increases the 
plasma half-life of LD from 50 minutes to 1.5 hours.  Carbidopa inhibits the conversion of LD 
into dopamine in the periphery, thereby reducing the peripheral side-effects caused by dopamine 
and increasing the amount of LD available for transport into the brain.  The administration of CD 
with LD reduces the dose of LD required to produce a dopaminergic response by about 
75 percent (Sinemet prescribing information, Appendix A). 
Due to its proven efficacy, LD is prescribed eventually to most subjects with PD.  However, 
long-term use of LD is associated with certain complications, including “wearing off” or “end-
of-dose effect,” where symptom control decreases resulting in the drug effects to wear off 
sooner.  As the disease progresses further, motor complications, namely dyskinesias and motor 
“on/off” fluctuations, develop in about 50% of the patients after 5 years of treatment (Fahn 
1999).  Such motor complications can be a significant source of disability and their management 
is a major unmet need in the treatment of PD. 
Mechanisms underlying motor complications involving dyskinesias and “on/off” fluctuations in 
PD are unclear.  The pulsatile nature of standard orally administered LD is thought to contribute 
to the appearance of motor complications.  Chronic intermittent pulsatile stimulation of the 
dopamine receptors that are under tonic control contributes to the development of dyskinesia in 
PD animal models as compared to animals treated with continuous infusion (Juncos 1989, 
Engber 1989, Blanchet 1995).  In addition, unreliable absorption of LD potentially due to erratic 
gastric empting and variable in vivo dissolution of LD products is thought to contribute to the 
delay or inadequate response after oral dosing with standard CD-LD products (Melamed 1986, 
Kurlan 1988, Stocchi 1994).  These findings suggest that motor complications in patients with 
PD may be less likely to develop with continuous dopaminergic stimulation. 
Intraduodenal infusion of LD has been shown to significantly reduce motor complications and to 
reduce “off” time.  The findings of infusion studies in PD patients indicate that the maintenance 
of stable plasma LD concentrations and the avoidance of low trough levels are effective in 
reducing “off” hours, increasing “on” hours without disabling dyskinesia, and reducing the 
severity of dyskinesia versus standard oral LD formulations (Mizuno 2007, Nilsson 2001, 
Nyholm 2005, Stocchi 2005).  These findings provide a strong rationale for the development of 
an extended release (ER) oral formulation that delivers a constant LD plasma concentration in 
order to optimize relief of PD symptoms, and to minimize “off” time and dyskinesia. 
IPX203 is an investigational product containing CD-LD that is being developed by Impax 
Laboratories, Inc. through its Impax Specialty Pharma division (Impax).  The primary objective 
of the IPX203 program is to develop an extended release product that can attain therapeutic LD 
plasma concentrations rapidly and maintain constant LD plasma concentrations for a longer 
duration than currently approved products with minimal peak to trough fluctuations.  IPX203 is 
designed to be dosed approximately every 8 hours, three times a day based on the plasma LD 


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concentration time profile observed in healthy subjects (Study IPX203-B14-01) and in subjects 
with advanced PD (Study IPX203-B14-02). 
Study IPX203-B14-02 characterized the PK and pharmacodynamics of IPX203 following a 
single dose in subjects with advanced PD versus IR CD-LD and Rytary.  Twenty-six 
(26) subjects have been randomized.  Preliminary results are based on data available as of 
August 4, 2016.  At the time of this cutoff, one subject had discontinued study early due to 
subject withdrawal.  Administration of IPX203 yielded an initial increase in LD plasma 
concentrations that was similar to both IR and Rytary but maintained LD concentrations longer 
than Rytary.  IPX203 provided a longer duration of effect compared with IR CD-LD and Rytary, 
including “Good On Time” based on the Assessment of Subject’s Motor State and on several of 
the MDS-UPDRS-III improvement thresholds.  In this ongoing single dose study, 5 (19.2%, 
5/26) subjects have reported adverse events.  Two subjects (8%, 2/25) reported 3 treatment-
related AEs after treatment with IPX203 compared with 4 subjects (16.7%, 4/24) who reported 
treatment-related AEs after treatment with IR CD-LD.  To date, no subjects in this study have 
reported serious or severe AEs, or have discontinued from the study because of AEs, irrespective 
of treatment. 
Study IPX203-B16-01 is designed to assess the single- and multiple-dose PK, 
pharmacodynamics, efficacy and safety of IPX203. 


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5. 
TRIAL OBJECTIVES 
5.1. 
Primary Objective 
 To compare the pharmacokinetics (PK) of single and multiple doses of IPX203 with 
immediate release (IR) CD-LD in subjects with advanced Parkinson’s disease (PD). 
5.2. 
Secondary Objectives 
 To compare the pharmacodynamics of single and multiple doses of IPX203 with 
IR CD-LD 
 To compare the efficacy of IPX203 with IR CD-LD following multiple doses 
 To evaluate the safety of IPX203. 


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6. 
INVESTIGATIONAL PLAN 
6.1. 
Overall Study Design 
This is a randomized, open-label, rater-blinded, multicenter, 2-treatment, 2-period, multiple-dose 
crossover study.  Approximately 30 advanced PD subjects will be randomized to 1 of 2 dosing 
sequences.  The study duration will be approximately 8 weeks, including the screening period. 
As shown in Figure 1, this study will consist of 4 study visits after Screening:  Day 1 of each 
treatment period (Visits 1 and 3), and Day 15 of each treatment period (Visits 2 and 4).  Study 
Exit procedures are done at the end of Visit 4 or within 3 days of Visit 4, or during an early 
withdrawal.  Between treatment periods, subjects will return to their prestudy PD medication 
regimen during the 1-week ( 2 days) washout period.  Subjects may continue to take allowed 
non-CD-LD based PD medications throughout the study if documented in their prestudy regimen 
and if dosing regimens have been stable for at least 4 weeks prior to Visit 1. 
Within 2 weeks following Screening, eligible subjects will complete their PD and Dosing diaries, 
and will wear the Kinesia 360 sensor bands on the more affected side at home immediately after 
waking on each of the 3 days prior to Visit 1.  Subjects will be instructed to take their last dose of 
CD-LD no later than 10:00 PM on the evening prior to Visits 1 and 3.  The first morning dose of 
study medication will be administered at the study site.  On Day 1 of the IR CD-LD treatment 
period, subjects will start with a single dose of their usual prestudy first morning IR CD-LD 
dose.  On Day 1 of the IPX203 treatment period, subjects will start with a single dose of IPX203 
based on their usual prestudy first morning IR CD-LD dose according to the guidance provided 
in Table 3.  During each treatment period subjects will dose for 15 days with study medication.  
During the IR CD-LD treatment period, the initial dosing regimen of IR CD-LD will be the same 
as the subject’s stable prestudy regimen unless they were taking a single daily bedtime dose of 
CR CD-LD, either alone or in combination with IR CD-LD, in which case, the CR CD-LD dose 
will be discontinued and substituted with a 1:1 milligram-equivalent IR CD-LD dose.  A 
“bedtime dose” is defined as a dose of CR CD-LD taken within 1 hour of the subject’s normal 
nighttime sleep period.  During the IPX203 treatment period, subjects are assigned their initial 
IPX203 dosing regimen according to the guidance provided in Table 4 (see Section 6.4.2), which 
is based on each individual’s prestudy IR CD-LD morning dose and daily dosing regimen.  The 
typical dosing regimen for IPX203 will be three times a day, dosed approximately every 7 to 
8 hours.  Some subjects may require more or less frequent dosing to optimize therapeutic effect 
(minimize “off” time without causing troublesome dyskinesia or other dopaminergic side 
effects).  Nighttime dosing of study medication is allowed as needed with the exception of the 
evening prior to Day 15 (withhold dosing for at least 5 hours before arriving at the site) of each 
treatment period.  Subjects may continue to take allowed non-CD-LD based PD medications 
throughout the study if documented in their prestudy regimen and if dosing regimens have been 
stable for at least 4 weeks prior to Visit 1. 
During Days 1 through 9 of both treatment periods, investigators may adjust each subject’s study 
medication regimen if necessary to optimize efficacy and safety. 
Pharmacokinetic and pharmacodynamic measures are assessed in the clinic for up to 8 hours 
postdose on Day 1 of each treatment period (Visits 1 and 3), and for up to 10 hours on Day 15 of 


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each treatment period (Visits 2 and 4).  Additionally, subjects will complete the PD and Dosing 
diaries, and use the Kinesia 360 sensor bands on the ankle and wrist of their more affected side 
immediately after waking on each of the 3 days prior to Visits 1, 2, and 4. 
Figure 1: 
Study Flow Chart 
 
6.2. 
Number of Subjects 
A sufficient number of subjects will be screened to ensure that approximately 30 subjects are 
randomized to complete 26 subjects.  Subjects who discontinue will not be replaced. 
6.3. 
Treatment Assignment 
Investigational product:  IPX203 (carbidopa-levodopa) Extended-Release Capsules, containing 
180 mg and 270 mg of LD, for oral administration. 
Reference therapy:  Immediate-release carbidopa-levodopa (IR CD-LD) tablet containing 
100 mg of LD, for oral administration. 
Subjects will be randomly assigned to one of the treatment sequences to receive IPX203 and 
IR CD-LD (Table 2). 
Table 2: 
Randomization Schedule for IPX203-B16-01 
 
Treatment Period 1 
Treatment Period 2 
Sequence 1 
IPX203 
IR CD-LD 
Sequence 2 
IR CD-LD 
IPX203 


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6.4. 
Dosing and Dose Determination Criteria 
IR CD-LD will be supplied as tablets containing 100 mg of LD.  IR CD-LD tablets may be split 
using a pill cutter. 
IPX203 will be supplied as capsules containing 180 mg and 270 mg LD.  The suggested doses 
and regimen of IPX203 are intended to provide an onset of effect comparable to the subject’s 
prestudy IR LD regimen and to extend the duration of effect.  . 
Doses of IPX203 should be based on the subject’s prestudy stable LD dose regimen and the 
response to IPX203.  The typical dosing regimen for IPX203 will be three times a day, dosed 
approximately every 7 to 8 hours.  Some subjects may require more or less frequent dosing to 
optimize therapeutic effect (minimize “off” time without causing troublesome dyskinesia or 
other dopaminergic side effects). 
6.4.1. 
Day 1 In-Clinic Dosing at Visit 1 and at Visit 3 
There are two treatment periods in this study.  On Day 1 of the IR CD-LD treatment period, 
subjects will receive a single dose of their usual prestudy first morning IR CD-LD dose.  The 
“first morning dose” is defined as the subject’s first dose upon awakening for the day 
immediately following the subject’s usual nocturnal sleep period intended to achieve an “on” 
state. 
On Day 1 of the IPX203 treatment period, subjects will start with a single dose of IPX203 based 
on their usual prestudy first morning dose of IR CD-LD as shown in Table 3. 
Table 3: 
Day 1 In-clinic Dosing — First Morning Dose of Study Medication 
Prestudy Morning 
IR  LD Dose (mg) 
IR CD-LD 
LD (mg) 
(100 mg Tablets) 
IPX203 
LD (mg) 
(180 mg and 270 mg Capsules) 
100 
100 (1 tablet) 
360 (180 mg × 2 capsules) 
150 
150 (1.5 tablets) 
540 (270 mg × 2 capsules) 
200 
200 (2 tablets) 
720 (270 mg × 2 capsules plus 180 mg 
× 1 capsule) 
250 
250 (2.5 tablets) 
900 (270 mg × 2 capsules plus 180 mg 
× 2 capsules) 
Rescue:  Subjects who need rescue during the IR CD-LD treatment will receive a dose of 
IR CD-LD that corresponds to their typical pretreatment regimen based on the subject’s dosing 
diary.  For rescue during the IPX203 treatment, subject will receive a dose of IPX203 that is 
based on Table 4 in Section 6.4.2. 
6.4.2. 
Study Drug Regimen following First In-Clinic Dose at Visits 1 and 3 
The IR CD-LD and IPX203 dosing regimen may be adjusted if needed during the first 9 days of 
each treatment period to achieve adequate efficacy and safety.  The dosing regimen should be 
stable for the last 5 days of each treatment period (Days 10 – 14). 


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IR LD Dose Adjustment (Days 1-9): 
 During the IR CD-LD treatment period, the initial dosing regimen of IR CD-LD will be 
the subject’s stable prestudy CD-LD regimen. 
 If the subject’s prestudy regimen included a single daily bedtime dose of CR CD-LD, 
either alone or in combination with IR CD-LD, the CR CD-LD dose will be discontinued 
and substituted with a 1:1 milligram-equivalent IR CD-LD dose.  A “bedtime dose” is 
defined as a dose of CR CD-LD taken within 1 hour of the subject’s normal nighttime 
sleep period.  For example, a 200-mg daily bedtime dose of CR CD-LD will be replaced 
with a 200-mg bedtime dose of IR CD-LD. 
IPX203 Dose Adjustment (Days 1-9): 
Table 4 outlines the suggested initial conversion from a prestudy regimen of CD-LD to an 
IPX203 regimen.  The suggested initial dosing of IPX203 is three times a day, approximately 
every 7 to 8 hours. 
The recommended morning dose of IPX203 is based on Table 3. 
To determine the IPX203 regimen of subsequent doses for the day, identify the most frequent 
prestudy LD dose in milligrams that the subject receives in the afternoon and evening and 
administer IPX203 according to Table 4. 
 If the subject takes different prestudy LD doses with equal frequency, determine the 
IPX203 dose based on the highest LD dose. 
 When determining the most frequent prestudy LD dose for subsequent IPX203 doses, 
consider all prestudy LD doses taken from noon to bedtime.  If the subject takes a 
bedtime CR CD-LD dose and the subject also takes a dose of IR CD-LD within one hour 
of the bedtime dose of CR CD-LD, then add the CR and IR LD doses together. 
 
Table 4: 
Initial IPX203 LD Dosing Regimen Subsequent to IPX203 Morning Dose 
Based on Prestudy Regimen of LD 
Most Frequent Afternoon and 
Evening LD Unit Dose (mg) 
IPX203 Regimen Post Morning Dose 
100 - 125 
270 (270 mg × 1) mg every 7 to 8 hours 
150 - 175 
450 (180 mg × 1 + 270 mg × 1) mg every 7 to 8 hours 
200 - 225 
540 (270 mg × 2) mg every 7 to 8 hours 
250- 275 
720 (270 mg × 2 + 180 mg × 1) mg every 7 to 8 hours 
300 
810 (270 mg × 3) mg every 7 to 8 hours 
Note:  a 100-mg unit dose of IR LD converts approximately to a 270-mg unit dose of IPX203. 
 


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The examples below illustrate the IPX203 dosing regimen. 
Example: 
Pre-study IR LD 
Morning Dose (mg) 
Most Frequent Pre-
study LD Dose (mg) 
Afternoon and 
Evening 
IPX203 Regimen 
100 
100 
360 mg as the morning dose followed by 
270 mg approximately every 7 to 8 hours 
200 
100 
720 mg as the morning dose followed by 
270 mg approximately every 7 to 8 hours 
 The IPX203 dosing regimen may be adjusted as needed based on the subject’s response 
to the previous day’s dosing.  Doses of IPX203 may be adjusted in increments of 90 mg 
to achieve adequate therapeutic effects.  The 90 mg adjustments can be achieved by 
adjusting the number of 180 mg and 270 mg capsules.  For example, a 360 mg dose 
(180 mg × 2 capsules) can be increased by 90 mg (to 450 mg) by administering a 270 mg 
capsule and a 180 mg capsule. 
 If a subject experiences bothersome peak-related or levodopa-related side effects, the 
doses of IPX203 may be reduced in steps of 90 mg. 
 If a subject experiences end-of-dose “off” episodes with the suggested dose regimen or if 
persistent “off” periods occur during the day,  
o the IPX203 dose may be increased (if the subject does not experience troublesome 
dyskinesia), or 
o the time between two doses may be decreased, or 
o the dosing frequency may be increased to achieve an adequate therapeutic effect. 
 IPX203 should not require dosing more than four times a day.  For subjects who require 
an adjustment from three times a day to a four times a day dosing of IPX203, each 
individual dose may need to be reduced by 90-180 mg depending on response. 
Dosing of Study Medication on Days 10 – 14 
For Days 10-14 subjects should maintain the dosing regimen achieved by Day 9. 
Dosing of Study Medication on Day 15 
The IR CD-LD and IPX203 dosing regimens during the clinic visit on Day 15 should be the 
same as the regimens reflected on the last day in the Dosing diary on Days 12-14. 
6.5. 
Dose Adjustment Criteria 
As detailed in Section 6.4.2 above, a subject’s IR CD-LD and IPX203 dosing regimen may be 
adjusted for the first 9 days in order to achieve adequate efficacy and safety. 


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6.6. 
Criteria for Study Termination 
The Sponsor has the right to terminate this study and remove all study material from the study 
site at any time for medical or administrative reasons.  The Sponsor will endeavor to give 
adequate notice to allow safe withdrawal of subjects from the study. 


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7. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
Each subject must meet all of the following inclusion and exclusion criteria to qualify for 
enrollment. 
7.1. 
Subject Inclusion Criteria 
1. Male or female subjects diagnosed with idiopathic PD at age ≥40 years who are being 
chronically treated with stable regimens of CD-LD but experiencing motor 
complications.  Idiopathic PD is defined by United Kingdom Parkinson’s Disease Society 
Brain Bank Diagnostic Criteria (Appendix B).  There are no known secondary causes 
(eg, vascular, toxin or medication-induced, metabolic, or infectious) for subject’s 
Parkinsonism nor does subject have another neurodegenerative disorder with 
Parkinsonism symptoms (eg, progressive supranuclear palsy, corticobasal degeneration, 
multiple-system atrophy). 
2. Able to provide written informed consent and willing to sign Health Insurance Portability 
and Accountability Act (HIPAA) authorization prior to the conduct of any study-specific 
procedures. 
3. Female subjects of childbearing potential must have a negative urine pregnancy test at 
Screening Visit. 
4. Negative urine screen for drugs of abuse and negative alcohol breath test at Screening. 
5. Hoehn and Yahr Stages 2, 3, or 4 (part of MDS-UPDRS Part III) 
6. Agrees to use a medically acceptable method of contraception throughout the study and 
for 6 weeks after completing the study.  Medically acceptable methods of contraception 
that may be used by the subject and/or partner include but are not limited to:  abstinence, 
oral contraception, NuvaRing or transdermal systems, diaphragm with vaginal 
spermicide, intrauterine device, condom and partner using vaginal spermicide, surgical 
sterilization (6 months), progestin implant or injection, or postmenopausal female (no 
menstrual period for ˃ 2 years) or vasectomy (˃6 months). 
7. Montreal Cognitive Assessment (MoCA) score ≥ 24 at Screening Visit in “on” state. 
8. For the 4 weeks prior to Screening, the subject experiences daily “wearing-off” episodes 
with periods of bradykinesia and rigidity, and experiences an “off” state upon awakening 
on most mornings by history. 
9. At Visit 1, review of the 3-day PD diary confirms the following:  that the subject is able 
to properly complete the diary with valid entries; and that the subject has an average of at 
least 2.5 hours per day of “off” time during the waking hours over the 3 days with at least 
1.5 hours “off” time on each day.  Inability to properly complete the diary is indicated 
when more than 1 day of the diary is not returned or when more than 2 hours (4 half-hour 
periods) of one 24-hour diary day are missing (Appendix H). 
10. Responsive to CD-LD therapy and currently being treated on a stable regimen with 
CD-LD for at least 4 weeks prior to Visit 1 and: 


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a. requires 100 to 250 mg (in units of 50 mg) of IR CD-LD for the morning dose 
b. requires a total daily dose of at least 400 mg of IR CD-LD 
c. takes a maximum total daily dose of 1800 mg LD, comprising IR CD-LD alone or 
IR CD-LD in combination with a single daily bedtime dose of CR CD-LD. 
d. has a dosing frequency of 4 to 9 times daily of CD-LD 
e. typically experiences an “on” response with the first dose of IR CD-LD of the day (by 
subject history) 
f. by history, efficacy of the first morning dose of IR CD-LD lasts less than 4 hours, 
typically wearing “off” prior to the next dose; or subject takes the second dose of PD 
medications prior to 4 hours to avoid an “off.” 
11. Has not used doses of controlled-release (CR) CD-LD apart from a single daily bedtime 
dose for at least 4 weeks prior to Visit 1. 
12. Has not used any doses of Rytary for the past 4 weeks prior to Visit 1. 
13. At Screening, the MDS-UPDRS Part III total score in the “off” state is: 
a. at least 20 units  
b. at least 25% or 10 units greater than in the “on” state 
14. At Screening, the subject has predictable “off” periods defined by a score of 1 or 2 on 
Item #4.5 (Complexity of Motor Fluctuations) of the MDS-UPDRS Part IV B (Motor 
Fluctuations) (Appendix D). 
15. Has a score of ≥ 1 on Item #4.3 (Time Spent in the “off” State) of the MDS-UPDRS 
Part IV B at Screening (Appendix D). 
16. Hemoglobin level must be above the lower limits of the laboratory’s normal reference 
range. 
17. Able and willing to comply with the protocol, including completion of diaries and 
availability for all scheduled study visits and data and blood-sample collection times. 
7.2. 
Subject Exclusion Criteria 
1. Female subjects who are currently breastfeeding or lactating. 
2. Had prior neurosurgical ablation treatment for PD or if such procedure is planned or 
anticipated during the study period.  Previous implantation of a deep brain stimulator 
(DBS) for the treatment of PD is permitted as long as the DBS settings have been stable 
for at least 4 weeks prior to Screening and the procedure is not planned during this study 
or for up to 6 weeks after study participation. 
3. Allergic to any excipients of IPX203 (Appendix E). 
4. History of medical conditions or of a prior surgical procedure that would interfere with 
LD absorption, such as gastrectomy or proximal small-bowel resection. 
5. History of peptic ulcer disease or upper gastrointestinal hemorrhage within the past 
5 years. 
6. History of narrow angle glaucoma with intraocular pressures that are elevated despite 
appropriate medical management. 


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7. History of seizure or epilepsy and experienced at least 1 seizure during the past 
12 months or has not been compliant with medically recommended therapy or visits. 
8. History of myocardial infarction with residual atrial, nodal, or ventricular arrhythmias 
that are not controlled with medical and/or surgical interventions. 
9. History of neuroleptic malignant syndrome or of nontraumatic rhabdomyolysis. 
10. Liver enzyme values ≥ 2.5 times the upper limit of normal; or history of severe hepatic 
impairment. 
11. Serum creatinine level ≥ 1.75 times the upper limit of normal; or requires dialysis at the 
time of Screening. 
12. Subject with a history of malignant melanoma or with a suspicious undiagnosed skin 
lesion which in the opinion of the investigator could be melanoma. 
13. History of drug or alcohol abuse within the 12 months prior to Screening. 
14. Received within 4 weeks of Visit 1 or planning to take during participation in the clinical 
study:  any doses of a controlled-release (CR) LD apart from a single daily bedtime dose 
or any doses of Rytary, additional CD (eg, Lodosyn) or benserazide (eg, Serazide), or 
catechol-O-methyl transferase inhibitors (entacapone or tolcapone) or medications 
containing these inhibitors (Stalevo).  Received within 4 weeks of Visit 1 or planning to 
take during participation in the clinical study: nonselective MAO inhibitors, 
apomorphine, or dopaminergic blocking agents including antiemetics. 
15. History of psychosis within the past 10 years.  Mild PD-associated illusions are not 
exclusionary provided that they do not occur more than once per week and the subject 
does not lose insight. 
16. Treatment with any dopamine antagonist antipsychotics for the purposes of psychosis or 
bipolar disorder within the last 2 years. 
17. Subjects considered IPX066 or Rytary failures for reasons of efficacy or safety. 
18. Donated blood or plasma within 6 weeks prior to Visit 1 or planning to donate blood or 
plasma within 12 weeks after Study Exit. 
19. Answered “YES” on Questions 4 or 5 on the Suicidal Ideation subscale of the C-SSRS 
(Appendix F) at Screening (defined period as 3 months prior to Screening) or evidence of 
suicidal behavior within 6 months of Screening as measured by the Suicidal Behavior 
subscale of the C-SSRS. 
20. Employees or family members of the Investigator, study site, or Sponsor. 
21. Subjects who, in the opinion of the clinical investigator, should not participate in the 
study. 
22. Based on clinical assessment, subject does not adequately comprehend the terminology 
needed to complete the PD diary. 


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7.3. 
Subject Withdrawal Criteria 
Site personnel should make every effort to conduct all protocol-specific procedures to complete 
the study.  A subject may be discontinued from the study due to the following reasons: 
1. Withdrawal by subject 
2. Adverse event (AE) 
3. Lack of efficacy 
4. Study terminated by Sponsor 
5. Protocol deviation 
6. Noncompliance with study drug 
7. Lost to follow-up 
8. Death 
9. Other 
Subjects who withdraw early from the study will not be replaced. 


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8. 
STUDY PROCEDURES 
The procedures to be performed at each study visit are described below and summarized in 
Table 5. 
Table 5: 
Events Schedule for Impax Study IPX203-B16-01 
Assessment 
Screening 
Visit 1 
(Day 1) 
Visit 2 
(Day 15) 
7-Day 
Washout 
Period 
Visit 3 
(Day 22) 
Visit 4 
(Day 36) 
Study 
Exita 
Study Week 
–2 
0 
2 
3 
4 
5 
 
ICF & HIPAA 
Authorization 
X 
 
 
 
 
 
 
Assign Subject ID 
X 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
Inclusion/Exclusion 
X 
X 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
Hoehn and Yahr Staging 
(MDS-UPDRS) 
X 
 
 
 
 
 
 
Physical Examination 
X 
 
 
 
 
 
X 
Vital Signsb 
X 
X 
X 
 
X 
X 
X 
Height and Weight 
X 
 
 
 
 
 
Xc 
C-SSRSd 
X 
X 
X 
 
X 
X 
X 
Clinical Laboratory 
Testse 
X 
 
 
 
 
 
X 
Urine Pregnancy Test 
X 
 
 
 
 
 
 
Urine Screen for Drug 
Abuse 
X 
 
 
 
 
 
 
Alcohol Breath Test 
X 
 
 
 
 
 
 
ECGf 
X 
X 
X 
 
X 
X 
X 
MoCAg 
X 
 
 
 
 
 
 
MDS-UPDRS Parts I, II, 
and IVh 
X 
 
X 
 
 
X 
 
MDS-UPDRS Part III 
Motor Examinationi 
X 
X 
X 
 
X 
X 
 
Assessment of Subject’s 
Motor Statej 
 
X 
X 
 
X 
X 
 
PD Diary, Dosing Diary, 
Kinesia 360 Trainingk 
X 
X 
X 
 
X 
 
 
Dispense PD Diary, 
Dosing Diary, 
Kinesia 360l 
X 
X 
 
 
X 
 
 


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Assessment 
Screening 
Visit 1 
(Day 1) 
Visit 2 
(Day 15) 
7-Day 
Washout 
Period 
Visit 3 
(Day 22) 
Visit 4 
(Day 36) 
Study 
Exita 
Study Week 
–2 
0 
2 
3 
4 
5 
 
Review PD and Dosing 
diaries, Kinesia 360m 
 
X 
X 
 
 
X 
 
PK Samplingn 
 
X 
X 
 
X 
X 
 
Resume Prestudy 
Meds/Dosing 
 
 
 
X 
 
 
 
Reminder phone callsl,o,p 
Xo 
Xp 
Xp 
 
Xp 
Xp 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
Provide low protein 
breakfast/and provide 
snacks and other meals 
 
X 
X 
 
X 
X 
 
C-SSRS = Columbia-Suicide Severity Rating Scale, ECG = electrocardiogram, HIPAA = Health Insurance Portability and 
Accountability Act, ICF = informed consent form, MoCA = Montreal Cognitive Assessment, PD = Parkinson’s disease, 
PK = pharmacokinetics, MDS-UPDRS = MDS version of Unified Parkinson’s Disease Rating Scale. 
a 
Study Exit procedures to be conducted at the end of Visit 4 or within 3 days of Visit 4, or during an early withdrawal visit. 
b Record vital signs (blood pressure, heart rate, respiratory rate, and temperature [Screening and Study Exit only]) after subject 
has been resting supine for at least 5 minutes, then record orthostatic blood pressure and heart rate after subject has been 
standing for approximately 2 minutes.  During Visits 1 and 3, vital signs are recorded at predose, 2, 4, and 8 hours postdose.  
During Visits 2 and 4, vital signs are recorded at predose, 2, 4, and 10 hours postdose. 
c 
Weight only. 
d C-SSRS: Columbia Suicide Severity Rating Scale.  See Appendix F. 
e 
See Appendix J. 
f 
ECGs done at Screening and during Visits 1 - 4, at predose and 2 hours postdose. 
g Montreal Cognitive Assessment in the “on” state: see Appendix C. 
h MDS-UPDRS Parts I, II, and IV:  At Screening, Parts I, II and IV will be conducted during the “on” state, and at Visits 2 and 
4 will be done at predose. 
i 
MDS-UPDRS Part III (Motor Examination):  At Screening, Part III is conducted during both the “on” and “off” state.  Ensure 
that the MDS-UPDRS Part III total score in the “off” state is at least 20 units and is at least 25% or at least 10 units greater 
than in the “on” state.  Part III is performed by a rater blinded to treatment assignment at predose and hourly for up to 8 hours 
postdose for Visits 1 and 3; Part III is performed at predose and hourly for up to 10 hours postdose for Visits 2 and 4. 
j 
Assessment of Subject’s Motor State:  Rated assessment of motor state (“on” and “off,” and state of dyskinesia) performed by 
a rater blinded to treatment assignment at –1, –0.5, and 0, and at half hourly intervals postdose for up to 8 hours on Visits 1 
and 3 and for up to 10 hours on Visits 2 and 4. 
k 
Train at Screening and then as needed at subsequent visits. 
l 
Dispense PD and dosing diaries and Kinesia 360 at Screening, Visit 1, and Visit 3.  Call Subjects 4 days prior to Visits 1, 2 
and 4 and to remind them to begin PD Diary and Dosing Diary.  Subjects record diary information for 3 consecutive days 
prior to each of the visits (Days -3, -2, and -1).  Subjects wear their Kinesia 360 sensor bands on the more affected side 
immediately upon awakening and throughout their waking hours on each of the 3 days prior to the visits (Days -3, -2, and -1).  
Call subjects the day prior to each visit to remind them to bring the diaries, Kinesia 360, and all study medication and PD and 
non-PD medication to the site visits. 
m Review PD and Dosing diaries and Kinesia 360 at Visits 1, 2, and 4. 
n PK Sampling:  Day 1 of each treatment period (Visits 1 and 3) – at predose and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 5.5, 6, 6.5, 7, 7.5, 
and 8 hours postdose.  Day 15 of each treatment period (Visits 2 and 4) – at predose and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 
6, 7, 8, and 10 hours postdose. 
o Reminder phone calls to notify individuals who successfully complete screening procedures following review of all study 
entry criteria and clinical laboratory results that they may enroll in the study.  The interval between Screening and Visit 1 
should not exceed 2 weeks.  Call subjects at least 4 days prior to Visit 1 to remind them to complete their PD diary and 
Dosing diary and to put on the Kinesia 360 sensor bands.  Subjects will record diary information for 3 consecutive days 
starting 3 days prior to Visit 1 (Days -3, -2, and -1).  Subjects should wear their Kinesia 360 sensor bands on the more 


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Impax Laboratories, Inc. 
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affected side immediately upon awakening and throughout their waking hours on each of the 3 days prior to each of the visits 
(Days -3, -2, and -1). 
p Reminder phone calls on the days prior to all treatment visits (Visits 1-4), remind subjects to: 
 Call subjects 4 days prior to Visits 1, 2 and 4 to remind them to begin PD and Dosing Diaries and the Kinesia 360 
system.  Call subjects the day prior to Visits 1, 2 and 4 to remind them to bring the diaries and the Kinesia 360 system 
to the office on Visits 1, 2 and 4. 
 Take their last doses of CD-LD no later than 10:00 PM on the evening prior to Visits 1 and 3.  Withhold their last dose 
of study medication for at least 5 hours prior to arriving at the clinic for Visits 2 and 4.  Inform subjects that their first 
morning dose of CD-LD (study medication) will be administered at the study site under the supervision of site 
personnel.  Subjects should not withhold their non-CD-LD medications. 
 Fast for at least 8 hours prior to arriving at the clinic except that coffee, tea, water, and juice are allowed for up to 
1 hour predose.  Breakfast containing approximately 5 grams of protein will be served at the study site approximately 
1 hour postdose (Appendix L). 
 Report to the study site early the next morning. 
 Continue to take all of their other non-CD-LD medications per their usual routine prescription instructions and schedule 
until they arrive at the study site for each treatment visit. 
 Bring all their current PD and non-PD medication containers to the study site for each treatment visit (Visits 1-4).  
Concomitant non-CD-LD medications (including non-PD medications) will be made available to subjects with site staff 
oversight during the treatment visits so that subjects can take their regular medications per their usual schedule. 
8.1. 
Screening Visit 
After the subject has signed the informed consent and HIPAA authorization, complete the 
following procedures and assessments: 
 Obtain an identification number from the interactive web response system (IWRS). 
 Review and record study entry criteria (Section 7). 
 Perform urine pregnancy test for females of childbearing potential. 
 Perform urine screen for drugs of abuse. 
 Perform alcohol breath test. 
 Complete medical history. 
 Perform physical examination, including height and weight. 
 Assess vital signs after subject is supine for at least 5 minutes (blood pressure, heart 
rate, temperature and respiratory rate) and then assess orthostatic blood pressure and 
heart rate after subject is standing (for approximately 2 minutes). 
 Record current CD-LD regimen, other PD medications and their dosing schedule, and 
other concomitant medications. 
 Conduct an ECG. 
 Administer C-SSRS (Appendix F). 
 Determine MoCA Score in the “on” state (Appendix C). 
 Collect blood and urine samples for clinical laboratory studies (Appendix J). 
 Determine Hoehn and Yahr staging of PD (part of Part III Motor Examination of the 
MDS-UPDRS (Appendix D). 


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 Determine MDS-UPDRS Parts I through IV in the “on” state, and Part III also done 
in the “off” state (Appendix D).  Determine the more affected side. 
 Dispense 3-day PD diaries (Appendix H) and train the subject how to complete the 
PD diary to assess his/her “on” and “off” states, including assessment of any 
dyskinesia.  Then instruct the subject to complete the PD diary on 3 consecutive days 
prior to Visit 1. 
 Dispense 3-day Dosing diaries and train the subject how to complete the Dosing 
diary.  Then instruct the subject to complete the Dosing diary on 3 consecutive days 
prior to Visit 1.  These should be the same 3 days that the PD diary is being 
completed. 
 Dispense the Kinesia 360 system and the subject instruction sheet (Appendix G).  
Train the subject on how to use the system and how to attach the sensor bands to the 
wrist and ankle of the more affected side.  Instruct the subject to attach the sensor 
bands immediately after waking on the morning that the PD and Dosing diaries are 
started and to continue to wear the sensor bands on each of the 3 days prior to Visit 1 
while the subject is awake.  The Kinesia 360 sensor bands should be removed during 
showers, baths, swimming, and before going to bed at night. 
Notify individuals who successfully complete screening procedures following review of all study 
entry criteria and clinical laboratory results. 
The interval between Screening and Visit 1 (Day 1) should not exceed 2 weeks. 
8.2. 
Visits 1 and 3 
8.2.1. 
Prior to Visit 1 
Contact the subject at least 4 days prior to Visit 1 to remind him/her to complete the 3-day PD 
and Dosing diaries, and to use the Kinesia 360 sensor bands starting 3 days prior to Visit 1. 
The day prior to Visit 1, remind subjects to bring their completed 3-day PD diary and Dosing 
diary and the Kinesia 360 system to the clinic. 
8.2.2. 
Prior to Visits 1 and 3 
Contact the subject the day before each Visit to remind the subject about the following: 
 Take their last doses of CD-LD no later than 10:00 PM on the evening prior to each 
treatment visit. 
 Withhold first morning dose of CD-LD medication and inform subjects that their first 
morning dose of CD-LD (study medication) will be administered at the study site 
under the supervision of site personnel.  Subjects should not withhold their non-CD-
LD medications. 
 Fast for at least 8 hours prior to arriving at the clinic except that coffee, tea, water, 
and juice are allowed up to 1 hour predose.  Breakfast containing approximately 
5 grams of protein will be served at the study site approximately 1 hour postdose 
(Appendix L). 


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 Report to the study site early the next morning. 
 Continue to take all of their other non-CD-LD medications (including PD and non-PD 
medications) per their usual routine prescription instructions and schedule until they 
arrive at the study site for each treatment visit. 
 Bring all their current PD and non-PD medication containers to the study site for each 
treatment visit.  Concomitant medications will be made available to subjects with site 
staff oversight during the treatment visits so that subjects can take their regular 
medications per their usual schedule. 
 Bring the 3-day PD Diary, the 3-day Dosing diary, and the Kinesia 360 system with 
them to the clinic (Visit 1 only). 
8.2.3. 
Predose at Visit 1 
 On the morning of Visit 1, collect and review the subject’s 3-day PD and Dosing 
Diaries and ensure that the subject continues to meet study inclusion criteria. 
 Review the use of the Kinesia 360 system, if needed. 
 At Visit 1, randomize eligible subjects using the IWRS. 
8.2.4. 
Predose at Visits 1 and 3 
For Visits 1 and 3 complete the following procedures: 
 Record any AEs and update changes in concomitant medication since the previous 
visit. 
 Measure predose vital signs (temperature, respiratory rate, blood pressure, heart rate 
after supine for at least 5 minutes and orthostatic pulse and blood pressure after 
standing for approximately 2 minutes). 
 Conduct a predose ECG. 
 Collect a predose PK blood sample (6 mL) within 1 hour predose. 
 Qualified clinical staff blinded to the subject’s treatment assignment perform the 
following predose assessments in the “off” state: 1) MDS-UPDRS Part III (Motor 
Examination) at predose; 2) Assessment of Subject’s Motor State (of “on” and “off,” 
and state of dyskinesia) –1, –0.5, and 0 hour. 
 Administer C-SSRS. 
 Administer the study medication upon completion of predose procedures.  To ensure 
unbiased data, treatments should be administered by clinical staff not directly 
involved in the assessment of the MDS-UPDRS Part III (Motor Examination) and 
Assessment of Subject’s Motor State. 
8.2.5. 
Postdose at Visits 1 and 3 
 Collect postdose blood samples (6 mL) for PK analysis at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 
5.5, 6, 6.5, 7, 7.5, and 8 hours postdose. 


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 Qualified staff who are blinded to treatment assignment perform Assessment of 
Subject’s Motor State (of “on” and “off,” and state of dyskinesia) at half-hour 
intervals at approximately 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, and 
8 hours postdose.  For each subject, the preference is to have the same rater perform 
the assessment at every time point throughout the study. 
 Qualified staff who are blinded to treatment assignment perform MDS-UPDRS 
Part III (Motor Examination) hourly at approximately 1, 2, 3, 4, 5, 6, 7, and 8 hours 
postdose.  For each subject, the preference is to have the same rater perform the 
assessment at every time point throughout the study. 
 When PK sampling and other procedures or measurements are scheduled at the same 
time, the PK sampling should occur as close as possible to the nominal time. 
 Provide a breakfast containing approximately 5 grams of protein approximately 
1 hour following the morning dose (Appendix L).  Lunch may be provided no earlier 
than 4 hours following the morning dose.  Subjects may be provided dinner if needed.  
Subjects may also be provided snacks as long as it is not within 1 hour before or after 
their morning dose. 
 Perform 12-lead ECG at 2 hours postdose. 
 Assess vital signs at 2, 4, and 8 hours postdose:  blood pressure, heart rate, and 
respiratory rate will be measured after the subject has been supine for at least 
5 minutes.  Orthostatic blood pressure and heart rate will be measured after the 
subject has been standing for approximately 2 minutes. 
 If a subject experiences an “off” state for ≥ 3 consecutive hours postdose, the subject 
may receive rescue medication.  Subjects who need rescue during the IR CD-LD 
treatment will receive a dose of IR CD-LD that corresponds to their typical 
pretreatment regimen based on the subject’s dosing diary.  For rescue during the 
IPX203 treatment, subject will receive a dose of IPX203 that the subject would 
typically have received following their morning dose (see Table 4).  At the 
Investigator’s discretion, the subject may be rescued prior to 3 hours.  Site staff will 
record the time of administration of any rescue medication.  PK sampling and 
pharmacodynamic assessments will continue after subject receives rescue 
medication. 
 After completion of the 8-hour PK sampling and pharmacodynamic assessments: 
 Provide study medication and dosing instructions to the subject.  Inform the 
subject to call the site prior to making changes to the dose regimen. 
 Inform the subject that the site will be calling every 1-3 days over the next 9 days 
to discuss dosing. 
 Provide PD and dosing diaries and the Kinesia 360 system to subject. 


Protocol No. IPX203-B16-01 
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8.3. 
Days 2-14 (Visits 1 and 3) 
Days 2 to 9: 
 Site staff should follow-up with the subject every 1-3 days to check how the subject is 
doing and to facilitate any dose regimen changes. 
 Site staff should record any changes to the dosing regimen. 
 The subject should be instructed to call the site and report to site staff before making 
changes in dosing regimen. 
 The subject’s dosing regimen may be adjusted during Days 2 to 9.  The dosing 
regimen should not be modified after this period. 
 Site staff should check with subject on Day 9 and remind the subject to not make 
changes in dosing regimen for the rest of the treatment period. 
Days 10 through 14: 
 The subject should remain on a stable dosing regimen until the next visit (Visit 2 or 
Visit 4). 
8.4. 
Washout Period (Between Visit 2 and 3) 
Following the completion of Visit 2, subjects will return to their prestudy PD medication 
regimen during the 1-week ( 2 days) washout period between Visits 2 and 3. 
8.5. 
Visits 2 and 4 
8.5.1. 
Prior to Visits 2 and 4 
Four days prior to Visits 2 and 4, site staff should contact the subject and ensure that the study 
medication regimen is stable.  Remind him/her to complete the 3-day PD and Dosing diaries 
starting 3 days prior to the next visit (Visit 2 or Visit 4).  Also remind the subject to use their 
Kinesia 360 system on each of the 3 days prior to the next visit. 
One day prior to Visit 2 and 4, site staff should contact the subject to remind him/her of the 
following: 
 Withhold dosing of study medication for at least 5 hours before arriving at the site; 
the first morning dose will be administered at the study site under the supervision of 
site personnel.  Subjects should not withhold their non-CD-LD medications. 
 Subjects must be fasting for at least 8 hours prior to dosing (except that coffee, tea, 
water, and juice are allowed up to 1 hour predose). 
 Bring all their current PD and non-PD medication containers to the study site for each 
treatment visit (Visits 2 to 4).  Concomitant medications will be made available to 
subjects with site staff oversight during the treatment visits so that subjects can take 
their regular medications per their usual schedule. 
 Bring the Kinesia 360 system and their completed 3-day PD and Dosing diaries to the 
clinic. 


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Amendment 2: October 5, 2016 
Impax Laboratories, Inc. 
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8.5.2. 
Predose at Visits 2 and 4 
For Visits 2 and 4 complete the following procedures: 
 Record any AEs and update changes in concomitant medication since the previous 
visit. 
 Measure predose vital signs (temperature, respiratory rate, blood pressure, and heart 
rate after supine for at least 5 minutes; orthostatic pulse and blood pressure after 
standing for approximately 2 minutes). 
 Conduct a predose ECG. 
 Collect a predose PK blood sample (6 mL) within 1 hour predose. 
 Qualified clinical staff blinded to the subject’s treatment assignment perform the 
following predose assessments: 1) MDS-UPDRS Parts I-IV; 2) Assessment of 
Subject’s Motor State (of “on” and “off,” and state of dyskinesia) –1, –0.5, and 
0 hour. 
 Administer C-SSRS. 
 Administer the study medication upon completion of predose procedures.  The 
IR CD-LD and IPX203 dosing regimens during the clinic visit for Day 15 should be 
the same as the regimens reflected on the last day in the Dosing diary on Days 12-14.  
To ensure unbiased data, treatments should be administered by clinical staff not 
directly involved in the assessment of the MDS-UPDRS Part III (Motor Examination) 
and Assessment of Subject’s Motor State. 
8.5.3. 
Postdose at Visits 2 and 4 
 Collect postdose blood samples (6 mL) for PK analysis at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 
4.5, 5, 6, 7, 8, and 10 hours postdose. 
 Qualified staff who are blinded to treatment assignment perform Assessment of 
Subject’s Motor State (of “on” and “off,” and state of dyskinesia) at half-hour 
intervals at approximately 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 
9, 9.5, and 10 hours postdose.  For each subject, the preference is to have the same 
rater perform the assessment at every time point throughout the study. 
 Qualified staff who are blinded to treatment assignment perform MDS-UPDRS 
Part III (Motor Examination) hourly at approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, and 
10 hours postdose.  For each subject, the preference is to have the same rater perform 
the assessment at every time point throughout the study. 
 When PK sampling and other procedures or measurements are scheduled at the same 
time, the PK sampling shall be done as close as possible to the nominal time. 
 Provide a breakfast containing approximately 5 grams of protein approximately 
1 hour following the morning dose (Appendix L).  Lunch may be provided no earlier 
than 4 hours following the morning dose.  Subjects may be provided dinner if needed.  
Subjects may also be provided snacks as long as it is not within 1 hour before or after 
their morning dose. 


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 Perform 12-lead ECG at 2 hours postdose. 
 Assess vital signs at 2, 4, and 10 hours postdose:  blood pressure, heart rate, and 
respiratory rate will be measured after the subject has been supine for at least 
5 minutes.  Orthostatic blood pressure and heart rate will be measured after the 
subject has been standing for approximately 2 minutes. 
 After completion of the10-hour PK sampling and pharmacodynamic assessments 
instruct the subject to switch back to taking their prestudy PD medications, including 
CD-LD, taking into account the timing of the last dose of study medication (Visits 2 
and 4) and to maintain this regimen until 10:00 PM on the night before the next visit 
(Visit 2 only). 
 If the current study medication is IPX203, it is recommended that the next dose of 
CD-LD be withheld for at least 5 hours after the last dose of IPX203. 
8.6. 
Study Exit/Early Withdrawal Procedures 
All enrolled subjects must complete Study Exit procedures at the end of Visit 4 or within 3 days 
of Visit 4, or during an early withdrawal visit: 
 Complete physical examination. 
 Vital signs (temperature, respiration, blood pressure and heart rate after supine for at 
least 5 minutes) and orthostatic standing vital signs (blood pressure and heart rate 
after standing for approximately 2 minutes). 
 Perform a 12-lead ECG. 
 Perform C-SSRS. 
 Obtain samples for clinical laboratory evaluations (chemistry, hematology, and 
urinalysis). 
 Update concomitant medications. 
 Update AEs.  All ongoing AEs must be followed until the event has resolved or has 
stabilized. 
 Instruct the subject to switch back to their prestudy PD medications and regimen 
(including IR CD-LD) and to maintain this dosing regimen unless or until they 
receive alternative instructions from their regularly treating physician or health care 
provider. 
8.7. 
Early Withdrawal 
Subjects who withdraw early should complete Study Exit procedures. 
8.8. 
Blood Volume 
Safety blood draws:  Approximately 10 mL of blood will be drawn at Screening and at 
Study Exit, for a combined total of 20 mL. 
PK blood draws:  Up to 472 mL will be drawn for subjects who complete both treatment periods. 


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9. 
TREATMENT OF SUBJECTS 
9.1. 
Description of Study Drug 
Study drugs will be provided by Impax for this study: 
 IPX203 (carbidopa-levodopa) Extended-Release Capsules, in two strengths, containing 
180 mg and 270 mg of LD, for oral administration. 
 Immediate-release carbidopa-levodopa (IR CD-LD) tablet containing 100 mg of LD, for 
oral administration. 
Table 6: 
Study Drugs for Study IPX209-B16-01 
Investigational Product 
Dosage Form and Strength 
Manufacturer 
IPX203 (carbidopa-levodopa) 
Extended-Release Capsules 
45-180 mg 
67.5-270 mg 
oral administration 
Impax 
Sinemet® (carbidopa levodopa) 
tablets (IR CD-LD) 
25-100 mg 
oral administration 
Merck & Co, Inc. 
9.2. 
Concomitant Medications 
9.2.1. 
Permitted PD Medications 
Concomitant therapy with amantadine, selective monoamine oxidase (MAO) type B inhibitors 
(eg, selegiline, rasagiline), anticholinergic PD medications (eg, benztropine, trihexyphenidyl), 
GABAergic hypnotics, and/or dopamine agonists (except apomorphine) is allowed provided the 
doses and regimens have been stable for at least 4 weeks prior to Visit 1 and the therapy is 
intended to be constant throughout the course of the study.  Use of CR CD-LD as a single 
bedtime dose is permitted during the wash-out period if this was part of their pre-study regimen. 
9.2.2. 
Prohibited PD Medications 
Prohibited medications include the following: 
 Received within 4 weeks of Visit 1 or planning to take during participation in the 
clinical study:  any doses of a controlled-release (CR) LD apart from a single daily 
bedtime dose or any doses of Rytary, additional CD (eg, Lodosyn) or benserazide (eg, 
Serazide), or catechol-O-methyl transferase inhibitors (entacapone or tolcapone) or 
medications containing these inhibitors (Stalevo). 
 Received within 4 weeks of Visit 1 or planning to take during participation in the 
clinical study:  nonselective MAO inhibitors, apomorphine, or dopaminergic blocking 
agents including antiemetics. 


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 Treatment with any dopamine antagonist antipsychotic agents for the purposes of 
psychosis or bipolar disorder within the last 2 years.  Use of antipsychotics to treat 
conditions other than psychosis or bipolar disorders may be allowed only after 
consultation with the medical monitor. 
A subject who reports the use of any prohibited medications will be discontinued. 
All medications taken within 30 days prior to signing the informed consent form (ICF) and all 
concomitant medications taken during the study will be recorded on the case report form (CRF). 
9.3. 
Treatment Compliance 
Study drug accountability and reconciliation will be performed by the study monitor. 
9.4. 
Randomization and Blinding 
At Visit 1, the subject will be randomized into 1 of 2 treatment sequences (Table 2). 
This is an open-label study with pharmacodynamic assessments done by qualified raters who are 
blinded to treatment assignments. 


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10. 
STUDY DRUG MATERIALS AND MANAGEMENT 
10.1. 
Study Drug 
Study drugs include IPX203 and the reference treatment Sinemet IR (CD-LD: 25-100 mg). 
IPX203 is an extended-release (ER) capsule formulation of CD-LD.  IPX203 is manufactured by 
Impax and will be supplied by Impax. 
Sinemet IR is commercially available and will be provided by Impax. 
10.2. 
Study Drug Packaging and Labeling 
Impax or designee will provide study medications in bottles with appropriate labeling affixed. 
Labels on the study medication may include the following information: 
 protocol number 
 study medication name and strength 
 unique bottle identifier 
 investigator name and site number 
 lot number 
 number (quantity) of capsules or tablets 
 directions for use 
 caution statement:  Caution: New Drug—Limited by Federal (or United States) law to 
investigational use. 
 storage information:  Store at 25°C (77°F), with excursions permitted to 15°C to 30°C 
(59°F to 86°F).  Protect from light and moisture. 
 sponsor’s name and address 
10.3. 
Study Drug Storage 
The study medications should be stored at 25°C (77°F), with excursions permitted to 15°C to 
30°C (59°F to 86°F).  They should be stored in a tightly closed container, protected from light 
and moisture. Storage temperature excursions above 30°C (86°F) should be reported to Product 
Development at Impax or its designee. 
10.4. 
Study Drug Administration 
Subjects will be instructed to take their medications with approximately 240 mL of room-
temperature water.  The capsules or tablets should not be crushed or chewed. 
IR CD-LD tablets may be split using a pill cutter. 


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10.5. 
Study Drug Dispensing and Accountability 
The Investigator must ensure that all study medication received at the study site is inventoried 
and accounted for, and that dispensed study medication is recorded in the subject’s source 
documents, the CRF, and the study medication inventory log.  Site personnel must not relabel or 
reassign study medication to other subjects or to individuals not enrolled in the study.  The study 
monitor verifies medication accountability during monitoring visits. 
10.6. 
Study Drug Handling and Disposal 
The Investigator must retain and properly store all partially used and unused study medication 
until authorized by Impax regarding disposition. 
 


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11. 
ASSESSMENT OF EFFICACY 
11.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the percent “off” time during waking hours, based on subject 
PD diaries for the last 3 days collected at the end of each treatment period. 
11.2. 
Secondary Efficacy Endpoints 
Secondary endpoints include the following: 
 Subject PD diaries for the last 3 days collected at the end of each treatment period:  
 Average of (1) total “off” time (2) total “on” time with no troublesome dyskinesia 
[good on] (3) total “on” time with no dyskinesia (4) total “on” time with 
troublesome dyskinesia (5) total “on” time with non-troublesome dyskinesia 
(6) total time asleep 
 Proportion of subjects with an improvement of at least 0.5, 1, 1.5, 2, and 3 hours 
in the total “off” time based on PD Diaries from baseline 
 Proportion of subjects in “off” state within the first 30 minutes of awakening for 
the day immediately following the subject’s usual nocturnal sleep period 
 Average total “off” time and total “on” time with no troublesome dyskinesia 
normalized for a 16-hour wake period 
 Change in the dyskinesia, mobility, and tremor measures obtained using the 
Kinesia 360 
 MDS-UPDRS collected predose on Day 15 of each treatment period – Average of  
 Total MDS-UPDRS score for the sum of Parts I to IV 
 Total scores for each of the 4 parts of the MDS-UPDRS 
 Total MDS-UPDRS score for the sum of Parts II and III 
 


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12. 
PHARMACOKINETIC AND PHARMACODYNAMIC 
ASSESSMENTS 
12.1. 
Pharmacokinetic Assessments 
The following single-dose PK parameters will be calculated from CD and LD plasma 
concentrations for each treatment:  observed maximum CD and LD plasma concentrations (Cmax) 
and time to maximum concentration (Tmax); area under the plasma concentration-time curve from 
time zero to the last measurable concentration (AUC0-t), and from time zero to infinity (AUC0-∞); 
apparent elimination half-life (t1/2); and bioavailability of IPX203 relative to IR CD-LD.  
Additionally, time to 50% Cmax of LD and duration > 50% Cmax of LD will be calculated for 
IPX203, and IR CD-LD.  Data after redosing on Day 1 (Visit 1 and 3) will not be included in 
these assessments. 
The following parameters will be estimated for LD and CD using data on Day 15 (Visits 2 and 
4): 
 Cmax over the dosing regimen 
 Tmax over the dosing regimen 
 AUC0-10 
 Accumulation calculated as AUC0-τ on Day 15/AUC0-τ on Day 1 
 Fluctuation calculated as (Cmax – Cmin)/Cavg (maximum [peak] drug concentration 
minus minimum drug concentration divided by average drug concentration), Cavg = 
average drug concentration. 
12.1.1. 
Blood Sample Collection Schedule in Each Study Period 
Blood samples (6 mL) for measurement of plasma LD and CD concentrations will be collected at 
the following time points: 
 Day 1 of each treatment period (Visits 1 and 3) – at predose and at 0.5, 1, 1.5, 2, 2.5, 
3, 4, 5, 5.5, 6, 6.5, 7, 7.5, and 8 hours postdose. 
 Day 15 of each treatment period (Visits 2 and 4) – at predose and at 0.5, 1, 1.5, 2, 2.5, 
3, 3.5, 4, 4.5, 5, 6, 7, 8, and 10 hours postdose. 
12.1.2. 
Samples per Subject 
A total of 60 PK blood samples will be collected if a subject completes the entire study. 
12.1.3. 
Pharmacokinetic Blood Sample Collection and Processing 
See Appendix K for blood-sample labeling, processing, storage, and shipment instructions. 


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12.2. 
Pharmacodynamic Assessments Endpoints 
The Movement Disorders Society—Unified Parkinson’s Disease Rating Scale and the 
Assessment of Subject’s Motor State will be assessed by qualified clinical staff blinded to 
treatment. 
12.2.1. 
MDS-UPDRS 
The following endpoints will be used to evaluate the difference between IPX203 and IR CD-LD 
using MDS-UPDRS Part III — Day 1 and Day 15 of each treatment period: 
 Average of change in MDS-UPDRS Part III score from Day 1 predose value at each 
time point 
 Area under the curve (AUC) of change in MDS-UPDRS Part III motor score value 
from predose value on Day 1 
 Average duration of effect estimated using the time point at which an improvement of 
at least (1) 4 points (2) 7 points (3) 13 points in the MDS-UPDRS Part III score from 
predose value on Day 1 is first observed and continuing until the time point at which 
the improvement is no longer observed. 
 Average of change in sum of questions 4 through 8 and question 14 MDS-UPDRS 
Part III score from Day 1 predose value at each time point to assess bradykinesia. 
 Average of change in each question 4, 5, 6, 7, 8 and 14 of MDS-UPDRS Part III 
separately from Day 1 predose value at each time point to assess bradykinesia. 
12.2.2. 
Assessment of Subject’s Motor State 
The following endpoints will be analyzed to compare IPX203 with IR CD-LD using Assessment 
of Subject’s Motor State — Day 1 and Day 15 of each treatment period: 
 Average of (1) total off time (2) total “on” time with no troublesome dyskinesia [good 
on] (3) total “on” time with no dyskinesia (4) total “on” time with troublesome 
dyskinesia (5) total “on” time with non-troublesome dyskinesia (6) total time asleep,  
 Proportion of subjects who are “off” and proportion of subjects “on” without 
troublesome dyskinesia will be presented at each time point. 
 


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13. 
ASSESSMENT OF SAFETY 
13.1. 
Safety Parameters 
Safety will be assessed by the following parameters: 
 ECGs, clinical laboratory tests, physical examinations, the C-SSRS, and vital signs. 
 Adverse events and concomitant medications will be evaluated over the course of the 
study. 
13.2. 
Adverse Events 
13.2.1. 
Definition of Adverse Event 
An adverse event (adverse experience) is any untoward medical occurrence in a patient or 
clinical trial subject administered a medicinal product and which does not necessarily have to 
have a causal relationship with this treatment.  An adverse event can therefore be any 
unfavorable and unintended sign (eg, an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal product, whether or not considered related to 
the medicinal product. 
All AEs and any clinically significant physical examination findings, 12-lead ECG 
abnormalities, or clinical laboratory measurements occurring during the study that were not 
present prior to administration of study medication and that continue at Study Exit should be 
followed and evaluated with additional tests, if necessary, until the AEs are medically stable or 
resolved.  Follow-up on these AEs should be recorded on the source documents and reported to 
Impax. 
13.2.2. 
Recording Adverse Events 
Elicit information about AEs with nonselective questions such as:  “Have you experienced any 
changes in your health status since your last visit?”  Encourage subjects to report AEs at onset. 
Record information for any AE that emerges from the time the subject signs the ICF until Study 
Exit. 
Monitor each subject closely for the development of AEs and record all such events on the AE 
page of the CRF.  Whenever possible, group signs and symptoms that constitute a single 
diagnosis.  For example, cough, rhinitis, and sneezing might be grouped as upper respiratory 
infection. 
For each AE, record the onset date, severity, seriousness, relationship to study medication, date 
of resolution (or continuing), action taken, and outcome in the CRF.  The Investigator is to make 
a causality assessment (relationship to study medication) for every AE. 
13.2.3. 
Follow-up 
The Investigator must follow each AE until resolved or medically stable. 


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13.2.4. 
Relationship to Study Drug 
The Investigator documents his/her opinion of the relationship of the AE to the study medication 
as follows: 
 Not Related—the experience can be readily explained by the subject’s underlying 
medical condition or concomitant medications and no relationship exists between the 
study medication and the experience. 
 Unlikely Related—the temporal relationship between the AE and the administration 
of the study medication is uncertain and it is likely that the AE can be explained by 
the subject’s medical condition or other therapies. 
 Possibly Related—there is some logical temporal relationship between the AE and 
the administration of the study medication and the experience is unlikely to be 
explained by the subject’s medical condition or other therapies. 
 Related—the temporal relationship is compelling between the administration of the 
study medication and the AE cannot be explained by the subject’s medical condition 
or other therapies. 
13.2.5. 
Assessment of Severity 
Grade each AE for severity and note in the description of the AE.  Determine the severity 
category of mild, moderate, or severe, as defined below, and enter the information on the AE 
page of the CRF. 
 Mild—causing no limitation of usual activities 
 Moderate—causing some limitation of usual activities 
 Severe—causing inability to carry out usual activities 
13.3. 
Serious Adverse Events 
13.3.1. 
Definition of Serious Adverse Event 
A serious adverse event (SAE) is any AE occurring at any dose that results in any of the 
following outcomes, regardless of relationship to the study medication: 
 Death 
 A life-threatening adverse drug experience 
 Inpatient hospitalization or prolongation of existing hospitalization 
 A persistent or significant disability/incapacity 
 A congenital anomaly/birth defect 
 Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical 
judgment, they may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. 


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13.3.2. 
Reporting Serious Adverse Events 
Any SAE that occurs from the time the subject signs an ICF until 30 days after taking the final 
dose of study medication must be reported by the investigative staff to the Sponsor or the 
Sponsor’s representative within 24 hours of knowledge of the event (see Study Contact 
Information). 
An SAE form must be completed and sent to the Sponsor and/or the Sponsor’s representative.  
All SAEs must also be recorded on the AE page of the CRF.  Additionally, all SAEs must be 
reported to the institutional review board (IRB) per the IRB’s requirements. 
Those SAEs that are considered both serious and unexpected and related to the study drug are 
subject to expedited reporting.  An “unexpected AE” is any AE where the nature or severity is 
not consistent with the current investigator brochure (IB) or if an IB is not required or available, 
the specificity or severity is not consistent with the provided risk information. 
Unexpected fatal or life-threatening SAEs related to the study drug must be reported by the 
Sponsor to the appropriate regulatory authority in an expedited manner (ie, first report within 
7 days of first knowledge by the Sponsor).  The Sponsor will provide a final written report to that 
authority within 15 days of initial receipt of information on the event.  The Sponsor or the 
Sponsor’s representative will also inform all participating Investigators of the SAE. 
Unexpected SAEs that are not fatal or life-threatening must be reported by the Sponsor to the 
appropriate regulatory authority as soon as possible but no later than 15 calendar days after first 
knowledge of the SAE by the Sponsor.  The Sponsor or the Sponsor’s representative also 
informs all participating Investigators of the SAE. 
Subjects withdrawn from the study due to any SAE will be followed until the SAE is resolved or 
medically stable.  Record all SAEs, regardless of severity and whether or not related to the study 
medication, on the appropriate page of the CRF. 
The Investigator must determine whether the seriousness of the event warrants removal of the 
subject from the study.  He/she should, in any case, institute appropriate diagnostic and 
therapeutic measures and keep the subject under observation for as long as is medically 
indicated, or refer the subject to appropriate health professionals. 
13.4. 
Pregnancy 
Any pregnancy that occurs from the time the subject signs an ICF until 30 days after taking the 
final dose of study medication must be reported within 24 hours to the Sponsor or the Sponsor’s 
representative and the subject should be terminated from the study.  All pregnancies will be 
followed through to delivery of the infant.  If the subject experiences a termination of the 
pregnancy, it should be reported as defined in Section 13.3.2. 
13.5. 
Other Safety Parameters and Related Information 
Additional safety parameters (laboratory tests, 12-lead ECGs, physical examinations, and vital 
signs), the C-SSRS, and concomitant medications are collected as shown in the Schedule of 
Assessments in Table 5 and evaluated over the course of the study.  Clinical laboratory studies 
are listed in Appendix J. 


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14. 
STATISTICS 
14.1. 
Study Design and Sample Size Estimation 
Assuming a difference of 1.75 hours between the treatments in “off” time and the standard 
deviation of the treatment differences to be 3 hours, this 2-way crossover design will have 80% 
power to detect a difference between IPX203 and IR CD-LD with at least 26 subjects completing 
the study (level of significance = 0.05). 
To allow for a dropout rate of approximately 15%, at least 30 subjects will be randomized to 
ensure at least 26 completers. 
For efficacy, a subject will be considered a completer if the subject receives treatments in both 
periods and has at least 2 days of evaluable PD diary data for each period. 
For pharmacodynamic assessments, a completer will be defined as a subject who has received 
both treatments and has completed at least 4 postdose Assessments of Subjects’ Motor State in 
each period. 
14.2. 
Demographics/Baseline Comparability 
The demographics and baseline characteristics for all subjects enrolled in the study will be 
summarized. 
14.3. 
Analysis of Pharmacokinetic Data 
The following PK parameters will be calculated from the CD and LD plasma concentrations 
following single doses of each treatment (IPX203 and IR CD-LD): 
Cmax 
maximum observed plasma concentration 
Tmax 
time to maximum concentration 
AUC0-t 
area under the plasma concentration-time curve from time zero to the last 
measurable concentration  
AUC0-∞ 
AUC value extrapolated to infinity will be calculated as the sum of AUC0-t and 
the area extrapolated to infinity, calculated by the last measurable concentration 
(Clast) divided by λz 
t1/2  
apparent elimination half-life (t1/2) values will be calculated as 0.693/λz 
λz 
apparent elimination rate constant will be estimated by linear regression of the 
log-transformed plasma concentrations during the terminal log-linear decline 
phase 
The bioavailability of IPX203 relative to IR CD-LD will also be calculated. 


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Additionally, time to 50% Cmax of LD and duration > 50% Cmax of LD will be calculated for 
IPX203, and IR CD-LD.  Data after redosing on Day 1 (Visit 1 and 3) will not be included in 
these assessments. 
The following parameters will be estimated for LD and CD following multiple dosing (Day 15): 
 Cmax over the dosing regimen 
 Tmax over the dosing regimen 
 AUC0-10 
 Accumulation 
 Fluctuation 
 
Descriptive statistics will be presented by treatment group and LD dose for the PK parameters 
for IR CD-LD and IPX203.  Following natural logarithm transformation, analyses of variance 
(ANOVA) will be performed on CD and LD AUC and Cmax adjusted for dose, fluctuation, and 
accumulation.  Additionally, duration of LD plasma concentration above 50% of Cmax values will 
be analyzed using ANOVA.  Comparisons will be performed using a mixed-effect ANOVA 
model that includes treatment, period, and sequence as fixed effects and subject-within-sequence 
as a random effect for the following treatments: IPX203 versus IR CD-LD.  All PK analyses will 
be done following current recommendations (Food and Drug Administration 2003). 
14.4. 
Analysis of Efficacy Data 
Descriptive statistics and frequency distributions will be displayed for all endpoints. 
14.4.1. 
Primary Efficacy Endpoint 
The primary efficacy parameter for this study will be the average percent “off” time during 
waking hours based on subject PD diaries collected at the end of each treatment period.  For each 
day it will be calculated as the number of half-hour intervals in which “off” is checked.  The 
average percent “off” time will be defined as the average of percent “off” time (total “off” time 
divided by the total time not “asleep,” (ie, waking hours) from the subject PD diaries completed 
for the 3 days immediately prior to the visit.  The difference between the average percent “off” 
time between treatments will be analyzed using a standard mixed-model analysis of variance at a 
0.05 level of significance.  This model will include the fixed-effect factors of treatment, and 
period and the random-effect inter- and intra-subject factors.   
14.4.2. 
Secondary Efficacy Endpoint 
The continuous efficacy endpoints will be evaluated for differences between treatments using a 
standard mixed-model analysis of variance at a 0.05 level of significance.  This model will 
include the fixed-effect factors of treatment, sequence and period and the random-effect inter- 
and intra-subject factors.  All comparisons of secondary endpoint will be tested at 5% 
significance level without any multiplicity correction. 
The following efficacy parameters will be analyzed using mixed-model analysis in a fashion 
similar to the primary efficacy endpoint: 


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 Average off time – From the subject PD diaries, the number of half-hour intervals 
marked “off” will be calculated.  The difference between the averages of total “off” 
time between the two treatments will be analyzed. 
 Average time “on” with no troublesome dyskinesia (good on) – From the subject PD 
diaries, the sum of the number of half-hour intervals marked “on without dyskinesia” 
and “on with non-troublesome dyskinesia” will be calculated.  The difference 
between the averages of total time “on with no troublesome dyskinesia” between the 
two treatments will be analyzed. 
 Average of total “on” time with no dyskinesia – From the subject PD diaries, the sum 
of the number of half-hour intervals marked “on without dyskinesia” will be 
calculated.  The difference between the averages of total time “on time with no 
troublesome dyskinesia” between the two treatments will be analyzed. 
 Average of total “on” time with troublesome dyskinesia – From the subject PD 
diaries, the sum of the number of half-hour intervals marked “on with troublesome 
dyskinesia” will be calculated.  The difference between the averages of total time “on 
with troublesome dyskinesia” between the two treatments will be analyzed. 
 Average of total “on” time with non-troublesome dyskinesia – From the subject PD 
diaries, the sum of the number of half-hour intervals marked “on with non-
troublesome dyskinesia” will be calculated.  The difference between the averages of 
total time “on with non-troublesome dyskinesia” between the two treatments will be 
analyzed. 
 Average of total time asleep – From the subject PD diaries, the sum of the number of 
half-hour intervals marked “asleep” will be calculated.  The difference between the 
averages of total time “asleep” between the two treatments will be analyzed. 
 Average of total off time normalized for 16 waking hours:  Normalize the off time by 
multiplying the proportion of off time during the waking hours with 16 hours.  The 
difference between the averages of total off time normalized for 16 waking hours 
between the two treatments will be analyzed. 
 Average of total on time with no troublesome dyskinesia normalized for 16 waking 
hours:  Normalize the on time with no troublesome dyskinesia by multiplying the 
proportion of on time with no troublesome dyskinesia time during the waking hours 
with 16 hours.  The difference between the averages of total on time with no 
troublesome dyskinesia normalized for 16 waking hours between the two treatments 
will be analyzed. 
 Average of total MDS-UPDRS Score – The sum of the scores of Parts I, II, III and IV 
will be calculated.  The difference between the averages of the total MDS-UPDRS 
scores for the two treatments will be analyzed. 
 Average of total Score of individual Parts of MDS-UPDRS:  The total scores of each 
of the 4 parts of the MDS-UPDRS will be calculated and the difference between the 
averages of scores of each part for the two treatments will be analyzed. 


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 Average of total of MDS-UPDRS Parts II and III:  Since both treatments are likely to 
have the greatest effect on Part II (activities of daily living) and Part III (motor 
examination), the sum of these two parts will be analyzed.  The difference between 
the averages of the total MDS-UPDRS Parts II and III scores for the two treatments 
will be analyzed. 
 Change in the dyskinesia, mobility, and tremor measures obtained using the 
Kinesia 360. 
The proportion of subjects with an improvement of at least 0.5, 1, 1.5, 2, and 3 hours in the “off” 
time will be analyzed using generalized estimating equations methods.  The model will include 
treatment and period.  The proportion of subjects in “off” state within the first 30 minutes of 
awakening for the day immediately following the subject’s usual nocturnal sleep period will also 
tabulated by day.  The proportion of subjects who may have no, 1, 2 or 3 instances of “off” over 
the three days will also be analyzed. 
14.5. 
Analysis of Pharmacodynamics Data 
Descriptive statistics and frequency distributions will be displayed for all pharmacodynamic 
endpoints. 
The continuous endpoints will be evaluated for differences between treatments using a standard 
mixed-model analysis of variance at a 0.05 level of significance.  This model will include the 
fixed-effect factors of treatment, sequence and period and the random-effect inter- and intra-
subject factors.  The following analysis will be conducted for Day 1 and Day 15 endpoints: 
 Average total “off” time will be derived from the Assessment of Subject’s Motor State 
every 30 minutes.  It will be based on the sum of half-hour intervals marked “off”. 
 Average total time “on” without troublesome dyskinesia (good on):  Estimated using total 
“on” time without dyskinesia and “on” with nontroublesome dyskinesia based on the sum 
of half-hour intervals marked “on” without dyskinesia and “on” with non-troublesome 
dyskinesia. 
 Average total time “on” with no dyskinesia:  Estimated using total “on” with no 
dyskinesia based on sum of half-hour intervals marked “on” without dyskinesia. 
 Average total time “on” with troublesome dyskinesia:  Estimated using total “on” with 
troublesome dyskinesia will be based on sum of half-hour intervals marked “on” with 
troublesome dyskinesia. 
 Average total time “on” with non-troublesome dyskinesia:  Estimated using total “on” 
with non-troublesome dyskinesia based on sum of half-hour intervals marked “on” with 
non-troublesome dyskinesia. 
 Average total time asleep:  Estimated using total time asleep based on sum of half-hour 
intervals marked asleep. 
 Average of change in MDS-UPDRS Part III score from Day 1 predose value to each 
postdose time point. 


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 To determine the effect of IPX203, average of the area under the curve (AUC) for the 
change from predose in the MDS-UPDRS Part III score 
 Duration of effect using time points at which an improvement of at least 4 points in the 
MDS-UPDRS Part III score from predose is observed will be estimated.  The difference 
in mean duration of effect between treatments will be analyzed using a mixed-effect 
ANOVA model which will include treatment, period, and sequence as fixed effects and 
subject-within-sequence as a random effect.  To determine the duration of effect, the 
midway point between two adjacent time points will be used.  For example, if a subject 
does not have 4 units of improvement from the predose MDS-UPDRS Part III assessment 
at the 1-hour postdose assessment, but has an improvement at the 2-hour postdose 
assessment, and loses the 4-unit improvement at the 3-hour assessment, the duration of 
effect will be considered as 1 hour using the interpolated time value.  Similar analysis 
will be conducted for an improvement of at least 7 and 13 points in the MDS-UPDRS 
Part III score from predose. 
 Average of change in sum of questions 4 through 8 and question 14 MDS-UPDRS 
Part III score from Day 1 predose value at each time point to assess bradykinesia. 
 Average of change in each question 4, 5, 6, 7, 8 and 14 of MDS-UPDRS Part III 
separately from Day 1 predose value at each time point to assess bradykinesia. 
The categorical endpoints will be analyzed using generalized estimating equations methods.  The 
model will include treatment and period.  All comparisons of secondary endpoint will be tested 
at 5% significance level without any multiplicity correction. 
14.6. 
Analysis of Dosing Data 
The IPX203 daily dose and frequency of dosing will be collected during this study to further 
assess optimal dosing and dosing instructions for advanced-stage PD population subjects who 
were treated with IR CD-LD previously. 
14.7. 
Population Analysis and Handling of Dropouts 
Subjects who discontinue early will not be replaced. 
All subjects treated with any study medication will be included in the safety analyses. 
For pharmacodynamic analysis, all available data obtained on subjects who receive both 
treatments and have at least 4 postdose Assessment of Subject’s Motor State for each treatment 
will be included in the analysis. 
For subjects who receive rescue medication or who discontinue the study assessments prior to 
the Hour 8 (Visit 1 and 3) and Hour 10 (Visit 2 and 4) assessment on Day 1, the following rules 
will be applied for various evaluations: 
 Assessment of Subject’s Motor State—all half-hour assessments after rescue 
medication is administered will be considered as “off” for the remainder of the 
evaluation period. 
 MDS-UPDRS Part III—the predose sum of MDS-UPDRS Part III will be carried 
forward for all time points after rescue medication administration. 


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Imputation of missing data for subject PD diaries will be required if the PD diary is not 
completed for a day (6 am to 6 am).  In this case, the method of imputation will be dependent 
upon the amount and pattern of missing data: 
 If more than four half-hour time intervals are missing, then that particular day will not 
be included in the analysis. 
 If a half-hour time interval is missing and the observations on either side of the time 
interval are not missing, then the missing time interval will be imputed by assigning a 
value of the previous measurement for the first 15 minutes and the value of the next 
measurement for the second 15 minutes. 
 If two or more consecutive half-hour time intervals are missing, not to exceed a total 
of four, and these time intervals are available from other days of the visit, then the 
following rules will be applied: 
 For missing values on Day 1, data from Day 2 will be used for imputation for the 
same time intervals.  If Day 2 data is also incomplete then Day 3 data will be 
used. 
 For missing values on Day 2, data from Day 3 will be used for imputation if 
available; otherwise Day 1 data will be used. 
 For missing values on Day 3, data from Day 2 will be used for imputation if 
available; otherwise Day 1 data will be used for imputation. 
 If data at the same time period is missing across all days, the individual missing 
half-hour intervals will be split into two periods, with the first half-interval being 
imputed with data from the immediate previous nonmissing time period and the 
second half-interval being imputed with the next nonmissing time interval. 
14.8. 
Safety 
The safety analysis will include all subjects who receive at least 1 dose of study medication.  
Reported AEs will be coded to standard terms using a standard dictionary (Medical Dictionary 
for Regulatory Activities [MedDRA]).  All AEs will be summarized by body system, and by 
preferred terms within a body system, by severity, and by relation to study medication.  Each AE 
(based on preferred terminology) is counted only once for a given subject within a treatment.  If 
the same AE occurred on multiple occasions, the highest severity and least complimentary 
relationship was assumed.  If two or more AEs were reported as a unit, the individual terms will 
be reported as separate AEs. 
The incidence of treatment-emergent AEs, as well as, SAEs will be analyzed. 
The secondary safety variables including early termination data, laboratory test data, physical 
examination data, vital signs, ECGs, the C-SSRS and concomitant medications will be tabulated.  
Clinical laboratory values are to be summarized by visit, including change from baseline.  
Medically significant laboratory values outside of normal reference ranges will also be tabulated 
and assessed. 


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15. 
ADMINISTRATIVE PROCEDURES 
15.1. 
Guidelines for Good Clinical Practice 
This study will be conducted in accordance with principles of Good Clinical Practice (GCP) as 
promulgated by the ICH.  Good Clinical Practice is an international ethical and scientific quality 
standard for designing, conducting, recording, and reporting trials that involve the participation 
of human subjects.  Compliance with this standard provides public assurance that the rights, 
safety, and well-being of human subjects are protected under current ethical principles, and that 
the clinical trial data are credible.  Current GCP standards may be found in ICH Guidance E6 
(Good Clinical Practice:  Consolidated Guidance).  This guidance describes the principles of 
GCP and the obligations of the institutional review board (IRB), the Investigator and the Sponsor 
in conducting this study in accordance with those principles. 
15.2. 
Institutional Review Board Approval 
The review of this protocol by an IRB and the performance of all aspects of the study, including 
the methods used for obtaining informed consent, must be in accordance with principles 
enunciated in the ICH and GCP Guidelines and by the appropriate regulatory authorities. 
The Investigator is responsible for preparing documents for submission to the relevant IRB and 
obtaining written approval for this study.  Institutional Review Board approval must be obtained 
prior to the initiation of the study.  The Investigator’s continued participation in the study is 
contingent on renewing approval with the IRB at least annually. 
15.3. 
Informed Consent 
Site personnel should prepare an Informed Consent Form (ICF) incorporating the necessary 
elements of consent.  The ICF is to be approved by Impax prior to submission to the IRB.  The 
Investigator or his/her staff must explain the nature of the investigation and the risks involved to 
each subject prior to screening, and obtain a signed ICF.  The subject should also be informed 
that he/she is free to voluntarily withdraw from the study at any time. 
15.4. 
Study Monitoring 
Impax representatives or designees will conduct site visits to the investigational facilities for the 
purpose of monitoring the study.  The Investigator agrees to allow the monitor to inspect the 
drug storage area, study drug stocks, drug accountability records, subject charts and study source 
documents, and other records relevant to study conduct.  The Investigator must permit access to 
such records if a regulatory or compliance audit is required. 
15.5. 
Protocol Amendments 
All amendments to the protocol must be documented in writing, reviewed and approved by the 
Sponsor and Investigator, and submitted to the IRB for approval prior to implementation.  If the 
protocol amendment substantially alters the study design or potential risk to the subject, a new 
written ICF for continued participation in the study must be obtained from each subject affected 
by the change. 


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15.6. 
Termination of Study 
The Sponsor has the right to terminate this study and remove all study material from the site at 
any time for medical or administrative reasons.  In this event, the Sponsor will endeavor to give 
adequate notice to allow safe withdrawal of subjects from the study. 
15.7. 
Case Report Forms 
Site personnel should collect and record data for the study as source documents, and transfer the 
data into the CRF. 
The Investigator must ensure that complete data for the clinical study are collected and 
accurately documented in the appropriate sections of the CRF and adequately supported by the 
appropriate source documentation.  In addition, it is the Investigator’s responsibility to provide 
signatures where requested indicating concurrence with data in the CRF. 
15.8. 
Investigator’s Final Conduct Report 
At the completion of the study, the Investigator must provide Impax a copy of the final conduct 
report that was submitted to their IRB, including a review of AEs. 
15.9. 
Records Retention 
International Conference on Harmonization, GCP, and US FDA guidelines require that essential 
documents be retained until at least 2 years after the last approval of a marketing application and 
until there are no pending or contemplated marketing applications, or at least 2 years have 
elapsed since the formal discontinuation of clinical development of the investigational product. 
However, the essential documents should be retained for a longer period if required by the 
applicable regulatory requirements or by an agreement with the Sponsor.  Records should never 
be destroyed without written approval from the Sponsor. 
If an Investigator leaves the institution, he/she must transfer responsibilities for record retention 
to another individual willing to accept them.  The Investigator must notify the Sponsor in writing 
of the transfer of study documents before the transfer of the study documents. 
 


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16. 
PUBLICATION POLICY 
Study results may not be published without prior written approval from Impax. 
 


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17. 
LIST OF REFERENCES 
Blanchet PJ, Calon F, Martel JC, et al. Continuous administration decreases and pulsatile 
administration increases behavioral sensitivity to a novel dopamine D2 agonist (U-91356A) in 
MPTP-exposed monkeys. J Pharmacol Exp Ther. 1995;272:854-859. 
Engber TM, Susel Z, Juncos JL, Chase TN. Continuous and intermittent levodopa differentially 
affect rotation induced by D-1 and D-2 dopamine agonists. European Journal of Pharmacology. 
1989;168:291-298. 
Fahn S. Parkinson disease, the effect of levodopa, and the ELLDOPA trial. Earlier vs Later L 
DOPA. Arch Neurol. 1999 May;56(5):529-35. 
Food and Drug Administration 2003.  Guidance for Industry.  Bioavailability and 
Bioequivalence Studies for Orally Administered Drug Products — General Considerations.  U.S. 
Department of Health and Human Services.  Food and Drug Administration. Center for Drug 
Evaluation and Research (CDER). March 2003. 
Juncos JL, Engber TM, Raisman R, et al. Continuous and intermittent levodopa differentially 
affect basal ganglia function. Ann Neurol. 1989;25:473-478. 
Kurlan R, Rothfield KP, Woodward WR, Nutt JG, Miller C, Lichter D, et al. Erratic gastric 
emptying of levodopa may cause "random" fluctuations of parkinsonian mobility. Neurology. 
1988;38(3):419-21. 
Melamed E, Bitton V, Zelig O. Delayed onset of responses to single doses of L-dopa in 
parkinsonian fluctuators on long-term L-dopa therapy. Clin Neuropharmacol. 1986;9(2):182-8. 
Mizuno Y. Where do we stand in the treatment of Parkinson's disease? Neurology. 2007;254:13-
18. 
Nilsson D, Nyholm D, Aquilonius S-M. Duodenal levodopa infusion in Parkinson's disease--
long-term experience. Acta Neurologica Scandinavica. 2001;104:343-348. 
Nyholm D, Nilsson Remahl AI, Dizdar N, et al. Duodenal levodopa infusion monotherapy vs 
oral polypharmacy in advanced Parkinson disease. Neurology. 2005;64:216-223. 
Sinemet (Carbidopa-Levodopa) Tablets Prescribing Information. Whitehouse Station, NJ: 
Manufactured by Merck & Co., Inc.; Marketed by Bristol-Myers Squibb Company; 2013. 
Stocchi F, Quinn NP, Barbato L, Patsalos PN, O’Connel MT, Ruggieri S, et al. Comparison 
between a fast and a slow release preparation of levodopa and a combination of the two:  a 
clinical and pharmacokinetic study. Clinical Neuropharmacol. 1994;17(1):38-44. 
Stocchi F, Vacca L, et al. Intermittent vs continuous levodopa administration in patients with 
advanced Parkinson disease: a clinical and pharmacokinetic study. Arch Neurol. 2005:62(6):905-
910. 


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18. 
APPENDICES 
 
APPENDIX A. SINEMET PRESCRIBING INFORMATION 
 
 


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APPENDIX B. UNITED KINGDOM PARKINSON’S DISEASE SOCIETY 
BRAIN BANK DIAGNOSTIC CRITERIA FOR 
PARKINSON’S DISEASE 
 


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APPENDIX C. MONTREAL COGNITIVE ASSESSMENT (MOCA) 


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APPENDIX D. MDS-UPDRS 


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APPENDIX E. COMPONENTS OF IPX203 
 
Active ingredients:  carbidopa and levodopa 
 
Inactive ingredients:  The excipients in the IPX203 investigational formulations include the 
following: microcrystalline cellulose, mannitol, amino methacrylate copolymer, sodium lauryl 
sulfate, methacrylic acid copolymer Type A, copovidone, cellulose acetate, croscarmellose 
sodium, talc, triethyl citrate, povidone, magnesium stearate.  All these excipients are United 
States Pharmacopeia and National Formulary.  The investigational formulations will be enclosed 
in hard gelatin capsules. 


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APPENDIX F. COLUMBIA-SUICIDE SEVERITY RATING SCALE 


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APPENDIX G. KINESIA 360 SYSTEM 
 
The Kinesia 360 system allows for continuous, passive symptom monitoring using motion 
sensors worn on the wrist and ankle.  Data collected by the motion sensors is transformed and 
analyzed using validated algorithms to provide data on tremor, akinesia, dyskinesia, and 
mobility. 
Included in the Kinesia 360 system is a smartphone configured with the Kinesia 360 application 
and two motion sensors.  Upon waking on the scheduled days of use, subjects press the Start 
button within the Kinesia 360 application and put the motion sensors on the wrist and ankle of 
the more affected side of the body.  Subjects then go about their day as they normally would.  At 
the end of the day before going to bed, subjects remove the motion sensors and press the End 
button within the Kinesia 360 application.  Motion sensor data is uploaded to the cloud where it 
is processed using validated algorithms, and a report is generated which displays symptom 
detection and severity details.  Overnight, the motion sensors and smartphone recharge so they 
are ready for the next day of use. 
 
Please see the following Quick Start Guide for instructions on set up and use of the Kinesia 360 
system. 
 
 


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APPENDIX H. PARKINSON’S DISEASE DIARY 
 


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APPENDIX I. ASSESSMENT OF SUBJECT’S MOTOR STATE 
Time (hours) 
Asleep 
OFF 
ON without 
dyskinesia 
ON with 
non-
troublesome 
dyskinesia 
ON with 
troublesome 
dyskinesia 
–1 predosea 
 
 
 
 
 
–0.5 (predose) 
 
 
 
 
 
0 (predose) 
 
 
 
 
 
0.5 
 
 
 
 
 
1 
 
 
 
 
 
1.5 
 
 
 
 
 
2 
 
 
 
 
 
2.5 
 
 
 
 
 
3 
 
 
 
 
 
3.5 
 
 
 
 
 
4 
 
 
 
 
 
4.5 
 
 
 
 
 
5 
 
 
 
 
 
5.5 
 
 
 
 
 
6 
 
 
 
 
 
6.5 
 
 
 
 
 
7 
 
 
 
 
 
7.5 
 
 
 
 
 
8 
 
 
 
 
 
8.5 
 
 
 
 
 
9 
 
 
 
 
 
9.5 
 
 
 
 
 
10 
 
 
 
 
 
 


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APPENDIX J. CLINICAL LABORATORY STUDIES 
HEMATOLOGY 
hemoglobin 
hematocrit 
red blood cell count 
white blood cell count 
% neutrophils 
% lymphocytes 
% monocytes 
% basophils 
% eosinophils 
absolute neutrophils 
absolute lymphocytes 
absolute monocytes 
absolute basophils 
absolute eosinophils 
platelet count 
CHEMISTRY 
sodium 
potassium 
chloride 
carbon dioxide 
blood urea nitrogen (BUN) 
creatinine 
glucose 
calcium 
phosphorous 
albumin 
total protein 
uric acid 
total bilirubin 
direct bilirubin 
indirect bilirubin 
alkaline phosphatase 
alanine aminotransferase 
(ALT, SGPT) 
aspartate aminotransferase 
(AST, SGOT) 
creatine phosphokinase 
lactate dehydrogenase 
URINALYSIS  
pH 
specific gravity 
blood 
glucose 
ketones 
microscopic exam (RBC 
and WBC, only when 
indicated) 
leukocyte esterase 
protein
URINE DRUG TEST 
amphetamines 
barbiturates 
cannabinoids 
cocaine metabolites 
opiates 
phencyclidines 
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ALCOHOL BREATH TEST 
PREGNANCY TEST 
Urine pregnancy test (to be completed on site) for female subjects of childbearing potential. 


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APPENDIX K. BLOOD SAMPLE LABELING, PROCESSING, STORAGE 
AND SHIPMENT 
Sample Labeling:  The labels for all sample collection and storage containers will contain the 
subject ID (include all six digits), the subject’s initials, dosing period, nominal time, collection 
date, study number, and sample number (sequentially per period, eg, 1-1 to 1-15 for Period 1 and 
2-1 to 2-15 for Period 2). 
Collection of PK Blood Samples:  Blood samples for PK analysis will be collected at times as 
specified in the protocol.  The actual time of sample collection will be recorded. 
Sample Processing and Storage:  One 6 mL sample of blood will be drawn at each sampling 
time point.  Approximately 2 mL of blood will be drawn and discarded before collection of each 
PK sample, except for the predose PK sample.  Prior to dosing, an IV catheter will be inserted 
into an arm vein.  The catheter site will be covered with a clear sterile dressing and the catheter 
will be maintained until after the 10-hour PK sample has been obtained.  Each PK sample will be 
collected into a chilled (~4°C) 6 mL K2-EDTA vacutainer tube.  The tube must be placed 
immediately into an ice bath or a Kryorack (or similar) that has been chilled in the freezer (~0°C) 
overnight and equilibrated at room temperature for 1 hour before use to prevent hemolysis due to 
freezing.  Each Kryorack should only be used for a maximum of 6 hours.  Therefore, samples 
from later time points must use a freshly equilibrated Kryorack. 
Blood samples must be centrifuged within 30 minutes of collection for approximately 15 minutes 
at approximately 3400 rpm at 4°C.  Immediately pipette 1.0 mL of plasma from each sample into 
each of 2 polypropylene tubes pretreated with sodium metabisulfite and hydrazine 
dihydrochloride (see below) labeled as “Aliquot A” and “Aliquot B” and vortex for 
approximately 20 seconds.  Immediately store samples at –70°C ± 15°C until shipment. 
The time between sample collection and freezer storage should not exceed 1.5 hours.  The 
prepared plasma samples will be shipped to a bioanalytical laboratory for sample analysis. 
For each 1 mL of plasma, each pretreated polypropylene tube must contain 25 μL of 20% (w/v) 
hydrazine dihydrochloride solution and 25 µL of 20% (w/v) sodium metabisulfite solution.  The 
20% (w/v) hydrazine dihydrochloride solution and the 20% (w/v) sodium metabisulfite solution 
should be prepared and stored separately not more than 4 days before each treatment period.  The 
solutions should not be used after 4 days.  The pretreated tubes should be prepared on the day of 
use or at the earliest on Day –1.  If prepared on Day –1, the capped pretreated tubes should be 
kept in fridge (4°C) but may be kept at room temperature away from heat and tightly capped.  
Detailed instructions for the preparation of the two solutions and the pretreated tubes are 
provided in a separate document. 
In cases where the plasma volume is less than 1.0 mL, use the following guide to correct the 
volume. 


Protocol No. IPX203-B16-01 
CONFIDENTIAL 
Amendment 2: October 5, 2016 
Impax Laboratories, Inc. 
Page 134 of 136 
Plasma volume 
(mL) 
20% (w/v) hydrazine 
dihydrochloride solution 
(μL) 
20% (w/v) sodium 
metabisulfite solution 
(μL) 
0.8 
20 
20 
0.7 
18 
18 
0.6 
15 
15 
0.5 
13 
13 
0.4 
10 
10 
 
 
 
Transfer or Shipment of Samples:  The sample inventory record must accompany the frozen 
plasma samples. 
For sample transfer, the inventoried samples will be released to the custody of the bioanalytical 
laboratory staff for audit, inventory control, and storage.  Notification of sample transfer must be 
communicated to the Sponsor in writing. 
For shipment, the samples should be packed in ample dry ice within a container and shipped by 
overnight express to the bioanalytical laboratory.  Notification of sample shipment should be 
communicated in writing to the bioanalytical laboratory and Sponsor.  The samples should be 
tracked by clinical site staff to confirm delivery in a safe and timely manner.  The second set of 
samples must only be shipped after the Bioanalytical laboratory has confirmed receipt of the first 
set. 
 
BIOANALYTICAL LAB: 
Biotrial Bioanalytical Services 
3885 Blvd Industriel, Laval, Quebec, H7L 4S3 Canada 
Attention:  Mr. Nick Diakoumakos 
Phone:  450-663-6724 Ext.: 451 
nick.diakoumakos@biotrial.com  
 


Protocol No. IPX203-B16-01 
CONFIDENTIAL 
Amendment 2: October 5, 2016 
Impax Laboratories, Inc. 
Page 135 of 136 
APPENDIX L. EXAMPLES OF PROTEIN CONTENT 
 
American diet typically comprises 12% to 15% protein; a low protein diet contains 4% to 8% 
protein. 
egg 
6 grams per each  
lean meat, fish, poultry  
25–30 grams per 3 1/2 oz.  
tofu  
20 grams per cup- 8oz.  
tempeh  
30 grams per cup-8oz.  
milk  
8–9 grams per cup-8oz.  
yogurt  
8–10 grams per cup-8oz.  
cream cheese  
2 grams per oz.  
cheddar/jack  
7 grams per oz.  
parmesan  
10 grams per oz.  
cottage cheese  
28 grams per cup  
nuts and seeds  
2–3 grams per tablespoon  
rice, cooked  
5 grams per cup  
corn meal, cooked  
2 grams per cup  
bulgar, cooked  
8 grams per cup  
oatmeal, cooked  
5 grams per cup  
wheat germ, toasted  
8 grams per 1/4 cup  
bread  
2-11 grams per slice check the label  


Protocol No. IPX203-B16-01 
CONFIDENTIAL 
Amendment 2: October 5, 2016 
Impax Laboratories, Inc. 
Page 136 of 136 
adzuki beans, cooked  
17 grams per cup  
kidney beans, cooked  
15 grams per cup  
potato, baked with skin, medium  
5 grams  
nutritional yeast, flakes  
4 grams per heaping tablespoon.  
most fruits  
1 gram per fruit  
vegetables  
1-3 grams per 1/2 cup  
Source: http://krispin.com/protein_basics.htm#sources_of_protein  
 


Protocol No. IPX203-B16-01 
CONFIDENTIAL 
Amendment 2: October 5, 2016 Summary of Changes 
Impax Laboratories, Inc. 
Page 1 
Summary of Changes 
Study IPX203-B16-01 Amendment 2 
 
Protocol No.: 
IPX203-B16-01, Amendment 2 
Protocol Title: 
A Randomized, Multiple Dose Study to Assess the Pharmacokinetics 
and Pharmacodynamics of IPX203 in Subjects with Advanced 
Parkinson’s Disease 
Date:  
October 5, 2016 
 
The main purpose of issuing Amendment 2 for the IPX203-B16-01 protocol is 
summarized as follows: 
• Wording was added to inclusion criteria #10 for clarification purposes. 
• Wording was added to the IPX203 dose adjustment instructions in 
Section 6.4.2 for clarification and to Table 4 to accommodate subjects who 
may be taking levodopa doses in 25 mg units and subjects whose most 
frequent afternoon/evening dose of LD is 300 mg. 
• Wording deleted throughout protocol regarding a 100-mg unit dose of IR LD 
converting to approximately an approximately 360-mg unit dose of IPX203 
due to the fact that this conversion ratio applies only to the morning dose, but 
not to the afternoon/evening doses. 
• The definition of a “bedtime dose” was changed throughout the protocol. 
• Additional study design details were included in Section 6.1. 
• The wording of subject withdrawal criteria # 5 in Section 7.3 was modified. 
• Wording was added in Section 8.2.2 for clarification purposes. 
• Three staff members were changed on the Approval Signature page, and one 
staff member was changed in the Study Contact Information table. 
• The instructions for cutting pills were modified. 
• The footnote in Appendix I was deleted. 
• Minor wording changes were made in Appendix K in regards to information 
to be included on plasma sample labels. 
 
The table below provides the specific changes made to the protocol in Amendment 2.  
Bolded text indicates new text and strikethroughs indicate deletion. 
 


Protocol No. IPX203-B16-01 
CONFIDENTIAL 
Amendment 2: October 5, 2016 Summary of Changes 
Impax Laboratories, Inc. 
 
Page 2 
Section 
Protocol Amendment 1 − September 1, 2016 
Protocol Amendment 2 − October 5, 2016 
Signature Page  
Barbara Pruitt, RN, BS 
Associate Director, Clinical Operations 
Barbara Pruitt, RN, BS 
Associate Director, Clinical Operations 
Weiru Hong, MS 
Senior CRA, Clinical Operations 
Signature Page  
Daven Mody, PharmD, MBA 
Director, Regulatory Affairs 
Daven Mody, PharmD, MBA 
Director, Regulatory Affairs 
Itrat Harrold, PhD 
Senior Associate, Regulatory Affairs 
Signature Page  
Sarita Khanna, PhD 
Senior Director, Biostatistics and Data Management 
Sarita Khanna, PhD 
Senior Director, Biostatistics and Data Management 
Phillip Dinh, PhD 
Director, Statistics 
Study Contact 
Information  
Sarita Khanna, PhD 
Senior Director, Biostatistics and Data Management 
(510) 240-6425 
E-mail:  skhanna@impaxlabs.com 
Sarita Khanna, PhD 
Senior Director, Biostatistics and Data Management 
(510) 240-6425 
E-mail:  skhanna@impaxlabs.com 
Phillip Dinh, PhD 
Director, Statistics 
(510) 240-6402 
E-mail:  Phillip.Dinh@impaxlabs.com 


Protocol No. IPX203-B16-01 
CONFIDENTIAL 
Amendment 2: October 5, 2016 Summary of Changes 
Impax Laboratories, Inc. 
 
Page 3 
Section 
Protocol Amendment 1 − September 1, 2016 
Protocol Amendment 2 − October 5, 2016 
Synopsis,  
6.1 Overall 
Study Design, 
and 6.4.2 Study 
Drug Regimen 
following First 
In-Clinic Dose at 
Visits 1 and 3 
A “bedtime dose” is defined as a dose of CR CD-LD 
taken within 2 hours of the subject’s normal 
nighttime sleep period. 
A “bedtime dose” is defined as a dose of CR CD-LD 
taken within 2 1 hours of the subject’s normal nighttime 
sleep period. 
Synopsis, 
Methodology 
During the IPX203 treatment period, the initial doses 
of IPX203 will be based on the subject’s prestudy 
stable LD regimen and the initial response to IPX203.  
A 100-mg unit dose of IR LD converts approximately 
to a 360-mg unit dose of IPX203.  The typical dosing 
regimen for IPX203 will be three times a day, dosed 
approximately every 7 to 8 hours. 
During the IPX203 treatment period, the initial doses of 
IPX203 will be based on the subject’s prestudy stable LD 
regimen and the initial response to IPX203.  A 100-mg 
unit dose of IR LD converts approximately to a 360-mg 
unit dose of IPX203.  The typical dosing regimen for 
IPX203 will be three times a day, dosed approximately 
every 7 to 8 hours. 
Synopsis, 
Diagnosis and 
main criteria for 
inclusion: 
• Responsive to CD-LD therapy and currently 
being treated on a stable regimen with CD-LD for 
at least 4 weeks and: 
o requires 100 to 250 mg of IR CD-LD for the 
morning dose 
• Responsive to CD-LD therapy and currently being 
treated on a stable regimen with CD-LD for at least 
4 weeks prior to Visit 1 and: 
o requires 100 to 250 mg (in units of 50 mg) of 
IR CD-LD for the morning dose 


Protocol No. IPX203-B16-01 
CONFIDENTIAL 
Amendment 2: October 5, 2016 Summary of Changes 
Impax Laboratories, Inc. 
 
Page 4 
Section 
Protocol Amendment 1 − September 1, 2016 
Protocol Amendment 2 − October 5, 2016 
6.1 Overall 
Study Design 
On Day 1 of the IR CD-LD treatment period, subjects 
will start with a single dose of their usual prestudy 
first morning IR CD-LD dose. 
Within 2 weeks following Screening, eligible subjects 
will complete their PD and Dosing diaries, and will 
wear the Kinesia 360 sensor bands on the more 
affected side at home immediately after waking on 
each of the 3 days prior to Visit 1.  Subjects will be 
instructed to take their last dose of CD-LD no later 
than 10:00 PM on the evening prior to Visits 1 and 3.  
The first morning dose of study medication will be 
administered at the study site.  On Day 1 of the 
IR CD-LD treatment period, subjects will start with a 
single dose of their usual prestudy first morning IR CD-
LD dose. 
6.1 Overall 
Study Design 
and 6.4 Dosing 
and Dose 
Determination 
Criteria 
A 100-mg unit dose of IR LD converts approximately 
to a 360-mg unit dose of IPX203. 
A 100-mg unit dose of IR LD converts approximately to 
a 360-mg unit dose of IPX203. 
6.4 Dosing and 
Dose 
Determination 
Criteria 
IR CD-LD will be supplied as tablets containing 
100 mg of LD.  IR CD-LD tablets may be split in half 
using a pill cutter to accommodate the 150 mg and 
250 mg LD doses. 
IR CD-LD will be supplied as tablets containing 100 mg 
of LD.  IR CD-LD tablets may be split in half using a 
pill cutter to accommodate the 150 mg and 250 mg LD 
doses. 
6.4.1 Table 3 
Title 
Day 1 In-clinic Dosing — IPX203-B16-01 
Day 1 In-clinic Dosing — IPX203-B16-01First 
Morning Dose of Study Medication 


Protocol No. IPX203-B16-01 
CONFIDENTIAL 
Amendment 2: October 5, 2016 Summary of Changes 
Impax Laboratories, Inc. 
 
Page 5 
Section 
Protocol Amendment 1 − September 1, 2016 
Protocol Amendment 2 − October 5, 2016 
6.4.1 Day 1 In-
Clinic Dosing at 
Visit 1 and at 
Visit 3 
Rescue:  Subjects who need rescue during the IR CD-
LD treatment will receive a dose of IR CD-LD that 
corresponds to their typical pretreatment regimen 
based on the subject’s dosing diary.  For rescue during 
the IPX203 treatment, subject will receive a dose of 
IPX203 that the subject would typically have received 
following their morning dose (see Section 6.4.2 for 
details). 
Rescue:  Subjects who need rescue during the IR CD-
LD treatment will receive a dose of IR CD-LD that 
corresponds to their typical pretreatment regimen based 
on the subject’s dosing diary.  For rescue during the 
IPX203 treatment, subject will receive a dose of IPX203 
that the subject would typically have received following 
their morning dose is based on Table 4 in (see Section 
6.4.2 for details). 
6.4.2 Title 
Study Drug Regimen following In-Clinic Dosing 
Visits 1 and 3 
Study Drug Regimen following First In-Clinic Dose at 
ing Visits 1 and 3 


Protocol No. IPX203-B16-01 
CONFIDENTIAL 
Amendment 2: October 5, 2016 Summary of Changes 
Impax Laboratories, Inc. 
 
Page 6 
Section 
Protocol Amendment 1 − September 1, 2016 
Protocol Amendment 2 − October 5, 2016 
6.4.2 Study Drug 
Regimen 
following First 
In-Clinic Dose at 
Visits 1 and 3 
IPX203 Dose Adjustment (Days 1-9): 
Table 4 outlines the suggested initial conversion from 
a prestudy regimen of CD-LD to an IPX203 regimen. 
The morning dose of IPX203 will be based on the 
recommended dose shown in Table 3. 
To determine the IPX203 regimen of subsequent 
doses for the day, determine the most frequent 
prestudy LD dose in milligrams that the subject 
receives in the afternoon and evening and administer 
IPX203 according to Table 4.  Dose IPX203 three 
times a day, approximately every 7 to 8 hours. 
IPX203 Dose Adjustment (Days 1-9): 
Table 4 outlines the suggested initial conversion from a 
prestudy regimen of CD-LD to an IPX203 regimen.  
The suggested initial dosing of IPX203 is three times 
a day, approximately every 7 to 8 hours.   
The recommended morning dose of IPX203 is will be 
based on the recommended dose shown in Table 3. 
To determine the IPX203 regimen of subsequent doses 
for the day, determine identify the most frequent 
prestudy LD dose in milligrams that the subject receives 
in the afternoon and evening and administer IPX203 
according to Table 4.  Dose IPX203 three times a day, 
approximately every 7 to 8 hours. 
• If the subject takes different prestudy LD doses 
with equal frequency, determine the IPX203 
dose based on the highest LD dose. 
• 
When determining the most frequent prestudy 
LD dose for subsequent IPX203 doses, consider 
all prestudy LD doses taken from noon to 
bedtime.  If the subject takes a bedtime CR CD-
LD dose and the subject also takes a dose of IR 
CD-LD within one hour of the bedtime dose of 
CR CD-LD, then add the CR and IR LD doses 
together. 


Protocol No. IPX203-B16-01 
CONFIDENTIAL 
Amendment 2: October 5, 2016 Summary of Changes 
Impax Laboratories, Inc. 
 
Page 7 
Section 
Protocol Amendment 1 − September 1, 2016 
Protocol Amendment 2 − October 5, 2016 
Table 4,  
Section 6.4.2 
Study Drug 
Regimen 
following First 
In-Clinic Dose at 
Visits 1 and 3 
Most Frequent 
Afternoon and 
Evening LD Unit 
Dose (mg) 
IPX203 Regimen Post Morning Dose 
100 
270 (270 mg × 1) mg every 7 to 8 hours 
150 
450 (180 mg × 1 + 270 mg × 1) mg every 7 to 8 
hours 
200 
630 (180 mg × 2 + 270 mg x 1) mg every 7 to 8 hours 
250 
810 (270 mg × 3) mg every 7 to 8 hours 
 
Most Frequent 
Afternoon and 
Evening LD Unit 
Dose (mg) 
IPX203 Regimen Post Morning Dose 
100 - 125 
270 (270 mg × 1) mg every 7 to 8 hours 
150 - 175 
450 (180 mg × 1 + 270 mg × 1) mg every 7 to 8 hours 
200 - 225 
540 (270 mg × 2) mg every 7 to 8 hours 
250- 275 
720 (270 mg × 2 + 180 mg × 1) mg every 7 to 8 hours 
300 
810 (270 mg × 3) mg every 7 to 8 hours 
Note:  a 100-mg unit dose of IR LD converts approximately to a 270-mg 
unit dose of IPX203. 
Section 6.4.2, 
Column Headers 
for Example 
Table 
Prestudy LD Morning IR 
Dose (mg) 
Most Frequent IR LD 
Dose (mg) Afternoon 
and Evening 
 
Pre-study IR LD Morning 
IR Dose (mg) 
Most Frequent Pre-
study IR LD Dose (mg) 
Afternoon and Evening 
 
7.1 Subject 
Inclusion 
Criteria 
10. Responsive to CD-LD therapy and currently 
being treated on a stable regimen with CD-LD 
for at least 4 weeks and: 
a. 
requires 100 to 250 mg of IR CD-LD for 
the morning dose… 
10. Responsive to CD-LD therapy and currently 
being treated on a stable regimen with CD-LD for 
at least 4 weeks prior to Visit 1 and: 
a. requires 100 to 250 mg (in units of 50 mg) of 
IR CD-LD for the morning dose… 


Protocol No. IPX203-B16-01 
CONFIDENTIAL 
Amendment 2: October 5, 2016 Summary of Changes 
Impax Laboratories, Inc. 
 
Page 8 
Section 
Protocol Amendment 1 − September 1, 2016 
Protocol Amendment 2 − October 5, 2016 
7.3 Subject 
Withdrawal 
Criteria  
5. Protocol violation 
5.  Protocol violationdeviation 
8. Study 
Procedures 
footnote b 
b  Record vital signs (blood pressure, heart rate, 
temperature, respiratory rate, and temperature 
[Screening and Study Exit only]) after subject has 
been resting supine for at least 5 minutes, then 
record orthostatic blood pressure and heart rate 
after subject has been standing for approximately 
2 minutes.  During Visits 1 and 3, vital signs are 
recorded at predose, 2, 4, and 8 hours postdose.  
During Visits 2 and 4, vital signs are recorded at 
predose, 2, 4, and 10 hours postdose. 
b  Record vital signs (blood pressure, heart rate, 
temperature, respiratory rate, and temperature 
[Screening and Study Exit only]) after subject has 
been resting supine for at least 5 minutes, then record 
orthostatic blood pressure and heart rate after subject 
has been standing for approximately 2 minutes.  
During Visits 1 and 3, vital signs are recorded at 
predose, 2, 4, and 8 hours postdose.  During Visits 2 
and 4, vital signs are recorded at predose, 2, 4, and 10 
hours postdose. 
8.2.2 Prior to 
Visits 1 and 3 
• Bring the 3-day PD Diary, the 3-day Dosing 
diary and the Kinesia 360 system with them to 
the clinic. 
• Bring the 3-day PD Diary, the 3-day Dosing 
diary, and the Kinesia 360 system with them to 
the clinic (Visit 1 only). 
10.4 Study Drug 
Administration 
IR CD-LD tablets may be split in half using a pill 
cutter to accommodate the 150 mg and 250 mg LD 
doses, as appropriate. 
IR CD-LD tablets may be split in half using a pill cutter 
to accommodate the 150 mg and 250 mg LD doses, as 
appropriate. 


Protocol No. IPX203-B16-01 
CONFIDENTIAL 
Amendment 2: October 5, 2016 Summary of Changes 
Impax Laboratories, Inc. 
 
Page 9 
Section 
Protocol Amendment 1 − September 1, 2016 
Protocol Amendment 2 − October 5, 2016 
Appendix I, 
Assessment of 
Subject’s Motor 
State, footnote 
a  Confirm that subject is in the “off” state before 
starting -1 hour predose assessment 
a  Confirm that subject is in the “off” state before starting 
-1 hour predose assessment 
Appendix K 
Blood Sample 
Labeling, 
Processing, 
Storage and 
Shipment 
Sample Labeling:  The labels for all sample collection 
and storage containers will contain the subject ID, the 
subject’s initials, dosing period, collection date and 
actual time, study number, and sample number 
(sequentially per period, eg, 1-1 to 1-15 for Period 1 
and 2-1 to 2-15 for Period 2). 
Sample Labeling:  The labels for all sample collection 
and storage containers will contain the subject ID 
(include all six digits), the subject’s initials, dosing 
period, nominal time, collection date and actual time, 
study number, and sample number (sequentially per 
period, eg, 1-1 to 1-15 for Period 1 and 2-1 to 2-15 for 
Period 2). 
 

SAP_001.pdf: 
Clinical Study Report 
IPX203-B16-01 
16.1 Study Information 
Impax Laboratories, Inc. 
CONFIDENTIAL 
9.
DOCUMENTATION OF STATISTICAL METHODS
•
Statistical Analysis Plan, Version 1, 29 September 2017


IPX203–B16-01 
Statistical Analysis Plan 
 
 
 
Impax Laboratories, Inc 
CONFIDENTIAL 
Page 1 of 43 
 
STATISTICAL ANALYSIS PLAN 
 
 
Study Title: 
A RANDOMIZED, MULTIPLE DOSE STUDY TO 
ASSESS THE PHARMACOKINETICS AND 
PHARMACODYNAMICS OF IPX203 IN SUBJECTS 
WITH ADVANCED PARKINSON’S DISEASE 
 
Name of Test Drug: 
IPX203 
 
Protocol Number: 
IPX203-B16-01 
 
Protocol Version (Date): 
Original, 08Aug16 
Amendment 1, 01Sep16 
Amendment 2, 05Oct16 
 
Analysis Type: 
Final 
 
Analysis Plan Version: 
Version 1 
 
Analysis Plan Date: 
29Sep17  
 
Analysis Plan Author: 
Phillip Dinh, PhD 
 
 
 
SPONSOR 
Impax Laboratories, Inc., 
acting through its Impax Specialty Pharma division (Impax) 
30831 Huntwood Ave. 
Hayward, CA 94544 
 
CONFIDENTIAL AND PROPRIETARY INFORMATION 


IPX203–B16-01 
Statistical Analysis Plan 
 
 
 
Impax Laboratories, Inc 
CONFIDENTIAL 
Page 2 of 43 
SIGNATURE PAGE 
 


IPX203–B16-01 
Statistical Analysis Plan 
 
 
 
Impax Laboratories, Inc 
CONFIDENTIAL 
Page 3 of 43 
TABLE OF CONTENTS 
1. 
INTRODUCTION ......................................................................................................11 
1.1. 
Study Objectives .........................................................................................................11 
1.2. 
Sample Size and Power ..............................................................................................13 
2. 
GENERAL CONSIDERATIONS FOR DATA ANALYSIS ....................................14 
2.1. 
Analysis Sets ...............................................................................................................14 
2.1.1. 
Screened Analysis Set .................................................................................................14 
2.1.2. 
Screened but Not Treated Analysis Set ......................................................................14 
2.1.3. 
Randomized Analysis Set ...........................................................................................14 
2.1.4. 
Completers Analysis Set .............................................................................................14 
2.1.5. 
Diary Completers Analysis Set ...................................................................................14 
2.1.6. 
Pharmacodynamic Completers Analysis Set ..............................................................14 
2.1.7. 
Kinesia 360 Completers Analysis Set.........................................................................15 
2.1.8. 
Pharmacokinetic (PK) Completers Analysis Set ........................................................15 
2.2. 
Randomization and Description of Study Drug ..........................................................15 
2.3. 
Examination of Subject Subgroups ............................................................................15 
2.4. 
Missing Data and Outliers ..........................................................................................15 
2.4.1. 
Missing Data ...............................................................................................................15 
2.4.1.1. 
Imputation Method for PD Diary Data .......................................................................15 
2.4.1.2. 
Imputation Method for Assessment of Subject’s Motor State ....................................16 
2.4.1.3. 
Imputation Method for the Movement Disorder Society Version of the 
Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) .......................................17 
2.4.1.4. 
Imputation Method for Missing Vitals and Electrocardiogram (ECG) ......................18 
2.4.2. 
Outliers .......................................................................................................................18 
2.5. 
Data Handling Conventions and Transformations .....................................................18 
2.6. 
Definitions of Baseline and Study Day ......................................................................18 
2.6.1. 
Definition of Baseline .................................................................................................18 
2.6.2. 
Definition of Study Day ..............................................................................................18 
3. 
SUBJECT DISPOSITION ..........................................................................................20 
3.1. 
Subject Enrollment and Disposition ...........................................................................20 
3.2. 
Extent of Prestudy Drug Exposure and Study Drug Exposure ...................................20 
3.2.1. 
Prestudy Levodopa Dosing .........................................................................................20 


IPX203–B16-01 
Statistical Analysis Plan 
 
 
 
Impax Laboratories, Inc 
CONFIDENTIAL 
Page 4 of 43 
3.2.2. 
Study Drug Exposure ..................................................................................................20 
3.2.2.1. 
Study Drug Exposure at Study Site ............................................................................20 
3.2.2.2. 
Study Drug Dosing Diary ...........................................................................................21 
3.2.2.3. 
Dosing Adjustment .....................................................................................................21 
3.3. 
Protocol Deviations ....................................................................................................22 
4. 
BASELINE CHARACTERISTICS ............................................................................23 
4.1. 
Demographics .............................................................................................................23 
4.2. 
Other Baseline Characteristics ....................................................................................23 
4.3. 
Parkinson’s Disease Characteristics and Measures ....................................................23 
4.4. 
Medical History and Physical Findings ......................................................................24 
5. 
EFFICACY AND PHARMACODYNAMIC ANALYSES .......................................25 
5.1. 
Primary Endpoint ........................................................................................................25 
5.2. 
Secondary Endpoints ..................................................................................................25 
5.2.1. 
Secondary Endpoints Based on PD Diaries ................................................................25 
5.2.1.1. 
Average “Off” Time ...................................................................................................25 
5.2.1.2. 
Average “On” Time with No Troublesome Dyskinesia (“Good On”) .......................25 
5.2.1.3. 
Average “On” Time without Dyskinesia ....................................................................26 
5.2.1.4. 
Average “On” Time with Nontroublesome Dyskinesia .............................................26 
5.2.1.5. 
Average “On” Time with Troublesome Dyskinesia ...................................................26 
5.2.1.6. 
Average Asleep Time .................................................................................................26 
5.2.1.7. 
Average “Off” Time Normalized for 16 Waking Hours ............................................27 
5.2.1.8. 
Average Total “Good On” Time Normalized for 16 Waking Hours ..........................27 
5.2.1.9. 
Proportion of Subjects with a Reduction in “Off” Time of at Least 0.5, 1, 
1.5, 2, 3, and 4 Hours ..................................................................................................27 
5.2.1.10. 
“On” and “Off” State in First 30 Minutes upon Awakening from Nocturnal 
Sleep ...........................................................................................................................27 
5.2.1.11. 
Clinical Fluctuations ...................................................................................................27 
5.2.1.12. 
Duration of “Good On” ..............................................................................................28 
5.2.2. 
Secondary Endpoints Based on the Assessment of Subject Motor State ...................28 
5.2.2.1. 
“Off” Time ..................................................................................................................28 
5.2.2.2. 
“Good On” Time .........................................................................................................29 
5.2.2.3. 
“On” Time without Dyskinesia ..................................................................................29 
5.2.2.4. 
“On” Time with Nontroublesome Dyskinesia ............................................................29 


IPX203–B16-01 
Statistical Analysis Plan 
 
 
 
Impax Laboratories, Inc 
CONFIDENTIAL 
Page 5 of 43 
5.2.2.5. 
“On” Time with Troublesome Dyskinesia .................................................................29 
5.2.2.6. 
“Asleep” Time ............................................................................................................30 
5.2.2.7. 
Time from First Dose to First Morning “On” and “Good On” State after 
Dosing on Day 1 and Day 15 ......................................................................................30 
5.2.3. 
Secondary Endpoints Based on MDS-UPDRS...........................................................30 
5.2.3.1. 
Predose MDS-UPDRS ................................................................................................30 
5.2.3.2. 
MDS-UPDRS Part III .................................................................................................30 
5.2.3.3. 
Mean Change in MDS-UPDRS Part III ......................................................................31 
5.2.3.4. 
Duration of Effect of at Least 4, 7, and 13 Units Improvement from Day 1 
Predose MDS-UPDRS Part III ...................................................................................31 
5.2.3.5. 
Proportions of Subjects with at Least 4, 7, and 13 Units Improvement from 
Day 1 Predose MDS-UPDRS Part III Over Time ......................................................31 
5.2.3.6. 
MDS-UPDRS Part III, Sum of Questions 4 through 8 and 14 ...................................32 
5.2.3.7. 
MDS-UPDRS Part IV .................................................................................................32 
5.2.4. 
Secondary Endpoints Based on Kinesia 360 ..............................................................32 
5.2.4.1. 
Tremor ........................................................................................................................32 
5.2.4.2. 
Dyskinesia ...................................................................................................................32 
5.2.4.3. 
Mobility ......................................................................................................................33 
5.3. 
Changes From Protocol-Specified Efficacy Analyses ................................................33 
6. 
SAFETY ANALYSES ...............................................................................................34 
6.1. 
Adverse Events and Deaths ........................................................................................34 
6.1.1. 
Adverse Event Dictionary ...........................................................................................34 
6.1.2. 
Adverse Event Severity ..............................................................................................34 
6.1.3. 
Relationship of Adverse Events to Study Drug ..........................................................34 
6.1.4. 
Serious Adverse Events ..............................................................................................34 
6.1.5. 
Treatment-emergent Adverse Events .........................................................................34 
6.1.6. 
Summaries of Adverse Events and Deaths .................................................................34 
6.1.7. 
Additional Analysis of Adverse Events ......................................................................35 
6.2. 
Laboratory Evaluations ...............................................................................................35 
6.2.1. 
Summaries of Numeric Laboratory Results ...............................................................35 
6.2.2. 
Shifts Relative to the Baseline Value .........................................................................35 
6.2.3. 
Other Laboratory Results ............................................................................................35 
6.3. 
Vital Signs ..................................................................................................................35 


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6.4. 
Concomitant Medications ...........................................................................................36 
6.5. 
Electrocardiogram Results ..........................................................................................36 
6.5.1. 
Investigator Electrocardiogram Assessment ...............................................................36 
6.5.2. 
Corrected QT Intervals ...............................................................................................37 
6.6. 
Other Safety Measures ................................................................................................38 
6.7. 
Changes From Protocol-Specified Safety Analyses ...................................................38 
7. 
PHARMACOKINETIC ANALYSES ........................................................................39 
7.1. 
PK Sample Collection .................................................................................................39 
7.2. 
PK Analyses ................................................................................................................39 
7.2.1. 
Pharmacokinetic Parameters .......................................................................................39 
7.2.2. 
Statistical Analysis Methods.......................................................................................40 
7.3. 
Changes from Protocol-Specified PK Analyses .........................................................40 
8. 
SOFTWARE ...............................................................................................................42 
9. 
REFERENCES ...........................................................................................................43 
 
LIST OF TABLES 
Table 1: 
Day 1 In-clinic Dosing — First Morning Dose of Study Medication ........................13 
Table 2: 
Initial IPX203 LD Dosing Regimen Subsequent to IPX203 Morning Dose 
Based on Prestudy Regimen of LD ............................................................................13 
Table 3: 
Randomization Schedule for IPX203-B16-01 ............................................................15 
Table 4: 
Pharmacokinetic Parameters for Each Analyte ..........................................................39 
 
LIST OF FIGURES 
Figure 1: 
Study Flow Chart ........................................................................................................12 
 


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LIST OF ABBREVIATIONS 
AE 
adverse event 
ANCOVA 
analysis of covariance 
ANOVA 
analysis of variance 
BLOCF 
baseline observation carried forward 
BLQ 
below the limit of quantification 
BMI 
body mass index 
CD 
carbidopa 
CLE 
carbidopa/levodopa/entacapone 
CR 
controlled release 
CRF 
case report form 
CSR 
clinical study report 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CV 
coefficient of variation 
ECG 
electrocardiogram 
ER 
extended release 
IR 
immediate release 
IWRS 
interactive web response system 
LD 
levodopa 
LOCF 
last observation carried forward 
LOQ 
lower limit of quantification 
MAO 
monoamine oxidase 
MDS-UPDRS 
Movement Disorder Society version of the Unified Parkinson’s Disease 
Rating Scale 
MedDRA 
Medical Dictionary for Regulatory Activities 
MoCA 
Montreal Cognitive Assessment 
PD 
Parkinson’s disease 
PK 
pharmacokinetic(s) 
QTc 
corrected QT 


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QTcF 
Fridericia’s corrected QT 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
TEAE 
treatment-emergent adverse event 
TLFs 
tables, listings, figures 
 
 


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PHARMACOKINETIC TERMS AND DEFINITIONS 
Accumulation ratio 
parameter used to quantify the extent to which a compound accumulates after 
repeated dosing relative to the first dose, defined as the ratio of AUC over a 
dosing interval at steady state divided by AUC over the same interval 
following a single dose, calculated as (AUCtau(Day 15)/AUCtau(Day 1)). 
AUC 
area under the curve 
AUCs-t or AUC(s-t) 
area under the curve from time s to time t, denote partial AUC values 
AUCinf or AUC0-∞ 
area under the plasma concentration-time curve from time 0 to time infinity 
for one treatment dose 
AUClast 
area under the plasma concentration-time curve up to the last measurable 
concentration 
AUC%ext 
area under the plasma concentration-time curve extrapolated from time t to 
infinity as a percentage of AUC0-inf 
AUCtau 
area under the plasma concentration-time curve over a dosing interval 
BA 
bioavailability [defined as (AUCinf/dose) of test treatment/(AUCinf/dose of 
reference treatment)] 
Cavg 
average observed plasma concentration (calculated on Day 15 of treatment as 
AUC0-10/10) 
Cmax 
maximum observed plasma concentration 
Cmin 
minimum observed plasma concentration 
Ctau 
observed plasma concentration at time tau following first dose on a treatment 
day at the nearest sampling time prior to the subsequent (2nd) dose 
Dur(>50%Cmax) 
duration of plasma concentrations above 50% of Cmax value 
Fluctuation index 
peak-trough fluctuation, calculated as 
[(Cmax(Day15)-Cmin(Day15) ) /Cavg(Day15)] 
k 
apparent elimination rate constant (denoted by λz in the protocol) 
T(430ng/mL) 
time to reach a concentration of 430 ng/mL 
T(50%Cmax) 
time to reach a concentration of 50% of Cmax 
T(1000ng/mL) 
time to reach a concentration of 1000 ng/mL 
Tau 
dosing interval (defined as the interval between first and second doses on a 
treatment day (Day 15)) 
 
 
 
 


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Time invariance ratio 
parameter used to assess if the pharmacokinetics vary over time during 
repeated dosing, quantifies how the concentration-time profile at steady state 
compares to the profile on Day 1, calculated as AUCtau(Day 15) / AUCinf(Day 
1) 
Tmax 
time to maximum observed plasma concentration 
t1/2 
apparent elimination half-life 
 


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1. 
INTRODUCTION 
This statistical analysis plan (SAP) describes the statistical analysis methods and data 
presentations to be used in tables, listings, and figures (TLFs) in the clinical study report (CSR) 
for Study IPX203-B16-01.  This SAP is based on the study protocol amendment 2 dated 
05OCT16.  The SAP will be finalized before database finalization. Any changes made after the 
finalization of the SAP will be documented in the CSR. 
1.1. 
Study Objectives 
This is a randomized, open-label, rater-blinded, multicenter, 2-treatment, 2-period, multiple-dose 
crossover study.  Approximately 30 advanced Parkinson’s disease (PD) subjects will be 
randomized to 1 of 2 dosing sequences.  The study duration will be approximately 8 weeks, 
including the screening period. 
As shown in Figure 1, this study will consist of 4 study visits after Screening:  Day 1 of each 
treatment period (Visits 1 and 3), and Day 15 of each treatment period (Visits 2 and 4).  Study 
Exit procedures are done at the end of Visit 4 or within 3 days of Visit 4, or during an early 
withdrawal.  Between treatment periods, subjects will return to their prestudy PD medication 
regimen during the 1-week (± 2 days) washout period.  Subjects may continue to take allowed 
non-carbidopa (CD)-levodopa (LD) based PD medications throughout the study if documented 
in their prestudy regimen and if dosing regimens have been stable for at least 4 weeks prior to 
Visit 1. 
Within 2 weeks following Screening, on each of the 3 days prior to Visit 1, eligible subjects will 
complete their PD and Dosing diaries, and will wear the Kinesia 360 sensor bands on the more 
affected side at home immediately after waking.  Subjects will be instructed to take their last 
dose of CD-LD no later than 10:00 PM on the evening prior to Visits 1 and 3.  The first morning 
dose of study medication will be administered at the study site.  On Day 1 of the immediate 
release (IR) CD-LD treatment period, subjects will start with a single dose of their usual prestudy 
first morning IR CD-LD dose.  On Day 1 of the IPX203 treatment period, subjects will start with 
a single dose of IPX203 based on their usual prestudy first morning IR CD-LD dose according to 
the guidance provided in Table 1.  During each treatment period subjects will dose for 15 days 
with study medication.  During the IR CD-LD treatment period, the initial dosing regimen of 
IR CD-LD will be the same as the subject’s stable prestudy regimen unless they were taking a 
single daily bedtime dose of controlled release (CR) CD-LD, either alone or in combination with 
IR CD-LD, in which case, the CR CD-LD dose will be discontinued and substituted with a 1:1 
milligram-equivalent IR CD-LD dose.  A “bedtime dose” is defined as a dose of CR CD-LD 
taken within 1 hour of the subject’s normal nighttime sleep period.  During the IPX203 treatment 
period, subjects are assigned their initial IPX203 dosing regimen according to the guidance 
provided in Table 1 and Table 2.  This regimen is based on each individual’s prestudy IR CD-LD 
morning dose and daily dosing regimen.  The typical dosing regimen for IPX203 will be three 
times a day, dosed approximately every 7 to 8 hours.  Some subjects may require more or less 
frequent dosing to optimize therapeutic effect (minimize “Off” time without causing troublesome 
dyskinesia or other dopaminergic side effects).  Nighttime dosing of study medication is allowed 
as needed with the exception of the evening prior to Day 15 (withhold dosing for at least 5 hours 
before arriving at the site) of each treatment period.  Subjects may continue to take allowed non-


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CD-LD based PD medications throughout the study if documented in their prestudy regimen and 
if dosing regimens have been stable for at least 4 weeks prior to Visit 1. 
During Days 1 through 9 of both treatment periods, investigators may adjust each subject’s study 
medication regimen if necessary to optimize efficacy and safety. 
Pharmacokinetic and pharmacodynamic measures are assessed in the clinic for up to 8 hours 
postdose on Day 1 of each treatment period (Visits 1 and 3), and for up to 10 hours on Day 15 of 
each treatment period (Visits 2 and 4).  Additionally, on each of the 3 days prior to Visits 1, 2, 
and 4, subjects will complete the PD and Dosing diaries, and use the Kinesia 360 sensor bands 
on the ankle and wrist of their more affected side immediately after waking. 
Figure 1: 
Study Flow Chart 
 
 


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Table 1: 
Day 1 In-clinic Dosing — First Morning Dose of Study Medication 
Prestudy Morning 
IR  LD Dose (mg) 
IR CD-LD 
LD (mg) 
(100 mg Tablets) 
IPX203 
LD (mg) 
(180 mg and 270 mg Capsules) 
100 
100 (1 tablet) 
360 (180 mg × 2 capsules) 
150 
150 (1.5 tablets) 
540 (270 mg × 2 capsules) 
200 
200 (2 tablets) 
720 (270 mg × 2 capsules plus 180 mg 
× 1 capsule) 
250 
250 (2.5 tablets) 
900 (270 mg × 2 capsules plus 180 mg 
× 2 capsules) 
 
Table 2: 
Initial IPX203 LD Dosing Regimen Subsequent to IPX203 Morning Dose 
Based on Prestudy Regimen of LD 
Most Frequent Afternoon and 
Evening LD Unit Dose (mg) 
IPX203 Regimen Post Morning Dose 
100 - 125 
270 (270 mg × 1) mg every 7 to 8 hours 
150 - 175 
450 (180 mg × 1 + 270 mg × 1) mg every 7 to 8 hours 
200 - 225 
540 (270 mg × 2) mg every 7 to 8 hours 
250- 275 
720 (270 mg × 2 + 180 mg × 1) mg every 7 to 8 hours 
300 
810 (270 mg × 3) mg every 7 to 8 hours 
 
1.2. 
Sample Size and Power 
Assuming a difference of 1.75 hours between the treatments in “Off” time and the standard 
deviation of the treatment differences to be 3 hours, this 2-way crossover design will have 80% 
power to detect a difference between IPX203 and IR CD-LD with at least 26 subjects completing 
the study (level of significance = 0.05). 
To allow for a dropout rate of approximately 15%, at least 30 subjects will be randomized to 
ensure at least 26 completers. 


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2. 
GENERAL CONSIDERATIONS FOR DATA ANALYSIS 
The database will be locked and final analysis of the data will be performed after all subjects 
have completed the study, outstanding data queries have been resolved or adjudicated as 
unresolvable, and the data have been cleaned and finalized. 
Analysis results will be presented using descriptive statistics. For categorical variables, the 
number and percentage of subjects in each category will be presented; for continuous variables, 
descriptive statistics (the number of subjects [n], mean, standard deviation [SD], median, 
minimum, and maximum) will be presented. 
All statistical tests will be 2-sided and performed at the 5% significance level, without 
multiplicity adjustment. 
2.1. 
Analysis Sets 
Analysis sets define the subjects to be included in an analysis. Analysis sets and their definitions 
are provided in this section. The analysis set will be identified and included as a subtitle of each 
table, listing, and figure. 
2.1.1. 
Screened Analysis Set 
The screened analysis set (Screened) includes all subjects who were screened for the study. 
2.1.2. 
Screened but Not Treated Analysis Set 
The screened but not treated analysis set includes all subjects who were screened for the study 
but were not dosed with a study drug. 
2.1.3. 
Randomized Analysis Set 
The randomized analysis set (Randomized) includes all subjects who were randomized into the 
study and received at least one dose of study drug. 
2.1.4. 
Completers Analysis Set 
The completers analysis set (Completers) includes all subjects who completed both treatment 
periods of the study and were indicated as “Completed” on the case report form (CRF) study 
disposition form. 
2.1.5. 
Diary Completers Analysis Set 
The diary completer analysis set (PD Diary Completers) includes all subjects who received both 
treatments and had 1 day of evaluable PD diary at Visits 1, 2, and 4.  An evaluable PD diary day 
will have no more than 4 half-hour entries missing. 
2.1.6. 
Pharmacodynamic Completers Analysis Set 
The pharmacodynamic completer analysis set (Pharmacodynamic completers) includes all 
subjects who received both treatments and had at least 1 predose and 4 postdose motor state 
assessments at each visit. 


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2.1.7. 
Kinesia 360 Completers Analysis Set 
The Kinesia 360 completer analysis set (Kinesia completers) includes all subjects who received 
both treatments and had 1 day of evaluable Kinesia data at Visits 1, 2, and 4.  Evaluable Kinesia 
data is defined as having at least 2 hours of Kinesia data for the particular day. 
2.1.8. 
Pharmacokinetic (PK) Completers Analysis Set 
The PK completers analysis set (PK Completers) includes all subjects for whom at least one PK 
parameter (AUClast or Cmax) was calculable on Days 1 and 15 for both treatments. 
2.2. 
Randomization and Description of Study Drug 
Subjects are randomly assigned to one of the two treatment sequences via the interactive web 
response system (IWRS) in a 1:1 ratio.  The two treatment sequences are as follows 
Table 3: 
Randomization Schedule for IPX203-B16-01 
 
Treatment Period 1 
Treatment Period 2 
Sequence 1 
IPX203 
IR CD-LD 
Sequence 2 
IR CD-LD 
IPX203 
 
2.3. 
Examination of Subject Subgroups 
There are no prespecified subject subgroupings for efficacy and safety analyses.  PK endpoints 
are evaluated overall and by dose levels. 
2.4. 
Missing Data and Outliers 
2.4.1. 
Missing Data 
In general, missing data will not be imputed unless methods for handling missing data are 
specified below. 
2.4.1.1. 
Imputation Method for PD Diary Data 
When more than one status is checked at a particular time point in the PD Diary or the 
Assessment of Subject’s Motor State, the worse result is selected as the final reported outcome.  
The selection order is defined below: 
1. Off 
2. On with Troublesome Dyskinesia 
3. Asleep 
4. On with Nontroublesome Dyskinesia 
5. On without Dyskinesia 


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Imputation of missing data for subject PD diaries will be required if the PD diary is incomplete 
over a 24-hour period (from 6:00 am to 6:00 am the next day).  In this case, the method of 
imputation depends on the amount and pattern of missing data: 
• If more than four half-hour time intervals are missing, then that particular day will not 
be included in the analysis. 
• If a half-hour time interval is missing and the observations on either side of the time 
interval are not missing, then the missing time interval will be imputed by assigning a 
value of the previous measurement for the first 15 minutes and the value of the next 
measurement for the second 15 minutes. 
• If two or more consecutive half-hour time intervals are missing, not to exceed a total 
of four, and these time intervals are available from other days of the visit, then the 
following rules will be applied: 
− For missing values on Day -3, data from Day -2 will be used for imputation for 
the same time intervals.  If Day -2 data is also incomplete then Day -1 data will be 
used. 
− For missing values on Day -2, data from Day -1 will be used for imputation if 
available; otherwise Day -3 data will be used. 
− For missing values on Day -1, data from Day -2 will be used for imputation if 
available; otherwise Day -3 data will be used for imputation. 
− If data at the same time period is missing across all days, the individual missing 
half-hour intervals will be split into two periods, with the first half-interval being 
imputed with data from the immediate previous nonmissing time period and the 
second half-interval being imputed with the next nonmissing time interval. 
2.4.1.2. 
Imputation Method for Assessment of Subject’s Motor State 
Imputation of missing data for Assessment of Subject’s Motor State is affected by whether or not 
subjects receive rescue medication on Day 1 and whether or not the missingness is monotone.  
The imputation rules are as follows: 
• Prior to or equal to time of rescue medication:  
− If surrounding values exist and are prior to rescue time, the missing results are 
assigned half the missing time to the previous value and half the missing time to 
the next value. 
− If the next result occurs after rescue or if next result is not available, then assign 
the entire missing time to the previous value (a.k.a “last observation carried 
forward” (LOCF)).  For example, if a subject has 
o assessment at hour 4, 
o missing assessment at hour 4.5, 
o rescue at hour 4.75, 
o assessment at hour 5. 


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In this case, the assessment at hour 4 will be carried forward to the hour 4.5. 
• Following rescue medication:  Missing results after rescue are assigned “Off.”  Actual 
values after rescue are not used in analysis.  Instead, values are assigned the “Off” 
status. 
For Day 15, all assessments, regardless of whether they were done before or after redose, will be 
used in analyses.  If there is a missing assessment, half of the missing time will be assigned to 
the previous value and half of the missing time will be assigned to next value.  If next value does 
not exist, then assign the entire missing time to the previous value (LOCF). 
2.4.1.3. 
Imputation Method for the Movement Disorder Society Version of the Unified 
Parkinson’s Disease Rating Scale (MDS-UPDRS) 
• Imputation of missing individual questions: 
For each assessment time point, if results are missing for a particular part of the 
MDS-UPDRS questionnaire, the missing items are assigned the average value of the 
other items in that part.  The numbers of missing items allowed for imputation are as 
follows (Goetz 2015). 
− For Part I (13 questions), up to 1 result is imputed, 
− For Part II (13 questions), up to 2 results are imputed, 
− For Part III (33 questions), up to 7 results are imputed, 
− For Part IV (6 questions), no imputation is done. 
If the number of missing items in each part is more than the above, the entire 
assessment for that part will be excluded from the analysis. 
• Results included in predose average calculations: 
Predose average values are the mean of the results at time points -1, -0.5, and 0 hours. 
• Imputation of results for particular time points for Day 1: 
− Prior to or equal to time of rescue medication: 
o If actual results exist before and after the missing time point, calculate the 
average of the results at time points just prior and immediately after the 
missing value.  Assign the missing value to that average. 
o If actual results only exist prior to the missing time point then assign the 
missing value to the last actual result available (LOCF). 
− Following rescue medication: 
o Missing values at time points following rescue medication were assigned the 
predose average value.  Actual values observed at time points following 
rescue medication are not used in analysis.  Instead, values are assigned the 
predose average value and are used in analysis. 
• Imputation method prior to or equal to time of rescue medication for Day 1 also 
applies to all time points for Day 15. 


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• Postdose averages are the mean of the results from hour 1 to hour 8 for Day 1 and 
hour 1 to hour 10 for Day 15.  Postdose average for Day 1 includes actual results 
prior to or equal to rescue time, imputed results prior to or equal to rescue time when 
actual results are missing, and imputed results following rescue. 
2.4.1.4. 
Imputation Method for Missing Vitals and Electrocardiogram (ECG) 
• If Vitals and ECG measurements expected at End of Study are missing, they will be 
imputed using the last actual postdose result available. 
2.4.2. 
Outliers 
All data will be included in the data analysis.  No sensitivity analysis will be conducted with 
respect to any potential outliers. 
2.5. 
Data Handling Conventions and Transformations 
Selected by-subject listings will be presented for all subjects in the Randomized analysis set and 
Screened but Not Treated analysis set and sorted by subject ID number, treatment period, and 
study day (if applicable). Data collected on log forms, such as AEs, will be presented in 
chronological order by preferred terms (for AEs) or medication verbatim (for concomitant 
medications) within subject. 
Concentrations of LD and CD at predose that are below the limit of quantification (BLQ) will be 
listed as BLQ of the respective analyte.  For analyses at predose, BLQ values are set to zero.  For 
analyses at postdose, they are considered as missing.  Any predose or postdose concentrations 
that were deemed “Not Reportable” by the Analytical Lab are excluded from the PK analysis.  
Plasma concentrations after rescue medication for Day 1 will not be included in the calculation 
of Day 1 PK parameters.  
 
2.6. 
Definitions of Baseline and Study Day 
2.6.1. 
Definition of Baseline 
For diary data and Kinesia360 data, baseline is defined as the average of 3 diary/kinesia days 
before Visit 1. 
For pharmacodynamics data and safety, baseline is defined as the last value before dosing. 
For certain MDS-UPDRS analyses, predose values will also be used for assessing of change.  
Predose value is defined as the average of the results at time points -1 hour, -0.5 hours, and 
Predose (0 hour). 
2.6.2. 
Definition of Study Day 
Study day will be calculated from the first dosing date of study drug and derived as follows: 
• For postdose study days: Assessment Date – First Dosing Date + 1 
• For days prior to the first dose: Assessment Date – First Dosing Date 


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Therefore, study day 1 is the day of first dose of study drug administration. 


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3. 
SUBJECT DISPOSITION 
3.1. 
Subject Enrollment and Disposition 
A summary of subject enrollment will be provided for each investigator for the screened, 
randomized, completed, and early terminated subjects. 
A summary of subject disposition will be provided by treatment group and period.  This 
summary will present the number of subjects who received treatment, discontinued treatment and 
the reasons for early discontinuation.  The summary will be based on the randomized analysis 
set. 
3.2. 
Extent of Prestudy Drug Exposure and Study Drug Exposure 
3.2.1. 
Prestudy Levodopa Dosing 
Duration of prestudy levodopa dosing will be summarized for the Screened, Randomized, 
Completers, and Early Terminated subjects.  Frequencies (< 3, 3 to < 6, 6 to < 9, 9 to < 12, ≥ 12 
years) and descriptive statistics will be presented. 
Total daily dose of prestudy levodopa will be summarized for the Screened, Randomized, 
Completers, and Early Terminated subjects.  Frequencies of IR CD-LD, CR CD-LD, and total 
LD (< 400, 400 to < 800, 800 to < 1200, 1200 to < 1600, and ≥ 1600 mg) and descriptive 
statistics will be presented. 
Frequencies and durations of current IR CD-LD, CR CD-LD dosing, and the first morning 
IR CD-LD dose prestudy will also be summarized for the Screened, Randomized, Completers, 
and Early Terminated subjects. 
3.2.2. 
Study Drug Exposure 
3.2.2.1. 
Study Drug Exposure at Study Site 
The distribution of levodopa dose administered at the study site on Day 1 and Day 15 will be 
summarized by dose (Dose 1, 2, 3, and 4) between the two treatment groups using descriptive 
statistics (N, mean, SD, median, min, max).  Categorical summaries (<= 100 mg, 101 to 150 mg, 
151 to 200 mg, 201 to 400 mg, 401 to 600 mg, 601 to 800 mg, > 800 mg) will also be tabulated 
by dose for Day 1 and Day 15. 
The distribution of time to rescue (Day 1) will be provided along with categories: < 2 hours, 2 to 
< 4 hours, 4 to < 6 hours, 6 to < 8 hours, and ≥ 8 hours.  The proportion of subjects who required 
rescue between the two treatment groups will also be summarized. 
A Cox regression model adjusting for period, sequence, and treatment will be used to compare 
the time to rescue between treatment groups.  In this analysis, if a subject does not need rescue, 
the subject will be censored at the last observation of MDS-UPDRS, vital signs, and PK samples 
for the particular visit. 
Likewise, the distribution of time to redose (Day 15) will be provided along with categories: < 2 
hours, 2 to < 4 hours, 4 to < 6 hours, 6 to < 8 hours, and ≥ 8 hours.  The proportion of subjects 
who required redose between the two treatment groups will also be summarized. 


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A Cox regression model adjusting for period, sequence, and treatment will be used to compare 
the time to redose between treatment groups.  In this analysis, if a subject does not need redose, 
the subject will be censored at the last observation of MDS-UPDRS, vital signs, and PK samples 
for the particular visit. 
In the analyses of time to rescue (Day 1) and time to redose (Day 15), if an in-clinic dose is taken 
beyond the last assessment (8 hours for Visit 1 and 10 hours for Visit 2), then this in-clinic dose 
is not considered a rescue dose (Day 1) or redose (Day 15). 
3.2.2.2. 
Study Drug Dosing Diary 
The actual first morning dose at stable dosing versus the recommended first morning dose will 
be cross-tabulated for IPX203.  The recommended first morning dose is based on Table 1. 
The actual stable dosing regimen versus the recommended dosing regimen will also be cross-
tabulated for IPX203.  The recommended dosing regimen is based on Table 1 and Table 2.  The 
amount of adjustment (in mg) will also be summarized for each dose comparing the actual dose 
versus the recommended dose for IPX203. 
The actual dosing is based on the 3-day dosing diary before Day 15 visit of each treatment period 
where the subjects are expected to be on stable dosing.  If there is a deviation from the stable 
dosing over the 3-day before Day 15 visit, the mode of the three days will be used. 
The distribution and summary of levodopa dosing frequency based on the dosing diary will be 
provided.  The number and percentage of subjects with 2, 3, 4, 5, 6, and > 6 doses/day will be 
tabulated for each treatment group.  The average number of doses/day will be compared between 
the two treatment groups using a mixed effect ANOVA model with treatment, period, and 
sequence as fixed effects and subject-within-sequence as a random effect.  The degrees of 
freedom for the denominator will be estimated using the Kenward-Roger method.  The “AR(1)” 
within subject covariance structure will be employed.  If convergence is an issue, a “Variance 
Components” covariance structure will be employed. 
Average daytime dosing interval and nighttime dosing interval will be summarized based on the 
dosing diary and compared between the two treatment groups using a mixed effect ANOVA 
model with treatment, period, and sequence as fixed effects and subject-within-sequence as a 
random effect.  The degrees of freedom for the denominator will be estimated using the 
Kenward-Roger method.  The “AR(1)” within subject covariance structure will be employed.  If 
convergence is an issue, a “Variance Components” covariance structure will be employed.  The 
dosing interval between Dose 1 and Dose 2 will also be compared in a similar manner.  For other 
dosing intervals (between Dose 2 and Dose 3, Dose 3 and Dose 4, etc.), only descriptive 
summaries will be provided. 
The final total daily LD dose for IPX203 and IR CD-LD and the ratio of LD of 
IPX203/IR CD-LD will be summarized descriptively. 
3.2.2.3. 
Dosing Adjustment 
The number of titration steps to stable dosing will be summarized descriptively as well as 
categorically (0, 1 to 2, 3 to 4, 5 to 6, and > 6 steps). 


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The number of days to stable dosing will be summarized descriptively as well as categorically (0, 
1 to 2 days, 3 to 4 days, 5 to 6 days, 7 to 9 days, and > 9 days). 
3.3. 
Protocol Deviations 
Protocol deviations, such as subjects who did not meet eligibility criteria at study entry and those 
occurring after subjects entered the study, are documented during routine monitoring.  Details of 
protocol deviations for each study site will be provided by the Clinical Operations Group to the 
Statistics and Data Management Group prior to database finalization.  These protocol deviations 
will be listed. 


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4. 
BASELINE CHARACTERISTICS 
4.1. 
Demographics 
Subject demographic variables (age, sex, race, and ethnicity) will be summarized for the 
Screened, Randomized, Completers, and Early Terminated subjects using descriptive statistics. 
Age at baseline is calculated in years at screening date. 
A by-subject demographic listing, including the prestudy treatment LD dose in mg (first morning 
dose, most frequent afternoon/evening dose, and total daily dose), will be provided by subject ID 
number in ascending order. 
4.2. 
Other Baseline Characteristics 
Other baseline characteristics include body weight (in kg), height (in cm), and body mass index 
(BMI; in kg/m2). These baseline characteristics will be summarized for the Screened, 
Randomized, Completers, and Early Terminated subjects using descriptive statistics for both 
continuous and categorical variables. 
A by-subject listing of other baseline characteristics will be provided by subject ID number in 
ascending order, along with the demographic information. 
4.3. 
Parkinson’s Disease Characteristics and Measures 
PD characteristics and measures will be summarized for Screened, Randomized, Completers, and 
Early Terminated subjects. 
Age at onset of PD diagnosis will be summarized using continuous descriptive statistics (N, 
mean, SD, median, min, max) as well as frequencies and percentages of subjects with onset age 
between < 55, 55 to < 65, 65 to < 75, and ≥ 75 years. 
Duration of PD will be summarized using continuous descriptive statistics (N, mean, SD, 
median, min, max) as well as frequencies and percentages of subjects with PD duration < 2, 2 to 
< 5, 5 to < 10, 10 to < 15, 15 to < 20, ≥ 20 years. 
Descriptive statistics as well as frequencies and percentages of subjects with Hoehn and Yahr PD 
stages (in “On” state) I, II, III, IV and Montreal Cognitive Assessment (MoCA) (in “On” state) 
(< 24, 24 to < 26, 26 to < 28, 28 to < 30, 30) will be provided. 
Descriptive statistics of MDS-UPDRS scores in the “On” state (Parts I, II, III, IV, II + III, total 
score) and the “Off” state (Part III) will be provided. 
The total “Off” time, “On” time without dyskinesia, “On” time with nontroublesome dyskinesia, 
“On” time with troublesome dyskinesia, and time asleep will be summarized based on the 
subjects’ diaries for the Randomized, Completers, and Early Terminated subjects.  The total 
“On” time without troublesome dyskinesia (ie, “Good on” time = total “On” time without 
dyskinesia plus “On” time with nontroublesome dyskinesia) will also be summarized. 


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4.4. 
Medical History and Physical Findings 
Summaries of clinically significant medical history and abnormal physical findings at baseline 
will be provided for all Screened, Randomized, Completers, and Early Terminated subjects. 


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5. 
EFFICACY AND PHARMACODYNAMIC ANALYSES 
For all primary and secondary endpoints analyses using mixed-effect analysis of variance 
(ANOVA) or analysis of covariance (ANCOVA), the degrees of freedom for the denominator 
will be estimated using the Kenward-Roger method.  The within subject covariance structure will 
be “AR(1).”  If convergence is an issue, a “Variance Components” covariance structure will be 
employed. 
5.1. 
Primary Endpoint 
The primary efficacy parameter for this study is the average percent “Off” time during waking 
hours based on subject PD diaries collected at the end of each treatment period.  For each day it 
will be calculated as the number of half-hour intervals in which “Off” is checked.  The average 
percent “Off” time will be defined as the average of percent “Off” time (total “Off” time divided 
by the total time not “asleep,” (ie, waking hours) per day) from the subject PD diaries completed 
for the 3 days immediately prior to the visit. 
The primary endpoint will be analyzed using a mixed-effect analysis of variance (ANOVA) 
model which will include treatment, period, and sequence as fixed effects and subject-within-
sequence as a random effect. 
Analyses will be done for the Completers analysis sets as defined in Section 2.1.  Data from the 
early terminated subject will be listed. 
5.2. 
Secondary Endpoints 
For secondary endpoints, the Completers analysis set will be used.  Data from the early 
terminated subject will be listed. 
5.2.1. 
Secondary Endpoints Based on PD Diaries 
5.2.1.1. 
Average “Off” Time 
From the subject PD diaries, the number of half-hour intervals marked “Off” will be calculated.  
The difference between the two treatments will be evaluated using a mixed-effect model with 
treatment, period, and sequence as fixed effects and subject-within-sequence as random effect. 
The total “Off” time will also be categorized into intervals: 0 hours, > 0 to < 2 hours, 2 to < 4 
hours, 4 to < 6 hours, 6 to < 8 hours, and ≥ 8 hours, and will be summarized across the 
treatments. 
5.2.1.2. 
Average “On” Time with No Troublesome Dyskinesia (“Good On”) 
From the subject PD diaries, the sum of the number of half-hour intervals marked “on without 
dyskinesia” and “on with nontroublesome dyskinesia” will be calculated.  The difference 
between the averages of “Good on” time between the two treatments will be analyzed using a 
mixed-effect model with treatment, period, and sequence as fixed effects and subject-within-
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The total “Good on” time will also be categorized into intervals: < 4 hours, 4 to < 6 hours, 6 to < 
8 hours, 8 to < 10 hours, 10 to < 12 hours, 12 to < 14 hours, and ≥ 14 hours and will be 
summarized across the treatments. 
5.2.1.3. 
Average “On” Time without Dyskinesia 
From the subject PD diaries, the sum of the number of half-hour intervals marked “on without 
dyskinesia” will be calculated.  The difference between the averages of total time “On” time 
without dyskinesia between the two treatments will be analyzed using a mixed-effect model with 
treatment, period, and sequence as fixed effects and subject-within-sequence as random effect. 
The total “On” time without dyskinesia will also be categorized into intervals: < 2 hours, 2 to < 4 
hours, 4 to < 6 hours, 6 to < 8 hours, 8 to < 10 hours, 10 to < 12 hours, and ≥ 12 hours and will 
be summarized across the treatments. 
5.2.1.4. 
Average “On” Time with Nontroublesome Dyskinesia 
From the subject PD diaries, the sum of the number of half-hour intervals marked “on with 
nontroublesome dyskinesia” will be calculated.  The difference between the averages of total 
time “On” time with nontroublesome dyskinesia between the two treatments will be analyzed 
using a mixed-effect model with treatment, period, and sequence as fixed effects and subject-
within-sequence as random effect. 
The total “On” time with nontroublesome dyskinesia will also be categorized into intervals:  
0 hours, 0 to < 2 hours, 2 to < 4 hours, 4 to < 6 hours, 6 to < 8 hours, 8 to < 10 hours, and ≥ 10 
hours and will be summarized across the treatments. 
5.2.1.5. 
Average “On” Time with Troublesome Dyskinesia 
From the subject PD diaries, the sum of the number of half-hour intervals marked “On with 
troublesome dyskinesia” will be calculated.  The difference between the averages of total time 
“On” time with troublesome dyskinesia between the two treatments will be analyzed using a 
mixed-effect model with treatment, period, and sequence as fixed effects and subject-within-
sequence as random effect. 
The total “On” time with troublesome dyskinesia will also be categorized into intervals: 0 hours, 
> 0 to < 1 hour, 1 to < 2 hours, 2 to < 3 hours, 3 to < 4 hours, and ≥ 4 hours and will be 
summarized across the treatments. 
5.2.1.6. 
Average Asleep Time 
From the subject PD diaries, the sum of the number of half-hour intervals marked “asleep” will 
be calculated.  The difference between the averages of total time “asleep” between the two 
treatments will be analyzed using a mixed-effect model with treatment, period, and sequence as 
fixed effects and subject-within-sequence as random effect. 
The total “asleep” time will also be categorized into intervals: < 5 hours, 5 to < 7.5 hours, 7.5 to 
< 9 hours, 9 to < 11 hours, and ≥ 11 hours and will be summarized across the treatments. 


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5.2.1.7. 
Average “Off” Time Normalized for 16 Waking Hours 
The average “Off” time normalized for 16 waking hours is calculated by taking the proportion of 
“Off” time during the waking hours multiplied by 16 hours.  The difference between the two 
groups will be summarized.  The treatment difference will be evaluated using a mixed model 
with treatment, period, and sequence as fixed effects and subject within sequence as random 
effect.  In addition, the “Off” time normalized to 16 waking hours will be tabulated using 
categories 0 hours, > 0 to < 2 hours, 2 to < 4 hours, 4 to < 6 hours, 6 to < 8 hours, and ≥ 8 hours. 
5.2.1.8. 
Average Total “Good On” Time Normalized for 16 Waking Hours 
The average “Good on” time normalized for 16 waking hours is calculated by taking the 
proportion of “Good on” time during the waking hours multiplied by 16 hours.  The difference 
between the two groups will be summarized.  The treatment difference will be evaluated using a 
mixed model with treatment, period, and sequence as fixed effects and subject within sequence 
as random effect.  In addition, the “Good On” time normalized to 16 waking hours will be 
tabulated using categories < 4 hours, 4 to < 6 hours, 6 to < 8 hours, 8 to < 10 hours, 10 to < 12 
hours, and ≥ 12 hours. 
5.2.1.9. 
Proportion of Subjects with a Reduction in “Off” Time of at Least 0.5, 1, 1.5, 2, 
3, and 4 Hours 
Proportion of subjects with a reduction in “Off” time from baseline by at least 0.5, 1, 1.5, 2, 3, 
and 4 hours will be tabulated between the two treatment groups and compared using Fisher’s 
Exact test.  Baseline is defined as an average of “Off” hours from the 3 days of the PD Diary 
prior to Visit 1 Day 1. 
5.2.1.10. “On” and “Off” State in First 30 Minutes upon Awakening from Nocturnal 
Sleep 
The proportions of subjects with 0 days, 1 day, 2 days, and 3 days in “On” and in “Off” states in 
the first 30 minutes upon awakening from nocturnal sleep will be summarized by treatment 
groups and compared using Fisher’s Exact test. Subjects will be classified into waking up in 
“On” state, “Off” state, or “Non-classifiable.”  
Awakening from nocturnal sleep is defined as having at least one “asleep” status post-midnight 
and 3 consecutive hours of non-asleep after 3:00 AM and after the post-midnight “asleep” 
episode.  For those who don’t meet the above 3 consecutive hours of non-asleep after 3:00 AM, 
they will be considered a non-classifiable outcome.  Likewise, for those who don’t have any 
“asleep” status between 12:00 AM and 3:00 AM, the subjects will be considered non-
classifiable. 
For the Diary Day -3, because diary starts at 6:00 AM, the consideration of “3 consecutive hours 
of non-asleep” will start at 6:00 AM.  Thus, for Diary Day -3, awakening from nocturnal sleep is 
defined as having 3 consecutive hours of non-asleep after 6:00 AM. 
5.2.1.11. Clinical Fluctuations 
From the subject PD diaries, clinical fluctuation is defined as a change from “On” to “Off” state 
or “Off” to “On” state over the 3-day PD Diaries.  The number of clinical fluctuations per day 


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will be the number of clinical fluctuations over the 3-day PD Diaries divided by 3.  The 
difference between the numbers of fluctuations between the two treatments will be analyzed 
using a mixed-effect model with treatment, period, and sequence as fixed effects and subject-
within-sequence as random effect. 
If there is a missing or invalid diary data for the middle day of the 3 days, a continuation from 
Day -3 to Day -1 is not assumed.  Instead, two additional fluctuations are assumed (one 
fluctuation goes from end of Day -3 to Day -2 and one fluctuation goes from end of Day -2 to 
Day -1). 
If there is a missing diary day(s) and the remaining diary days are contiguous, the clinical 
fluctuations will be calculated out of the remaining day(s). 
The number of clinical fluctuations will also be tabulated using categories < 2, 2 to < 4, 4 to < 6, 
6 to < 8, 8 to < 10, and ≥ 10 and will be summarized between the two treatments. 
5.2.1.12. Duration of “Good On” 
The average duration of “Good on” is the sum of all “Good on” durations over 3 days divided by 
the number of “Good on” episodes during those 3 days.  The average duration of “Good on” will 
be summarized and compared between the two treatment groups using a mixed-effect model 
with treatment, period, and sequence as fixed effects and subject-within-sequence as random 
effect.   
If there is a missing or invalid diary day(s), then the duration of “Good on” will be calculated out 
of the remaining day(s). 
The average duration of “Good on” will also be tabulated between two treatment groups using 
categories 0 to < 2 hours, 2 to < 4 hours, 4 to < 6 hours, 6 to < 8 hours, and ≥ 8 hours. 
5.2.2. 
Secondary Endpoints Based on the Assessment of Subject Motor State 
For the Day 1 and Day 15 in-clinic visits, the blinded rater determined the subject’s motor state 
hourly using the scale “Off”, “On” without dyskinesia, “On” with nontroublesome dyskinesia, 
“On” with troublesome dyskinesia, and Asleep.  On Day 1, assessments were performed at every 
half an hour interval from 1 hour predose to 8 hours postdose.  On Day 15, assessments were 
performed at every half an hour interval from 1 hour predose to 10 hours postdose. The 
assessment of the subject’s motor state is summarized as follows for Day 1 and Day 15 
separately.  Summaries will be based on Completers analysis set.  Data from the early terminated 
subject will be listed. 
5.2.2.1. 
“Off” Time 
The number of half-hour intervals marked “Off” will be calculated.  The difference between the 
two treatments will be evaluated using a mixed-effect ANOVA model with treatment, period, 
and sequence as fixed effects and subject-within-sequence as random effect. 
The total “Off” time will also be categorized into intervals: 0 hours, > 0 to < 2 hours, 2 to < 4 
hours, 4 to < 6 hours, and ≥ 6 hours, and will be summarized across the treatments. 


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In addition, the proportion of subjects in “Off” state at each time point will also be presented.  
Comparisons between two treatments will be done via Fisher’s exact test. 
5.2.2.2. 
“Good On” Time 
The number of half-hour intervals marked with either “On” without dyskinesia or “On” with 
nontroublesome dyskinesia will be calculated.  The difference between the two treatments will 
be evaluated using a mixed-effect ANOVA model with treatment, period, and sequence as fixed 
effects and subject-within-sequence as random effect. 
The total “Good on” time will also be categorized into intervals: < 2 hours, 2 to < 3 hours, 3 to < 
4 hours, 4 to < 5 hours, 5 to < 6 hours, 6 to < 7 hours, and ≥ 7 hours for Day 1, and < 4 hours, 4 
to < 5 hours, 5 to < 6 hours, 6 to < 7 hours, 7 to < 8 hours, 8 to < 9 hours, ≥ 9 hours for Day 15, 
and will be summarized across the treatments. 
In addition, the proportion of subjects in “Good on” state at each time point will also be 
presented.  Comparisons between two treatments will be done via Fisher’s exact test. 
5.2.2.3. 
“On” Time without Dyskinesia 
The number of half-hour intervals marked with “On” without dyskinesia will be calculated.  The 
difference between the two treatments will be evaluated using a mixed-effect ANOVA model 
with treatment, period, and sequence as fixed effects and subject-within-sequence as random 
effect.   
The total “On” time without dyskinesia will also be categorized into intervals: 0 hours, > 0 to < 1 
hours, 1 to < 2 hours, 2 to < 3 hours, 3 to < 4 hours, 4 to < 5 hours, 5 to < 6 hours, and ≥ 6 hours 
for Day 1, and < 3 hours, 3 to < 4 hours, 4 to < 5 hours, 5 to < 6 hours, 6 to < 7 hours, 7 to < 8 
hours, 8 to < 9 hours, and ≥ 9 hours for Day 15, and will be summarized across the treatments. 
5.2.2.4. 
“On” Time with Nontroublesome Dyskinesia 
The number of half-hour intervals marked with “On” with nontroublesome dyskinesia will be 
calculated.  The difference between the two treatments will be evaluated using a mixed-effect 
ANOVA model with treatment, period, and sequence as fixed effects and subject-within-
sequence as random effect. 
The total “On” time with nontroublesome dyskinesia will also be categorized into intervals:  
0 hours, > 0 to < 1 hours, 1 to < 2 hours, 2 to < 3 hours, 3 to < 4 hours, 4 to < 5 hours, 5 to < 6 
hours, 6 to < 7 hours, and ≥ 7 hours for Day 1, and < 1 hours, 1 to < 2 hours, 2 to < 3 hours, 3 to 
< 4 hours, 4 to < 5 hours, 5 to < 6 hours, 6 to < 7 hours, and ≥ 7 hours for Day 15, and will be 
summarized across the treatments. 
5.2.2.5. 
“On” Time with Troublesome Dyskinesia 
The number of half-hour intervals marked with “On” with troublesome dyskinesia will be 
calculated.  The difference between the two treatments will be evaluated using a mixed-effect 
ANOVA model with treatment, period, and sequence as fixed effects and subject-within-
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The total “On” time with troublesome dyskinesia will also be categorized into intervals: < 1 
hours, 1 to < 2 hours, 2 to < 3 hours, 3 to < 4 hours, and ≥ 4 hours for Day 1, and < 1 hours, 1 to 
< 2 hours, 2 to < 3 hours, 3 to < 4 hours, ≥ 4 hours for Day 15, and will be summarized across 
the treatments. 
5.2.2.6. 
“Asleep” Time 
The number of half-hour intervals marked with “Asleep” will be calculated.  The difference 
between the two treatments will be evaluated using a mixed-effect ANOVA model with 
treatment, period, and sequence as fixed effects and subject-within-sequence as random effect. 
The total time “Asleep” will also be categorized into intervals: 0 hours, > 0 to < 1 hours, 1 to < 2 
hours, 2 to < 3 hours, and 3 to < 4 hours and will be summarized across the treatments. 
5.2.2.7. 
Time from First Dose to First Morning “On” and “Good On” State after Dosing 
on Day 1 and Day 15 
The average time to first morning “On” state after first dosing in clinic on Day 1 and Day 15 will 
be summarized and compared between the two treatment groups using a mixed-effect model 
with treatment, period, and sequence as fixed effects and subject-within-sequence as random 
effect.  If a subject doesn’t achieve an “On” state before redose, then the subject will be censored 
at the second dose.  If a subject doesn’t have the second dose in clinic or if the second dose is 
beyond the 8 hours on Day 1 or 10 hours on Day 15, then the time to first morning “On” is 
censored at the 8 hour for Day 1 and 10 hour for Day 15. 
The average time to first morning “On” state will also be tabulated using categories 0 hours, > 0 
to < 1 hour, 1 to < 2 hours, 2 to < 3 hours, 3 to < 4 hours, and ≥ 4 hours and will be summarized 
between two treatments. 
Similar analyses will be performed for “Good on” state. 
5.2.3. 
Secondary Endpoints Based on MDS-UPDRS 
5.2.3.1. 
Predose MDS-UPDRS 
For this analysis, “Baseline” is defined as values at Screening. 
The predose MDS-UPDRS and change from baseline in predose MDS-UPDRS Parts I, II, III, 
IV, II+III, and Total will be summarized and compared between the two treatment groups using 
a mixed-effect model with treatment, period, sequence as fixed effects, baseline as a covariate, 
and subject-within-sequence as random effect.  Baseline values for all parts were assessed in 
“On” state. 
For predose MDS-UPDRS Part III, “Off” state score at baseline was also assessed.  The predose 
MDS-UPDRS and change from baseline in predose MDS-UPDRS Part III using “Off” state 
baseline values will also be summarized similarly. 
5.2.3.2. 
MDS-UPDRS Part III 
The MDS-UPDRS Part III on Day 1 and Day 15 will be summarized at each time point (predose 
to 8 hours on Day 1; predose to 10 hours on Day 15). 


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At predose on Day 1, the two treatments will be compared via a mixed-model ANOVA with 
treatment, period, and sequence as fixed effects and subject-within-sequence as random effect. 
For postdose on Day 1 and for all time points on Day 15, the two treatments will be compared 
via a mixed-model analysis of covariance (ANCOVA) with treatment, period, sequence as fixed 
effects, baseline (Day 1 predose) as covariate, and subject-within-sequence as random effect. 
The postdose average MDS-UPDRS Part III for Day 1 and Day 15 will also be summarized and 
compared between the two treatment groups using an ANCOVA model similar to above. 
5.2.3.3. 
Mean Change in MDS-UPDRS Part III 
The change from predose in MDS-UPDRS Part III over time on Day 1 will be summarized 
between two treatments and compared via a mixed-model ANCOVA with treatment, period, and 
sequence as fixed effects, baseline (Day 1 predose) as covariate, and subject-within-sequence as 
random effect. 
The change from Day 1 predose in MDS-UPDRS Part III over time on Day 15 will be 
summarized between two treatments and compared via a mixed-model ANCOVA with 
treatment, period, and sequence as fixed effects, baseline (Day 1 predose) as covariate, and 
subject-within-sequence as random effect. 
The postdose average of the change from Day 1 predose in MDS-UPDRS Part III for Day 1 and 
Day 15 will also be summarized and compared between the two treatment groups using an 
ANCOVA model similar to above. 
5.2.3.4. 
Duration of Effect of at Least 4, 7, and 13 Units Improvement from Day 1 
Predose MDS-UPDRS Part III 
The duration of having at least 4, 7, and 13 units improvement from Day 1 predose MDS-
UPDRS Part III on Day 1 and Day 15 will be will be summarized between two treatments and 
compared via a mixed-model ANOVA with treatment, period, sequence as fixed effects, and 
subject-within-sequence as random effect.     
To determine the duration of effect, the midway point between two adjacent time points will be 
used.  For example, if a subject does not have 4 units of improvement from the predose MDS-
UPDRS Part III assessment at the 1-hour postdose assessment, but has an improvement at the 2-
hour post dose assessment, and loses the 4-unit improvement at the 3-hour assessment, the 
duration of effect will be considered as 1 hour using the interpolated time value. 
The duration of having at least 4, 7, and 13 units improvement will also be categorically 
summarized using categories : < 2 hours, 2 to < 3 hours, 3 to < 4 hours, 4 to < 5 hours, 5 to < 6 
hours, 6 to < 7 hours, and ≥ 7 hours for Day 1, and < 4 hours, 4 to < 5 hours, 5 to < 6 hours, 6 to 
< 7 hours, 7 to < 8 hours, 8 to < 9 hours, ≥ 9 hours for Day 15. 
5.2.3.5. 
Proportions of Subjects with at Least 4, 7, and 13 Units Improvement from 
Day 1 Predose MDS-UPDRS Part III Over Time 
The proportions of subjects with at least 4, 7, and 13 units improvement from Day 1 predose 
MDS-UPDRS Part III will be summarized over time for Day 1 and Day 15.  Comparisons 
between the two treatments will be done based on Fisher’s exact test. 


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5.2.3.6. 
MDS-UPDRS Part III, Sum of Questions 4 through 8 and 14 
Questions 4 through 8 and 14 assess the bradykinesia of subjects. For questions 4 through 8, 
assessments were performed on both left and right side.  The left side score will be added to the 
right side score before analyses. 
To assess bradykinesia, the change from Day 1 predose in the sum of questions 4 through 8 and 
14 in the MDS-UPDRS Part III over time on Day 1 will be summarized between two treatments 
and compared via a mixed-model ANCOVA with treatment, period, sequence as fixed effects, 
baseline (Day 1 predose) as covariate, and subject-within-sequence as random effect. 
The change from Day 1 predose in the sum of questions 4 through 8 and 14 in the MDS-UPDRS 
Part III over time on Day 15 will be summarized between two treatments and compared via a 
mixed-model ANCOVA with treatment, period, sequence as fixed effects, baseline (Day 1 
predose) as covariate, and subject-within-sequence as random effect. 
The postdose average of the change from Day 1 predose in the sum of questions 4 through 8 and 
14 in the MDS-UPDRS Part III for Day 1 and Day 15 will also be summarized and compared 
between the two treatment groups using an ANCOVA model similar to above. 
Similar analyses will be performed for individual questions 4, 5, 6, 7, 8, and 14. 
5.2.3.7. 
MDS-UPDRS Part IV 
Individual components of the MDS-UPDRS Part IV and the change from Screening in individual 
components of MDS-UPDRS Part IV will be summarized and compared between the two 
treatment groups using a mixed-effect ANCOVA with treatment, period, sequence as fixed 
effects, baseline as a covariate, and subject-within-sequence as random effect. 
5.2.4. 
Secondary Endpoints Based on Kinesia 360 
For Kinesia 360 data, summaries will be based on the Kinesia 360 completers analysis set. Data 
from the early terminated subject will be listed. 
5.2.4.1. 
Tremor 
The distribution of tremor will be summarized and compared between the two treatments using a 
mixed model ANOVA with treatment, period, and sequence as fixed effects and subject-within-
sequence as a random effect.  Summaries will include the total wear time, proportion of subjects 
with at least one tremor detected, total wear time with tremor detected, and the percent of wear 
time with tremor detected. 
5.2.4.2. 
Dyskinesia 
The distribution of dyskinesia will be summarized and compared between the two treatments 
using a mixed model ANOVA with treatment, period, and sequence as fixed effects and subject-
within-sequence as a random effect.  Summaries will include the total wear time, proportion of 
subjects with at least one dyskinesia detected, total wear time with dyskinesia detected, and the 
percent of wear time with dyskinesia detected. 


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5.2.4.3. 
Mobility 
The distribution of mobility measures based on Kinesia 360 device will be summarized and 
compared between the two treatments using a mixed model ANOVA with treatment, period, and 
sequence as fixed effects and subject-within-sequence as a random effect.  Summaries will 
include the total wear time, total time rest as a percent of the wear time, total time active (non-
gait) as a percent of wear time, total time gait as a percent of wear time, total active time as a 
percent of wear time, percent arm swing during gait, wear time steps, and wear time steps 
normalized for wear time (steps/hour). 
5.3. 
Changes From Protocol-Specified Efficacy Analyses 
The following efficacy endpoints were added to fully characterize the efficacy and 
pharmacodynamics of IPX203: 
• Clinical fluctuations 
• Time to first morning “On” state after first dosing 
• Duration of “Good on” 
• Proportion of subjects who are “On” in first 30 minutes upon awakening 
• Proportion of subjects with a 4-hour reduction in “Off” time from Baseline 
The protocol states that for efficacy, a subject will be considered a completer if the subject 
receives treatments in both periods and has at least 2 days of evaluable PD diary data for each 
period.  The “at least 2 days” in the definition above has been revised to “at least 1 day” per FDA 
feedback on the Phase 3 protocol (IPX203-B16-02). 
The protocol states that categorical pharmacodynamics endpoints will be analyzed using 
generalized estimating equations methods.  The model will include treatment and period.  Due to 
small sample sizes and sparse data, this has been changed to Fisher’s Exact test to simplify the 
analyses. 


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6. 
SAFETY ANALYSES 
6.1. 
Adverse Events and Deaths 
6.1.1. 
Adverse Event Dictionary 
Reported AEs will be coded to standard terms using a standard dictionary (Medical Dictionary 
for Regulatory Activities [MedDRA]) Version 20 or latest version at the time of the database 
finalization. 
6.1.2. 
Adverse Event Severity 
Severity of adverse events will be determined by the investigator as mild, moderate, or severe.  
AEs with missing severity will be queried to resolution. 
6.1.3. 
Relationship of Adverse Events to Study Drug 
Related AEs are those for which the investigator selected “Related,” “Possibly Related,” or 
“Unlikely Related” on the AE CRF to the question of “Relationship to Study Treatment.” 
Relatedness will always default to the investigator’s choice, not that of the medical monitor.  
AEs with missing relationship to study drug will be queried to resolution. 
6.1.4. 
Serious Adverse Events 
Serious adverse events (SAEs) will be identified and captured as SAEs if AEs met the definitions 
of SAE specified in the study protocol. Serious adverse events captured and stored in the clinical 
database will be reconciled with the SAE database from the Drug Safety database before data 
finalization. 
6.1.5. 
Treatment-emergent Adverse Events 
Treatment-emergent adverse events (TEAE) are defined as events with an onset date on or after 
the study drug start date, up to and including 1 day after the last dose of study drug in each 
treatment period.  A worsening of previous illnesses or experience from baseline while on study 
drug is also considered a TEAE.  Otherwise the experience is defined as prior to treatment if it 
begins before the first dose of study drug; washout if it occurs more than 1 day after the last dose 
of the first period, but prior to the first dose of the second period; or post treatment if it occurs 
more than 1 day after the last dose of study medication.  An AE with a missing start date is 
considered a TEAE unless the stop date is non-missing and is prior to the first administration of 
study medication. 
6.1.6. 
Summaries of Adverse Events and Deaths 
TEAEs will be summarized based on the Randomized analysis set.  All TEAEs will be 
summarized by body system, and by preferred terms within a body system, by severity, and by 
relation to study medication.  Each AE (based on preferred terminology) is counted only once for 
a given subject within a specified treatment or study period.  If the same AE occurred on 
multiple occasions, the highest severity and least complimentary relationship was assumed.  If 
two or more AEs were reported as a unit, the individual terms will be reported as separate AEs. 


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The incidence of treatment-emergent AEs, as well as, SAEs will be summarized. 
6.1.7. 
Additional Analysis of Adverse Events 
Summaries of the Columbia-Suicide Severity Rating Scale (C-SSRS) (suicidal ideation and 
suicidal behavior) will be provided for subjects in the Randomized analysis set.  Individual 
responses will be listed. 
6.2. 
Laboratory Evaluations 
Laboratory data are collected at Screening and at End of Study for this study.  Laboratory data 
collected will be summarized using the Randomized analysis set.  The analysis will be based on 
values reported in conventional units. 
A by-subject listing for laboratory test results will be provided by subject ID number and time 
point in chronological order for hematology, chemistry, urinalysis, and urine drug test, alcohol 
breath test, and pregnancy test.  Values falling outside the normal reference range and/or having 
a clinical significance (with “clinical significance” determined by the investigator) will be 
flagged in the data listings, as appropriate. 
A listing of normal ranges of laboratory test results will also be provided. 
No formal statistical testing is planned. 
6.2.1. 
Summaries of Numeric Laboratory Results 
Descriptive statistics (N, mean, standard deviation, median, minimum, and maximum) will be 
provided for Screening and End of Study time points for each laboratory test specified in the 
study protocol.  The proportion of subjects with Low (below the lower limit of normal range), 
Normal (within the limit of normal range), High (above the upper limit of normal range) will be 
presented. 
6.2.2. 
Shifts Relative to the Baseline Value 
Shift tables will be presented by showing changes in results from screening value (low, normal, 
and high) to the end of study for hematology, blood chemistry, and urinalysis. 
6.2.3. 
Other Laboratory Results 
Because all subjects were either surgically sterile or post-menopausal, a summary of urine 
pregnancy test results will not be summarized. 
Positive alcohol breath test and urine drug screen at Screening will be provided. 
 
6.3. 
Vital Signs 
Descriptive statistics of systolic blood pressure, diastolic blood pressure, heart rate, respiratory 
rate, and body temperature will be provided at Screening, during Day 1 and Day 15 of each 
treatment period, and at End of Study.  The change from baseline at hours 2, 4, and 8 on Day 1, 
and to hours 2, 4, and 10 on Day 15 of each treatment period will be summarized similarly.  


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Baseline is defined as the predose assessment at Visit 1 for vital signs analyses.  The change 
from Baseline at the End of Study (Study Exit Visit) in systolic blood pressure, diastolic blood 
pressure, heart rate, respiratory rate, and body temperature will be summarized for Randomized 
Subjects.  In addition, the change from supine to standing in blood pressure and heart rate will 
also be summarized. 
Systolic blood pressure will also be tabulated for subjects with < 90 mmHg, 90 to < 140 mmHg, 
and ≥ 140 mmHg. 
Diastolic blood pressure will also be tabulated for subjects with < 60 mmHg, 60 to < 90 mmHg, 
and ≥ 90 mmHg. 
Heart rate will also be tabulated for subjects with < 60 beats/min, 60 to < 100 beats/min, and ≥ 
100 beats/min. 
Respiratory rate will also be tabulated for subjects with < 9 breaths/min, 9 to < 20 breaths/min, ≥ 
20 breaths/min. 
Body temperature will also be tabulated for subjects with < 36.5ºC, 36.5ºC to < 37.5ºC, 37.5ºC to 
< 38.5ºC, and ≥ 38.5 ºC. 
6.4. 
Concomitant Medications 
Concomitant medications are defined as medications taken while a subject took study drug or 
prior to taking study drug and continued during the study.  Use of concomitant medications will 
be summarized by reported name using the number and percentage of subjects for each of the 
Randomized, Completers, and Early Terminated subjects.  A subject reporting the same 
medication more than once will be counted only once when calculating the number and 
percentage of subjects who received that medication.  The summary will be ordered 
alphabetically by reported term. 
Concomitant medications will also be grouped into various anti-PD medication classes 
(amantadine, anticholinergic, dopamine agonist, monoamine oxidase (MAO) type B inhibitor, 
CD-LD IR, CD-LD CR, CD-LD extended release (ER), entacapone, 
carbidopa/levodopa/entacapone (CLE)), as well as antidepressants, sleep aids, and others.  
Frequencies and percentages of subjects taking these classes of medications as well as each 
medication under the class will be summarized for Randomized, Completers, and Early 
Terminated subjects.  Prohibited medications will not be included in the summaries. 
Summaries will be based on the Randomized Analysis Set.  No formal statistical testing is 
planned. 
6.5. 
Electrocardiogram Results 
6.5.1. 
Investigator Electrocardiogram Assessment 
Descriptive statistics of ventricular rate, PR interval, QRS interval, QT interval, and RR interval 
at Screening will be provided for Screened, Randomized, Completers, and Early Terminated 
subjects.  Descriptive statistics will also be provided during each treatment period at Day 1 and 
Day 15 for Randomized subjects.  For each day, summaries will be provided at predose, at 2 
hours postdose, and the change from Day 1 predose values.  Summaries will also be provided at 


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End of Study as well as the change from Baseline.  Baseline is the defined as the predose 
assessment at Visit 1. 
Ventricular rate will also be categorized into < 60 beats/min, 60 to 100 beats/min, and > 100 
beats/min.  The change from Day 1 Predose at hour 2 of each treatment period and the change 
from Baseline at the End of Study in ventricular rates will also be summarized with the following 
categories: < -10 beats/min, -10 to < 0 beats/min, 0 to < 10 beats/min, and ≥ 10 beats/min. 
PR interval will also be categorized into < 120 msec, 120 to 200 msec, and > 200 msec.  The 
change from Predose at hour 2 of each treatment period and the change from Baseline at the End 
of Study in PR interval will also be summarized with the following categories: < -1 msec, -1 to 5 
msec, and ≥ 5 msec. 
QRS interval will also be categorized into < 60 msec, 60 to 100 msec, and > 100 msec.  The 
change from Predose at hour 2 of each treatment period and the change from Baseline at the End 
of Study in QRS interval will also be summarized with the following categories: < 0 msec, 0 to < 
3 msec, and ≥ 3 msec. 
QT interval will also be categorized into < 200 msec, 200 to 430 msec, >430 to 450 msec, > 450 
to 500 msec, and > 500 msec.  The change from Predose at hour 2 of each treatment period and 
the change from Baseline at the End of Study in QT interval will also be summarized with the 
following categories: < 30 msec, 30 to < 60 msec, and ≥ 60 msec. 
RR interval will also be categorized into < 600 msec, 600 to 1000 msec, and > 1000 msec.  The 
change from Predose at hour 2 of each treatment period and the change from Baseline at the End 
of Study in ventricular rates will also be summarized with the following categories: < -33 msec, -
33 to < 12 msec, and ≥ 12 msec. 
6.5.2. 
Corrected QT Intervals 
The QT interval (measured in millisecond [msec]) is a measure of the time between the start of 
the Q wave and the end of the T wave in the heart’s electrical cycle.  The QT interval represents 
electrical depolarization and repolarization of the ventricles.  The QT interval is affected by heart 
rate, and a number of methods have been proposed to correct QT for heart rate. 
Corrected QT (QTc) intervals will be derived using Fridericia’s correction (QTcF) as follows:  
𝑄𝑄𝑄𝑄𝑄𝑄𝑄𝑄= 𝑄𝑄𝑄𝑄
√𝑅𝑅𝑅𝑅
3
 
where QT is measured in msec; RR = 60/Heart Rate (beats per min [bpm]) and RR is 
measured in seconds 
The QTcF interval values at Screening, during each treatment period (predose and at 2 hours 
postdose), and at Baseline and End of Study will be summarized within the following categories: 
< 200 msec, 200 to 430 msec, > 430 to 450 msec, > 450 to 500 msec, and > 500 msec. 
The change from Predose at hour 2 of each treatment period and the change from Baseline at the 
End of Study in QTcF interval values obtained during the study will also be summarized within 
the following categories: < 30 msec, 30 to < 60 msec, and ≥ 60 msec. 


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6.6. 
Other Safety Measures 
The frequency distribution of abnormal physical findings at baseline and at Study Exit for 
Randomized subjects will also be tabulated. 
6.7. 
Changes From Protocol-Specified Safety Analyses 
There are no deviations from the protocol-specified safety analyses. 
 


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7. 
PHARMACOKINETIC ANALYSES 
7.1. 
PK Sample Collection 
On Day 1 of each treatment period, PK samples will be collected at predose, and at 0.5, 1, 1.5, 2, 
2.5, 3, 4, 5, 5.5, 6, 6.5, 7, 7.5 and 8 hours postdose.  On Day 15 of each treatment period, PK 
samples will be collected at predose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, and 10 hours. 
7.2. 
PK Analyses 
PK over an 8-hour dosing interval (for Day 1) and a 10-hour dosing interval (for Day 15) will be 
determined. Concentrations of levodopa and carbidopa in plasma will be determined using a 
validated bioanalytical assay. In summaries and in PK parameter calculations, plasma 
concentrations with BLQ values at predose will be set to zero, those with BLQ values at 
postdose time points will be considered missing.  Any predose or postdose concentration that 
was deemed "Not Reportable" by the Analytical Lab was excluded from PK analysis. 
7.2.1. 
Pharmacokinetic Parameters 
Pharmacokinetic parameters will be generated for all subjects with PK samples in whom plasma 
concentrations were available.  Levodopa and carbidopa analytes will be evaluated.  
Concentrations and PK parameters normalized to 280 mg LD (70 mg CD) will also be generated. 
The analytes and parameters presented in Table 4 will be used to evaluate the PK objectives of 
the study.  
Table 4: 
Pharmacokinetic Parameters for Each Analyte 
Analyte 
Study Day 
Parameters 
Levodopa 
1 
Cmax, Tmax, tau, Ctau, AUCtau, AUClast, AUCinf, AUC%ext, t1/2, k, AUC0-2, 
AUC2-8, AUC8-inf, T(430ng/mL), T(1000ng/mL), T(50%Cmax), 
Dur(>50%Cmax), and BA relative to IR CD-LD 
Carbidopa 
1 
Cmax, Tmax, tau, Ctau, AUCtau, AUClast, AUCinf, AUC%ext, t1/2, k, AUC0-2, 
AUC2-8, AUC8-inf, and BA relative to IR CD-LD  
Levodopa 
15 
Cmax, Tmax, tau, Ctau, AUCtau, AUClast (equivalent to AUC0-10), Cavg, AUC0-2, 
AUC2-10, Tmax, T(430ng/mL), T(1000ng/mL), T(50%Cmax), Dur(>50%Cmax), 
fluctuation index, accumulation ratio, and time-invariance ratio 
Carbidopa 
15 
Cmax, Tmax, tau, Ctau, AUCtau, AUClast (equivalent to AUC0-10), Cavg, AUC0-2, 
AUC2-10, Tmax, fluctuation index, accumulation ratio, and time-invariance 
ratio 
 
Individual subject concentration data and individual subject PK parameters for levodopa and 
carbidopa will be listed and summarized using descriptive statistics by treatment for the 
Completer analysis sets. Data from the early terminated subject will be included in listings.  
Summary statistics (n, mean, SD, coefficient of variation [%CV], median, minimum, and 
maximum) will be presented within treatments for both individual subject concentration data by 


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time point and individual subject PK parameters.  Summaries for all subjects, for subgroups 
differentiated by dose levels, and for dose-normalized values will be presented.  Moreover, the 
geometric mean, the mean and SD of the natural log-transformed values will be presented for 
individual subject PK parameter data. 
7.2.2. 
Statistical Analysis Methods 
Descriptive statistics (mean, SD, coefficient of variation [CV %], median, minimum, and 
maximum) will be used to summarize the PK parameters for each treatment group on Day 1 and 
Day 15.  Following natural logarithm transformation, ANOVA model will be performed on AUC 
and concentration parameters.  The model will include treatment, period, and sequence as fixed 
effects and subject-within-sequence as a random effect.  ANOVA models on untransformed data 
will also be performed on AUC and concentration parameters, accumulation ratio, fluctuation 
index, and time invariance.  These analyses will be done on Day 1 and Day 15 and the AUC and 
concentration parameters will be dose-normalized to the lowest treatment dose of the reference 
treatment (100 mg). 
Plasma PK parameters for LD and CD will be listed by subject and summarized by treatment 
using descriptive statistics.  Noncompartmental methods will be used to estimate Tmax, Cmax, 
AUCs-t, AUC0-∞, k, and t½ for LD and CD (Phoenix WinNonlin version 6.4.0).  Descriptive 
statistics (mean, SD, coefficient of variation, median, minimum, and maximum) will be used to 
summarize the PK parameters for each treatment group.  To assess the bioavailability of IPX203 
relative to the IR CD-LD reference treatment, analyses of variance will be performed on natural 
log transformed AUC and Cmax values using a mixed-effect model that included treatment, 
period, and sequence as fixed effects and subject-within-sequence as a random effect.  In these 
analyses, all treatments are dose-normalized to the lowest treatment dose of the reference 
treatment (100 mg of levodopa).  Additionally, time for plasma concentrations of LD to reach 
50% of its Cmax and duration of LD plasma concentrations >50% Cmax will be calculated for both 
treatments.  The extent of LD exposure following the treatments on Day 1 will also be assessed 
by calculating partial AUC between 0-2 hours, 2-8 hours, and 8 hours extrapolated to infinity to 
yield values for AUC0-2, AUC2-8 and AUC8–∞, respectively.  On Day 15, partial AUC between 
0-2 hours and 2-10 hours (AUC0-2 and AUC2-10, respectively) will be calculated. 
The time to 50% Cmax and duration above 50% Cmax will be estimated using a linear interpolation 
between the two adjacent time points. 
The Wilcoxon Signed Rank test will be used to compare LD Tmax, duration above 50% Cmax, 
time to reach 430ng/mL, and time to reach 1000ng/mL between treatments on Day 1 and Day 15.  
Tau will be added to the Day 15 comparison.  The Wilcoxon Signed Rank test will also be used 
to compare CD Tmax on Day 1, and CD Tmax and Tau on Day 15. 
The mean LD and CD plasma concentration time profiles will be plotted as well as the plasma 
concentration time profiles for each subject.  For both Day 1 and Day 15, mean LD plasma 
concentration will be plotted based on the first dose only and based on all doses. 
7.3. 
Changes from Protocol-Specified PK Analyses 
Additional PK parameters were added to fully elucidate the PK profiles of IPX203.  They are 
AUC(0-2), AUC2-8, AUC8-inf, AUC%ext, Cavg, T(430ng/mL), T(1000ng/mL), tau, and time 


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invariance parameter.  AUC0-10 stated in the protocol is replaced by AUClast as the AUC0-10 is 
best represented by AUClast. 
The protocol stated that the duration of LD concentration above 50% of Cmax values would be 
analyzed using ANOVA based on the protocol.  The analysis method has been updated to signed 
rank test. 
The protocol stated that, following natural logarithm transformation, analyses of variance 
(ANOVA) will be performed on CD and LD AUC and Cmax adjusted for dose, fluctuation, and 
accumulation.  It was clarified that ANOVA will be performed on the fluctuation index, 
accumulation index, in addition to log-transformed dose-normalized AUC and Cmax. 


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8. 
SOFTWARE 
SAS® Software Version 9.4. SAS Institute Inc., Cary, NC, USA. 
Phoenix WinNonlin Software Version 6.4.0.  Certara, Princeton, NJ, USA 
 
 


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9. 
REFERENCES 
Goetz CG, Luo S, Wang L, Tilley BC, LaPelle NR, Stebbins GT. Handling missing values in the 
MDS-UPDRS. Mov Disord. 2015 Oct;30(12):1632-8. 
Kenward MG, Roger JH. Small sample inference for fixed effects from restricted maximum 
likelihood. Biometrics. 1997 Sep;53(3):983-97.